Publications

[{"pmid": "42509025", "title": "Fishing with two lines: a hybrid approach to spatial transcriptomics discovery.", "authors": ["Williams-Katek AL", "Mallapragada S", "Mee ED", "Fischer BK", "Vannan A", "Eldredge LC", "Deutsch GH", "Kropski JA", "Sucre JM", "Banovich NE"], "journal": "Life Sci Alliance", "journal_title": "Life science alliance", "citation": "Life science alliance, 10 2026", "abstract": "Spatial transcriptomics faces a trade-off between the number of genes assayed and depth of per-gene sensitivity. We developed a \"dual-chemistry\" method that combines the high sensitivity of a 10x Genomics Xenium V1 custom panel (up to 480 genes) with the broad coverage of the Prime 5K panel (5,001 genes) on a single tissue section. This involved co-hybridizing Prime and V1 probes and sequentially running the V1 and Prime decoding chemistries. Applied to a human lung tissue microarray, we observed high concordance between the V1 and Prime chemistries when run independently (on serial sections) and the dual-chemistry runs. Overlapping genes (profiled on both V1 and Prime chemistries) showed similar expression patterns in the dual run demonstrating the fidelity of the assay. By combining information from both the V1 and Prime chemistries within the same cell, we retain more cells, gain valuable additional information, and enable both high-sensitivity profiling and discovery.", "year": "2026", "month": "10", "volume": "9", "issue": "10", "pages": "", "doi": "10.26508/lsa.202603690", "link": "https://www.ncbi.nlm.nih.gov/pubmed/42509025", "sort_key": "2026-10-fishing with two lin", "quarter": "q4"}, {"pmid": "41543033", "title": "Recurrent Respiratory Papillomatosis Foundation Position Statement on the Management of Adults With RRP.", "authors": ["Best SR", "Friedman AD", "Rosen CA", "Sataloff RT", "Matrka LA", "Sims HS", "Rosow DE", "Saba NF", "Lott DG", "Klein AM", "Mau T", "Amin MR", "Wikenheiser-Brokamp KA", "Norberg SM", "McClellan K", "Young GD", "Allen CT", "Recurrent Respiratory Papillomatosis Foundation"], "journal": "Laryngoscope", "journal_title": "The Laryngoscope", "citation": "The Laryngoscope, 09 2026", "abstract": "OBJECTIVE: With regulatory approval of HPV-specific immunotherapy for recurrent respiratory papillomatosis (RRP) and growing experience with systemic bevacizumab, a management algorithm incorporating these medical treatments is warranted. DATA SOURCES AND METHODS: RRP Foundation (RRPF) Key Opinion Leaders offer a proposed management algorithm for adults with RRP considering published literature and commercial drug availability. RESULTS: Preventative HPV vaccination should be considered for all patients. Determination of HPV type and pulmonary imaging are important for contemporary RRP patient care and assist in decision making. Risks and benefits of papilloma debulking as needed versus medical management of RRP must be deliberated on a patient case-by-case basis. HPV-specific immunotherapy that induces an HPV-specific T cell response to target the underlying HPV infection that is the cause of RRP is safe, offers the possibility of durable disease control following a short treatment course and is the recommended first-line medical treatment for patients who wish to avoid the risks of repeat procedural management. Papilloma disease control with systemic bevacizumab, which carries defined risks and must be continued for clinical benefit is the recommended second-line medical treatment for patients who do not achieve a complete response with immunotherapy and wish to continue medical management. For patients who elect to be treated with debulking procedures as needed, use of locally-administered adjuvant should be considered. CONCLUSION: This proposed management algorithm from the RRPF serves as a contemporary resource and information guide for adult patients with RRP and their physicians considering treatment options.", "year": "2026", "month": "09", "volume": "136 Suppl 4", "issue": "Suppl 4", "pages": "S7-S17", "doi": "10.1002/lary.70379", "link": "https://www.ncbi.nlm.nih.gov/pubmed/41543033", "sort_key": "2026-09-recurrent respirator", "quarter": "q3"}, {"pmid": "42708365", "title": "Multiomic analysis identifies T cell subsets and mechanisms of epithelial interaction in idiopathic pulmonary fibrosis.", "authors": ["Serezani AP", "Bazzano JM", "Pascoalino BD", "da Silva L", "Dietrich AJ", "Taylor CJ", "Sherrill T", "Vannan A", "Calvi CL", "Gonzalez-Ericsson PI", "Wilfong EM", "Bacchetta M", "Shaver CM", "Ware LB", "Salisbury ML", "Van Kaer L", "Banovich NE", "Kropski JA", "Blackwell TS"], "journal": "JCI Insight", "journal_title": "JCI insight", "citation": "JCI insight, 09 2026", "abstract": "Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease characterized by progressive scarring and respiratory failure. While T cells are elevated in IPF lungs, their contributions to fibrosis beyond inflammation remain poorly understood. Here, we performed multiplex imaging and single-cell RNA and protein profiling on about 90,000 CD3+ T cells from control and fibrotic lungs, revealing 11 distinct subsets of CD4+ and CD8+ T cells, including a rare CD56+ regulatory T cell. In addition to increased T cell numbers in severely fibrotic lungs compared with non-diseased controls, we observed CD4+ and CD8+ T cells localized near epithelial cells and in niches of abnormal epithelium. CXCR4/MIF signaling emerged as a central axis mediating T cell-epithelial interactions, while epidermal growth factor receptor (EGFR) and TGF-\u03b2 pathways dominated in multiple T cell subsets. Our findings support the concept that T cells in IPF adopt nonclassical activation patterns that are driven by epithelial interactions within the fibrotic microenvironment. These studies provide a foundation for exploring alternative therapeutic strategies in IPF lungs by modulating T cell behavior and communication networks.", "year": "2026", "month": "09", "volume": "11", "issue": "17", "pages": "", "doi": "10.1172/jci.insight.203080", "link": "https://www.ncbi.nlm.nih.gov/pubmed/42708365", "sort_key": "2026-09-multiomic analysis i", "quarter": "q3"}, {"pmid": "42710471", "title": "Lending an ear to the lung.", "authors": ["Yao B", "Sun X"], "journal": "Immunity", "journal_title": "Immunity", "citation": "Immunity, 09 2026", "abstract": "The unprecedented recent advancement in the field of interoception (sensing self) has introduced neuromodulation as a realistic treatment approach. Shibuya et al. identified an ear-to-lung reflex in which activation of auricular-innervating TRPV1+ vagal sensory neurons functions through neuropeptide CGRP\u03b2 to suppress allergic airway inflammation, providing an elegant example of exteroceptive control of interoception and a mechanism for transcutaneous neuromodulation.", "year": "2026", "month": "09", "volume": "59", "issue": "9", "pages": "2351-2353", "doi": "10.1016/j.immuni.2026.08.005", "link": "https://www.ncbi.nlm.nih.gov/pubmed/42710471", "sort_key": "2026-09-lending an ear to th", "quarter": "q3"}, {"pmid": "42274447", "title": "International Society for Heart and Lung Transplantation Scientific Statement on pulmonary antibody-mediated rejection and proposed graft, antibody, and pathology (GAP)\u00a0definition.", "authors": ["Calabrese F", "Levine DJ", "Adam BA", "Agbor-Enoh S", "Benden C", "Budev MM", "Cochrane AB", "Cozzi E", "Darley DR", "Fishbein GA", "Gelman AE", "Glanville AR", "Greenland JR", "Hickey MJ", "Ius F", "Jaksch P", "Jackson AM", "Joerns JO", "Lor H", "Lowery EM", "Mangiola M", "Morlacchi LC", "Murray MA", "Nair A", "Ocagli H", "Parmar JS", "Pavlisko EN", "Perch M", "Rahaghi FF", "Roden AC", "Roux A", "Snyder L", "Sweet S", "Verleden SE", "Visner GA", "Vos R", "Wikenheiser-Brokamp KA", "Zeevi A", "Hachem RR"], "journal": "J Heart Lung Transplant", "journal_title": "The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation", "citation": "The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation, 09 2026", "abstract": "Antibody-mediated rejection (AMR) is an increasingly recognized form of rejection and cause of graft failure after lung transplantation. AMR has been the focus of extensive research over the past decade. Despite growing awareness and recent advances in our understanding of AMR, outcomes remain dismal with a 2-year survival of only 20%. The International Society for Heart and Lung Transplantation convened a multidisciplinary workgroup of experts in AMR to review the most up-to-date research and clinical experience and to update the 2016 definition. The workgroup was divided into 9 subgroups covering a broad range of topics pertaining to AMR and used the modified Delphi method to synthesize a cohesive summary of the literature. A multidimensional definition was developed to enhance precision by reporting the specific presenting features. This Graft, Antibody, and Pathology (GAP) definition is based on the presence of Graft dysfunction, the presence and characteristics of Antibodies, and Pathological findings. The workgroup emphasized that identifying better treatments for AMR is a critical unmet need and proposed that a more precise definition might allow better management by providing a platform for testing and developing new therapies.", "year": "2026", "month": "09", "volume": "45", "issue": "9", "pages": "1357-1374", "doi": "10.1016/j.healun.2026.04.019", "link": "https://www.ncbi.nlm.nih.gov/pubmed/42274447", "sort_key": "2026-09-international societ", "quarter": "q3"}, {"pmid": "42662918", "title": "Double-stranded DNA donors and CRISPR-Cas9 for universal correction of mutations causing cystic fibrosis in human airway cells.", "authors": ["Sinha V", "Ayoub PG", "Juett CJ", "Lathrop LE", "Foley RA", "Sims RA", "Long JD", "Duggan EC", "Fernandes NR", "Illek B", "Gomperts BN", "Jonas SJ", "Kohn DB"], "journal": "Mol Ther Nucleic Acids", "journal_title": "Molecular therapy. Nucleic acids", "citation": "Molecular therapy. Nucleic acids, 09 2026", "abstract": "Cystic fibrosis (CF) is a devastating genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. As morbidity and mortality from CF results from a lack of mucus clearance that leads to chronic bacterial infections and progressive loss of lung function, site-specific insertion of a CFTR cDNA into the endogenous CFTR locus in airway basal stem cells (ABSCs) could prove curative for all disease-causing mutations. This study describes the development of genome-editing approach utilizing nonviral reagents, designed to be packaged into nonviral delivery systems. An sgRNA targeting the 5' untranslated region (UTR) of CFTR was characterized as directing high on-target cutting and displaying a safe off-target profile. Airway cell lines electroporated with chemically modified (1-Aminohexane, AmC6), linear double-stranded DNA (ldsDNA) constructs were utilized as a homology directed repair (HDR) donor, initially optimized with an mCitrine reporter. Expectedly, when the 780 bp mCitrine cDNA was replaced with the 4.4 kb CFTR cDNA, integration efficiency dropped significantly. However, 1%-2% integration of codon-optimized donors was sufficient to restore CFTR expression in the bulk-edited population of a human bronchial epithelial cell line, 16HBE14o- (16HBE), to levels reaching 50% of wild-type expression as measured by western blot. Electrophysiological validation of CFTR ion channel function measured via Ussing chamber assay revealed that these bulk-edited populations exhibit greater than 40% restoration of the chloride ion currents of the measured wild-type controls. These results demonstrate that low levels of CFTR integration can be made therapeutically relevant by optimizing the designs of gene editing reagents. Importantly, this work utilizes nonviral-editing reagents, an essential step toward in vivo gene therapy for CF.", "year": "2026", "month": "09", "volume": "37", "issue": "3", "pages": "103049", "doi": "10.1016/j.omtn.2026.103049", "link": "https://www.ncbi.nlm.nih.gov/pubmed/42662918", "sort_key": "2026-09-double-stranded dna ", "quarter": "q3"}, {"pmid": "42704712", "title": "Apoptosis inhibition reprograms alveolar myofibroblasts toward ductal myofibroblasts.", "authors": ["Gacha-Garay MJ", "Liu H", "Evans SE", "Mills TW", "Chen J"], "journal": "Cell Rep", "journal_title": "Cell reports", "citation": "Cell reports, 09 2026", "abstract": "The epithelial tree of the lung is shaped proximo-distally by airway smooth muscle cells (ASMCs), ductal myofibroblasts (DMFs), and, transiently, alveolar myofibroblasts (AMFs). Lineage tracing and snapshot imaging suggest the clearance of AMFs via apoptosis post-alveologenesis, although definitive evidence is lacking. Here, we generate an inducible BCL2 overexpression mouse allele to inhibit AMF apoptosis. Using three independent Cre drivers and single-cell RNA sequencing, we show that BCL2-rescued AMFs persist around distal alveolar ducts and alveoli and, unexpectedly, mature toward DMFs. Both normal DMFs and rescued DMF-like cells upregulate contractile proteins in a house dust mite-induced asthma model. Our findings demonstrate apoptosis as the chief mechanism of AMF clearance, as well as fate plasticity and pathophysiological convergence of lung mesenchymal cells of the epithelial axis.", "year": "2026", "month": "09", "volume": "45", "issue": "9", "pages": "117891", "doi": "10.1016/j.celrep.2026.117891", "link": "https://www.ncbi.nlm.nih.gov/pubmed/42704712", "sort_key": "2026-09-apoptosis inhibition", "quarter": "q3"}, {"pmid": "42547983", "title": "Unusual Clinical Course of Pediatric Pulmonary Hypertension with Underlying SOX17 Mutation.", "authors": ["Rojas A", "Morales DLS", "Wikenheiser-Brokamp KA", "Hayes D"], "journal": "Ann Am Thorac Soc", "journal_title": "Annals of the American Thoracic Society", "citation": "Annals of the American Thoracic Society, 08 2026", "abstract": "", "year": "2026", "month": "08", "volume": "", "issue": "", "pages": "", "doi": "10.1093/annalsats/aaoag216", "link": "https://www.ncbi.nlm.nih.gov/pubmed/42547983", "sort_key": "2026-08-unusual clinical cou", "quarter": "q3"}, {"pmid": "42262884", "title": "Sustained YAP/TAZ activation promotes aberrant alveolar epithelial cell differentiation and drives persistent fibrotic remodeling.", "authors": ["Gaona IP", "McCall AS", "Geis NM", "Colvard AC", "DiGiovanni GT", "Sherrill TP", "Singha UK", "Nichols DS", "Serezani AP", "David HE", "Cartailler JP", "Shrestha S", "Gutor SS", "Blackwell TS", "Kropski JA", "Gokey JJ"], "journal": "JCI Insight", "journal_title": "JCI insight", "citation": "JCI insight, 08 2026", "abstract": "YAP/TAZ signaling is required for initiation of lung alveolar repair, yet previous studies in idiopathic pulmonary fibrosis (IPF) predicted increased YAP/TAZ signaling in alveolar epithelial cells. We investigated whether persistent YAP/TAZ alveolar epithelial cell signaling contributes to failed epithelial repair and persistent fibrotic remodeling. In IPF lungs, we identified increased YAP+TAZ+ alveolar epithelial cells and increased transcriptional target expression. Pharmacological YAP/TAZ activation in human alveolar epithelial cell organoids and in murine AT2 cell organoids generated with genetic YAP/TAZ activation (YTactive) (via deletion of Hippo kinases Stk3 and Stk4) resulted in phenotype shifts into aberrant transitional and airway-like states. Bleomycin injury of YTactive mice resulted in persistent fibrotic remodeling at 28 and 56 days after bleomycin injury. Gene promoter activity associated with transitional cell markers (Krt19, Hopx, and Runx2) was increased in YTactive AT2 cells. Immunofluorescent staining showed a loss of AT2-associated Cebpa and increased Krt19 in YTactive lineage-traced AT2 cells 28 days after injury. Inhibition of YAP/TAZ using verteporfin resulted in improved lung repair in YTactive mouse lungs, including restored Cebpa and decreased Krt19+ transitional cells. These findings demonstrate that sustained YAP/TAZ activation drives abnormal alveolar repair and persistent fibrotic remodeling. Blocking aberrant persistent YAP/TAZ activity promotes adaptive repair and has potential as a therapeutic strategy for pulmonary fibrosis.", "year": "2026", "month": "08", "volume": "11", "issue": "15", "pages": "", "doi": "10.1172/jci.insight.198113", "link": "https://www.ncbi.nlm.nih.gov/pubmed/42262884", "sort_key": "2026-08-sustained yap/taz ac", "quarter": "q3"}, {"pmid": "42089300", "title": "Lentiviral-mediated gene complementation to rescue pathogenic ABCA3 variants.", "authors": ["Cooney AL", "Lamer S", "Yang P", "Wegner DJ", "White FV", "Cole FS", "Wohlford-Lenane C", "Hennessey E", "Bawa P", "Kotton DN", "Sinn PL", "Wambach JA", "McCray PB"], "journal": "Am J Respir Cell Mol Biol", "journal_title": "American journal of respiratory cell and molecular biology", "citation": "American journal of respiratory cell and molecular biology, 08 2026", "abstract": "The ATP-binding cassette subfamily A member 3 (ABCA3) protein in the limiting membrane of lamellar bodies in alveolar type 2 (AT2) cells transports phospholipids required for pulmonary surfactant assembly. ABCA3 deficiency results from biallelic pathogenic variants in ABCA3 and causes progressive neonatal respiratory failure or childhood interstitial lung disease. Palliative care or lung transplantation are the only current definitive treatments for progressive respiratory failure due to ABCA3 deficiency. Complementing dysfunctional ABCA3 by gene addition has therapeutic potential. Previous studies show that repairing or complementing ABCA3 in induced pluripotent stem cell-derived AT2 cells rescues lamellar body morphology and surfactant phospholipid composition. Pathogenic variants disrupt ABCA3 function through altered protein trafficking (type 1) or by impaired phospholipid transport (type 2) into lamellar bodies. Here, we tested ABCA3 gene complementation using a human pulmonary epithelial cell line (A549) with a genomically silenced ABCA3 locus (ABCA3KO). Using this line, we generated additional cell lines that stably express individual ABCA3 variant cDNA constructs from a single genomic locus: L101P (type 1), E292V (type 2), E690K (type 2), or wild-type (WT) ABCA3. Lentiviral-mediated delivery of WT ABCA3 to each cell line partially rescued localization to LAMP3+ vesicles, lamellar body-like structure morphology, and cell proliferation. A functional assay measuring NF-\u03baB signaling suggested that ABCA3 complementation ameliorated aberrant inflammatory signaling in E292V or E690K (type 2) mutant lines, but not in L101P (type 1) or knockout lines. These studies highlight the therapeutic potential of gene complementation as well as differences between ABCA3 pathogenic variants that may influence genetic therapy outcomes.", "year": "2026", "month": "08", "volume": "74", "issue": "8", "pages": "1089-1102", "doi": "10.1093/ajrcmb/aanag043", "link": "https://www.ncbi.nlm.nih.gov/pubmed/42089300", "sort_key": "2026-08-lentiviral-mediated ", "quarter": "q3"}, {"pmid": "42089342", "title": "Infants who develop bronchopulmonary dysplasia have an airway endotype defined by vimentin expression and ciliary loss.", "authors": ["Eldredge LC", "Han Y", "Deutsch GH", "Sucre JMS", "Shirazi SP", "Stefani C", "Pribitzer S", "Reeves SR", "Rich LM", "Vanderwall ER", "Ziegler SF", "Debley JS"], "journal": "Am J Respir Cell Mol Biol", "journal_title": "American journal of respiratory cell and molecular biology", "citation": "American journal of respiratory cell and molecular biology, 08 2026", "abstract": "RATIONALE: Bronchopulmonary dysplasia (BPD) arises from disrupted lung development after preterm birth and produces structural deficits at every level of the respiratory tree. Lower airway disease is emerging as a clinically significant BPD phenotype with increased mortality, yet the molecular mechanisms whereby preterm birth disrupts airway development remain poorly defined. OBJECTIVES: To develop a human model of lower airway disease following preterm birth and to define a molecular endotype of evolving BPD (eBPD) at baseline and in response to injury. METHODS: An ex vivo organotypic airway epithelial cell (AEC) model was combined with well-characterized pathologic and transcriptomic patient samples for quantitative immunohistochemistry and RNA-sequencing analyses. MEASUREMENTS AND MAIN RESULTS: Compared to AECs from healthy controls, eBPD-derived AECs exhibited reduced proliferation, impaired differentiation to ciliated epithelium, and expansion of a vimentin-positive population with a transcriptional profile associated with impaired AEC differentiation. Following hyperoxia exposure, eBPD-derived AECs mounted a robust vimentin response ex vivo, paralleling increased vimentin expression observed in airway cells from lung tissue of human infants with BPD. CONCLUSIONS: Using an organotypic model of neonatal airway differentiation, we demonstrate eBPD is associated with impaired AEC differentiation, increased vimentin-expression and concomitant loss of ciliated cells, and an exaggerated vimentin response to hyperoxic injury. These findings mimic the effects of prematurity in airway cells in human patients. These data support a mechanism whereby hyperoxia leads to impaired epithelial differentiation and associated lower airway dysfunction in BPD and inform future mechanistic studies interrogating the role of intermediate filaments in maladaptive epithelial repair.", "year": "2026", "month": "08", "volume": "74", "issue": "8", "pages": "1044-1057", "doi": "10.1093/ajrcmb/aanag044", "link": "https://www.ncbi.nlm.nih.gov/pubmed/42089342", "sort_key": "2026-08-infants who develop ", "quarter": "q3"}, {"pmid": "42599223", "title": "Consensus Lung Cell Reference: The Collaborative Cross-Consortium and Country Lung Cell Nomenclature Project (C3LCN). An Official American Thoracic Society Workshop Report.", "authors": ["Pryhuber GS", "Nawijn M", "Alam DA", "Aronow B", "Banchero M", "Banovich N", "Barbry P", "Basil M", "Burns K", "Burgess J", "Cardoso WV", "Clair G", "Clifford R", "Danopoulos S", "Deutsch G", "Duong TE", "Fortriede J", "Frank D", "Gosens R", "Gu M", "Guo M", "Hagood J", "Kfuri-Rubens R", "Koppelman GH", "Krick S", "Kropski JA", "Lin QS", "Lloyd C", "Luecken MD", "Majka S", "Meyer K", "Misharin A", "Misra RS", "Mora A", "Neptune E", "Niethamer TK", "Okuda K", "Osumi-Sutherland D", "Perl AK", "Planer JD", "Puig-Barb\u00e9 A", "Quardokus EM", "Rahimi R", "Rajagopal J", "Randell S", "Redente E", "Sajti E", "Salomonis N", "Samakovlis C", "Scheuermann R", "Schniering J", "Sun X", "Tata P", "Villani AC", "Walters MS", "Wikenheiser-Brokamp KA", "Xu Y", "Zaragosi LE", "American Thoracic Society Assembly on Respiratory Cell and Molecular Biology"], "journal": "Am J Respir Cell Mol Biol", "journal_title": "American journal of respiratory cell and molecular biology", "citation": "American journal of respiratory cell and molecular biology, 08 2026", "abstract": "Rapid advances in single-cell technologies now allow measurement of thousands of transcripts and other molecular features of individual cells offering unprecedented insight into lung biology in homeostasis and in disease. The accelerated generation of multimodal data has, however, been accompanied by the reporting of putatively \"novel\" cell types described without consensus regarding their ontogeny, identity, function, or defining markers. To fully realize the value of the technological advances and to enable rigorous comparison across studies, respiratory research will benefit from standardized, quantitative, and biologically grounded cell classifications and nomenclature. Achieving the transformative potential of the multimodal data will depend on common, machine- and human-readable nomenclature, structured and expandable dictionary and atlas resources, and clear methodological standards that ensure consistency as technologies evolve. The American Thoracic Society (ATS) recognized the importance of promoting a common nomenclature to enhance equitable access and utility of the vast amounts of multimodal data generated by the lung research community. The Collaborative Cross-Consortium and Country Lung Cell Nomenclature Project (C3LCN) was adopted as an ATS Assembly Project in 2024. This is the consensus report outlining the goals and framework of the Project to foster coordinated progressive lung cell research to include: 1) providing best practices for analysis, publication and reporting of lung single-cell transcriptomic datasets; 2) establishing a contemporary lexicon for healthy adult human cells of the lower respiratory tract with structured, persistent, and resolvable identifiers; 3) defining a scalable taxonomy to organize a common lung cell nomenclature; 4) offering tools to support collaboration, knowledge dissemination, and translational advances rooted in modern lung biology augmenting, not replacing, pre-genomic biological knowledge; and 5) describing an infrastructure capable of incorporating new ontological refinements as higher-resolution, multimodal single-cell and spatial datasets emerge, cellular heterogeneity is better defined, and disease-associated abnormal cell types and reactive cell states are increasingly recognized and mechanistically interrogated. Together, this coordinated effort aims to provide the foundation necessary for a robust, harmonized, and expandable nomenclature for lung science.", "year": "2026", "month": "08", "volume": "", "issue": "", "pages": "", "doi": "10.1093/ajrcmb/aanag144", "link": "https://www.ncbi.nlm.nih.gov/pubmed/42599223", "sort_key": "2026-08-consensus lung cell ", "quarter": "q3"}, {"pmid": "42660929", "title": "CD97/ADGRE5 attenuates the induction of adaptive type 2 immune responses in allergic asthma.", "authors": ["Aust G", "Hoh AL", "Alladina J", "Smith NP", "H\u00f6hna F", "Wang B", "Kerner C", "Wagner M", "Krohn K", "Pierzchalski A", "H\u00e4ussler N", "Villani AC", "Cho JL", "Medoff BD", "Zenclussen AC", "Steinert M", "Hamann J", "Quaas M", "Polte T"], "journal": "Nat Commun", "journal_title": "Nature communications", "citation": "Nature communications, 08 2026", "abstract": "Allergic asthma results from an uncontrolled type 2 immune response to inhaled allergens. Here, we investigate the function of CD97/ADGRE5, expressed in mouse and human immune and lung epithelial cells, in this disease. Female Cd97-/- mice exhibit an exacerbated asthmatic phenotype across multiple models, primarily due to CD97 loss on immune cells. A single CD97 antibody treatment before allergen sensitization worsens allergic responses, highlighting a role for CD97 in early immune regulation. Post-sensitization, Cd97-/- mice display higher frequencies of lung conventional type 2 and monocyte-derived dendritic cells (DCs). Allergen-pulsed Cd97-/- bone marrow-derived DCs are more activated, promote enhanced proliferation and type 2 cytokine secretion by CD4\u207a OT-II cells, and induce stronger airway inflammation. Consistently, ADGRE5 expression is reduced in airway mucosa-derived mononuclear phagocyte subsets in human asthmatics after allergen-induced exacerbation. These results identify CD97 as an important regulator of DC-driven type 2 allergic responses and a potential target in asthma.", "year": "2026", "month": "08", "volume": "17", "issue": "1", "pages": "", "doi": "10.1038/s41467-026-76948-9", "link": "https://www.ncbi.nlm.nih.gov/pubmed/42660929", "sort_key": "2026-08-cd97/adgre5 attenuat", "quarter": "q3"}, {"pmid": "42227649", "title": "Piecing together the alveolar-capillary unit: arterial-venous capillary polarization.", "authors": ["Majka SM", "Niethamer TK", "Caporarello N", "Thorndyke HF", "Clair G", "West JD", "Karmouty-Quintana H", "Alvira CM"], "journal": "Am J Physiol Lung Cell Mol Physiol", "journal_title": "American journal of physiology. Lung cellular and molecular physiology", "citation": "American journal of physiology. Lung cellular and molecular physiology, 07 2026", "abstract": "Pulmonary capillary endothelial cells (ECs) form a highly specialized vascular interface that sustains gas exchange and organismal survival across species. Recent advances in single-cell transcriptomics and lineage tracing have revealed substantial heterogeneity within the pulmonary endothelium, redefining traditional views of capillary structure and function. In the adult lung, two major capillary populations, general capillary ECs (CAP1) and aerocyte capillary ECs (CAP2), have been identified, with CAP1 cells increasingly recognized as a heterogeneous and functionally diverse compartment that includes EC progenitors and reparative subpopulations. Emerging datasets further demonstrate arterial-venous polarization within the capillary bed and reveal gradients of gene expression that extend from macrovascular arteries and veins into the alveolar microvasculature. Within this polarized CAP1 landscape, several transcriptionally distinct EC subsets exhibit enhanced angiogenic potential and may contribute to EC regeneration during injury. This review synthesizes current knowledge of pulmonary capillary EC heterogeneity, emphasizing arterial-venous polarization of the capillary network, and the identification of reparative EC progenitors within the CAP1 population. We highlight emerging technologies, including EC enrichment strategies, transcriptomics, and epigenomic profiling, that are beginning to resolve rare EC states and functional niches within the alveolar microvasculature. A deeper understanding of capillary EC diversity and lineage dynamics will be essential for identifying therapeutic targets aimed at restoring vascular stability, promoting regenerative angiogenesis, and preserving gas exchange in aging lungs and chronic lung diseases. Ethics: No Human or Animal subjects. Publicly available data sets: Gene Expression Omnibus (GEO)/NCBI: Human ILD data: GSE227136; Mouse data: GSE242065.", "year": "2026", "month": "07", "volume": "331", "issue": "1", "pages": "L57-L69", "doi": "10.1152/ajplung.00101.2026", "link": "https://www.ncbi.nlm.nih.gov/pubmed/42227649", "sort_key": "2026-07-piecing together the", "quarter": "q3"}, {"pmid": "42384176", "title": "Opportunities for Human Lung Tissue-Based Studies in Fibrotic ILD Research.", "authors": ["Sturek JM", "Kim JS", "Podolanczuk A", "Hannan RT", "Limper AH", "Hariri LP", "Richeldi L", "Rosas IO", "Jenkins G", "Luo F", "Tomassetti S", "Roman J", "Sime PJ", "Thannickal VJ", "Kropski JA", "Kaminski N", "Martinez FJ", "Noth I"], "journal": "Am J Respir Crit Care Med", "journal_title": "American journal of respiratory and critical care medicine", "citation": "American journal of respiratory and critical care medicine, 07 2026", "abstract": "", "year": "2026", "month": "07", "volume": "", "issue": "", "pages": "", "doi": "10.1093/ajrccm/aamag346", "link": "https://www.ncbi.nlm.nih.gov/pubmed/42384176", "sort_key": "2026-07-opportunities for hu", "quarter": "q3"}, {"pmid": "42440319", "title": "Neonatal Outcomes Following Selective Serotonin Reuptake Inhibitor Use During Pregnancy.", "authors": ["Aref L", "Hughey JJ", "Shirazi S", "Sucre JMS", "Bastarache L"], "journal": "JAMA Netw Open", "journal_title": "JAMA network open", "citation": "JAMA network open, 07 2026", "abstract": "IMPORTANCE: Evaluating the safety of selective serotonin reuptake inhibitors (SSRIs) during pregnancy is challenging due to ethical barriers to randomized trials and potential confounding in observational studies. OBJECTIVE: To compare neonatal outcomes for pregnancies with SSRI continuation vs those with SSRI discontinuation using a target trial framework. DESIGN, SETTING, AND PARTICIPANTS: This cohort study comprised target trials using electronic health records of linked mothers and neonates from a single academic center. The periconception trial examined congenital anomalies with first-trimester exposure, and the early-pregnancy trial evaluated nonanomaly outcomes with first- or second-trimester exposure. Participants were women with singleton pregnancies (2006 to 2022) with SSRI use within the 2 years before conception and at least 1 prenatal visit during the first trimester (periconception trial) or during the first or second trimester (early-pregnancy trial). Data were analyzed from May 2022 to December 2023. EXPOSURE: SSRI continuation vs discontinuation during pregnancy. MAIN OUTCOMES AND MEASURES: Apgar scores, meconium in amniotic fluid, neonatal intensive care unit (NICU) admission, preterm birth, birth weight, respiratory distress, feeding problems, hypoglycemia, hypothermia, pulmonary hypertension, cesarean delivery, and congenital anomalies. RESULTS: The early-pregnancy trial included 1014 pregnancies (mean [SD] maternal age, 30.3 [5.4] years). The periconception trial included 807 pregnancies (mean [SD] maternal age, 30.4 [5.5] years). SSRI continuation was associated with lower Apgar scores at 1 minute (mean difference [MD], -0.39; 95% CI, -0.60 to -0.18) and 5 minutes (MD, -0.28; 95% CI, -0.42 to -0.13), and increased risk of meconium in amniotic fluid (odds ratio [OR], 1.73; 95% CI, 1.22 to 2.45). No significant associations were found for congenital anomalies (OR, 1.09; 95% CI, 0.63 to 1.90), though this result should be interpreted with caution given limited sample size. No differences were found for neonatal intensive care unit admission (OR, 1.23; 95% CI, 0.82 to 1.83) or other outcomes. CONCLUSIONS AND RELEVANCE: In this cohort study, SSRI continuation during pregnancy was associated with impaired neonatal adaptation but not with severe complications or NICU admission. These findings highlight the importance of appropriate comparator selection to minimize confounding and illustrate how target trial emulation can improve causal inference in studies of medication safety during pregnancy.", "year": "2026", "month": "07", "volume": "9", "issue": "7", "pages": "e2622790", "doi": "10.1001/jamanetworkopen.2026.22790", "link": "https://www.ncbi.nlm.nih.gov/pubmed/42440319", "sort_key": "2026-07-neonatal outcomes fo", "quarter": "q3"}, {"pmid": "42418587", "title": "Multiscale metabolic mapping of lung tissue via coregistered mass spectrometry and nonlinear optical imaging.", "authors": ["Gorman BL", "Li Z", "Deutsch G", "Huyck HL", "Beishembieva N", "Bhotika H", "Olson H", "Villazon J", "Yu P", "Pryhuber GS", "Clair G", "Shi L", "Anderton CR"], "journal": "Sci Adv", "journal_title": "Science advances", "citation": "Science advances, 07 2026", "abstract": "The lung is a highly heterogeneous organ that is composed of numerous microanatomical units, each essential for maintaining intricate functions that work in concert. Disruptions in the molecular and cellular mechanisms can cause tissue fibrosis, inflammation, and severe breathing difficulties, which are common characteristics of the disease of prematurity, bronchopulmonary dysplasia (BPD). BPD's molecular changes are not well understood, and this has hindered effective diagnosis and treatment. Here, we present a multimodal imaging workflow for detailed molecular and metabolic characterization of lung tissue at multiple spatial scales. We also developed a hierarchical multimodal registration network for precise coregistration of the data from each modality. Our results show that this approach can reveal previously unknown metabolic changes in distinct functional tissue units affected by disease, including altered lipid distributions, reduced optical redox states, and collagen remodeling. This multimodal approach provided detailed maps of molecular shifts occurring in distinct microanatomical features that, when adopted to interrogate this and other tissue types, has the potential to enable the discovery of new therapeutics.", "year": "2026", "month": "07", "volume": "12", "issue": "28", "pages": "eaec3544", "doi": "10.1126/sciadv.aec3544", "link": "https://www.ncbi.nlm.nih.gov/pubmed/42418587", "sort_key": "2026-07-multiscale metabolic", "quarter": "q3"}, {"pmid": "41259123", "title": "Lung-Innervating Neurons in Lung Homeostasis and Diseases.", "authors": ["Su Y", "Zhu Z", "Sun X"], "journal": "Physiology (Bethesda)", "journal_title": "Physiology (Bethesda, Md.)", "citation": "Physiology (Bethesda, Md.), 07 2026", "abstract": "The lung, classically viewed as a gas exchange organ, is increasingly recognized as a dynamic sensory interface that continuously monitors the external environment and communicates with the brain to shape physiology and disease. Vagal sensory neurons provide the predominant afferent innervation of the airways, displaying striking molecular diversity, distinct projection patterns, and specialized terminal morphologies that enable detection of mechanical, chemical, and immune-derived signals. These neurons orchestrate critical homeostatic functions, including breathing regulation, airway protection, and cardiopulmonary integration, while also contributing to pathological processes such as airway hyperreactivity, inflammation, and neuroimmune remodeling. Recent advances in molecular profiling, genetic tools, and circuit-mapping approaches have revealed new principles of vagal sensory organization, yet fundamental questions remain about how specific neuronal subtypes encode diverse environmental inputs, how their signals are integrated within central circuits, and how disease reshapes these pathways. This review synthesizes current knowledge of lung-innervating vagal sensory neurons, emphasizing their roles in neuroimmune cross talk, central integration, and disease pathogenesis. We highlight unresolved controversies and propose future directions aimed at decoding the molecular logic of airway sensation, mapping neuroimmune signaling, and developing organ-specific neuromodulation strategies to treat lung diseases. Together, these insights position vagal sensory pathways as central players in the lung-brain axis and promising therapeutic targets at the intersection of respiratory, immune, and neural health.", "year": "2026", "month": "07", "volume": "41", "issue": "4", "pages": "0", "doi": "10.1152/physiol.00036.2025", "link": "https://www.ncbi.nlm.nih.gov/pubmed/41259123", "sort_key": "2026-07-lung-innervating neu", "quarter": "q3"}, {"pmid": "42458790", "title": "Innate Immune Cell and Epithelial Subsets Coordinate Airway Responses to Allergen.", "authors": ["Murphy RC", "L\u00f3pez-Mart\u00ednez C", "Kooistra T", "Lai Y", "Liu M", "Dela Cruz PC", "Powell WT", "Benson B", "Krueger M", "Alladina J", "Cho JL", "Piliponsky AM", "Debley JS", "Sehmi R", "Gauvreau GM", "Medoff BD", "Gharib SA", "Hallstrand TS"], "journal": "Am J Respir Cell Mol Biol", "journal_title": "American journal of respiratory cell and molecular biology", "citation": "American journal of respiratory cell and molecular biology, 07 2026", "abstract": "RATIONALE: The mechanisms responsible for promoting allergic asthma remain incompletely understood, particularly the role of the crosstalk between innate immune cells and airway epithelium in coordinating the response to inhaled allergen. OBJECTIVE: Identify transcriptional responses to allergen exposure in human airway samples and ex vivo airway epithelial cell (AEC) model systems. METHODS: RNA-sequencing (RNA-seq) analyses were performed on induced sputum samples from individuals with allergic asthma that underwent inhaled allergen challenge. We integrated these results with a single cell RNA-seq (scRNA-seq) data set of epithelial brushings obtained before and after segmental allergen challenge (SAC). Finally, we performed RNA-seq analyses of primary AECs following house dust mite exposure in the context of priming with IL-13 (simulating a type-2 (T2) environment) or IFN-\u03b3 (simulating a type-1 (T1) environment). RESULTS: Distinct kinetic patterns were identified in the diverse inflammatory response to allergen in induced sputum samples, including activation of mast cell (MC) and AEC genes. Using the SAC scRNA-seq data set, we demonstrated that MCs modestly increase in the airways following SAC and are a key source of IL5 and IL18 expression. In contrast, basophils are near absent in the airways at baseline but are present in the airways following allergen challenge and are key sources of IL4 and IL13 expression. RNA-seq analyses of AECs in ex vivo culture demonstrate a core AEC allergen response enriched in genes associated with glycolysis and cadherin binding but is significantly altered in the presence of either IL-13 or IFN-\u03b3 exposure. Finally, we integrate these data sets to demonstrate that basophil chemotaxis to the airways in allergic asthma is partly mediated by epithelial-derived CCL26. CONCLUSION: Allergen challenge promotes diverse pro-inflammatory transcriptional responses in the airways, and MCs, basophils, and AECs play distinct but critical roles in coordinating this response. However, airway responses to allergen may vary considerably based on the baseline airway inflammatory endotype.", "year": "2026", "month": "07", "volume": "", "issue": "", "pages": "", "doi": "10.1093/ajrcmb/aanag149", "link": "https://www.ncbi.nlm.nih.gov/pubmed/42458790", "sort_key": "2026-07-innate immune cell a", "quarter": "q3"}, {"pmid": "42085270", "title": "Idiopathic pulmonary fibrosis risk loci in East Asian populations mirror those of European populations.", "authors": ["Peljto AL", "Furusawa H", "Puthenvedu D", "Lee JS", "Steele MP", "Brancato J", "Cardwell J", "Blumhagen RZ", "de Andrade J", "Bendstrup E", "Blackwell TS", "Bonella F", "Borie R", "Braybrooke R", "Brown KK", "Carbone RG", "Christie JD", "Costabel U", "Crestani B", "Davidsen JR", "Dieude P", "Donnelly SC", "Egan J", "Eickelberg O", "Fern\u00e1ndez P\u00e9rez ER", "Fiddler CA", "Foster EE", "Gibson KF", "Gudmundsson G", "Guthridge JM", "Henry MT", "Hirani N", "Jenkins RG", "Kass DJ", "Keane MP", "Kokturk N", "Kropski JA", "Lederer D", "Leone PM", "Linderholm AL", "Maher TM", "Mathai SK", "McCarthy C", "McElroy AN", "Mogulkoc N", "Molina-Molina M", "Molyneaux PL", "Montesi SB", "Nathan SD", "Noth I", "Olaniyi JA", "Oldham JM", "O'Reilly KMA", "Palmisciano AJ", "Pardo A", "Parfrey H", "Planas-Cerezales L", "Poletti V", "Porteous MK", "Puppo F", "Richeldi L", "Rojas M", "Salinas M", "Schluger N", "Selman M", "Shea BS", "Sterclova M", "Solomon JJ", "Tomassetti S", "Vasakova MK", "Zhang Y", "Corte TJ", "Dickinson JL", "Glaspole I", "Moodley YP", "Prele CMA", "Ryerson CJ", "Wolters PJ", "Jinno M", "Miyata Y", "Akagawa S", "Narumoto O", "Kita T", "Shibayama T", "Li T", "Owan I", "Wakamatsu K", "Arai T", "Hirose M", "Kim DS", "Ohta K", "Ohta S", "Park JS", "Park MS", "Yang IV", "Fingerlin TE", "Miyazaki Y", "Okamoto T", "Inoue Y", "Song JW", "Schwartz DA"], "journal": "Am J Respir Crit Care Med", "journal_title": "American journal of respiratory and critical care medicine", "citation": "American journal of respiratory and critical care medicine, 07 2026", "abstract": "RATIONALE: Common and rare variants that are associated with the risk of developing idiopathic pulmonary fibrosis (IPF) have been identified predominantly in European ancestry populations. OBJECTIVES: To better understand the genetic variants that contribute to IPF in individuals with Asian ancestry, we conducted a genome-wide association study of IPF in East Asian populations. METHODS: We included 1026 patients with IPF and compared them to 1723 unaffected controls of Japanese and Korean ancestry. Genome-wide association analysis was conducted in the Japanese and Korean ancestry cohorts separately and combined using meta-analysis. Restricted maximum likelihood was used to estimate the SNP-based heritability and local ancestry of chromosome 11 was inferred for each subject. MEASUREMENTS AND MAIN RESULTS: We identified loci on chromosomes 4 (FAM13A; rs7690839), 5 (TERT; rs7734992), 6 (DSP; rs2076295), and 11 (MUC5B; rs35705950) that were significantly associated with risk of IPF. Importantly, the sentinel variants in each of these loci are the same as, or in strong linkage disequilibrium with, the risk variants that have been observed in studies of European ancestry populations. In aggregate, common variants (not including the MUC5B promoter variant) account for approximately 25% of the risk of developing IPF in these East Asian ancestry cohorts. Moreover, local ancestry analysis indicates that the presence of MUC5B promoter variant in the East Asian population is not a result of admixture with European ancestry populations. CONCLUSIONS: We conclude that the IPF risk loci in East Asian populations are shared with those of European ancestry populations, although their risk allele frequencies and effect sizes differ. These findings indicate shared genetic risk factors of IPF across ancestries.", "year": "2026", "month": "07", "volume": "212", "issue": "7", "pages": "1522-1532", "doi": "10.1093/ajrccm/aamag152", "link": "https://www.ncbi.nlm.nih.gov/pubmed/42085270", "sort_key": "2026-07-idiopathic pulmonary", "quarter": "q3"}, {"pmid": "42485316", "title": "Emergence of Disease-relevant Aberrant Epithelial Cell States in Human Alveolar Organoids.", "authors": ["David HE", "Dietrich AJ", "Calvi CL", "Ware LB", "Gokey JJ", "Kropski JA", "McCall AS"], "journal": "Am J Respir Cell Mol Biol", "journal_title": "American journal of respiratory cell and molecular biology", "citation": "American journal of respiratory cell and molecular biology, 07 2026", "abstract": "Dysregulated alveolar epithelial repair is a central aspect of Idiopathic Pulmonary Fibrosis but it has proven challenging to reliably model alveolar epithelial cell biology in-vitro. We previously reported persistent activation of Hypoxia-inducible Factor 2 (HIF2) is a hallmark of aberrant epithelial cell phenotypes in IPF. We hypothesized that HIF2 activation primes AECs for aberrant differentiation. In these studies, we investigated how primary human alveolar epithelial organoids respond to a commonly-used commercial alveolar differentiation media intended to facilitate AT2->AT1 differentiation (ADM; which includes human serum and withdrawal of multiple growth factors/inhibitors) in isolation and following biased HIF activation. Alveolar organoids from donor lungs were expanded and transitioned to ADM with pharmacologic modulators to establish HIF-biased signaling. Multimodal analysis integrating scRNA-seq, quantitative label-free proteomics, and Cell Painting revealed that ADM induces expression of several AT1 markers, yet these conditions are insufficient to generate mature AT1-like cells but drives the emergence of KRT17+/KRT5- \"aberrant basaloid\" -like cells which demonstrate high transcriptional similarity to populations in end-stage IPF lungs (p = 3x10-286). HIF2-biased activation significantly exacerbated these aberrant transitions. Gene module co-expression analysis (hdWGCNA) linked ADM to cytoskeletal modulation and HIF2-biased signaling to metabolic shifts and cytoskeletal rearrangement. Proteomics reinforced protein-level induction of aberrant markers (e.g., GDF15) and revealed novel signatures, including increased complement production. Orthogonal transmission electron microscopy confirmed ultrastructural remodeling, including lysosomal inclusions and mitochondrial modulation. Collectively, these data establish that ADM models disease-emergent transitional states rather than homeostatic AT1 differentiation. These data further position HIF2 as a critical potentiator of aberrant alveolar epithelial cell states in PF.", "year": "2026", "month": "07", "volume": "", "issue": "", "pages": "", "doi": "10.1093/ajrcmb/aanag150", "link": "https://www.ncbi.nlm.nih.gov/pubmed/42485316", "sort_key": "2026-07-emergence of disease", "quarter": "q3"}, {"pmid": "41738289", "title": "CD44 is critical for TLR4-mediated NLRP3 inflammasome activation and the development of bronchopulmonary dysplasia.", "authors": ["Liao J", "Longoria C", "Lal CV", "Cheong N", "McCurnin DC", "Blanco C", "Cantu A", "Lingappan K", "Jehrio MG", "Misra RS", "Pryhuber GS", "Petovari G", "Reszegi A", "Savani RC"], "journal": "Am J Respir Cell Mol Biol", "journal_title": "American journal of respiratory cell and molecular biology", "citation": "American journal of respiratory cell and molecular biology, 07 2026", "abstract": "RATIONALE: Bronchopulmonary dysplasia (BPD) is a chronic lung disease of preterm infants. We previously established the NLRP3 inflammasome as critical in the pathogenesis of BPD. The hyaluronan receptor CD44 interacts with TLR4 to propagate extracellular signals driving inflammation. The role of CD44 in BPD is unclear. OBJECTIVES: To determine the contribution of CD44 to NLRP3 inflammasome activation and the development of BPD. METHODS: The activation of the NLRP3 inflammasome and the development of BPD were studied in CD44 and TLR4 knockout (KO) mice. Lipopolysaccharide (LPS) was used to study TLR4-specific responses. MEASUREMENTS AND MAIN RESULTS: In normal mice, lung CD44 decreased in the first 2 postnatal weeks but increased with exposure to neonatal hyperoxia. CD44 KO mice exposed to hyperoxia were protected from decreased alveolarization and inflammatory responses. Increased IL-1\u03b2 mRNA and protein and cleaved caspase-1 observed in CD44 wild-type (WT) mice were not seen in CD44 KO mice, indicating a failure to activate the NLRP3 inflammasome. Intraperitoneal LPS resulted in increased plasma IL-1\u03b2 concentrations in CD44 WT mice, which were decreased in CD44 KO mice. Intratracheal LPS caused a neutrophilic inflammation in CD44 WT lungs, which was absent in CD44 KO mice. TLR4 KO mice were protected from neonatal hyperoxia and showed less lung IL-1\u03b2 and inflammation. Increased lung CD44 expression was observed in the lungs of preterm baboons developing experimental BPD and in the lungs of preterm-born humans at extended corrected ages. CONCLUSIONS: Collectively, these data implicate CD44 in the pathogenesis of BPD and identify a novel therapeutic target to limit NLRP3 inflammasome activation.", "year": "2026", "month": "07", "volume": "74", "issue": "7", "pages": "869-880", "doi": "10.1093/ajrcmb/aanag025", "link": "https://www.ncbi.nlm.nih.gov/pubmed/41738289", "sort_key": "2026-07-cd44 is critical for", "quarter": "q3"}, {"pmid": "42530358", "title": "AP-1 mediated chromatin changes govern alveolar type 2 cell transition in lung injury-repair.", "authors": ["Lynch AM", "Noun T", "Yang S", "Zhou T", "Chen M", "Evans SE", "Kadara H", "Chen J"], "journal": "Am J Respir Cell Mol Biol", "journal_title": "American journal of respiratory cell and molecular biology", "citation": "American journal of respiratory cell and molecular biology, 07 2026", "abstract": "Facultative stem cells including lung alveolar type 2 (AT2) cells must toggle between unipotent specialization at baseline and multipotent plasticity during injury-repair. The underlying molecular switches and epigenetic changes remain unclear yet dictate regenerative versus pathological outcomes. Using multiomics and mouse genetics, we show that AP-1 members FOS, FOSB, and JUNB promote an injury-induced transitional AT2 cell state and associated chromatin landscape. Joint transcriptomic-epigenomic profiling and immunostaining distinguish CLDN4+ AT2 cells as a KRT8high subset with open chromatin highly enriched for AP-1 motifs. JUNB and FOSB accumulate in these cells upon viral injury and, along with constitutive FOS, are required for CLDN4 induction, AT2 cell dispersion, senescence signaling, and fibroblast activation, while impacting region-specific alveolar type 1 (AT1) differentiation. AP-1 activation also occurs in mouse AT2 cells expressing oncogenic Kras and transitional cells in human lung tissues with premalignant or adenocarcinoma lesions. Our work refines AT2 transitional states and reveals a gene regulatory logic shared by tissue repair and tumorigenesis.", "year": "2026", "month": "07", "volume": "", "issue": "", "pages": "", "doi": "10.1093/ajrcmb/aanag157", "link": "https://www.ncbi.nlm.nih.gov/pubmed/42530358", "sort_key": "2026-07-ap-1 mediated chroma", "quarter": "q3"}, {"pmid": "42496593", "title": "An Update to the Classification, Evaluation, and Management of Childhood Interstitial Lung Disease in Infancy: An Official American Thoracic Society Clinical Practice Guideline.", "authors": ["McGraw MD", "DeBoer E", "Weinman JP", "Deutsch GH", "Pogoriler J", "Parenti MB", "Kurland G", "Blatter J", "Casey AM", "Deterding RR", "Fiorino EK", "Young LR", "Barnes H", "Balasubramaniam V", "Brennan SK", "Charoenpong P", "Craven D", "Dell S", "Epaud R", "Fishman MP", "Gettys A", "Goldfarb S", "Gower WA", "Ha DM", "Hagood JS", "Hamvas A", "Jaffe A", "Kennedy JC", "Krivchenia K", "Liptzin DR", "Nathan N", "Nevel RJ", "Ocasio-Ramirez V", "Pryhuber G", "Raby BA", "Sadreameli SC", "Teper A", "Vargas SO", "Vece TJ", "Iyer NP", "Nogee LM", "Wambach JA", "American Thoracic Society Assembly on Pediatrics"], "journal": "Am J Respir Crit Care Med", "journal_title": "American journal of respiratory and critical care medicine", "citation": "American journal of respiratory and critical care medicine, 07 2026", "abstract": "BACKGROUND: Childhood interstitial lung diseases (chILD) are a heterogeneous group of rare disorders. In 2013, the American Thoracic Society (ATS) developed a guideline regarding the classification, evaluation, and management of children <2 years old with chILD. The current guideline provides updated recommendations regarding genetic testing, chest imaging, lung biopsy, and lung transplant referral. METHODS: The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach was used to form clinical questions, summarize evidence, and develop recommendations, following ATS policies and procedures. A multidisciplinary panel with expertise in chILD formulated recommendations addressing diagnostic tools and referral for lung transplant evaluation. RESULTS: Rapid and broad genetic testing is recommended for infants with chILD and respiratory failure (strong recommendation). Chest CT remains an important part of the diagnostic evaluation (conditional recommendation). Surgical lung biopsy is recommended when there is urgency to identify a specific chILD disorder and genetic testing is not feasible, timely, or inconclusive, to identify histopathologic 'treatable traits', or to inform prognosis (strong recommendation). Referral for lung transplant evaluation is recommended for children with specific chILD disorders with predictably poor outcomes (strong recommendation). Repeat chest CT to aid decision-making, prognosis, and/or change therapies is suggested for children with chILD diagnosed before age 2 years (conditional recommendation). CONCLUSIONS: This guideline provides evidence-based recommendations for genetic testing, chest imaging, lung biopsy, and referral for lung transplant evaluation to improve the diagnostic evaluation and management of children <2 years with chILD. Implementing this guideline will hopefully increase genetic testing for chILD, inform the diagnostic evaluation and disease monitoring of chILD, and identify future research priorities for chILD.", "year": "2026", "month": "07", "volume": "", "issue": "", "pages": "", "doi": "10.1093/ajrccm/aamag375", "link": "https://www.ncbi.nlm.nih.gov/pubmed/42496593", "sort_key": "2026-07-an update to the cla", "quarter": "q3"}, {"pmid": "42518202", "title": "ADAMTS14 is a Novel Modulator of Fibroblast Mechanoactivation in Pulmonary Fibrosis.", "authors": ["Ganzleben I", "Jaiswal A", "Yang Y", "Santos DM", "Segal A", "McCabe MC", "Medina EM", "Reynolds G", "Zhang J", "Yun SH", "Krug T", "Weitz DA", "Chow Ming Chia D", "Ortiz Diaz B", "Pantano L", "Ho Sui S", "Knipe RS", "Brazee P", "Pronzati G", "Black K", "Hariri LP", "Godbout C", "Maier C", "Altenburger LM", "Kooistra T", "Mempel TR", "Seither P", "Herrmann F", "Xavier RJ", "Medoff BD"], "journal": "Am J Respir Crit Care Med", "journal_title": "American journal of respiratory and critical care medicine", "citation": "American journal of respiratory and critical care medicine, 07 2026", "abstract": "RATIONALE: Yes-associated protein (YAP)-mediated fibroblast mechanoactivation is an important driver of fibrosis in idiopathic pulmonary fibrosis (IPF). OBJECTIVE: To characterize the role of ADAM with Thrombospondin motifs 14 (ADAMTS14) in YAP-mediated fibroblast mechanoactivation and pulmonary fibrosis. METHODS: We disrupted ADAMTS14 expression in primary human lung fibroblasts (HLFs) and demonstrated its role in YAP nuclear translocation and fibroblast activation. We confirmed the in vivo relevance of ADAMTS14 in an IPF patient cohort using transcriptomic studies. ADAMTS14-deficient fibroblasts were further characterized in mechanistic studies combining advanced microscopy, unbiased proteomics, and co-immunoprecipitation with functional mechanobiology assays to delineate substrate-matrix interactions. RESULTS: An unbiased siRNA screen identified ADAMTS14 as a regulator of YAP-mediated fibroblast activation and pro-fibrotic activity. Transcriptomic analyses of patient samples with fibrotic lung disease identified an ADAMTS14-expressing fibroblast population characterized by excessive collagen matrix synthesis and located within fibroblastic foci of IPF patients. Disruption of ADAMTS14 expression in IPF patient-derived HLFs reduced pro-fibrotic gene expression and attenuated the response to TGF\u03b2. Mechanistically, we identified collagen V as a novel functionally relevant ADAMTS14 substrate essential for matrix stability. ADAMTS14-deficient fibroblasts produced an unstable extracellular matrix, leading to disorganized focal adhesions, impaired force transmission, and reduced focal adhesion-FAK-AKT signaling. CONCLUSION: We identify a novel ADAMTS14-collagen V-focal adhesion axis as a potential driver of fibroblast activation in IPF, linking extracellular proteolytic matrix remodeling to focal adhesion dynamics and YAP-mediated mechanoactivation. This feed-forward circuit provides a new mechanistic framework for pulmonary fibrosis and identifies potential novel therapeutic targets.", "year": "2026", "month": "07", "volume": "", "issue": "", "pages": "", "doi": "10.1093/ajrccm/aamag396", "link": "https://www.ncbi.nlm.nih.gov/pubmed/42518202", "sort_key": "2026-07-adamts14 is a novel ", "quarter": "q3"}, {"pmid": "41086376", "title": "Toward human lung regeneration: gaining insights from the axolotl salamander Ambystoma mexicanum.", "authors": ["Dobie AC", "Win W", "Kotton DN", "Monaghan JR"], "journal": "Am J Respir Cell Mol Biol", "journal_title": "American journal of respiratory cell and molecular biology", "citation": "American journal of respiratory cell and molecular biology, 06 2026", "abstract": "", "year": "2026", "month": "06", "volume": "74", "issue": "6", "pages": "718-726", "doi": "10.1165/rcmb.2025-0097PS", "link": "https://www.ncbi.nlm.nih.gov/pubmed/41086376", "sort_key": "2026-06-toward human lung re", "quarter": "q2"}, {"pmid": "42298125", "title": "KLF6 activation marks an angiogenic and apoptosis resistant endothelial phenotype in pulmonary arterial hypertension.", "authors": ["Alharbi R", "Keles M", "Fernandes N", "Maude H", "Fellows A", "Williams RD", "Chen CN", "Lambie N", "Matthews N", "Al-Sahaf M", "Barnett SN", "Guo M", "Zhao L", "Lawrie A", "Whitsett JA", "Cebola I", "Wojciak-Stothard B"], "journal": "Commun Biol", "journal_title": "Communications biology", "citation": "Communications biology, 06 2026", "abstract": "Pulmonary arterial hypertension (PAH) is a severe, currently incurable lung disease characterized by endothelial injury and excessive repair, leading to arterial narrowing. However, the contributory mechanisms remain poorly understood. Here we show that Kr\u00fcppel-like factor 6 (KLF6) is a feature of vascular pathology in PAH. KLF6 expression is elevated in human PAH and preclinical models of PAH and promotes endothelial repair and angiogenesis through transcriptomic remodelling, with effects distinct from those of KLF2 and KLF4. Endothelial KLF6 also stimulates vascular smooth muscle cell proliferation, which is attenuated by bosentan and imatinib. DisGeNET and spatial transcriptomic analyses of control and PAH lungs reveal elevated KLF6 in PAH endothelium, endothelial progenitor cells, and PAH with alveolar capillary dysplasia. In summary, KLF6 activation uniquely orchestrates endothelial repair and is a feature of the angio-proliferative vascular phenotype in PAH.", "year": "2026", "month": "06", "volume": "9", "issue": "1", "pages": "", "doi": "10.1038/s42003-026-10493-5", "link": "https://www.ncbi.nlm.nih.gov/pubmed/42298125", "sort_key": "2026-06-klf6 activation mark", "quarter": "q2"}, {"pmid": "42373667", "title": "Emergence of fibrotic pericytes and their transcriptional regulation in pulmonary fibrosis.", "authors": ["Gao W", "Lan YW", "Deng Z", "Li E", "Acharya A", "Do J", "Xia X", "Marquez N", "Lu D", "Siraj AA", "Banovich NE", "Sureshbabu A", "Bremner R", "Kalinichenko VV", "Kalin TV"], "journal": "Nat Commun", "journal_title": "Nature communications", "citation": "Nature communications, 06 2026", "abstract": "Multiple cell types have been implicated in pathogenesis of pulmonary fibrosis with pericytes emerging as a new focus due to their role in promoting fibrotic remodeling. Fibrotic environment changes normal pericyte functions, but transcriptional programs regulating pericyte transition towards fibrotic state remain unclear. Utilizing single cell RNA-sequencing of human pulmonary fibrotic lungs and mouse genetic models, we identified a unique cluster of fibrosis-associated pericytes which was not present in normal lungs and exhibited a distinctive transcriptional signature indicating transition of normal pericytes to a fibrotic state. FOXF1 was identified as one of the transcription factors decreased in fibrotic pericytes. Pericyte-specific deletion of Foxf1 increased severity of pulmonary fibrosis in bleomycin mouse model as demonstrated by reduced survival, impaired lung functions, increased body weight loss and increased fibrotic remodeling. Pericyte-specific overexpression of Foxf1 attenuated pulmonary fibrosis, reversed fibrotic changes and improved survival outcomes. Based on single cell RNA-sequencing and chromatin immunoprecipitation sequencing, FOXF1 transcriptionally regulates an extensive pericyte signaling network critical for pulmonary fibrosis. In vitro, FOXF1 transcriptionally activated ID3 which inhibited fibroblast activation through decreased secretion of IL8 and CXCL1 by pericytes. Altogether, FOXF1 prevents transition of pericytes to a fibrotic state, suggesting new therapeutic opportunities for treatment of pulmonary fibrosis.", "year": "2026", "month": "06", "volume": "17", "issue": "1", "pages": "", "doi": "10.1038/s41467-026-74910-3", "link": "https://www.ncbi.nlm.nih.gov/pubmed/42373667", "sort_key": "2026-06-emergence of fibroti", "quarter": "q2"}, {"pmid": "42350068", "title": "Decoding the Lymphangioleiomyomatosis (LAM) Niche Microenvironment via Integrative Analysis of Single Cell Multiomics and Spatial Transcriptomics.", "authors": ["Chen K", "Zhao S", "Guo M", "Reza H", "Wagner A", "Cakar AC", "Jiang C", "Zhang E", "Green J", "Martin EP", "Wikenheiser GA", "Wikenheiser-Brokamp KA", "Perl AK", "Sinner D", "Yu JJ", "Xu Y"], "journal": "Eur Respir J", "journal_title": "The European respiratory journal", "citation": "The European respiratory journal, 06 2026", "abstract": "Lymphangioleiomyomatosis (LAM) is a rare, destructive lung disease caused by mutations in TSC1 or TSC2, leading to mTORC1 hyperactivation. While mTOR inhibitor sirolimus, the only FDA approved drug for this disease, stabilizes lung function in most LAM patients, the drug does not eliminate LAM cells, underscoring a critical gap in our understanding of the tumor microenvironment and cellular heterogeneity that drive disease progression. This study provides the first comprehensive multiomics atlas of the human LAM niche, integrating single-cell/nucleus RNA-seq, single-nucleus ATAC-seq, and spatial transcriptomics to deconvolute its complex architecture. We elucidate LAM cellular heterogeneity by identifying three distinct subtypes: the canonical, uterine smooth muscle-like, mTORC1-hyperactive LAMCORE1; a novel, fibroblast-like LAMCORE2 subtype with potent extracellular matrix (ECM) remodeling activity; and LAMCORE3, a substate of LAMCORE1 that shares LAM and myogenic signatures but is characterized by a lower transcriptional activity and specific functional enrichment in protein translation.Our analysis reveals the transcriptomic heterogeneity of the LAM subtypes, orchestrated by distinct transcriptional drivers and networks. Furthermore, we uncover spatially resolved LAM-associated fibroblast (LAF) states, LAF-seed and LAF-niche, that orchestrate TGF-\u03b2 signaling, ECM deposition and remodeling, and niche expansion. Spatial mapping uncovers a structured ecosystem where LAMCORE1 cells form a central core enmeshed with the lymphatic endothelium, which is surrounded by LAFs, LAMCORE2 cells, and reprogrammed immune and epithelial cells. Findings were validated through multimodal imaging technologies. Present work advances the field by providing the first high-resolution blueprint of the LAM niche microenvironment, revealing novel cell states and crosstalk that identify promising therapeutic targets.", "year": "2026", "month": "06", "volume": "", "issue": "", "pages": "", "doi": "10.1183/13993003.02049-2025", "link": "https://www.ncbi.nlm.nih.gov/pubmed/42350068", "sort_key": "2026-06-decoding the lymphan", "quarter": "q2"}, {"pmid": "42326523", "title": "Connexin 43 Loss in Endothelial Progenitors Facilitates Functional Airway Adaptation After Lung Injury.", "authors": ["Dawon M", "Thorndyke HF", "Hollaway JM", "Patel P", "Richmond BW", "Cool CD", "Manning EP", "Kropski JA", "Ghosh M", "Tata A", "Geraghty P", "Majka SM"], "journal": "Res Sq", "journal_title": "Research square", "citation": "Research square, 06 2026", "abstract": "Connexin 43 mediated gap junction signaling between ABCG2hi endothelial progenitor cells and alveolar epithelium governs epithelial differentiation and injury response. Here, we identify a previously unrecognized endothelial - epithelial communication axis that regulates AT2-to-AT1 transition during fibrotic repair. Disruption of ABCG2hi derived endothelial Cx43 impairs canonical regeneration but activates an alternative basal cell driven repair program. These findings reveal intercellular communication as a key determinant of lung repair trajectory.", "year": "2026", "month": "06", "volume": "", "issue": "", "pages": "", "doi": "10.21203/rs.3.rs-9727235/v1", "link": "https://www.ncbi.nlm.nih.gov/pubmed/42326523", "sort_key": "2026-06-connexin 43 loss in ", "quarter": "q2"}, {"pmid": "42286788", "title": "Brillouin microscopy for contact- and label-free quantification of tissue stiffness in lung fibrosis.", "authors": ["Ganzleben I", "Zhang J", "Lane CP", "Chow Ming Chia D", "Zhou H", "Segal A", "Shih AR", "Yun SH", "Medoff BD"], "journal": "Am J Respir Cell Mol Biol", "journal_title": "American journal of respiratory cell and molecular biology", "citation": "American journal of respiratory cell and molecular biology, 06 2026", "abstract": "Pathologically altered physical properties of the extracellular matrix are increasingly recognized as an active player in fibrosis inception and progression. Fibroblasts produce an increasingly stiff matrix, which in turn perpetuates fibroblast activation and transdifferentiation into myofibroblasts. Yet, there is still an unmet need for accessible technologies allowing detailed characterization of tissue stiffness to study this relationship. In our current study, we demonstrate the feasibility of a Brillouin microscopy-based quantitative spatial stiffness measurement for the characterization of lung tissue samples with variable degrees of fibrosis. First, we validated our Brillouin microscopy setup using hydrogels with defined levels of stiffness. We then devised a workflow to measure native murine lung tissue cryosections and successfully characterized stiffness levels of lung tissue sections with fibrosis and in non-fibrotic controls. Finally, we successfully applied our setup to fibrotic human lung tissue sections. In conclusion, our proof-of-concept study shows the feasibility of quantitative spatial lung tissue stiffness assessment by Brillouin microscopy in a setup that can easily be integrated into common research workflows. Stiffness measurements through label- and contact-free Brillouin microscopy in combination with techniques such as immunofluorescence staining, RNA-scope, spatial transcriptomics, spatial proteomics, and others have great potential to generate new insights into the mechanobiology of pulmonary fibrosis and a multitude of other diseases in the future.", "year": "2026", "month": "06", "volume": "", "issue": "", "pages": "", "doi": "10.1093/ajrcmb/aanag114", "link": "https://www.ncbi.nlm.nih.gov/pubmed/42286788", "sort_key": "2026-06-brillouin microscopy", "quarter": "q2"}, {"pmid": "42265991", "title": "Beyond Breathing: Lung as a Sensory Organ A Report from the NHLBI Workshop on Lung Sensing and its Implication in Diseases.", "authors": ["Jendzjowsky N", "Kuo CS", "Reznikov LR", "Chen Z", "Li P", "Prescott S", "Liu Y", "Seeholzer L", "Tschumperlin DJ", "Taylor-Clark TE", "Rajagopal J", "Haber AL", "No\u00ebl A", "Kotas M", "Drake M", "Pabelick C", "Rosenblatt J", "Mouradian G", "Su Y", "Gomez C", "Lin Q", "Lu Q", "Mongodin EF", "Vuga L", "Zhou G", "Prakash YS", "Sun X"], "journal": "Am J Respir Cell Mol Biol", "journal_title": "American journal of respiratory cell and molecular biology", "citation": "American journal of respiratory cell and molecular biology, 06 2026", "abstract": "The lung, one the largest branching organs in our body and vital for survival at first breath, is commonly known as the gas-exchange organ. Recent novel findings on lung sensing cells, molecules, and lung-brain crosstalk in the emerging discipline of interoception have highlighted the consideration of the lung as a sensory organ. Acknowledging the central importance of lung sensing to human health and disease, NHLBI convened a workshop to synthesize the past, current, and future of lung sensing research, with in-person presentations by \u223c20 interdisciplinary experts and a large virtual audience. Here, we highlight the key topics discussed and summarize a blueprint for the future in this important field.", "year": "2026", "month": "06", "volume": "", "issue": "", "pages": "", "doi": "10.1093/ajrcmb/aanag111", "link": "https://www.ncbi.nlm.nih.gov/pubmed/42265991", "sort_key": "2026-06-beyond breathing: lu", "quarter": "q2"}, {"pmid": "42065675", "title": "AlveolEye: rapid and precise lung morphometry guided by computer vision.", "authors": ["Hirsh J", "Hirsh S", "Shirazi SP", "Hirsh J", "Douglas I", "Garg S", "Son Y", "Pierre-Louis A", "Bunn C", "Jetter CS", "James TJ", "Sharkey AL", "Benjamin JT", "Gokey JJ", "Ochi A", "Reese J", "Renfree MB", "Shaw G", "Kropski JA", "Sucre JMS", "Negretti NM"], "journal": "Am J Physiol Lung Cell Mol Physiol", "journal_title": "American journal of physiology. Lung cellular and molecular physiology", "citation": "American journal of physiology. Lung cellular and molecular physiology, 06 2026", "abstract": "Rigorous and reproducible evaluation of lung tissue under different conditions is necessary to interpret development, injury, and pharmacologic interventions. Common histological measurements in the distal lung include mean linear intercept (MLI) as a metric of alveolarization and airspace volume density (ASVD) as a metric of airspaces relative to tissue. Historically, these have been performed manually in a time-intensive process, with reproducible trends but a high degree of variability between individuals. To improve the reproducibility and throughput of lung morphometry, we developed AlveolEye, an open-source, semiautomated, computer vision-assisted tool that rapidly and reproducibly calculates MLI and ASVD from images of standard hematoxylin and eosin-stained tissue sections. AlveolEye-assisted MLI calculation closely aligns with manually derived measurements for corresponding images, with preservation of trends in measurements between noninjured controls and neonatal mice subjected to two different injury models. Analyzing human tissue of varying ages suggests that the approach developed in AlveolEye is generalizable across species. Notably, AlveolEye markedly reduced the average variation across individual analyzers, with the greatest improvement in precision among individuals with the least experience in performing lung morphometry. The design of AlveolEye is intentionally semiautomated, preserving the investigator's ability to assess and adjust parameters based on sample characteristics. AlveolEye facilitates efficient lung morphological measurements on larger sample sizes, allowing for greater statistical power for preclinical studies, and improves precision across individual observers, allowing for improved rigor in experimental design and execution.NEW & NOTEWORTHY Calculating lung morphometric measurements is time-intensive, with a high degree of interrater variability. We developed a semiautomated tool, AlveolEye, which uses computer vision to perform rapid and precise lung morphometry, reducing variability and improving efficiency. AlveolEye presents an opportunity for improved rigor, efficiency, and reproducibility in studies of lung development, injury, and regeneration.", "year": "2026", "month": "06", "volume": "330", "issue": "6", "pages": "L755-L766", "doi": "10.1152/ajplung.00337.2025", "link": "https://www.ncbi.nlm.nih.gov/pubmed/42065675", "sort_key": "2026-06-alveoleye: rapid and", "quarter": "q2"}, {"pmid": "42024502", "title": "Vip+ vagal neurons control allergen-induced responses.", "authors": ["Zhu Z", "Su Y", "Sun X"], "journal": "Cell Rep", "journal_title": "Cell reports", "citation": "Cell reports, 05 2026", "abstract": "Vagal sensory neurons innervating the lung control respiratory physiology and immunity, yet the subtypes mediating responses to specific inputs, i.e., allergen, remain undefined. Here, we identify Vip+ and Tac1+ neurons as two vagal subsets with non-overlapping expression and divergent innervation profiles. Selective ablation of Vip+, but not Tac1+, neurons leads to reduced airway hyperreactivity and type 2 cytokine expression, whereas chemogenetic activation of Vip+ neurons leads to elevated responses. Bulk RNA sequencing of allergen-treated vagal ganglia reveals upregulation of Ngfr, the highly enriched receptor in Vip+ vagal neurons. NGFR signaling is required for Vip+-mediated airway hyperreactivity. Furthermore, Vip+ neurons project to the nucleus of the solitary tract (nTS) in the brainstem, and unilateral genetic ablation reduces FOS+ activation in the ipsilateral nTS. These findings specify a vagal population that bridges peripheral allergen sensing and central output, revealing a neuroimmune mechanism along the body-brain axis that contributes to asthma.", "year": "2026", "month": "05", "volume": "45", "issue": "5", "pages": "117287", "doi": "10.1016/j.celrep.2026.117287", "link": "https://www.ncbi.nlm.nih.gov/pubmed/42024502", "sort_key": "2026-05-vip+ vagal neurons c", "quarter": "q2"}, {"pmid": "42115292", "title": "Transcriptional landscape of pulmonary artery endothelium reveals subpopulation- and disease-specific remodeling signatures.", "authors": ["Lins T", "Valzano F", "Flie\u00dfer E", "Borek I", "Crnkovic S", "Morley M", "Basil MC", "Katzen J", "Cantu E", "Schupp JC", "Kneidinger N", "Lindenmann J", "Aigner C", "Benazzo A", "Morrisey EE", "Bartkuhn M", "Marsh LM", "Birnhuber A", "Kwapiszewska G"], "journal": "Commun Biol", "journal_title": "Communications biology", "citation": "Communications biology, 05 2026", "abstract": "The physiological state of endothelial cells (ECs) is a central determinant of organ health. Distinct endothelial phenotypes and transcriptional programs are linked to vessel size and anatomical location, but it remains unclear how this intrinsic heterogeneity is organized within a particular niche. We performed compartment-specific single-cell profiling of human pulmonary artery (PA) ECs from healthy donors and from patients with two clinically divergent forms of pulmonary hypertension (PH): pulmonary arterial hypertension (PAH) and pulmonary hypertension associated with pulmonary fibrosis (PH-PF). We identified and localized three major EC subsets in healthy and remodeled PAs termed immuno-, vascular tone- and vascular plasticity modulatory, reflecting their enrichment for distinct biological processes. Expression signatures defining each subset were shared with other arterial beds, including the aorta and coronary arteries, and murine PA. Both PAH and PH-PF altered PAEC subset compositions, with increased immunomodulatory and decreased vascular plasticity modulatory PAECs. PH-PF PAECs were generally defined by dysregulated angiogenesis and antigen presentation, whereas PAH PAECs exhibited lipid metabolic dysfunction and enhanced vasoregulatory signaling. By uncovering endothelial heterogeneity and pathology-specific transcriptional programs in PAs, this study underscores the need of disease-specific therapeutic targeting.", "year": "2026", "month": "05", "volume": "9", "issue": "1", "pages": "", "doi": "10.1038/s42003-026-10204-0", "link": "https://www.ncbi.nlm.nih.gov/pubmed/42115292", "sort_key": "2026-05-transcriptional land", "quarter": "q2"}, {"pmid": "41134976", "title": "Sexually distinct multi-omic responses to progressive endurance exercise training in the rat lung.", "authors": ["Many GM", "Sagendorf TJ", "Mitchell H", "Sanford JA", "Cohen SE", "Misra RS", "Estevao I", "Ludovico ID", "Gaul DA", "Lindholm ME", "Ushakumary MG", "Pino JC", "Musi N", "Nie J", "Fern\u00e1ndez FM", "Ortlund EA", "Esser KA", "Bodine SC", "Schenk S", "Clair G", "Adkins JN", "MoTrPAC Study Group"], "journal": "Am J Respir Cell Mol Biol", "journal_title": "American journal of respiratory cell and molecular biology", "citation": "American journal of respiratory cell and molecular biology, 05 2026", "abstract": "Endurance exercise is broadly beneficial to cardiopulmonary function, with these benefits thought to be driven by extrapulmonary factors rather than direct structural changes in the lungs. Thus, to address how endurance exercise training and sex impact molecular responses in the lungs, we used a multi-omics approach to study 6-month-old Fischer 344 rats that undertook a progressive endurance treadmill training protocol for 1 to 8 weeks. Specifically, we reannotated publicly accessible transcriptomics, metabolomics, proteomics and phosphoproteomics data from the Molecular Transducers of Physical Activity Consortium and integrated newly analyzed acetylproteomics data to assess multi-omic sex differences in sedentary and treadmill trained rats. Female rats displayed enrichment in immune-related features and pathways at the transcriptome and proteome level that were largely maintained with training. However, both sexes exhibited decreases in immune pathway activity following 8 weeks of training, although the effect was more pronounced in males. Shared responses to training included increased enrichment in transcriptomic pathways related to type I alveoli, proteomic pathways related to cilia, and decreased acetylation of pathways linked to mitochondrial function. Furthermore, features known to be enriched in lung diseases were attenuated with training in both sexes. Together, our findings provide novel insight into responses to endurance exercise training in the healthy rat lung and may offer translational insight into sex-specific differences in lung disease pathogenesis and treatment.", "year": "2026", "month": "05", "volume": "74", "issue": "5", "pages": "675-689", "doi": "10.1165/rcmb.2025-0249OC", "link": "https://www.ncbi.nlm.nih.gov/pubmed/41134976", "sort_key": "2026-05-sexually distinct mu", "quarter": "q2"}, {"pmid": "42202213", "title": "Progenitor Resilience and the Early Onset of Chronic Lung Diseases: NHLBI workshop report.", "authors": ["Han S", "Zhou AX", "Jamieson AM", "Wilson AA", "Zhou B", "Weiss DJ", "Jiang D", "McKeon F", "Chapman H", "Miranda H", "Schiller HB", "Rajagopal J", "Yun JH", "Que J", "Engelhardt JF", "Basil MC", "Raredon MSB", "Gu M", "Ghosh M", "Kadur Lakshminarasimha Murthy P", "Tata PR", "Wang R", "Davidson S", "Majka SM", "Tesfaigzi Y", "Gomez CR", "Lu Q", "Ordovas-Montanes J", "Kalhan R"], "journal": "Am J Respir Cell Mol Biol", "journal_title": "American journal of respiratory cell and molecular biology", "citation": "American journal of respiratory cell and molecular biology, 05 2026", "abstract": "Lung function peaks in young adulthood and declines with age. Studies suggest that this trajectory may be modifiable, potentially enhancing lung health and resilience to prevent or delay the onset of chronic lung disease. Although significant progress has been made in identifying the lung stem/progenitor cell populations involved in lung repair and homeostasis, their regulation and potential for manipulation to promote respiratory health and resilience remain elusive. To explore these issues, the NHLBI organized a virtual workshop on November 7-8, 2024 that aimed to cover the current scientific landscape, address critical research gaps, and identify challenges, opportunities, and key research questions related to chronic lung disease, with a focus on lung stem/progenitor resilience and its applications in the early diagnosis, prevention, and treatment of chronic lung diseases. This report summarizes the scientific presentations, discussions, and recommendations from the workshop.", "year": "2026", "month": "05", "volume": "", "issue": "", "pages": "", "doi": "10.1093/ajrcmb/aanag107", "link": "https://www.ncbi.nlm.nih.gov/pubmed/42202213", "sort_key": "2026-05-progenitor resilienc", "quarter": "q2"}, {"pmid": "41642658", "title": "TP53/TAU axis regulates microtubule bundling to control alveolar stem cell-mediated regeneration.", "authors": ["Konishi S", "Enkhbayar K", "Liu S", "Miyashita N", "Kobayashi Y", "Hutchison V", "Sai A", "Agarwal P", "Witonsky J", "Jackson ND", "Seibold MA", "Chen J", "Tata A", "Tata PR"], "journal": "J Clin Invest", "journal_title": "The Journal of clinical investigation", "citation": "The Journal of clinical investigation, 04 2026", "abstract": "Cells exhibit diverse sizes and shapes, tailored for functional needs of tissues. Lung alveoli are lined by large, extremely thin epithelial alveolar type 1 cells (AT1s). Their characteristic morphology is essential for lung function and must be restored after injury. The mechanisms underlying small, cuboidal alveolar type 2 cell (AT2) differentiation into thin AT1s remain elusive. Here, we demonstrated that AT2s undergo a stepwise morphological transformation characterized by the development of a unique thick microtubule (MT) bundle organization, critical for AT1 morphology. Using AT2 cultures and in vivo genetic loss-of-function models, we found that MT bundling occurred in a transitional cell state during AT2 differentiation and was regulated by the TP53/TAU (encoded by the microtubule-associated protein tau [MAPT] gene) signaling axis. Notably, TAU underwent a linear clustering process, forming beads-on-a-string-like pattern that preceded thick MT bundle formation. Genetic gain or loss of function of TAU in mouse or human models prevented the formation of thick MT bundles, highlighting the critical role of precise TAU levels in generating ultrathin AT1s. This defect was associated with increased tissue fibrosis following bleomycin-induced injury in vivo. GWAS analysis revealed risk variants in the MAPT locus in lung diseases. Moreover, TP53 controlled TAU expression and its loss phenocopied TAU deficiency. This work revealed an unexpected role for TAU in organizing MT bundles during AT2 differentiation.", "year": "2026", "month": "04", "volume": "136", "issue": "7", "pages": "", "doi": "10.1172/JCI194762", "link": "https://www.ncbi.nlm.nih.gov/pubmed/41642658", "sort_key": "2026-04-tp53/tau axis regula", "quarter": "q2"}, {"pmid": "42012958", "title": "The intestinal microbiota impacts nutritional immunity and resistance to Acinetobacter baumannii pneumonia.", "authors": ["Green ER", "Negretti NM", "Brunner TH", "Shealy NG", "Moser FA", "Drury SL", "Traina KA", "Reyes Ruiz VM", "Yang TS", "Lehmann CJ", "Byndloss MX", "van de Plas R", "Zackular JP", "Light SH", "Sucre JMS", "Skaar EP"], "journal": "Proc Natl Acad Sci U S A", "journal_title": "Proceedings of the National Academy of Sciences of the United States of America", "citation": "Proceedings of the National Academy of Sciences of the United States of America, 04 2026", "abstract": "Broad-spectrum antibiotics are frequently administered to intensive care unit patients as part of empiric care. This treatment has been associated with subsequent infections by the emerging nosocomial pathogen Acinetobacter baumannii; however, the mechanisms underlying this linkage remain unclear. Here, we observe an association between antibiotic treatment and microbiota disruption that precedes A. baumannii infection in a hospitalized patient cohort and demonstrate in a murine model that broad-spectrum antibiotic administration drives susceptibility to intranasal infection with this pathogen. Reconstitution of the intestinal microbiota by fecal microbiota transplant restores control of A. baumannii bloodstream dissemination, implicating microbiota dysbiosis as a key driver of pulmonary disease. Using single-cell RNA sequencing, we determine that antibiotic pretreatment reduces the abundance of transcripts related to phagocyte effector functions in the lung, including nutritional immunity pathways that restrict pathogen access to essential nutrient metals. Depletion studies identify neutrophils and inflammatory monocytes as central mediators of microbiota-dependent protection, and loss of the nutritional immunity components lipocalin-2 or calprotectin abrogates the effects of antibiotics on infected mice, demonstrating a causal relationship between microbiota dysbiosis and impaired phagocyte-mediated nutritional immunity. Together, these findings provide a mechanism for the increased severity of A. baumannii pneumonia following antibiotic exposure and highlight the intestinal microbiota as a potential therapeutic target to prevent nosocomial infections with this and other healthcare-associated pathogens.", "year": "2026", "month": "04", "volume": "123", "issue": "17", "pages": "e2534432123", "doi": "10.1073/pnas.2534432123", "link": "https://www.ncbi.nlm.nih.gov/pubmed/42012958", "sort_key": "2026-04-the intestinal micro", "quarter": "q2"}, {"pmid": "41891295", "title": "Prophylactic Inhaled Pattern Recognition Receptor Agonists Reprogram Lung Epithelial Response and Prevent Type 2 Allergic Inflammation.", "authors": ["Ntita M", "Kong CSL", "Hassan D", "Nayak R", "Garc\u00eda JP", "Wang Y", "Chen J", "Evans SE"], "journal": "Eur J Immunol", "journal_title": "European journal of immunology", "citation": "European journal of immunology, 04 2026", "abstract": "Prophylactic inhalation of the synergistic agents ODN M362 and Pam2CSK4 (\"Pam2ODN\") protects mice against allergic lung disease, including allergic inflammation caused by house dust mite (HDM). By preventing sensitization, Pam2ODN reduces HDM-induced eosinophilic and lymphocytic inflammation. How Pam2ODN affects interactions among lung epithelial cells, dendritic cells, and T cells to prevent eosinophilic lung inflammation remains unclear. In the present study, we show that a single inhaled dose of Pam2ODN before HDM sensitization reduces airway Th2 polarization without affecting Th1 or Treg responses. Furthermore, Pam2ODN pretreatment inhibits the recruitment of lung monocyte-derived dendritic cells (moDCs) and conventional Type 2 dendritic cells (DC2s), while preventing the HDM-induced decrease in conventional Type 1 dendritic cells (DC1s). Bulk RNA-seq of the whole lung reveals that Pam2ODN pretreatment restricts the expression of proinflammatory transcripts induced by HDM sensitization. This tolerogenic effect is also reflected at the single-cell level in lung epithelial cells, where proinflammatory transcripts, pathways, and chromatin accessibility are inhibited. These results indicate that Pam2ODN reprograms lung epithelial cells to attenuate allergen-induced Th2-promoting cytokines and DCs while maintaining the population of protective DC1s. These findings suggest a strategy to mitigate chronic allergic lung diseases.", "year": "2026", "month": "04", "volume": "56", "issue": "4", "pages": "e70172", "doi": "10.1002/eji.70172", "link": "https://www.ncbi.nlm.nih.gov/pubmed/41891295", "sort_key": "2026-04-prophylactic inhaled", "quarter": "q2"}, {"pmid": "42010330", "title": "PCBP1 regulates alternative splicing of AARS2 in congenital cardiomyopathy.", "authors": ["Lu YW", "Liang Z", "Dorr K", "Ruiz S", "Huang X", "Fangnibo Hanvi D", "Juntilla SM", "Beutner G", "Lyu S", "Guo H", "Fernandes T", "Espinoza-Lewis RA", "Wang T", "Li K", "Li X", "Bir Singh G", "Wang Y", "Deng R", "Cowan D", "Mably JD", "Pu WT", "Huang J", "Porter GA", "Conlon F", "Chen H", "Wang DZ"], "journal": "Nat Cardiovasc Res", "journal_title": "Nature cardiovascular research", "citation": "Nature cardiovascular research, 04 2026", "abstract": "Mutations in the AARS2 gene are linked to infantile cardiomyopathy; however, the underlying molecular mechanism remains unknown. Here we report that PCBP1, a poly(rC) binding protein, interacts with the AARS2 transcript to mediate its alternative splicing. Cardiomyocyte-specific deletion of Pcbp1 in mice impairs normal splicing and causes premature termination of Aars2, leading to defects in heart development and postnatal lethality. Similarly, mice with a deletion in Aars2 that mimics a disease-causing splicing lesion display heart developmental abnormalities, reminiscent of those in patients with infantile mitochondrial cardiomyopathy. Mechanistically, loss of Pcbp1 or Aars2 in the heart reduces oxidative phosphorylation, a hallmark of patients with AARS2 mutations. This reduction in mitochondrial-encoded proteome activates mitonuclear communication and the unfolded protein response pathway, thereby inducing a compensatory nuclear-encoded mitochondrial gene program. Our findings provide insights into the PCBP1-AARS2 regulatory axis in mitochondrial cardiomyopathy.", "year": "2026", "month": "04", "volume": "5", "issue": "4", "pages": "328-350", "doi": "10.1038/s44161-026-00798-3", "link": "https://www.ncbi.nlm.nih.gov/pubmed/42010330", "sort_key": "2026-04-pcbp1 regulates alte", "quarter": "q2"}, {"pmid": "41785017", "title": "Mechanical compression causes lung hypoplasia in congenital diaphragmatic hernia with GATA4 genetic variants.", "authors": ["Pham B", "Li Z", "Luna G", "Talaba N", "Zhang N", "Stokes GM", "Wienhold M", "Xu J", "Su Y", "Hernan R", "Chung WK", "Sun X", "McCulley DJ"], "journal": "Am J Physiol Lung Cell Mol Physiol", "journal_title": "American journal of physiology. Lung cellular and molecular physiology", "citation": "American journal of physiology. Lung cellular and molecular physiology, 04 2026", "abstract": "Congenital diaphragmatic hernia (CDH) is a common and severe structural malformation in which the high rate of morbidity and mortality is caused by lung hypoplasia and pulmonary hypertension. The severity of lung and pulmonary vascular defects in patients with CDH is heterogeneous with both intrinsic defects during development and mechanical compression playing important roles. Genetic variants have been identified in 30% of CDH patients and are associated with increased morbidity and mortality, but it is unclear how these variants impact lung and pulmonary vascular defect severity. Deletions of 8p23.1 account for 3-5% of cases and encompass GATA4, a transcription factor that directs gene expression throughout the developing embryo. CDH patients with GATA4 haploinsufficiency have high mortality, severe lung hypoplasia, and pulmonary hypertension. Given this information, our aim was to characterize the role of GATA4 during lung and pulmonary vascular development. We generated mice with lung-specific deletion of Gata4 and found that GATA4 is not required during lung or pulmonary vascular development. However, mice with diaphragm-specific inactivation of Gata4 die after birth with abnormal diaphragm formation and lung hypoplasia. Mechanical compression of the embryonic lungs was associated with abnormal gene expression and increased phosphorylation of mechanosensory protein YAP1 resulting in decreased cell cycling. Our data suggest that the lung and pulmonary vascular phenotype of patients with CDH and GATA4 haploinsufficiency is due to mechanical compression. Strategies that promote lung growth before delivery such as fetal tracheal occlusion may be beneficial in these patients.NEW & NOTEWORTHY Congenital diaphragmatic hernia (CDH) is a common and severe malformation associated with abnormal lung and pulmonary vascular development. This study investigates GATA4 haploinsufficiency, a common CDH-associated variant linked to higher morbidity and mortality. We establish mechanical compression as the mechanism leading to abnormal lung and pulmonary vascular development, which differs from other CDH-associated variants. Findings support using patient genotype to identify those most likely to benefit from fetal procedures that improve lung growth and survival.", "year": "2026", "month": "04", "volume": "330", "issue": "4", "pages": "L457-L475", "doi": "10.1152/ajplung.00203.2025", "link": "https://www.ncbi.nlm.nih.gov/pubmed/41785017", "sort_key": "2026-04-mechanical compressi", "quarter": "q2"}, {"pmid": "41556834", "title": "Genetic and chemical correction of cystic fibrosis reduces airway susceptibility to SARS-CoV-2.", "authors": ["Rollins SD", "Hume AJ", "Chen DY", "Yeboah RL", "Singh Bawa P", "Simone-Roach C", "Yin J", "Little A", "Fatima A", "Murano H", "Tavares LP", "Okuda K", "Huang J", "Kotton DN", "Saeed M", "M\u00fchlberger E", "Wang R"], "journal": "Am J Physiol Lung Cell Mol Physiol", "journal_title": "American journal of physiology. Lung cellular and molecular physiology", "citation": "American journal of physiology. Lung cellular and molecular physiology, 04 2026", "abstract": "The airway epithelium, a primary target for viral infection, plays a critical role in disease response-particularly in individuals with preexisting airway conditions such as cystic fibrosis (CF). At the onset of the SARS-CoV-2 pandemic, individuals with CF were expected to have severe outcomes based on earlier viral outbreaks; however, those on effective CF transmembrane conductance regulator (CFTR) modulators showed milder disease. Patients with CF on the CFTR modulator combination elexacaftor/tezacaftor/ivacaftor (ETI) combination therapy showed attenuated viral infection and reduced airway epithelial damage. To investigate how this is accomplished, we used an induced pluripotent stem cells (iPSC)-derived airway epithelium model of CF and syngeneic CFTR-corrected cells to examine responses to SARS-CoV-2 infection. CF iPSC-airways were significantly more susceptible to viral infection and epithelial injury compared with their corrected counterparts, despite comparable expression of viral entry factors. Strikingly, pretreatment with ETI conferred significant protection in CFTR-corrected and non-CF, wild-type (WT) airway epithelia, as well as in iPSC-derived and primary epithelia. Single-cell RNA sequencing analysis confirmed a heightened infection and proinflammatory response in CF iPSC-airways, whereas ETI treatment significantly reduced these responses in both CF and CFTR-corrected iPSC-airways. Mechanistically, ETI treatment led to increased type I interferon signaling and induction of antiviral genes, whereas expression of many other proinflammatory genes was suppressed in both CF and non-CF iPSC-airways. These results underscore the therapeutic promise of CFTR-modulators such as ETI in mitigating SARS-CoV-2 infection and inflammation, not only in CF airways but also in non-CF airways, highlighting the broad applicability of CFTR-modulators as a therapeutic strategy in viral pneumonia and inflammatory lung disease.NEW & NOTEWORTHY Using rigorously controlled iPSC-derived airway models, the study shows that CFTR-deficient cells are more vulnerable to SARS-CoV-2 and display stronger inflammation than syngeneic CFTR-corrected controls. The CFTR modulator ETI reduces viral injury and boosts antiviral pathways in both CF and non-CF cells. Even at baseline, CFTR modulation enhances antiviral responses and lowers inflammation. Overall, the findings reveal a broad protective antiviral effect of CFTR modulators and highlight their therapeutic promise in inflammatory lung disease.", "year": "2026", "month": "04", "volume": "330", "issue": "4", "pages": "L344-L367", "doi": "10.1152/ajplung.00223.2025", "link": "https://www.ncbi.nlm.nih.gov/pubmed/41556834", "sort_key": "2026-04-genetic and chemical", "quarter": "q2"}, {"pmid": "41986692", "title": "End-to-End Multimodal Multiple Instance Learning for Cancer Histopathology Classification with Dual-Attention Fusion.", "authors": ["Shirae S", "Debsarkar SS", "Kawanaka H", "Aronow BJ", "Prasath VBS"], "journal": "J Med Syst", "journal_title": "Journal of medical systems", "citation": "Journal of medical systems, 04 2026", "abstract": "In recent years, computational pathology has advanced toward integrating histopathological images and genomic data to improve diagnostic accuracy and biological interpretability. In this study, we propose a lightweight end-to-end multi-instance learning model that integrates whole slide images (WSIs) with gene expression profiles. The proposed method efficiently extracts image features using a reduced MobileNetV4 and treats gene information at the gene set level based on Gene Set Enrichment Analysis (GSEA) to capture functional relationships among genes. Image and gene features are aggregated within and across modalities through self-attention and cross-attention mechanisms. Our experiments on three cancer types, namely low-grade glioma (LGG), non-small cell lung cancer (NSCLC), and breast cancer (BRCA) showed that the proposed model outperformed image-only models and conventional single-vector gene input models. In particular, the ROC-AUC reached 0.740 for LGG, 0.982 for NSCLC, and 0.966 for BRCA, with a notable improvement in PR-AUC observed for BRCA classification. These results indicate that the integration of morphological and molecular information is effective for capturing disease characteristics. Furthermore, the proposed model maintains high classification performance while reducing computational resources, suggesting its potential applicability to large-scale pathological datasets and clinical applications.", "year": "2026", "month": "04", "volume": "50", "issue": "1", "pages": "", "doi": "10.1007/s10916-026-02379-0", "link": "https://www.ncbi.nlm.nih.gov/pubmed/41986692", "sort_key": "2026-04-end-to-end multimoda", "quarter": "q2"}, {"pmid": "41519381", "title": "Distinct phenotypes and repertoires of bronchoalveolar and airway mucosal T cells in health and allergic asthma.", "authors": ["Rahimi RA", "Smith NP", "Selle A", "Best R", "Martin S", "Tuttle E", "Said W", "Samanta N", "Ling MF", "Medoff BD", "Villani AC", "Luster AD"], "journal": "Mucosal Immunol", "journal_title": "Mucosal immunology", "citation": "Mucosal immunology, 04 2026", "abstract": "T cells play a central role in host protection against respiratory pathogens, but a maladaptive T cell response can lead to pulmonary diseases. Previous studies have examined T cells from the lungs captured via bronchoalveolar lavage (BAL), endobronchial brushings, or biopsies. However, whether these different approaches are capturing distinct T cell phenotypes and/or clonotypes remains unclear. Here, using single cell RNA- and T cell receptor (TCR)-sequencing, we report unique phenotypes and clonotypes of T cells isolated via BAL versus endobronchial brushings in healthy controls (HCs) and allergic asthmatics (AAs). The most significant difference in T cell subset abundance between AAs and HCs was the enrichment of CD4 T helper type 2 (TH2) cells when comparing endobronchial brush samples (OR = 20.8, P = 0.004), but not when examining BAL (OR = 1.8, P = 0.38), indicating differences in the T cell subsets captured from the BAL versus airway mucosa. In further support of this observation, comparing the BAL and brush T cells across all subjects revealed an up-regulation of resident-memory T (TRM) cell markers (i.e. ITGAE, CD69) in brush T cells in both CD4 and CD8 lineages. In contrast, BAL CD8 and CD4 T cells exhibited an enriched type I and II interferon signature compared to brush T cells. We validated these findings by generating an independent cohort from publicly available single cell RNA-sequencing data of BAL and brush T cells. Lastly, leveraging the paired samples from our derivation cohort, we performed TCR repertoire analysis, revealing that brush T cells contained expanded TCR clones that were in low abundance or absent in the BAL. Expanded T cell clones from the brush expressed high levels of TRM cell markers, suggesting the airway mucosa is enriched for TRM cells with unique TCR specificity. In sum, sampling T cells via BAL versus airway brushings yielded distinct T cell phenotypes and clonotypes with important implications for future research in lung immunology.", "year": "2026", "month": "04", "volume": "19", "issue": "2", "pages": "1799-1807", "doi": "10.1016/j.mucimm.2026.01.001", "link": "https://www.ncbi.nlm.nih.gov/pubmed/41519381", "sort_key": "2026-04-distinct phenotypes ", "quarter": "q2"}, {"pmid": "41947764", "title": "Distinct inflammatory programming of thoracic cavity white adipose immune cells regulates influenza pathogenesis.", "authors": ["Ulanowicz CJ", "Alarcon PC", "Damen MSMA", "Wayland JL", "Sawada K", "Eom J", "Stankiewicz TE", "Chung H", "Lampe K", "Szabo S", "Moreno-Fernandez ME", "Salomonis N", "Divanovic S"], "journal": "J Infect Dis", "journal_title": "The Journal of infectious diseases", "citation": "The Journal of infectious diseases, 04 2026", "abstract": "BACKGROUND: Obesity-associated inflammation in white adipose tissue (WAT) worsens outcomes of influenza A virus (IAV) infection. A recently identified thoracic cavity WAT (tcWAT) supports IAV replication. However, tcWAT's immune cell composition, functional properties and role in IAV disease severity remains unclear. METHODS: Using a mouse model of diet-induced obesity, flow cytometry and single cell RNA-sequencing, we compared tcWAT with lung-distal visceral WAT assessing immune cell composition, transcriptomic profiles, inflammatory potential, and impact on IAV pathogenesis. RESULTS: At baseline, tcWAT was uniquely enriched for immune cells with heightened proinflammatory capacity and exhibited a striking predominance of lymphocytic populations, including immature and Satb1+ T cells, the latter expressing gene signatures associated with elevated T cell activation. Transfer of tcWAT immune cells into IAV infected recipients accelerated IAV disease severity. IAV infection robustly reshaped tcWAT immune landscape, driving expansion of a B cell population expressing Zbtb32 and upregulating genes involved in immune regulation and antiviral responses. Concurrently, IAV infection reduced immune populations linked to neutrophil regulation in tcWAT, while these same populations were expanded in the lung. CONCLUSIONS: These findings identify lung-proximal tcWAT as a distinct inflammatory tissue that may amplify pathogenic immune responses during IAV infection.", "year": "2026", "month": "04", "volume": "", "issue": "", "pages": "", "doi": "10.1093/infdis/jiag201", "link": "https://www.ncbi.nlm.nih.gov/pubmed/41947764", "sort_key": "2026-04-distinct inflammator", "quarter": "q2"}, {"pmid": "42014719", "title": "Cell fate specification during respiratory development requires ARID1A-containing canonical BAF complex activity.", "authors": ["Lee H", "Jaquish A", "Fernandes S", "Zhao B", "Elitz A", "Cook K", "Trovillion S", "Bottasso-Arias N", "Han SJY", "Goodwin S", "Russell NX", "Saunders G", "Zacharias AL", "Brugmann SA", "Whitsett JA", "Sinner D", "Sun X", "Swarr DT", "Zacharias WJ"], "journal": "Nat Commun", "journal_title": "Nature communications", "citation": "Nature communications, 04 2026", "abstract": "Mammalian lung development requires coordinated gene regulation to drive lung bud formation, branching morphogenesis, proximal-distal patterning, and epithelial specification. While key transcriptional and signaling regulators are known, the epigenetic regulators are less well studied. Here, we identify the canonical BAF complex as essential for lung epithelial development. Complete loss of BAF complex function causes failure of lung formation, and selective deletion of ARID1A leads to loss of distal patterning and reduced alveolar type 1 (AT1) cell differentiation, with emergence of a highly proliferative cell state defined by joint activation of YAP and WNT signaling and loss of BMP response. Epigenomic analyses demonstrate broad failure of cell type-specific enhancer activation. Notably, exogenous BMP4 rescues distal differentiation in embryonic murine lung organoids, while YAP and WNT signaling require functional BAF complex. These data demonstrate a requirement for BAF complex activity during lung epithelial development and reveal a surprising differential specificity between signaling pathways.", "year": "2026", "month": "04", "volume": "17", "issue": "1", "pages": "", "doi": "10.1038/s41467-026-71954-3", "link": "https://www.ncbi.nlm.nih.gov/pubmed/42014719", "sort_key": "2026-04-cell fate specificat", "quarter": "q2"}, {"pmid": "41867819", "title": "The chromatin remodeling complex PRC2 safeguards cell fate in alveolar epithelial type 2 cells.", "authors": ["Warheit-Niemi HI", "Huang J", "Cook KCS", "Alysandratos KD", "Fernandes S", "Basak P", "Zhao B", "Vilker E", "Villacorta-Martin C", "Elitz A", "Bawa P", "Toth A", "Herriges MJ", "Kotton DN", "Zacharias WJ"], "journal": "bioRxiv", "journal_title": "bioRxiv : the preprint server for biology", "citation": "bioRxiv : the preprint server for biology, 03 2026", "abstract": "Maintenance of the gas exchange surface throughout life and regeneration of the lung after injury requires tight regulation of epithelial cell fate and function. Alveolar epithelial type 2 (AT2) cells serve as the progenitors of the distal epithelium, differentiating into alveolar epithelial type 1 (AT1) cells or proliferating to maintain the quorum of AT2 cells. Here we describe the role of the chromatin regulator polycomb repressive complex 2 (PRC2) in the maintenance of AT2 cell fate in the adult alveolus. Cross-species single-cell transcriptomic analyses identified PRC2 activation in proliferative AT2 populations. PRC2 loss of function in human iPSC-derived AT2 (iAT2) cells and primary murine AT2 cells in vitro resulted in loss of AT2 cell state and emergence of programs reminiscent of alveolar-basal intermediate (ABI) cell states, while overexpression of the PRC2 enzymatic component EZH2 in human iAT2 cells augmented the AT2 cell program. Genetic loss of PRC2 function in the AT2 lineage in adult mice in vivo led to emphysematous remodeling of the lung and induced a time-dependent series of transitions of AT2 cells through an alveolar-basal intermediate (ABI) state into Krt5+ basal-like cells. Comparison of murine ABI cells to human disease-associated ABI cells demonstrates de-repression of canonical PRC2 targets during transition to ABI and basal-like states in human fibrosis, implicating PRC2 is a conserved regulator of AT2 cell fate. Together, these findings define PRC2 complex function during AT2 cell self-renewal as a critical guardrail for maintaining epithelial cell fate in the adult lung.", "year": "2026", "month": "03", "volume": "", "issue": "", "pages": "", "doi": "10.64898/2026.03.03.708777", "link": "https://www.ncbi.nlm.nih.gov/pubmed/41867819", "sort_key": "2026-03-the chromatin remode", "quarter": "q1"}, {"pmid": "41576947", "title": "Spatial transcriptomics reveals altered communities and drivers of aberrant epithelia and pro-fibrotic fibroblasts in interstitial lung diseases.", "authors": ["Jaiswal A", "Kooistra T", "Pokatayev V", "Bastos HN", "Santos RF", "Sarraf TR", "Segerstolpe \u00c5", "Lin C", "Amir-Zilberstein L", "Twardus S", "Shannon K", "Murphy SP", "Knipe R", "Ganzleben IK", "Black KE", "Delorey TM", "Graham DB", "Hung YP", "Hariri LP", "Deguine J", "Carvalho A", "Medoff BD", "Xavier RJ"], "journal": "Cell Genom", "journal_title": "Cell genomics", "citation": "Cell genomics, 03 2026", "abstract": "Interstitial lung diseases (ILD) are characterized by fibrotic scarring of the lung parenchyma with remarkably unfavorable prognosis. Using single-nucleus RNA sequencing and spatial transcriptomics, we generated a comprehensive cellular network of the distal lung and its alterations in fibrosis. Integration with histopathology revealed that the transformation of normal parenchyma into fibrotic tissue is accompanied by ectopic bronchiolization and decellularization. Areas of active fibrosis were characterized by co-localization of pro-fibrotic CTHRC1-hi fibroblasts and aberrant transitional epithelial cells. We modeled this maladaptive differentiation of alveolar epithelial cells using organoids, demonstrating that all three pro-inflammatory ligands present in this pathogenic niche, TGF-\u03b2, IL-1\u03b2, and TNF-\u03b1, are jointly required for their induction. Additionally, we identified a requirement for the transcription factor NFATC4 during myofibroblast differentiation driven by soluble factors or mechanosensing. Collectively, this work identifies essential molecular drivers of the cellular interactions underlying lung fibrosis.", "year": "2026", "month": "03", "volume": "6", "issue": "3", "pages": "101066", "doi": "10.1016/j.xgen.2025.101066", "link": "https://www.ncbi.nlm.nih.gov/pubmed/41576947", "sort_key": "2026-03-spatial transcriptom", "quarter": "q1"}, {"pmid": "41558485", "title": "MYRF controls mesothelium specification, signaling, and plasticity in lung development.", "authors": ["Luna G", "Verheyden JM", "Tan C", "Kim E", "Zhu Z", "Hwa M", "Sahi J", "Shen Y", "Chung WK", "McCulley DJ", "Sun X"], "journal": "Dev Cell", "journal_title": "Developmental cell", "citation": "Developmental cell, 03 2026", "abstract": "The mesothelium is a squamous monolayer that ensheathes internal organs and lines the body cavities. Aside from facilitating tissue sliding, its additional functions remain poorly understood. Here, we study the mesothelium through investigating myelin regulatory factor (Myrf), a transcription factor expressed in the mesothelium and a top mutated gene in congenital diaphragmatic hernia (CDH), a developmental disorder that affects the lung and diaphragm. In mice, inactivation of Myrf early in embryogenesis resulted in CDH and defective mesothelium specification, compromising its role as a signaling center for lung growth. Inactivation after mesothelium specification led to additional defects, including enhanced differentiation into various mesenchymal cell types, causing a striking accumulation of elastin-expressing smooth muscle/myofibroblasts encasing the lung, mimicking pleuroparenchymal fibroelastosis (PPFE), a rare adult lung condition. Compound mutants demonstrate that MYRF functions synergistically with YAP/TAZ in mesothelium differentiation. Together, these findings highlight the complex role of the mesothelium in development and disease.", "year": "2026", "month": "03", "volume": "61", "issue": "3", "pages": "536-552.e4", "doi": "10.1016/j.devcel.2025.12.011", "link": "https://www.ncbi.nlm.nih.gov/pubmed/41558485", "sort_key": "2026-03-myrf controls mesoth", "quarter": "q1"}, {"pmid": "40700713", "title": "Multi-Omic and Single-Cell Approaches for Elucidating Cell Biology and Pathobiology of Lung Disease.", "authors": ["Sarma A", "Sun X", "Sucre J", "Hong J", "Medzikovic L", "Jakubzick CV", "Li X", "Zemans RL", "Singer BD"], "journal": "Am J Respir Cell Mol Biol", "journal_title": "American journal of respiratory cell and molecular biology", "citation": "American journal of respiratory cell and molecular biology, 03 2026", "abstract": "In this Perspective, we review the major themes from a Basic Science Core session at the American Thoracic Society 2024 International Conference: multi-omic and single-cell approaches for elucidating cellular biology and pathobiology of lung disease, with a focus on novel biology identified in human lungs. Recent advances have enabled researchers to study nucleic acids, proteins, and metabolites at single-cell resolution in the lung. These tools can be integrated with complementary methods to lead to new discoveries about lung function and develop treatments for respiratory diseases. We discuss the role of multicenter consortia in developing lung cell atlases and highlight the role of single-cell methods in identifying new respiratory cell types. We then review advances in several respiratory diseases that demonstrate the use of these tools to study lung development, injury, and repair. Finally, we consider future directions for the field, including efforts to harmonize cell types across studies and to develop more robust analytical pipelines.", "year": "2026", "month": "03", "volume": "74", "issue": "3", "pages": "287-294", "doi": "10.1165/rcmb.2025-0092PS", "link": "https://www.ncbi.nlm.nih.gov/pubmed/40700713", "sort_key": "2026-03-multi-omic and singl", "quarter": "q1"}, {"pmid": "41496696", "title": "MEK Inhibition Reduces Vascular Malformations and Gene Dysregulation in NRASQ61R Human Endothelial Cells.", "authors": ["Alharbi S", "Wagner A", "Merkle S", "Pastura P", "McDaniel CG", "Fox D", "Xu Y", "Le Cras TD"], "journal": "Pediatr Blood Cancer", "journal_title": "Pediatric blood & cancer", "citation": "Pediatric blood & cancer, 03 2026", "abstract": "BACKGROUND: An activating NRAS p.Q61R (NRASQ61R) somatic mutation occurs in the lesions of patients with kaposiform lymphangiomatosis (KLA). Therapies for KLA patients are limited and since the mitogen-activated protein kinase pathway is hyperactivated by NRASQ61R, we evaluated the potency of Mitogen-activated protein kinase kinase (MEK) inhibitors (trametinib, selumetinib, and cobimetinib) on human NRASQ61R endothelial cells (ECs). RNA sequencing analysis was performed to identify dysregulated genes and those restored by trametinib. Trametinib was tested in a mouse xenograft model of NRASQ61R ECs. PROCEDURE: Doxycycline (Dox)-inducible NRASQ61R ECs were treated with trametinib, selumetinib, cobimetinib, or vehicle (control). Cell signaling pathways, proliferation, migration, morphology, and angiopoietin-2 (ANG-2) levels were assessed. RNA-sequencing analysis was performed on Dox-induced NRAS wild-type (NRASWT), NRASQ61R, and trametinib-treated NRASQ61R ECs. Selected proteins were verified by immunoblotting. NRASQ61R ECs were injected into nude mice on Dox-containing diet to generate xenografts and treated with trametinib or vehicle. RESULTS: Trametinib reduced NRASQ61R-activated ERK phosphorylation, cell proliferation, migration, spindling, and ANG-2 at lower doses than selumetinib or cobimetinib. RNA-sequencing detected 1315 upregulated and 1773 downregulated genes in NRASQ61R ECs compared with NRASWT. Trametinib corrected 19% upregulated and 8% downregulated genes, including elevated Notch ligands (DLL4, JAG1), activated Notch 1, and HES1. Trametinib reduced NRASQ61R ECs xenograft weights by 46%, vascular area by 63%, and phosphorylated ERK staining. CONCLUSION: Trametinib was the most effective MEK inhibitor, correcting some dysregulated genes in NRASQ61R ECs, including some in the Notch pathway. Trametinib reduced vessel overgrowth in xenografts of NRASQ61R ECs. These studies support using trametinib treatment for KLA patients with an NRASQ61R mutation.", "year": "2026", "month": "03", "volume": "73", "issue": "3", "pages": "e70002", "doi": "10.1002/1545-5017.70002", "link": "https://www.ncbi.nlm.nih.gov/pubmed/41496696", "sort_key": "2026-03-mek inhibition reduc", "quarter": "q1"}, {"pmid": "42089305", "title": "Efficient CRISPR-Cas RNP-based gene targeting of human AT2 cells.", "authors": ["Kooistra T", "Sarraf TR", "Chen M", "Gally CK", "Medoff BD"], "journal": "Am J Respir Cell Mol Biol", "journal_title": "American journal of respiratory cell and molecular biology", "citation": "American journal of respiratory cell and molecular biology, 03 2026", "abstract": "Alveolar type 2 (AT2) cells play numerous roles in the alveolus related to stem cell, immunoregulatory, and secretory functions. Primary human AT2 cells can now be isolated and studied as organoids consisting of self-organizing epithelial tissues as pure populations without the need for stromal support cells. However, genetic manipulation of AT2 cells to investigate their biology has relied on expensive and time-consuming processes requiring the use of viral vectors or conducting gene editing with induced pluripotent stem cells (iPSCs)-derived AT2 cells. Here we describe a high-efficiency method of accomplishing highly effective gene editing in cultured primary human AT2 cells, which can be done rapidly and at significantly lower costs. Using an optimized CRISPR ribonucleoprotein (RNP) approach, we can achieve nearly complete genetic knockout while preserving AT2 identity and viability. Our results simplify the process of genetically manipulating human AT2 cells to better understand the role of the alveolar epithelium in human lung biology.", "year": "2026", "month": "03", "volume": "", "issue": "", "pages": "", "doi": "10.1093/ajrcmb/aanag062", "link": "https://www.ncbi.nlm.nih.gov/pubmed/42089305", "sort_key": "2026-03-efficient crispr-cas", "quarter": "q1"}, {"pmid": "41654130", "title": "Divergent pathways of surfactant protein C maturation for disease-associated isoforms.", "authors": ["Bui S", "Reineberg A", "Jones D", "Na CL", "Kitzmiller J", "Rodriguez LR", "Murthy A", "Iyer S", "Cooper C", "Chroneos R", "Tomer Y", "Mulugeta S", "Weaver TE", "Kotton DN", "Alysandratos KD", "Whitsett JA", "Beers MF"], "journal": "J Biol Chem", "journal_title": "The Journal of biological chemistry", "citation": "The Journal of biological chemistry, 03 2026", "abstract": "Surfactant protein C (SP-C), a hydrophobic protein exclusively synthesized and secreted by alveolar type II (AT2) cells, is important for reducing alveolar surface tension in the distal lung. Chronic interstitial pulmonary diseases have been associated with SFTPC mutations. However, a detailed understanding of SP-C maturation in the secretory pathway and disruptions caused by mutations has remained incomplete. The goal of this study was to comprehensively ascertain differences in trafficking and posttranslational processing between WT and disease-associated SP-C mutants using doxycycline-inducible mouse lung epithelial cell lines expressing either WT SP-C or the common clinical variant SP-CI73T, validated using primary AT2 cells isolated from a murine SP-CI73T pulmonary fibrosis model and induced pluripotent stem cell-derived human AT2 cells expressing the same mutant. In all three models SP-CWT was highly concentrated in acidic lysosomal-related organelles while SP-CI73T accumulated on the plasma membrane, which was corroborated by inhibition of clathrin-mediated endocytosis, surface biotinylation, immunogold electron microscopy, immunofluorescent staining, and proteinase K protection assays supporting divergence of SP-CI73T trafficking from SP-CWT. The exclusion of SP-CI73T from normal routing occurred early in the biosynthetic pathway as brefeldin A blocked processing of both SP-C proproteins, while a 20 \u02daC temperature shift caused selective accumulation of a processed proSP-CWT intermediate, suggesting initial C-terminal cleavage of proSP-CWT occurs in late-Golgi/trans-Golgi network. This cleavage event was sensitive to DC1, an inhibitor of furin-related subtilisin-like proprotein convertase (PPC) family members. Site-directed mutagenesis of canonical residues K160/R167 within a predicted PPC recognition site in the proSP-C COOH domain blocked its processing. Expression constructs encoding inhibitory pre-proprotein peptide fragments of furin and PC7 each inhibited cleavage of proSP-CWT in mouse lung epithelial-12 cells. Collectively, our data demonstrate that trafficking pathways for maturation of WT and mutant I73T SP-C diverge prior to the trans-Golgi network, where initial cleavage of the COOH-terminal SP-C propeptide occurs via a furin-like proprotein convertase.", "year": "2026", "month": "03", "volume": "302", "issue": "3", "pages": "111252", "doi": "10.1016/j.jbc.2026.111252", "link": "https://www.ncbi.nlm.nih.gov/pubmed/41654130", "sort_key": "2026-03-divergent pathways o", "quarter": "q1"}, {"pmid": "41741435", "title": "Targeting integrin beta 4 in diacetyl-induced anoikis of the airway epithelium.", "authors": ["Kim SY", "Pitonzo A", "Huyck H", "Pryhuber GS", "Mariani TJ", "McGraw MD"], "journal": "Cell Death Discov", "journal_title": "Cell death discovery", "citation": "Cell death discovery, 02 2026", "abstract": "Diacetyl (DA) is a flavoring chemical commonly found in food and beverages. When inhaled at occupationally relevant concentrations, DA can cause bronchiolitis obliterans (BO), yet the mechanisms remain poorly understood. Common to all forms of BO is airway epithelial injury, with failed epithelial cell survival contributing to BO development. The purpose of the current study was to target integrin beta 4 (ITG\u03b24) - one of the primary integrins that connect airway epithelial cells to the basement membrane - in DA-exposed airway epithelial cells to prevent adhesion-related cell apoptosis ('anoikis'). Sprague-Dawley rats were exposed to 200 parts-per-million DA vapor or filtered air for 6 hours per day for 5 consecutive days, then monitored for 5 weeks post-exposure and assessed for airway remodeling using Trichrome staining and the hydroxyproline assay. ITG\u03b24 protein expression was assessed via western blot as well as co-immunofluorescent staining using common airway epithelial cell markers. In parallel, primary human airway epithelial cells and human bronchial epithelial cells (16HBE14o-) were grown in vitro, exposed to DA, and treated with the pan-caspase inhibitor Z-VAD-FMK or transfected with ITGB4. End-points included viability staining, extracellular caspase 3/7 activity, and ITG\u03b24 protein expression. Rats exposed to DA vapors developed significant airway remodeling with increased total lung collagen content and sub-epithelial airway collagen deposition. Airway epithelial ITG\u03b24 expression remained decreased weeks after DA exposure with expansion of pan-cytokeratin positive epithelial cells, independent of ciliated and club cell markers. In parallel, DA-exposed human airway epithelial cells exposed in vitro developed significant anoikis. Treatment with Z-VAD-FMK reduced anoikis and improved ITG\u03b24 cytoplasmic surface expression but failed to improve total ITG\u03b24 protein expression. ITGB4 overexpression failed to suppress ITG\u03b24 cleavage or prevent anoikis. In summary, DA exposure in both rats and human airway epithelial cells results in caspase-mediated cleavage of ITG\u03b24. Future studies targeting post-translational modifications of ITG\u03b24 may prevent airway epithelial cell anoikis and fibrotic remodeling.", "year": "2026", "month": "02", "volume": "12", "issue": "1", "pages": "", "doi": "10.1038/s41420-026-02980-9", "link": "https://www.ncbi.nlm.nih.gov/pubmed/41741435", "sort_key": "2026-02-targeting integrin b", "quarter": "q1"}, {"pmid": "40540686", "title": "Targeted Preconditioning and Cell Transplantation in the Murine Lower Respiratory Tract.", "authors": ["Kohn A", "Herriges MJ", "Basak P", "Ma L", "Thapa BR", "Kotton DN", "Hawkins FJ"], "journal": "Am J Respir Cell Mol Biol", "journal_title": "American journal of respiratory cell and molecular biology", "citation": "American journal of respiratory cell and molecular biology, 02 2026", "abstract": "Transplantation of airway basal stem cells could achieve a durable cure for genetic diseases of the airway, such as cystic fibrosis and primary ciliary dyskinesia. Recent work demonstrated the potential of primary and pluripotent stem cell-derived basal cells to efficiently engraft into the mouse trachea after injury. However, there are many hurdles to overcome in translating these approaches to humans, including developing safe and efficient methods for delivery in larger animal models. We propose a model that targets preconditioning and cell delivery to intrapulmonary airways using a microbronchoscope for delivery. The detergent polidocanol was adapted for distal lung preconditioning, inducing intrapulmonary airway epithelial denudation by 5 and 24 hours after delivery. Although initial reepithelialization of airways occurred later than that of tracheas, complete repair was observed within 7 days. Both pluripotent stem cell-derived and primary basal cells delivered via microbronchoscope after polidocanol injury engrafted in tracheas and intrapulmonary airways, respectively. Transplanted cells differentiated into ciliated and secretory lineages while maintaining a population of basal cells. These findings demonstrate the utility of bronchoscopically targeted preconditioning and cell delivery to the conducting intrapulmonary airways, thus providing an important framework for preclinical translation of approaches for engineered airway epithelial regeneration.", "year": "2026", "month": "02", "volume": "74", "issue": "2", "pages": "155-166", "doi": "10.1165/rcmb.2024-0597MA", "link": "https://www.ncbi.nlm.nih.gov/pubmed/40540686", "sort_key": "2026-02-targeted preconditio", "quarter": "q1"}, {"pmid": "41901694", "title": "RSV-NTHi Co-Infection Skews Host Immunity by Suppressing Type I IFN Responses and Enhancing Pro-Inflammatory Responses.", "authors": ["Zhou Z", "Brennan JW", "Gill AL", "Anderson CS", "Ward BM", "Pryhuber G", "Mariani TJ", "Gill SR", "Sun Y"], "journal": "Pathogens", "journal_title": "Pathogens (Basel, Switzerland)", "citation": "Pathogens (Basel, Switzerland), 02 2026", "abstract": "Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract disease in young children, yet determinants of disease severity in otherwise healthy infants remain poorly understood. RSV disease severity has been linked to temporal differences in airway epithelial type I/III IFN and inflammatory responses, with defective viral genomes (DVGs) acting as potent inducers of type I/III IFNs. Additionally, an increased abundance of nontypeable Haemophilus influenzae (NTHi) is associated with more severe RSV disease, although the mechanisms underlying this association and the impacts of NTHi on DVG replication and DVG-driven host responses remain unclear. To address this knowledge gap, we modeled a clinically relevant but underexplored scenario of simultaneous transmission by performing concurrent RSV-NTHi co-infection experiments. Co-infection reduced titers of RSV but not of NTHi. Mechanistically, extracellular NTHi inhibited RSV particle binding to host cells. Using A549 cells and human precision-cut lung slices, we found that NTHi alone was a weak inducer of type I/III IFNs but a strong inducer of pro-inflammatory cytokines. Accordingly, RSV-NTHi co-infection suppressed DVG replication and DVG-driven IFN responses while enhancing inflammatory signaling, potentially driven by increased cell-associated NTHi. Together, these findings provide a mechanistic basis for how NTHi exacerbates RSV disease severity through dysregulated host immune responses rather than increased viral burden.", "year": "2026", "month": "02", "volume": "15", "issue": "3", "pages": "", "doi": "10.3390/pathogens15030240", "link": "https://www.ncbi.nlm.nih.gov/pubmed/41901694", "sort_key": "2026-02-rsv-nthi co-infectio", "quarter": "q1"}, {"pmid": "41202811", "title": "Multimodal spatial-omics reveal co-evolution of alveolar progenitors and proinflammatory niches in progression of lung precursor lesions.", "authors": ["Peng F", "Sinjab A", "Dai Y", "Treekitkarnmongkol W", "Yang S", "Gomez Bolanos LI", "Zhou T", "Chen M", "Serrano AG", "Krishna A", "Karimi N", "Sharma M", "Basi A", "Pei G", "Liao J", "Liu Y", "Feng J", "Rahal Z", "Liu Y", "Jiang J", "Yu K", "Noun T", "Liu Y", "Khan K", "Cho KS", "Chen J", "Solis LM", "Mazzilli S", "Dubinett S", "Cascone T", "Spira AE", "Swisher S", "Jimbo N", "Hayashi T", "Kishikawa S", "Takamochi K", "Itoh T", "Yao T", "Suzuki K", "Kalhor N", "Wistuba II", "Li M", "Moghaddam SJ", "Fujimoto J", "Burks J", "Myers J", "Akdemir K", "Wang L", "Kadara H"], "journal": "Cancer Cell", "journal_title": "Cancer cell", "citation": "Cancer cell, 02 2026", "abstract": "The co-evolution of different cell subsets in the progression of precursor lesions to lung adenocarcinoma (LUAD) is incompletely understood. We generated spatial transcriptomic maps of 56 human precursor lesions and LUADs from 25 patients and of an independent cohort of 36 lesions from 19 patients, analyzing a total of 486,519 spots and 5.4 million cells. We identify region-specific programs that distinguish precursors from LUADs. Spatially resolved clonal architectures reveal patient-specific heterogeneity in evolution of precursors to LUADs. We find epithelial alveolar progenitors expressing tumor-associated meta-programs and residing in niches enriched with proinflammatory subsets including IL1B high macrophages. Epithelial-proinflammatory niches are prevalent in precursor lesions but become less frequent in LUADs. These niches are conserved in mice and promote alveolar progenitor growth. Targeting inflammation alone or in combination with immune checkpoint blockade in precancerous phase reduces alveolar progenitors. Epithelial-inflammatory niches are stage-specific, shape early LUAD development and represent promising targets for interception.", "year": "2026", "month": "02", "volume": "44", "issue": "2", "pages": "321-339.e13", "doi": "10.1016/j.ccell.2025.10.004", "link": "https://www.ncbi.nlm.nih.gov/pubmed/41202811", "sort_key": "2026-02-multimodal spatial-o", "quarter": "q1"}, {"pmid": "41676623", "title": "Modeling cell-cell interactions to advance drug discovery in Idiopathic Pulmonary Fibrosis.", "authors": ["Sen C", "Langerman J", "Alysandratos K", "Alber AB", "Cherry C", "Castillo K", "Siegel S", "Chandran RR", "Choi W", "Rickabaugh T", "Kotton DN", "Plath K", "Gomperts BN"], "journal": "bioRxiv", "journal_title": "bioRxiv : the preprint server for biology", "citation": "bioRxiv : the preprint server for biology, 02 2026", "abstract": "Idiopathic Pulmonary Fibrosis (IPF) is characterized by scarring and remodeling of lung tissue, leading to progressive pulmonary dysfunction. Currently, very little is known about the steps involved in disease initiation and progression because models of IPF poorly replicate these processes. However, understanding the pathogenesis of IPF is essential to developing effective therapies. To address this, we developed a scaffold-based human co-culture alveolar organoid model that utilizes healthy and IPF human primary lung fibroblasts and induced pluripotent stem cell-derived alveolar type 2 (iAT2) cells carrying the surfactant protein C (SFTPC) 173T mutation of familial IPF, or their syngeneic corrected controls, to recapitulate epithelial-mesenchymal cellular communication during fibrosis initiation and progression. We found that the interaction between epithelial cells and fibroblasts plays a key role in inducing fibrotic responses in this model, with the secretion of chemokines, cytokines, TGF\u03b2, and matrix metalloproteinases that mirror those observed in the serum of patients with pulmonary fibrosis. Single-cell RNA sequencing revealed the emergence of many cell subtypes observed in progressive lung fibrosis, along with key cellular interactions that correlated with the initial upregulation of fibrosis pathways, extracellular matrix (ECM) remodeling, inflammation, and changes in lipid metabolism. The anti-fibrotic compounds, Nintedanib and the TGF\u03b2 inhibitor, SB431542, demonstrated dose-dependent efficacy in the model, with IC50 values comparable to those observed in the clinic, and significantly reduced secretion of fibrosis-related factors. Overall, this study shows that the three-dimensional cell co-culture organoid effectively models progressive lung fibrosis, facilitating the investigation of epithelial-mesenchymal interactions and serving as a patient-relevant model to better predict the efficacy of therapeutics in the clinic.", "year": "2026", "month": "02", "volume": "", "issue": "", "pages": "", "doi": "10.64898/2026.01.29.702646", "link": "https://www.ncbi.nlm.nih.gov/pubmed/41676623", "sort_key": "2026-02-modeling cell-cell i", "quarter": "q1"}, {"pmid": "41738263", "title": "Identification of a conserved sequence of disease progression in Idiopathic Pulmonary Fibrosis.", "authors": ["Huang X", "Wu P", "Guttentag AR", "Quintana M", "Kropski JA", "Blackwell TS", "Salisbury ML"], "journal": "Am J Respir Crit Care Med", "journal_title": "American journal of respiratory and critical care medicine", "citation": "American journal of respiratory and critical care medicine, 02 2026", "abstract": "RATIONALE: Idiopathic pulmonary fibrosis (IPF) begins years before symptoms appear, but the natural history is incompletely understood. OBJECTIVES: To describe and quantify IPF disease progression using four pulmonary function test (PFT) parameters. METHODS: Two cohorts included 245 adults with subclinical through advanced familial pulmonary fibrosis (FPF) or 347 placebo-treated IPF patients enrolled in two randomized controlled trials (RCTs). A Bayesian joint repeated measures model was fit to describe the observed PFT values as a function of the estimated years since onset (EYO). A latent variable estimated the subject-level chronological age at onset. Onset was assumed to occur when the diffusion capacity for carbon monoxide (DLCO) was 70%-predicted. The relationships between EYO and clinical outcomes not included in the model (e.g., transplant-free survival) were evaluated, adjusting for age and sex. RESULTS: In FPF, the DLCO declined steadily starting around EYO -10, reaching 86.8%-predicted by EYO -5 and 45.3%-predicted by + 5. The forced vital capacity (FVC) declined later, reaching 98.6%-predicted by EYO -5 and 76.2%-predicted by + 5. The annualized decline in FVC was 12-fold greater in the year after EYO + 5 (6.14%-predicted) than -5 (0.49%-predicted). There was a 31% higher risk of death or transplant (HR 1.31, 95% CI 1.25-1.37) per 1-year increase in EYO. Similar findings were observed in the RCTs. CONCLUSIONS: We identified a conserved sequential decline in lung function in IPF, which has important implications for the design of clinical trials. The DPM provides a powerful framework to investigate the clinical and/or biological processes that initiate and propagate IPF.", "year": "2026", "month": "02", "volume": "", "issue": "", "pages": "", "doi": "10.1093/ajrccm/aamag075", "link": "https://www.ncbi.nlm.nih.gov/pubmed/41738263", "sort_key": "2026-02-identification of a ", "quarter": "q1"}, {"pmid": "41697734", "title": "Hyperactivation of mTORC1 signaling mediates folliculin deficiency-induced pulmonary cyst formation in Birt-Hogg-Dub\u00e9 syndrome.", "authors": ["Cao K", "Chen H", "Chu L", "Wang HJ", "Zhang J", "Luo Y", "Chiu J", "Khabibullin D", "Alesi N", "Thornton ME", "Grubbs BH", "Ataya A", "Gupta N", "McCormack FX", "Wikenheiser-Brokamp KA", "Henske EP", "Shi W"], "journal": "J Clin Invest", "journal_title": "The Journal of clinical investigation", "citation": "The Journal of clinical investigation, 02 2026", "abstract": "Germline loss-of-function folliculin (FLCN) gene mutations cause Birt-Hogg-Dub\u00e9 (BHD) syndrome, in which pulmonary cysts are present in up to 90% of the patients. The pathogenic mechanisms underlying lung cyst development in BHD are almost entirely unknown because of the limited availability of BHD patient lung samples and the lack of authentic BHD lung disease models. We generated lung mesenchyme-specific and lung epithelium-specific Flcn-knockout mice using a Cre/loxP approach. We found that deletion of Flcn in lung mesenchymal cells, but not in lung epithelial cells, resulted in alveolar enlargement starting from early postnatal life, with evidence of cyst formation in adult mice, resembling the pulmonary disease in human BHD. These changes were associated with increased mechanistic target of rapamycin complex 1 (mTORC1) activity in the lungs of both patients with BHD and Flcn-knockout mice. Attenuation of mTORC1 activity by knocking out Raptor gene (Rptor) or pharmacologic inhibition using rapamycin substantially rescued the pulmonary pathology caused by Flcn deletion in mice. Taken together, these human and mouse data support a model in which mTORC1 hyperactivation drives pulmonary cystic pathology in BHD.", "year": "2026", "month": "02", "volume": "136", "issue": "4", "pages": "", "doi": "10.1172/JCI194300", "link": "https://www.ncbi.nlm.nih.gov/pubmed/41697734", "sort_key": "2026-02-hyperactivation of m", "quarter": "q1"}, {"pmid": "41680210", "title": "FOXF2 regulates pericyte-endothelial signaling required for vascular homeostasis after neonatal hyperoxic lung injury.", "authors": ["Sun F", "Zhao Y", "Do J", "Cheng P", "Li E", "Liu Y", "Shirazi SP", "Sucre JMS", "Kalin TV", "He H", "Kalinichenko VV"], "journal": "Nat Commun", "journal_title": "Nature communications", "citation": "Nature communications, 02 2026", "abstract": "Pulmonary vascular development is essential for alveolarization, and disruption of this process contributes to pathogenesis of bronchopulmonary dysplasia (BPD). Proper vascular development requires an orchestration of many cell types within the lung. However, the transcriptional mechanisms by which pericytes support the endothelium in the postnatal lung remain poorly understood. Herein, we identify FOXF2 as a critical transcription factor that governs pericyte maturation and function during postnatal lung development and regeneration. FOXF2 expression in pericytes increases postnatally and is selectively downregulated after neonatal hyperoxic injury. Pdgfrb-CreER mediated Foxf2 deletion in pericytes leads to pericyte hyperplasia, impaired migration, and reduced expression of angiogenic factors such as ANGPTL4. Transcriptomic and genomic studies demonstrate that FOXF2 maintains chromatin accessibility at pro-angiogenic loci and modulates paracrine signaling essential for endothelial regeneration. Loss of FOXF2 disrupts pericyte-endothelial crosstalk, leading to impaired angiogenesis and alveolarization as well as increased vascular permeability after neonatal lung injury. Altogether, FOXF2 acts as a key transcriptional regulator of the pericyte-driven vascular niche in the neonatal lung, highlighting the pathogenic role of pericyte dysfunction in BPD.", "year": "2026", "month": "02", "volume": "17", "issue": "1", "pages": "", "doi": "10.1038/s41467-026-69525-7", "link": "https://www.ncbi.nlm.nih.gov/pubmed/41680210", "sort_key": "2026-02-foxf2 regulates peri", "quarter": "q1"}, {"pmid": "41672577", "title": "Assessment of mosaic loss of chromosome Y in pulmonary fibrosis reveals limited association with susceptibility or disease severity.", "authors": ["Wang D", "Hadad N", "Moss S", "Lopez-Jimenez E", "Johnson SR", "Maher TM", "Molyneaux PL", "Zhao Y", "Perry JRB", "Wolters PJ", "Kropski JA", "Jenkins RG", "Banovich NE", "Stewart I"], "journal": "BMJ Open Respir Res", "journal_title": "BMJ open respiratory research", "citation": "BMJ open respiratory research, 02 2026", "abstract": "BACKGROUND: Pulmonary fibrosis (PF) is a rare lung disease with diverse pathogenesis and biological mechanisms. Mosaic loss of chromosome Y (mLOY) has been reported to be associated with increased risk of fibrotic diseases. However, the exact role of mLOY in the development of PF remains to be elucidated. METHODS: Copy number on chromosome Y was used to estimate mLOY comparing patients in PROFILE and gnomAD cohorts and between cases and control patients from the GE100KGP cohort. Correlation of mLOY with demographic and clinical variables was tested using patients from the PROFILE cohort. Lung single-cell transcriptomic data were analysed to assess the cell types implicated in mLOY. Mendelian randomisation was performed to examine the causal relationship between mLOY, idiopathic pulmonary fibrosis (IPF) and telomere length. RESULTS: The genetic analysis suggests that mLOY is found in PF from both case cohorts but when compared with an age matched population the effect is minimal (p=0.00316, median: 0.288 vs 0.291). mLOY is related to age (p=0.000214) and shorter telomere length (p=0.00815) rather than PF severity or progression. Single-cell analysis indicates that mLOY appears to be found primarily in immune cells. Mendelian randomisation demonstrates that mLOY is not on the causal pathway for IPF, but partial evidence supports that telomere shortening is on the causal pathway for mLOY. CONCLUSIONS: Our study confirms the existence of mLOY in PF patients, suggests that mLOY is not a major driver of IPF, and might support a triangulation model where telomere shortening leads to both IPF and mLOY.", "year": "2026", "month": "02", "volume": "13", "issue": "1", "pages": "", "doi": "10.1136/bmjresp-2025-003846", "link": "https://www.ncbi.nlm.nih.gov/pubmed/41672577", "sort_key": "2026-02-assessment of mosaic", "quarter": "q1"}, {"pmid": "41578022", "title": "Aberrant cellular communities underlying disease heterogeneity in chronic obstructive pulmonary disease.", "authors": ["Zhang Y", "Wei H", "Nouws J", "Jiang W", "Brewster RM", "Nguyen JP", "Liang S", "Pass SM", "Wang W", "Collin F", "Oill AT", "Kim SH", "Siller SS", "Liu J", "Zhao AY", "Hansbro P", "Dela Cruz C", "Britto C", "Gomez J", "Cloonan SM", "Herzog EL", "Lam TT", "Banovich NE", "Raredon MSB", "Zhang X", "Mangiola S", "Homer RJ", "Kaminski N", "McDonough J", "Polverino F", "Yan X", "Sauler M"], "journal": "Nat Genet", "journal_title": "Nature genetics", "citation": "Nature genetics, 02 2026", "abstract": "Chronic obstructive pulmonary disease (COPD) is clinically and molecularly heterogeneous. To investigate COPD heterogeneity, we profiled lung tissue by single-nucleus RNA sequencing from 141 study participants (1,516,727 nuclei) and identified shifts in cell composition and emergent cell states that correlated with lung function, emphysema and composite symptom scores. Epithelial regenerative states peaked in early COPD and declined thereafter, whereas inflamed nonimmune cells and profibrotic/remodeling states, together with select immune populations, expanded with disease progression. Clustering study participants by the proportion of pathologic cells coupled with spatial transcriptomics identified distinct patterns of cellular co-occurrence within spatially localized niches. Proteomic analyses identified plasma biomarkers of cell states and their impact on the extracellular matrix. Mediation and cell communication analyses revealed cell-autonomous and intercellular communication networks associated with disease. These data define the cellular landscape of COPD heterogeneity, revealing molecular drivers and biomarkers that could inform therapeutic strategies.", "year": "2026", "month": "02", "volume": "58", "issue": "2", "pages": "376-391", "doi": "10.1038/s41588-025-02480-z", "link": "https://www.ncbi.nlm.nih.gov/pubmed/41578022", "sort_key": "2026-02-aberrant cellular co", "quarter": "q1"}, {"pmid": "41509430", "title": "A non-canonical role of Myc in programming basal cells as sentinels of upper airway immunity during influenza infection.", "authors": ["Foote AG", "Xu L", "Verheyden J", "Pan B", "Katoch N", "Sun X"], "journal": "bioRxiv", "journal_title": "bioRxiv : the preprint server for biology", "citation": "bioRxiv : the preprint server for biology, 02 2026", "abstract": "The upper respiratory epithelium is a specialized barrier that integrates immune surveillance with the biomechanical requirements of the laryngotracheal axis. Despite the clinical prevalence of persistent airway dysfunction following viral infection, the region-specific mechanisms governing laryngotracheal injury and repair remain poorly defined. Using integrated mouse models, imaging, and single-cell transcriptomics, we dissected IAV-induced injury in the upper respiratory tract. We found that infection displays regionally restricted tropism to subglottic and tracheal pseudostratified epithelia, targeting ciliated, secretory, neuroendocrine, and basal cells. Rapid viral clearance was accompanied by acute neutrophil infiltration and the emergence of a previously unrecognized intraepithelial CD8+ natural killer T (NKT)-like effector population. Functional studies revealed that injury-induced Myc expression in KRT5+ basal progenitors is required for mucosal restoration; while basal-specific Myc deletion preserved viral clearance, it attenuated proliferation and impaired the recruitment of CD8+ NKT cells. Together, these findings delineate a coordinated epithelial-immune circuit governing post-viral mucosal restoration, positioning basal cells as specialized epithelial sentinels that orchestrate acute repair and recruit cytotoxic effectors via a MYC-dependent CXCL10-CXCR3 axis.", "year": "2026", "month": "02", "volume": "", "issue": "", "pages": "", "doi": "10.64898/2025.12.22.696065", "link": "https://www.ncbi.nlm.nih.gov/pubmed/41509430", "sort_key": "2026-02-a non-canonical role", "quarter": "q1"}, {"pmid": "40880213", "title": "The evolving pathophysiology of bronchopulmonary dysplasia.", "authors": ["Ambalavanan N", "Deutsch G", "Pryhuber G", "Travers CP", "Willis KA"], "journal": "Physiol Rev", "journal_title": "Physiological reviews", "citation": "Physiological reviews, 01 2026", "abstract": "Bronchopulmonary dysplasia (BPD) is the most common morbidity in very preterm infants and is characterized by abnormal development of the lung. The pathophysiology of BPD is primarily due to the effects of placental dysfunction, hyperoxia, ventilator-induced lung injury, poor nutrition, abnormal blood flow, and genomic/epigenomic factors on an immature lung. These adverse factors act on multiple cell types through many interacting signaling pathways. Abnormal development impacts most structures of the lung, including the alveoli, blood vessels, and airways, and frequently results in long-term impairment of lung mechanics and function. In this review, we provide a detailed overview of the processes involved in lung development and function and how these pathways are disrupted in BPD. The resulting effects on lung histology and lung mechanics and gas exchange are described. Insights derived from recent molecular and cellular characterization of lungs derived from normal and BPD-affected infants indicate possible mechanisms of pathogenesis and suggest potential new therapeutic strategies. The long-term implications of abnormal lung development as seen in BPD on later childhood and adult life are discussed.", "year": "2026", "month": "01", "volume": "106", "issue": "1", "pages": "197-237", "doi": "10.1152/physrev.00042.2024", "link": "https://www.ncbi.nlm.nih.gov/pubmed/40880213", "sort_key": "2026-01-the evolving pathoph", "quarter": "q1"}, {"pmid": "41881452", "title": "Targeting the epithelium in pulmonary fibrosis.", "authors": ["Liz\u00e9 M", "Mayr CH", "Bleck M", "Wollin L", "Wohnhaas CT", "Shalashova I", "Olbrich H", "Heilker R", "Engler A", "Bammert MT", "Schl\u00fcter H", "Geillinger-K\u00e4stle K", "Soetopo D", "Klee S", "Wolf F", "Gokey JJ", "Stahl H", "Klimowicz AC", "McCall AS", "Kropski JA", "Blackwell TS", "Thomas MJ"], "journal": "Eur Respir Rev", "journal_title": "European respiratory review : an official journal of the European Respiratory Society", "citation": "European respiratory review : an official journal of the European Respiratory Society, 01 2026", "abstract": "Idiopathic pulmonary fibrosis (IPF) is characterised by progressive scarring primarily of the distal regions of the lung in a distinctive histological pattern. Consequently, drug discovery has focused on the activity of scar-forming fibroblasts, with some success shown by the pharmaceutical agents nintedanib and pirfenidone, and more recently nerandomilast. Yet an unmet medical need remains, pointing toward pathobiology not addressed by standard-of-care therapies. In recent years, single-cell sequencing of patient lung tissue has revealed several novel disease-associated epithelial populations. In addition, we are now beginning to understand, through functional co-culture studies, the importance of cellular crosstalk in both lung homeostasis and disease. Here, we review the advances made in \"omic\" technologies, the approaching spatial profiling revolution, current and future functional cell systems, novel in vivo models, how we assign disease-relevance to test systems via computational gene set enrichment analysis, and link all these elements to clinically relevant biomarkers. We show how epithelial populations, identified and validated through cutting-edge technologies, may provide targets for the next wave of therapeutics for patients with IPF.", "year": "2026", "month": "01", "volume": "35", "issue": "179", "pages": "", "doi": "10.1183/16000617.0225-2025", "link": "https://www.ncbi.nlm.nih.gov/pubmed/41881452", "sort_key": "2026-01-targeting the epithe", "quarter": "q1"}, {"pmid": "41390915", "title": "SpatialRNA: a Python package for easy application of Graph Neural Network models on single-molecule spatial transcriptomics dataset.", "authors": ["Lyu R", "Vannan A", "Kropski JA", "Banovich NE", "McCarthy DJ"], "journal": "Bioinformatics", "journal_title": "Bioinformatics (Oxford, England)", "citation": "Bioinformatics (Oxford, England), 01 2026", "abstract": "SUMMARY: Image-based spatial transcriptomics (iST) deliver gene expression measurements of RNA transcripts in tissue slices with single-molecule resolution and spatial context preserved. Modern Graph Neural Network (GNN) models are promising methods for capturing the complex molecular and cellular phenotypes in tissues at single-transcript and single-cell levels. A key application of GNNs is the detection of spatial domains or niches, that is, groups of molecules and/or cells that collaboratively work together to produce complex phenotypes. Due to the vast number of detected transcripts in (iST) dataset, applying GNNs on RNA molecule graphs is not trivial. We present a Python package, SpatialRNA, for easy (sub)graph generation from tissue samples and provide comprehensive tutorials for convenient and efficient application of Graph Neural Network models under the PyG framework. This highly scalable tool comprehensively segments tissue into spatial domains, aiding in biological interpretation of iST data and its underlying molecular microenvironments. AVAILABILITY AND IMPLEMENTATION: The SpatialRNA package is freely accessible from online repository https://github.com/ruqianl/spatialrna and can be installed via pip. Comprehensive tutorials, guidance on parameter selection, and complete workflows of case studies are available from the documentation website https://ruqianl.github.io/spatialrna_docs/, and uploaded on Zenodo with a DOI 10.5281/zenodo.17339575.", "year": "2026", "month": "01", "volume": "42", "issue": "1", "pages": "", "doi": "10.1093/bioinformatics/btaf659", "link": "https://www.ncbi.nlm.nih.gov/pubmed/41390915", "sort_key": "2026-01-spatialrna: a python", "quarter": "q1"}, {"pmid": "41484334", "title": "Spatial transcriptomics of developing human lungs defines cellular phenotypes associated with age, lineage and location.", "authors": ["Ren Y", "Danopoulos S", "Deutsch GH", "Glass IA", "Mariani TJ", "Bhattacharya S"], "journal": "Sci Rep", "journal_title": "Scientific reports", "citation": "Scientific reports, 01 2026", "abstract": "Despite significant advances in understanding lung development, the intricate cellular interactions and spatial organization of the developing human lung remain incompletely defined. Spatial transcriptomics enables gene expression profiling within the native tissue context, providing unprecedented insights into complex developmental processes. In this study, we applied the 10X Genomics Visium platform to characterize spatially resolved transcriptional profiles of prenatal human lungs during the pseudoglandular and canalicular stages.Spatial transcriptomic analysis of 12 prenatal lung samples (13\u201320 weeks gestation) identified 10 distinct transcriptional niches corresponding to unique combinations of epithelial, mesenchymal, endothelial, and immune cell populations. Unsupervised clustering revealed developmental shifts in spot/niche composition from the pseudoglandular to canalicular stage, with a progressive increase in alveolar epithelial spots and a concomitant decline in mesenchymal regions, particularly in peripheral lung areas. Differential gene expression analysis demonstrated stage-specific transcriptional transitions in individual spot types, including downregulation of cell cycle and structural pathways and upregulation of secretory pathways as the lung matures. Spatial organization analysis revealed increasing compartmentalization of pulmonary cell types, highlighting the progressive structuring of the distal lung microenvironment. In summary, this study provides a spatial map of the developing human lung, offering novel insights into pulmonary lineage dynamics and cellular interactions during early organogenesis.", "year": "2026", "month": "01", "volume": "16", "issue": "1", "pages": "4573", "doi": "10.1038/s41598-025-34594-z", "link": "https://www.ncbi.nlm.nih.gov/pubmed/41484334", "sort_key": "2026-01-spatial transcriptom", "quarter": "q1"}, {"pmid": "41448181", "title": "Rebalancing NTRK2 isoforms promotes vascular regeneration in bronchopulmonary dysplasia.", "authors": ["Zhang Y", "Tan C", "Liu Z", "Mao X", "Jiang C", "Mohammed AN", "Li X", "Lu R", "Wang A", "Maihemuti W", "Pek N", "Fu H", "Milbes O", "Pandrangi K", "Johnson CP", "Sekar V", "Liu Y", "Lai L", "Pryhuber GS", "Kalinichenko VV", "Miao Y", "Guo M", "Gu M"], "journal": "Cell Stem Cell", "journal_title": "Cell stem cell", "citation": "Cell stem cell, 01 2026", "abstract": "Bronchopulmonary dysplasia (BPD) is a chronic lung disease of prematurity with no curative therapy, characterized by impaired alveologenesis and capillary formation. However, the molecular mechanisms underlying endothelial dysfunction, a key driver of BPD pathogenesis, remain poorly understood. Through multiomic profiling of endothelial cells isolated from human BPD lungs, we identified an expansion of general capillary endothelial cells (gCaps) marked by neurotrophic receptor tyrosine kinase 2 (NTRK2). Notably, we uncovered a critical isoform switch that governs gCap regeneration. Full-length NTRK2 (NTRK2-FL) promoted gCap repair after hyperoxic injury, whereas RBFOX2-mediated splicing of NTRK2-FL into a truncated isoform (NTRK2-T1) contributed to maladaptive responses and persistent alveolar simplification. Restoring NTRK2-FL using lipid nanoparticle-delivered mRNA promoted angiogenesis in vessel organoids and reversed alveolar simplification in hyperoxic mice. These findings identified NTRK2 isoform imbalance as a key driver of endothelial dysfunction and support isoform-specific RNA therapy as a promising strategy for vascular regeneration and repair.", "year": "2026", "month": "01", "volume": "33", "issue": "1", "pages": "125-141.e11", "doi": "10.1016/j.stem.2025.12.006", "link": "https://www.ncbi.nlm.nih.gov/pubmed/41448181", "sort_key": "2026-01-rebalancing ntrk2 is", "quarter": "q1"}, {"pmid": "41580551", "title": "MI-181 enhances ciliation and cilia length in a cigarette smoke exposed airway epithelial model.", "authors": ["Gholkar AA", "Cherry C", "Gimeno TV", "Nocon C", "Zhu C", "Gomperts BN", "Torres JZ"], "journal": "Sci Rep", "journal_title": "Scientific reports", "citation": "Scientific reports, 01 2026", "abstract": "Multiciliated airway epithelial cells possess motile cilia, which are essential for mucociliary clearance, facilitating the removal of particulates from the respiratory system. Previous studies showed that exposure to cigarette toxins causes damage to motile cilia formation, length, and function, and can lead to reduced mucociliary clearance and lung diseases like COPD. Given the limited options for treating smoking-related diseases, it is imperative to define novel therapeutics to address this need. Recently, we discovered that, contrary to its ability to depolymerize microtubules, the small molecule MI-181 can induce ciliogenesis and increase the length of primary cilia in retinal pigment epithelial cells without adverse effects on cell health. Here, we utilized a human airway basal stem cell derived air-liquid interface mucociliary airway epithelium model system, coupled with smoke exposure, to test the effect of MI-181 on motile cilia. We determined that MI-181 promotes the recovery of motile cilia length. Additionally, the effect of MI-181 on the area covered by motile cilia and levels of the FOXJ1 motile cilia transcription factor showed inter-donor heterogeneity. Importantly, transmission electron microscopy analysis of motile cilia axonemes showed that MI-181-treated motile cilia displayed a normal 9 + 2 arrangement of microtubules. Together, these data suggest that MI-181 promotes the recovery of motile cilia length after smoke exposure and that these cilia are structurally intact.", "year": "2026", "month": "01", "volume": "16", "issue": "1", "pages": "6136", "doi": "10.1038/s41598-026-37296-2", "link": "https://www.ncbi.nlm.nih.gov/pubmed/41580551", "sort_key": "2026-01-mi-181 enhances cili", "quarter": "q1"}, {"pmid": "41542551", "title": "Fishing with Two Lines: A Hybrid Approach to Spatial Transcriptomic Discovery.", "authors": ["Williams-Katek AL", "Mallapragada S", "Mee ED", "Fischer BK", "Eldredge LC", "Deutsch GH", "Kropski JA", "Sucre JMS", "Banovich NE"], "journal": "bioRxiv", "journal_title": "bioRxiv : the preprint server for biology", "citation": "bioRxiv : the preprint server for biology, 01 2026", "abstract": "Spatial transcriptomics faces a trade-off between the number of genes assayed and depth of per-gene sensitivity. We developed a 'dual chemistry' method that combines the high sensitivity of a 10X Genomics Xenium V1 custom panel (up to 480 genes) with the broad coverage of the Prime 5K panel (5001 genes) on a single tissue section. This involved co-hybridizing Prime and V1 probes and sequentially running the V1 and Prime decoding chemistries. Applied to a human lung tissue microarray, we observed high concordance between the V1 and Prime chemistries when run independently (on serial sections) and the dual chemistry runs. Overlapping genes (profiled on both V1 and Prime chemistries) showed similar expression patterns in the dual run demonstrating the fidelity of the assay. By combining information from both the V1 and Prime chemistries within the same cell, we retain more cells, gain valuable additional information, and enable both high sensitivity profiling and discovery.", "year": "2026", "month": "01", "volume": "", "issue": "", "pages": "", "doi": "10.64898/2026.01.07.698201", "link": "https://www.ncbi.nlm.nih.gov/pubmed/41542551", "sort_key": "2026-01-fishing with two lin", "quarter": "q1"}, {"pmid": "41587178", "title": "Dose-dependent activation of the Hippo pathway by Type I and Type III interferons suppresses tissue repair by human bronchial epithelial cells.", "authors": ["Subramaniam KV", "Lim HJ", "Wang B", "Mihaylova VT", "Thompson EN", "Krause DS", "Foxman EF"], "journal": "PLoS Biol", "journal_title": "PLoS biology", "citation": "PLoS biology, 01 2026", "abstract": "Interferons (IFNs) are potent antiviral cytokines that are rapidly activated when infected cells sense a virus, but continued IFN production following acute infection is linked to impaired recovery. IFNs protect against infection by inducing a suite of antiviral effectors in IFN receptor-expressing cells via JAK/STAT signaling. However, how IFNs curtail tissue repair is not fully understood. Here, we studied the effects of Type III IFNs (IFN\u03bb1 and IFN\u03bb2) and Type I IFN (IFN\u03b2) on tissue repair functions of human bronchial epithelial cells (HBEC). We show that both Type III IFNs and IFN\u03b2 reduce bronchial epithelial cell migration and proliferation through a common upstream mechanism: activation of LATS1, a kinase best known for limiting organ growth as part of the Hippo signaling pathway. Mechanistically, Type III IFN or IFN\u03b2 curtailed wound healing by triggering phosphorylation of LATS1 via JAK activity, bypassing activation of MST1/2, the canonical activator of LATS1 in the Hippo pathway. Further experiments showed that distinct signaling pathways lead to LATS1 and STAT1 phosphorylation downstream of IFN receptor signaling. STAT1 was dispensable for IFN-mediated LATS1 phosphorylation and suppression of tissue repair, although as expected STAT1 was required for IFN-mediated protection from rhinovirus or influenza infection. Dose-response curve experiments revealed that higher concentrations of IFN were required to trigger LATS1 phosphorylation compared to STAT1 phosphorylation. Consistently, during rhinovirus or influenza virus infection of organotypic HBEC cultures, we observed phosphorylation of both LATS1 and STAT1, but with different kinetics, with LATS1 activation showing earlier resolution compared to STAT1 activation. These results provide a conceptual framework for understanding how IFN receptor signaling differentially controls epithelial functions required for tissue repair and antiviral defense, and inform efforts to target pathological effects of IFNs following viral infection and in other high IFN states.", "year": "2026", "month": "01", "volume": "24", "issue": "1", "pages": "e3003615", "doi": "10.1371/journal.pbio.3003615", "link": "https://www.ncbi.nlm.nih.gov/pubmed/41587178", "sort_key": "2026-01-dose-dependent activ", "quarter": "q1"}, {"pmid": "40845320", "title": "Capillary Endothelial Cell Subtypes in the Lung: Markers and Response to Developmental Lung Injury.", "authors": ["Thakur A", "Clair G", "Zhang L", "Soni S", "Mariani TJ", "\u00c7ataltepe S"], "journal": "Am J Respir Cell Mol Biol", "journal_title": "American journal of respiratory cell and molecular biology", "citation": "American journal of respiratory cell and molecular biology, 01 2026", "abstract": "Bronchopulmonary dysplasia (BPD) is a chronic lung disease that affects preterm infants. Disrupted microvascular growth is a well-recognized pathologic feature of BPD, which plays a critical role in arrested alveologenesis. Recent studies have identified two subpopulations of pulmonary microvascular endothelial cells (ECs): general capillary (gCap) and aerocyte (aCap) cells. In this study, we validated proposed markers for gCap (GPIHBP1, PLVAP, CD93) and aCap (CA4, HPGD) at the protein level and investigated their abundance during late-stage lung development in murine and nonhuman primate (NHP) lungs. We also examined alterations in the abundance and proliferation of gCap and aCap cells in NHP and murine models of BPD. Our studies confirmed CA4 and HPGD as specific markers for aCap, and all three putative gCap markers were also detected in nonmicrovascular ECs. All markers except for HPGD showed a gradual increase in abundance during the saccular and alveolar stages of development in NHP lungs. In the NHP model of BPD, the abundance of both aCap markers and GPIHBP1 were decreased, whereas those of PLVAP and CD93 were increased. Additionally, there was an emergence of CA4+HPGD- aCap cells in BPD lungs. In late-stage control lungs, aCap proliferation was more robust than gCap proliferation, whereas no significant differences were observed between aCap and gCap proliferation rates in NHP BPD. Notably, in BPD lungs, gCap proliferation was more robust compared with control lungs. This study provides new insights into the distinct regulation patterns of microvascular ECs during lung development and neonatal lung injury in a translationally relevant NHP model.", "year": "2026", "month": "01", "volume": "74", "issue": "1", "pages": "119-128", "doi": "10.1165/rcmb.2025-0009OC", "link": "https://www.ncbi.nlm.nih.gov/pubmed/40845320", "sort_key": "2026-01-capillary endothelia", "quarter": "q1"}, {"pmid": "41659605", "title": "Bidirectional fibrogenic cross-talk revealed in a human iPSC-derived epithelial-mesenchymal co-culture model of pulmonary fibrosis.", "authors": ["Alber AB", "Kwong G", "Gupta VK", "Dooley PE", "Patel JR", "Bawa PS", "Minakin K", "Jones D", "Gopal D", "Souza H", "Yampolskaya M", "Vilker E", "Sen C", "Conchola AS", "Mehta P", "Gomperts BN", "Frum T", "Spence JR", "Alysandratos KD", "Kotton DN"], "journal": "bioRxiv", "journal_title": "bioRxiv : the preprint server for biology", "citation": "bioRxiv : the preprint server for biology, 01 2026", "abstract": "Pulmonary fibrosis (PF) can arise from mutations in alveolar epithelial type 2 (AT2) cell-specific genes, but manifests in fibrotic activation of mesenchymal cells, thus involving fibrogenic epithelial-mesenchymal crosstalk. The ligand-receptor interactions underlying the onset and early progression of PF remain poorly understood. Induced pluripotent stem cell (iPSC)-derived models are powerful tools to study respiratory diseases, yet are currently limited to reductionist single lineage epithelial models or multi-lineage systems that lack purity and lung-specificity of the mesenchyme. Here we generate a human iPSC line carrying both a lung mesenchyme-specific reporter (TBX4-LERtdTomato) and a reporter for mesenchymal activation/differentiation (ACTA2GFP). Applying this line, we develop a directed differentiation protocol capable of generating cells that express key molecular and functional features of primary human developing lung mesenchyme across multiple iPSC genetic backgrounds. We then establish co-cultures of these iPSC-derived lung mesenchymal cells (iLM) with patient-specific iPSC-derived alveolar epithelial type 2 cells (iAT2s) carrying an SFTPCI73T mutation as a model for PF. We find increased expression of fibrotic markers in co-cultures with mutant iAT2s as compared to co-cultures with gene-corrected iAT2s. Moreover, mutant iAT2s express markers of alveolar-basal intermediate (ABI) cells only in the presence of iLM, suggesting that bidirectional crosstalk promotes this aberrant cell state. We identify ligand-receptor pairs enriched in co-cultures with mutant iAT2s, including TGF\u03b2, multiple integrins, and additional genes that have not been previously linked to PF. Finally, we show that small molecule-mediated inhibition of TGF\u03b2 or integrins \u03b1V\u03b21/\u03b1V\u03b26 attenuates both fibrotic mesenchymal activation and the presence of ABI cells in iLM/iAT2 co-cultures. Thus, we have established a human iPSC-derived co-culture system that recapitulates key molecular hallmarks of bidirectional fibrogenic epithelial-mesenchymal crosstalk in pulmonary fibrosis, and enables the identification and study of potentially druggable pathways involved in disease initiation and progression.", "year": "2026", "month": "01", "volume": "", "issue": "", "pages": "", "doi": "10.64898/2026.01.30.702837", "link": "https://www.ncbi.nlm.nih.gov/pubmed/41659605", "sort_key": "2026-01-bidirectional fibrog", "quarter": "q1"}, {"pmid": "42339368", "title": "Deep learning\u2011based cell type prediction in lung tissue from brightfield histology using CODEX-derived labels.", "authors": ["Devarasetty S", "Lucarelli N", "Mimar S", "Jain S", "El-Achkar TM", "Purkerson J", "Pryhuber G", "Sarder P"], "journal": "Proc SPIE Int Soc Opt Eng", "journal_title": "Proceedings of SPIE--the International Society for Optical Engineering", "citation": "Proceedings of SPIE--the International Society for Optical Engineering, 2026", "abstract": "Identifying cell types present in lung biopsies can provide critical information on pathological processes, tissue organization, and organ health, and are valuable in both clinical and research settings. Knowledge of cell types, their distributions, and spatial relationships can assist pathologists and researchers in diagnosis, prognosis, and mechanistic investigations. Multiplex imaging technologies such as Phenocycler\u2122, based on co-detection by indexing (CODEX) can provide whole-slide spatial maps of protein expression and can accurately identify cell types; however, CODEX shares limitations including high costs of antibodies and reagents, as well as labor-intensive conjugation and validation steps. In contrast, hematoxylin and eosin (H&E) staining is inexpensive and routinely available, offering the potential for scalable cell-type mapping if robust prediction can be achieved directly from histology. In this work, we develop a deep learning pipeline to automatically detect cell types in H&E-stained lung tissue sections by leveraging ground-truth annotations from paired CODEX images. The dataset comprises over 2.3 million labeled cells, segmented from lung tissue sections obtained from multiple donors, and grouped into five broad classes: epithelial, immune, endothelial, stromal, and contractile. We train a DeepLabV3+ semantic segmentation model with ResNet backbone on patches from these annotated slides and reserve a subset for testing. Our model achieved 51.3% balanced accuracy across five classes, which is ~2.5x the random-guessing baseline of 20%. This framework demonstrates the feasibility of approximating multiplexed imaging-based cell type maps from routine histology.", "year": "2026", "month": "", "volume": "13932", "issue": "", "pages": "", "doi": "10.1117/12.3088120", "link": "https://www.ncbi.nlm.nih.gov/pubmed/42339368", "sort_key": "2026-00-deep learning\u2011based ", "quarter": "q0"}, {"pmid": "42111280", "title": "Cross-Architecture Knowledge Distillation for Histopathological Image Analysis.", "authors": ["Boudissa S", "Kawanaka H", "Aronow B", "Prasath VBS"], "journal": "IEEE Access", "journal_title": "IEEE access : practical innovations, open solutions", "citation": "IEEE access : practical innovations, open solutions, 2026", "abstract": "Histopathological image analysis presents unique challenges due to subtle inter-class variations, complex tissue structures, and high intra-class heterogeneity. Convolutional neural networks (CNNs) have traditionally dominated this domain by leveraging strong inductive biases toward locality, while vision transformers (ViTs) have recently emerged as a promising alternative due to their ability to model long-range dependencies. However, ViTs often struggle to capture fine-grained spatial patterns critical to histopathology, particularly when trained on limited data. In this work, we propose a knowledge distillation (KD) framework that transfers spatial and semantic knowledge from a CNN teacher to a ViT student while explicitly addressing representation and spatial misalignment between heterogeneous architectures. We analyze the limitations of conventional feature based distillation methods, which commonly rely on naive layer matching or pixel wise feature alignment, leading to suboptimal knowledge transfer. To overcome these issues, we introduce a principled layer alignment strategy based on representation similarity analysis using centered kernel alignment (CKA) and kernel canonical correlation analysis (KCCA). These measures enable architecture agnostic comparison of internal representations and facilitate the identification of semantically aligned stages between teacher and student models without enforcing strict spatial correspondence. Furthermore, we propose a stage-level representation alignment mechanism that preserves semantic consistency across representations while accommodating architectural differences between CNNs and ViTs, ensuring effective knowledge transfer at both representation and spatial levels. Extensive experiments on the BreakHis histopathological dataset demonstrate consistent performance improvements, particularly across fine-grained subtypes. Notably, our method achieves 96.87% using a ViT-Large student with a ResNet152 teacher on the patient-wise split setting and 98.82% accuracy on the image-wise subtype split, outperforming the best-performing state-of-the-art KD-based methods by 4% showing the promise of cross architecture KD in computational pathology.", "year": "2026", "month": "", "volume": "14", "issue": "", "pages": "58187-58209", "doi": "10.1109/access.2026.3683880", "link": "https://www.ncbi.nlm.nih.gov/pubmed/42111280", "sort_key": "2026-00-cross-architecture k", "quarter": "q0"}, {"pmid": "41067869", "title": "Targeting IL6-Edn1-FoxO1 axis enables lung growth in mechanically ventilated newborn mice.", "authors": ["Hirani D", "Selle J", "Wagde V", "Klymenko O", "Kuiper-Makris C", "Danopoulos S", "Donato M", "Preuss S", "Preuss M", "Mujahid S", "Vohlen C", "Wulf K", "van Koningsbruggen-Rietschel S", "Khatri P", "Wunderlich T", "Koch M", "Rose-John S", "Sucre JMS", "Al-Alam D", "Seeger W", "D\u00f6tsch J", "Bland RD", "Rabinovitch M", "Alejandre Alcazar MA"], "journal": "Eur Respir J", "journal_title": "The European respiratory journal", "citation": "The European respiratory journal, 12 2025", "abstract": "RATIONALE: Mechanical ventilation is a life-saving treatment for preterm infants that often leads to bronchopulmonary dysplasia (BPD). We previously demonstrated a reduced number of alveolar epithelial cells with a depletion of alveolar epithelial type 2 cells (AT2) in lungs of infants with BPD. OBJECTIVE: To investigate and target the mechanisms by which mechanical ventilation causes an arrest of alveolarisation. METHODS: Experimental mouse model of neonatal ventilation-induced lung injury (VILI) in wild-type mice, Il6-null mice, and pharmacological inhibition of interleukin (IL)-6 and endothelin receptors. Complementary, precision-cut lung slices (PCLS) and primary cells were analysed. Moreover, lungs of infants with BPD were studied. RESULTS: Mechanical ventilation leads to an AT2 depletion and arrest of alveolar growth. Transcriptomic profiling, measurement of gene and protein expression, immunofluorescent staining as well as cell culture studies identified an IL-6-mediated expression of Endothelin-1 (Edn1) and a nuclear sequestration of the antiproliferative transcription factor FoxO1 in AT2. These findings were confirmed using murine PCLS, lung epithelial cells and transgenic mice with inducible constitutive active FoxO1. In vivo, Il6-null mice and pharmacological inhibition of IL-6 or endothelin A and B receptors prevented nuclear sequestration of FoxO1, thereby enabling lung growth of newborn mice exposed to mechanical ventilation. CONCLUSION: Mechanical ventilation causes an arrest of alveolarisation in newborn mice through an IL-6-mediated activation of Edn1 signalling and nuclear sequestration of FoxO1 in AT2. Thus, this study provides rationale for considering pharmacological inhibition of IL-6 and/or endothelin receptors as a therapeutic strategy for preterm newborns at risk of VILI-associated lung growth arrest.", "year": "2025", "month": "12", "volume": "66", "issue": "6", "pages": "", "doi": "10.1183/13993003.01580-2024", "link": "https://www.ncbi.nlm.nih.gov/pubmed/41067869", "sort_key": "2025-12-targeting il6-edn1-f", "quarter": "q4"}, {"pmid": "41110929", "title": "Genetic Familial Interstitial Lung Disease.", "authors": ["Fernandez RJ", "Kropski JA"], "journal": "Clin Chest Med", "journal_title": "Clinics in chest medicine", "citation": "Clinics in chest medicine, 12 2025", "abstract": "Interstitial lung diseases (ILDs) are a heterogenous group of disorders leading to progressive loss of lung function. A subset of ILD cases can be linked to specific single-gene causes. The available evidence suggests that known genetic etiologies should influence pharmacotherapy decisions for ILD patients, particularly when immunosuppression is considered. There is emerging consensus supporting screening of unaffected relatives of familial ILD patients to enhance early disease detection, while future studies exploring primary and secondary prevention of ILD in high-risk individuals offer hope of preventing the life-limited complications of these disorders.", "year": "2025", "month": "12", "volume": "46", "issue": "4", "pages": "685-699", "doi": "10.1016/j.ccm.2025.07.008", "link": "https://www.ncbi.nlm.nih.gov/pubmed/41110929", "sort_key": "2025-12-genetic familial int", "quarter": "q4"}, {"pmid": "40175585", "title": "Bronchopulmonary dysplasia: signatures of monocyte-macrophage reactivity and tolerance define novel placenta-lung endotypes.", "authors": ["Mestan KK", "Sharma AM", "Lazar S", "Pandey S", "Parast MM", "Laurent LC", "Prince LS", "Sahoo D"], "journal": "Pediatr Res", "journal_title": "Pediatric research", "citation": "Pediatric research, 12 2025", "abstract": "BACKGROUND: Bronchopulmonary dysplasia (BPD) is a complex disease involving aberrant immune responses across the lifespan, but these mechanisms are challenging to follow in human infants. Leveraging novel Signatures of Macrophage Reactivity and Tolerance (SMaRT), we hypothesized that distinct profiles of immune cell polarization in blood and lung are associated with BPD. METHODS: Published transcriptomic datasets of cord blood-derived monocytes (CB-MNC), peripheral blood monocytes (PBMC) and tracheal aspirate-derived lung macrophages were linked to placental inflammatory (PID) and vascular (PVD) disease states using Amsterdam criteria, and BPD outcomes using NIH consensus criteria. Datasets were integrated using SMaRT to investigate monocyte-macrophage polarization tracked over the neonatal course. RESULTS: At birth and day 1 (D1), CB-MNCs and lung macrophages exhibited significant reactivity with PID versus PVD. After D14, macrophages from PID versus PVD-exposed infants exhibited reactive phenotypes (p = 0.002), with convergence towards original placental disease. Macrophages exhibited reactivity with BPD on D1-D7 (p = 0.007), but no difference after D14. At birth, CB-MNCs from BPD patients exhibited tolerance, which persisted in PBMCs throughout the neonatal period. CONCLUSION: Inflammatory versus vascular-mediated processes in developing lungs are influenced by immune cells programmed by distinct placental disease states. Circulating monocytes may play a role in attenuating macrophage reactivity towards a tolerant phenotype. IMPACT: Bronchopulmonary dysplasia is a complex, multifactorial chronic lung disease in which the mechanisms of placenta-lung crosstalk are poorly understood. This study uses novel AI approaches to understand how fetal monocytes and lung macrophages contribute to the pathogenesis of BPD. The study identified changes in macrophage reactivity versus tolerance that could explain the heterogeneity and adaptability of immune cells and the placenta in modulating health and disease in the developing fetus and neonate.", "year": "2025", "month": "12", "volume": "98", "issue": "6", "pages": "2352-2362", "doi": "10.1038/s41390-025-04025-w", "link": "https://www.ncbi.nlm.nih.gov/pubmed/40175585", "sort_key": "2025-12-bronchopulmonary dys", "quarter": "q4"}, {"pmid": "40542107", "title": "A deep generative model for deciphering cellular dynamics and in silico drug discovery in complex diseases.", "authors": ["Zheng Y", "Schupp JC", "Adams T", "Clair G", "Justet A", "Ahangari F", "Yan X", "Hansen P", "Carlon M", "Cortesi E", "Vermant M", "Vos R", "De Sadeleer LJ", "Rosas IO", "Pineda R", "Sembrat J", "K\u00f6nigshoff M", "McDonough JE", "Vanaudenaerde BM", "Wuyts WA", "Kaminski N", "Ding J"], "journal": "Nat Biomed Eng", "journal_title": "Nature biomedical engineering", "citation": "Nature biomedical engineering, 12 2025", "abstract": "Human diseases are characterized by intricate cellular dynamics. Single-cell transcriptomics provides critical insights, yet a persistent gap remains in computational tools for detailed disease progression analysis and targeted in silico drug interventions. Here we introduce UNAGI, a deep generative neural network tailored to analyse time-series single-cell transcriptomic data. This tool captures the complex cellular dynamics underlying disease progression, enhancing drug perturbation modelling and screening. When applied to a dataset from patients with idiopathic pulmonary fibrosis, UNAGI learns disease-informed cell embeddings that sharpen our understanding of disease progression, leading to the identification of potential therapeutic drug candidates. Validation using proteomics reveals the accuracy of UNAGI's cellular dynamics analysis, and the use of the fibrotic cocktail-treated human precision-cut lung slices confirms UNAGI's predictions that nifedipine, an antihypertensive drug, may have anti-fibrotic effects on human tissues. UNAGI's versatility extends to other diseases, including COVID, demonstrating adaptability and confirming its broader applicability in decoding complex cellular dynamics beyond idiopathic pulmonary fibrosis, amplifying its use in the quest for therapeutic solutions across diverse pathological landscapes.", "year": "2025", "month": "12", "volume": "9", "issue": "12", "pages": "2155-2180", "doi": "10.1038/s41551-025-01423-7", "link": "https://www.ncbi.nlm.nih.gov/pubmed/40542107", "sort_key": "2025-12-a deep generative mo", "quarter": "q4"}, {"pmid": "40960949", "title": "Sorted-cell proteomics reveals an AT1-associated epithelial cornification phenotype and suggests endothelial redox imbalance in human bronchopulmonary dysplasia.", "authors": ["Ushakumary MG", "Chrisler WB", "Bandyopadhyay G", "Huyck H", "Gorman BL", "Beishembieva N", "Pitonzo A", "Lai ZJ", "Fillmore TL", "Attah IK", "Deutsch G", "Purkerson JM", "Dylag AM", "Misra RS", "Carson JP", "Adkins JN", "Pryhuber GS", "Clair GC"], "journal": "Am J Physiol Lung Cell Mol Physiol", "journal_title": "American journal of physiology. Lung cellular and molecular physiology", "citation": "American journal of physiology. Lung cellular and molecular physiology, 11 2025", "abstract": "Bronchopulmonary dysplasia (BPD) is a neonatal lung disease characterized by inflammation and scarring leading to long-term tissue damage. Previous whole tissue proteomics identified BPD-specific proteome changes and cell type shifts. Little is known about the proteome-level changes within specific cell populations in disease. Here, we sorted epithelial (EPI) and endothelial (ENDO) cell populations based on their differential surface markers from normal and BPD human lungs. Using a low-input compatible sample preparation method (MicroPOT), proteins were extracted and digested into peptides and subjected to liquid chromatography-tandem mass spectrometry (LC-MS/MS) proteome analysis. Of the 4,970 proteins detected, 293 were modulated in abundance or detection in the EPI population and 422 were modulated in ENDO cells. Modulation of proteins associated with actin-cytoskeletal function, such as SCEL, LMO7, and TBA1B was observed in the BPD EPIs. Using confocal imaging and analysis, we validated the presence of aberrant multilayer-like structures comprising SCEL and LMO7, known to be associated with epidermal cornification, in the human BPD lung. This is the first report of the accumulation of cornification-associated proteins in BPD. Their localization in the alveolar parenchyma, primarily associated with alveolar type 1 (AT1) cells, suggests a role in the BPD postinjury response. In the ENDOs, redox balance and mitochondrial function pathways were modulated. Alternative mRNA splicing and cell proliferative functions were elevated in both populations, suggesting potential dysregulation of cell progenitor fate. This study characterized the proteome of epithelial and endothelial cells from the BPD lung for the first time, identifying population-specific changes in BPD pathogenesis.NEW & NOTEWORTHY The study is the first to perform proteomics on sorted pulmonary epithelial and endothelial populations from bronchopulmonary dysplasia (BPD) and age-matched control human donors. We identified an increase in cornification-associated proteins in BPD (e.g., SCEL and LMO7), and evidenced the presence of multilayered structures unique to BPD alveolar regions, associated with alveolar type 1 (AT1) cells. By changing the nature and/or biomechanical properties of the epithelium, these structures may alter the behavior of other alveolar cell types potentially contributing to the arrested alveolarization observed in BPD. Finally, our data suggest the modulation of cell proliferation and redox homeostasis in BPD providing potential mechanisms for the reduced vascular growth associated with BPD.", "year": "2025", "month": "11", "volume": "329", "issue": "5", "pages": "L570-L582", "doi": "10.1152/ajplung.00098.2025", "link": "https://www.ncbi.nlm.nih.gov/pubmed/40960949", "sort_key": "2025-11-sorted-cell proteomi", "quarter": "q4"}, {"pmid": "40766488", "title": "Postnatal Abrogation of VEGFR2 Blocks Terminal Cap2 Differentiation by Preventing the Developmental Progression from a Capillary Intermediate Cell State.", "authors": ["Zhang D", "Knutsen C", "Stroud DJ", "Che X", "Cornfield DN", "Zanini F", "Alvira CM"], "journal": "bioRxiv", "journal_title": "bioRxiv : the preprint server for biology", "citation": "bioRxiv : the preprint server for biology, 11 2025", "abstract": "After birth, the alveolar capillary network expands to increase gas exchange surface area and endothelial-derived signals promote alveolarization. Lung capillaries are comprised of two distinct subsets, one with proliferative potential to facilitate growth and repair (Cap1), and the other serving a specialized role in gas exchange (Cap2). However, the molecular mechanisms directing capillary speciation, developmental plasticity, and fate transitions during development and repair are not well understood. Here, we show that Cap2 are absent in late embryonic life but rapidly appear and expand immediately after birth. We show that Cap1 progenitors first transition to a novel, intermediate cell state (CapINT), characterized by co-expression of Cap1 and Cap2 markers, and heightened proliferation. CapINT are present in both the developing mouse and human lung. Hyperoxia, an experimental model of bronchopulmonary dysplasia (BPD), a chronic lung disease marked by impaired alveolarization, increases CapINT abundance and persistence and expands Cap2 EC. CapINT EC are also increased in human infants dying with active BPD. Using genetic lineage tracing, single cell transcriptomics, ATAC-sequencing and a mouse model that permits inducible deletion of VEGFR2 in CapINT and Cap2 EC, we show that postnatal abrogation of VEGFR2 markedly increases CapINT EC abundance, blocks Cap2 terminal differentiation, impairs alveolarization, and activates alveolar fibroblasts. Finally, we identify ERG as a putative VEGFR2-downstream mechanism that promotes CapINT to Cap2 differentiation. Taken together, our data show that Cap1-Cap2 differentiation is a two-step process that only requires VEGFR2 for the second step. Elucidation of the physiologic and molecular pathways that control the initial transition of Cap1 to CapINT EC has the potential to reveal new therapeutic targets for lung diseases that disrupt the alveolar capillary formation and integrity.", "year": "2025", "month": "11", "volume": "", "issue": "", "pages": "", "doi": "10.1101/2025.07.23.666389", "link": "https://www.ncbi.nlm.nih.gov/pubmed/40766488", "sort_key": "2025-11-postnatal abrogation", "quarter": "q4"}, {"pmid": "40106801", "title": "Single-Cell RNA Sequencing Identifies a Unique Macrophage Population in a Mouse Model of Ozone-induced Asthma Exacerbation.", "authors": ["Ray JL", "Walum J", "Jelic D", "Barnes R", "Bentley ID", "Britt RD", "Englert JA", "Ballinger MN"], "journal": "Am J Respir Cell Mol Biol", "journal_title": "American journal of respiratory cell and molecular biology", "citation": "American journal of respiratory cell and molecular biology, 10 2025", "abstract": "Ozone (O3) inhalation triggers asthmatic airway hyperresponsiveness (AHR), but the mechanisms are unknown. Previously, we developed a murine model of dust mite, ragweed, and Aspergillus (DRA)-induced allergic lung inflammation followed by O3 exposure for mechanistic investigation. The present study used single-cell RNA sequencing for unbiased profiling of cells within the lungs of mice exposed to DRA, O3, or DRA + O3 to identify components of the immune cell niche that contribute to AHR. Alveolar macrophages (AMs) had the greatest number of differentially expressed genes after DRA + O3, most of which were unique to the two-hit exposure. After DRA + O3, AMs activated transcriptional pathways related to cholesterol biosynthesis, degradation of the extracellular matrix, endosomal Toll-like receptor processing, and various cytokine signals. We also identified AM and monocyte subset populations that were unique to the DRA + O3 group. These unique AMs activated gene pathways related to inflammation, sphingolipid metabolism, and bronchial constriction. The unique monocyte population had a gene signature that suggested phospholipase activation and increased degradation of the extracellular matrix. Flow cytometric analysis of BAL immune cells showed recruited monocyte-derived AMs after DRA and DRA + O3, but not after O3 exposure alone. O3 alone increased BAL neutrophils, but this response was attenuated in DRA + O3 mice. DRA-induced changes in the airspace immune cell profile were reflected in elevated BAL cytokine/chemokine levels after DRA + O3 compared with O3 alone. The present work highlights the role of monocytes and AMs in the response to O3 and suggests that the presence of distinct subpopulations after allergic inflammation may contribute to O3-induced AHR.", "year": "2025", "month": "10", "volume": "73", "issue": "4", "pages": "586-599", "doi": "10.1165/rcmb.2024-0358OC", "link": "https://www.ncbi.nlm.nih.gov/pubmed/40106801", "sort_key": "2025-10-single-cell rna sequ", "quarter": "q4"}, {"pmid": "41068078", "title": "mTOR dysregulation induces IL-6 and paracrine AT2 cell senescence impeding lung repair in lymphangioleiomyomatosis.", "authors": ["Babaei-Jadidi R", "Clements D", "Wu Y", "Chen K", "Miller S", "Plat\u00e9 M", "Lim K", "Rue R", "Krymskaya VP", "Chambers R", "Rawlins EL", "Xu Y", "Johnson SR"], "journal": "Nat Commun", "journal_title": "Nature communications", "citation": "Nature communications, 10 2025", "abstract": "Lymphangioleiomyomatosis (LAM) is a rare disease of women in which TSC2 deficient 'LAM cells' with dysregulated mTOR signalling and recruited fibroblasts form nodules causing lung cysts and respiratory failure. We examine if mTOR dysregulation can induce senescence and impair the response to lung injury in LAM. The senescence markers p21, p16 and the SenMayo gene set are increased in LAM lungs and colocalise with alveolar type 2 cells. LAM models induce mTOR dependent senescence in alveolar type 2 cell organoids in vitro and in vivo. IL-6 produced by LAM cells, induces p16 and p21 in alveolar type 2 cells, inhibits epithelial wound resolution and is related to lung function in LAM patients. Rapamycin and the IL-6 receptor antagonist Tocilizumab reduce alveolar type 2 cell organoid p21 accumulation and Tocilizumab enhances epithelial wound repair. Targeting IL-6 signalling in parallel with mTOR inhibition, may reduce lung damage in LAM.", "year": "2025", "month": "10", "volume": "16", "issue": "1", "pages": "8996", "doi": "10.1038/s41467-025-64036-3", "link": "https://www.ncbi.nlm.nih.gov/pubmed/41068078", "sort_key": "2025-10-mtor dysregulation i", "quarter": "q4"}, {"pmid": "40763040", "title": "p53 maintains lineage fidelity during lung capillary injury-repair in neonatal hyperoxia.", "authors": ["Vila Ellis L", "Bywaters JD", "Ceas A", "Liu Y", "Sucre JM", "Chen J"], "journal": "JCI Insight", "journal_title": "JCI insight", "citation": "JCI insight, 09 2025", "abstract": "Bronchopulmonary dysplasia (BPD), a prevalent and chronic lung disease affecting premature newborns, results in vascular rarefaction and alveolar simplification. Although the vasculature has been recognized as a main player in this disease, the recently found capillary heterogeneity and cellular dynamics of endothelial subpopulations in BPD remain unclear. Here, we showed that Cap2 cells were damaged during neonatal hyperoxic injury, leading to their replacement by Cap1 cells, which, in turn, significantly declined. Single-cell RNA-Seq identified the activation of numerous p53 target genes in endothelial cells (ECs), including Cdkn1a (p21). While global deletion of p53 resulted in worsened vasculature, EC-specific deletion of p53 reversed the vascular phenotype and improved alveolar simplification during hyperoxia. This recovery was associated with the emergence of a transitional EC state, enriched for oxidative stress response genes and growth factors. Notably, this transitional EC gene signature was conserved in an aberrant capillary population identified in human BPD with pulmonary hypertension, underscoring the biological and clinical relevance of our findings. These results reveal a key role for p53 in maintaining endothelial lineage fidelity during pulmonary capillary repair following hyperoxic injury and highlight the critical contribution of the endothelium to BPD pathogenesis.", "year": "2025", "month": "09", "volume": "10", "issue": "17", "pages": "", "doi": "10.1172/jci.insight.182880", "link": "https://www.ncbi.nlm.nih.gov/pubmed/40763040", "sort_key": "2025-09-p53 maintains lineag", "quarter": "q3"}, {"pmid": "40998789", "title": "FUSION: a web-based application for in-depth exploration of multi-omics data with brightfield histology.", "authors": ["Border SP", "Ferreira RM", "Lucarelli N", "Kumar SKC", "Paul AS", "Manthey D", "Barisoni L", "Levites Strekalova YA", "Ray J", "Cheng YH", "Rosenberg AZ", "Tomaszewski JE", "Mimar S", "Hodgin JB", "Hickey JW", "Wei B", "Ginty F", "Karunamurthy A", "Wang J", "Raina M", "Pryhuber GS", "Purkerson J", "HuBMAP consortium", "El-Achkar TM", "Jain S", "Eadon MT", "Sarder P"], "journal": "Nat Commun", "journal_title": "Nature communications", "citation": "Nature communications, 09 2025", "abstract": "Spatial technologies examining the cell and tissue microenvironment at near single-cell resolution are revealing important molecular insights. However, few tools enable integrated, interactive analysis of spatial-omics with tissue morphology in the same functional tissue unit. Here, we present FUSION (Functional Unit State Identification in Whole Slide Images), a web-based platform for visualizing and analyzing spatial-omics data with high-resolution histology. FUSION provides workflows for assessing cell compositions, quantitative morphometrics, and comparative tissue analyses. We demonstrate applicability across spatial assays, including 10x Visium, Visium HD, 10x Xenium, Cell DIVE, and PhenoCycler, applied to healthy and diseased tissues from kidney, small intestine, lung, and skin in the Human BioMolecular Atlas Program. FUSION is cloud-based, open-source, and accessible at https://fusion.hubmapconsortium.org/ , hosting over 50 paired datasets and tutorials. In a series of use cases, we show its capacity to distinguish renal glomeruli injury states, quantify morphometric changes, and characterize fibrosis with immune infiltration.", "year": "2025", "month": "09", "volume": "16", "issue": "1", "pages": "8388", "doi": "10.1038/s41467-025-63050-9", "link": "https://www.ncbi.nlm.nih.gov/pubmed/40998789", "sort_key": "2025-09-fusion: a web-based ", "quarter": "q3"}, {"pmid": "41040203", "title": "Exploring endothelial cell environments across organs in spatially resolved omics data.", "authors": ["Jain Y", "Jepson J", "Chen R", "Maier E", "Herr BW", "Puig-Barbe A", "Quardokus EM", "Qaurooni D", "Yapp C", "Ewing SL", "Enninful A", "Farzad N", "Bueckle A", "Easter QT", "Matuck B", "Zhu C", "Monte EM", "Purkerson JM", "Jehrio M", "Misra RS", "Fan R", "Ginty F", "Karunamurthy A", "Fan J", "Campbell-Thompson M", "Pryhuber GS", "Byrd KM", "Hickey JW", "B\u00f6rner K"], "journal": "bioRxiv", "journal_title": "bioRxiv : the preprint server for biology", "citation": "bioRxiv : the preprint server for biology, 09 2025", "abstract": "Endothelial cells are ubiquitously present in the human body and line the luminal surface of blood and lymphatic vessels. The oxygen-dependence of cells impacts their proximity to blood vessels, and consequently, to endothelial cells depending on their functional properties and priorities. This paper presents cell-to-nearest-endothelial-cell distance distributions for various cell types using 399 spatially resolved omics datasets from 14 studies comprising 12 tissue types with a total of 47,349,496 cells. Additionally, we developed an open-source web-based interactive tool, Cell Distance Explorer, that allows researchers to interactively visualize cell graphs and linkages in 2D and 3D datasets. Finally, we present a hierarchical neighborhood analysis focused on the endothelial cell neighborhoods in small and large intestine datasets. This paper provides an open-access resource (datasets, tools, and analyses) to characterize and compare cell distances and cell neighborhoods in spatially resolved omics data.", "year": "2025", "month": "09", "volume": "", "issue": "", "pages": "", "doi": "10.1101/2025.09.23.678129", "link": "https://www.ncbi.nlm.nih.gov/pubmed/41040203", "sort_key": "2025-09-exploring endothelia", "quarter": "q3"}, {"pmid": "40789650", "title": "Alterations of the skeletal muscle nuclear proteome after acute exercise reveals a posttranscriptional influence.", "authors": ["Martin RA", "Zhang X", "Viggars MR", "Sanford JA", "Taylor ZW", "Hansen JR", "Clair GC", "Douglas CM", "Hesketh SJ", "Adkins JN", "Esser KA"], "journal": "Am J Physiol Cell Physiol", "journal_title": "American journal of physiology. Cell physiology", "citation": "American journal of physiology. Cell physiology, 09 2025", "abstract": "Exercise is firmly established as a key contributor to overall well-being and is frequently employed as a therapeutic approach to mitigate various health conditions. One pivotal aspect of the impact of exercise lies in the systemic transcriptional response, which underpins its beneficial adaptations. Although extensive research has been devoted to understanding the transcriptional response to exercise, our knowledge of the protein constituents of nuclear processes accompanying gene expression in skeletal muscle remains largely elusive. We hypothesize that alterations in the nuclear proteome following exercise hold vital clues for comprehending exercise-induced transcriptional regulation and related nuclear functions. We first detail the successful isolation of skeletal muscle nuclei from C57BL/6 mice, encapsulating 2,030 proteins linked to nuclear processes such as transcription, RNA processing, chromatin modifications, and nuclear transport. We then used this approach to isolate muscle nuclei in sedentary, immediately post-, 1-h, and 4-h after a 30-min treadmill running session, to gain insight into the nuclear proteome after exercise. We found 54 proteins linked to mRNA splicing and nucleocytoplasmic transport, many of which were substantially reduced immediately postexercise followed by a rapid increase 1- and 4-h postexercise. Super-resolution microscopy experiments highlight localization changes in mRNA processing proteins postexercise, further suggesting changes in nuclear transport dynamics. Our data provide important insight into changes in the nuclear proteome following exercise. In particular, it highlights proteins contributing to mRNA processing and splicing in addition to transcriptional processes, with exercise offering broader changes in mechanisms modulating the molecular response to acute exercise.NEW & NOTEWORTHY Exercise plays a crucial role in promoting muscle health, but our understanding of nuclear proteins orchestrating the molecular response to exercise is limited. Isolation of skeletal muscle nuclei coupled with mass spectrometry enhanced the identification of nuclear proteins. This approach was used to investigate the temporal changes in the muscle nuclear proteome postexercise, including proteins linked to posttranscriptional processing and nuclear transport. Our findings offer new insights into potential mechanisms contributing to exercise-induced adaptations.", "year": "2025", "month": "09", "volume": "329", "issue": "3", "pages": "C953-C971", "doi": "10.1152/ajpcell.00575.2024", "link": "https://www.ncbi.nlm.nih.gov/pubmed/40789650", "sort_key": "2025-09-alterations of the s", "quarter": "q3"}, {"pmid": "40748676", "title": "A spatial transcriptomic atlas of acute neonatal lung injury across development and disease severity.", "authors": ["Mallapragada S", "Lyu R", "Williams-Katek AL", "Fischer BK", "Vannan A", "Hadad N", "Mee ED", "Shirazi SP", "Jetter CS", "Negretti NM", "Hilgendorff A", "Eldredge LC", "Deutsch GH", "McCarthy DJ", "Kropski JA", "Sucre JMS", "Banovich NE"], "journal": "Am J Physiol Lung Cell Mol Physiol", "journal_title": "American journal of physiology. Lung cellular and molecular physiology", "citation": "American journal of physiology. Lung cellular and molecular physiology, 09 2025", "abstract": "A molecular understanding of lung organogenesis requires delineation of the timing and regulation of the cellular transitions that ultimately form and support a surface capable of gas exchange. Although the advent of single-cell transcriptomics has allowed for the discovery and identification of transcriptionally distinct cell populations present during lung development, the spatiotemporal dynamics of these transcriptional shifts remain undefined. With imaging-based spatial transcriptomics, we analyzed the gene expression patterns in 17 human infant lungs at varying stages of development and injury, creating a spatial transcriptomic atlas of approximately 1.2 million cells. We applied computational clustering approaches to identify shared molecular patterns among this cohort, informing how tissue architecture and molecular spatial relationships are coordinated during development and disrupted in disease. Recognizing that all preterm birth represents an injury to the developing lung, we created a simplified classification scheme that relies upon the routinely collected objective measures of gestational age and lifespan. Within this framework, we have identified cell type patterns across gestational age and life span variables that would likely be overlooked when using the conventional \"disease versus control\" binary comparison. Together, these data represent an open resource for the lung research community, supporting discovery-based inquiry and identification of targetable molecular mechanisms in both normal and arrested human lung development.NEW & NOTEWORTHY Mapping the spatial and temporal transcriptional relationships during lung development is fundamental to understanding regeneration and chronic lung disease; however, the classification of samples as control or disease is especially challenging in the setting of preterm birth (itself a lung injury). Here, we report the largest neonatal lung transcriptomic atlas to date and an analysis framework based only on gestational age and lifespan, providing a new resource for hypothesis generation to the lung community.", "year": "2025", "month": "09", "volume": "329", "issue": "3", "pages": "L376-L388", "doi": "10.1152/ajplung.00191.2025", "link": "https://www.ncbi.nlm.nih.gov/pubmed/40748676", "sort_key": "2025-09-a spatial transcript", "quarter": "q3"}, {"pmid": "40494345", "title": "Microbiota-derived inosine programs protective CD8+ T cell responses against influenza in newborns.", "authors": ["Stevens J", "Culberson E", "Kinder J", "Ramiriqui A", "Gray J", "Bonfield M", "Shao TY", "Al Gharaibeh F", "Peterson L", "Steinmeyer S", "Eshleman EM", "Negi S", "Zacharias W", "Pryhuber G", "Paul O", "Sengupta S", "Alenghat T", "Way SS", "Deshmukh H"], "journal": "Cell", "journal_title": "Cell", "citation": "Cell, 08 2025", "abstract": "Early-life susceptibility to respiratory viral infections remains a major public health concern, yet the underlying mechanisms are poorly understood. We demonstrate that antibiotic-induced dysbiosis impairs influenza-specific CD8+ T cell immunity in infant mice and humans through the disruption of nuclear factor interleukin 3 (NFIL3)-dependent T cell programming. Mechanistically, we show that dysbiosis reduces intestinal and circulating inosine levels, disrupting NFIL3's epigenetic regulation of T cell factor 1 (TCF1) expression. This leads to intrinsic defects in CD8+ T cell proliferation and differentiation, diminished effector responses, and impaired formation of tissue-resident memory cells. Bifidobacterium colonization restores intestinal and pulmonary inosine levels, establishing a specific pathway of gut-lung metabolic communication. Notably, inosine supplementation rescues NFIL3-dependent regulation of TCF1, enhancing CD8+ T cell responses and protection against influenza infection in dysbiotic infants. Our findings reveal how early-life microbial communities shape antiviral immunity and identify inosine as a therapeutic target for enhancing respiratory defenses in infants.", "year": "2025", "month": "08", "volume": "188", "issue": "16", "pages": "4239-4256.e19", "doi": "10.1016/j.cell.2025.05.013", "link": "https://www.ncbi.nlm.nih.gov/pubmed/40494345", "sort_key": "2025-08-microbiota-derived i", "quarter": "q3"}, {"pmid": "40494897", "title": "Ki-67 promotes inflammatory signaling governing neutrophil recruitment during respiratory infections.", "authors": ["Yee M", "Misra R", "Vesecky S", "Barravecchia M", "Najar RA", "Rahman A", "Pryhuber GS", "Dean DA", "Lawrence BP", "Fisher D", "O'Reilly MA"], "journal": "EMBO Mol Med", "journal_title": "EMBO molecular medicine", "citation": "EMBO molecular medicine, 08 2025", "abstract": "Neutrophils defend against respiratory infections but cause acute lung injury (ALI) when excessively recruited to the lung. Early life environmental factors can shape lung development, but how they impact neutrophil recruitment is not known. We show that exposing newborn mice to hyperoxia increases the number of adult alveolar type 1 (AT1) epithelial cells expressing the proliferation marker Ki-67. Although these cells were not proliferating, they expressed high levels of chemokines that stimulated neutrophil recruitment and ALI when mice were infected with influenza A virus or exposed to lipopolysaccharide (LPS). Neutrophil recruitment and chemokine production were attenuated in Ki-67 hypomorph mice infected with virus or exposed to LPS and enhanced by genetically overexpressing Ki-67 in their lungs. Silencing Ki-67 in a mouse AT1-like cell line reduced basal and IL-1\u03b2 stimulation of RelA/p65 and NF-\u03baB-dependent transcription of the chemokines Cxcl1 and Cxcl5. Our findings reveal a novel role for Ki-67 to modulate the intensity of epithelial pro-inflammatory signaling, controlling neutrophil recruitment. The severity of respiratory infections may be influenced by mitogens and environmental factors that increase the expression of Ki-67.", "year": "2025", "month": "08", "volume": "17", "issue": "8", "pages": "2011-2039", "doi": "10.1038/s44321-025-00261-z", "link": "https://www.ncbi.nlm.nih.gov/pubmed/40494897", "sort_key": "2025-08-ki-67 promotes infla", "quarter": "q3"}, {"pmid": "40863384", "title": "Dysfunctional Electron Transport Chain Assembly in COXPD8.", "authors": ["Beutner G", "Huyck HL", "Deutsch G", "Pryhuber GS", "Porter GA"], "journal": "J Cardiovasc Dev Dis", "journal_title": "Journal of cardiovascular development and disease", "citation": "Journal of cardiovascular development and disease, 08 2025", "abstract": "Combined oxidative phosphorylation deficiency type 8 (COXPD8) is an autosomal recessive mitochondrial disorder caused by a mutation of the nuclear encoded mitochondrial alanyl-tRNA synthetase gene (AARS2). Clinical manifestations of COXPD8 include lethal infantile hypertrophic cardiomyopathy, pulmonary hypoplasia, generalized muscle weakness, and neurological involvement. We report a patient with COXPD8 caused by two mutations in the AARS2 gene. The c.1738 C>G mutation has not been previously reported, while the c.2872 C>T mutation has been associated with pulmonary hypoplasia and hypertrophic cardiomyopathy. Cardiac tissue, obtained through the LungMAP program, showed that, compared to other patients of similar ages, these two mutations affect not only the assembly of functional monomeric complexes (Cx) I and IV of the electron transport chain (ETC) but also limit the formation of respiratory supercomplexes. This patient had altered expression of some ETC proteins but normal expression of several enzymes of the tricarboxylic acid cycle. We also show that one of the control/comparison patients had an undiagnosed ETC Cx IV deficiency. In conclusion, our data demonstrate that the two mutations of the AARS2 gene are associated with failed assembly of Cx I and Cx IV and reduced formation of respiratory supercomplexes of the ETC, likely leading to acute bioenergetic stress.", "year": "2025", "month": "08", "volume": "12", "issue": "8", "pages": "", "doi": "10.3390/jcdd12080318", "link": "https://www.ncbi.nlm.nih.gov/pubmed/40863384", "sort_key": "2025-08-dysfunctional electr", "quarter": "q3"}, {"pmid": "39903571", "title": "Don't Just Do Something, Stand There: Pressing Pause on Acetaminophen Use in Infants and Children.", "authors": ["Sucre JMS", "Hilgendorff A", "Eldredge LC"], "journal": "Am J Respir Cell Mol Biol", "journal_title": "American journal of respiratory cell and molecular biology", "citation": "American journal of respiratory cell and molecular biology, 08 2025", "abstract": "", "year": "2025", "month": "08", "volume": "73", "issue": "2", "pages": "159-160", "doi": "10.1165/rcmb.2025-0014ED", "link": "https://www.ncbi.nlm.nih.gov/pubmed/39903571", "sort_key": "2025-08-don't just do someth", "quarter": "q3"}, {"pmid": "40687816", "title": "Truncated NTRK2 is induced in CAP1 endothelial cells during mouse lung injury-repair.", "authors": ["Kong CSL", "V M", "Pantale\u00f3n-Garc\u00eda J", "Evans SE", "Chen J"], "journal": "iScience", "journal_title": "iScience", "citation": "iScience, 07 2025", "abstract": "Pulmonary capillary endothelial cells (ECs) consist of two populations, CAP1 and CAP2; how each population reacts to diverse tissue injury is incompletely understood. Using single-cell multiome and mouse genetics, we characterize the induction and function of a truncated isoform of Ntrk2, Ntrk2-T1, in multiple lung injury models. Upon Sendai parainfluenza infection, Ntrk2-T1 is broadly induced in CAP1s after the initial interferon response, associated with increased intronic chromatin accessibility, and persists for weeks. Ntrk2-T1 ECs arise from CAP1s but not CAP2s-traced by Kit CreER and Car4 CreER , respectively-and proliferate and give rise to CAP1s but not CAP2s, as traced by Ntrk2 CreER . Although also induced by lipopolysaccharide, H3N2 influenza, and COVID-19 injuries, EC-specific deletion of Ntrk2 has limited molecular and cellular consequences. Individuals with incident and prevalent respiratory diseases have lower plasma NTRK2. Our data identifies Ntrk2-T1 as an EC marker of lung injury-repair and enhances our understanding of EC heterogeneity.", "year": "2025", "month": "07", "volume": "28", "issue": "7", "pages": "112973", "doi": "10.1016/j.isci.2025.112973", "link": "https://www.ncbi.nlm.nih.gov/pubmed/40687816", "sort_key": "2025-07-truncated ntrk2 is i", "quarter": "q3"}, {"pmid": "40631293", "title": "Pulsatile flow dynamics determine pulmonary arterial architecture.", "authors": ["Spurgin S", "Thai L", "Wan T", "Chaney CP", "Cowdin MA", "Reddy SV", "Tarique Hussain M", "Fares M", "Carroll T", "Spearman AD", "Cleaver O"], "journal": "bioRxiv", "journal_title": "bioRxiv : the preprint server for biology", "citation": "bioRxiv : the preprint server for biology, 07 2025", "abstract": "BACKGROUND: Single ventricle congenital heart disease (SV-CHD) is a uniformly lethal condition. Survival depends upon the Glenn surgery, which shunts venous blood directly to the pulmonary arteries without the support of a pumping ventricle. In the context of this altered circulation (loss of cardiac-driven pulsatility), diverse pulmonary vascular complications develop, severely limiting survival. To date, the relationship between loss of arterial pulsatility and pulmonary vascular changes has not yet been investigated at the cellular level. METHODS: Using combined cardiac catheterization and cardiac MRI, we defined pulsatility loss in three dimensions (flow, pressure, and stretch) in the pulmonary arteries of SV-CHD patients in the Glenn stage. To assess the impact of pulsatility loss on endothelial cells (ECs), we exposed cultured human pulmonary artery endothelial cells to individual dimensions of force. We used bulk RNA sequencing, GSEA, ELISA, and immunofluorescent staining to investigate cellular changes. A rat model of the Glenn circulation was used to further assess the cellular adaptation of pulmonary arteries to non-pulsatile hemodynamic forces. RESULTS: We identify and quantify pulsatility loss in Glenn patients, occurring in all three dimensions of hemodynamic force. We show unique transcriptional signatures of pulsatility within each dimension of force, affecting key structural and signaling pathways in ECs. We identify pulsatile stretch as a critical stimulus for endothelial secretion of PDGFB-a known driver of vascular smooth muscle cell (vSMC) proliferation and vascular wall recruitment. Moreover, we show that loss of arterial pulsatility in vivo leads to thinning of the vascular wall and reduction of VSMCs. CONCLUSIONS: This work identifies a novel and critical role for blood flow pulsatility in maintenance of the pulmonary vascular architecture. Our study provides a mechanistic understanding of the role of pulsatile, arterial forces in maintaining normal pulmonary vascular architecture through EC-SMC crosstalk. Arterial pulsatility is sensed by stretch of endothelial cells and relayed via PDGFB to the vascular smooth muscle, thus maintaining a vascular structure that can support arterial hemodynamic force.", "year": "2025", "month": "07", "volume": "", "issue": "", "pages": "", "doi": "10.1101/2025.06.30.662470", "link": "https://www.ncbi.nlm.nih.gov/pubmed/40631293", "sort_key": "2025-07-pulsatile flow dynam", "quarter": "q3"}, {"pmid": "40392055", "title": "Integrating N-glycan and CODEX imaging reveal cell-specific protein glycosylation in healthy human lung.", "authors": ["Veli\u010dkovi\u0107 D", "Purkerson J", "Bhotika H", "Huyck H", "Clair G", "Pryhuber GS", "Anderton C"], "journal": "Mol Omics", "journal_title": "Molecular omics", "citation": "Molecular omics, 07 2025", "abstract": "Identifying cell-specific glycan structures in human lungs is critical for understanding the chemistry and mechanisms that guide cell-cell and cell-matrix interactions and determining nuanced functions of specific glycosylation. Our dual-modality omics platform, which uses matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) to profile glycan chemistry at 50 \u03bcm \u00d7 50 \u03bcm scale, combined with co-detection by indexing (CODEX) to provide cell identification from the exact same tissue section, is a significant step in this direction. It enabled us to detect, differentiate, and reveal chemical properties of N-glycans in the various cell types of a human lung, suggesting the cell-specific function of distinct carbohydrate moieties. This innovative technological combination bridges the gap between the specific protein glycosylation and their cellular origin, paving the way for targeted studies in the lungs and many other human tissues where glycans mediate cell-cell recognition events.", "year": "2025", "month": "07", "volume": "21", "issue": "4", "pages": "334-342", "doi": "10.1039/d4mo00230j", "link": "https://www.ncbi.nlm.nih.gov/pubmed/40392055", "sort_key": "2025-07-integrating n-glycan", "quarter": "q3"}, {"pmid": "40681510", "title": "Bering: joint cell segmentation and annotation for spatial transcriptomics with transferred graph embeddings.", "authors": ["Jin K", "Zhang Z", "Zhang K", "Viggiani F", "Callahan C", "Tang J", "Aronow BJ", "Shu J"], "journal": "Nat Commun", "journal_title": "Nature communications", "citation": "Nature communications, 07 2025", "abstract": "Single-cell spatial transcriptomics can provide subcellular resolution for a deep understanding of molecular mechanisms. However, accurate segmentation and annotation remain a major challenge that limits downstream analysis. Current machine learning methods heavily rely on nuclei or cell body staining, resulting in the significant loss of both transcriptome depth and the limited ability to learn spatial colocalization patterns. Here, we propose Bering, a graph deep learning model that leverages transcript colocalization relationships for joint noise-aware cell segmentation and molecular annotation in 2D and 3D spatial transcriptomics data. To evaluate performance, we benchmark Bering with state-of-the-art methods and observe better cell segmentation accuracies and more detected transcripts across technologies and tissues. To streamline segmentation processes, we construct expansive pre-trained models, which yield high segmentation accuracy in new data through transfer learning and self-distillation. These improved capabilities enable Bering to enhance cell annotations for the rapidly expanding field of spatial omics.", "year": "2025", "month": "07", "volume": "16", "issue": "1", "pages": "6618", "doi": "10.1038/s41467-025-60898-9", "link": "https://www.ncbi.nlm.nih.gov/pubmed/40681510", "sort_key": "2025-07-bering: joint cell s", "quarter": "q3"}, {"pmid": "40461472", "title": "Three dimensional multiscalar neurovascular nephron connectivity map of the human kidney across the lifespan.", "authors": ["McLaughlin L", "Zhang B", "Sharma S", "Knoten AL", "Kaushal M", "Purkerson JM", "Huyck HL", "Pryhuber GS", "Gaut JP", "Jain S"], "journal": "Nat Commun", "journal_title": "Nature communications", "citation": "Nature communications, 06 2025", "abstract": "The human kidney maintains homeostasis through a complex network of up to a million nephrons, its fundamental tissue units. Using innovative tissue processing and light sheet fluorescence microscopy, we mapped the 3D neurovascular connectivity of nephrons to understand how their structural organization enables coordinated functions like filtration, absorption, and blood pressure regulation. Our analysis revealed developmental changes in glomerular orientation, density, volume, and innervation from birth through aging. We discovered an extensive nerve network connecting different nephron segments and organizing glomeruli into distinct communities. These communities are linked through \"mother glomeruli\" that serve as control centers, creating a repeating pattern throughout the cortex. This sophisticated neural organization, which is underdeveloped in newborn kidneys and disrupted in conditions like diabetes and hydronephrosis, appears to facilitate synchronized responses to maintain fluid balance. The findings provide insights into how the kidney's structural architecture enables coordinated function across its numerous nephrons.", "year": "2025", "month": "06", "volume": "16", "issue": "1", "pages": "5161", "doi": "10.1038/s41467-025-60435-8", "link": "https://www.ncbi.nlm.nih.gov/pubmed/40461472", "sort_key": "2025-06-three dimensional mu", "quarter": "q2"}, {"pmid": "40467553", "title": "Single cell profiling of human airway identifies tuft-ionocyte progenitor cells displaying cytokine-dependent differentiation bias in vitro.", "authors": ["Shah VS", "Waghray A", "Lin B", "Bhagwat A", "Monga I", "Slyper M", "Giotti B", "Kim S", "Sun D", "Xu K", "Park E", "Bairakdar M", "Xu J", "Waldman J", "Dionne D", "Nguyen LT", "Lou W", "Cai P", "Muus C", "Sun J", "Surve MV", "Yang LCC", "Rozenblatt-Rosen O", "Delorey TM", "Saladi SV", "Regev A", "Rajagopal J", "Tsankov AM"], "journal": "Nat Commun", "journal_title": "Nature communications", "citation": "Nature communications, 06 2025", "abstract": "Human airways contain specialized rare epithelial cells including CFTR-rich ionocytes that regulate airway surface physiology and chemosensory tuft cells that produce asthma-associated inflammatory mediators. Here, using a lung cell atlas of 311,748 single cell RNA-Seq profiles, we identify 687 ionocytes (0.45%). In contrast to prior reports claiming a lack of ionocytes in the small airways, we demonstrate that ionocytes are present in small and large airways in similar proportions. Surprisingly, we find only 3 mature tuft cells (0.002%), and demonstrate that previously annotated tuft-like cells are instead highly replicative progenitor cells. These tuft-ionocyte progenitor (TIP) cells produce ionocytes as a default lineage. However, Type 2 and Type 17 cytokines divert TIP cell lineage in vitro, resulting in the production of mature tuft cells at the expense of ionocyte differentiation. Our dataset thus provides an updated understanding of airway rare cell composition, and further suggests that clinically relevant cytokines may skew the composition of disease-relevant rare cells.", "year": "2025", "month": "06", "volume": "16", "issue": "1", "pages": "5180", "doi": "10.1038/s41467-025-60441-w", "link": "https://www.ncbi.nlm.nih.gov/pubmed/40467553", "sort_key": "2025-06-single cell profilin", "quarter": "q2"}, {"pmid": "40473305", "title": "Screening relatives of familial pulmonary fibrosis patients: who, when, how and why?", "authors": ["Borie R", "Kropski JA"], "journal": "Eur Respir J", "journal_title": "The European respiratory journal", "citation": "The European respiratory journal, 06 2025", "abstract": "", "year": "2025", "month": "06", "volume": "65", "issue": "6", "pages": "", "doi": "10.1183/13993003.00019-2025", "link": "https://www.ncbi.nlm.nih.gov/pubmed/40473305", "sort_key": "2025-06-screening relatives ", "quarter": "q2"}, {"pmid": "40288291", "title": "Benchmarking HEp-2 cell segmentation methods in indirect immunofluorescence images - standard models to deep learning.", "authors": ["Iyer B", "Deoghare S", "Ranjan K", "Aronow BJ", "Prasath VBS"], "journal": "Comput Biol Med", "journal_title": "Computers in biology and medicine", "citation": "Computers in biology and medicine, 06 2025", "abstract": "Indirect Immunofluorescence (IIF) stained Human Epithelial (HEp-2) cells are considered the gold standard for detecting autoimmune diseases. Accurate cell segmentation, though often viewed as an intermediary step to downstream tasks like classification, significantly enhances overall performance when executed with precision. In this study, we conduct a systematic literature review of HEp-2 cell segmentation techniques, identifying 28 key papers utilizing traditional image processing, machine learning classifiers, deep convolutional neural networks (CNNs), and generative adversarial network (GAN) frameworks. Building on these insights, we benchmark 17 CNN models without pretraining and 8 CNN models pretrained on ImageNet using both Frozen Encoder and Tunable Encoder strategies on the I3A dataset. Cross-validation (CV) and Benjamini-Hochberg (BH) significance correction were employed to ensure statistical rigor in model comparisons. Domain-Specific Pretraining (DSPT) experiments demonstrated performance improvements, particularly for underrepresented classes, while Data Augmentation strategies (DA-1 and DA-2) revealed distinct impacts across model categories. GAN-based segmentation experiments using the top-performing CNN architectures as generators within a Pix2Pix framework revealed performance degradation due to data limitations and adversarial training instabilities. Nonetheless, GANs displayed class-specific improvements in visual alignment of segmentation masks. Results were evaluated comprehensively across eight performance metrics, including Dice, IOU, Accuracy, Precision, Sensitivity, Specificity, AU-ROC and AU-PR. This work offers a robust benchmarking of state-of-the-art CNN, GAN, and Transformer-based models for HEp-2 cell segmentation, providing valuable insights for future research directions, including ensemble approaches, dynamic patch sampling, and diffusion models.", "year": "2025", "month": "06", "volume": "192", "issue": "Pt A", "pages": "110150", "doi": "10.1016/j.compbiomed.2025.110150", "link": "https://www.ncbi.nlm.nih.gov/pubmed/40288291", "sort_key": "2025-06-benchmarking hep-2 c", "quarter": "q2"}, {"pmid": "40512621", "title": "Airway basal stem cells are necessary for the maintenance of functional intraepithelial airway macrophages.", "authors": ["Kooistra T", "Saez B", "Roche M", "Egea-Zorrilla A", "Li D", "Anketell D", "Nguyen N", "Villoria J", "Gillis J", "Petri E", "Vera L", "Blasco-Iturri Z", "Smith NP", "Alladina J", "Zhang Y", "Vinarsky V", "Shivaraju M", "Sheng SL", "Chen M", "Gonzalez-Celeiro M", "Mou H", "Waghray A", "Lin B", "Paksa A", "Yanger K", "Tata PR", "Zhao R", "Causton B", "Zulueta JJ", "Prosper F", "Cho JL", "Villani AC", "Haber A", "Rajagopal J", "Medoff BD", "Pardo-Saganta A"], "journal": "Cell Rep", "journal_title": "Cell reports", "citation": "Cell reports, 06 2025", "abstract": "Stem cells are known to provide signals that contribute to the maintenance and function of neighboring cells. We demonstrate that Notch signaling arising from airway basal stem cells is necessary for the function of a unique population of intraepithelial airway macrophages (IAMs) in the murine trachea. Without this stem cell signaling, IAMs lose MHC II expression, which in turn prevents antigen-induced allergic inflammation. Distal murine airways do not harbor basal stem cells, and, in this region of the lung, allergic inflammation proceeds unperturbed. We speculate that the functional coupling of specific anatomically restricted stem cell populations and adjacent immune cells is one mechanism for ensuring that inflammatory responses are compartmentalized to regions of injury. Basal stem cells are found throughout the human airway tree and we demonstrate the existence of human IAM-like cells, suggesting that their interaction may influence airways disease.", "year": "2025", "month": "06", "volume": "44", "issue": "6", "pages": "115860", "doi": "10.1016/j.celrep.2025.115860", "link": "https://www.ncbi.nlm.nih.gov/pubmed/40512621", "sort_key": "2025-06-airway basal stem ce", "quarter": "q2"}, {"pmid": "40502191", "title": "A spatial transcriptomic atlas of acute neonatal lung injury across development and disease severity.", "authors": ["Mallapragada S", "Lyu R", "Williams-Katek AL", "Fischer BK", "Vannan A", "Hadad N", "Mee ED", "Shirazi SP", "Jetter CS", "Negretti NM", "Hilgendorff A", "Eldredge LC", "Deutsch GH", "McCarthy DJ", "Kropski JA", "Sucre JMS", "Banovich NE"], "journal": "bioRxiv", "journal_title": "bioRxiv : the preprint server for biology", "citation": "bioRxiv : the preprint server for biology, 06 2025", "abstract": "A molecular understanding of lung organogenesis requires delineation of the timing and regulation of the cellular transitions that ultimately form and support a surface capable of gas exchange. While the advent of single-cell transcriptomics has allowed for the discovery and identification of transcriptionally distinct cell populations present during lung development, the spatiotemporal dynamics of these transcriptional shifts remain undefined. With imaging-based spatial transcriptomics, we analyzed the gene expression patterns in 17 human infant lungs at varying stages of development and injury, creating a spatial transcriptomic atlas of ~1.2 million cells. We applied computational clustering approaches to identify shared molecular patterns among this cohort, informing how tissue architecture and molecular spatial relationships are coordinated during development and disrupted in disease. Recognizing that all preterm birth represents an injury to the developing lung, we created a simplified classification scheme that relies upon the routinely collected objective measures of gestational age and life span. Within this framework, we have identified cell type patterns across gestational age and life span variables that would likely be overlooked when using the conventional \"disease vs. control\" binary comparison. Together, these data represent an open resource for the lung research community, supporting discovery-based inquiry and identification of targetable molecular mechanisms in both normal and arrested human lung development.", "year": "2025", "month": "06", "volume": "", "issue": "", "pages": "", "doi": "10.1101/2025.06.02.656433", "link": "https://www.ncbi.nlm.nih.gov/pubmed/40502191", "sort_key": "2025-06-a spatial transcript", "quarter": "q2"}, {"pmid": "40667045", "title": "A multimodal imaging approach for imaging the metabolic changes resulting from bronchopulmonary dysplasia.", "authors": ["Gorman BL", "Li Z", "Deutsch G", "Huyck HL", "Beishembieva N", "Olson H", "Villazon J", "Yu P", "Pryhuber GS", "Clair G", "Shi L", "Anderton CR"], "journal": "bioRxiv", "journal_title": "bioRxiv : the preprint server for biology", "citation": "bioRxiv : the preprint server for biology, 06 2025", "abstract": "Lung tissue is composed of various functional units, each essential for maintaining the intricate functions of the lung. Disruptions in the molecular and cellular mechanisms in the lung can cause tissue fibrosis, inflammation, and severe breathing difficulties, which are common in conditions such as bronchopulmonary dysplasia (BPD). BPD's molecular changes are not well understood, which hinders effective diagnosis and treatment. Here, we present a new multimodal imaging workflow for detailed molecular and metabolic characterization of tissues at multiple spatial scales. We applied a combined imaging approach using matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) and ultrafast focused light-based imaging & photonics platform (U-FLIP) that included two-photon fluorescence (TPF), second harmonic generation (SHG), and stimulated Raman scattering (SRS). We also developed a hierarchical multimodal registration network (HiMReg) for the precise co-registration of each modality. This approach revealed previously unknown metabolic changes in distinct functional tissue units affected by BPD, including altered lipid distributions, reduced optical redox states, and specific collagen remodeling in bronchioles. Our findings evidenced alterations in lipid composition and metabolism of BPD-affected alveoli compared to healthy tissue, providing novel insights into disease pathophysiology. Our findings elucidate the intricate spatial and molecular complexity of BPD, building on prior research that did not provide the spatial resolution necessary to capture the nuances of metabolic alterations. This multimodal approach offers exceptional insights into disease exploration and could transform the way we study spatially heterogeneous conditions. By providing detailed maps of the metabolic shifts occurring in distinct tissue microanatomical features, the methods developed here could enable the discovery of new therapeutic avenues, making it highly attractive for the field of biomedical research.", "year": "2025", "month": "06", "volume": "", "issue": "", "pages": "", "doi": "10.1101/2025.06.16.660017", "link": "https://www.ncbi.nlm.nih.gov/pubmed/40667045", "sort_key": "2025-06-a multimodal imaging", "quarter": "q2"}, {"pmid": "39642382", "title": "From Epithelium to Therapy: Transitional Cells in Lung Fibrosis.", "authors": ["Shin SY", "Chen J", "Milman Krentsis I", "Reisner Y", "Abrencillo R", "Hussain R", "Wu D", "Karmouty-Quintana H"], "journal": "Am J Respir Cell Mol Biol", "journal_title": "American journal of respiratory cell and molecular biology", "citation": "American journal of respiratory cell and molecular biology, 05 2025", "abstract": "Patients with idiopathic pulmonary fibrosis and lung fibrosis secondary to infections such as influenza A and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have limited treatment options outside of supportive therapy and lung transplantation. Multiple lung stem cell populations have been implicated in the pathogenesis of lung fibrosis, and more progenitor cell populations continue to be discovered and characterized. In this review, we summarize the functions and differentiation pathways of various cells that constitute the lung epithelium. We then focus on two subpopulations of KRT5+ or KRT8+ transitional cells that both originate from alveolar type II cells but experience different cell fates and play important roles in lung regeneration and repair. We address these transitional cells' potential role in fibrosis and bronchiolization of the alveoli, as they are correlated to aggregate near fibrotic foci in both in vivo models and in human fibrotic lung disease. We conclude by discussing recent advances in cell and organoid therapy to replace aberrant transitional cells and treat lung fibrosis. Namely, we focus on strategies to minimize immune clearance of transplanted cells and to optimize engraftment by transplanting cells precultured as three-dimensional organoids.", "year": "2025", "month": "05", "volume": "72", "issue": "5", "pages": "472-483", "doi": "10.1165/rcmb.2024-0372TR", "link": "https://www.ncbi.nlm.nih.gov/pubmed/39642382", "sort_key": "2025-05-from epithelium to t", "quarter": "q2"}, {"pmid": "39447176", "title": "Cell Population-resolved Multiomics Atlas of the Developing Lung.", "authors": ["Ushakumary MG", "Feng S", "Bandyopadhyay G", "Olson H", "Weitz KK", "Huyck HL", "Poole C", "Purkerson JM", "Bhattacharya S", "Ljungberg MC", "Mariani TJ", "Deutsch GH", "Misra RS", "Carson JP", "Adkins JN", "Pryhuber GS", "Clair G"], "journal": "Am J Respir Cell Mol Biol", "journal_title": "American journal of respiratory cell and molecular biology", "citation": "American journal of respiratory cell and molecular biology, 05 2025", "abstract": "The lung is a vital organ that undergoes extensive morphological and functional changes during postnatal development. To disambiguate how different cell populations contribute to organ development, we performed proteomic and transcriptomic analyses of four sorted cell populations from the lung of human subjects 0-8 years of age with a focus on early life. The cell populations analyzed included epithelial, endothelial, mesenchymal, and immune cells. Our results revealed distinct molecular signatures for each of the sorted cell populations that enable the description of molecular shifts occurring in these populations during postnatal development. We confirmed that the proteome of the different cell populations was distinct regardless of age and identified functions specific to each population. We identified a series of cell population protein markers, including those located at the cell surface, that show differential expression and distribution on RNA in situ hybridization and immunofluorescence imaging. We validated the spatial distribution of alveolar type 1 and endothelial cell surface markers. Temporal analyses of the proteomes of the four populations revealed processes modulated during postnatal development and clarified the findings obtained from whole-tissue proteome studies. Finally, the proteome was compared with a transcriptomics survey performed on the same lung samples to evaluate processes under post-transcriptional control.", "year": "2025", "month": "05", "volume": "72", "issue": "5", "pages": "484-495", "doi": "10.1165/rcmb.2024-0105OC", "link": "https://www.ncbi.nlm.nih.gov/pubmed/39447176", "sort_key": "2025-05-cell population-reso", "quarter": "q2"}, {"pmid": "40442177", "title": "Bronchopulmonary dysplasia with pulmonary hypertension associates with semaphorin signaling loss and functionally decreased FOXF1 expression.", "authors": ["Shirazi SP", "Negretti NM", "Jetter CS", "Sharkey AL", "Garg S", "Kapp ME", "Wilkins D", "Fortier G", "Mallapragada S", "Banovich NE", "Eldredge LC", "Deutsch GH", "Wright CVE", "Frank DB", "Kropski JA", "Sucre JMS"], "journal": "Nat Commun", "journal_title": "Nature communications", "citation": "Nature communications, 05 2025", "abstract": "Lung injury in preterm infants leads to structural and functional respiratory deficits, with a risk for bronchopulmonary dysplasia (BPD) that in its most severe form is accompanied by pulmonary hypertension (PH). To identify potential cellular and molecular drivers of BPD in humans, we performed single-cell RNA sequencing of preterm infant lungs with evolving BPD and BPD + PH compared to term infants. Examination of endothelial cells reveals a unique, aberrant capillary cell-state in BPD + PH defined by ANKRD1 expression. Within the alveolar parenchyma in infants with BPD/BPD + PH, predictive signaling analysis identifies surprising deficits in the semaphorin guidance-cue pathway, with decreased expression of pro-angiogenic transcription factor FOXF1. Loss of semaphorin signaling is replicated in a murine BPD model and in humans with causal FOXF1 mutations for alveolar capillary dysplasia (ACDMPV), suggesting a mechanistic link between developmental programs underlying BPD and ACDMPV and uncovering a critical role for semaphorin signaling in normal lung development.", "year": "2025", "month": "05", "volume": "16", "issue": "1", "pages": "5004", "doi": "10.1038/s41467-025-60371-7", "link": "https://www.ncbi.nlm.nih.gov/pubmed/40442177", "sort_key": "2025-05-bronchopulmonary dys", "quarter": "q2"}, {"pmid": "40138968", "title": "Advancements in automated nuclei segmentation for histopathology using you only look once-driven approaches: A systematic review.", "authors": ["Debsarkar SS", "Aronow B", "Prasath VBS"], "journal": "Comput Biol Med", "journal_title": "Computers in biology and medicine", "citation": "Computers in biology and medicine, 05 2025", "abstract": "Histopathology image analysis plays a pivotal role in disease diagnosis and treatment planning, relying heavily on accurate nuclei segmentation for extracting vital cellular information. In recent years, artificial intelligence (AI) and in particular deep learning models have been applied successfully in solving computational pathology image analysis tasks. The You Only Look Once (YOLO) object detection framework, which is based on a convolutional neural network (CNN) architecture has gained traction across various domains for its real-time processing capabilities. This systematic review aims to comprehensively explore and evaluate the advancements, challenges, and applications of YOLO-based methodologies in nuclei segmentation within the domain of histopathological images. The review encompasses a structured analysis of recent literature, focusing on the utilization of YOLO variants for nuclei segmentation. Key methodologies, training strategies, dataset specifics, and performance metrics are evaluated to elucidate the strengths and limitations of YOLO in this context. Additionally, the review highlights the unique characteristics of YOLO that enable efficient object detection and delineation of nuclei structures, offering a comparative analysis against traditional segmentation approaches. This systematic review underscores the promising outcomes achieved through YOLO-based architectures, emphasizing their potential for accurate and rapid nuclei segmentation. Furthermore, it identifies persistent challenges such as handling variances in nuclei appearances, optimizing model architectures for histopathological images, and improving generalization across diverse datasets. Insights derived from this review can provide a foundation for future research directions and enhancements in nuclei segmentation methodologies using YOLO within histopathology, fostering advancements in disease diagnosis and biomedical research.", "year": "2025", "month": "05", "volume": "190", "issue": "", "pages": "110072", "doi": "10.1016/j.compbiomed.2025.110072", "link": "https://www.ncbi.nlm.nih.gov/pubmed/40138968", "sort_key": "2025-05-advancements in auto", "quarter": "q2"}, {"pmid": "40475598", "title": "A Multimodal Spatial and Epigenomic Atlas of Human Adult Lung Topography.", "authors": ["Duong TE", "Diep D", "Conklin KY", "Bui I", "Purkerson JM", "Boone E", "Olness J", "Patel S", "Peng B", "Kern C", "Zhao Z", "Misra RS", "Huyck HL", "Verheyden JM", "Borok Z", "Zhang Y", "Scheuermann RH", "Zhu Q", "Deutsch G", "Hagood J", "Sun X", "Zhang K", "Pryhuber GS"], "journal": "bioRxiv", "journal_title": "bioRxiv : the preprint server for biology", "citation": "bioRxiv : the preprint server for biology, 05 2025", "abstract": "Developing high-resolution reference maps of disease-susceptible spatial niches is a critical step to mitigating the profound effects of lung disease. Here, we present an integrated multimodal single-nucleus human lung atlas (snHLA) profiling 746,047 nuclei from 49 mapped lung blocks spanning clinically relevant distal airways, alveoli, and interstitium across 11 healthy adults. Integrating snRNA-seq and SNARE-seq2, which co-assays chromatin accessibility and gene expression from the same nucleus, we resolved 70 molecularly distinct populations and captured 332,846 accessible chromatin regions, nominating new transcriptional regulators of human lung cell diversity. Spatial transcriptomics using MERFISH mapped 25 cell populations across 7 structural neighborhoods and multiplexed immunofluorescence localized cell subtypes and distal airway-defining protein markers, expanding and validating distinct lung structure-specific cell populations. This open access snHLA and companion Cell Type and Marker Gene Dictionary with anatomically aligned nomenclature delivers a foundational resource at an unprecedented resolution to interrogate the origins of lung pathophysiology.", "year": "2025", "month": "05", "volume": "", "issue": "", "pages": "", "doi": "10.1101/2025.05.23.655666", "link": "https://www.ncbi.nlm.nih.gov/pubmed/40475598", "sort_key": "2025-05-a multimodal spatial", "quarter": "q2"}, {"pmid": "40082611", "title": "Human BioMolecular Atlas Program (HuBMAP): 3D Human Reference Atlas construction and usage.", "authors": ["B\u00f6rner K", "Blood PD", "Silverstein JC", "Ruffalo M", "Satija R", "Teichmann SA", "Pryhuber GJ", "Misra RS", "Purkerson JM", "Fan J", "Hickey JW", "Molla G", "Xu C", "Zhang Y", "Weber GM", "Jain Y", "Qaurooni D", "Kong Y", "HRA Team", "Bueckle A", "Herr BW"], "journal": "Nat Methods", "journal_title": "Nature methods", "citation": "Nature methods, 04 2025", "abstract": "The Human BioMolecular Atlas Program (HuBMAP) aims to construct a 3D Human Reference Atlas (HRA) of the healthy adult body. Experts from 20+ consortia collaborate to develop a Common Coordinate Framework (CCF), knowledge graphs and tools that describe the multiscale structure of the human body (from organs and tissues down to cells, genes and biomarkers) and to use the HRA to characterize changes that occur with aging, disease and other perturbations. HRA v.2.0 covers 4,499 unique anatomical structures, 1,195 cell types and 2,089 biomarkers (such as genes, proteins and lipids) from 33 ASCT+B tables and 65 3D Reference Objects linked to ontologies. New experimental data can be mapped into the HRA using (1) cell type annotation tools (for example, Azimuth), (2) validated antibody panels or (3) by registering tissue data spatially. This paper describes HRA user stories, terminology, data formats, ontology validation, unified analysis workflows, user interfaces, instructional materials, application programming interfaces, flexible hybrid cloud infrastructure and previews atlas usage applications.", "year": "2025", "month": "04", "volume": "22", "issue": "4", "pages": "845-860", "doi": "10.1038/s41592-024-02563-5", "link": "https://www.ncbi.nlm.nih.gov/pubmed/40082611", "sort_key": "2025-04-human biomolecular a", "quarter": "q2"}, {"pmid": "39901013", "title": "Spatial transcriptomics identifies molecular niche dysregulation associated with distal lung remodeling in pulmonary fibrosis.", "authors": ["Vannan A", "Lyu R", "Williams AL", "Negretti NM", "Mee ED", "Hirsh J", "Hirsh S", "Hadad N", "Nichols DS", "Calvi CL", "Taylor CJ", "Polosukhin VV", "Serezani APM", "McCall AS", "Gokey JJ", "Shim H", "Ware LB", "Bacchetta MJ", "Shaver CM", "Blackwell TS", "Walia R", "Sucre JMS", "Kropski JA", "McCarthy DJ", "Banovich NE"], "journal": "Nat Genet", "journal_title": "Nature genetics", "citation": "Nature genetics, 03 2025", "abstract": "Large-scale changes in the structure and cellular makeup of the distal lung are a hallmark of pulmonary fibrosis (PF), but the spatial contexts that contribute to disease pathogenesis have remained uncertain. Using image-based spatial transcriptomics, we analyzed the gene expression of 1.6 million cells from 35 unique lungs. Through complementary cell-based and innovative cell-agnostic analyses, we characterized the localization of PF-emergent cell types, established the cellular and molecular basis of classical PF histopathologic features and identified a diversity of distinct molecularly defined spatial niches in control and PF lungs. Using machine learning and trajectory analysis to segment and rank airspaces on a gradient of remodeling severity, we identified compositional and molecular changes associated with progressive distal lung pathology, beginning with alveolar epithelial dysregulation and culminating with changes in macrophage polarization. Together, these results provide a unique, spatially resolved view of PF and establish methods that could be applied to other spatial transcriptomic studies.", "year": "2025", "month": "03", "volume": "57", "issue": "3", "pages": "647-658", "doi": "10.1038/s41588-025-02080-x", "link": "https://www.ncbi.nlm.nih.gov/pubmed/39901013", "sort_key": "2025-03-spatial transcriptom", "quarter": "q1"}, {"pmid": "40166356", "title": "Sorted-Cell Proteomics Reveals an AT1-Associated Epithelial Cornification Phenotype and Suggests Endothelial Redox Imbalance in Human Bronchopulmonary Dysplasia.", "authors": ["Ushakumary MG", "Chrisler WB", "Bandyopadhyay G", "Huyck H", "Gorman BL", "Beishembieva N", "Pitonza A", "Lai ZJ", "Fillmore TL", "Attah IK", "Dylag AM", "Misra R", "Carson JP", "Adkins JN", "Pryhuber GS", "Clair G"], "journal": "bioRxiv", "journal_title": "bioRxiv : the preprint server for biology", "citation": "bioRxiv : the preprint server for biology, 03 2025", "abstract": "UNLABELLED: Bronchopulmonary dysplasia (BPD) is a neonatal lung disease characterized by inflammation and scarring leading to long-term tissue damage. Previous whole tissue proteomics identified BPD-specific proteome changes and cell type shifts. Little is known about the proteome-level changes within specific cell populations in disease. Here, we sorted epithelial (EPI) and endothelial (ENDO) cell populations based on their differential surface markers from normal and BPD human lungs. Using a low-input compatible sample preparation method (MicroPOT), proteins were extracted and digested into peptides and subjected to Liquid Chromatography-tandem Mass Spectrometry (LC-MS/MS) proteome analysis. Of the 4,970 proteins detected, 293 were modulated in abundance or detection in the EPI population and 422 were modulated in ENDO cells. Modulation of proteins associated with actin-cytoskeletal function such as SCEL, LMO7, and TBA1B were observed in the BPD EPIs. Using confocal imaging and analysis, we validated the presence of aberrant multilayer-like structures comprising SCEL and LMO7, known to be associated with epidermal cornification, in the human BPD lung. This is the first report of accumulation of cornification-associated proteins in BPD. Their localization in the alveolar parenchyma, primarily associated with alveolar type 1 (AT1) cells, suggests a role in the BPD post-injury response. In the ENDOs, redox balance and mitochondrial function pathways were modulated. Alternative mRNA splicing and cell proliferative functions were elevated in both populations suggesting potential dysregulation of cell progenitor fate. This study characterized the proteome of epithelial and endothelial cells from the BPD lung for the first time, identifying population-specific changes in BPD pathogenesis. NEW & NOTEWORTHY: The study is the first to perform proteomics on sorted pulmonary epithelial and endothelial populations from BPD and age-matched control human donors. We identified an increase in cornification-associated proteins in BPD (e.g., SCEL and LMO7), and evidenced the presence of multilayered structures unique to BPD alveolar regions, associated with alveolar type 1 (AT1) cells. By changing the nature and/or biomechanical properties of the epithelium, these structures may alter the behavior of other alveolar cell types potentially contributing to the arrested alveolarization observed in BPD. Lastly, our data suggest the modulation of cell proliferation and redox homeostasis in BPD providing potential mechanisms for the reduced vascular growth associated with BPD.", "year": "2025", "month": "03", "volume": "", "issue": "", "pages": "", "doi": "10.1101/2025.03.20.644398", "link": "https://www.ncbi.nlm.nih.gov/pubmed/40166356", "sort_key": "2025-03-sorted-cell proteomi", "quarter": "q1"}, {"pmid": "40087882", "title": "Innate Immunity and Asthma Exacerbations: Insights From Human Models.", "authors": ["Alladina J", "Medoff BD", "Cho JL"], "journal": "Immunol Rev", "journal_title": "Immunological reviews", "citation": "Immunological reviews, 03 2025", "abstract": "Asthma is a common chronic respiratory disease characterized by the presence of airway inflammation, airway hyperresponsiveness, and mucus hypersecretion. Repeated asthma exacerbations can lead to progressive airway remodeling and irreversible airflow obstruction. Thus, understanding and preventing asthma exacerbations are of paramount importance. Although multiple endotypes exist, asthma is most often driven by type 2 airway inflammation. New therapies that target specific type 2 mediators have been shown to reduce the frequency of asthma exacerbations but are incompletely effective in a significant number of asthmatics. Furthermore, it remains unknown whether current treatments lead to sustained changes in the airway or if targeting additional pathways may be necessary to achieve asthma remission. Activation of innate immunity is the initial event in the inflammatory sequence that occurs during an asthma exacerbation. However, there continue to be critical gaps in our understanding of the innate immune response to asthma exacerbating factors. In this review, we summarize the current understanding of the role of innate immunity in asthma exacerbations and the methods used to study them. We also identify potential novel therapeutic targets for asthma and future areas for investigation.", "year": "2025", "month": "03", "volume": "330", "issue": "1", "pages": "e70016", "doi": "10.1111/imr.70016", "link": "https://www.ncbi.nlm.nih.gov/pubmed/40087882", "sort_key": "2025-03-innate immunity and ", "quarter": "q1"}, {"pmid": "40226365", "title": "Development of a 3D bioengineered human lung submucosal gland ductal airway model to study mucociliary clearance in vitro.", "authors": ["Kim H", "Yi S", "Liyanage P", "Zhao S", "Wikenheiser-Brokamp KA", "McMillin L", "Xu Y", "Kitzmiller JA", "Whitsett JA", "Naren AP", "Mun KS"], "journal": "Cell Biomater", "journal_title": "Cell biomaterials", "citation": "Cell biomaterials, 03 2025", "abstract": "Mucociliary clearance (MCC) is critical in maintaining lung health and preventing respiratory infections. MCC is impaired in people with cystic fibrosis, due to accumulation of thick, sticky mucus resulting from defective cystic fibrosis transmembrane conductance regulator channel function. In this study, we developed a unique 3D lung submucosal gland ductal airway model utilizing primary human submucosal gland epithelial cells, which enables the formation of physiologically relevant architecture of the ductal epithelium including ciliary cells within a 3D bioprinted scaffold. Our observation demonstrates that this model not only enables the fabrication of human lung submucosal gland ductal airway-like structure mimicking in vivo physiology, also facilitates quantitative measurement of patient-specific MCC and determines pharmacological effects. Our results suggest that this model could be a valuable tool for understanding mechanisms underlying impaired MCC and testing the efficacy of novel therapeutic strategies for the treatment of respiratory diseases such as cystic fibrosis.", "year": "2025", "month": "03", "volume": "1", "issue": "2", "pages": "", "doi": "10.1016/j.celbio.2025.100013", "link": "https://www.ncbi.nlm.nih.gov/pubmed/40226365", "sort_key": "2025-03-development of a 3d ", "quarter": "q1"}, {"pmid": "39494998", "title": "Obesity Uncovers the Presence of Inflammatory Lung Macrophage Subsets With an Adipose Tissue Transcriptomic Signature in Influenza Virus Infection.", "authors": ["Alarcon PC", "Ulanowicz CJ", "Damen MSMA", "Eom J", "Sawada K", "Chung H", "Alahakoon T", "Oates JR", "Wayland JL", "Stankiewicz TE", "Moreno-Fernandez ME", "Zacharias WJ", "Salomonis N", "Divanovic S"], "journal": "J Infect Dis", "journal_title": "The Journal of infectious diseases", "citation": "The Journal of infectious diseases, 02 2025", "abstract": "Obesity is an independent risk factor for increased disease severity during influenza A virus (IAV) infection. White adipose tissue (WAT) inflammation promotes disease pathogenesis in obesity. Whether obesity modifies lung and WAT immune cells to amplify influenza severity is unknown. We show that obesity establishes a proinflammatory transcriptome in lung immune cells that is augmented during IAV infection and that IAV infection changes WAT immune cell milieu in obesity. Notably, a decrease in WAT macrophages (ATM) inversely correlates with an increase in infiltrating lung macrophages in obese IAV-infected mice. Further analyses of lung immune cell uncovered a macrophage subset that shares a transcriptomic signature with inflammatory ATMs. Importantly, adoptive transfer of ATMs from obese mice into lean IAV infected mice promotes host immune cell infiltration to the lungs. These findings suggest that, in an obese state, ATMs may exacerbate the inflammatory milieu important in pathologic responses to IAV infection.", "year": "2025", "month": "02", "volume": "231", "issue": "2", "pages": "e317-e327", "doi": "10.1093/infdis/jiae535", "link": "https://www.ncbi.nlm.nih.gov/pubmed/39494998", "sort_key": "2025-02-obesity uncovers the", "quarter": "q1"}, {"pmid": "39818203", "title": "Longitudinal single-cell profiles of lung regeneration after viral infection reveal persistent injury-associated cell states.", "authors": ["Niethamer TK", "Planer JD", "Morley MP", "Babu A", "Zhao G", "Basil MC", "Cantu E", "Frank DB", "Diamond JM", "Nottingham AN", "Li S", "Sharma A", "Hallquist H", "Levin LI", "Zhou S", "Vaughan AE", "Morrisey EE"], "journal": "Cell Stem Cell", "journal_title": "Cell stem cell", "citation": "Cell stem cell, 02 2025", "abstract": "Functional regeneration of the lung's gas exchange surface following injury requires the coordination of a complex series of cell behaviors within the alveolar niche. Using single-cell transcriptomics combined with lineage tracing of proliferating progenitors, we examined mouse lung regeneration after influenza injury, demonstrating an asynchronously phased response across different cellular compartments. This longitudinal atlas of injury responses has produced a catalog of transient and persistent transcriptional alterations in cells as they transit across axes of differentiation. These cell states include an injury-induced capillary endothelial cell (iCAP) that arises after injury, persists indefinitely, and shares hallmarks with developing lung endothelium and endothelial aberrations found in degenerative human lung diseases. This dataset provides a foundational resource to understand the complexity of cellular and molecular responses to injury and correlations to responses found in human development and disease.", "year": "2025", "month": "02", "volume": "32", "issue": "2", "pages": "302-321.e6", "doi": "10.1016/j.stem.2024.12.002", "link": "https://www.ncbi.nlm.nih.gov/pubmed/39818203", "sort_key": "2025-02-longitudinal single-", "quarter": "q1"}, {"pmid": "39189851", "title": "Toll-like Receptor 9 Inhibition Mitigates Fibroproliferative Responses in Translational Models of Pulmonary Fibrosis.", "authors": ["Trujillo G", "Regueiro-Ren A", "Liu C", "Hu B", "Sun Y", "Ahangari F", "Fiorini V", "Ishikawa G", "Al Jumaily K", "Khoury J", "McGovern J", "Lee CJ", "Peng XY", "Pivarnik T", "Sun H", "Walia A", "Woo S", "Yu S", "Antin-Ozerkis DE", "Sauler M", "Kaminski N", "Herzog EL", "Ryu C"], "journal": "Am J Respir Crit Care Med", "journal_title": "American journal of respiratory and critical care medicine", "citation": "American journal of respiratory and critical care medicine, 01 2025", "abstract": "Rationale: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease for which current treatment options only slow clinical progression. Previously, we identified a subset of patients with IPF with an accelerated disease course associated with fibroblast expression of Toll-like receptor 9 (TLR9) mediated by interactions with its ligand mitochondrial DNA. Objectives: We aimed to show that TLR9 activation induces fibroproliferative responses that are abrogated by its antagonism by using two commercially available indirect inhibitors and a proprietary, selective direct small-molecule inhibitor. Methods: We employed two independent cohorts of patients with IPF, multiple in vitro fibroblast cell culture platforms, an in vivo mouse model, and an ex vivo human precision-cut lung slices system to investigate the clinical and biologic significance of TLR9 in this disease. Measurements and Main Results: In two independent IPF cohorts, plasma mitochondrial DNA activates TLR9 in a manner associated with the expression of monocyte chemoattractant protein 1, IL-6, tumor necrosis factor-\u03b1, and IFN-\u03b3-inducible protein 10 and worsened transplant-free survival. Our cell culture platform showed that TLR9 mediates fibroblast activation via transforming growth factor-\u03b21 and stiff substrates and that its antagonism, particularly direct inhibition, ameliorates this process, including production of these TLR9-associated pharmacodynamic endpoints. We further demonstrated that direct TLR9 inhibition mitigates these fibroproliferative responses in our in vivo and ex vivo models of pulmonary fibrosis. Conclusions: In this novel study, we found that direct TLR9 inhibition mitigates fibroproliferative responses in preclinical models of pulmonary fibrosis. Our work demonstrates the therapeutic potential of direct TLR9 antagonism in IPF and related fibrotic lung diseases.", "year": "2025", "month": "01", "volume": "211", "issue": "1", "pages": "91-102", "doi": "10.1164/rccm.202401-0065OC", "link": "https://www.ncbi.nlm.nih.gov/pubmed/39189851", "sort_key": "2025-01-toll-like receptor 9", "quarter": "q1"}, {"pmid": "39780400", "title": "Single-cell analysis of lung epithelial cells reveals age and cell population-specific responses to SARS-CoV-2 infection in ciliated cells.", "authors": ["Osborn RM", "Anderson CS", "Leach JR", "Chu C", "Dewhurst S", "Mariani TJ", "Thakar J"], "journal": "Clin Exp Immunol", "journal_title": "Clinical and experimental immunology", "citation": "Clinical and experimental immunology, 01 2025", "abstract": "INTRODUCTION: The ability of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to evade antiviral immune signaling in the airway contributes to the severity of coronavirus disease 2019 (COVID-19). Additionally, COVID-19 is influenced by age and has more severe presentations in older individuals. Hence we investigate the role of innate immune signaling as a function of lung development and age. METHOD: We investigated the transcriptome of the airway epithelium using pediatric and adult lung tissue samples from the LungMAP Human Tissue Core Biorepository. Specifically, lung lobes were digested and cultured into a biomimetic model of the airway epithelium on an air-liquid interface. Cells were then infected with SARS-CoV-2 and subjected to single-cell RNA sequencing. The data was analyzed using Seurat, scType, Monacle and tools to infer cell-cell communication. RESULTS: The clustering analysis identified following six cell populations: club cells, proliferating epithelial cells, multiciliated precursor cells, ionocytes, and two biologically distinct clusters of ciliated cells (FOXJ1high and FOXJ1low). Interestingly, the two ciliated cell clusters showed different infection rates and enrichment of processes involved in ciliary biogenesis and function; we observed a cell-type-specific suppression of innate immunity in infected cells from the FOXJ1low subset. We also identified a significant number of genes that were differentially expressed in lung cells derived from children as compared to adults, suggesting the differential pathogenesis of SARS-CoV-2 infection in children versus adults. CONCLUSION: This work reveals age dependent differences in the lung epithelial cell response to SARS-CoV-2 infection. The results can be used to identify drug targets to modulate molecular signaling cascades that mediate an innate immune response.", "year": "2025", "month": "01", "volume": "219", "issue": "1", "pages": "", "doi": "10.1093/cei/uxae118", "link": "https://www.ncbi.nlm.nih.gov/pubmed/39780400", "sort_key": "2025-01-single-cell analysis", "quarter": "q1"}, {"pmid": "39499861", "title": "Precision-Cut Lung Slices: Emerging Tools for Preclinical and Translational Lung Research: An Official American Thoracic Society Workshop Report.", "authors": ["Lehmann M", "Krishnan R", "Sucre J", "Kulkarni HS", "Pineda RH", "Anderson C", "Banovich NE", "Behrsing HP", "Dean CH", "Haak A", "Gosens R", "Kaminski N", "Zagorska A", "Koziol-White C", "Metcalf JP", "Kim YH", "Loebel C", "Neptune E", "Noel A", "Raghu G", "Sewald K", "Sharma A", "Suki B", "Sperling A", "Tatler A", "Turner S", "Rosas IO", "Van Ry P", "Wille T", "Randell SH", "Pryhuber G", "Rojas M", "Bourke J", "K\u00f6nigshoff M"], "journal": "Am J Respir Cell Mol Biol", "journal_title": "American journal of respiratory cell and molecular biology", "citation": "American journal of respiratory cell and molecular biology, 01 2025", "abstract": "The urgent need for effective treatments for acute and chronic lung diseases underscores the significance of developing innovative preclinical human research tools. The 2023 American Thoracic Society Workshop on Precision-Cut Lung Slices (PCLSs) brought together 35 experts to discuss and address the role of human tissue-derived PCLSs as a unique tool for target and drug discovery and validation in pulmonary medicine. With increasing interest and usage, together with advancements in methods and technology, there is a growing need for consensus on PCLS methodology and readouts. The current document recommends standard reporting criteria and emphasizes the requirement for careful collection and integration of clinical metadata. We further discuss current clinically relevant readouts that can be applied to PCLSs and highlight recent developments and future steps for implementing novel technologies for PCLS modeling and analysis. The collection and correlation of clinical metadata and multiomic analysis will further advance the integration of this preclinical platform into patient endotyping and the development of tailored therapies for patients with lung disease.", "year": "2025", "month": "01", "volume": "72", "issue": "1", "pages": "16-31", "doi": "10.1165/rcmb.2024-0479ST", "link": "https://www.ncbi.nlm.nih.gov/pubmed/39499861", "sort_key": "2025-01-precision-cut lung s", "quarter": "q1"}, {"pmid": "39565217", "title": "Impact of Viral Lower Respiratory Tract Infection (LRTI) in Early Childhood (0-2 Years) on Lung Growth and Development and Lifelong Trajectories of Pulmonary Health: A National Institutes of Health (NIH) Workshop Summary.", "authors": ["Deshmukh H", "Whitsett J", "Zacharias W", "Way SS", "Martinez FD", "Mizgerd J", "Pryhuber G", "Ambalavanan N", "Bacharier L", "Natarajan A", "Tamburro R", "Lin S", "Randolph A", "Nino G", "Mejias A", "Ramilo O", "NIH Workshop Participants of the \u2018Viral Lower Respiratory Tract Infections in Infancy and Early Childhood\u2010Immunological and Developmental Aspects\u2019"], "journal": "Pediatr Pulmonol", "journal_title": "Pediatric pulmonology", "citation": "Pediatric pulmonology, 01 2025", "abstract": "Viral lower respiratory tract infections (LRTI) are ubiquitous in early life. They are disproportionately severe in infants and toddlers (0-2 years), leading to more than 100,000 hospitalizations in the United States per year. The recent relative resilience to severe Coronavirus disease (COVID-19) observed in young children is surprising. These observations, taken together, underscore current knowledge gaps in the pathogenesis of viral lower respiratory tract diseases in young children and respiratory developmental immunology. Further, early-life respiratory viral infections could have a lasting impact on lung development with potential life-long pulmonary sequelae. Modern molecular methods, including high-resolution spatial and single-cell technologies, in concert with longitudinal observational studies beginning in the prenatal period and continuing into early childhood, promise to elucidate developmental pulmonary and immunophenotypes following early-life viral infections and their impact on trajectories of future respiratory health. In November 2019, under the auspices of a multi-disciplinary Workshop convened by the National Heart Lung Blood Institute and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, experts came together to highlight the challenges of respiratory viral infections, particularly in early childhood, and emphasize the knowledge gaps in immune, virological, developmental, and clinical factors that contribute to disease severity and long-term pulmonary morbidity from viral LRTI in children. We hope that the scientific community will view these challenges in clinical care on pulmonary health trajectories and disease burden not as a window of susceptibility but as a window of opportunity.", "year": "2025", "month": "01", "volume": "60", "issue": "1", "pages": "e27357", "doi": "10.1002/ppul.27357", "link": "https://www.ncbi.nlm.nih.gov/pubmed/39565217", "sort_key": "2025-01-impact of viral lowe", "quarter": "q1"}, {"pmid": "39772774", "title": "Hypoxia-inducible factor 2 regulates alveolar regeneration after repetitive injury in three-dimensional cellular and in vivo models.", "authors": ["McCall AS", "Gutor S", "Tanjore H", "Burman A", "Sherrill T", "Chapman M", "Calvi CL", "Han D", "Camarata J", "Hunt RP", "Nichols D", "Banovich NE", "Lawson WE", "Gokey JJ", "Kropski JA", "Blackwell TS"], "journal": "Sci Transl Med", "journal_title": "Science translational medicine", "citation": "Science translational medicine, 01 2025", "abstract": "Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease in which repetitive epithelial injury and incomplete alveolar repair result in accumulation of profibrotic intermediate/transitional \"aberrant\" epithelial cell states. The mechanisms leading to the emergence and persistence of aberrant epithelial populations in the distal lung remain incompletely understood. By interrogating single-cell RNA sequencing (scRNA-seq) data from patients with IPF and a mouse model of repeated lung epithelial injury, we identified persistent activation of hypoxia-inducible factor (HIF) signaling in these aberrant epithelial cells. Using mouse genetic lineage-tracing strategies together with scRNA-seq, we found that these disease-emergent aberrant epithelial cells predominantly arose from airway-derived (Scgb1a1-CreER-traced) progenitors and exhibited transcriptional programs of Hif2a activation. In mice treated with repetitive intratracheal bleomycin, deletion of Epas1 (Hif2a) but not Hif1a, from airway-derived progenitors, or administration of the small-molecule HIF2 inhibitor PT-2385, using both prevention and rescue approaches, attenuated experimental lung fibrosis, reduced the appearance of aberrant epithelial cells, and promoted alveolar repair. In mouse alveolar organoids, genetic or pharmacologic inhibition of Hif2 promoted alveolar differentiation of airway-derived epithelial progenitors. In addition, treatment of human distal lung organoids with PT-2385 increased colony-forming efficiency, enhanced protein and transcriptional markers of alveolar type 2 epithelial cell maturation, and prevented the emergence of aberrant epithelial cells. Together, these studies showed that HIF2 activation drives the emergence of aberrant epithelial populations after repetitive injury and that targeted HIF2 inhibition may represent an effective therapeutic strategy to promote functional alveolar repair in IPF and other interstitial lung diseases.", "year": "2025", "month": "01", "volume": "17", "issue": "780", "pages": "eadk8623", "doi": "10.1126/scitranslmed.adk8623", "link": "https://www.ncbi.nlm.nih.gov/pubmed/39772774", "sort_key": "2025-01-hypoxia-inducible fa", "quarter": "q1"}, {"pmid": "39773701", "title": "Epithelial outgrowth through mesenchymal rings drives lung alveologenesis.", "authors": ["Negretti NM", "Son Y", "Crooke P", "Plosa EJ", "Benjamin JT", "Jetter CS", "Bunn C", "Mignemi N", "Marini J", "Hackett AN", "Ransom M", "Garg S", "Nichols D", "Guttentag SH", "Pua HH", "Blackwell TS", "Zacharias W", "Frank DB", "Kozub JA", "Mahadevan-Jansen A", "Krystofiak E", "Kropski JA", "Wright CV", "Millis B", "Sucre JM"], "journal": "JCI Insight", "journal_title": "JCI insight", "citation": "JCI insight, 01 2025", "abstract": "Determining how alveoli are formed and maintained is critical to understanding lung organogenesis and regeneration after injury. To study the cellular dynamics of this critical stage of lung development, we have used scanned oblique-plane illumination microscopy of living lung slices to observe alveologenesis in real time at high resolution over several days. Contrary to the prevailing notion that alveologenesis occurs by airspace subdivision via ingrowing septa, we found that alveoli form by ballooning epithelial outgrowth supported by contracting mesenchymal ring structures. Systematic analysis has produced a computational model of finely timed cellular structural changes that drive normal alveologenesis. With this model, we can now quantify how perturbing known regulatory intercellular signaling pathways and cell migration processes affects alveologenesis. In the future, this paradigm and platform can be leveraged for mechanistic studies and screening for therapies to promote lung regeneration.", "year": "2025", "month": "01", "volume": "10", "issue": "4", "pages": "", "doi": "10.1172/jci.insight.187876", "link": "https://www.ncbi.nlm.nih.gov/pubmed/39773701", "sort_key": "2025-01-epithelial outgrowth", "quarter": "q1"}, {"pmid": "39641142", "title": "EMC3 is critical for CFTR function and calcium mobilization in the mouse intestinal epithelium.", "authors": ["Penrod S", "Tang X", "Moon C", "Whitsett JA", "Naren AP", "Huang Y"], "journal": "Am J Physiol Gastrointest Liver Physiol", "journal_title": "American journal of physiology. Gastrointestinal and liver physiology", "citation": "American journal of physiology. Gastrointestinal and liver physiology, 01 2025", "abstract": "Membrane proteins, such as the cystic fibrosis transmembrane-conductance regulator (CFTR), play a crucial role in gastrointestinal functions and health. Endoplasmic reticulum (ER) membrane protein complex (EMC), a multi-subunit insertase, mediates the incorporation of membrane segments into lipid bilayers during protein synthesis. Whether EMC regulates membrane proteins' processing and function in intestinal epithelial cells remains unclear. To investigate the role of EMC in the intestinal epithelium, we generated mice in which EMC subunit 3 (EMC3) was deleted in intestinal epithelial cells (EMC3\u0394IEC). EMC3\u0394IEC mice were viable but notably smaller compared with their wild-type littermates. Although the intestinal structure was generally maintained, EMC3\u0394IEC crypts exhibited altered morphology, particularly at the base of the crypts with decreased goblet cells and paneth cells. Levels of multiple polytopic membrane proteins, including CFTR, were decreased in EMC3-deficient epithelial cells. Several calcium ATPase pumps were downregulated, and calcium mobilization was impaired in EMC3\u0394IEC enteroids. CFTR-mediated organoid swelling in EMC3\u0394IEC mice was impaired in response to both cAMP-dependent signaling and calcium-secretagogue stimulation. Our study demonstrated that EMC plays a critical role in maintaining intestinal epithelium homeostasis by regulating membrane protein biogenesis and intracellular calcium homeostasis. Maintaining intracellular calcium homeostasis may be a universal cellular function regulated by EMC.NEW & NOTEWORTHY We generated mice in which endoplasmic reticulum membrane protein complex (EMC) subunit 3 was deleted from intestinal epithelium cells and studied the molecular functions of EMC in vivo. Our findings demonstrate the importance of intestinal EMC in the biogenesis of membrane proteins in vivo, including CFTR, and highlight its critical role in maintaining intracellular calcium homeostasis and, consequently, in calcium-dependent functions in the intestine and beyond.", "year": "2025", "month": "01", "volume": "328", "issue": "1", "pages": "G72-G82", "doi": "10.1152/ajpgi.00066.2024", "link": "https://www.ncbi.nlm.nih.gov/pubmed/39641142", "sort_key": "2025-01-emc3 is critical for", "quarter": "q1"}, {"pmid": "40271154", "title": "Wnt5a and Notum influence the temporal dynamics of cartilaginous mesenchymal condensations in developing trachea.", "authors": ["Bottasso-Arias N", "Mohanakrishnan M", "Trovillion S", "Burra K", "Russell NX", "Wu Y", "Xu Y", "Sinner D"], "journal": "Front Cell Dev Biol", "journal_title": "Frontiers in cell and developmental biology", "citation": "Frontiers in cell and developmental biology, 2025", "abstract": "INTRODUCTION: The trachea is essential for proper airflow to the lungs for gas exchange. Frequent congenital tracheal malformations affect the cartilage, causing the collapse of the central airway during the respiratory cycle. We have shown that Notum, a Wnt ligand de-acylase that attenuates the canonical branch of the Wnt signaling pathway, is necessary for cartilaginous mesenchymal condensations. In Notum deficient tracheas, chondrogenesis is delayed, and the tracheal lumen is narrowed. It is unknown if Notum attenuates non-canonical Wnt signaling. We observed premature tracheal chondrogenesis after mesenchymal deletion of the non-canonical Wnt5a ligand. We hypothesize that Notum and Wnt5a are required to mediate the timely formation of mesenchymal condensations, giving rise to the tracheal cartilage. METHODS/RESULTS: Ex vivo culture of tracheal tissue shows that chemical inhibition of the Wnt non-canonical pathway promotes earlier condensations, while Notum inhibition presents delayed condensations. Furthermore, non-canonical Wnt induction prevents the formation of cartilaginous mesenchymal condensations. On the other hand, cell-cell interactions among chondroblasts increase in the absence of mesenchymal Wnt5a. By performing an unbiased analysis of the gene expression in Wnt5a and Notum deficient tracheas, we detect that by E11.5, mRNA of genes essential for chondrogenesis and extracellular matrix formation are upregulated in Wnt5a mutants. The expression profile supports the premature and delayed chondrogenesis observed in Wnt5a and Notum deficient tracheas, respectively. CONCLUSION: We conclude that Notum and Wnt5a are necessary for proper tracheal cartilage patterning by coordinating timely chondrogenesis. Thus, these studies shed light on molecular mechanisms underlying congenital anomalies of the trachea.", "year": "2025", "month": "", "volume": "13", "issue": "", "pages": "1523833", "doi": "10.3389/fcell.2025.1523833", "link": "https://www.ncbi.nlm.nih.gov/pubmed/40271154", "sort_key": "2025-00-wnt5a and notum infl", "quarter": "q0"}, {"pmid": "40260100", "title": "Multimodal Ensemble Fusion Deep Learning Using Histopathological Images and Clinical Data for Glioma Subtype Classification.", "authors": ["Shirae S", "Debsarkar SS", "Kawanaka H", "Aronow B", "Prasath VBS"], "journal": "IEEE Access", "journal_title": "IEEE access : practical innovations, open solutions", "citation": "IEEE access : practical innovations, open solutions, 2025", "abstract": "Glioma is the most common malignant tumor of the central nervous system, and diffuse Glioma is classified as grades II-IV by world health organization (WHO). In the the cancer genome atlas (TCGA) Glioma dataset, grade II and III Gliomas are classified as low-grade glioma (LGG), and grade IV Gliomas as glioblastoma multiforme (GBM). In clinical practice, the survival and treatment process with Glioma patients depends on properly diagnosing the subtype. With this background, there has been much research on Glioma over the years. Among these researches, the origin and evolution of whole slide images (WSIs) have led to many attempts to support diagnosis by image analysis. On the other hand, due to the disease complexities of Glioma patients, multimodal analysis using various types of data rather than a single data set has been attracting attention. In our proposed method, multiple deep learning models are used to extract features from histopathology images, and the features of the obtained images are concatenated with those of the clinical data in a fusion approach. Then, we perform patch-level classification by machine learning (ML) using the concatenated features. Based on the performances of the deep learning models, we ensemble feature sets from top three models and perform further classifications. In the experiments with our proposed ensemble fusion AI (EFAI) approach using WSIs and clinical data of diffuse Glioma patients on TCGA dataset, the classification accuracy of the proposed multimodal ensemble fusion method is 0.936 with an area under the curve (AUC) value of 0.967 when tested on a balanced dataset of 240 GBM, 240 LGG patients. On an imbalanced dataset of 141 GBM, 242 LGG patients the proposed method obtained the accuracy of 0.936 and AUC of 0.967. Our proposed ensemble fusion approach significantly outperforms the classification using only histopathology images alone with deep learning models. Therefore, our approach can be used to support the diagnosis of Glioma patients and can lead to better diagnosis.", "year": "2025", "month": "", "volume": "13", "issue": "", "pages": "57780-57797", "doi": "10.1109/access.2025.3556713", "link": "https://www.ncbi.nlm.nih.gov/pubmed/40260100", "sort_key": "2025-00-multimodal ensemble ", "quarter": "q0"}, {"pmid": "39601538", "title": "Yield and Diversity of Human Distal Lung Epithelial Cells Isolated by Different Sorting Strategies.", "authors": ["McCall AS", "Singha UK", "Blackwell TS", "Gokey JJ", "Kropski JA"], "journal": "Am J Respir Cell Mol Biol", "journal_title": "American journal of respiratory cell and molecular biology", "citation": "American journal of respiratory cell and molecular biology, 12 2024", "abstract": "", "year": "2024", "month": "12", "volume": "71", "issue": "6", "pages": "743-745", "doi": "10.1165/rcmb.2024-0206LE", "link": "https://www.ncbi.nlm.nih.gov/pubmed/39601538", "sort_key": "2024-12-yield and diversity ", "quarter": "q4"}, {"pmid": "39713456", "title": "STAT1 Promotes PD-L1 Activation and Tumor Growth in Lymphangioleiomyomatosis.", "authors": ["Olatoke T", "Zhang EY", "Wagner A", "He Q", "Li S", "Astreinidis A", "McCormack FX", "Xu Y", "Yu JJ"], "journal": "bioRxiv", "journal_title": "bioRxiv : the preprint server for biology", "citation": "bioRxiv : the preprint server for biology, 12 2024", "abstract": "Lymphangioleiomyomatosis (LAM) is a cystic lung disease that primarily affects women. LAM is caused by the invasion of metastatic smooth muscle-like cells into the lung parenchyma, leading to abnormal cell proliferation, lung remodeling and progressive respiratory failure. LAM cells have TSC gene mutations, which occur sporadically or in people with Tuberous Sclerosis Complex. Although it is known that hyperactivation of the mechanistic target of rapamycin complex 1 (mTORC1) due to TSC2 gene mutations contributes to aberrant cell growth in LAM lung, tumor origin and invasive mechanism remain unclear. To determine molecular drivers responsible for aberrant LAM cell growth, we performed integrative single-cell transcriptomic analysis and predicted that STAT1 interacts with Pre-B cell leukemia transcription factor (PBX1) to regulate LAM cell survival. Here, we show activation of STAT1 and STAT3 proteins in TSC2-deficient LAM models. Fludarabine, a potent STAT1 inhibitor, induced the death of TSC2-deficient cells, increased caspase-3 cleavage, and phosphorylation of necroptosis marker RIP1. Fludarabine treatment impeded lung colonization of TSC2-deficient cells and uterine tumor progression, associated with reduced percentage of PCNA-positive cells in vivo. Interestingly, IFN-\u03b3 treatment increased STAT1 phosphorylation and PD-L1 expression, indicating that STAT1 aids TSC2-deficient tumor cells in evading immune surveillance in LAM. Our findings indicate that STAT1 signaling is critical for LAM cell survival and could be targeted to treat LAM and other mTORC1 hyperactive tumors.", "year": "2024", "month": "12", "volume": "", "issue": "", "pages": "", "doi": "10.1101/2024.12.11.627871", "link": "https://www.ncbi.nlm.nih.gov/pubmed/39713456", "sort_key": "2024-12-stat1 promotes pd-l1", "quarter": "q4"}, {"pmid": "39117421", "title": "Plasma collagen neoepitopes are associated with multiorgan disease in the ACCESS and GRADS sarcoidosis cohorts.", "authors": ["Sand JMB", "Jessen H", "Leeming DJ", "Yu S", "Lee CJ", "Hu B", "Sun Y", "Adams T", "Pivarnik T", "Liu A", "Woo S", "McGovern JR", "Fiorini V", "Saber T", "Higuero-Sevilla JP", "Gulati M", "Kaminski N", "Damsky W", "Shaw AC", "Mohanty S", "Goobie G", "Zhang Y", "Herzog EL", "Ryu C"], "journal": "Thorax", "journal_title": "Thorax", "citation": "Thorax, 11 2024", "abstract": "INTRODUCTION: The pathogenesis of sarcoidosis involves tissue remodelling mediated by the accumulation of abnormal extracellular matrix, which is partly the result of an imbalance in collagen synthesis, cross-linking and degradation. During this process, collagen fragments or neoepitopes, are released into the circulation. The significance of these circulating collagen neoepitopes in sarcoidosis remains unknown. METHODS: We employed plasma samples from patients with sarcoidosis enrolled in A Case Control Etiologic Study of Sarcoidosis (ACCESS) and Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis (GRADS), and healthy control patients recruited from the Yale community. Plasma concentrations of type III and VI collagen degradation (C3M and C6M) and formation (PRO-C3 and PRO-C6) were quantified via neoepitope-specific competitive ELISA, and statistical associations were sought with clinical phenotypes. RESULTS: Relative to healthy controls, the plasma of both sarcoidosis cohorts was enriched for C3M and C6M, irrespective of corticosteroid use and disease duration. While circulating collagen neoepitopes were independent of Scadding stage, there was a significant association between multiorgan disease and PRO-C3, PRO-C6 and C3M in the ACCESS cohort; PRO-C3 and C6M displayed this property in GRADS. These findings were unrelated to plasma levels of interleukin-4 (IL-4), IL-5, IL-6, IL-9, IL-10 and IL-13. Moreover, PRO-C3 was associated with dermatological disease in both cohorts. DISCUSSION: In two well-characterised sarcoidosis cohorts, we discovered that the plasma is enriched for neoepitopes of collagen degradation (C3M and C6M). In multiorgan disease, there was an association with circulating neoepitopes of type III formation (PRO-C3), perhaps mediated by dermatological sarcoidosis. Further investigation in this arena has the potential to foster new insights into the pathogenic mechanisms of this complex disease.", "year": "2024", "month": "11", "volume": "79", "issue": "12", "pages": "1136-1144", "doi": "10.1136/thorax-2023-221095", "link": "https://www.ncbi.nlm.nih.gov/pubmed/39117421", "sort_key": "2024-11-plasma collagen neoe", "quarter": "q4"}, {"pmid": "39416038", "title": "Integrating N -glycan and CODEX imaging reveal cell-specific protein glycosylation in healthy human lung.", "authors": ["Veli\u010dkovi\u0107 D", "Purkerson J", "Bhotika H", "Huyck H", "Clair G", "Pryhuber GS", "Anderton C"], "journal": "bioRxiv", "journal_title": "bioRxiv : the preprint server for biology", "citation": "bioRxiv : the preprint server for biology, 10 2024", "abstract": "N -linked glycosylation, the major post-translational modification of cellular proteins, is important for proper lung functioning, serving to fold, traffic, and stabilize protein structures and to mediate various cell-cell recognition events. Identifying cell-specific N -glycan structures in human lungs is critical for understanding the chemistry and mechanisms that guide cell-cell and cell-matrix interactions and determining nuanced functions of specific N -glycosylation. Our study, which used matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) combined with co-detection by indexing (CODEX) to reveal the cellular origin of N -glycans, is a significant step in this direction. This innovative technological combination enabled us to detect and differentiate N -glycans located in the vicinity of cells surrounding airways and blood vessels, parenchyma, submucosal glands, cartilage, and smooth muscles. The potential impact of our findings on future research is immense. For instance, our algorithm for grouping N -glycans based on their functional chemical features, combined with identifying group niches, paves the way for targeted studies. We found that fucosylated N -glycans are dominant around immune cells, tetra antennary N -glycans in the cartilage, high-mannose N -glycans surrounding the bronchus originate from associated collagenous structures, complex fucosylated-tetra antennary-polylactosamine N -glycans are spread over smooth muscle structures and in epithelial cells surrounding arteries, and N -glycans with Hex:6 HexNAc:6 compositions, which, according to our algorithm, can be ascribed to either tetra antennary or bisecting N -glycan, are highly abundant in the parenchyma. The findings suggest cell or region-specific functions for these localized glycan structures.", "year": "2024", "month": "10", "volume": "", "issue": "", "pages": "", "doi": "10.1101/2024.10.08.617274", "link": "https://www.ncbi.nlm.nih.gov/pubmed/39416038", "sort_key": "2024-10-integrating n -glyca", "quarter": "q4"}, {"pmid": "39405113", "title": "EMC3 regulates trafficking and pulmonary toxicity of the SFTPCI73T mutation associated with interstitial lung disease.", "authors": ["Tang X", "Wei W", "Sun Y", "Weaver TE", "Nakayasu ES", "Clair G", "Snowball JM", "Na CL", "Apsley KS", "Martin EP", "Kotton DN", "Alysandratos KD", "Huo J", "Molkentin JD", "Gower WA", "Lin X", "Whitsett JA"], "journal": "J Clin Invest", "journal_title": "The Journal of clinical investigation", "citation": "The Journal of clinical investigation, 10 2024", "abstract": "The most common mutation in surfactant protein C gene (SFTPC), SFTPCI73T, causes interstitial lung disease with few therapeutic options. We previously demonstrated that EMC3, an important component of the multiprotein endoplasmic reticulum membrane complex (EMC), is required for surfactant homeostasis in alveolar type 2 epithelial (AT2) cells at birth. In the present study, we investigated the role of EMC3 in the control of SFTPCI73T metabolism and its associated alveolar dysfunction. Using a knock-in mouse model phenocopying the I73T mutation, we demonstrated that conditional deletion of Emc3 in AT2 cells rescued alveolar remodeling/simplification defects in neonatal and adult mice. Proteomic analysis revealed that Emc3 depletion reversed the disruption of vesicle trafficking pathways and rescued the mitochondrial dysfunction associated with I73T mutation. Affinity purification-mass spectrometry analysis identified potential EMC3 interacting proteins in lung AT2 cells, including valosin containing protein (VCP) and its interactors. Treatment of SftpcI73T knock-in mice and SFTPCI73T-expressing iAT2 cells derived from SFTPCI73T patient-specific iPSCs with the VCP inhibitor CB5083 restored alveolar structure and SFTPCI73T trafficking, respectively. Taken together, the present work identifies the EMC complex and VCP in the metabolism of the disease-associated SFTPCI73T mutant, providing therapeutical targets for SFTPCI73T-associated interstitial lung disease.", "year": "2024", "month": "10", "volume": "134", "issue": "23", "pages": "", "doi": "10.1172/JCI173861", "link": "https://www.ncbi.nlm.nih.gov/pubmed/39405113", "sort_key": "2024-10-emc3 regulates traff", "quarter": "q4"}, {"pmid": "41257248", "title": "A novel circRNA-miRNA-mRNA regulatory axis as a sex-specific biological variable in bronchopulmonary dysplasia.", "authors": ["Das P", "Shyamal S", "Prahaladan VM", "Mishra SS", "Takada X", "Chandran S", "Addya S", "Agarwal B", "Andersson S", "Panda AC", "Bhandari V"], "journal": "NAR Mol Med", "journal_title": "NAR molecular medicine", "citation": "NAR molecular medicine, 10 2024", "abstract": "Babies born prematurely with gestational age <28 weeks usually develop a severe pulmonary complication called Bronchopulmonary Dysplasia (BPD) in response to hyperoxia. BPD is a sexually dimorphic pediatric disease with no curative options. Several micro RNAs (miRNAs) are implicated in BPD and are expressed differentially in males and females. Circular (circ) RNAs serve as sponges for their dedicated miRNAs to influence transcription and translation. We tested the dimorphism of these circular RNAs in BPD to assess their biological significance and unravel a circRNA-miRNA-mRNA regulatory axis in response to hyperoxia. Our RNA-Sequencing assay identified approximately 33 000 circRNAs at the alveolar stage of development with only a handful of them being expressed differentially between males and females in the control room air (RA) and hyperoxia-treated (BPD) groups. One circRNA, i.e circNfix was found to be associated with miR204-5p that targets the downstream mRNA target Ntrk2. To prove that circNfix regulates Ntrk2, we silenced circNfix using a GapmeR and found that Ntrk2 was also suppressed, leading to an improved alveolar phenotype in BPD male pups. From the results of our study, we can propose circNfix and Ntrk2 as novel key regulators in the pathogenesis and sexual dimorphism of BPD, while simultaneously proposing the use of circNfix GapmeR towards a potential therapeutic application.", "year": "2024", "month": "10", "volume": "1", "issue": "4", "pages": "ugae014", "doi": "10.1093/narmme/ugae014", "link": "https://www.ncbi.nlm.nih.gov/pubmed/41257248", "sort_key": "2024-10-a novel circrna-mirn", "quarter": "q4"}, {"pmid": "39038392", "title": "Deep learning-based IDH1 gene mutation prediction using histopathological imaging and clinical data.", "authors": ["Nakagaki R", "Debsarkar SS", "Kawanaka H", "Aronow BJ", "Prasath VBS"], "journal": "Comput Biol Med", "journal_title": "Computers in biology and medicine", "citation": "Computers in biology and medicine, 09 2024", "abstract": "In the field of histopathology, many studies on the classification of whole slide images (WSIs) using artificial intelligence (AI) technology have been reported. We have studied the disease progression assessment of glioma. Adult-type diffuse gliomas, a type of brain tumor, are classified into astrocytoma, oligodendroglioma, and glioblastoma. Astrocytoma and oligodendroglioma are also called low grade glioma (LGG), and glioblastoma is also called glioblastoma multiforme (GBM). LGG patients frequently have isocitrate dehydrogenase (IDH) mutations. Patients with IDH mutations have been reported to have a better prognosis than patients without IDH mutations. Therefore, IDH mutations are an essential indicator for the classification of glioma. That is why we focused on the IDH1 mutation. In this paper, we aimed to classify the presence or absence of the IDH1 mutation using WSIs and clinical data of glioma patients. Ensemble learning between the WSIs model and the clinical data model is used to classify the presence or absence of IDH1 mutation. By using slide level labels, we combined patch-based imaging information from hematoxylin and eosin (H & E) stained WSIs, along with clinical data using deep image feature extraction and machine learning classifier for predicting IDH1 gene mutation prediction versus wild-type across cohort of 546 patients. We experimented with different deep learning (DL) models including attention-based multiple instance learning (ABMIL) models on imaging data along with gradient boosting machine (LightGBM) for the clinical variables. Further, we used hyperparameter optimization to find the best overall model in terms of classification accuracy. We obtained the highest area under the curve (AUC) of 0.823 for WSIs, 0.782 for clinical data, and 0.852 for ensemble results using MaxViT and LightGBM combination, respectively. Our experimental results indicate that the overall accuracy of the AI models can be improved by using both clinical data and images.", "year": "2024", "month": "09", "volume": "179", "issue": "", "pages": "108902", "doi": "10.1016/j.compbiomed.2024.108902", "link": "https://www.ncbi.nlm.nih.gov/pubmed/39038392", "sort_key": "2024-09-deep learning-based ", "quarter": "q3"}, {"pmid": "39253423", "title": "Bronchopulmonary Dysplasia with Pulmonary Hypertension Associates with Loss of Semaphorin Signaling and Functional Decrease in FOXF1 Expression.", "authors": ["Shirazi SP", "Negretti NM", "Jetter CS", "Sharkey AL", "Garg S", "Kapp ME", "Wilkins D", "Fortier G", "Mallapragada S", "Banovich NE", "Wright CVE", "Frank DB", "Kropski JA", "Sucre JMS"], "journal": "bioRxiv", "journal_title": "bioRxiv : the preprint server for biology", "citation": "bioRxiv : the preprint server for biology, 09 2024", "abstract": "Lung injury in preterm infants leads to structural and functional respiratory deficits, with a risk for bronchopulmonary dysplasia (BPD) that in its most severe form is accompanied by pulmonary hypertension (PH). To examine cellular and molecular dynamics driving evolving BPD in humans, we performed single-cell RNA sequencing of preterm infant lungs in early stages of BPD and BPD+PH compared to term infants. Analysis of the endothelium revealed a unique aberrant capillary cell-state primarily in BPD+PH marked by ANKRD1 expression. Predictive signaling analysis identified deficits in the semaphorin guidance-cue signaling pathway and decreased expression of pro-angiogenic transcription factor FOXF1 within the alveolar parenchyma in neonatal lung samples with BPD/BPD+PH. Loss of semaphorin signaling was replicated in a murine BPD model and in humans with alveolar capillary dysplasia (ACDMPV), suggesting a mechanistic link between the developmental programs underlying BPD and ACDMPV and a critical role for semaphorin signaling in normal lung development.", "year": "2024", "month": "09", "volume": "", "issue": "", "pages": "", "doi": "10.1101/2024.08.27.609955", "link": "https://www.ncbi.nlm.nih.gov/pubmed/39253423", "sort_key": "2024-09-bronchopulmonary dys", "quarter": "q3"}, {"pmid": "39090672", "title": "MAMS: matrix and analysis metadata standards to facilitate harmonization and reproducibility of single-cell data.", "authors": ["Sarfraz I", "Wang Y", "Shastry A", "Teh WK", "Sokolov A", "Herb BR", "Creasy HH", "Virshup I", "Dries R", "Degatano K", "Mahurkar A", "Schnell DJ", "Madrigal P", "Hilton J", "Gehlenborg N", "Tickle T", "Campbell JD"], "journal": "Genome Biol", "journal_title": "Genome biology", "citation": "Genome biology, 08 2024", "abstract": "Many datasets are being produced by consortia that seek to characterize healthy and disease tissues at single-cell resolution. While biospecimen and experimental information is often captured, detailed metadata standards related to data matrices and analysis workflows are currently lacking. To address this, we develop the matrix and analysis metadata standards (MAMS) to serve as a resource for data centers, repositories, and tool developers. We define metadata fields for matrices and parameters commonly utilized in analytical workflows and developed the rmams package to extract MAMS from single-cell objects. Overall, MAMS promotes the harmonization, integration, and reproducibility of single-cell data across platforms.", "year": "2024", "month": "08", "volume": "25", "issue": "1", "pages": "205", "doi": "10.1186/s13059-024-03349-w", "link": "https://www.ncbi.nlm.nih.gov/pubmed/39090672", "sort_key": "2024-08-mams: matrix and ana", "quarter": "q3"}, {"pmid": "38826261", "title": "Human BioMolecular Atlas Program (HuBMAP): 3D Human Reference Atlas Construction and Usage.", "authors": ["B\u00f6rner K", "Blood PD", "Silverstein JC", "Ruffalo M", "Satija R", "Teichmann SA", "Pryhuber G", "Misra RS", "Purkerson J", "Fan J", "Hickey JW", "Molla G", "Xu C", "Zhang Y", "Weber G", "Jain Y", "Qaurooni D", "Kong Y", "HRA Team", "Bueckle A", "Herr BW"], "journal": "bioRxiv", "journal_title": "bioRxiv : the preprint server for biology", "citation": "bioRxiv : the preprint server for biology, 08 2024", "abstract": "The Human BioMolecular Atlas Program (HuBMAP) aims to construct a reference 3D structural, cellular, and molecular atlas of the healthy adult human body. The HuBMAP Data Portal (https://portal.hubmapconsortium.org) serves experimental datasets and supports data processing, search, filtering, and visualization. The Human Reference Atlas (HRA) Portal (https://humanatlas.io) provides open access to atlas data, code, procedures, and instructional materials. Experts from more than 20 consortia are collaborating to construct the HRA's Common Coordinate Framework (CCF), knowledge graphs, and tools that describe the multiscale structure of the human body (from organs and tissues down to cells, genes, and biomarkers) and to use the HRA to understand changes that occur at each of these levels with aging, disease, and other perturbations. The 6th release of the HRA v2.0 covers 36 organs with 4,499 unique anatomical structures, 1,195 cell types, and 2,089 biomarkers (e.g., genes, proteins, lipids) linked to ontologies and 2D/3D reference objects. New experimental data can be mapped into the HRA using (1) three cell type annotation tools (e.g., Azimuth) or (2) validated antibody panels (OMAPs), or (3) by registering tissue data spatially. This paper describes the HRA user stories, terminology, data formats, ontology validation, unified analysis workflows, user interfaces, instructional materials, application programming interface (APIs), flexible hybrid cloud infrastructure, and previews atlas usage applications.", "year": "2024", "month": "08", "volume": "", "issue": "", "pages": "", "doi": "10.1101/2024.03.27.587041", "link": "https://www.ncbi.nlm.nih.gov/pubmed/38826261", "sort_key": "2024-08-human biomolecular a", "quarter": "q3"}, {"pmid": "39211059", "title": "Three Dimensional Multiscalar Neurovascular Nephron Connectivity Map of the Human Kidney Across the Lifespan.", "authors": ["McLaughlin L", "Zhang B", "Sharma S", "Knoten AL", "Kaushal M", "Purkerson JM", "Huyck H", "Pryhuber GS", "Gaut JP", "Jain S"], "journal": "bioRxiv", "journal_title": "bioRxiv : the preprint server for biology", "citation": "bioRxiv : the preprint server for biology, 07 2024", "abstract": "The human kidney is a vital organ with a remarkable ability to coordinate the activity of up to a million nephrons, its main functional tissue unit (FTU), and maintain homeostasis. We developed tissue processing and analytical methods to construct a 3D map of neurovascular nephron connectivity of the human kidney and glean insights into how this structural organization enables coordination of various functions of the nephron, such as glomerular filtration, solute and water absorption, secretion by the tubules, and regulation of blood flow and pressure by the juxtaglomerular apparatus, in addition to how these functions change across disease and lifespans. Using light sheet fluorescence microscopy (LSFM) and morphometric analysis we discovered changes in anatomical orientation of the vascular pole, glomerular density, volume, and innervation through postnatal development and ageing. The extensive nerve network exists from cortex FTUs to medullary loop of Henle, providing connectivity within segments of the same nephron, and between separate nephrons. The nerves organize glomeruli into discreet communities (in the same network of nerves). Adjacent glomerular communities are connected to intercommunal \"mother glomeruli\" by nerves, a pattern repeating throughout the cortex. These neuro-nephron networks are not developed in postnatal kidneys and are disrupted in diseased kidneys (diabetic or hydronephrosis). This structural organization likely poises the entire glomerular and juxtaglomerular FTUs to synchronize responses to perturbations in fluid homeostasis, utilizing mother glomeruli as network control centers.", "year": "2024", "month": "07", "volume": "", "issue": "", "pages": "", "doi": "10.1101/2024.07.29.605633", "link": "https://www.ncbi.nlm.nih.gov/pubmed/39211059", "sort_key": "2024-07-three dimensional mu", "quarter": "q3"}, {"pmid": "38948835", "title": "Cell type-specific expression of angiotensin receptors in the human lung with implications for health, aging, and chronic disease.", "authors": ["Benjamin KJ", "Sauler M", "Poonyagariyagorn H", "Neptune ER"], "journal": "bioRxiv", "journal_title": "bioRxiv : the preprint server for biology", "citation": "bioRxiv : the preprint server for biology, 06 2024", "abstract": "The renin-angiotensin system is a highly characterized integrative pathway in mammalian homeostasis whose clinical spectrum has been expanded to lung disorders such as chronic obstructive pulmonary disease (COPD)-emphysema, idiopathic pulmonary fibrosis (IPF), and COVID pathogenesis. Despite this widespread interest, specific localization of this receptor family in the mammalian lung is limited, partially due to the imprecision of available antibody reagents. In this study, we establish the expression pattern of the two predominant angiotensin receptors in the human lung, AGTR1 and AGTR2, using complementary and comprehensive bulk and single-cell RNA-sequence datasets that are publicly available. We show these two receptors have distinct localization patterns and developmental trajectories in the human lung, pericytes for AGTR1 and a subtype of alveolar epithelial type 2 cells for AGTR2. In the context of disease, we further pinpoint AGTR2 localization to the COPD-associated subpopulation of alveolar epithelial type 2 (AT2B) and AGTR1 localization to fibroblasts, where their expression is upregulated in individuals with COPD, but not in individuals with IPF. Finally, we examine the genetic variation of the angiotensin receptors, finding AGTR2 associated with lung phenotype (i.e., cystic fibrosis) via rs1403543. Together, our findings provide a critical foundation for delineating this pathway's role in lung homeostasis and constructing rational approaches for targeting specific lung disorders.", "year": "2024", "month": "06", "volume": "", "issue": "", "pages": "", "doi": "10.1101/2024.06.17.599425", "link": "https://www.ncbi.nlm.nih.gov/pubmed/38948835", "sort_key": "2024-06-cell type-specific e", "quarter": "q2"}, {"pmid": "37977267", "title": "Circulating Mitochondrial DNA Is Associated With High Levels of Fatigue in Two Independent Sarcoidosis Cohorts.", "authors": ["Fiorini V", "Hu B", "Sun Y", "Yu S", "McGovern J", "Gandhi S", "Woo S", "Turcotte-Foster SJ", "Pivarnik T", "Khan Z", "Adams T", "Herzog EL", "Kaminski N", "Gulati M", "Ryu C"], "journal": "Chest", "journal_title": "Chest", "citation": "Chest, 05 2024", "abstract": "BACKGROUND: Patients with sarcoidosis who develop severe clinical phenotypes of pulmonary fibrosis or multiorgan disease experience debilitating symptoms, with fatigue being a common chief complaint. Studies that have investigated this patient-related outcome measure (PROM) have used the Fatigue Assessment Scale (FAS), a self-reported questionnaire that reflects mental and physical domains. Despite extensive work, its cause is unknown and treatment options remain limited. Previously, we showed that the plasma of patients with sarcoidosis with extrapulmonary disease endorsing fatigue was enriched for mitochondrial DNA (mtDNA), a ligand for the innate immune receptor toll-like receptor 9 (TLR9). Through our cross-disciplinary platform, we investigated a relationship between sarcoidosis-induced fatigue and circulating mtDNA. RESEARCH QUESTION: Is there a psychobiologic mechanism that connects sarcoidosis-induced fatigue and mtDNA-mediated TLR9 activation? STUDY DESIGN AND METHODS: Using a local cohort of patients at Yale (discovery cohort) and the National Institutes of Health-sponsored Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis study (validation cohort), we scored the FAS and quantified in the plasma, mtDNA concentrations, TLR9 activation, and cytokine levels. RESULTS: Although FAS scores were independent of corticosteroid use and Scadding stage, we observed a robust association between FAS scores, which included mental and physical domains, and multiorgan sarcoidosis. Subsequently, we identified a significant correlation between plasma mtDNA concentrations and all domains of fatigue. Additionally, we found that TLR9 activation is associated with all aspects of the FAS and partially mediates this PROM through mtDNA. Last, we found that TLR9-associated soluble mediators in the plasma are independent of all facets of fatigue. INTERPRETATION: Through our cross-disciplinary translational platform, we identified a previously unrecognized psychobiologic connection between sarcoidosis-induced fatigue and circulating mtDNA concentrations. Mechanistic work that investigates the contribution of mtDNA-mediated innate immune activation in this PROM and clinical studies with prospective cohorts has the potential to catalyze novel therapeutic strategies for this patient population and those with similar conditions.", "year": "2024", "month": "05", "volume": "165", "issue": "5", "pages": "1174-1185", "doi": "10.1016/j.chest.2023.11.020", "link": "https://www.ncbi.nlm.nih.gov/pubmed/37977267", "sort_key": "2024-05-circulating mitochon", "quarter": "q2"}, {"pmid": "38442187", "title": "Bulk RNA sequencing of human pediatric lung cell populations reveals unique transcriptomic signature associated with postnatal pulmonary development.", "authors": ["Bandyopadhyay G", "Jehrio MG", "Baker C", "Bhattacharya S", "Misra RS", "Huyck HL", "Chu C", "Myers JR", "Ashton J", "Polter S", "Cochran M", "Bushnell T", "Dutra J", "Katzman PJ", "Deutsch GH", "Mariani TJ", "Pryhuber GS"], "journal": "Am J Physiol Lung Cell Mol Physiol", "journal_title": "American journal of physiology. Lung cellular and molecular physiology", "citation": "American journal of physiology. Lung cellular and molecular physiology, 05 2024", "abstract": "Postnatal lung development results in an increasingly functional organ prepared for gas exchange and pathogenic challenges. It is achieved through cellular differentiation and migration. Changes in the tissue architecture during this development process are well-documented and increasing cellular diversity associated with it are reported in recent years. Despite recent progress, transcriptomic and molecular pathways associated with human postnatal lung development are yet to be fully understood. In this study, we investigated gene expression patterns associated with healthy pediatric lung development in four major enriched cell populations (epithelial, endothelial, and nonendothelial mesenchymal cells, along with lung leukocytes) from 1-day-old to 8-yr-old organ donors with no known lung disease. For analysis, we considered the donors in four age groups [less than 30 days old neonates, 30 days to < 1 yr old infants, toddlers (1 to < 2 yr), and children 2 yr and older] and assessed differentially expressed genes (DEG). We found increasing age-associated transcriptional changes in all four major cell types in pediatric lung. Transition from neonate to infant stage showed highest number of DEG compared with the number of DEG found during infant to toddler- or toddler to older children-transitions. Profiles of differential gene expression and further pathway enrichment analyses indicate functional epithelial cell maturation and increased capability of antigen presentation and chemokine-mediated communication. Our study provides a comprehensive reference of gene expression patterns during healthy pediatric lung development that will be useful in identifying and understanding aberrant gene expression patterns associated with early life respiratory diseases.NEW & NOTEWORTHY This study presents postnatal transcriptomic changes in major cell populations in human lung, namely endothelial, epithelial, mesenchymal cells, and leukocytes. Although human postnatal lung development continues through early adulthood, our results demonstrate that greatest transcriptional changes occur in first few months of life during neonate to infant transition. These early transcriptional changes in lung parenchyma are particularly notable for functional maturation and activation of alveolar type II cell genes.", "year": "2024", "month": "05", "volume": "326", "issue": "5", "pages": "L604-L617", "doi": "10.1152/ajplung.00385.2023", "link": "https://www.ncbi.nlm.nih.gov/pubmed/38442187", "sort_key": "2024-05-bulk rna sequencing ", "quarter": "q2"}, {"pmid": "38693267", "title": "Airway hillocks are injury-resistant reservoirs of unique plastic stem cells.", "authors": ["Lin B", "Shah VS", "Chernoff C", "Sun J", "Shipkovenska GG", "Vinarsky V", "Waghray A", "Xu J", "Leduc AD", "Hintschich CA", "Surve MV", "Xu Y", "Capen DE", "Villoria J", "Dou Z", "Hariri LP", "Rajagopal J"], "journal": "Nature", "journal_title": "Nature", "citation": "Nature, 05 2024", "abstract": "Airway hillocks are stratified epithelial structures of unknown function1. Hillocks persist for months and have a unique population of basal stem cells that express genes associated with barrier function and cell adhesion. Hillock basal stem cells continually replenish overlying squamous barrier cells. They exhibit dramatically higher turnover than the abundant, largely quiescent classic pseudostratified airway epithelium. Hillocks resist a remarkably broad spectrum of injuries, including toxins, infection, acid and physical injury because hillock squamous cells shield underlying hillock basal stem cells from injury. Hillock basal stem cells are capable of massive clonal expansion that is sufficient to resurface denuded airway, and eventually regenerate normal airway epithelium with each of its six component cell types. Hillock basal stem cells preferentially stratify and keratinize in the setting of retinoic acid signalling inhibition, a known cause of squamous metaplasia2,3. Here we show that mouse hillock expansion is the cause of vitamin A deficiency-induced squamous metaplasia. Finally, we identify human hillocks whose basal stem cells generate functional squamous barrier structures in culture. The existence of hillocks reframes our understanding of airway epithelial regeneration. Furthermore, we show that hillocks are one origin of 'squamous metaplasia', which is long thought to be a precursor of lung cancer.", "year": "2024", "month": "05", "volume": "629", "issue": "8013", "pages": "869-877", "doi": "10.1038/s41586-024-07377-1", "link": "https://www.ncbi.nlm.nih.gov/pubmed/38693267", "sort_key": "2024-05-airway hillocks are ", "quarter": "q2"}, {"pmid": "38377991", "title": "Stem cell migration drives lung repair in living mice.", "authors": ["Chioccioli M", "Liu S", "Magruder S", "Tata A", "Borriello L", "McDonough JE", "Konkimalla A", "Kim SH", "Nouws J", "Gonzalez DG", "Traub B", "Ye X", "Yang T", "Entenberg DR", "Krishnaswamy S", "Hendry CE", "Kaminski N", "Tata PR", "Sauler M"], "journal": "Dev Cell", "journal_title": "Developmental cell", "citation": "Developmental cell, 04 2024", "abstract": "Tissue repair requires a highly coordinated cellular response to injury. In the lung, alveolar type 2 cells (AT2s) act as stem cells to replenish both themselves and alveolar type 1 cells (AT1s); however, the complex orchestration of stem cell activity after injury is poorly understood. Here, we establish longitudinal imaging of AT2s in murine intact tissues ex vivo and in vivo in order to track their dynamic behavior over time. We discover that a large fraction of AT2s become motile following injury and provide direct evidence for their migration between alveolar units. High-resolution morphokinetic mapping of AT2s further uncovers the emergence of distinct motile phenotypes. Inhibition of AT2 migration via genetic depletion of ArpC3 leads to impaired regeneration of AT2s and AT1s in vivo. Together, our results establish a requirement for stem cell migration between alveolar units and identify properties of stem cell motility at high cellular resolution.", "year": "2024", "month": "04", "volume": "59", "issue": "7", "pages": "830-840.e4", "doi": "10.1016/j.devcel.2024.02.003", "link": "https://www.ncbi.nlm.nih.gov/pubmed/38377991", "sort_key": "2024-04-stem cell migration ", "quarter": "q2"}, {"pmid": "38645130", "title": "Microbiota-derived inosine programs protective CD8+ T cell responses against influenza in newborns.", "authors": ["Stevens J", "Culberson E", "Kinder J", "Ramiriqui A", "Gray J", "Bonfield M", "Shao TY", "Al Gharabieh F", "Peterson L", "Steinmeyer S", "Zacharias W", "Pryhuber G", "Paul O", "Sengupta S", "Alenghat T", "Way SS", "Deshmukh H"], "journal": "bioRxiv", "journal_title": "bioRxiv : the preprint server for biology", "citation": "bioRxiv : the preprint server for biology, 04 2024", "abstract": "The immunological defects causing susceptibility to severe viral respiratory infections due to early-life dysbiosis remain ill-defined. Here, we show that influenza virus susceptibility in dysbiotic infant mice is caused by CD8+ T cell hyporesponsiveness and diminished persistence as tissue-resident memory cells. We describe a previously unknown role for nuclear factor interleukin 3 (NFIL3) in repression of memory differentiation of CD8+ T cells in dysbiotic mice involving epigenetic regulation of T cell factor 1 (TCF 1) expression. Pulmonary CD8+ T cells from dysbiotic human infants share these transcriptional signatures and functional phenotypes. Mechanistically, intestinal inosine was reduced in dysbiotic human infants and newborn mice, and inosine replacement reversed epigenetic dysregulation of Tcf7 and increased memory differentiation and responsiveness of pulmonary CD8+ T cells. Our data unveils new developmental layers controlling immune cell activation and identifies microbial metabolites that may be used therapeutically in the future to protect at-risk newborns.", "year": "2024", "month": "04", "volume": "", "issue": "", "pages": "", "doi": "10.1101/2024.04.09.588427", "link": "https://www.ncbi.nlm.nih.gov/pubmed/38645130", "sort_key": "2024-04-microbiota-derived i", "quarter": "q2"}, {"pmid": "38540357", "title": "Single-Cell Transcriptomic Profiling Identifies Molecular Phenotypes of Newborn Human Lung Cells.", "authors": ["Bhattacharya S", "Myers JA", "Baker C", "Guo M", "Danopoulos S", "Myers JR", "Bandyopadhyay G", "Romas ST", "Huyck HL", "Misra RS", "Dutra J", "Holden-Wiltse J", "McDavid AN", "Ashton JM", "Al Alam D", "Potter SS", "Whitsett JA", "Xu Y", "Pryhuber GS", "Mariani TJ"], "journal": "Genes (Basel)", "journal_title": "Genes", "citation": "Genes, 02 2024", "abstract": "While animal model studies have extensively defined the mechanisms controlling cell diversity in the developing mammalian lung, there exists a significant knowledge gap with regards to late-stage human lung development. The NHLBI Molecular Atlas of Lung Development Program (LungMAP) seeks to fill this gap by creating a structural, cellular and molecular atlas of the human and mouse lung. Transcriptomic profiling at the single-cell level created a cellular atlas of newborn human lungs. Frozen single-cell isolates obtained from two newborn human lungs from the LungMAP Human Tissue Core Biorepository, were captured, and library preparation was completed on the Chromium 10X system. Data was analyzed in Seurat, and cellular annotation was performed using the ToppGene functional analysis tool. Transcriptional interrogation of 5500 newborn human lung cells identified distinct clusters representing multiple populations of epithelial, endothelial, fibroblasts, pericytes, smooth muscle, immune cells and their gene signatures. Computational integration of data from newborn human cells and with 32,000 cells from postnatal days 1 through 10 mouse lungs generated by the LungMAP Cincinnati Research Center facilitated the identification of distinct cellular lineages among all the major cell types. Integration of the newborn human and mouse cellular transcriptomes also demonstrated cell type-specific differences in maturation states of newborn human lung cells. Specifically, newborn human lung matrix fibroblasts could be separated into those representative of younger cells (n = 393), or older cells (n = 158). Cells with each molecular profile were spatially resolved within newborn human lung tissue. This is the first comprehensive molecular map of the cellular landscape of neonatal human lung, including biomarkers for cells at distinct states of maturity.", "year": "2024", "month": "02", "volume": "15", "issue": "3", "pages": "", "doi": "10.3390/genes15030298", "link": "https://www.ncbi.nlm.nih.gov/pubmed/38540357", "sort_key": "2024-02-single-cell transcri", "quarter": "q1"}, {"pmid": "38084407", "title": "Single-cell resolution of human airway epithelial cells exposed to bronchiolitis obliterans-associated chemicals.", "authors": ["Chu CY", "Kim SY", "Pryhuber GS", "Mariani TJ", "McGraw MD"], "journal": "Am J Physiol Lung Cell Mol Physiol", "journal_title": "American journal of physiology. Lung cellular and molecular physiology", "citation": "American journal of physiology. Lung cellular and molecular physiology, 02 2024", "abstract": "Bronchiolitis obliterans (BO) is a fibrotic lung disease characterized by progressive luminal narrowing and obliteration of the small airways. In the nontransplant population, inhalation exposure to certain chemicals is associated with BO; however, the mechanisms contributing to disease induction remain poorly understood. This study's objective was to use single-cell RNA sequencing for the identification of transcriptomic signatures common to primary human airway epithelial cells after chemical exposure to BO-associated chemicals-diacetyl or nitrogen mustard-to help explain BO induction. Primary airway epithelial cells were cultured at air-liquid interface and exposed to diacetyl, nitrogen mustard, or control vapors. Cultures were dissociated and sequenced for single-cell RNA. Differential gene expression and functional pathway analyses were compared across exposures. In total, 75,663 single cells were captured and sequenced from all exposure conditions. Unbiased clustering identified 11 discrete phenotypes, including 5 basal, 2 ciliated, and 2 secretory cell clusters. With chemical exposure, the proportion of cells assigned to keratin 5+ basal cells decreased, whereas the proportion of cells aligned to secretory cell clusters increased compared with control exposures. Functional pathway analysis identified interferon signaling and antigen processing/presentation as pathways commonly upregulated after diacetyl or nitrogen mustard exposure in a ciliated cell cluster. Conversely, the response of airway basal cells differed significantly with upregulation of the unfolded protein response in diacetyl-exposed basal cells, not seen in nitrogen mustard-exposed cultures. These new insights provide early identification of airway epithelial signatures common to BO-associated chemical exposures.NEW & NOTEWORTHY Bronchiolitis obliterans (BO) is a devastating fibrotic lung disease of the small airways, or bronchioles. This original manuscript uses single-cell RNA sequencing for identifying common signatures of chemically exposed airway epithelial cells in BO induction. Chemical exposure reduced the proportion of keratin 5+ basal cells while increasing the proportion of keratin 4+ suprabasal cells. Functional pathways contributory to these shifts differed significantly across exposures. These new results highlight similarities and differences in BO induction across exposures.", "year": "2024", "month": "02", "volume": "326", "issue": "2", "pages": "L135-L148", "doi": "10.1152/ajplung.00304.2023", "link": "https://www.ncbi.nlm.nih.gov/pubmed/38084407", "sort_key": "2024-02-single-cell resoluti", "quarter": "q1"}, {"pmid": "36413377", "title": "LungMAP Portal Ecosystem: Systems-level Exploration of the Lung.", "authors": ["Gaddis N", "Fortriede J", "Guo M", "Bardes EE", "Kouril M", "Tabar S", "Burns K", "Ardini-Poleske ME", "Loos S", "Schnell D", "Jin K", "Iyer B", "Du Y", "Huo BX", "Bhattacharjee A", "Korte J", "Munshi R", "Smith V", "Herbst A", "Kitzmiller JA", "Clair GC", "Carson JP", "Adkins J", "Morrisey EE", "Pryhuber GS", "Misra R", "Whitsett JA", "Sun X", "Heathorn T", "Paten B", "Prasath VBS", "Xu Y", "Tickle T", "Aronow BJ", "Salomonis N"], "journal": "Am J Respir Cell Mol Biol", "journal_title": "American journal of respiratory cell and molecular biology", "citation": "American journal of respiratory cell and molecular biology, 02 2024", "abstract": "An improved understanding of the human lung necessitates advanced systems models informed by an ever-increasing repertoire of molecular omics, cellular imaging, and pathological datasets. To centralize and standardize information across broad lung research efforts, we expanded the LungMAP.net website into a new gateway portal. This portal connects a broad spectrum of research networks, bulk and single-cell multiomics data, and a diverse collection of image data that span mammalian lung development and disease. The data are standardized across species and technologies using harmonized data and metadata models that leverage recent advances, including those from the Human Cell Atlas, diverse ontologies, and the LungMAP CellCards initiative. To cultivate future discoveries, we have aggregated a diverse collection of single-cell atlases for multiple species (human, rhesus, and mouse) to enable consistent queries across technologies, cohorts, age, disease, and drug treatment. These atlases are provided as independent and integrated queryable datasets, with an emphasis on dynamic visualization, figure generation, reanalysis, cell-type curation, and automated reference-based classification of user-provided single-cell genomics datasets (Azimuth). As this resource grows, we intend to increase the breadth of available interactive interfaces, supported data types, data portals and datasets from LungMAP, and external research efforts.", "year": "2024", "month": "02", "volume": "70", "issue": "2", "pages": "129-139", "doi": "10.1165/rcmb.2022-0165OC", "link": "https://www.ncbi.nlm.nih.gov/pubmed/36413377", "sort_key": "2024-02-lungmap portal ecosy", "quarter": "q1"}, {"pmid": "38232136", "title": "Splicing neoantigen discovery with SNAF reveals shared targets for cancer immunotherapy.", "authors": ["Li G", "Mahajan S", "Ma S", "Jeffery ED", "Zhang X", "Bhattacharjee A", "Venkatasubramanian M", "Weirauch MT", "Miraldi ER", "Grimes HL", "Sheynkman GM", "Tilburgs T", "Salomonis N"], "journal": "Sci Transl Med", "journal_title": "Science translational medicine", "citation": "Science translational medicine, 01 2024", "abstract": "Immunotherapy has emerged as a crucial strategy to combat cancer by \"reprogramming\" a patient's own immune system. Although immunotherapy is typically reserved for patients with a high mutational burden, neoantigens produced from posttranscriptional regulation may provide an untapped reservoir of common immunogenic targets for new targeted therapies. To comprehensively define tumor-specific and likely immunogenic neoantigens from patient RNA-Seq, we developed Splicing Neo Antigen Finder (SNAF), an easy-to-use and open-source computational workflow to predict splicing-derived immunogenic MHC-bound peptides (T cell antigen) and unannotated transmembrane proteins with altered extracellular epitopes (B cell antigen). This workflow uses a highly accurate deep learning strategy for immunogenicity prediction (DeepImmuno) in conjunction with new algorithms to rank the tumor specificity of neoantigens (BayesTS) and to predict regulators of mis-splicing (RNA-SPRINT). T cell antigens from SNAF were frequently evidenced as HLA-presented peptides from mass spectrometry (MS) and predict response to immunotherapy in melanoma. Splicing neoantigen burden was attributed to coordinated splicing factor dysregulation. Shared splicing neoantigens were found in up to 90% of patients with melanoma, correlated to overall survival in multiple cancer cohorts, induced T cell reactivity, and were characterized by distinct cells of origin and amino acid preferences. In addition to T cell neoantigens, our B cell focused pipeline (SNAF-B) identified a new class of tumor-specific extracellular neoepitopes, which we termed ExNeoEpitopes. ExNeoEpitope full-length mRNA predictions were tumor specific and were validated using long-read isoform sequencing and in vitro transmembrane localization assays. Therefore, our systematic identification of splicing neoantigens revealed potential shared targets for therapy in heterogeneous cancers.", "year": "2024", "month": "01", "volume": "16", "issue": "730", "pages": "eade2886", "doi": "10.1126/scitranslmed.ade2886", "link": "https://www.ncbi.nlm.nih.gov/pubmed/38232136", "sort_key": "2024-01-splicing neoantigen ", "quarter": "q1"}, {"pmid": "38212075", "title": "Single-cell transcriptomic analysis of human pleura reveals stromal heterogeneity and informs in vitro models of mesothelioma.", "authors": ["Obacz J", "Valer JA", "Nibhani R", "Adams TS", "Schupp JC", "Veale N", "Lewis-Wade A", "Flint J", "Hogan J", "Aresu G", "Coonar AS", "Peryt A", "Biffi G", "Kaminski N", "Francies H", "Rassl DM", "Garnett MJ", "Rintoul RC", "Marciniak SJ"], "journal": "Eur Respir J", "journal_title": "The European respiratory journal", "citation": "The European respiratory journal, 01 2024", "abstract": "The pleural lining of the thorax regulates local immunity, inflammation and repair. A variety of conditions, both benign and malignant, including pleural mesothelioma, can affect this tissue. A lack of knowledge concerning the mesothelial and stromal cells comprising the pleura has hampered the development of targeted therapies. Here, we present the first comprehensive single-cell transcriptomic atlas of the human parietal pleura and demonstrate its utility in elucidating pleural biology. We confirm the presence of known universal fibroblasts and describe novel, potentially pleural-specific, fibroblast subtypes. We also present transcriptomic characterisation of multiple in vitro models of benign and malignant mesothelial cells, and characterise these through comparison with in vivo transcriptomic data. While bulk pleural transcriptomes have been reported previously, this is the first study to provide resolution at the single-cell level. We expect our pleural cell atlas will prove invaluable to those studying pleural biology and disease. It has already enabled us to shed light on the transdifferentiation of mesothelial cells, allowing us to develop a simple method for prolonging mesothelial cell differentiation in vitro.", "year": "2024", "month": "01", "volume": "63", "issue": "1", "pages": "", "doi": "10.1183/13993003.00143-2023", "link": "https://www.ncbi.nlm.nih.gov/pubmed/38212075", "sort_key": "2024-01-single-cell transcri", "quarter": "q1"}, {"pmid": "37734036", "title": "Prenatal FGFR2 Signaling via PI3K/AKT Specifies the PDGFRA+ Myofibroblast.", "authors": ["Riccetti MR", "Green J", "Taylor TJ", "Perl AT"], "journal": "Am J Respir Cell Mol Biol", "journal_title": "American journal of respiratory cell and molecular biology", "citation": "American journal of respiratory cell and molecular biology, 01 2024", "abstract": "It is well known that FGFR2 (fibroblast growth factor receptor 2) signaling is critical for proper lung development. Recent studies demonstrate that epithelial FGFR2 signaling during the saccular phase of lung development (sacculation) regulates alveolar type 1 (AT1) and AT2 cell differentiation. During sacculation, PDGFRA (platelet-derived growth factor receptor-\u03b1)-positive lung fibroblasts exist as three functional subtypes: contractile myofibroblasts, extracellular matrix-producing matrix fibroblasts, and lipofibroblasts. All three subtypes are required during alveolarization to establish a niche that supports AT2 epithelial cell self-renewal and AT1 epithelial cell differentiation. FGFR2 signaling directs myofibroblast differentiation in PDGFRA+ fibroblasts during alveolar reseptation after pneumonectomy. However, it remains unknown if FGFR2 signaling regulates PDGFRA+ myo-, matrix, or lipofibroblast differentiation during sacculation. In this study, FGFR2 signaling was inhibited by temporal expression of a secreted dominant-negative FGFR2b (dnFGFR2) by AT2 cells from embryonic day (E) 16.5 to E18.5. Fibroblast and epithelial differentiation were analyzed at E18.5 and postnatal days 7 and 21. At all time points, the number of myofibroblasts was reduced and the number of lipo-/matrix fibroblasts was increased. AT2 cells are increased and AT1 cells are reduced postnatally, but not at E18.5. Similarly, in organoids made with PDGFRA+ fibroblasts from dnFGFR2 lungs, increased AT2 cells and reduced AT1 cells were observed. In vitro treatment of primary wild-type E16.5 adherent saccular lung fibroblasts with recombinant dnFGFR2b/c resulted in reduced myofibroblast contraction. Treatment with the PI3K/AKT activator 740 Y-P rescued the lack of myofibroblast differentiation caused by dnFGFR2b/2c. Moreover, treatment with the PI3K/AKT activator 740 Y-P rescued myofibroblast differentiation in E18.5 fibroblasts isolated from dnFGFR2 lungs.", "year": "2024", "month": "01", "volume": "70", "issue": "1", "pages": "63-77", "doi": "10.1165/rcmb.2023-0245OC", "link": "https://www.ncbi.nlm.nih.gov/pubmed/37734036", "sort_key": "2024-01-prenatal fgfr2 signa", "quarter": "q1"}, {"pmid": "40893796", "title": "Discovery of optimal cell type classification marker genes from single cell RNA sequencing data.", "authors": ["Liu A", "Peng B", "Pankajam AV", "Duong TE", "Pryhuber G", "Scheuermann RH", "Zhang Y"], "journal": "BMC Methods", "journal_title": "BMC methods", "citation": "BMC methods, 2024", "abstract": "BACKGROUND: The use of single cell/nucleus RNA sequencing (scRNA-seq) technologies that quantitively describe cell transcriptional phenotypes is revolutionizing our understanding of cell biology, leading to new insights in cell type identification, disease mechanisms, and drug development. The tremendous growth in scRNA-seq data has posed new challenges in efficiently characterizing data-driven cell types and identifying quantifiable marker genes for cell type classification. The use of machine learning and explainable artificial intelligence has emerged as an effective approach to study large-scale scRNA-seq data. METHODS: NS-Forest is a random forest machine learning-based algorithm that aims to provide a scalable data-driven solution to identify minimum combinations of necessary and sufficient marker genes that capture cell type identity with maximum classification accuracy. Here, we describe the latest version, NS-Forest version 4.0 and its companion Python package (https://github.com/JCVenterInstitute/NSForest), with several enhancements to select marker gene combinations that exhibit highly selective expression patterns among closely related cell types and more efficiently perform marker gene selection for large-scale scRNA-seq data atlases with millions of cells. RESULTS: By modularizing the final decision tree step, NS-Forest v4.0 can be used to compare the performance of user-defined marker genes with the NS-Forest computationally-derived marker genes based on the decision tree classifiers. To quantify how well the identified markers exhibit the desired pattern of being exclusively expressed at high levels within their target cell types, we introduce the On-Target Fraction metric that ranges from 0 to 1, with a metric of 1 assigned to markers that are only expressed within their target cell types and not in cells of any other cell types. NS-Forest v4.0 outperforms previous versions in simulation studies and on its ability to identify markers with higher On-Target Fraction values for closely related cell types in real data, and outperforms other marker gene selection approaches for cell type classification with significantly higher F-beta scores when applied to datasets from three human organs-brain, kidney, and lung. DISCUSSION: Finally, we discuss potential use cases of the NS-Forest marker genes, including for designing spatial transcriptomics gene panels and semantic representation of cell types in biomedical ontologies, for the broad user community.", "year": "2024", "month": "", "volume": "1", "issue": "", "pages": "", "doi": "10.1186/s44330-024-00015-2", "link": "https://www.ncbi.nlm.nih.gov/pubmed/40893796", "sort_key": "2024-00-discovery of optimal", "quarter": "q0"}, {"pmid": "39271260", "title": "Deep learning-based multimodal spatial transcriptomics analysis for cancer.", "authors": ["Rajdeo P", "Aronow B", "Surya Prasath VB"], "journal": "Adv Cancer Res", "journal_title": "Advances in cancer research", "citation": "Advances in cancer research, 2024", "abstract": "The advent of deep learning (DL) and multimodal spatial transcriptomics (ST) has revolutionized cancer research, offering unprecedented insights into tumor biology. This book chapter explores the integration of DL with ST to advance cancer diagnostics, treatment planning, and precision medicine. DL, a subset of artificial intelligence, employs neural networks to model complex patterns in vast datasets, significantly enhancing diagnostic and treatment applications. In oncology, convolutional neural networks excel in image classification, segmentation, and tumor volume analysis, essential for identifying tumors and optimizing radiotherapy. The chapter also delves into multimodal data analysis, which integrates genomic, proteomic, imaging, and clinical data to offer a holistic understanding of cancer biology. Leveraging diverse data sources, researchers can uncover intricate details of tumor heterogeneity, microenvironment interactions, and treatment responses. Examples include integrating MRI data with genomic profiles for accurate glioma grading and combining proteomic and clinical data to uncover drug resistance mechanisms. DL's integration with multimodal data enables comprehensive and actionable insights for cancer diagnosis and treatment. The synergy between DL models and multimodal data analysis enhances diagnostic accuracy, personalized treatment planning, and prognostic modeling. Notable applications include ST, which maps gene expression patterns within tissue contexts, providing critical insights into tumor heterogeneity and potential therapeutic targets. In summary, the integration of DL and multimodal ST represents a paradigm shift towards more precise and personalized oncology. This chapter elucidates the methodologies and applications of these advanced technologies, highlighting their transformative potential in cancer research and clinical practice.", "year": "2024", "month": "", "volume": "163", "issue": "", "pages": "1-38", "doi": "10.1016/bs.acr.2024.08.001", "link": "https://www.ncbi.nlm.nih.gov/pubmed/39271260", "sort_key": "2024-00-deep learning-based ", "quarter": "q0"}, {"pmid": "37733441", "title": "Population-level single-cell genomics reveals conserved gene programs in systemic juvenile idiopathic arthritis.", "authors": ["Verweyen EL", "Thakkar K", "Dhakal S", "Baker E", "Chetal K", "Schnell D", "Canna S", "Grom AA", "Salomonis N", "Schulert GS"], "journal": "J Clin Invest", "journal_title": "The Journal of clinical investigation", "citation": "The Journal of clinical investigation, 11 2023", "abstract": "Systemic autoimmune and autoinflammatory diseases are characterized by genetic and cellular heterogeneity. While current single-cell genomics methods provide insights into known disease subtypes, these analysis methods do not readily reveal novel cell-type perturbation programs shared among distinct patient subsets. Here, we performed single-cell RNA-Seq of PBMCs of patients with systemic juvenile idiopathic arthritis (SJIA) with diverse clinical manifestations, including macrophage activation syndrome (MAS) and lung disease (LD). We introduced two new computational frameworks called UDON and SATAY-UDON, which define patient subtypes based on their underlying disrupted cellular programs as well as associated biomarkers or clinical features. Among twelve independently identified subtypes, this analysis uncovered what we believe to be a novel complement and interferon activation program identified in SJIA-LD monocytes. Extending these analyses to adult and pediatric lupus patients found new but also shared disease programs with SJIA, including interferon and complement activation. Finally, supervised comparison of these programs in a compiled single-cell pan-immune atlas of over 1,000 healthy donors found a handful of normal healthy donors with evidence of early inflammatory activation in subsets of monocytes and platelets, nominating possible biomarkers for early disease detection. Thus, integrative pan-immune single-cell analysis resolved what we believe to be new conserved gene programs underlying inflammatory disease pathogenesis and associated complications.", "year": "2023", "month": "11", "volume": "133", "issue": "22", "pages": "", "doi": "10.1172/JCI166741", "link": "https://www.ncbi.nlm.nih.gov/pubmed/37733441", "sort_key": "2023-11-population-level sin", "quarter": "q4"}, {"pmid": "37824216", "title": "Functional Pdgfra fibroblast heterogeneity in normal and fibrotic mouse lung.", "authors": ["Trempus CS", "Papas BN", "Sifre MI", "Bortner CD", "Scappini E", "Tucker CJ", "Xu X", "Johnson KL", "Deterding LJ", "Williams JG", "Johnson DJ", "Li JL", "Sutton D", "Ganta C", "Mahapatra D", "Arif M", "Basu A", "Pommerolle L", "Cinar R", "Perl AK", "Garantziotis S"], "journal": "JCI Insight", "journal_title": "JCI insight", "citation": "JCI insight, 11 2023", "abstract": "Aberrant fibroblast function plays a key role in the pathogenesis of idiopathic pulmonary fibrosis, a devastating disease of unrelenting extracellular matrix deposition in response to lung injury. Platelet-derived growth factor \u03b1-positive (Pdgfra+) lipofibroblasts (LipoFBs) are essential for lung injury response and maintenance of a functional alveolar stem cell niche. Little is known about the effects of lung injury on LipoFB function. Here, we used single-cell RNA-Seq (scRNA-Seq) technology and PdgfraGFP lineage tracing to generate a transcriptomic profile of Pdgfra+ fibroblasts in normal and injured mouse lungs 14 days after bleomycin exposure, generating 11 unique transcriptomic clusters that segregated according to treatment. While normal and injured LipoFBs shared a common gene signature, injured LipoFBs acquired fibrogenic pathway activity with an attenuation of lipogenic pathways. In a 3D organoid model, injured Pdgfra+ fibroblast-supported organoids were morphologically distinct from those cultured with normal fibroblasts, and scRNA-Seq analysis suggested distinct transcriptomic changes in alveolar epithelia supported by injured Pdgfra+ fibroblasts. In summary, while LipoFBs in injured lung have not migrated from their niche and retain their lipogenic identity, they acquire a potentially reversible fibrogenic profile, which may alter the kinetics of epithelial regeneration and potentially contribute to dysregulated repair, leading to fibrosis.", "year": "2023", "month": "11", "volume": "8", "issue": "22", "pages": "", "doi": "10.1172/jci.insight.164380", "link": "https://www.ncbi.nlm.nih.gov/pubmed/37824216", "sort_key": "2023-11-functional pdgfra fi", "quarter": "q4"}, {"pmid": "37489262", "title": "New insights into the natural history of bronchopulmonary dysplasia from proteomics and multiplexed immunohistochemistry.", "authors": ["Dylag AM", "Misra RS", "Bandyopadhyay G", "Poole C", "Huyck HL", "Jehrio MG", "Haak J", "Deutsch GH", "Dvorak C", "Olson HM", "Paurus V", "Katzman PJ", "Woo J", "Purkerson JM", "Adkins JN", "Mariani TJ", "Clair GC", "Pryhuber GS"], "journal": "Am J Physiol Lung Cell Mol Physiol", "journal_title": "American journal of physiology. Lung cellular and molecular physiology", "citation": "American journal of physiology. Lung cellular and molecular physiology, 10 2023", "abstract": "Bronchopulmonary dysplasia (BPD) is a disease of prematurity related to the arrest of normal lung development. The objective of this study was to better understand how proteome modulation and cell-type shifts are noted in BPD pathology. Pediatric human donors aged 1-3 yr were classified based on history of prematurity and histopathology consistent with \"healed\" BPD (hBPD, n = 3) and \"established\" BPD (eBPD, n = 3) compared with respective full-term born (n = 6) age-matched term controls. Proteins were quantified by tandem mass spectroscopy with selected Western blot validations. Multiplexed immunofluorescence (MxIF) microscopy was performed on lung sections to enumerate cell types. Protein abundances and MxIF cell frequencies were compared among groups using ANOVA. Cell type and ontology enrichment were performed using an in-house tool and/or EnrichR. Proteomics detected 5,746 unique proteins, 186 upregulated and 534 downregulated, in eBPD versus control with fewer proteins differentially abundant in hBPD as compared with age-matched term controls. Cell-type enrichment suggested a loss of alveolar type I, alveolar type II, endothelial/capillary, and lymphatics, and an increase in smooth muscle and fibroblasts consistent with MxIF. Histochemistry and Western analysis also supported predictions of upregulated ferroptosis in eBPD versus control. Finally, several extracellular matrix components mapping to angiogenesis signaling pathways were altered in eBPD. Despite clear parsing by protein abundance, comparative MxIF analysis confirms phenotypic variability in BPD. This work provides the first demonstration of tandem mass spectrometry and multiplexed molecular analysis of human lung tissue for critical elucidation of BPD trajectory-defining factors into early childhood.NEW & NOTEWORTHY We provide new insights into the natural history of bronchopulmonary dysplasia in donor human lungs after the neonatal intensive care unit hospitalization. This study provides new insights into how the proteome and histopathology of BPD changes in early childhood, uncovering novel pathways for future study.", "year": "2023", "month": "10", "volume": "325", "issue": "4", "pages": "L419-L433", "doi": "10.1152/ajplung.00130.2023", "link": "https://www.ncbi.nlm.nih.gov/pubmed/37489262", "sort_key": "2023-10-new insights into th", "quarter": "q4"}, {"pmid": "37876024", "title": "CXCL10 deficiency limits macrophage infiltration, preserves lung matrix, and enables lung growth in bronchopulmonary dysplasia.", "authors": ["Hirani DV", "Thielen F", "Mansouri S", "Danopoulos S", "Vohlen C", "Haznedar-Karakaya P", "Mohr J", "Wilke R", "Selle J", "Grosch T", "Mizik I", "Odenthal M", "Alvira CM", "Kuiper-Makris C", "Pryhuber GS", "Pallasch C", "van Koningsbruggen-Rietschel S", "Al-Alam D", "Seeger W", "Savai R", "D\u00f6tsch J", "Alejandre Alcazar MA"], "journal": "Inflamm Regen", "journal_title": "Inflammation and regeneration", "citation": "Inflammation and regeneration, 10 2023", "abstract": "Preterm infants with oxygen supplementation are at high risk for bronchopulmonary dysplasia (BPD), a neonatal chronic lung disease. Inflammation with macrophage activation is central to the pathogenesis of BPD. CXCL10, a chemotactic and pro-inflammatory chemokine, is elevated in the lungs of infants evolving BPD and in hyperoxia-based BPD in mice. Here, we tested if CXCL10 deficiency preserves lung growth after neonatal hyperoxia by preventing macrophage activation. To this end, we exposed Cxcl10 knockout (Cxcl10-/-) and wild-type mice to an experimental model of hyperoxia (85% O2)-induced neonatal lung injury and subsequent regeneration. In addition, cultured primary human macrophages and murine macrophages (J744A.1) were treated with CXCL10 and/or CXCR3 antagonist. Our transcriptomic analysis identified CXCL10 as a central hub in the inflammatory network of neonatal mouse lungs after hyperoxia. Quantitative histomorphometric analysis revealed that Cxcl10-/- mice are in part protected from reduced alveolar. These findings were related to the preserved spatial distribution of elastic fibers, reduced collagen deposition, and protection from macrophage recruitment/infiltration to the lungs in Cxcl10-/- mice during acute injury and regeneration. Complimentary, studies with cultured human and murine macrophages showed that hyperoxia induces Cxcl10 expression that in turn triggers M1-like activation and migration of macrophages through CXCR3. Finally, we demonstrated a temporal increase of macrophage-related CXCL10 in the lungs of infants with BPD. In conclusion, our data demonstrate macrophage-derived CXCL10 in experimental and clinical BPD that drives macrophage chemotaxis through CXCR3, causing pro-fibrotic lung remodeling and arrest of alveolarization. Thus, targeting the CXCL10-CXCR3 axis could offer a new therapeutic avenue for BPD.", "year": "2023", "month": "10", "volume": "43", "issue": "1", "pages": "52", "doi": "10.1186/s41232-023-00301-6", "link": "https://www.ncbi.nlm.nih.gov/pubmed/37876024", "sort_key": "2023-10-cxcl10 deficiency li", "quarter": "q4"}, {"pmid": "37463497", "title": "Single Cell Multiomics Identifies Cells and Genetic Networks Underlying Alveolar Capillary Dysplasia.", "authors": ["Guo M", "Wikenheiser-Brokamp KA", "Kitzmiller JA", "Jiang C", "Wang G", "Wang A", "Preissl S", "Hou X", "Buchanan J", "Karolak JA", "Miao Y", "Frank DB", "Zacharias WJ", "Sun X", "Xu Y", "Gu M", "Stankiewicz P", "Kalinichenko VV", "Wambach JA", "Whitsett JA"], "journal": "Am J Respir Crit Care Med", "journal_title": "American journal of respiratory and critical care medicine", "citation": "American journal of respiratory and critical care medicine, 09 2023", "abstract": "Rationale: Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a lethal developmental disorder of lung morphogenesis caused by insufficiency of FOXF1 (forkhead box F1) transcription factor function. The cellular and transcriptional mechanisms by which FOXF1 deficiency disrupts human lung formation are unknown. Objectives: To identify cell types, gene networks, and cell-cell interactions underlying the pathogenesis of ACDMPV. Methods: We used single-nucleus RNA and assay for transposase-accessible chromatin sequencing, immunofluorescence confocal microscopy, and RNA in situ hybridization to identify cell types and molecular networks influenced by FOXF1 in ACDMPV lungs. Measurements and Main Results: Pathogenic single-nucleotide variants and copy-number variant deletions involving the FOXF1 gene locus in all subjects with ACDMPV (n = 6) were accompanied by marked changes in lung structure, including deficient alveolar development and a paucity of pulmonary microvasculature. Single-nucleus RNA and assay for transposase-accessible chromatin sequencing identified alterations in cell number and gene expression in endothelial cells (ECs), pericytes, fibroblasts, and epithelial cells in ACDMPV lungs. Distinct cell-autonomous roles for FOXF1 in capillary ECs and pericytes were identified. Pathogenic variants involving the FOXF1 gene locus disrupt gene expression in EC progenitors, inhibiting the differentiation or survival of capillary 2 ECs and cell-cell interactions necessary for both pulmonary vasculogenesis and alveolar type 1 cell differentiation. Loss of the pulmonary microvasculature was associated with increased VEGFA (vascular endothelial growth factor A) signaling and marked expansion of systemic bronchial ECs expressing COL15A1 (collagen type XV \u03b1 1 chain). Conclusions: Distinct FOXF1 gene regulatory networks were identified in subsets of pulmonary endothelial and fibroblast progenitors, providing both cellular and molecular targets for the development of therapies for ACDMPV and other diffuse lung diseases of infancy.", "year": "2023", "month": "09", "volume": "208", "issue": "6", "pages": "709-725", "doi": "10.1164/rccm.202210-2015OC", "link": "https://www.ncbi.nlm.nih.gov/pubmed/37463497", "sort_key": "2023-09-single cell multiomi", "quarter": "q3"}, {"pmid": "37786667", "title": "Bering: joint cell segmentation and annotation for spatial transcriptomics with transferred graph embeddings.", "authors": ["Jin K", "Zhang Z", "Zhang K", "Viggiani F", "Callahan C", "Tang J", "Aronow BJ", "Shu J"], "journal": "bioRxiv", "journal_title": "bioRxiv : the preprint server for biology", "citation": "bioRxiv : the preprint server for biology, 09 2023", "abstract": "Single-cell spatial transcriptomics such as in-situ hybridization or sequencing technologies can provide subcellular resolution that enables the identification of individual cell identities, locations, and a deep understanding of subcellular mechanisms. However, accurate segmentation and annotation that allows individual cell boundaries to be determined remains a major challenge that limits all the above and downstream insights. Current machine learning methods heavily rely on nuclei or cell body staining, resulting in the significant loss of both transcriptome depth and the limited ability to learn latent representations of spatial colocalization relationships. Here, we propose Bering , a graph deep learning model that leverages transcript colocalization relationships for joint noise-aware cell segmentation and molecular annotation in 2D and 3D spatial transcriptomics data. Graph embeddings for the cell annotation are transferred as a component of multi-modal input for cell segmentation, which is employed to enrich gene relationships throughout the process. To evaluate performance, we benchmarked Bering with state-of-the-art methods and observed significant improvement in cell segmentation accuracies and numbers of detected transcripts across various spatial technologies and tissues. To streamline segmentation processes, we constructed expansive pre-trained models, which yield high segmentation accuracy in new data through transfer learning and self-distillation, demonstrating the generalizability of Bering.", "year": "2023", "month": "09", "volume": "", "issue": "", "pages": "", "doi": "10.1101/2023.09.19.558548", "link": "https://www.ncbi.nlm.nih.gov/pubmed/37786667", "sort_key": "2023-09-bering: joint cell s", "quarter": "q3"}, {"pmid": "37468619", "title": "Organ Mapping Antibody Panels: a community resource for standardized multiplexed tissue imaging.", "authors": ["Quardokus EM", "Saunders DC", "McDonough E", "Hickey JW", "Werlein C", "Surrette C", "Rajbhandari P", "Casals AM", "Tian H", "Lowery L", "Neumann EK", "Bj\u00f6rklund F", "Neelakantan TV", "Croteau J", "Wiblin AE", "Fisher J", "Livengood AJ", "Dowell KG", "Silverstein JC", "Spraggins JM", "Pryhuber GS", "Deutsch G", "Ginty F", "Nolan GP", "Melov S", "Jonigk D", "Caldwell MA", "Vlachos IS", "Muller W", "Gehlenborg N", "Stockwell BR", "Lundberg E", "Snyder MP", "Germain RN", "Camarillo JM", "Kelleher NL", "B\u00f6rner K", "Radtke AJ"], "journal": "Nat Methods", "journal_title": "Nature methods", "citation": "Nature methods, 08 2023", "abstract": "Multiplexed antibody-based imaging enables the detailed characterization of molecular and cellular organization in tissues. Advances in the field now allow high-parameter data collection (>60 targets); however, considerable expertise and capital are needed to construct the antibody panels employed by these methods. Organ mapping antibody panels are community-validated resources that save time and money, increase reproducibility, accelerate discovery and support the construction of a Human Reference Atlas.", "year": "2023", "month": "08", "volume": "20", "issue": "8", "pages": "1174-1178", "doi": "10.1038/s41592-023-01846-7", "link": "https://www.ncbi.nlm.nih.gov/pubmed/37468619", "sort_key": "2023-08-organ mapping antibo", "quarter": "q3"}, {"pmid": "37553579", "title": "Loss of microRNA-30a and sex-specific effects on the neonatal hyperoxic lung injury.", "authors": ["Grimm SL", "Reddick S", "Dong X", "Leek C", "Wang AX", "Gutierrez MC", "Hartig SM", "Moorthy B", "Coarfa C", "Lingappan K"], "journal": "Biol Sex Differ", "journal_title": "Biology of sex differences", "citation": "Biology of sex differences, 08 2023", "abstract": "BACKGROUND: Bronchopulmonary dysplasia (BPD) is characterized by an arrest in lung development and is a leading cause of morbidity in premature neonates. It has been well documented that BPD disproportionally affects males compared to females, but the molecular mechanisms behind this sex-dependent bias remain unclear. Female mice show greater preservation of alveolarization and angiogenesis when exposed to hyperoxia, accompanied by increased miR-30a expression. In this investigation, we tested the hypothesis that loss of miR-30a would result in male and female mice experiencing similar impairments in alveolarization and angiogenesis under hyperoxic conditions. METHODS: Wild-type and miR-30a-/- neonatal mice were exposed to hyperoxia [95% FiO2, postnatal day [PND1-5] or room air before being euthanized on PND21. Alveolarization, pulmonary microvascular development, differences in lung transcriptome, and miR-30a expression were assessed in lungs from WT and miR-30a-/- mice of either sex. Blood transcriptomic signatures from preterm newborns (with and without BPD) were correlated with WT and miR-30a-/- male and female lung transcriptome data. RESULTS: Significantly, the sex-specific differences observed in WT mice were abrogated in the miR-30a-/- mice upon exposure to hyperoxia. The loss of miR-30a expression eliminated the protective effect in females, suggesting that miR-30a plays an essential role in regulating alveolarization and angiogenesis. Transcriptome analysis by whole lung RNA-Seq revealed a significant response in the miR-30a-/- female hyperoxia-exposed lung, with enrichment of pathways related to cell cycle and neuroactive ligand-receptor interaction. Gene expression signature in the miR-30a-/- female lung associated with human BPD blood transcriptomes. Finally, we showed the spatial localization of miR-30a transcripts in the bronchiolar epithelium. CONCLUSIONS: miR-30a could be one of the biological factors mediating the resilience of the female preterm lung to neonatal hyperoxic lung injury. A better understanding of the effects of miR-30a on pulmonary angiogenesis and alveolarization may lead to novel therapeutics for treating BPD.", "year": "2023", "month": "08", "volume": "14", "issue": "1", "pages": "50", "doi": "10.1186/s13293-023-00535-6", "link": "https://www.ncbi.nlm.nih.gov/pubmed/37553579", "sort_key": "2023-08-loss of microrna-30a", "quarter": "q3"}, {"pmid": "37516747", "title": "Guided construction of single cell reference for human and mouse lung.", "authors": ["Guo M", "Morley MP", "Jiang C", "Wu Y", "Li G", "Du Y", "Zhao S", "Wagner A", "Cakar AC", "Kouril M", "Jin K", "Gaddis N", "Kitzmiller JA", "Stewart K", "Basil MC", "Lin SM", "Ying Y", "Babu A", "Wikenheiser-Brokamp KA", "Mun KS", "Naren AP", "Clair G", "Adkins JN", "Pryhuber GS", "Misra RS", "Aronow BJ", "Tickle TL", "Salomonis N", "Sun X", "Morrisey EE", "Whitsett JA", "NHLBI LungMAP Consortium", "Xu Y"], "journal": "Nat Commun", "journal_title": "Nature communications", "citation": "Nature communications, 07 2023", "abstract": "Accurate cell type identification is a key and rate-limiting step in single-cell data analysis. Single-cell references with comprehensive cell types, reproducible and functionally validated cell identities, and common nomenclatures are much needed by the research community for automated cell type annotation, data integration, and data sharing. Here, we develop a computational pipeline utilizing the LungMAP CellCards as a dictionary to consolidate single-cell transcriptomic datasets of 104 human lungs and 17 mouse lung samples to construct LungMAP single-cell reference (CellRef) for both normal human and mouse lungs. CellRefs define 48 human and 40 mouse lung cell types catalogued from diverse anatomic locations and developmental time points. We demonstrate the accuracy and stability of LungMAP CellRefs and their utility for automated cell type annotation of both normal and diseased lungs using multiple independent methods and testing data. We develop user-friendly web interfaces for easy access and maximal utilization of the LungMAP CellRefs.", "year": "2023", "month": "07", "volume": "14", "issue": "1", "pages": "4566", "doi": "10.1038/s41467-023-40173-5", "link": "https://www.ncbi.nlm.nih.gov/pubmed/37516747", "sort_key": "2023-07-guided construction ", "quarter": "q3"}, {"pmid": "36813173", "title": "Influence of the irradiated pulmonary microenvironment on macrophage and T cell dynamics.", "authors": ["Groves AM", "Misra R", "Clair G", "Hernady E", "Olson H", "Orton D", "Finkelstein J", "Marples B", "Johnston CJ"], "journal": "Radiother Oncol", "journal_title": "Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology", "citation": "Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology, 06 2023", "abstract": "BACKGROUND: The lung is sensitive to radiation, increasing normal tissue toxicity risks following radiation therapy. Adverse outcomes include pneumonitis and pulmonary fibrosis, which result from dysregulated intercellular communication within the pulmonary microenvironment. Although macrophages are implicated in these pathogenic outcomes, the impact of their microenvironment is not well understood. MATERIALS AND METHODS: C57BL/6J mice received 6Gyx5 irradiation to the right lung. Macrophage and T cell dynamics were investigated in ipsilateral right lungs, contralateral left lungs and non-irradiated control lungs 4-26wk post exposure. Lungs were evaluated by flow cytometry, histology and proteomics. RESULTS: Following uni-lung irradiation, focal regions of macrophage accumulation were noted in both lungs by 8wk, however by 26wk fibrotic lesions were observed only in ipsilateral lungs. Infiltrating and alveolar macrophages populations expanded in both lungs, however transitional CD11b + alveolar macrophages persisted only in ipsilateral lungs and expressed lower CD206. Concurrently, arginase-1 + macrophages accumulated in ipsilateral but not contralateral lungs at 8 and 26wk post exposure, while CD206 + macrophages were absent from these accumulations. While radiation expanded CD8 + T cells in both lungs, T regulatory cells only increased in ipsilateral lungs. Unbiased proteomics analysis of immune cells revealed a substantial number of differentially expressed proteins in ipsilateral lungs when compared to contralateral lungs and both differed from non-irradiated controls. CONCLUSIONS: Pulmonary macrophage and T cell dynamics are impacted by the microenvironmental conditions that develop following radiation exposure, both locally and systemically. While macrophages and T cells infiltrate and expand in both lungs, they diverge phenotypically depending on their environment.", "year": "2023", "month": "06", "volume": "183", "issue": "", "pages": "109543", "doi": "10.1016/j.radonc.2023.109543", "link": "https://www.ncbi.nlm.nih.gov/pubmed/36813173", "sort_key": "2023-06-influence of the irr", "quarter": "q2"}, {"pmid": "37074178", "title": "Generation and Functional Analysis of Defective Viral Genomes during SARS-CoV-2 Infection.", "authors": ["Zhou T", "Gilliam NJ", "Li S", "Spandau S", "Osborn RM", "Connor S", "Anderson CS", "Mariani TJ", "Thakar J", "Dewhurst S", "Mathews DH", "Huang L", "Sun Y"], "journal": "mBio", "journal_title": "mBio", "citation": "mBio, 06 2023", "abstract": "Defective viral genomes (DVGs) have been identified in many RNA viruses as a major factor influencing antiviral immune response and viral pathogenesis. However, the generation and function of DVGs in SARS-CoV-2 infection are less known. In this study, we elucidated DVG generation in SARS-CoV-2 and its relationship with host antiviral immune response. We observed DVGs ubiquitously from transcriptome sequencing (RNA-seq) data sets of in vitro infections and autopsy lung tissues of COVID-19 patients. Four genomic hot spots were identified for DVG recombination, and RNA secondary structures were suggested to mediate DVG formation. Functionally, bulk and single-cell RNA-seq analysis indicated the interferon (IFN) stimulation of SARS-CoV-2 DVGs. We further applied our criteria to the next-generation sequencing (NGS) data set from a published cohort study and observed a significantly higher amount and frequency of DVG in symptomatic patients than those in asymptomatic patients. Finally, we observed exceptionally diverse DVG populations in one immunosuppressive patient up to 140 days after the first positive test of COVID-19, suggesting for the first time an association between DVGs and persistent viral infections in SARS-CoV-2. Together, our findings strongly suggest a critical role of DVGs in modulating host IFN responses and symptom development, calling for further inquiry into the mechanisms of DVG generation and into how DVGs modulate host responses and infection outcome during SARS-CoV-2 infection. IMPORTANCE Defective viral genomes (DVGs) are generated ubiquitously in many RNA viruses, including SARS-CoV-2. Their interference activity to full-length viruses and IFN stimulation provide the potential for them to be used in novel antiviral therapies and vaccine development. SARS-CoV-2 DVGs are generated through the recombination of two discontinuous genomic fragments by viral polymerase complex, and this recombination is also one of the major mechanisms for the emergence of new coronaviruses. Focusing on the generation and function of SARS-CoV-2 DVGs, these studies identify new hot spots for nonhomologous recombination and strongly suggest that the secondary structures within viral genomes mediate the recombination. Furthermore, these studies provide the first evidence for IFN stimulation activity of de novo DVGs during natural SARS-CoV-2 infection. These findings set up the foundation for further mechanism studies of SARS-CoV-2 recombination and provide evidence to harness the immunostimulatory potential of DVGs in the development of a vaccine and antivirals for SARS-CoV-2.", "year": "2023", "month": "06", "volume": "14", "issue": "3", "pages": "e0025023", "doi": "10.1128/mbio.00250-23", "link": "https://www.ncbi.nlm.nih.gov/pubmed/37074178", "sort_key": "2023-06-generation and funct", "quarter": "q2"}, {"pmid": "37291214", "title": "An integrated cell atlas of the lung in health and disease.", "authors": ["Sikkema L", "Ram\u00edrez-Su\u00e1stegui C", "Strobl DC", "Gillett TE", "Zappia L", "Madissoon E", "Markov NS", "Zaragosi LE", "Ji Y", "Ansari M", "Arguel MJ", "Apperloo L", "Banchero M", "B\u00e9cavin C", "Berg M", "Chichelnitskiy E", "Chung MI", "Collin A", "Gay ACA", "Gote-Schniering J", "Hooshiar Kashani B", "Inecik K", "Jain M", "Kapellos TS", "Kole TM", "Leroy S", "Mayr CH", "Oliver AJ", "von Papen M", "Peter L", "Taylor CJ", "Walzthoeni T", "Xu C", "Bui LT", "De Donno C", "Dony L", "Faiz A", "Guo M", "Gutierrez AJ", "Heumos L", "Huang N", "Ibarra IL", "Jackson ND", "Kadur Lakshminarasimha Murthy P", "Lotfollahi M", "Tabib T", "Talavera-L\u00f3pez C", "Travaglini KJ", "Wilbrey-Clark A", "Worlock KB", "Yoshida M", "Lung Biological Network Consortium", "van den Berge M", "Boss\u00e9 Y", "Desai TJ", "Eickelberg O", "Kaminski N", "Krasnow MA", "Lafyatis R", "Nikolic MZ", "Powell JE", "Rajagopal J", "Rojas M", "Rozenblatt-Rosen O", "Seibold MA", "Sheppard D", "Shepherd DP", "Sin DD", "Timens W", "Tsankov AM", "Whitsett J", "Xu Y", "Banovich NE", "Barbry P", "Duong TE", "Falk CS", "Meyer KB", "Kropski JA", "Pe'er D", "Schiller HB", "Tata PR", "Schultze JL", "Teichmann SA", "Misharin AV", "Nawijn MC", "Luecken MD", "Theis FJ"], "journal": "Nat Med", "journal_title": "Nature medicine", "citation": "Nature medicine, 06 2023", "abstract": "Single-cell technologies have transformed our understanding of human tissues. Yet, studies typically capture only a limited number of donors and disagree on cell type definitions. Integrating many single-cell datasets can address these limitations of individual studies and capture the variability present in the population. Here we present the integrated Human Lung Cell Atlas (HLCA), combining 49 datasets of the human respiratory system into a single atlas spanning over 2.4 million cells from 486 individuals. The HLCA presents a consensus cell type re-annotation with matching marker genes, including annotations of rare and previously undescribed cell types. Leveraging the number and diversity of individuals in the HLCA, we identify gene modules that are associated with demographic covariates such as age, sex and body mass index, as well as gene modules changing expression along the proximal-to-distal axis of the bronchial tree. Mapping new data to the HLCA enables rapid data annotation and interpretation. Using the HLCA as a reference for the study of disease, we identify shared cell states across multiple lung diseases, including SPP1+ profibrotic monocyte-derived macrophages in COVID-19, pulmonary fibrosis and lung carcinoma. Overall, the HLCA serves as an example for the development and use of large-scale, cross-dataset organ atlases within the Human Cell Atlas.", "year": "2023", "month": "06", "volume": "29", "issue": "6", "pages": "1563-1577", "doi": "10.1038/s41591-023-02327-2", "link": "https://www.ncbi.nlm.nih.gov/pubmed/37291214", "sort_key": "2023-06-an integrated cell a", "quarter": "q2"}, {"pmid": "37097893", "title": "pyInfinityFlow: optimized imputation and analysis of high-dimensional flow cytometry data for millions of cells.", "authors": ["Ferchen K", "Salomonis N", "Grimes HL"], "journal": "Bioinformatics", "journal_title": "Bioinformatics (Oxford, England)", "citation": "Bioinformatics (Oxford, England), 05 2023", "abstract": "MOTIVATION: While conventional flow cytometry is limited to dozens of markers, new experimental and computational strategies, such as Infinity Flow, allow for the generation and imputation of hundreds of cell surface protein markers in millions of cells. Here, we describe an end-to-end analysis workflow for Infinity Flow data in Python. RESULTS: pyInfinityFlow enables the efficient analysis of millions of cells, without down-sampling, through direct integration with well-established Python packages for single-cell genomics analysis. pyInfinityFlow accurately identifies both common and extremely rare cell populations which are challenging to define from single-cell genomics studies alone. We demonstrate that this workflow can nominate novel markers to design new flow cytometry gating strategies for predicted cell populations. pyInfinityFlow can be extended to diverse cell discovery analyses with flexibility to adapt to diverse Infinity Flow experimental designs. AVAILABILITY AND IMPLEMENTATION: pyInfinityFlow is freely available in GitHub (https://github.com/KyleFerchen/pyInfinityFlow) and on PyPI (https://pypi.org/project/pyInfinityFlow/). Package documentation with tutorials on a test dataset is available by Read the Docs (pyinfinityflow.readthedocs.io). The scripts and data for reproducing the results are available at https://github.com/KyleFerchen/pyInfinityFlow/tree/main/analysis_scripts, along with the raw flow cytometry input data.", "year": "2023", "month": "05", "volume": "39", "issue": "5", "pages": "", "doi": "10.1093/bioinformatics/btad287", "link": "https://www.ncbi.nlm.nih.gov/pubmed/37097893", "sort_key": "2023-05-pyinfinityflow: opti", "quarter": "q2"}, {"pmid": "37086403", "title": "Emergence of division of labor in tissues through cell interactions and spatial cues.", "authors": ["Adler M", "Moriel N", "Goeva A", "Avraham-Davidi I", "Mages S", "Adams TS", "Kaminski N", "Macosko EZ", "Regev A", "Medzhitov R", "Nitzan M"], "journal": "Cell Rep", "journal_title": "Cell reports", "citation": "Cell reports, 05 2023", "abstract": "Most cell types in multicellular organisms can perform multiple functions. However, not all functions can be optimally performed simultaneously by the same cells. Functions incompatible at the level of individual cells can be performed at the cell population level, where cells divide labor and specialize in different functions. Division of labor can arise due to instruction by tissue environment or through self-organization. Here, we develop a computational framework to investigate the contribution of these mechanisms to division of labor within a cell-type population. By optimizing collective cellular task performance under trade-offs, we find that distinguishable expression patterns can emerge from cell-cell interactions versus instructive signals. We propose a method to construct ligand-receptor networks between specialist cells and use it to infer division-of-labor mechanisms from single-cell RNA sequencing (RNA-seq) and spatial transcriptomics data of stromal, epithelial, and immune cells. Our framework can be used to characterize the complexity of cell interactions within tissues.", "year": "2023", "month": "05", "volume": "42", "issue": "5", "pages": "112412", "doi": "10.1016/j.celrep.2023.112412", "link": "https://www.ncbi.nlm.nih.gov/pubmed/37086403", "sort_key": "2023-05-emergence of divisio", "quarter": "q2"}, {"pmid": "36917181", "title": "Thyroid hormone modulates hyperoxic neonatal lung injury and mitochondrial function.", "authors": ["Vamesu BM", "Nicola T", "Li R", "Hazra S", "Matalon S", "Kaminski N", "Ambalavanan N", "Kandasamy J"], "journal": "JCI Insight", "journal_title": "JCI insight", "citation": "JCI insight, 04 2023", "abstract": "Mitochondrial dysfunction at birth predicts bronchopulmonary dysplasia (BPD) in extremely low-birth weight (ELBW) infants. Recently, nebulized thyroid hormone (TH), given as triiodothyronine (T3), was noted to decrease pulmonary fibrosis in adult animals through improved mitochondrial function. In this study, we tested the hypothesis that TH may have similar effects on hyperoxia-induced neonatal lung injury and mitochondrial dysfunction by testing whether i.n. T3 decreases neonatal hyperoxic lung injury in newborn mice; whether T3 improves mitochondrial function in lung homogenates, neonatal murine lung fibroblasts (NMLFs), and umbilical cord-derived mesenchymal stem cells (UC-MSCs) obtained from ELBW infants; and whether neonatal hypothyroxinemia is associated with BPD in ELBW infants. We found that inhaled T3 (given i.n.) attenuated hyperoxia-induced lung injury and mitochondrial dysfunction in newborn mice. T3 also reduced bioenergetic deficits in UC-MSCs obtained from both infants with no or mild BPD and those with moderate to severe BPD. T3 also increased the content of peroxisome proliferator-activated receptor \u03b3 coactivator 1\u03b1 in lung homogenates of mice exposed to hyperoxia as well as mitochondrial potential in both NMLFs and UC-MSCs. ELBW infants who died or developed moderate to severe BPD had lower total T4 (TT4) compared with survivors with no or mild BPD. In conclusion, TH signaling and function may play a critical role in neonatal lung injury, and inhaled T3 supplementation may be useful as a therapeutic strategy for BPD.", "year": "2023", "month": "04", "volume": "8", "issue": "8", "pages": "", "doi": "10.1172/jci.insight.160697", "link": "https://www.ncbi.nlm.nih.gov/pubmed/36917181", "sort_key": "2023-04-thyroid hormone modu", "quarter": "q2"}, {"pmid": "36577717", "title": "Characterization of a novel Hoxa5eGFP mouse line.", "authors": ["Li MH", "Kuetemeyer JM", "Yallowitz AR", "Wellik DM"], "journal": "Dev Dyn", "journal_title": "Developmental dynamics : an official publication of the American Association of Anatomists", "citation": "Developmental dynamics : an official publication of the American Association of Anatomists, 04 2023", "abstract": "BACKGROUND: Hox genes encode transcription factors that are important for establishing the body plan. Hoxa5 is a member of the mammalian Hox5 paralogous group that regulates the patterning and morphology of the cervical-thoracic region of the axial skeleton. Hoxa5 also plays crucial functions in lung morphogenesis. RESULTS: We generated a Hoxa5eGFP reporter mouse line using CRISPR technology, allowing real-time visualization of Hoxa5 expression. Hoxa5eGFP recapitulates reported embryonic Hoxa5 mRNA expression patterns. Specifically, Hoxa5eGFP can be visualized in the developing mouse neural tube, somites, lung, diaphragm, foregut, and midgut, among other organs. In the stomach, posteriorly biased Hoxa5eGFP expression correlates with a drastic morphological reduction of the corpus in Hox5 paralogous mutants. Expression of Hoxa5eGFP in the lung continues in all lung fibroblast populations through postnatal and adult stages. CONCLUSIONS: We identified cell types that express Hoxa5 in postnatal and adult mouse lungs, including various fibroblasts and vascular endothelial cells. This reporter line will be a powerful tool for studies of the function of Hoxa5 during mouse development, homeostasis, and disease processes.", "year": "2023", "month": "04", "volume": "252", "issue": "4", "pages": "536-546", "doi": "10.1002/dvdy.563", "link": "https://www.ncbi.nlm.nih.gov/pubmed/36577717", "sort_key": "2023-04-characterization of ", "quarter": "q2"}, {"pmid": "36945543", "title": "Matrix and analysis metadata standards (MAMS) to facilitate harmonization and reproducibility of single-cell data.", "authors": ["Wang Y", "Sarfraz I", "Teh WK", "Sokolov A", "Herb BR", "Creasy HH", "Virshup I", "Dries R", "Degatano K", "Mahurkar A", "Schnell DJ", "Madrigal P", "Hilton J", "Gehlenborg N", "Tickle T", "Campbell JD"], "journal": "bioRxiv", "journal_title": "bioRxiv : the preprint server for biology", "citation": "bioRxiv : the preprint server for biology, 03 2023", "abstract": "A large number of genomic and imaging datasets are being produced by consortia that seek to characterize healthy and disease tissues at single-cell resolution. While much effort has been devoted to capturing information related to biospecimen information and experimental procedures, the metadata standards that describe data matrices and the analysis workflows that produced them are relatively lacking. Detailed metadata schema related to data analysis are needed to facilitate sharing and interoperability across groups and to promote data provenance for reproducibility. To address this need, we developed the Matrix and Analysis Metadata Standards (MAMS) to serve as a resource for data coordinating centers and tool developers. We first curated several simple and complex \"use cases\" to characterize the types of feature-observation matrices (FOMs), annotations, and analysis metadata produced in different workflows. Based on these use cases, metadata fields were defined to describe the data contained within each matrix including those related to processing, modality, and subsets. Suggested terms were created for the majority of fields to aid in harmonization of metadata terms across groups. Additional provenance metadata fields were also defined to describe the software and workflows that produced each FOM. Finally, we developed a simple list-like schema that can be used to store MAMS information and implemented in multiple formats. Overall, MAMS can be used as a guide to harmonize analysis-related metadata which will ultimately facilitate integration of datasets across tools and consortia. MAMS specifications, use cases, and examples can be found at https://github.com/single-cell-mams/mams/.", "year": "2023", "month": "03", "volume": "", "issue": "", "pages": "", "doi": "10.1101/2023.03.06.531314", "link": "https://www.ncbi.nlm.nih.gov/pubmed/36945543", "sort_key": "2023-03-matrix and analysis ", "quarter": "q1"}, {"pmid": "36738870", "title": "Informative missingness: What can we learn from patterns in missing laboratory data in the electronic health record?", "authors": ["Tan ALM", "Getzen EJ", "Hutch MR", "Strasser ZH", "Guti\u00e9rrez-Sacrist\u00e1n A", "Le TT", "Dagliati A", "Morris M", "Hanauer DA", "Moal B", "Bonzel CL", "Yuan W", "Chiudinelli L", "Das P", "Zhang HG", "Aronow BJ", "Avillach P", "Brat GA", "Cai T", "Hong C", "La Cava WG", "Hooi Will Loh H", "Luo Y", "Murphy SN", "Yuan Hgiam K", "Omenn GS", "Patel LP", "Jebathilagam Samayamuthu M", "Shriver ER", "Shakeri Hossein Abad Z", "Tan BWL", "Visweswaran S", "Wang X", "Weber GM", "Xia Z", "Verdy B", "COVID-19 by EHR (4CE)", "Long Q", "Mowery DL", "Holmes JH"], "journal": "J Biomed Inform", "journal_title": "Journal of biomedical informatics", "citation": "Journal of biomedical informatics, 03 2023", "abstract": "BACKGROUND: In electronic health records, patterns of missing laboratory test results could capture patients' course of disease as well as \u200b\u200breflect clinician's concerns or worries for possible conditions. These patterns are often understudied and overlooked. This study aims to identify informative patterns of missingness among laboratory data collected across 15 healthcare system sites in three countries for COVID-19 inpatients. METHODS: We collected and analyzed demographic, diagnosis, and laboratory data for 69,939 patients with positive COVID-19 PCR tests across three countries from 1 January 2020 through 30 September 2021. We analyzed missing laboratory measurements across sites, missingness stratification by demographic variables, temporal trends of missingness, correlations between labs based on missingness indicators over time, and clustering of groups of labs based on their missingness/ordering pattern. RESULTS: With these analyses, we identified mapping issues faced in seven out of 15 sites. We also identified nuances in data collection and variable definition for the various sites. Temporal trend analyses may support the use of laboratory test result missingness patterns in identifying severe COVID-19 patients. Lastly, using missingness patterns, we determined relationships between various labs that reflect clinical behaviors. CONCLUSION: In this work, we use computational approaches to relate missingness patterns to hospital treatment capacity and highlight the heterogeneity of looking at COVID-19 over time and at multiple sites, where there might be different phases, policies, etc. Changes in missingness could suggest a change in a patient's condition, and patterns of missingness among laboratory measurements could potentially identify clinical outcomes. This allows sites to consider missing data as informative to analyses and help researchers identify which sites are better poised to study particular questions.", "year": "2023", "month": "03", "volume": "139", "issue": "", "pages": "104306", "doi": "10.1016/j.jbi.2023.104306", "link": "https://www.ncbi.nlm.nih.gov/pubmed/36738870", "sort_key": "2023-03-informative missingn", "quarter": "q1"}, {"pmid": "36879800", "title": "Developmental diversity and unique sensitivity to injury of lung endothelial subtypes during postnatal growth.", "authors": ["Zanini F", "Che X", "Knutsen C", "Liu M", "Suresh NE", "Domingo-Gonzalez R", "Dou SH", "Zhang D", "Pryhuber GS", "Jones RC", "Quake SR", "Cornfield DN", "Alvira CM"], "journal": "iScience", "journal_title": "iScience", "citation": "iScience, 03 2023", "abstract": "At birth, the lung is still immature, heightening susceptibility to injury but enhancing regenerative capacity. Angiogenesis drives postnatal lung development. Therefore, we profiled the transcriptional ontogeny and sensitivity to injury of pulmonary endothelial cells (EC) during early postnatal life. Although subtype speciation was evident at birth, immature lung EC exhibited transcriptomes distinct from mature counterparts, which progressed dynamically over time. Gradual, temporal changes in aerocyte capillary EC (CAP2) contrasted with more marked alterations in general capillary EC (CAP1) phenotype, including distinct CAP1 present only in the early alveolar lung expressing Peg3, a paternally imprinted transcription factor. Hyperoxia, an injury that impairs angiogenesis induced both common and unique endothelial gene signatures, dysregulated capillary EC crosstalk, and suppressed CAP1 proliferation while stimulating venous EC proliferation. These data highlight the diversity, transcriptomic evolution, and pleiotropic responses to injury of immature lung EC, possessing broad implications for lung development and injury across the lifespan.", "year": "2023", "month": "03", "volume": "26", "issue": "3", "pages": "106097", "doi": "10.1016/j.isci.2023.106097", "link": "https://www.ncbi.nlm.nih.gov/pubmed/36879800", "sort_key": "2023-03-developmental divers", "quarter": "q1"}, {"pmid": "36626225", "title": "microRNA-33 deficiency in macrophages enhances autophagy, improves mitochondrial homeostasis, and protects against lung fibrosis.", "authors": ["Ahangari F", "Price NL", "Malik S", "Chioccioli M", "B\u00e4rnthaler T", "Adams TS", "Kim J", "Pradeep SP", "Ding S", "Cosmos C", "Rose KS", "McDonough JE", "Aurelien NR", "Ibarra G", "Omote N", "Schupp JC", "DeIuliis G", "Villalba Nunez JA", "Sharma L", "Ryu C", "Dela Cruz CS", "Liu X", "Prasse A", "Rosas I", "Bahal R", "Fern\u00e1ndez-Hernando C", "Kaminski N"], "journal": "JCI Insight", "journal_title": "JCI insight", "citation": "JCI insight, 02 2023", "abstract": "Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal disease. Recent findings have shown a marked metabolic reprogramming associated with changes in mitochondrial homeostasis and autophagy during pulmonary fibrosis. The microRNA-33 (miR-33) family of microRNAs (miRNAs) encoded within the introns of sterol regulatory element binding protein (SREBP) genes are master regulators of sterol and fatty acid (FA) metabolism. miR-33 controls macrophage immunometabolic response and enhances mitochondrial biogenesis, FA oxidation, and cholesterol efflux. Here, we show that miR-33 levels are increased in bronchoalveolar lavage (BAL) cells isolated from patients with IPF compared with healthy controls. We demonstrate that specific genetic ablation of miR-33 in macrophages protects against bleomycin-induced pulmonary fibrosis. The absence of miR-33 in macrophages improves mitochondrial homeostasis and increases autophagy while decreasing inflammatory response after bleomycin injury. Notably, pharmacological inhibition of miR-33 in macrophages via administration of anti-miR-33 peptide nucleic acids (PNA-33) attenuates fibrosis in different in vivo and ex vivo mice and human models of pulmonary fibrosis. These studies elucidate a major role of miR-33 in macrophages in the regulation of pulmonary fibrosis and uncover a potentially novel therapeutic approach to treat this disease.", "year": "2023", "month": "02", "volume": "8", "issue": "4", "pages": "", "doi": "10.1172/jci.insight.158100", "link": "https://www.ncbi.nlm.nih.gov/pubmed/36626225", "sort_key": "2023-02-microrna-33 deficien", "quarter": "q1"}, {"pmid": "36351366", "title": "Lung Cell Atlases in Health and Disease.", "authors": ["Adams TS", "Marlier A", "Kaminski N"], "journal": "Annu Rev Physiol", "journal_title": "Annual review of physiology", "citation": "Annual review of physiology, 02 2023", "abstract": "The human lung cellular portfolio, traditionally characterized by cellular morphology and individual markers, is highly diverse, with over 40 cell types and a complex branching structure highly adapted for agile airflow and gas exchange. While constant during adulthood, lung cellular content changes in response to exposure, injury, and infection. Some changes are temporary, but others are persistent, leading to structural changes and progressive lung disease. The recent advance of single-cell profiling technologies allows an unprecedented level of detail and scale to cellular measurements, leading to the rise of comprehensive cell atlas styles of reporting. In this review, we chronical the rise of cell atlases and explore their contributions to human lung biology in health and disease.", "year": "2023", "month": "02", "volume": "85", "issue": "", "pages": "47-69", "doi": "10.1146/annurev-physiol-032922-082826", "link": "https://www.ncbi.nlm.nih.gov/pubmed/36351366", "sort_key": "2023-02-lung cell atlases in", "quarter": "q1"}, {"pmid": "35961837", "title": "Super resolution microscopy analysis reveals increased Orai1 activity in asthma and cystic fibrosis lungs.", "authors": ["Goriounova AS", "Gilmore RC", "Wrennall JA", "Tarran R"], "journal": "J Cyst Fibros", "journal_title": "Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society", "citation": "Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society, 01 2023", "abstract": "QUESTION: In diseases such as asthma and cystic fibrosis (CF), the immune response is dysregulated and the lung is chronically inflamed. Orai1 activation is required for the initiation and persistence of inflammation. However, Orai1 expression in the lung is poorly understood. We therefore tested the hypothesis that Orai1 expression was upregulated in asthmatic and CF lungs. MATERIALS AND METHODS: We used LungMAP to analyze single-cell RNAseq data of Orai1 and stromal interaction molecule 1 (STIM1) expression in normal human lungs. We then performed RNAscope analysis and immunostaining on lung sections from normal, asthma, and CF donors. We imaged sections by confocal and super resolution microscopy, and analyzed Orai1 and STIM1 expression in different pulmonary cell types. RESULTS: Orai1 was broadly-expressed, but expression was greatest in immune cells. At mRNA and protein levels, there were no consistent trends in expression levels between the three phenotypes. Orai1 must interact with STIM1 in order to activate and conduct Ca2+. We therefore used STIM1/Orai1 co-localization as a marker of Orai1 activity. Using this approach, we found significantly increased co-localization between these proteins in epithelia, interstitial and luminal immune cells, but not alveoli, from asthma and CF lungs. Orai1 also aggregates as part of its activation process. Using super resolution microscopy, we also found significantly increased Orai1 aggregation in immune cells from asthmatic and CF lungs. CONCLUSION: We found evidence that Orai1 was more active in asthma and CF than normal lungs. These data suggest that Orai1 is a relevant target for reducing pulmonary inflammation.", "year": "2023", "month": "01", "volume": "22", "issue": "1", "pages": "161-171", "doi": "10.1016/j.jcf.2022.07.003", "link": "https://www.ncbi.nlm.nih.gov/pubmed/35961837", "sort_key": "2023-01-super resolution mic", "quarter": "q1"}, {"pmid": "36697445", "title": "Decision level integration of unimodal and multimodal single cell data with scTriangulate.", "authors": ["Li G", "Song B", "Singh H", "Surya Prasath VB", "Leighton Grimes H", "Salomonis N"], "journal": "Nat Commun", "journal_title": "Nature communications", "citation": "Nature communications, 01 2023", "abstract": "Decisively delineating cell identities from uni- and multimodal single-cell datasets is complicated by diverse modalities, clustering methods, and reference atlases. We describe scTriangulate, a computational framework to mix-and-match multiple clustering results, modalities, associated algorithms, and resolutions to achieve an optimal solution. Rather than ensemble approaches which select the \"consensus\", scTriangulate picks the most stable solution through coalitional iteration. When evaluated on diverse multimodal technologies, scTriangulate outperforms alternative approaches to identify high-confidence cell-populations and modality-specific subtypes. Unlike existing integration strategies that rely on modality-specific joint embedding or geometric graphs, scTriangulate makes no assumption about the distributions of raw underlying values. As a result, this approach can solve unprecedented integration challenges, including the ability to automate reference cell-atlas construction, resolve clonal architecture within molecularly defined cell-populations and subdivide clusters to discover splicing-defined disease subtypes. scTriangulate is a flexible strategy for unified integration of single-cell or multimodal clustering solutions, from nearly unlimited sources.", "year": "2023", "month": "01", "volume": "14", "issue": "1", "pages": "406", "doi": "10.1038/s41467-023-36016-y", "link": "https://www.ncbi.nlm.nih.gov/pubmed/36697445", "sort_key": "2023-01-decision level integ", "quarter": "q1"}, {"pmid": "36827401", "title": "Preparation of noninfectious scRNAseq samples from SARS-CoV-2-infected epithelial cells.", "authors": ["Osborn RM", "Leach J", "Zanche M", "Ashton JM", "Chu C", "Thakar J", "Dewhurst S", "Rosenberger S", "Pavelka M", "Pryhuber GS", "Mariani TJ", "Anderson CS"], "journal": "PLoS One", "journal_title": "PloS one", "citation": "PloS one, 2023", "abstract": "Coronavirus disease (COVID-19) is an infectious disease caused by the SARS coronavirus 2 (SARS-CoV-2) virus. Direct assessment, detection, and quantitative analysis using high throughput methods like single-cell RNA sequencing (scRNAseq) is imperative to understanding the host response to SARS-CoV-2. One barrier to studying SARS-CoV-2 in the laboratory setting is the requirement to process virus-infected cell cultures, and potentially infectious materials derived therefrom, under Biosafety Level 3 (BSL-3) containment. However, there are only 190 BSL3 laboratory facilities registered with the U.S. Federal Select Agent Program, as of 2020, and only a subset of these are outfitted with the equipment needed to perform high-throughput molecular assays. Here, we describe a method for preparing non-hazardous RNA samples from SARS-CoV-2 infected cells, that enables scRNAseq analyses to be conducted safely in a BSL2 facility-thereby making molecular assays of SARS-CoV-2 cells accessible to a much larger community of researchers. Briefly, we infected African green monkey kidney epithelial cells (Vero-E6) with SARS-CoV-2 for 96 hours, trypsin-dissociated the cells, and inactivated them with methanol-acetone in a single-cell suspension. Fixed cells were tested for the presence of infectious SARS-CoV-2 virions using the Tissue Culture Infectious Dose Assay (TCID50), and also tested for viability using flow cytometry. We then tested the dissociation and methanol-acetone inactivation method on primary human lung epithelial cells that had been differentiated on an air-liquid interface. Finally, we performed scRNAseq quality control analysis on the resulting cell populations to evaluate the effects of our virus inactivation and sample preparation protocol on the quality of the cDNA produced. We found that methanol-acetone inactivated SARS-CoV-2, fixed the lung epithelial cells, and could be used to obtain noninfectious, high-quality cDNA libraries. This methodology makes investigating SARS-CoV-2, and related high-containment RNA viruses at a single-cell level more accessible to an expanded community of researchers.", "year": "2023", "month": "", "volume": "18", "issue": "2", "pages": "e0281898", "doi": "10.1371/journal.pone.0281898", "link": "https://www.ncbi.nlm.nih.gov/pubmed/36827401", "sort_key": "2023-00-preparation of nonin", "quarter": "q0"}, {"pmid": "37483602", "title": "Editorial: Global excellence in inflammatory diseases: North America 2021.", "authors": ["Kusner LL", "Misra RS", "Lucas R"], "journal": "Front Immunol", "journal_title": "Frontiers in immunology", "citation": "Frontiers in immunology, 2023", "abstract": "", "year": "2023", "month": "", "volume": "14", "issue": "", "pages": "1245827", "doi": "10.3389/fimmu.2023.1245827", "link": "https://www.ncbi.nlm.nih.gov/pubmed/37483602", "sort_key": "2023-00-editorial: global ex", "quarter": "q0"}, {"pmid": "35998281", "title": "Saracatinib, a Selective Src Kinase Inhibitor, Blocks Fibrotic Responses in Preclinical Models of Pulmonary Fibrosis.", "authors": ["Ahangari F", "Becker C", "Foster DG", "Chioccioli M", "Nelson M", "Beke K", "Wang X", "Justet A", "Adams T", "Readhead B", "Meador C", "Correll K", "Lili LN", "Roybal HM", "Rose KA", "Ding S", "Barnthaler T", "Briones N", "DeIuliis G", "Schupp JC", "Li Q", "Omote N", "Aschner Y", "Sharma L", "Kopf KW", "Magnusson B", "Hicks R", "Backmark A", "Dela Cruz CS", "Rosas I", "Cousens LP", "Dudley JT", "Kaminski N", "Downey GP"], "journal": "Am J Respir Crit Care Med", "journal_title": "American journal of respiratory and critical care medicine", "citation": "American journal of respiratory and critical care medicine, 12 2022", "abstract": "Rationale: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and often fatal disorder. Two U.S. Food and Drug Administration-approved antifibrotic drugs, nintedanib and pirfenidone, slow the rate of decline in lung function, but responses are variable and side effects are common. Objectives: Using an in silico data-driven approach, we identified a robust connection between the transcriptomic perturbations in IPF disease and those induced by saracatinib, a selective Src kinase inhibitor originally developed for oncological indications. Based on these observations, we hypothesized that saracatinib would be effective at attenuating pulmonary fibrosis. Methods: We investigated the antifibrotic efficacy of saracatinib relative to nintedanib and pirfenidone in three preclinical models: 1) in vitro in normal human lung fibroblasts; 2) in vivo in bleomycin and recombinant Ad-TGF-\u03b2 (adenovirus transforming growth factor-\u03b2) murine models of pulmonary fibrosis; and 3) ex vivo in mice and human precision-cut lung slices from these two murine models as well as patients with IPF and healthy donors. Measurements and Main Results: In each model, the effectiveness of saracatinib in blocking fibrogenic responses was equal or superior to nintedanib and pirfenidone. Transcriptomic analyses of TGF-\u03b2-stimulated normal human lung fibroblasts identified specific gene sets associated with fibrosis, including epithelial-mesenchymal transition, TGF-\u03b2, and WNT signaling that was uniquely altered by saracatinib. Transcriptomic analysis of whole-lung extracts from the two animal models of pulmonary fibrosis revealed that saracatinib reverted many fibrogenic pathways, including epithelial-mesenchymal transition, immune responses, and extracellular matrix organization. Amelioration of fibrosis and inflammatory cascades in human precision-cut lung slices confirmed the potential therapeutic efficacy of saracatinib in human lung fibrosis. Conclusions: These studies identify novel Src-dependent fibrogenic pathways and support the study of the therapeutic effectiveness of saracatinib in IPF treatment.", "year": "2022", "month": "12", "volume": "206", "issue": "12", "pages": "1463-1479", "doi": "10.1164/rccm.202010-3832OC", "link": "https://www.ncbi.nlm.nih.gov/pubmed/35998281", "sort_key": "2022-12-saracatinib, a selec", "quarter": "q4"}, {"pmid": "36512353", "title": "Hospitalizations Associated With Mental Health Conditions Among Adolescents in the US and France During the COVID-19 Pandemic.", "authors": ["Guti\u00e9rrez-Sacrist\u00e1n A", "Serret-Larmande A", "Hutch MR", "S\u00e1ez C", "Aronow BJ", "Bhatnagar S", "Bonzel CL", "Cai T", "Devkota B", "Hanauer DA", "Loh NHW", "Luo Y", "Moal B", "Ahooyi TM", "Njoroge WFM", "Omenn GS", "Sanchez-Pinto LN", "South AM", "Sperotto F", "Tan ALM", "Taylor DM", "Verdy G", "Visweswaran S", "Xia Z", "Zahner J", "Avillach P", "Bourgeois FT", "Consortium for Clinical Characterization of COVID-19 by EHR (4CE)"], "journal": "JAMA Netw Open", "journal_title": "JAMA network open", "citation": "JAMA network open, 12 2022", "abstract": "IMPORTANCE: The COVID-19 pandemic has been associated with an increase in mental health diagnoses among adolescents, though the extent of the increase, particularly for severe cases requiring hospitalization, has not been well characterized. Large-scale federated informatics approaches provide the ability to efficiently and securely query health care data sets to assess and monitor hospitalization patterns for mental health conditions among adolescents. OBJECTIVE: To estimate changes in the proportion of hospitalizations associated with mental health conditions among adolescents following onset of the COVID-19 pandemic. DESIGN, SETTING, AND PARTICIPANTS: This retrospective, multisite cohort study of adolescents 11 to 17 years of age who were hospitalized with at least 1 mental health condition diagnosis between February 1, 2019, and April 30, 2021, used patient-level data from electronic health records of 8 children's hospitals in the US and France. MAIN OUTCOMES AND MEASURES: Change in the monthly proportion of mental health condition-associated hospitalizations between the prepandemic (February 1, 2019, to March 31, 2020) and pandemic (April 1, 2020, to April 30, 2021) periods using interrupted time series analysis. RESULTS: There were 9696 adolescents hospitalized with a mental health condition during the prepandemic period (5966 [61.5%] female) and 11 101 during the pandemic period (7603 [68.5%] female). The mean (SD) age in the prepandemic cohort was 14.6 (1.9) years and in the pandemic cohort, 14.7 (1.8) years. The most prevalent diagnoses during the pandemic were anxiety (6066 [57.4%]), depression (5065 [48.0%]), and suicidality or self-injury (4673 [44.2%]). There was an increase in the proportions of monthly hospitalizations during the pandemic for anxiety (0.55%; 95% CI, 0.26%-0.84%), depression (0.50%; 95% CI, 0.19%-0.79%), and suicidality or self-injury (0.38%; 95% CI, 0.08%-0.68%). There was an estimated 0.60% increase (95% CI, 0.31%-0.89%) overall in the monthly proportion of mental health-associated hospitalizations following onset of the pandemic compared with the prepandemic period. CONCLUSIONS AND RELEVANCE: In this cohort study, onset of the COVID-19 pandemic was associated with increased hospitalizations with mental health diagnoses among adolescents. These findings support the need for greater resources within children's hospitals to care for adolescents with mental health conditions during the pandemic and beyond.", "year": "2022", "month": "12", "volume": "5", "issue": "12", "pages": "e2246548", "doi": "10.1001/jamanetworkopen.2022.46548", "link": "https://www.ncbi.nlm.nih.gov/pubmed/36512353", "sort_key": "2022-12-hospitalizations ass", "quarter": "q4"}, {"pmid": "36388965", "title": "Cell-intrinsic differences between human airway epithelial cells from children and adults.", "authors": ["Maughan EF", "Hynds RE", "Pennycuick A", "Nigro E", "Gowers KHC", "Denais C", "G\u00f3mez-L\u00f3pez S", "Lazarus KA", "Orr JC", "Pearce DR", "Clarke SE", "Lee DDH", "Woodall MNJ", "Masonou T", "Case KM", "Teixeira VH", "Hartley BE", "Hewitt RJ", "Al Yaghchi C", "Sandhu GS", "Birchall MA", "O'Callaghan C", "Smith CM", "De Coppi P", "Butler CR", "Janes SM"], "journal": "iScience", "journal_title": "iScience", "citation": "iScience, 11 2022", "abstract": "The airway epithelium is a protective barrier that is maintained by the self-renewal and differentiation of basal stem cells. Increasing age is a principle risk factor for chronic lung diseases, but few studies have explored age-related molecular or functional changes in the airway epithelium. We retrieved epithelial biopsies from histologically normal tracheobronchial sites from pediatric and adult donors and compared their cellular composition and gene expression profile (in laser capture-microdissected whole epithelium, fluorescence-activated cell-sorted basal cells, and basal cells in cell culture). Histologically, pediatric and adult tracheobronchial epithelium was similar in composition. We observed age-associated changes in RNA sequencing studies, including higher interferon-associated gene expression in pediatric epithelium. In cell culture, pediatric cells had higher colony formation ability, sustained in vitro growth, and outcompeted adult cells in a direct competitive proliferation assay. Our results demonstrate cell-intrinsic differences between airway epithelial cells from children and adults in both homeostatic and proliferative states.", "year": "2022", "month": "11", "volume": "25", "issue": "11", "pages": "105409", "doi": "10.1016/j.isci.2022.105409", "link": "https://www.ncbi.nlm.nih.gov/pubmed/36388965", "sort_key": "2022-11-cell-intrinsic diffe", "quarter": "q4"}, {"pmid": "36172120", "title": "Generation and functional analysis of defective viral genomes during SARS-CoV-2 infection.", "authors": ["Zhou T", "Gilliam NJ", "Li S", "Spaudau S", "Osborn RM", "Anderson CS", "Mariani TJ", "Thakar J", "Dewhurst S", "Mathews DH", "Huang L", "Sun Y"], "journal": "bioRxiv", "journal_title": "bioRxiv : the preprint server for biology", "citation": "bioRxiv : the preprint server for biology, 09 2022", "abstract": "UNLABELLED: Defective viral genomes (DVGs) have been identified in many RNA viruses as a major factor influencing antiviral immune response and viral pathogenesis. However, the generation and function of DVGs in SARS-CoV-2 infection are less known. In this study, we elucidated DVG generation in SARS-CoV-2 and its relationship with host antiviral immune response. We observed DVGs ubiquitously from RNA-seq datasets of in vitro infections and autopsy lung tissues of COVID-19 patients. Four genomic hotspots were identified for DVG recombination and RNA secondary structures were suggested to mediate DVG formation. Functionally, bulk and single cell RNA-seq analysis indicated the IFN stimulation of SARS-CoV-2 DVGs. We further applied our criteria to the NGS dataset from a published cohort study and observed significantly higher DVG amount and frequency in symptomatic patients than that in asymptomatic patients. Finally, we observed unusually high DVG frequency in one immunosuppressive patient up to 140 days after admitted to hospital due to COVID-19, first-time suggesting an association between DVGs and persistent viral infections in SARS-CoV-2. Together, our findings strongly suggest a critical role of DVGs in modulating host IFN responses and symptom development, calling for further inquiry into the mechanisms of DVG generation and how DVGs modulate host responses and infection outcome during SARS-CoV-2 infection. IMPORTANCE: Defective viral genomes (DVGs) are ubiquitously generated in many RNA viruses, including SARS-CoV-2. Their interference activity to full-length viruses and IFN stimulation provide them the potential for novel antiviral therapies and vaccine development. SARS-CoV-2 DVGs are generated through the recombination of two discontinuous genomic fragments by viral polymerase complex and the recombination is also one of the major mechanisms for the emergence of new coronaviruses. Focusing on the generation and function of SARS-CoV-2 DVGs, these studies identify new hotspots for non-homologous recombination and strongly suggest that the secondary structures within viral genomes mediate the recombination. Furthermore, these studies provide the first evidence for IFN stimulation activity of de novo DVGs during natural SARS-CoV-2 infection. These findings set up the foundation for further mechanism studies of SARS-CoV-2 recombination and provide the evidence to harness DVGs\u00e2\u20ac\u2122 immunostimulatory potential in the development of vaccine and antivirals for SARS-CoV-2.", "year": "2022", "month": "09", "volume": "", "issue": "", "pages": "", "doi": "10.1101/2022.09.22.509123", "link": "https://www.ncbi.nlm.nih.gov/pubmed/36172120", "sort_key": "2022-09-generation and funct", "quarter": "q3"}, {"pmid": "35980752", "title": "Fetal maturation revealed by amniotic fluid cell-free transcriptome in rhesus macaques.", "authors": ["Schmidt AF", "Schnell DJ", "Eaton KP", "Chetal K", "Kannan PS", "Miller LA", "Chougnet CA", "Swarr DT", "Jobe AH", "Salomonis N", "Kamath-Rayne BD"], "journal": "JCI Insight", "journal_title": "JCI insight", "citation": "JCI insight, 09 2022", "abstract": "Accurate estimate of fetal maturity could provide individualized guidance for delivery of complicated pregnancies. However, current methods are invasive, have low accuracy, and are limited to fetal lung maturation. To identify diagnostic gestational biomarkers, we performed transcriptomic profiling of lung and brain, as well as cell-free RNA from amniotic fluid of preterm and term rhesus macaque fetuses. These data identify potentially new and prior-associated gestational age differences in distinct lung and neuronal cell populations when compared with existing single-cell and bulk RNA-Seq data. Comparative analyses found hundreds of genes coincidently induced in lung and amniotic fluid, along with dozens in brain and amniotic fluid. These data enable creation of computational models that accurately predict lung compliance from amniotic fluid and lung transcriptome of preterm fetuses treated with antenatal corticosteroids. Importantly, antenatal steroids induced off-target gene expression changes in the brain, impinging upon synaptic transmission and neuronal and glial maturation, as this could have long-term consequences on brain development. Cell-free RNA in amniotic fluid may provide a substrate of global fetal maturation markers for personalized management of at-risk pregnancies.", "year": "2022", "month": "09", "volume": "7", "issue": "18", "pages": "", "doi": "10.1172/jci.insight.162101", "link": "https://www.ncbi.nlm.nih.gov/pubmed/35980752", "sort_key": "2022-09-fetal maturation rev", "quarter": "q3"}, {"pmid": "35998893", "title": "CellDrift: inferring perturbation responses in temporally sampled single-cell data.", "authors": ["Jin K", "Schnell D", "Li G", "Salomonis N", "Prasath VBS", "Szczesniak R", "Aronow BJ"], "journal": "Brief Bioinform", "journal_title": "Briefings in bioinformatics", "citation": "Briefings in bioinformatics, 09 2022", "abstract": "Cells and tissues respond to perturbations in multiple ways that can be sensitively reflected in the alterations of gene expression. Current approaches to finding and quantifying the effects of perturbations on cell-level responses over time disregard the temporal consistency of identifiable gene programs. To leverage the occurrence of these patterns for perturbation analyses, we developed CellDrift (https://github.com/KANG-BIOINFO/CellDrift), a generalized linear model-based functional data analysis method that is capable of identifying covarying temporal patterns of various cell types in response to perturbations. As compared to several other approaches, CellDrift demonstrated superior performance in the identification of temporally varied perturbation patterns and the ability to impute missing time points. We applied CellDrift to multiple longitudinal datasets, including COVID-19 disease progression and gastrointestinal tract development, and demonstrated its ability to identify specific gene programs associated with sequential biological processes, trajectories and outcomes.", "year": "2022", "month": "09", "volume": "23", "issue": "5", "pages": "", "doi": "10.1093/bib/bbac324", "link": "https://www.ncbi.nlm.nih.gov/pubmed/35998893", "sort_key": "2022-09-celldrift: inferring", "quarter": "q3"}, {"pmid": "36163190", "title": "Airway basal cells show a dedifferentiated KRT17highPhenotype and promote fibrosis in idiopathic pulmonary fibrosis.", "authors": ["Jaeger B", "Schupp JC", "Plappert L", "Terwolbeck O", "Artysh N", "Kayser G", "Engelhard P", "Adams TS", "Zweigerdt R", "Kempf H", "Lienenklaus S", "Garrels W", "Nazarenko I", "Jonigk D", "Wygrecka M", "Klatt D", "Schambach A", "Kaminski N", "Prasse A"], "journal": "Nat Commun", "journal_title": "Nature communications", "citation": "Nature communications, 09 2022", "abstract": "Idiopathic pulmonary fibrosis (IPF) is a fatal disease with limited treatment options. In this study, we focus on the properties of airway basal cells (ABC) obtained from patients with IPF (IPF-ABC). Single cell RNA sequencing (scRNAseq) of bronchial brushes revealed extensive reprogramming of IPF-ABC towards a KRT17high PTENlow dedifferentiated cell type. In the 3D organoid model, compared to ABC obtained from healthy volunteers, IPF-ABC give rise to more bronchospheres, de novo bronchial structures resembling lung developmental processes, induce fibroblast proliferation and extracellular matrix deposition in co-culture. Intratracheal application of IPF-ABC into minimally injured lungs of Rag2-/- or NRG mice causes severe fibrosis, remodeling of the alveolar compartment, and formation of honeycomb cyst-like structures. Connectivity MAP analysis of scRNAseq of bronchial brushings suggested that gene expression changes in IPF-ABC can be reversed by SRC inhibition. After demonstrating enhanced SRC expression and activity in these cells, and in IPF lungs, we tested the effects of saracatinib, a potent SRC inhibitor previously studied in humans. We demonstrate that saracatinib modified in-vitro and in-vivo the profibrotic changes observed in our 3D culture system and novel mouse xenograft model.", "year": "2022", "month": "09", "volume": "13", "issue": "1", "pages": "5637", "doi": "10.1038/s41467-022-33193-0", "link": "https://www.ncbi.nlm.nih.gov/pubmed/36163190", "sort_key": "2022-09-airway basal cells s", "quarter": "q3"}, {"pmid": "35704600", "title": "The balance between protective and pathogenic immune responses to pneumonia in the neonatal lung is enforced by gut microbiota.", "authors": ["Stevens J", "Steinmeyer S", "Bonfield M", "Peterson L", "Wang T", "Gray J", "Lewkowich I", "Xu Y", "Du Y", "Guo M", "Wynn JL", "Zacharias W", "Salomonis N", "Miller L", "Chougnet C", "O'Connor DH", "Deshmukh H"], "journal": "Sci Transl Med", "journal_title": "Science translational medicine", "citation": "Science translational medicine, 06 2022", "abstract": "Although modern clinical practices such as cesarean sections and perinatal antibiotics have improved infant survival, treatment with broad-spectrum antibiotics alters intestinal microbiota and causes dysbiosis. Infants exposed to perinatal antibiotics have an increased likelihood of life-threatening infections, including pneumonia. Here, we investigated how the gut microbiota sculpt pulmonary immune responses, promoting recovery and resolution of infection in newborn rhesus macaques. Early-life antibiotic exposure interrupted the maturation of intestinal commensal bacteria and disrupted the developmental trajectory of the pulmonary immune system, as assessed by single-cell proteomic and transcriptomic analyses. Early-life antibiotic exposure rendered newborn macaques more susceptible to bacterial pneumonia, concurrent with increases in neutrophil senescence and hyperinflammation, broad inflammatory cytokine signaling, and macrophage dysfunction. This pathogenic reprogramming of pulmonary immunity was further reflected by a hyperinflammatory signature in all pulmonary immune cell subsets coupled with a global loss of tissue-protective, homeostatic pathways in the lungs of dysbiotic newborns. Fecal microbiota transfer was associated with partial correction of the broad immune maladaptations and protection against severe pneumonia. These data demonstrate the importance of intestinal microbiota in programming pulmonary immunity and support the idea that gut microbiota promote the balance between pathways driving tissue repair and inflammatory responses associated with clinical recovery from infection in infants. Our results highlight a potential role for microbial transfer for immune support in these at-risk infants.", "year": "2022", "month": "06", "volume": "14", "issue": "649", "pages": "eabl3981", "doi": "10.1126/scitranslmed.abl3981", "link": "https://www.ncbi.nlm.nih.gov/pubmed/35704600", "sort_key": "2022-06-the balance between ", "quarter": "q2"}, {"pmid": "35290476", "title": "Loss of function of renal Glut2 reverses hyperglycaemia and normalises body weight in mouse models of diabetes and obesity.", "authors": ["de Souza Cordeiro LM", "Bainbridge L", "Devisetty N", "McDougal DH", "Peters DJM", "Chhabra KH"], "journal": "Diabetologia", "journal_title": "Diabetologia", "citation": "Diabetologia, 06 2022", "abstract": "AIMS/HYPOTHESIS: Renal GLUT2 is increased in diabetes, thereby enhancing glucose reabsorption and worsening hyperglycaemia. Here, we determined whether loss of Glut2 (also known as Slc2a2) specifically in the kidneys would reverse hyperglycaemia and normalise body weight in mouse models of diabetes and obesity. METHODS: We used the tamoxifen-inducible CreERT2-Lox system in mice to knockout Glut2 specifically in the kidneys (Ks-Glut2 KO) to establish the contribution of renal GLUT2 to systemic glucose homeostasis in health and in insulin-dependent as well as non-insulin-dependent diabetes. We measured circulating glucose and insulin levels in response to OGTT or IVGTT under different experimental conditions in the Ks-Glut2 KO and their control mice. Moreover, we quantified urine glucose levels to explain the phenotype of the mice independently of insulin actions. We also used a transcription factor array to identify mechanisms underlying the crosstalk between renal GLUT2 and sodium-glucose cotransporter 2 (SGLT2). RESULTS: The Ks-Glut2 KO mice exhibited improved glucose tolerance and massive glucosuria. Interestingly, this improvement in blood glucose control was eliminated when we knocked out Glut2 in the liver in addition to the kidneys, suggesting that the improvement is attributable to the lack of renal GLUT2. Remarkably, induction of renal Glut2 deficiency reversed hyperglycaemia and normalised body weight in mouse models of diabetes and obesity. Longitudinal monitoring of renal glucose transporters revealed that Sglt2 (also known as Slc5a2) expression was almost abolished 3 weeks after inducing renal Glut2 deficiency. To identify a molecular basis for this crosstalk, we screened for renal transcription factors that were downregulated in the Ks-Glut2 KO mice. Hnf1\u03b1 (also known as Hnf1a) was among the genes most downregulated and its recovery restored Sglt2 expression in primary renal proximal tubular cells isolated from the Ks-Glut2 KO mice. CONCLUSIONS/INTERPRETATION: Altogether, these results demonstrate a novel crosstalk between renal GLUT2 and SGLT2 in regulating systemic glucose homeostasis via glucose reabsorption. Our findings also indicate that inhibiting renal GLUT2 is a potential therapy for diabetes and obesity.", "year": "2022", "month": "06", "volume": "65", "issue": "6", "pages": "1032-1047", "doi": "10.1007/s00125-022-05676-8", "link": "https://www.ncbi.nlm.nih.gov/pubmed/35290476", "sort_key": "2022-06-loss of function of ", "quarter": "q2"}, {"pmid": "35768548", "title": "International electronic health record-derived post-acute sequelae profiles of COVID-19 patients.", "authors": ["Zhang HG", "Dagliati A", "Shakeri Hossein Abad Z", "Xiong X", "Bonzel CL", "Xia Z", "Tan BWQ", "Avillach P", "Brat GA", "Hong C", "Morris M", "Visweswaran S", "Patel LP", "Guti\u00e9rrez-Sacrist\u00e1n A", "Hanauer DA", "Holmes JH", "Samayamuthu MJ", "Bourgeois FT", "L'Yi S", "Maidlow SE", "Moal B", "Murphy SN", "Strasser ZH", "Neuraz A", "Ngiam KY", "Loh NHW", "Omenn GS", "Prunotto A", "Dalvin LA", "Klann JG", "Schubert P", "Vidorreta FJS", "Benoit V", "Verdy G", "Kavuluru R", "Estiri H", "Luo Y", "Malovini A", "Tibollo V", "Bellazzi R", "Cho K", "Ho YL", "Tan ALM", "Tan BWL", "Gehlenborg N", "Lozano-Zahonero S", "Jouhet V", "Chiovato L", "Aronow BJ", "Toh EMS", "Wong WGS", "Pizzimenti S", "Wagholikar KB", "Bucalo M", "Consortium for Clinical Characterization of COVID-19 by EHR (4CE)", "Cai T", "South AM", "Kohane IS", "Weber GM"], "journal": "NPJ Digit Med", "journal_title": "NPJ digital medicine", "citation": "NPJ digital medicine, 06 2022", "abstract": "The risk profiles of post-acute sequelae of COVID-19 (PASC) have not been well characterized in multi-national settings with appropriate controls. We leveraged electronic health record (EHR) data from 277 international hospitals representing 414,602 patients with COVID-19, 2.3 million control patients without COVID-19 in the inpatient and outpatient settings, and over 221 million diagnosis codes to systematically identify new-onset conditions enriched among patients with COVID-19 during the post-acute period. Compared to inpatient controls, inpatient COVID-19 cases were at significant risk for angina pectoris (RR 1.30, 95% CI 1.09-1.55), heart failure (RR 1.22, 95% CI 1.10-1.35), cognitive dysfunctions (RR 1.18, 95% CI 1.07-1.31), and fatigue (RR 1.18, 95% CI 1.07-1.30). Relative to outpatient controls, outpatient COVID-19 cases were at risk for pulmonary embolism (RR 2.10, 95% CI 1.58-2.76), venous embolism (RR 1.34, 95% CI 1.17-1.54), atrial fibrillation (RR 1.30, 95% CI 1.13-1.50), type 2 diabetes (RR 1.26, 95% CI 1.16-1.36) and vitamin D deficiency (RR 1.19, 95% CI 1.09-1.30). Outpatient COVID-19 cases were also at risk for loss of smell and taste (RR 2.42, 95% CI 1.90-3.06), inflammatory neuropathy (RR 1.66, 95% CI 1.21-2.27), and cognitive dysfunction (RR 1.18, 95% CI 1.04-1.33). The incidence of post-acute cardiovascular and pulmonary conditions decreased across time among inpatient cases while the incidence of cardiovascular, digestive, and metabolic conditions increased among outpatient cases. Our study, based on a federated international network, systematically identified robust conditions associated with PASC compared to control groups, underscoring the multifaceted cardiovascular and neurological phenotype profiles of PASC.", "year": "2022", "month": "06", "volume": "5", "issue": "1", "pages": "81", "doi": "10.1038/s41746-022-00623-8", "link": "https://www.ncbi.nlm.nih.gov/pubmed/35768548", "sort_key": "2022-06-international electr", "quarter": "q2"}, {"pmid": "35697747", "title": "International comparisons of laboratory values from the 4CE collaborative to predict COVID-19 mortality.", "authors": ["Weber GM", "Hong C", "Xia Z", "Palmer NP", "Avillach P", "L'Yi S", "Keller MS", "Murphy SN", "Guti\u00e9rrez-Sacrist\u00e1n A", "Bonzel CL", "Serret-Larmande A", "Neuraz A", "Omenn GS", "Visweswaran S", "Klann JG", "South AM", "Loh NHW", "Cannataro M", "Beaulieu-Jones BK", "Bellazzi R", "Agapito G", "Alessiani M", "Aronow BJ", "Bell DS", "Benoit V", "Bourgeois FT", "Chiovato L", "Cho K", "Dagliati A", "DuVall SL", "Barrio NG", "Hanauer DA", "Ho YL", "Holmes JH", "Issitt RW", "Liu M", "Luo Y", "Lynch KE", "Maidlow SE", "Malovini A", "Mandl KD", "Mao C", "Matheny ME", "Moore JH", "Morris JS", "Morris M", "Mowery DL", "Ngiam KY", "Patel LP", "Pedrera-Jimenez M", "Ramoni RB", "Schriver ER", "Schubert P", "Balazote PS", "Spiridou A", "Tan ALM", "Tan BWL", "Tibollo V", "Torti C", "Trecarichi EM", "Wang X", "Consortium for Clinical Characterization of COVID-19 by EHR (4CE)", "Kohane IS", "Cai T", "Brat GA"], "journal": "NPJ Digit Med", "journal_title": "NPJ digital medicine", "citation": "NPJ digital medicine, 06 2022", "abstract": "Given the growing number of prediction algorithms developed to predict COVID-19 mortality, we evaluated the transportability of a mortality prediction algorithm using a multi-national network of healthcare systems. We predicted COVID-19 mortality using baseline commonly measured laboratory values and standard demographic and clinical covariates across healthcare systems, countries, and continents. Specifically, we trained a Cox regression model with nine measured laboratory test values, standard demographics at admission, and comorbidity burden pre-admission. These models were compared at site, country, and continent level. Of the 39,969 hospitalized patients with COVID-19 (68.6% male), 5717 (14.3%) died. In the Cox model, age, albumin, AST, creatine, CRP, and white blood cell count are most predictive of mortality. The baseline covariates are more predictive of mortality during the early days of COVID-19 hospitalization. Models trained at healthcare systems with larger cohort size largely retain good transportability performance when porting to different sites. The combination of routine laboratory test values at admission along with basic demographic features can predict mortality in patients hospitalized with COVID-19. Importantly, this potentially deployable model differs from prior work by demonstrating not only consistent performance but also reliable transportability across healthcare systems in the US and Europe, highlighting the generalizability of this model and the overall approach.", "year": "2022", "month": "06", "volume": "5", "issue": "1", "pages": "74", "doi": "10.1038/s41746-022-00601-0", "link": "https://www.ncbi.nlm.nih.gov/pubmed/35697747", "sort_key": "2022-06-international compar", "quarter": "q2"}, {"pmid": "35395180", "title": "Uncompensated mitochondrial oxidative stress underlies heart failure in an iPSC-derived model of congenital heart disease.", "authors": ["Xu X", "Jin K", "Bais AS", "Zhu W", "Yagi H", "Feinstein TN", "Nguyen PK", "Criscione JD", "Liu X", "Beutner G", "Karunakaran KB", "Rao KS", "He H", "Adams P", "Kuo CK", "Kostka D", "Pryhuber GS", "Shiva S", "Ganapathiraju MK", "Porter GA", "Lin JI", "Aronow B", "Lo CW"], "journal": "Cell Stem Cell", "journal_title": "Cell stem cell", "citation": "Cell stem cell, 05 2022", "abstract": "Hypoplastic left heart syndrome (HLHS) is a severe congenital heart disease with 30% mortality from heart failure (HF) in the first year of life, but the cause of early HF remains unknown. Induced pluripotent stem-cell-derived cardiomyocytes (iPSC-CM) from patients with HLHS showed that early HF is associated with increased apoptosis, mitochondrial respiration defects, and redox stress from abnormal mitochondrial permeability transition pore (mPTP) opening and failed antioxidant response. In contrast, iPSC-CM from patients without early HF showed normal respiration with elevated antioxidant response. Single-cell transcriptomics confirmed that early HF is associated with mitochondrial dysfunction accompanied with endoplasmic reticulum (ER) stress. These findings indicate that uncompensated oxidative stress underlies early HF in HLHS. Importantly, mitochondrial respiration defects, oxidative stress, and apoptosis were rescued by treatment with sildenafil to inhibit mPTP opening or TUDCA to suppress ER stress. Together these findings point to the potential use of patient iPSC-CM for modeling clinical heart failure and the development of therapeutics.", "year": "2022", "month": "05", "volume": "29", "issue": "5", "pages": "840-855.e7", "doi": "10.1016/j.stem.2022.03.003", "link": "https://www.ncbi.nlm.nih.gov/pubmed/35395180", "sort_key": "2022-05-uncompensated mitoch", "quarter": "q2"}, {"pmid": "35298923", "title": "Three-dimensional feature matching improves coverage for single-cell proteomics based on ion mobility filtering.", "authors": ["Woo J", "Clair GC", "Williams SM", "Feng S", "Tsai CF", "Moore RJ", "Chrisler WB", "Smith RD", "Kelly RT", "Pa\u0161a-Toli\u0107 L", "Ansong C", "Zhu Y"], "journal": "Cell Syst", "journal_title": "Cell systems", "citation": "Cell systems, 05 2022", "abstract": "Single-cell proteomics (scProteomics) promises to advance our understanding of cell functions within complex biological systems. However, a major challenge of current methods is their inability to identify and provide accurate quantitative information for low-abundance proteins. Herein, we describe an ion-mobility-enhanced mass spectrometry acquisition and peptide identification method, transferring identification based on FAIMS filtering (TIFF), to improve the sensitivity and accuracy of label-free scProteomics. TIFF extends the ion accumulation times for peptide ions by filtering out singly charged ions. The peptide identities are assigned by a three-dimensional MS1 feature matching approach (retention time, accurate mass, and FAIMS compensation voltage). The TIFF method enabled unbiased proteome analysis to a depth of >1,700 proteins in single HeLa cells, with >1,100 proteins consistently identified. As a demonstration, we applied the TIFF method to obtain temporal proteome profiles of >150 single murine macrophage cells during lipopolysaccharide stimulation and identified time-dependent proteome changes. A record of this paper's transparent peer review process is included in the supplemental information.", "year": "2022", "month": "05", "volume": "13", "issue": "5", "pages": "426-434.e4", "doi": "10.1016/j.cels.2022.02.003", "link": "https://www.ncbi.nlm.nih.gov/pubmed/35298923", "sort_key": "2022-05-three-dimensional fe", "quarter": "q2"}, {"pmid": "35628331", "title": "Expression of Oxidative Stress and Inflammation-Related Genes in Nasal Mucosa and Nasal Polyps from Patients with Chronic Rhinosinusitis.", "authors": ["Mihalj H", "Butkovi\u0107 J", "Toki\u0107 S", "\u0160tefani\u0107 M", "Kizivat T", "Bujak M", "Baus Lon\u010dar M", "Mihalj M"], "journal": "Int J Mol Sci", "journal_title": "International journal of molecular sciences", "citation": "International journal of molecular sciences, 05 2022", "abstract": "Chronic rhinosinusitis (CRS) is a prevalent, multifaceted inflammatory condition affecting the nasal cavity and the paranasal sinuses, frequently accompanied by formation of nasal polyps (CRSwNP). This apparently uniform clinical entity is preceded by heterogeneous changes in cellular and molecular patterns, suggesting the presence of multiple CRS endotypes and a diverse etiology. Alterations of the upper airway innate defense mechanisms, including antimicrobial and antioxidant capacity, have been implicated in CRSwNP etiology. The aim of this study was to investigate mRNA expression patterns of antioxidative enzymes, including superoxide dismutase (SOD) and peroxiredoxin-2 (PRDX2), and innate immune system defense players, namely the bactericidal/permeability-increasing fold-containing family A, member 1 (BPIFA1) and PACAP family members, particularly adenylate-cyclase-activating polypeptide receptor 1 (ADCYAP1) in nasal mucosa and nasal polyps from CRSwNP patients. Additional stratification based on age, sex, allergic comorbidity, and disease severity was applied. The results showed that ADCYAP1, BPIFA1, and PRDX2 transcripts are differentially expressed in nasal mucosa and scale with radiologically assessed disease severity in CRSwNP patients. Sinonasal transcriptome is not associated with age, sex, and smoking in CRSwNP. Surgical and postoperative corticosteroid (CS) therapy improves endoscopic appearance of the mucosa, but variably reverses target gene expression patterns in the nasal cavity of CRSwNP patients. Transcriptional cross-correlations analysis revealed an increased level of connectedness among differentially expressed genes under inflammatory conditions and restoration of basic network following CS treatment. Although results of the present study imply a possible engagement of ADCYAP1 and BPIFA1 as biomarkers for CRSwNP, a more profound study taking into account disease severity and CRSwNP endotypes prior to the treatment would provide additional information on their sensitivity.", "year": "2022", "month": "05", "volume": "23", "issue": "10", "pages": "", "doi": "10.3390/ijms23105521", "link": "https://www.ncbi.nlm.nih.gov/pubmed/35628331", "sort_key": "2022-05-expression of oxidat", "quarter": "q2"}, {"pmid": "35045271", "title": "Neonatal Hyperoxia Activates Activating Transcription Factor 4 to Stimulate Folate Metabolism and Alveolar Epithelial Type 2 Cell Proliferation.", "authors": ["Yee M", "McDavid AN", "Cohen ED", "Huyck HL", "Poole C", "Altman BJ", "Maniscalco WM", "Deutsch GH", "Pryhuber GS", "O'Reilly MA"], "journal": "Am J Respir Cell Mol Biol", "journal_title": "American journal of respiratory cell and molecular biology", "citation": "American journal of respiratory cell and molecular biology, 04 2022", "abstract": "Oxygen supplementation in preterm infants disrupts alveolar epithelial type 2 (AT2) cell proliferation through poorly understood mechanisms. Here, newborn mice are used to understand how hyperoxia stimulates an early aberrant wave of AT2 cell proliferation that occurs between Postnatal Days (PNDs) 0 and 4. RNA-sequencing analysis of AT2 cells isolated from PND4 mice revealed hyperoxia stimulates expression of mitochondrial-specific methylenetetrahydrofolate dehydrogenase 2 and other genes involved in mitochondrial one-carbon coupled folate metabolism and serine synthesis. The same genes are induced when AT2 cells normally proliferate on PND7 and when they proliferate in response to the mitogen fibroblast growth factor 7. However, hyperoxia selectively stimulated their expression via the stress-responsive activating transcription factor 4 (ATF4). Administration of the mitochondrial superoxide scavenger mitoTEMPO during hyperoxia suppressed ATF4 and thus early AT2 cell proliferation, but it had no effect on normative AT2 cell proliferation seen on PND7. Because ATF4 and methylenetetrahydrofolate dehydrogenase are detected in hyperplastic AT2 cells of preterm infant humans and baboons with bronchopulmonary dysplasia, dampening mitochondrial oxidative stress and ATF4 activation may provide new opportunities for controlling excess AT2 cell proliferation in neonatal lung disease.", "year": "2022", "month": "04", "volume": "66", "issue": "4", "pages": "402-414", "doi": "10.1165/rcmb.2021-0363OC", "link": "https://www.ncbi.nlm.nih.gov/pubmed/35045271", "sort_key": "2022-04-neonatal hyperoxia a", "quarter": "q2"}, {"pmid": "35303432", "title": "Excess neuropeptides in lung signal through endothelial cells to impair gas exchange.", "authors": ["Xu J", "Xu L", "Sui P", "Chen J", "Moya EA", "Hume P", "Janssen WJ", "Duran JM", "Thistlethwaite P", "Carlin A", "Gulleman P", "Banaschewski B", "Goldy MK", "Yuan JX", "Malhotra A", "Pryhuber G", "Crotty-Alexander L", "Deutsch G", "Young LR", "Sun X"], "journal": "Dev Cell", "journal_title": "Developmental cell", "citation": "Developmental cell, 04 2022", "abstract": "Although increased neuropeptides are often detected in lungs that exhibit respiratory distress, whether they contribute to the condition is unknown. Here, we show in a mouse model of neuroendocrine cell hyperplasia of infancy, a pediatric disease with increased pulmonary neuroendocrine cells (PNECs), excess PNEC-derived neuropeptides are responsible for pulmonary manifestations including hypoxemia. In mouse postnatal lung, prolonged signaling from elevated neuropeptides such as calcitonin gene-related peptide (CGRP) activate receptors enriched on endothelial cells, leading to reduced cellular junction gene expression, increased endothelium permeability, excess lung fluid, and hypoxemia. Excess fluid and hypoxemia were effectively attenuated by either prevention of PNEC formation, inactivation of CGRP gene, endothelium-specific inactivation of CGRP receptor gene, or treatment with CGRP receptor antagonist. Neuropeptides were increased in human lung diseases with excess fluid such as acute respiratory distress syndrome. Our findings suggest that restricting neuropeptide function may limit fluid and improve gas exchange in these conditions.", "year": "2022", "month": "04", "volume": "57", "issue": "7", "pages": "839-853.e6", "doi": "10.1016/j.devcel.2022.02.023", "link": "https://www.ncbi.nlm.nih.gov/pubmed/35303432", "sort_key": "2022-04-excess neuropeptides", "quarter": "q2"}, {"pmid": "35113810", "title": "Maladaptive functional changes in alveolar fibroblasts due to perinatal hyperoxia impair epithelial differentiation.", "authors": ["Riccetti MR", "Ushakumary MG", "Waltamath M", "Green J", "Snowball J", "Dautel SE", "Endale M", "Lami B", "Woods J", "Ahlfeld SK", "Perl AT"], "journal": "JCI Insight", "journal_title": "JCI insight", "citation": "JCI insight, 03 2022", "abstract": "Infants born prematurely worldwide have up to a 50% chance of developing bronchopulmonary dysplasia (BPD), a clinical morbidity characterized by dysregulated lung alveolarization and microvascular development. It is known that PDGFR alpha-positive (PDGFRA+) fibroblasts are critical for alveolarization and that PDGFRA+ fibroblasts are reduced in BPD. A better understanding of fibroblast heterogeneity and functional activation status during pathogenesis is required to develop mesenchymal population-targeted therapies for BPD. In this study, we utilized a neonatal hyperoxia mouse model (90% O2 postnatal days 0-7, PN0-PN7) and performed studies on sorted PDGFRA+ cells during injury and room air recovery. After hyperoxia injury, PDGFRA+ matrix and myofibroblasts decreased and PDGFRA+ lipofibroblasts increased by transcriptional signature and population size. PDGFRA+ matrix and myofibroblasts recovered during repair (PN10). After 7 days of in vivo hyperoxia, PDGFRA+ sorted fibroblasts had reduced contractility in vitro, reflecting loss of myofibroblast commitment. Organoids made with PN7 PDGFRA+ fibroblasts from hyperoxia in mice exhibited reduced alveolar type 1 cell differentiation, suggesting reduced alveolar niche-supporting PDGFRA+ matrix fibroblast function. Pathway analysis predicted reduced WNT signaling in hyperoxia fibroblasts. In alveolar organoids from hyperoxia-exposed fibroblasts, WNT activation by CHIR increased the size and number of alveolar organoids and enhanced alveolar type 2 cell differentiation.", "year": "2022", "month": "03", "volume": "7", "issue": "5", "pages": "", "doi": "10.1172/jci.insight.152404", "link": "https://www.ncbi.nlm.nih.gov/pubmed/35113810", "sort_key": "2022-03-maladaptive function", "quarter": "q1"}, {"pmid": "35353543", "title": "Inflammatory blockade prevents injury to the developing pulmonary gas exchange surface in preterm primates.", "authors": ["Toth A", "Steinmeyer S", "Kannan P", "Gray J", "Jackson CM", "Mukherjee S", "Demmert M", "Sheak JR", "Benson D", "Kitzmiller J", "Wayman JA", "Presicce P", "Cates C", "Rubin R", "Chetal K", "Du Y", "Miao Y", "Gu M", "Guo M", "Kalinichenko VV", "Kallapur SG", "Miraldi ER", "Xu Y", "Swarr D", "Lewkowich I", "Salomonis N", "Miller L", "Sucre JS", "Whitsett JA", "Chougnet CA", "Jobe AH", "Deshmukh H", "Zacharias WJ"], "journal": "Sci Transl Med", "journal_title": "Science translational medicine", "citation": "Science translational medicine, 03 2022", "abstract": "Perinatal inflammatory stress is associated with early life morbidity and lifelong consequences for pulmonary health. Chorioamnionitis, an inflammatory condition affecting the placenta and fluid surrounding the developing fetus, affects 25 to 40% of preterm births. Severe chorioamnionitis with preterm birth is associated with significantly increased risk of pulmonary disease and secondary infections in childhood, suggesting that fetal inflammation may markedly alter the development of the lung. Here, we used intra-amniotic lipopolysaccharide (LPS) challenge to induce experimental chorioamnionitis in a prenatal rhesus macaque (Macaca mulatta) model that mirrors structural and temporal aspects of human lung development. Inflammatory injury directly disrupted the developing gas exchange surface of the primate lung, with extensive damage to alveolar structure, particularly the close association and coordinated differentiation of alveolar type 1 pneumocytes and specialized alveolar capillary endothelium. Single-cell RNA sequencing analysis defined a multicellular alveolar signaling niche driving alveologenesis that was extensively disrupted by perinatal inflammation, leading to a loss of gas exchange surface and alveolar simplification, with notable resemblance to chronic lung disease in newborns. Blockade of the inflammatory cytokines interleukin-1\u03b2 and tumor necrosis factor-\u03b1 ameliorated LPS-induced inflammatory lung injury by blunting stromal responses to inflammation and modulating innate immune activation in myeloid cells, restoring structural integrity and key signaling networks in the developing alveolus. These data provide new insight into the pathophysiology of developmental lung injury and suggest that modulating inflammation is a promising therapeutic approach to prevent fetal consequences of chorioamnionitis.", "year": "2022", "month": "03", "volume": "14", "issue": "638", "pages": "eabl8574", "doi": "10.1126/scitranslmed.abl8574", "link": "https://www.ncbi.nlm.nih.gov/pubmed/35353543", "sort_key": "2022-03-inflammatory blockad", "quarter": "q1"}, {"pmid": "35342283", "title": "COMPUTATIONAL 2D and 3D MEDICAL IMAGE DATA COMPRESSION MODELS.", "authors": ["Boopathiraja S", "Punitha V", "Kalavathi P", "Surya Prasath VB"], "journal": "Arch Comput Methods Eng", "journal_title": "Archives of computational methods in engineering : state of the art reviews", "citation": "Archives of computational methods in engineering : state of the art reviews, 03 2022", "abstract": "In this world of big data, the development and exploitation of medical technology is vastly increasing and especially in big biomedical imaging modalities available across medicine. At the same instant, acquisition, processing, storing and transmission of such huge medical data requires efficient and robust data compression models. Over the last two decades, numerous compression mechanisms, techniques and algorithms were proposed by many researchers. This work provides a detailed status of these existing computational compression methods for medical imaging data. Appropriate classification, performance metrics, practical issues and challenges in enhancing the two dimensional (2D) and three dimensional (3D) medical image compression arena are reviewed in detail.", "year": "2022", "month": "03", "volume": "29", "issue": "2", "pages": "975-1007", "doi": "10.1007/s11831-021-09602-w", "link": "https://www.ncbi.nlm.nih.gov/pubmed/35342283", "sort_key": "2022-03-computational 2d and", "quarter": "q1"}, {"pmid": "35434692", "title": "A single-cell regulatory map of postnatal lung alveologenesis in humans and mice.", "authors": ["Duong TE", "Wu Y", "Sos BC", "Dong W", "Limaye S", "Rivier LH", "Myers G", "Hagood JS", "Zhang K"], "journal": "Cell Genom", "journal_title": "Cell genomics", "citation": "Cell genomics, 03 2022", "abstract": "Ex-utero regulation of the lungs' responses to breathing air and continued alveolar development shape adult respiratory health. Applying single-cell transposome hypersensitive site sequencing (scTHS-seq) to over 80,000 cells, we assembled the first regulatory atlas of postnatal human and mouse lung alveolar development. We defined regulatory modules and elucidated new mechanistic insights directing alveolar septation, including alveolar type 1 and myofibroblast cell signaling and differentiation, and a unique human matrix fibroblast population. Incorporating GWAS, we mapped lung function causal variants to myofibroblasts and identified a pathogenic regulatory unit linked to lineage marker FGF18, demonstrating the utility of chromatin accessibility data to uncover disease mechanism targets. Our regulatory map and analysis model provide valuable new resources to investigate age-dependent and species-specific control of critical developmental processes. Furthermore, these resources complement existing atlas efforts to advance our understanding of lung health and disease across the human lifespan.", "year": "2022", "month": "03", "volume": "2", "issue": "3", "pages": "", "doi": "10.1016/j.xgen.2022.100108", "link": "https://www.ncbi.nlm.nih.gov/pubmed/35434692", "sort_key": "2022-03-a single-cell regula", "quarter": "q1"}, {"pmid": "34446466", "title": "Macrophage-derived IL-6 trans-signalling as a novel target in the pathogenesis of bronchopulmonary dysplasia.", "authors": ["Hirani D", "Alvira CM", "Danopoulos S", "Milla C", "Donato M", "Tian L", "Mohr J", "Dinger K", "Vohlen C", "Selle J", "V Koningsbruggen-Rietschel S", "Barbarino V", "Pallasch C", "Rose-John S", "Odenthal M", "Pryhuber GS", "Mansouri S", "Savai R", "Seeger W", "Khatri P", "Al Alam D", "D\u00f6tsch J", "Alejandre Alcazar MA"], "journal": "Eur Respir J", "journal_title": "The European respiratory journal", "citation": "The European respiratory journal, 02 2022", "abstract": "RATIONALE: Premature infants exposed to oxygen are at risk for bronchopulmonary dysplasia (BPD), which is characterised by lung growth arrest. Inflammation is important, but the mechanisms remain elusive. Here, we investigated inflammatory pathways and therapeutic targets in severe clinical and experimental BPD. METHODS AND RESULTS: First, transcriptomic analysis with in silico cellular deconvolution identified a lung-intrinsic M1-like-driven cytokine pattern in newborn mice after hyperoxia. These findings were confirmed by gene expression of macrophage-regulating chemokines (Ccl2, Ccl7, Cxcl5) and markers (Il6, Il17A, Mmp12). Secondly, hyperoxia-activated interleukin 6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) signalling was measured in vivo and related to loss of alveolar epithelial type II cells (ATII) as well as increased mesenchymal marker. Il6 null mice exhibited preserved ATII survival, reduced myofibroblasts and improved elastic fibre assembly, thus enabling lung growth and protecting lung function. Pharmacological inhibition of global IL-6 signalling and IL-6 trans-signalling promoted alveolarisation and ATII survival after hyperoxia. Third, hyperoxia triggered M1-like polarisation, possibly via Kr\u00fcppel-like factor 4; hyperoxia-conditioned medium of macrophages and IL-6-impaired ATII proliferation. Finally, clinical data demonstrated elevated macrophage-related plasma cytokines as potential biomarkers that identify infants receiving oxygen at increased risk of developing BPD. Moreover, macrophage-derived IL6 and active STAT3 were related to loss of epithelial cells in BPD lungs. CONCLUSION: We present a novel IL-6-mediated mechanism by which hyperoxia activates macrophages in immature lungs, impairs ATII homeostasis and disrupts elastic fibre formation, thereby inhibiting lung growth. The data provide evidence that IL-6 trans-signalling could offer an innovative pharmacological target to enable lung growth in severe neonatal chronic lung disease.", "year": "2022", "month": "02", "volume": "59", "issue": "2", "pages": "", "doi": "10.1183/13993003.02248-2020", "link": "https://www.ncbi.nlm.nih.gov/pubmed/34446466", "sort_key": "2022-02-macrophage-derived i", "quarter": "q1"}, {"pmid": "33767374", "title": "Adiponectin ameliorates hyperoxia-induced lung endothelial dysfunction and promotes angiogenesis in neonatal mice.", "authors": ["Shah D", "Sandhu K", "Das P", "Bhandari V"], "journal": "Pediatr Res", "journal_title": "Pediatric research", "citation": "Pediatric research, 02 2022", "abstract": "BACKGROUND: Bronchopulmonary dysplasia (BPD) is a common respiratory disease of preterm infants. Lower circulatory/intrapulmonary levels of the adipokine, adiponectin (APN), occur in premature and small-for-gestational-age infants and at saccular/alveolar stages of lung development in the newborn rat. However, the role of low intrapulmonary APN during hyperoxia exposure in developing lungs is unknown. METHODS: We test the hypothesis that treatment of hyperoxia-exposed newborn mice with recombinant APN protein attenuates the BPD phenotype characterized by inflammation, impaired alveolarization, and dysregulated vascularization. We used developmentally appropriate in vitro and in vivo BPD modeling systems as well as human lung tissue. RESULTS: We observed reduced levels of intrapulmonary APN in experimental BPD mice and human BPD lungs. APN-deficient (APN-/-) newborn mice exposed to moderate (60% O2) hyperoxia showed a worse BPD pulmonary phenotype (inflammation, enhanced endothelial dysfunction, impaired pulmonary vasculature, and alveolar simplification) as compared to wild-type (WT) mice. Treatment of hyperoxia-exposed newborn WT mice with recombinant APN protein attenuated the BPD phenotype (diminished inflammation, decreased pulmonary vascular injury, and improved pulmonary alveolarization) and improved pulmonary function tests. CONCLUSIONS: Low intrapulmonary APN is associated with disruption of lung development during hyperoxia exposure, while recombinant APN protein attenuates the BPD pulmonary phenotype. IMPACT: Intrapulmonary APN levels were significantly decreased in lungs of experimental BPD mice and human BPD lung tissue at various stages of BPD development. Correlative data from human lung samples with decreased APN levels were associated with increased lung adhesion markers (intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin). Decreased APN levels were associated with endothelial dysfunction and moderate BPD phenotype in APN-deficient, as compared to WT, experimental BPD mice. WT experimental BPD mice treated with recombinant APN protein had an improved pulmonary structural and functional phenotype. Exogenous APN may be considered as a potential therapeutic agent to prevent BPD.", "year": "2022", "month": "02", "volume": "91", "issue": "3", "pages": "545-555", "doi": "10.1038/s41390-021-01442-5", "link": "https://www.ncbi.nlm.nih.gov/pubmed/33767374", "sort_key": "2022-02-adiponectin ameliora", "quarter": "q1"}, {"pmid": "35121658", "title": "A dominant negative variant of RAB5B disrupts maturation of surfactant protein B and surfactant protein C.", "authors": ["Huang H", "Pan J", "Spielberg DR", "Hanchard NA", "Scott DA", "Burrage LC", "Dai H", "Murdock D", "Rosenfeld JA", "Mohammad A", "Huang T", "Lindsey AG", "Kim H", "Chen J", "Ramu A", "Morrison SA", "Dawson ZD", "Hu AZ", "Tycksen E", "Silverman GA", "Baldridge D", "Wambach JA", "Undiagnosed Diseases Network", "Pak SC", "Brody SL", "Schedl T"], "journal": "Proc Natl Acad Sci U S A", "journal_title": "Proceedings of the National Academy of Sciences of the United States of America", "citation": "Proceedings of the National Academy of Sciences of the United States of America, 02 2022", "abstract": "Pathogenic variants in surfactant proteins SP-B and SP-C cause surfactant deficiency and interstitial lung disease. Surfactant proteins are synthesized as precursors (proSP-B, proSP-C), trafficked, and processed via a vesicular-regulated secretion pathway; however, control of vesicular trafficking events is not fully understood. Through the Undiagnosed Diseases Network, we evaluated a child with interstitial lung disease suggestive of surfactant deficiency. Variants in known surfactant dysfunction disorder genes were not found in trio exome sequencing. Instead, a de novo heterozygous variant in RAB5B was identified in the Ras/Rab GTPases family nucleotide binding domain, p.Asp136His. Functional studies were performed in Caenorhabditis elegans by knocking the proband variant into the conserved position (Asp135) of the ortholog, rab-5 Genetic analysis demonstrated that rab-5[Asp135His] is damaging, producing a strong dominant negative gene product. rab-5[Asp135His] heterozygotes were also defective in endocytosis and early endosome (EE) fusion. Immunostaining studies of the proband's lung biopsy revealed that RAB5B and EE marker EEA1 were significantly reduced in alveolar type II cells and that mature SP-B and SP-C were significantly reduced, while proSP-B and proSP-C were normal. Furthermore, staining normal lung showed colocalization of RAB5B and EEA1 with proSP-B and proSP-C. These findings indicate that dominant negative-acting RAB5B Asp136His and EE dysfunction cause a defect in processing/trafficking to produce mature SP-B and SP-C, resulting in interstitial lung disease, and that RAB5B and EEs normally function in the surfactant secretion pathway. Together, the data suggest a noncanonical function for RAB5B and identify RAB5B p.Asp136His as a genetic mechanism for a surfactant dysfunction disorder.", "year": "2022", "month": "02", "volume": "119", "issue": "6", "pages": "", "doi": "10.1073/pnas.2105228119", "link": "https://www.ncbi.nlm.nih.gov/pubmed/35121658", "sort_key": "2022-02-a dominant negative ", "quarter": "q1"}, {"pmid": "33883249", "title": "Sphingosine kinase 1 regulates lysyl oxidase through STAT3 in hyperoxia-mediated neonatal lung injury.", "authors": ["Ha AW", "Bai T", "Ebenezer DL", "Sethi T", "Sudhadevi T", "Mangio LA", "Garzon S", "Pryhuber GS", "Natarajan V", "Harijith A"], "journal": "Thorax", "journal_title": "Thorax", "citation": "Thorax, 01 2022", "abstract": "INTRODUCTION: Neonatal lung injury as a consequence of hyperoxia (HO) therapy and ventilator care contribute to the development of bronchopulmonary dysplasia (BPD). Increased expression and activity of lysyl oxidase (LOX), a key enzyme that cross-links collagen, was associated with increased sphingosine kinase 1 (SPHK1) in human BPD. We, therefore, examined closely the link between LOX and SPHK1 in BPD. METHOD: The enzyme expression of SPHK1 and LOX were assessed in lung tissues of human BPD using immunohistochemistry and quantified (Halo). In vivo studies were based on Sphk1-/- and matched wild type (WT) neonatal mice exposed to HO while treated with PF543, an inhibitor of SPHK1. In vitro mechanistic studies used human lung microvascular endothelial cells (HLMVECs). RESULTS: Both SPHK1 and LOX expressions were increased in lungs of patients with BPD. Tracheal aspirates from patients with BPD had increased LOX, correlating with sphingosine-1-phosphate (S1P) levels. HO-induced increase of LOX in lungs were attenuated in both Sphk1-/- and PF543-treated WT mice, accompanied by reduced collagen staining (sirius red). PF543 reduced LOX activity in both bronchoalveolar lavage fluid and supernatant of HLMVECs following HO. In silico analysis revealed STAT3 as a potential transcriptional regulator of LOX. In HLMVECs, following HO, ChIP assay confirmed increased STAT3 binding to LOX promoter. SPHK1 inhibition reduced phosphorylation of STAT3. Antibody to S1P and siRNA against SPNS2, S1P receptor 1 (S1P1) and STAT3 reduced LOX expression. CONCLUSION: HO-induced SPHK1/S1P signalling axis plays a critical role in transcriptional regulation of LOX expression via SPNS2, S1P1 and STAT3 in lung endothelium.", "year": "2022", "month": "01", "volume": "77", "issue": "1", "pages": "47-57", "doi": "10.1136/thoraxjnl-2020-216469", "link": "https://www.ncbi.nlm.nih.gov/pubmed/33883249", "sort_key": "2022-01-sphingosine kinase 1", "quarter": "q1"}, {"pmid": "34739767", "title": "Reduced Notch1 Cleavage Promotes the Development of Pulmonary Hypertension.", "authors": ["Wang S", "Zhu G", "Jiang D", "Rhen J", "Li X", "Liu H", "Lyu Y", "Tsai P", "Rose Y", "Nguyen T", "White RJ", "Pryhuber GS", "Mariani TJ", "Li C", "Mohan A", "Xu Y", "Pang J"], "journal": "Hypertension", "journal_title": "Hypertension (Dallas, Tex. : 1979)", "citation": "Hypertension (Dallas, Tex. : 1979), 01 2022", "abstract": "Clinical trials of Dll4 (Delta-like 4) neutralizing antibodies (Dll4nAbs) in cancer patients are ongoing. Surprisingly, pulmonary hypertension (PH) occurs in 14% to 18% of patients treated with Dll4nAbs, but the mechanisms have not been studied. Here, PH progression was measured in mice treated with Dll4nAbs. We detected Notch signaling in lung tissues and analyzed pulmonary vascular permeability and inflammation. Notch target gene array was performed on adult human pulmonary microvascular endothelial cells (ECs) after inhibiting Notch cleavage. Similar mechanisms were studied in PH mouse models and pulmonary arterial hypertension patients. The rescue effects of constitutively activated Notch1 in vivo were also measured. We observed that Dll4nAbs induced PH in mice as indicated by significantly increased right ventricular systolic pressure, as well as pulmonary vascular and right ventricular remodeling. Mechanistically, Dll4nAbs inhibited Notch1 cleavage and subsequently impaired lung endothelial barrier function and increased immune cell infiltration in vessel walls. In vitro, Notch targeted genes' expression related to cell growth and inflammation was decreased in human pulmonary microvascular ECs after the Notch1 inactivation. In lungs of PH mouse models and pulmonary arterial hypertension patients, Notch1 cleavage was inhibited. Consistently, EC cell-cell junction was leaky, and immune cell infiltration increased in PH mouse models. Overexpression activated Notch1-attenuated progression of PH in mice. In conclusion, Dll4nAbs led to PH development in mice by impaired EC barrier function and increased immune cell infiltration through inhibition of Notch1 cleavage in lung ECs. Reduced Notch1 cleavage in lung ECs could be an underlying mechanism of PH pathogenesis.", "year": "2022", "month": "01", "volume": "79", "issue": "1", "pages": "79-92", "doi": "10.1161/HYPERTENSIONAHA.120.16065", "link": "https://www.ncbi.nlm.nih.gov/pubmed/34739767", "sort_key": "2022-01-reduced notch1 cleav", "quarter": "q1"}, {"pmid": "34752721", "title": "Proteomic Analysis of Human Lung Development.", "authors": ["Clair G", "Bramer LM", "Misra R", "McGraw MD", "Bhattacharya S", "Kitzmiller JA", "Feng S", "Danna VG", "Bandyopadhyay G", "Bhotika H", "Huyck HL", "Deutsch GH", "Mariani TJ", "Carson JP", "Whitsett JA", "Pryhuber GS", "Adkins JN", "Ansong C"], "journal": "Am J Respir Crit Care Med", "journal_title": "American journal of respiratory and critical care medicine", "citation": "American journal of respiratory and critical care medicine, 01 2022", "abstract": "Rationale: The current understanding of human lung development derives mostly from animal studies. Although transcript-level studies have analyzed human donor tissue to identify genes expressed during normal human lung development, protein-level analysis that would enable the generation of new hypotheses on the processes involved in pulmonary development are lacking. Objectives: To define the temporal dynamic of protein expression during human lung development. Methods: We performed proteomics analysis of human lungs at 10 distinct times from birth to 8 years to identify the molecular networks mediating postnatal lung maturation. Measurements and Main Results: We identified 8,938 proteins providing a comprehensive view of the developing human lung proteome. The analysis of the data supports the existence of distinct molecular substages of alveolar development and predicted the age of independent human lung samples, and extensive remodeling of the lung proteome occurred during postnatal development. Evidence of post-transcriptional control was identified in early postnatal development. An extensive extracellular matrix remodeling was supported by changes in the proteome during alveologenesis. The concept of maturation of the immune system as an inherent part of normal lung development was substantiated by flow cytometry and transcriptomics. Conclusions: This study provides the first in-depth characterization of the human lung proteome during development, providing a unique proteomic resource freely accessible at Lungmap.net. The data support the extensive remodeling of the lung proteome during development, the existence of molecular substages of alveologenesis, and evidence of post-transcriptional control in early postnatal development.", "year": "2022", "month": "01", "volume": "205", "issue": "2", "pages": "208-218", "doi": "10.1164/rccm.202008-3303OC", "link": "https://www.ncbi.nlm.nih.gov/pubmed/34752721", "sort_key": "2022-01-proteomic analysis o", "quarter": "q1"}, {"pmid": "34936882", "title": "A census of the lung: CellCards from LungMAP.", "authors": ["Sun X", "Perl AK", "Li R", "Bell SM", "Sajti E", "Kalinichenko VV", "Kalin TV", "Misra RS", "Deshmukh H", "Clair G", "Kyle J", "Crotty Alexander LE", "Masso-Silva JA", "Kitzmiller JA", "Wikenheiser-Brokamp KA", "Deutsch G", "Guo M", "Du Y", "Morley MP", "Valdez MJ", "Yu HV", "Jin K", "Bardes EE", "Zepp JA", "Neithamer T", "Basil MC", "Zacharias WJ", "Verheyden J", "Young R", "Bandyopadhyay G", "Lin S", "Ansong C", "Adkins J", "Salomonis N", "Aronow BJ", "Xu Y", "Pryhuber G", "Whitsett J", "Morrisey EE", "NHLBI LungMAP Consortium"], "journal": "Dev Cell", "journal_title": "Developmental cell", "citation": "Developmental cell, 01 2022", "abstract": "The human lung plays vital roles in respiration, host defense, and basic physiology. Recent technological advancements such as single-cell RNA sequencing and genetic lineage tracing have revealed novel cell types and enriched functional properties of existing cell types in lung. The time has come to take a new census. Initiated by members of the NHLBI-funded LungMAP Consortium and aided by experts in the lung biology community, we synthesized current data into a comprehensive and practical cellular census of the lung. Identities of cell types in the normal lung are captured in individual cell cards with delineation of function, markers, developmental lineages, heterogeneity, regenerative potential, disease links, and key experimental tools. This publication will serve as the starting point of a live, up-to-date guide for lung research at https://www.lungmap.net/cell-cards/. We hope that Lung CellCards will promote the community-wide effort to establish, maintain, and restore respiratory health.", "year": "2022", "month": "01", "volume": "57", "issue": "1", "pages": "112-145.e2", "doi": "10.1016/j.devcel.2021.11.007", "link": "https://www.ncbi.nlm.nih.gov/pubmed/34936882", "sort_key": "2022-01-a census of the lung", "quarter": "q1"}, {"pmid": "36465564", "title": "An optimized approach and inflation media for obtaining complimentary mass spectrometry-based omics data from human lung tissue.", "authors": ["Lukowski JK", "Olson H", "Velickovic M", "Wang J", "Kyle JE", "Kim YM", "Williams SM", "Zhu Y", "Huyck HL", "McGraw MD", "Poole C", "Rogers L", "Misra R", "Alexandrov T", "Ansong C", "Pryhuber GS", "Clair G", "Adkins JN", "Carson JP", "Anderton CR"], "journal": "Front Mol Biosci", "journal_title": "Frontiers in molecular biosciences", "citation": "Frontiers in molecular biosciences, 2022", "abstract": "Human disease states are biomolecularly multifaceted and can span across phenotypic states, therefore it is important to understand diseases on all levels, across cell types, and within and across microanatomical tissue compartments. To obtain an accurate and representative view of the molecular landscape within human lungs, this fragile tissue must be inflated and embedded to maintain spatial fidelity of the location of molecules and minimize molecular degradation for molecular imaging experiments. Here, we evaluated agarose inflation and carboxymethyl cellulose embedding media and determined effective tissue preparation protocols for performing bulk and spatial mass spectrometry-based omics measurements. Mass spectrometry imaging methods were optimized to boost the number of annotatable molecules in agarose inflated lung samples. This optimized protocol permitted the observation of unique lipid distributions within several airway regions in the lung tissue block. Laser capture microdissection of these airway regions followed by high-resolution proteomic analysis allowed us to begin linking the lipidome with the proteome in a spatially resolved manner, where we observed proteins with high abundance specifically localized to the airway regions. We also compared our mass spectrometry results to lung tissue samples preserved using two other inflation/embedding media, but we identified several pitfalls with the sample preparation steps using this preservation method. Overall, we demonstrated the versatility of the inflation method, and we can start to reveal how the metabolome, lipidome, and proteome are connected spatially in human lungs and across disease states through a variety of different experiments.", "year": "2022", "month": "", "volume": "9", "issue": "", "pages": "1022775", "doi": "10.3389/fmolb.2022.1022775", "link": "https://www.ncbi.nlm.nih.gov/pubmed/36465564", "sort_key": "2022-00-an optimized approac", "quarter": "q0"}, {"pmid": "34049947", "title": "Fibroblasts positive for meflin have anti-fibrotic properties in pulmonary fibrosis.", "authors": ["Nakahara Y", "Hashimoto N", "Sakamoto K", "Enomoto A", "Adams TS", "Yokoi T", "Omote N", "Poli S", "Ando A", "Wakahara K", "Suzuki A", "Inoue M", "Hara A", "Mizutani Y", "Imaizumi K", "Kawabe T", "Rosas IO", "Takahashi M", "Kaminski N", "Hasegawa Y"], "journal": "Eur Respir J", "journal_title": "The European respiratory journal", "citation": "The European respiratory journal, 12 2021", "abstract": "The prognosis of elderly individuals with idiopathic pulmonary fibrosis (IPF) remains poor. Fibroblastic foci, in which aggregates of proliferating fibroblasts and myofibroblasts are involved, are the pathological hallmark lesions in IPF to represent focal areas of active fibrogenesis. Fibroblast heterogeneity in fibrotic lesions hampers the discovery of the pathogenesis of pulmonary fibrosis. Therefore, to determine the pathogenesis of IPF, identification of functional fibroblasts is warranted. The aim of this study was to determine the role of fibroblasts positive for meflin, identified as a potential marker for mesenchymal stromal cells, during the development of pulmonary fibrosis.We characterised meflin-positive cells in a single-cell atlas established by single-cell RNA sequencing (scRNA-seq)-based profiling of 243 472 cells from 32 IPF lungs and 29 normal lung samples. We determined the role of fibroblasts positive for meflin using bleomycin (BLM)-induced pulmonary fibrosis.scRNA-seq combined with in situ RNA hybridisation identified proliferating fibroblasts positive for meflin in fibroblastic foci, not dense fibrosis, of fibrotic lungs in IPF patients. A BLM-induced lung fibrosis model for meflin-deficient mice showed that fibroblasts positive for meflin had anti-fibrotic properties to prevent pulmonary fibrosis. Although transforming growth factor-\u03b2-induced fibrogenesis and cell senescence with the senescence-associated secretory phenotype were exacerbated in fibroblasts via the repression or lack of meflin, these were inhibited in meflin-deficient fibroblasts with meflin reconstitution.These findings provide evidence to show the biological importance of meflin expression on fibroblasts and myofibroblasts in the active fibrotic region of pulmonary fibrosis.", "year": "2021", "month": "12", "volume": "58", "issue": "6", "pages": "", "doi": "10.1183/13993003.03397-2020", "link": "https://www.ncbi.nlm.nih.gov/pubmed/34049947", "sort_key": "2021-12-fibroblasts positive", "quarter": "q4"}, {"pmid": "34581565", "title": "Rapid Automated Annotation and Analysis of N-Glycan Mass Spectrometry Imaging Data Sets Using NGlycDB in METASPACE.", "authors": ["Veli\u010dkovi\u0107 D", "Be\u010dejac T", "Mamedov S", "Sharma K", "Ambalavanan N", "Alexandrov T", "Anderton CR"], "journal": "Anal Chem", "journal_title": "Analytical chemistry", "citation": "Analytical chemistry, 10 2021", "abstract": "Imaging N-glycan spatial distribution in tissues using mass spectrometry imaging (MSI) is emerging as a promising tool in biological and clinical applications. However, there is currently no high-throughput tool for visualization and molecular annotation of N-glycans in MSI data, which significantly slows down data processing and hampers the applicability of this approach. Here, we present how METASPACE, an open-source cloud engine for molecular annotation of MSI data, can be used to automatically annotate, visualize, analyze, and interpret high-resolution mass spectrometry-based spatial N-glycomics data. METASPACE is an emerging tool in spatial metabolomics, but the lack of compatible glycan databases has limited its application for comprehensive N-glycan annotations from MSI data sets. We created NGlycDB, a public database of N-glycans, by adapting available glycan databases. We demonstrate the applicability of NGlycDB in METASPACE by analyzing MALDI-MSI data from formalin-fixed paraffin-embedded (FFPE) human kidney and mouse lung tissue sections. We added NGlycDB to METASPACE for public use, thus, facilitating applications of MSI in glycobiology.", "year": "2021", "month": "10", "volume": "93", "issue": "40", "pages": "13421-13425", "doi": "10.1021/acs.analchem.1c02347", "link": "https://www.ncbi.nlm.nih.gov/pubmed/34581565", "sort_key": "2021-10-rapid automated anno", "quarter": "q4"}, {"pmid": "34323115", "title": "Low-dose hyperoxia primes airways for fibrosis in mice after influenza A infection.", "authors": ["Dylag AM", "Haak J", "Warren R", "Yee M", "Pryhuber GS", "O'Reilly MA"], "journal": "Am J Physiol Lung Cell Mol Physiol", "journal_title": "American journal of physiology. Lung cellular and molecular physiology", "citation": "American journal of physiology. Lung cellular and molecular physiology, 10 2021", "abstract": "It is well known that supplemental oxygen used to treat preterm infants in respiratory distress is associated with permanently disrupting lung development and the host response to influenza A virus (IAV). However, many infants who go home with normally functioning lungs are also at risk for hyperreactivity after a respiratory viral infection. We recently reported a new, low-dose hyperoxia mouse model (40% for 8 days; 40\u00d78) that causes a transient change in lung function that resolves, rendering 40\u00d78 adult animals functionally indistinguishable from room air controls. Here we report that when infected with IAV, 40\u00d78 mice display an early transient activation of TGF\u03b2 signaling and later airway hyperreactivity associated with peribronchial inflammation (profibrotic macrophages) and fibrosis compared with infected room air controls, suggesting neonatal oxygen induced hidden molecular changes that prime the lung for hyperreactive airways disease. Although searching for potential activators of TGF\u03b2 signaling, we discovered that thrombospondin-1 (TSP-1) is elevated in na\u00efve 40\u00d78 mice compared with controls and localized to lung megakaryocytes and platelets before and during IAV infection. Elevated TSP-1 was also identified in human autopsy samples of former preterm infants with bronchopulmonary dysplasia. These findings reveal how low doses of oxygen that do not durably change lung function may prime it for hyperreactive airways disease by changing expression of genes, such as TSP-1, thus helping to explain why former preterm infants who have normal lung function are susceptible to airway obstruction and increased morbidity after viral infection.", "year": "2021", "month": "10", "volume": "321", "issue": "4", "pages": "L750-L763", "doi": "10.1152/ajplung.00289.2020", "link": "https://www.ncbi.nlm.nih.gov/pubmed/34323115", "sort_key": "2021-10-low-dose hyperoxia p", "quarter": "q4"}, {"pmid": "34716329", "title": "High-throughput and high-efficiency sample preparation for single-cell proteomics using a nested nanowell chip.", "authors": ["Woo J", "Williams SM", "Markillie LM", "Feng S", "Tsai CF", "Aguilera-Vazquez V", "Sontag RL", "Moore RJ", "Hu D", "Mehta HS", "Cantlon-Bruce J", "Liu T", "Adkins JN", "Smith RD", "Clair GC", "Pasa-Tolic L", "Zhu Y"], "journal": "Nat Commun", "journal_title": "Nature communications", "citation": "Nature communications, 10 2021", "abstract": "Global quantification of protein abundances in single cells could provide direct information on cellular phenotypes and complement transcriptomics measurements. However, single-cell proteomics is still immature and confronts many technical challenges. Herein we describe a nested nanoPOTS (N2) chip to improve protein recovery, operation robustness, and processing throughput for isobaric-labeling-based scProteomics workflow. The N2 chip reduces reaction volume to <30 nL and increases capacity to >240 single cells on a single microchip. The tandem mass tag (TMT) pooling step is simplified by adding a microliter droplet on the nested nanowells to combine labeled single-cell samples. In the analysis of ~100 individual cells from three different cell lines, we demonstrate that the N2 chip-based scProteomics platform can robustly quantify ~1500 proteins and reveal membrane protein markers. Our analyses also reveal low protein abundance variations, suggesting the single-cell proteome profiles are highly stable for the cells cultured under identical conditions.", "year": "2021", "month": "10", "volume": "12", "issue": "1", "pages": "6246", "doi": "10.1038/s41467-021-26514-2", "link": "https://www.ncbi.nlm.nih.gov/pubmed/34716329", "sort_key": "2021-10-high-throughput and ", "quarter": "q4"}, {"pmid": "34669442", "title": "Fatal enhanced respiratory syncytial virus disease in toddlers.", "authors": ["Polack FP", "Alvarez-Paggi D", "Libster R", "Caballero MT", "Blair RV", "Hijano DR", "de la Iglesia Niveyro PX", "Menendez DR", "Gladwell W", "Avendano LM", "Velozo L", "Wanek A", "Bergel E", "Prince GA", "Kleeberger SR", "Johnson J", "Pociask D", "Kolls JK"], "journal": "Sci Transl Med", "journal_title": "Science translational medicine", "citation": "Science translational medicine, 10 2021", "abstract": "In 1967, two toddlers immunized with a formalin-inactivated vaccine against respiratory syncytial virus (FIRSV) in the United States died from enhanced RSV disease (ERD), a severe form of illness resulting from aberrant priming of the antiviral immune response during vaccination. Up to 80% of immunized children subsequently exposed to wild-type virus were hospitalized. These events hampered RSV vaccine development for decades. Here, we provide a characterization of the clinical, immunopathological, and transcriptional signature of fatal human ERD, outlining evidence for safety evaluation of RSV vaccines and a framework for understanding disease enhancement for pathogens in general.", "year": "2021", "month": "10", "volume": "13", "issue": "616", "pages": "eabj7843", "doi": "10.1126/scitranslmed.abj7843", "link": "https://www.ncbi.nlm.nih.gov/pubmed/34669442", "sort_key": "2021-10-fatal enhanced respi", "quarter": "q4"}, {"pmid": "34522848", "title": "An interactive single cell web portal identifies gene and cell networks in COVID-19 host responses.", "authors": ["Jin K", "Bardes EE", "Mitelpunkt A", "Wang JY", "Bhatnagar S", "Sengupta S", "Krummel DP", "Rothenberg ME", "Aronow BJ"], "journal": "iScience", "journal_title": "iScience", "citation": "iScience, 10 2021", "abstract": "Numerous studies have provided single-cell transcriptome profiles of host responses to SARS-CoV-2 infection. Critically lacking however is a data mine that allows users to compare and explore cell profiles to gain insights and develop new hypotheses. To accomplish this, we harmonized datasets from COVID-19 and other control condition blood, bronchoalveolar lavage, and tissue samples, and derived a compendium of gene signature modules per cell type, subtype, clinical condition, and compartment. We demonstrate approaches to interacting with, exploring, and functional evaluating these modules via a new interactive web portal ToppCell (http://toppcell.cchmc.org/). As examples, we develop three hypotheses: (1) alternatively-differentiated monocyte-derived macrophages form a multicelllar signaling cascade that drives T cell recruitment and activation; (2) COVID-19-generated platelet subtypes exhibit dramatically altered potential to adhere, coagulate, and thrombose; and (3) extrafollicular B maturation is driven by a multilineage cell activation network that expresses an ensemble of genes strongly associated with risk for developing post-viral autoimmunity.", "year": "2021", "month": "10", "volume": "24", "issue": "10", "pages": "103115", "doi": "10.1016/j.isci.2021.103115", "link": "https://www.ncbi.nlm.nih.gov/pubmed/34522848", "sort_key": "2021-10-an interactive singl", "quarter": "q4"}, {"pmid": "34121026", "title": "Electrospun core-shell nanofibers with encapsulated enamel matrix derivative for guided periodontal tissue regeneration.", "authors": ["Lam LRW", "Schilling K", "Romas S", "Misra R", "Zhou Z", "Caton JG", "Zhang X"], "journal": "Dent Mater J", "journal_title": "Dental materials journal", "citation": "Dental materials journal, 09 2021", "abstract": "The osteogenic effect of a composite electrospun core-shell nanofiber membrane encapsulated with Emdogain\u00ae (EMD) was evaluated. The membrane was developed through coaxial electrospinning using polycaprolactone as the shell and polyethylene glycol as the core. The effects of the membrane on the osteogenic differentiation of periodontal ligament stem cells (PDLSCs) were examined using Alizarin Red S staining and qRT-PCR. Characterization of the nanofiber membrane demonstrated core-shell morphology with a mean diameter of ~1 \u00b5m. Examination of the release of fluorescein isothiocyanate-conjugated bovine serum albumin (FITC-BSA) from core-shell nanofibers over a 22-day period showed improved release profile of encapsulated proteins as compared to solid nanofibers. When cultured on EMD-containing core-shell nanofibers, PDLSCs showed significantly improved osteogenic differentiation with increased Alizarin Red S staining and enhanced osteogenic gene expression, namely OCN, RUNX2, ALP, and OPN. Core-shell nanofiber membranes may improve outcomes in periodontal regenerative therapy through simultaneous mechanical barrier and controlled drug delivery function.", "year": "2021", "month": "09", "volume": "40", "issue": "5", "pages": "1208-1216", "doi": "10.4012/dmj.2020-412", "link": "https://www.ncbi.nlm.nih.gov/pubmed/34121026", "sort_key": "2021-09-electrospun core-she", "quarter": "q3"}, {"pmid": "34138759", "title": "Surfactant protein C mutation links postnatal type 2 cell dysfunction to adult disease.", "authors": ["Sitaraman S", "Martin EP", "Na CL", "Zhao S", "Green J", "Deshmukh H", "Perl AT", "Bridges JP", "Xu Y", "Weaver TE"], "journal": "JCI Insight", "journal_title": "JCI insight", "citation": "JCI insight, 07 2021", "abstract": "Mutations in the gene SFTPC, encoding surfactant protein C (SP-C), are associated with interstitial lung disease in children and adults. To assess the natural history of disease, we knocked in a familial, disease-associated SFTPC mutation, L188Q (L184Q [LQ] in mice), into the mouse Sftpc locus. Translation of the mutant proprotein, proSP-CLQ, exceeded that of proSP-CWT in neonatal alveolar type 2 epithelial cells (AT2 cells) and was associated with transient activation of oxidative stress and apoptosis, leading to impaired expansion of AT2 cells during postnatal alveolarization. Differentiation of AT2 to AT1 cells was also inhibited in ex vivo organoid culture of AT2 cells isolated from LQ mice; importantly, treatment with antioxidant promoted alveolar differentiation. Upon completion of alveolarization, SftpcLQ expression was downregulated, leading to resolution of chronic stress responses; however, the failure to restore AT2 cell numbers resulted in a permanent loss of AT2 cells that was linked to decreased regenerative capacity in the adult lung. Collectively, these data support the hypothesis that susceptibility to disease in adult LQ mice is established during postnatal lung development, and they provide a potential explanation for the delayed onset of disease in patients with familial pulmonary fibrosis.", "year": "2021", "month": "07", "volume": "6", "issue": "14", "pages": "", "doi": "10.1172/jci.insight.142501", "link": "https://www.ncbi.nlm.nih.gov/pubmed/34138759", "sort_key": "2021-07-surfactant protein c", "quarter": "q3"}, {"pmid": "33624948", "title": "Resident interstitial lung fibroblasts and their role in alveolar stem cell niche development, homeostasis, injury, and regeneration.", "authors": ["Ushakumary MG", "Riccetti M", "Perl AT"], "journal": "Stem Cells Transl Med", "journal_title": "Stem cells translational medicine", "citation": "Stem cells translational medicine, 07 2021", "abstract": "Developing, regenerating, and repairing a lung all require interstitial resident fibroblasts (iReFs) to direct the behavior of the epithelial stem cell niche. During lung development, distal lung fibroblasts, in the form of matrix-, myo-, and lipofibroblasts, form the extra cellular matrix (ECM), create tensile strength, and support distal epithelial differentiation, respectively. During de novo septation in a murine pneumonectomy lung regeneration model, developmental processes are reactivated within the iReFs, indicating progenitor function well into adulthood. In contrast to the regenerative activation of fibroblasts upon acute injury, chronic injury results in fibrotic activation. In murine lung fibrosis models, fibroblasts can pathologically differentiate into lineages beyond their normal commitment during homeostasis. In lung injury, recently defined alveolar niche cells support the expansion of alveolar epithelial progenitors to regenerate the epithelium. In human fibrotic lung diseases like bronchopulmonary dysplasia (BPD), idiopathic pulmonary fibrosis (IPF), and chronic obstructive pulmonary disease (COPD), dynamic changes in matrix-, myo-, lipofibroblasts, and alveolar niche cells suggest differential requirements for injury pathogenesis and repair. In this review, we summarize the role of alveolar fibroblasts and their activation stage in alveolar septation and regeneration and incorporate them into the context of human lung disease, discussing fibroblast activation stages and how they contribute to BPD, IPF, and COPD.", "year": "2021", "month": "07", "volume": "10", "issue": "7", "pages": "1021-1032", "doi": "10.1002/sctm.20-0526", "link": "https://www.ncbi.nlm.nih.gov/pubmed/33624948", "sort_key": "2021-07-resident interstitia", "quarter": "q3"}, {"pmid": "35308599", "title": "POCASUM : Policy Categorizer and Summarizer Based on Text Mining and Machine Learning.", "authors": ["Deotale R", "Rawat S", "Vijayarajan V", "Prasath VBS"], "journal": "Soft comput", "journal_title": "Soft computing", "citation": "Soft computing, 07 2021", "abstract": "Having control over your data is a right and a duty that every citizen has in our digital society. It is often that users skip entire policies of applications or websites to save time and energy without realizing the potential sticky points in these policies. Due to obscure language and verbose explanations majority of users of hypermedia do not bother to read them. Further, sometimes digital media companies do not spend enough effort in stating their policies clearly which often time can also be incomplete. A summarized version of these privacy policies that can be categorized into the useful information can help the users. To solve this problem, in this work we propose to use machine learning based models for policy categorizer that classifies the policy paragraphs under the attributes proposed like security, contact etc. By benchmarking different machine learning based classifier models, we show that artificial neural network model performs with higher accuracy on a challenging dataset of textual privacy policies. We thus show that machine learning can help summarize the relevant paragraphs under the various attributes so that the user can get the gist of that topic within a few lines.", "year": "2021", "month": "07", "volume": "25", "issue": "14", "pages": "9365-9375", "doi": "10.1007/s00500-021-05916-w", "link": "https://www.ncbi.nlm.nih.gov/pubmed/35308599", "sort_key": "2021-07-pocasum : policy cat", "quarter": "q3"}, {"pmid": "34232960", "title": "A homozygous stop-gain variant in ARHGAP42 is associated with childhood interstitial lung disease, systemic hypertension, and immunological findings.", "authors": ["Li Q", "Dibus M", "Casey A", "Yee CSK", "Vargas SO", "Luo S", "Rosen SM", "Madden JA", "Genetti CA", "Brabek J", "Brownstein CA", "Kazerounian S", "Raby BA", "Schmitz-Abe K", "Kennedy JC", "Fishman MP", "Mullen MP", "Taylor JM", "Rosel D", "Agrawal PB"], "journal": "PLoS Genet", "journal_title": "PLoS genetics", "citation": "PLoS genetics, 07 2021", "abstract": "ARHGAP42 encodes Rho GTPase activating protein 42 that belongs to a member of the GTPase Regulator Associated with Focal Adhesion Kinase (GRAF) family. ARHGAP42 is involved in blood pressure control by regulating vascular tone. Despite these findings, disorders of human variants in the coding part of ARHGAP42 have not been reported. Here, we describe an 8-year-old girl with childhood interstitial lung disease (chILD), systemic hypertension, and immunological findings who carries a homozygous stop-gain variant (c.469G>T, p.(Glu157Ter)) in the ARHGAP42 gene. The family history is notable for both parents with hypertension. Histopathological examination of the proband lung biopsy showed increased mural smooth muscle in small airways and alveolar septa, and concentric medial hypertrophy in pulmonary arteries. ARHGAP42 stop-gain variant in the proband leads to exon 5 skipping, and reduced ARHGAP42 levels, which was associated with enhanced RhoA and Cdc42 expression. This is the first report linking a homozygous stop-gain variant in ARHGAP42 with a chILD disorder, systemic hypertension, and immunological findings in human patient. Evidence of smooth muscle hypertrophy on lung biopsy and an increase in RhoA/ROCK signaling in patient cells suggests the potential mechanistic link between ARHGAP42 deficiency and the development of chILD disorder.", "year": "2021", "month": "07", "volume": "17", "issue": "7", "pages": "e1009639", "doi": "10.1371/journal.pgen.1009639", "link": "https://www.ncbi.nlm.nih.gov/pubmed/34232960", "sort_key": "2021-07-a homozygous stop-ga", "quarter": "q3"}, {"pmid": "34010630", "title": "VEGF receptor 2 (KDR) protects airways from mucus metaplasia through a Sox9-dependent pathway.", "authors": ["Jiang M", "Fang Y", "Li Y", "Huang H", "Wei Z", "Gao X", "Sung HK", "Hu J", "Qiang L", "Ruan J", "Chen Q", "Jiang D", "Whitsett JA", "Ai X", "Que J"], "journal": "Dev Cell", "journal_title": "Developmental cell", "citation": "Developmental cell, 06 2021", "abstract": "Mucus-secreting goblet cells are the dominant cell type in pulmonary diseases, e.g., asthma and cystic fibrosis (CF), leading to pathologic mucus metaplasia and airway obstruction. Cytokines including IL-13 are the major players in the transdifferentiation of club cells into goblet cells. Unexpectedly, we have uncovered a previously undescribed pathway promoting mucous metaplasia that involves VEGFa and its receptor KDR. Single-cell RNA sequencing analysis coupled with genetic mouse modeling demonstrates that loss of epithelial VEGFa, KDR, or MEK/ERK kinase promotes excessive club-to-goblet transdifferentiation during development and regeneration. Sox9 is required for goblet cell differentiation following Kdr inhibition in both mouse and human club cells. Significantly, airway mucous metaplasia in asthmatic and CF patients is also associated with reduced KDR signaling and increased SOX9 expression. Together, these findings reveal an unexpected role for VEGFa/KDR signaling in the defense against mucous metaplasia, offering a potential therapeutic target for this common airway pathology.", "year": "2021", "month": "06", "volume": "56", "issue": "11", "pages": "1646-1660.e5", "doi": "10.1016/j.devcel.2021.04.027", "link": "https://www.ncbi.nlm.nih.gov/pubmed/34010630", "sort_key": "2021-06-vegf receptor 2 (kdr", "quarter": "q2"}, {"pmid": "34195595", "title": "The critical role of collagen VI in lung development and chronic lung disease.", "authors": ["Mereness JA", "Mariani TJ"], "journal": "Matrix Biol Plus", "journal_title": "Matrix biology plus", "citation": "Matrix biology plus, 06 2021", "abstract": "Type VI collagen (collagen VI) is an obligate extracellular matrix component found mainly in the basement membrane region of many mammalian tissues and organs, including skeletal muscle and throughout the respiratory system. Collagen VI is probably most recognized in medicine as the genetic cause of a spectrum of muscular dystrophies, including Ullrich Congenital Myopathy and Bethlem Myopathy. Collagen VI is thought to contribute to myopathy, at least in part, by mediating muscle fiber integrity by anchoring myoblasts to the muscle basement membrane. Interestingly, collagen VI myopathies present with restrictive respiratory insufficiency, thought to be due primarily to thoracic muscular weakening. Although it was recently recognized as one of the (if not the) most abundant collagens in the mammalian lung, there is a substantive knowledge gap concerning its role in respiratory system development and function. A few studies have suggested that collagen VI insufficiency is associated with airway epithelial cell survival and altered lung function. Our recent work suggested collagen VI may be a genomic risk factor for chronic lung disease in premature infants. Using this as motivation, we thoroughly assessed the role of collagen VI in lung development and in lung epithelial cell biology. Here, we describe the state-of-the-art for collagen VI cell and developmental biology within the respiratory system, and reveal its essential roles in normal developmental processes and airway epithelial cell phenotype and intracellular signaling.", "year": "2021", "month": "06", "volume": "10", "issue": "", "pages": "100058", "doi": "10.1016/j.mbplus.2021.100058", "link": "https://www.ncbi.nlm.nih.gov/pubmed/34195595", "sort_key": "2021-06-the critical role of", "quarter": "q2"}, {"pmid": "34115127", "title": "International Analysis of Electronic Health Records of Children and Youth Hospitalized With COVID-19 Infection in 6 Countries.", "authors": ["Bourgeois FT", "Guti\u00e9rrez-Sacrist\u00e1n A", "Keller MS", "Liu M", "Hong C", "Bonzel CL", "Tan ALM", "Aronow BJ", "Boeker M", "Booth J", "Cruz Rojo J", "Devkota B", "Garc\u00eda Barrio N", "Gehlenborg N", "Geva A", "Hanauer DA", "Hutch MR", "Issitt RW", "Klann JG", "Luo Y", "Mandl KD", "Mao C", "Moal B", "Moshal KL", "Murphy SN", "Neuraz A", "Ngiam KY", "Omenn GS", "Patel LP", "Jim\u00e9nez MP", "Sebire NJ", "Balazote PS", "Serret-Larmande A", "South AM", "Spiridou A", "Taylor DM", "Tippmann P", "Visweswaran S", "Weber GM", "Kohane IS", "Cai T", "Avillach P", "Consortium for Clinical Characterization of COVID-19 by EHR (4CE)"], "journal": "JAMA Netw Open", "journal_title": "JAMA network open", "citation": "JAMA network open, 06 2021", "abstract": "IMPORTANCE: Additional sources of pediatric epidemiological and clinical data are needed to efficiently study COVID-19 in children and youth and inform infection prevention and clinical treatment of pediatric patients. OBJECTIVE: To describe international hospitalization trends and key epidemiological and clinical features of children and youth with COVID-19. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study included pediatric patients hospitalized between February 2 and October 10, 2020. Patient-level electronic health record (EHR) data were collected across 27 hospitals in France, Germany, Spain, Singapore, the UK, and the US. Patients younger than 21 years who tested positive for COVID-19 and were hospitalized at an institution participating in the Consortium for Clinical Characterization of COVID-19 by EHR were included in the study. MAIN OUTCOMES AND MEASURES: Patient characteristics, clinical features, and medication use. RESULTS: There were 347 males (52%; 95% CI, 48.5-55.3) and 324 females (48%; 95% CI, 44.4-51.3) in this study's cohort. There was a bimodal age distribution, with the greatest proportion of patients in the 0- to 2-year (199 patients [30%]) and 12- to 17-year (170 patients [25%]) age range. Trends in hospitalizations for 671 children and youth found discrete surges with variable timing across 6 countries. Data from this cohort mirrored national-level pediatric hospitalization trends for most countries with available data, with peaks in hospitalizations during the initial spring surge occurring within 23 days in the national-level and 4CE data. A total of 27 364 laboratory values for 16 laboratory tests were analyzed, with mean values indicating elevations in markers of inflammation (C-reactive protein, 83 mg/L; 95% CI, 53-112 mg/L; ferritin, 417 ng/mL; 95% CI, 228-607 ng/mL; and procalcitonin, 1.45 ng/mL; 95% CI, 0.13-2.77 ng/mL). Abnormalities in coagulation were also evident (D-dimer, 0.78 ug/mL; 95% CI, 0.35-1.21 ug/mL; and fibrinogen, 477 mg/dL; 95% CI, 385-569 mg/dL). Cardiac troponin, when checked (n = 59), was elevated (0.032 ng/mL; 95% CI, 0.000-0.080 ng/mL). Common complications included cardiac arrhythmias (15.0%; 95% CI, 8.1%-21.7%), viral pneumonia (13.3%; 95% CI, 6.5%-20.1%), and respiratory failure (10.5%; 95% CI, 5.8%-15.3%). Few children were treated with COVID-19-directed medications. CONCLUSIONS AND RELEVANCE: This study of EHRs of children and youth hospitalized for COVID-19 in 6 countries demonstrated variability in hospitalization trends across countries and identified common complications and laboratory abnormalities in children and youth with COVID-19 infection. Large-scale informatics-based approaches to integrate and analyze data across health care systems complement methods of disease surveillance and advance understanding of epidemiological and clinical features associated with COVID-19 in children and youth.", "year": "2021", "month": "06", "volume": "4", "issue": "6", "pages": "e2112596", "doi": "10.1001/jamanetworkopen.2021.12596", "link": "https://www.ncbi.nlm.nih.gov/pubmed/34115127", "sort_key": "2021-06-international analys", "quarter": "q2"}, {"pmid": "34127975", "title": "Implicating Gene and Cell Networks Responsible for Differential COVID-19 Host Responses via an Interactive Single Cell Web Portal.", "authors": ["Jin K", "Bardes EE", "Mitelpunkt A", "Wang JY", "Bhatnagar S", "Sengupta S", "Krummel DP", "Rothenberg ME", "Aronow BJ"], "journal": "bioRxiv", "journal_title": "bioRxiv : the preprint server for biology", "citation": "bioRxiv : the preprint server for biology, 06 2021", "abstract": "Numerous studies have provided single-cell transcriptome profiles of host responses to SARS-CoV-2 infection. Critically lacking however is a datamine that allows users to compare and explore cell profiles to gain insights and develop new hypotheses. To accomplish this, we harmonized datasets from COVID-19 and other control condition blood, bronchoalveolar lavage, and tissue samples, and derived a compendium of gene signature modules per cell type, subtype, clinical condition, and compartment. We demonstrate approaches to probe these via a new interactive web portal (http://toppcell.cchmc.org/COVID-19). As examples, we develop three hypotheses: (1) a multicellular signaling cascade among alternatively differentiated monocyte-derived macrophages whose tasks include T cell recruitment and activation; (2) novel platelet subtypes with drastically modulated expression of genes responsible for adhesion, coagulation and thrombosis; and (3) a multilineage cell activator network able to drive extrafollicular B maturation via an ensemble of genes strongly associated with risk for developing post-viral autoimmunity.", "year": "2021", "month": "06", "volume": "", "issue": "", "pages": "", "doi": "10.1101/2021.06.07.447287", "link": "https://www.ncbi.nlm.nih.gov/pubmed/34127975", "sort_key": "2021-06-implicating gene and", "quarter": "q2"}, {"pmid": "33479039", "title": "Pretreatment of aged mice with retinoic acid supports alveolar regeneration via upregulation of reciprocal PDGFA signalling.", "authors": ["Gokey JJ", "Snowball J", "Green J", "Waltamath M", "Spinney JJ", "Black KE", "Hariri LP", "Xu Y", "Perl AK"], "journal": "Thorax", "journal_title": "Thorax", "citation": "Thorax, 05 2021", "abstract": "OBJECTIVES: Idiopathic pulmonary fibrosis (IPF) primarily affects the aged population and is characterised by failure of alveolar regeneration, leading to loss of alveolar type 1 (AT1) cells. Aged mouse models of lung repair have demonstrated that regeneration fails with increased age. Mouse and rat lung repair models have shown retinoic acid (RA) treatment can restore alveolar regeneration. Herein, we seek to determine the signalling mechanisms that become activated on RA treatment prior to injury, which support alveolar differentiation. DESIGN: Partial pneumonectomy lung injury model and next-generation sequencing of sorted cell populations were used to uncover molecular targets regulating alveolar repair. In vitro organoids generated from epithelial cells of mouse or patient with IPF co-cultured with young, aged or RA-pretreated murine fibroblasts were used to test potential targets. MAIN OUTCOME MEASUREMENTS: Known alveolar epithelial cell differentiation markers, including HOPX and AGER for AT1 cells, were used to assess outcome of treatments. RESULTS: Gene expression analysis of sorted fibroblasts and epithelial cells isolated from lungs of young, aged and RA-pretreated aged mice predicted increased platelet-derived growth factor subunit A (PDGFA) signalling that coincided with regeneration and alveolar epithelial differentiation. Addition of PDGFA induced AT1 and AT2 differentiation in both mouse and human IPF lung organoids generated with aged fibroblasts, and PDGFA monoclonal antibody blocked AT1 cell differentiation in organoids generated with young murine fibroblasts. CONCLUSIONS: Our data support the concept that RA indirectly induces reciprocal PDGFA signalling, which activates regenerative fibroblasts that support alveolar epithelial cell differentiation and repair, providing a potential therapeutic strategy to influence the pathogenesis of IPF.", "year": "2021", "month": "05", "volume": "76", "issue": "5", "pages": "456-467", "doi": "10.1136/thoraxjnl-2020-214986", "link": "https://www.ncbi.nlm.nih.gov/pubmed/33479039", "sort_key": "2021-05-pretreatment of aged", "quarter": "q2"}, {"pmid": "32926149", "title": "Airway Gene Expression Correlates of Respiratory Syncytial Virus Disease Severity and Microbiome Composition in Infants.", "authors": ["Chu CY", "Qiu X", "McCall MN", "Wang L", "Corbett A", "Holden-Wiltse J", "Slaunwhite C", "Grier A", "Gill SR", "Pryhuber GS", "Falsey AR", "Topham DJ", "Caserta MT", "Walsh EE", "Mariani TJ"], "journal": "J Infect Dis", "journal_title": "The Journal of infectious diseases", "citation": "The Journal of infectious diseases, 05 2021", "abstract": "BACKGROUND: Respiratory syncytial virus (RSV) is the leading cause of severe respiratory disease in infants. The causes and correlates of severe illness in the majority of infants are poorly defined. METHODS: We recruited a cohort of RSV-infected infants and simultaneously assayed the molecular status of their airways and the presence of airway microbiota. We used rigorous statistical approaches to identify gene expression patterns associated with disease severity and microbiota composition, separately and in combination. RESULTS: We measured comprehensive airway gene expression patterns in 106 infants with primary RSV infection. We identified an airway gene expression signature of severe illness dominated by excessive chemokine expression. We also found an association between Haemophilus influenzae, disease severity, and airway lymphocyte accumulation. Exploring the time of onset of clinical symptoms revealed acute activation of interferon signaling following RSV infection in infants with mild or moderate illness, which was absent in subjects with severe illness. CONCLUSIONS: Our data reveal that airway gene expression patterns distinguish mild/moderate from severe illness. Furthermore, our data identify biomarkers that may be therapeutic targets or useful for measuring efficacy of intervention responses.", "year": "2021", "month": "05", "volume": "223", "issue": "9", "pages": "1639-1649", "doi": "10.1093/infdis/jiaa576", "link": "https://www.ncbi.nlm.nih.gov/pubmed/32926149", "sort_key": "2021-05-airway gene expressi", "quarter": "q2"}, {"pmid": "33654293", "title": "Single-cell meta-analysis of SARS-CoV-2 entry genes across tissues and demographics.", "authors": ["Muus C", "Luecken MD", "Eraslan G", "Sikkema L", "Waghray A", "Heimberg G", "Kobayashi Y", "Vaishnav ED", "Subramanian A", "Smillie C", "Jagadeesh KA", "Duong ET", "Fiskin E", "Torlai Triglia E", "Ansari M", "Cai P", "Lin B", "Buchanan J", "Chen S", "Shu J", "Haber AL", "Chung H", "Montoro DT", "Adams T", "Aliee H", "Allon SJ", "Andrusivova Z", "Angelidis I", "Ashenberg O", "Bassler K", "B\u00e9cavin C", "Benhar I", "Bergenstr\u00e5hle J", "Bergenstr\u00e5hle L", "Bolt L", "Braun E", "Bui LT", "Callori S", "Chaffin M", "Chichelnitskiy E", "Chiou J", "Conlon TM", "Cuoco MS", "Cuomo ASE", "Deprez M", "Duclos G", "Fine D", "Fischer DS", "Ghazanfar S", "Gillich A", "Giotti B", "Gould J", "Guo M", "Gutierrez AJ", "Habermann AC", "Harvey T", "He P", "Hou X", "Hu L", "Hu Y", "Jaiswal A", "Ji L", "Jiang P", "Kapellos TS", "Kuo CS", "Larsson L", "Leney-Greene MA", "Lim K", "Litvi\u0148ukov\u00e1 M", "Ludwig LS", "Lukassen S", "Luo W", "Maatz H", "Madissoon E", "Mamanova L", "Manakongtreecheep K", "Leroy S", "Mayr CH", "Mbano IM", "McAdams AM", "Nabhan AN", "Nyquist SK", "Penland L", "Poirion OB", "Poli S", "Qi C", "Queen R", "Reichart D", "Rosas I", "Schupp JC", "Shea CV", "Shi X", "Sinha R", "Sit RV", "Slowikowski K", "Slyper M", "Smith NP", "Sountoulidis A", "Strunz M", "Sullivan TB", "Sun D", "Talavera-L\u00f3pez C", "Tan P", "Tantivit J", "Travaglini KJ", "Tucker NR", "Vernon KA", "Wadsworth MH", "Waldman J", "Wang X", "Xu K", "Yan W", "Zhao W", "Ziegler CGK", "NHLBI LungMap Consortium", "Human Cell Atlas Lung Biological Network"], "journal": "Nat Med", "journal_title": "Nature medicine", "citation": "Nature medicine, 03 2021", "abstract": "Angiotensin-converting enzyme 2 (ACE2) and accessory proteases (TMPRSS2 and CTSL) are needed for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cellular entry, and their expression may shed light on viral tropism and impact across the body. We assessed the cell-type-specific expression of ACE2, TMPRSS2 and CTSL across 107 single-cell RNA-sequencing studies from different tissues. ACE2, TMPRSS2 and CTSL are coexpressed in specific subsets of respiratory epithelial cells in the nasal passages, airways and alveoli, and in cells from other organs associated with coronavirus disease 2019 (COVID-19) transmission or pathology. We performed a meta-analysis of 31 lung single-cell RNA-sequencing studies with 1,320,896 cells from 377 nasal, airway and lung parenchyma samples from 228 individuals. This revealed cell-type-specific associations of age, sex and smoking with expression levels of ACE2, TMPRSS2 and CTSL. Expression of entry factors increased with age and in males, including in airway secretory cells and alveolar type 2 cells. Expression programs shared by ACE2+TMPRSS2+ cells in nasal, lung and gut tissues included genes that may mediate viral entry, key immune functions and epithelial-macrophage cross-talk, such as genes involved in the interleukin-6, interleukin-1, tumor necrosis factor and complement pathways. Cell-type-specific expression patterns may contribute to the pathogenesis of COVID-19, and our work highlights putative molecular pathways for therapeutic intervention.", "year": "2021", "month": "03", "volume": "27", "issue": "3", "pages": "546-559", "doi": "10.1038/s41591-020-01227-z", "link": "https://www.ncbi.nlm.nih.gov/pubmed/33654293", "sort_key": "2021-03-single-cell meta-ana", "quarter": "q1"}, {"pmid": "33683204", "title": "SARS-CoV-2 suppresses anticoagulant and fibrinolytic gene expression in the lung.", "authors": ["Mast AE", "Wolberg AS", "Gailani D", "Garvin MR", "Alvarez C", "Miller JI", "Aronow B", "Jacobson D"], "journal": "Elife", "journal_title": "eLife", "citation": "eLife, 03 2021", "abstract": "Extensive fibrin deposition in the lungs and altered levels of circulating blood coagulation proteins in COVID-19 patients imply local derangement of pathways that limit fibrin formation and/or promote its clearance. We examined transcriptional profiles of bronchoalveolar lavage fluid (BALF) samples to identify molecular mechanisms underlying these coagulopathies. mRNA levels for regulators of the kallikrein-kinin (C1-inhibitor), coagulation (thrombomodulin, endothelial protein C receptor), and fibrinolytic (urokinase and urokinase receptor) pathways were significantly reduced in COVID-19 patients. While transcripts for several coagulation proteins were increased, those encoding tissue factor, the protein that initiates coagulation and whose expression is frequently increased in inflammatory disorders, were not increased in BALF from COVID-19 patients. Our analysis implicates enhanced propagation of coagulation and decreased fibrinolysis as drivers of the coagulopathy in the lungs of COVID-19 patients.", "year": "2021", "month": "03", "volume": "10", "issue": "", "pages": "", "doi": "10.7554/eLife.64330", "link": "https://www.ncbi.nlm.nih.gov/pubmed/33683204", "sort_key": "2021-03-sars-cov-2 suppresse", "quarter": "q1"}, {"pmid": "33507880", "title": "Neonatal hyperoxia inhibits proliferation and survival of atrial cardiomyocytes by suppressing fatty acid synthesis.", "authors": ["Cohen ED", "Yee M", "Porter GA", "Ritzer E", "McDavid AN", "Brookes PS", "Pryhuber GS", "O'Reilly MA"], "journal": "JCI Insight", "journal_title": "JCI insight", "citation": "JCI insight, 03 2021", "abstract": "Preterm birth increases the risk for pulmonary hypertension and heart failure in adulthood. Oxygen therapy can damage the immature cardiopulmonary system and may be partially responsible for the cardiovascular disease in adults born preterm. We previously showed that exposing newborn mice to hyperoxia causes pulmonary hypertension by 1 year of age that is preceded by a poorly understood loss of pulmonary vein cardiomyocyte proliferation. We now show that hyperoxia also reduces cardiomyocyte proliferation and survival in the left atrium and causes diastolic heart failure by disrupting its filling of the left ventricle. Transcriptomic profiling showed that neonatal hyperoxia permanently suppressed fatty acid synthase (Fasn), stearoyl-CoA desaturase 1 (Scd1), and other fatty acid synthesis genes in the atria of mice, the HL-1 line of mouse atrial cardiomyocytes, and left atrial tissue explanted from human infants. Suppressing Fasn or Scd1 reduced HL-1 cell proliferation and increased cell death, while overexpressing these genes maintained their expansion in hyperoxia, suggesting that oxygen directly inhibits atrial cardiomyocyte proliferation and survival by repressing Fasn and Scd1. Pharmacologic interventions that restore Fasn, Scd1, and other fatty acid synthesis genes in atrial cardiomyocytes may, thus, provide a way of ameliorating the adverse effects of supplemental oxygen on preterm infants.", "year": "2021", "month": "03", "volume": "6", "issue": "5", "pages": "", "doi": "10.1172/jci.insight.140785", "link": "https://www.ncbi.nlm.nih.gov/pubmed/33507880", "sort_key": "2021-03-neonatal hyperoxia i", "quarter": "q1"}, {"pmid": "33591952", "title": "IGF1R controls mechanosignaling in myofibroblasts required for pulmonary alveologenesis.", "authors": ["He H", "Snowball J", "Sun F", "Na CL", "Whitsett JA"], "journal": "JCI Insight", "journal_title": "JCI insight", "citation": "JCI insight, 03 2021", "abstract": "Ventilation throughout life is dependent on the formation of pulmonary alveoli, which create an extensive surface area in which the close apposition of respiratory epithelium and endothelial cells of the pulmonary microvascular enables efficient gas exchange. Morphogenesis of the alveoli initiates at late gestation in humans and the early postnatal period in the mouse. Alveolar septation is directed by complex signaling interactions among multiple cell types. Here, we demonstrate that IGF1 receptor gene (Igf1r) expression by a subset of pulmonary fibroblasts is required for normal alveologenesis in mice. Postnatal deletion of Igf1r caused alveolar simplification, disrupting alveolar elastin networks and extracellular matrix without altering myofibroblast differentiation or proliferation. Moreover, loss of Igf1r impaired contractile properties of lung myofibroblasts and inhibited myosin light chain (MLC) phosphorylation and mechanotransductive nuclear YAP activity. Activation of p-AKT, p-MLC, and nuclear YAP in myofibroblasts was dependent on Igf1r. Pharmacologic activation of AKT enhanced MLC phosphorylation, increased YAP activation, and ameliorated alveolar simplification in vivo. IGF1R controls mechanosignaling in myofibroblasts required for lung alveologenesis.", "year": "2021", "month": "03", "volume": "6", "issue": "6", "pages": "", "doi": "10.1172/jci.insight.144863", "link": "https://www.ncbi.nlm.nih.gov/pubmed/33591952", "sort_key": "2021-03-igf1r controls mecha", "quarter": "q1"}, {"pmid": "33599610", "title": "Short-term exposure to intermittent hypoxia leads to changes in gene expression seen in chronic pulmonary disease.", "authors": ["Wu G", "Lee YY", "Gulla EM", "Potter A", "Kitzmiller J", "Ruben MD", "Salomonis N", "Whitsett JA", "Francey LJ", "Hogenesch JB", "Smith DF"], "journal": "Elife", "journal_title": "eLife", "citation": "eLife, 02 2021", "abstract": "Obstructive sleep apnea (OSA) results from episodes of airway collapse and intermittent hypoxia (IH) and is associated with a host of health complications. Although the lung is the first organ to sense changes in oxygen levels, little is known about the consequences of IH to the lung hypoxia-inducible factor-responsive pathways. We hypothesized that exposure to IH would lead to cell-specific up- and downregulation of diverse expression pathways. We identified changes in circadian and immune pathways in lungs from mice exposed to IH. Among all cell types, endothelial cells showed the most prominent transcriptional changes. Upregulated genes in myofibroblast cells were enriched for genes associated with pulmonary hypertension and included targets of several drugs currently used to treat chronic pulmonary diseases. A better understanding of the pathophysiologic mechanisms underlying diseases associated with OSA could improve our therapeutic approaches, directing therapies to the most relevant cells and molecular pathways.", "year": "2021", "month": "02", "volume": "10", "issue": "", "pages": "", "doi": "10.7554/eLife.63003", "link": "https://www.ncbi.nlm.nih.gov/pubmed/33599610", "sort_key": "2021-02-short-term exposure ", "quarter": "q1"}, {"pmid": "33622235", "title": "Ontology-guided segmentation and object identification for developmental mouse lung immunofluorescent images.", "authors": ["Masci AM", "White S", "Neely B", "Ardini-Polaske M", "Hill CB", "Misra RS", "Aronow B", "Gaddis N", "Yang L", "Wert SE", "Palmer SM", "Chan C", "LungMAP Consortium"], "journal": "BMC Bioinformatics", "journal_title": "BMC bioinformatics", "citation": "BMC bioinformatics, 02 2021", "abstract": "BACKGROUND: Immunofluorescent confocal microscopy uses labeled antibodies as probes against specific macromolecules to discriminate between multiple cell types. For images of the developmental mouse lung, these cells are themselves organized into densely packed higher-level anatomical structures. These types of images can be challenging to segment automatically for several reasons, including the relevance of biomedical context, dependence on the specific set of probes used, prohibitive cost of generating labeled training data, as well as the complexity and dense packing of anatomical structures in the image. The use of an application ontology helps surmount these challenges by combining image data with its metadata to provide a meaningful biological context, modeled after how a human expert would make use of contextual information to identify histological structures, that constrains and simplifies the process of segmentation and object identification. RESULTS: We propose an innovative approach for the semi-supervised analysis of complex and densely packed anatomical structures from immunofluorescent images that utilizes an application ontology to provide a simplified context for image segmentation and object identification. We describe how the logical organization of biological facts in the form of an ontology can provide useful constraints that facilitate automatic processing of complex images. We demonstrate the results of ontology-guided segmentation and object identification in mouse developmental lung images from the Bioinformatics REsource ATlas for the Healthy lung database of the Molecular Atlas of Lung Development (LungMAP1) program CONCLUSION: We describe a novel ontology-guided approach to segmentation and classification of complex immunofluorescence images of the developing mouse lung. The ontology is used to automatically generate constraints for each image based on its biomedical context, which facilitates image segmentation and classification.", "year": "2021", "month": "02", "volume": "22", "issue": "1", "pages": "82", "doi": "10.1186/s12859-021-04008-8", "link": "https://www.ncbi.nlm.nih.gov/pubmed/33622235", "sort_key": "2021-02-ontology-guided segm", "quarter": "q1"}, {"pmid": "33596914", "title": "MicroRNA 219-5p inhibits alveolarization by reducing platelet derived growth factor receptor-alpha.", "authors": ["Freeman A", "Qiao L", "Olave N", "Rezonzew G", "Gentle S", "Halloran B", "Pryhuber GS", "Gaggar A", "Tipple TE", "Ambalavanan N", "Lal CV"], "journal": "Respir Res", "journal_title": "Respiratory research", "citation": "Respiratory research, 02 2021", "abstract": "BACKGROUND: MicroRNA (miR) are small conserved RNA that regulate gene expression post-transcription. Previous genome-wide analysis studies in preterm infants indicate that pathways of miR 219-5p are important in infants with Bronchopulmonary Dysplasia (BPD). METHODS: Here we report a prospective cohort study of extremely preterm neonates wherein infants diagnosed with severe BPD expressed increased airway miR-219-5p and decreased platelet derived growth factor receptor alpha (PDGFR-\u03b1), a target of mir-219-5p and a key regulator of alveolarization, compared to post-conception age-matched term infants. RESULTS: miR-219-5p was highly expressed in the pulmonary epithelial lining in lungs of infants with BPD by in situ hybridization of human infant lungs. In both in vitro and in vivo (mouse) models of BPD, miR-219-5p was increased on exposure to hyperoxia compared with the normoxia control, with a complementary decrease of PDGFR-\u03b1. To further confirm the target relationship between miR-219 and PDGFR-\u03b1, pulmonary epithelial cells (MLE12) and lung primary fibroblasts were treated with a mimic of miR-219-5p and a locked nucleic acid (LNA) based inhibitor of miR-219-5p. In comparison with the control group, the level of miR-219 increased significantly after miR-219 mimic treatment, while the level of PDGFR-\u03b1 declined markedly. LNA exposure increased PDGFR-\u03b1. Moreover, in BPD mouse model, over-expression of miR-219-5p inhibited alveolar development, indicated by larger alveolar spaces accompanied by reduced septation. CONCLUSIONS: Taken together, our results demonstrate that increased miR-219-5p contributes to the pathogenesis of BPD by targeting and reducing PDGFR-\u03b1. The use of specific miRNA antagonists may be a therapeutic strategy for preventing the development of BPD.", "year": "2021", "month": "02", "volume": "22", "issue": "1", "pages": "57", "doi": "10.1186/s12931-021-01654-7", "link": "https://www.ncbi.nlm.nih.gov/pubmed/33596914", "sort_key": "2021-02-microrna 219-5p inhi", "quarter": "q1"}, {"pmid": "33564777", "title": "International Comparisons of Harmonized Laboratory Value Trajectories to Predict Severe COVID-19: Leveraging the 4CE Collaborative Across 342 Hospitals and 6 Countries: A Retrospective Cohort Study.", "authors": ["Weber GM", "Hong C", "Palmer NP", "Avillach P", "Murphy SN", "Guti\u00e9rrez-Sacrist\u00e1n A", "Xia Z", "Serret-Larmande A", "Neuraz A", "Omenn GS", "Visweswaran S", "Klann JG", "South AM", "Loh NHW", "Cannataro M", "Beaulieu-Jones BK", "Bellazzi R", "Agapito G", "Alessiani M", "Aronow BJ", "Bell DS", "Bellasi A", "Benoit V", "Beraghi M", "Boeker M", "Booth J", "Bosari S", "Bourgeois FT", "Brown NW", "Bucalo M", "Chiovato L", "Chiudinelli L", "Dagliati A", "Devkota B", "DuVall SL", "Follett RW", "Ganslandt T", "Garc\u00eda Barrio N", "Gradinger T", "Griffier R", "Hanauer DA", "Holmes JH", "Horki P", "Huling KM", "Issitt RW", "Jouhet V", "Keller MS", "Kraska D", "Liu M", "Luo Y", "Lynch KE", "Malovini A", "Mandl KD", "Mao C", "Maram A", "Matheny ME", "Maulhardt T", "Mazzitelli M", "Milano M", "Moore JH", "Morris JS", "Morris M", "Mowery DL", "Naughton TP", "Ngiam KY", "Norman JB", "Patel LP", "Pedrera Jimenez M", "Ramoni RB", "Schriver ER", "Scudeller L", "Sebire NJ", "Serrano Balazote P", "Spiridou A", "Tan AL", "Tan BW", "Tibollo V", "Torti C", "Trecarichi EM", "Vitacca M", "Zambelli A", "Zucco C", "Consortium for Clinical Characterization of COVID-19 by EHR (4CE)", "Kohane IS", "Cai T", "Brat GA"], "journal": "medRxiv", "journal_title": "medRxiv : the preprint server for health sciences", "citation": "medRxiv : the preprint server for health sciences, 02 2021", "abstract": "OBJECTIVES: To perform an international comparison of the trajectory of laboratory values among hospitalized patients with COVID-19 who develop severe disease and identify optimal timing of laboratory value collection to predict severity across hospitals and regions. DESIGN: Retrospective cohort study. SETTING: The Consortium for Clinical Characterization of COVID-19 by EHR (4CE), an international multi-site data-sharing collaborative of 342 hospitals in the US and in Europe. PARTICIPANTS: Patients hospitalized with COVID-19, admitted before or after PCR-confirmed result for SARS-CoV-2. PRIMARY AND SECONDARY OUTCOME MEASURES: Patients were categorized as \"ever-severe\" or \"never-severe\" using the validated 4CE severity criteria. Eighteen laboratory tests associated with poor COVID-19-related outcomes were evaluated for predictive accuracy by area under the curve (AUC), compared between the severity categories. Subgroup analysis was performed to validate a subset of laboratory values as predictive of severity against a published algorithm. A subset of laboratory values (CRP, albumin, LDH, neutrophil count, D-dimer, and procalcitonin) was compared between North American and European sites for severity prediction. RESULTS: Of 36,447 patients with COVID-19, 19,953 (43.7%) were categorized as ever-severe. Most patients (78.7%) were 50 years of age or older and male (60.5%). Longitudinal trajectories of CRP, albumin, LDH, neutrophil count, D-dimer, and procalcitonin showed association with disease severity. Significant differences of laboratory values at admission were found between the two groups. With the exception of D-dimer, predictive discrimination of laboratory values did not improve after admission. Sub-group analysis using age, D-dimer, CRP, and lymphocyte count as predictive of severity at admission showed similar discrimination to a published algorithm (AUC=0.88 and 0.91, respectively). Both models deteriorated in predictive accuracy as the disease progressed. On average, no difference in severity prediction was found between North American and European sites. CONCLUSIONS: Laboratory test values at admission can be used to predict severity in patients with COVID-19. Prediction models show consistency across international sites highlighting the potential generalizability of these models.", "year": "2021", "month": "02", "volume": "", "issue": "", "pages": "", "doi": "10.1101/2020.12.16.20247684", "link": "https://www.ncbi.nlm.nih.gov/pubmed/33564777", "sort_key": "2021-02-international compar", "quarter": "q1"}, {"pmid": "33568812", "title": "In situ mapping identifies distinct vascular niches for myelopoiesis.", "authors": ["Zhang J", "Wu Q", "Johnson CB", "Pham G", "Kinder JM", "Olsson A", "Slaughter A", "May M", "Weinhaus B", "D'Alessandro A", "Engel JD", "Jiang JX", "Kofron JM", "Huang LF", "Prasath VBS", "Way SS", "Salomonis N", "Grimes HL", "Lucas D"], "journal": "Nature", "journal_title": "Nature", "citation": "Nature, 02 2021", "abstract": "In contrast to nearly all other tissues, the anatomy of cell differentiation in the bone marrow remains unknown. This is owing to a lack of strategies for examining myelopoiesis-the differentiation of myeloid progenitors into a large variety of innate immune cells-in situ in the bone marrow. Such strategies are required to understand differentiation and lineage-commitment decisions, and to define how spatial organizing cues inform tissue function. Here we develop approaches for imaging myelopoiesis in mice, and generate atlases showing the differentiation of granulocytes, monocytes and dendritic cells. The generation of granulocytes and dendritic cells-monocytes localizes to different blood-vessel structures known as sinusoids, and displays lineage-specific spatial and clonal architectures. Acute systemic infection with Listeria monocytogenes induces lineage-specific progenitor clusters to undergo increased self-renewal of progenitors, but the different lineages remain spatially separated. Monocyte-dendritic cell progenitors (MDPs) map with nonclassical monocytes and conventional dendritic cells; these localize to a subset of blood vessels expressing a major regulator of myelopoiesis, colony-stimulating factor 1 (CSF1, also known as M-CSF)1. Specific deletion of Csf1 in endothelium disrupts the architecture around MDPs and their localization to sinusoids. Subsequently, there are fewer MDPs and their ability to differentiate is reduced, leading to a loss of nonclassical monocytes and dendritic cells during both homeostasis and infection. These data indicate that local cues produced by distinct blood vessels are responsible for the spatial organization of definitive blood cell differentiation.", "year": "2021", "month": "02", "volume": "590", "issue": "7846", "pages": "457-462", "doi": "10.1038/s41586-021-03201-2", "link": "https://www.ncbi.nlm.nih.gov/pubmed/33568812", "sort_key": "2021-02-in situ mapping iden", "quarter": "q1"}, {"pmid": "33290275", "title": "MicroRNA miR-24-3p reduces DNA damage responses, apoptosis, and susceptibility to chronic obstructive pulmonary disease.", "authors": ["Nouws J", "Wan F", "Finnemore E", "Roque W", "Kim SJ", "Bazan I", "Li CX", "Skold CM", "Dai Q", "Yan X", "Chioccioli M", "Neumeister V", "Britto CJ", "Sweasy J", "Bindra R", "Wheelock \u00c5M", "Gomez JL", "Kaminski N", "Lee PJ", "Sauler M"], "journal": "JCI Insight", "journal_title": "JCI insight", "citation": "JCI insight, 01 2021", "abstract": "The pathogenesis of chronic obstructive pulmonary disease (COPD) involves aberrant responses to cellular stress caused by chronic cigarette smoke (CS) exposure. However, not all smokers develop COPD and the critical mechanisms that regulate cellular stress responses to increase COPD susceptibility are not understood. Because microRNAs are well-known regulators of cellular stress responses, we evaluated microRNA expression arrays performed on distal parenchymal lung tissue samples from 172 subjects with and without COPD. We identified miR-24-3p as the microRNA that best correlated with radiographic emphysema and validated this finding in multiple cohorts. In a CS exposure mouse model, inhibition of miR-24-3p increased susceptibility to apoptosis, including alveolar type II epithelial cell apoptosis, and emphysema severity. In lung epithelial cells, miR-24-3p suppressed apoptosis through the BH3-only protein BIM and suppressed homology-directed DNA repair and the DNA repair protein BRCA1. Finally, we found BIM and BRCA1 were increased in COPD lung tissue, and BIM and BRCA1 expression inversely correlated with miR-24-3p. We concluded that miR-24-3p, a regulator of the cellular response to DNA damage, is decreased in COPD, and decreased miR-24-3p increases susceptibility to emphysema through increased BIM and apoptosis.", "year": "2021", "month": "01", "volume": "6", "issue": "2", "pages": "", "doi": "10.1172/jci.insight.134218", "link": "https://www.ncbi.nlm.nih.gov/pubmed/33290275", "sort_key": "2021-01-microrna mir-24-3p r", "quarter": "q1"}, {"pmid": "33385216", "title": "Lung Gene Expression Analysis Web Portal Version 3: Lung-at-a-Glance.", "authors": ["Du Y", "Ouyang W", "Kitzmiller JA", "Guo M", "Zhao S", "Whitsett JA", "Xu Y"], "journal": "Am J Respir Cell Mol Biol", "journal_title": "American journal of respiratory cell and molecular biology", "citation": "American journal of respiratory cell and molecular biology, 01 2021", "abstract": "", "year": "2021", "month": "01", "volume": "64", "issue": "1", "pages": "146-149", "doi": "10.1165/rcmb.2020-0308LE", "link": "https://www.ncbi.nlm.nih.gov/pubmed/33385216", "sort_key": "2021-01-lung gene expression", "quarter": "q1"}, {"pmid": "33214719", "title": "Leukocyte trafficking to the lungs and beyond: lessons from influenza for COVID-19.", "authors": ["Alon R", "Sportiello M", "Kozlovski S", "Kumar A", "Reilly EC", "Zarbock A", "Garbi N", "Topham DJ"], "journal": "Nat Rev Immunol", "journal_title": "Nature reviews. Immunology", "citation": "Nature reviews. Immunology, 01 2021", "abstract": "Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19). Understanding of the fundamental processes underlying the versatile clinical manifestations of COVID-19 is incomplete without comprehension of how different immune cells are recruited to various compartments of virus-infected lungs, and how this recruitment differs among individuals with different levels of disease severity. As in other respiratory infections, leukocyte recruitment to the respiratory system in people with COVID-19 is orchestrated by specific leukocyte trafficking molecules, and when uncontrolled and excessive it results in various pathological complications, both in the lungs and in other organs. In the absence of experimental data from physiologically relevant animal models, our knowledge of the trafficking signals displayed by distinct vascular beds and epithelial cell layers in response to infection by SARS-CoV-2 is still incomplete. However, SARS-CoV-2 and influenza virus elicit partially conserved inflammatory responses in the different respiratory epithelial cells encountered early in infection and may trigger partially overlapping combinations of trafficking signals in nearby blood vessels. Here, we review the molecular signals orchestrating leukocyte trafficking to airway and lung compartments during primary pneumotropic influenza virus infections and discuss potential similarities to distinct courses of primary SARS-CoV-2 infections. We also discuss how an imbalance in vascular activation by leukocytes outside the airways and lungs may contribute to extrapulmonary inflammatory complications in subsets of patients with COVID-19. These multiple molecular pathways are potential targets for therapeutic interventions in patients with severe COVID-19.", "year": "2021", "month": "01", "volume": "21", "issue": "1", "pages": "49-64", "doi": "10.1038/s41577-020-00470-2", "link": "https://www.ncbi.nlm.nih.gov/pubmed/33214719", "sort_key": "2021-01-leukocyte traffickin", "quarter": "q1"}, {"pmid": "33052459", "title": "Hypothalamic MC4R regulates glucose homeostasis through adrenaline-mediated control of glucose reabsorption via renal GLUT2 in mice.", "authors": ["de Souza Cordeiro LM", "Elsheikh A", "Devisetty N", "Morgan DA", "Ebert SN", "Rahmouni K", "Chhabra KH"], "journal": "Diabetologia", "journal_title": "Diabetologia", "citation": "Diabetologia, 01 2021", "abstract": "AIMS/HYPOTHESIS: Melanocortin 4 receptor (MC4R) mutation is the most common cause of known monogenic obesity in humans. Unexpectedly, humans and rodents with MC4R deficiency do not develop hyperglycaemia despite chronic obesity and insulin resistance. To explain the underlying mechanisms for this phenotype, we determined the role of MC4R in glucose homeostasis in the presence and absence of obesity in mice. METHODS: We used global and hypothalamus-specific MC4R-deficient mice to investigate the brain regions that contribute to glucose homeostasis via MC4R. We performed oral, intraperitoneal and intravenous glucose tolerance tests in MC4R-deficient mice that were either obese or weight-matched to their littermate controls to define the role of MC4R in glucose regulation independently of changes in body weight. To identify the integrative pathways through which MC4R regulates glucose homeostasis, we measured renal and adrenal sympathetic nerve activity. We also evaluated glucose homeostasis in adrenaline (epinephrine)-deficient mice to investigate the role of adrenaline in mediating the effects of MC4R in glucose homeostasis. We employed a graded [13C6]glucose infusion procedure to quantify renal glucose reabsorption in MC4R-deficient mice. Finally, we measured the levels of renal glucose transporters in hypothalamus-specific MC4R-deficient mice and adrenaline-deficient mice using western blotting to ascertain the molecular mechanisms underlying MC4R control of glucose homeostasis. RESULTS: We found that obese and weight-matched MC4R-deficient mice exhibited improved glucose tolerance due to elevated glucosuria, not enhanced beta cell function. Moreover, MC4R deficiency selectively in the paraventricular nucleus of the hypothalamus (PVH) is responsible for reducing the renal threshold for glucose as measured by graded [13C6]glucose infusion technique. The MC4R deficiency suppressed renal sympathetic nerve activity by 50% in addition to decreasing circulating adrenaline and renal GLUT2 levels in mice, which contributed to the elevated glucosuria. We further report that adrenaline-deficient mice recapitulated the increased excretion of glucose in urine observed in the MC4R-deficient mice. Restoration of circulating adrenaline in both the MC4R- and adrenaline-deficient mice reversed their phenotype of improved glucose tolerance and elevated glucosuria, demonstrating the role of adrenaline in mediating the effects of MC4R on glucose reabsorption. CONCLUSIONS/INTERPRETATION: These findings define a previously unrecognised function of hypothalamic MC4R in glucose reabsorption mediated by adrenaline and renal GLUT2. Taken together, our findings indicate that elevated glucosuria due to low sympathetic tone explains why MC4R deficiency does not cause hyperglycaemia despite inducing obesity and insulin resistance. Graphical abstract.", "year": "2021", "month": "01", "volume": "64", "issue": "1", "pages": "181-194", "doi": "10.1007/s00125-020-05289-z", "link": "https://www.ncbi.nlm.nih.gov/pubmed/33052459", "sort_key": "2021-01-hypothalamic mc4r re", "quarter": "q1"}, {"pmid": "34489955", "title": "Protectins PCTR1 and PD1 Reduce Viral Load and Lung Inflammation During Respiratory Syncytial Virus Infection in Mice.", "authors": ["Walker KH", "Krishnamoorthy N", "Br\u00fcggemann TR", "Shay AE", "Serhan CN", "Levy BD"], "journal": "Front Immunol", "journal_title": "Frontiers in immunology", "citation": "Frontiers in immunology, 2021", "abstract": "Viral pneumonias are a major cause of morbidity and mortality, owing in part to dysregulated excessive lung inflammation, and therapies to modulate host responses to viral lung injury are urgently needed. Protectin conjugates in tissue regeneration 1 (PCTR1) and protectin D1 (PD1) are specialized pro-resolving mediators (SPMs) whose roles in viral pneumonia are of interest. In a mouse model of Respiratory Syncytial Virus (RSV) pneumonia, intranasal PCTR1 and PD1 each decreased RSV genomic viral load in lung tissue when given after RSV infection. Concurrent with enhanced viral clearance, PCTR1 administration post-infection, decreased eosinophils, neutrophils, and NK cells, including NKG2D+ activated NK cells, in the lung. Intranasal PD1 administration post-infection decreased lung eosinophils and Il-13 expression. PCTR1 increased lung expression of cathelicidin anti-microbial peptide and decreased interferon-gamma production by lung CD4+ T cells. PCTR1 and PD1 each increased interferon-lambda expression in human bronchial epithelial cells in vitro and attenuated RSV-induced suppression of interferon-lambda in mouse lung in vivo. Liquid chromatography coupled with tandem mass spectrometry of RSV-infected and untreated mouse lungs demonstrated endogenous PCTR1 and PD1 that decreased early in the time course while cysteinyl-leukotrienes (cys-LTs) increased during early infection. As RSV infection resolved, PCTR1 and PD1 increased and cys-LTs decreased to pre-infection levels. Together, these results indicate that PCTR1 and PD1 are each regulated during RSV pneumonia, with overlapping and distinct mechanisms for PCTR1 and PD1 during the resolution of viral infection and its associated inflammation.", "year": "2021", "month": "", "volume": "12", "issue": "", "pages": "704427", "doi": "10.3389/fimmu.2021.704427", "link": "https://www.ncbi.nlm.nih.gov/pubmed/34489955", "sort_key": "2021-00-protectins pctr1 and", "quarter": "q0"}, {"pmid": "33744877", "title": "Commentary on the Truncated Splice Variant of the GM-CSF Receptor Beta-Chain in Peripheral Blood Serves as Severity Biomarker of Respiratory Failure in Newborns.", "authors": ["Whitsett JA", "Jobe AH"], "journal": "Neonatology", "journal_title": "Neonatology", "citation": "Neonatology, 2021", "abstract": "", "year": "2021", "month": "", "volume": "118", "issue": "2", "pages": "194-197", "doi": "10.1159/000514639", "link": "https://www.ncbi.nlm.nih.gov/pubmed/33744877", "sort_key": "2021-00-commentary on the tr", "quarter": "q0"}, {"pmid": "33188371", "title": "Guidelines for reporting single-cell RNA-seq experiments.", "authors": ["F\u00fcllgrabe A", "George N", "Green M", "Nejad P", "Aronow B", "Fexova SK", "Fischer C", "Freeberg MA", "Huerta L", "Morrison N", "Scheuermann RH", "Taylor D", "Vasilevsky N", "Clarke L", "Gehlenborg N", "Kent J", "Marioni J", "Teichmann S", "Brazma A", "Papatheodorou I"], "journal": "Nat Biotechnol", "journal_title": "Nature biotechnology", "citation": "Nature biotechnology, 12 2020", "abstract": "", "year": "2020", "month": "12", "volume": "38", "issue": "12", "pages": "1384-1386", "doi": "10.1038/s41587-020-00744-z", "link": "https://www.ncbi.nlm.nih.gov/pubmed/33188371", "sort_key": "2020-12-guidelines for repor", "quarter": "q4"}, {"pmid": "33398286", "title": "DeepImmuno: Deep learning-empowered prediction and generation of immunogenic peptides for T cell immunity.", "authors": ["Li G", "Iyer B", "Prasath VBS", "Ni Y", "Salomonis N"], "journal": "bioRxiv", "journal_title": "bioRxiv : the preprint server for biology", "citation": "bioRxiv : the preprint server for biology, 12 2020", "abstract": "UNLABELLED: T-cells play an essential role in the adaptive immune system by seeking out, binding and destroying foreign antigens presented on the cell surface of diseased cells. An improved understanding of T-cell immunity will greatly aid in the development of new cancer immunotherapies and vaccines for life threatening pathogens. Central to the design of such targeted therapies are computational methods to predict non-native epitopes to elicit a T cell response, however, we currently lack accurate immunogenicity inference methods. Another challenge is the ability to accurately simulate immunogenic peptides for specific human leukocyte antigen (HLA) alleles, for both synthetic biological applications and to augment real training datasets. Here, we proposed a beta-binomial distribution approach to derive epitope immunogenic potential from sequence alone. We conducted systematic benchmarking of five traditional machine learning (ElasticNet, KNN, SVM, Random Forest, AdaBoost) and three deep learning models (CNN, ResNet, GNN) using three independent prior validated immunogenic peptide collections (dengue virus, cancer neoantigen and SARS-Cov-2). We chose the CNN model as the best prediction model based on its adaptivity for small and large datasets, and performance relative to existing methods. In addition to outperforming two highly used immunogenicity prediction algorithms, DeepHLApan and IEDB, DeepImmuno-CNN further correctly predicts which residues are most important for T cell antigen recognition. Our independent generative adversarial network (GAN) approach, DeepImmuno-GAN, was further able to accurately simulate immunogenic peptides with physiochemical properties and immunogenicity predictions similar to that of real antigens. We provide DeepImmuno-CNN as source code and an easy-to-use web interface. DATA AVAILABILITY: DeepImmuno Python3 code is available at https://github.com/frankligy/DeepImmuno . The DeepImmuno web portal is available from https://deepimmuno.herokuapp.com . The data in this article is available in GitHub and supplementary materials.", "year": "2020", "month": "12", "volume": "", "issue": "", "pages": "", "doi": "10.1101/2020.12.24.424262", "link": "https://www.ncbi.nlm.nih.gov/pubmed/33398286", "sort_key": "2020-12-deepimmuno: deep lea", "quarter": "q4"}, {"pmid": "32603599", "title": "Single-Cell Transcriptomic Analysis Identifies a Unique Pulmonary Lymphangioleiomyomatosis Cell.", "authors": ["Guo M", "Yu JJ", "Perl AK", "Wikenheiser-Brokamp KA", "Riccetti M", "Zhang EY", "Sudha P", "Adam M", "Potter A", "Kopras EJ", "Giannikou K", "Potter SS", "Sherman S", "Hammes SR", "Kwiatkowski DJ", "Whitsett JA", "McCormack FX", "Xu Y"], "journal": "Am J Respir Crit Care Med", "journal_title": "American journal of respiratory and critical care medicine", "citation": "American journal of respiratory and critical care medicine, 11 2020", "abstract": "Rationale: Lymphangioleiomyomatosis (LAM) is a metastatic neoplasm of reproductive-age women associated with mutations in tuberous sclerosis complex genes. LAM causes cystic remodeling of the lung and progressive respiratory failure. The sources and cellular characteristics of LAM cells underlying disease pathogenesis remain elusive.Objectives: Identification and characterization of LAM cells in human lung and uterus using a single-cell approach.Methods: Single-cell and single-nuclei RNA sequencing on LAM (n = 4) and control (n = 7) lungs, immunofluorescence confocal microscopy, ELISA, and aptamer proteomics were used to identify and validate LAMCORE cells and secreted biomarkers, predict cellular origins, and define molecular and cellular networks in LAM.Measurements and Main Results: A unique cell type termed LAMCORE was identified, which was distinct from, but closely related to, lung mesenchymal cells. LAMCORE cells expressing signature genes included known LAM markers such as PMEL, FIGF, CTSK, and MLANA and novel biomarkers validated by aptamer screening, ELISA, and immunofluorescence microscopy. LAM cells in lung and uterus are morphologically indistinguishable and share similar gene expression profiles and biallelic TSC2 mutations, supporting a potential uterine origin for the LAMCORE cell. Effects of LAM on resident pulmonary cell types indicated recruitment and activation of lymphatic endothelial cells.Conclusions: A unique population of LAMCORE cells was identified in lung and uterus of patients with LAM, sharing close transcriptomic identity. LAM cell selective markers, secreted biomarkers, and the predicted cellular molecular features provide new insights into the signaling and transcriptional programs that may serve as diagnostic markers and therapeutic targets to influence the pathogenesis of LAM.", "year": "2020", "month": "11", "volume": "202", "issue": "10", "pages": "1373-1387", "doi": "10.1164/rccm.201912-2445OC", "link": "https://www.ncbi.nlm.nih.gov/pubmed/32603599", "sort_key": "2020-11-single-cell transcri", "quarter": "q4"}, {"pmid": "33164753", "title": "Single-cell multiomic profiling of human lungs reveals cell-type-specific and age-dynamic control of SARS-CoV2 host genes.", "authors": ["Wang A", "Chiou J", "Poirion OB", "Buchanan J", "Valdez MJ", "Verheyden JM", "Hou X", "Kudtarkar P", "Narendra S", "Newsome JM", "Guo M", "Faddah DA", "Zhang K", "Young RE", "Barr J", "Sajti E", "Misra R", "Huyck H", "Rogers L", "Poole C", "Whitsett JA", "Pryhuber G", "Xu Y", "Gaulton KJ", "Preissl S", "Sun X", "NHLBI LungMap Consortium"], "journal": "Elife", "journal_title": "eLife", "citation": "eLife, 11 2020", "abstract": "Respiratory failure associated with COVID-19 has placed focus on the lungs. Here, we present single-nucleus accessible chromatin profiles of 90,980 nuclei and matched single-nucleus transcriptomes of 46,500 nuclei in non-diseased lungs from donors of ~30 weeks gestation,~3 years and ~30 years. We mapped candidate cis-regulatory elements (cCREs) and linked them to putative target genes. We identified distal cCREs with age-increased activity linked to SARS-CoV-2 host entry gene TMPRSS2 in alveolar type 2 cells, which had immune regulatory signatures and harbored variants associated with respiratory traits. At the 3p21.31 COVID-19 risk locus, a candidate variant overlapped a distal cCRE linked to SLC6A20, a gene expressed in alveolar cells and with known functional association with the SARS-CoV-2 receptor ACE2. Our findings provide insight into regulatory logic underlying genes implicated in COVID-19 in individual lung cell types across age. More broadly, these datasets will facilitate interpretation of risk loci for lung diseases.", "year": "2020", "month": "11", "volume": "9", "issue": "", "pages": "", "doi": "10.7554/eLife.62522", "link": "https://www.ncbi.nlm.nih.gov/pubmed/33164753", "sort_key": "2020-11-single-cell multiomi", "quarter": "q4"}, {"pmid": "32878480", "title": "Elevated FiO2 increases SARS-CoV-2 co-receptor expression in respiratory tract epithelium.", "authors": ["Myti D", "Gunjak M", "Casado F", "Khaghani Raziabad S", "Nardiello C", "Vad\u00e1sz I", "Herold S", "Pryhuber G", "Seeger W", "Morty RE"], "journal": "Am J Physiol Lung Cell Mol Physiol", "journal_title": "American journal of physiology. Lung cellular and molecular physiology", "citation": "American journal of physiology. Lung cellular and molecular physiology, 10 2020", "abstract": "The severity of coronavirus disease 2019 (COVID-19) is linked to an increasing number of risk factors, including exogenous (environmental) stimuli such as air pollution, nicotine, and cigarette smoke. These three factors increase the expression of angiotensin I converting enzyme 2 (ACE2), a key receptor involved in the entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-the etiological agent of COVID-19-into respiratory tract epithelial cells. Patients with severe COVID-19 are managed with oxygen support, as are at-risk individuals with chronic lung disease. To date, no study has examined whether an increased fraction of inspired oxygen (FiO2) may affect the expression of SARS-CoV-2 entry receptors and co-receptors, including ACE2 and the transmembrane serine proteases TMPRSS1, TMPRSS2, and TMPRSS11D. To address this, steady-state mRNA levels for genes encoding these SARS-CoV-2 receptors were assessed in the lungs of mouse pups chronically exposed to elevated FiO2, and in the lungs of preterm-born human infants chronically managed with an elevated FiO2. These two scenarios served as models of chronic elevated FiO2 exposure. Additionally, SARS-CoV-2 receptor expression was assessed in primary human nasal, tracheal, esophageal, bronchial, and alveolar epithelial cells, as well as primary mouse alveolar type II cells exposed to elevated oxygen concentrations. While gene expression of ACE2 was unaffected, gene and protein expression of TMPRSS11D was consistently upregulated by exposure to an elevated FiO2. These data highlight the need for further studies that examine the relative contribution of the various viral co-receptors on the infection cycle, and point to oxygen supplementation as a potential risk factor for COVID-19.", "year": "2020", "month": "10", "volume": "319", "issue": "4", "pages": "L670-L674", "doi": "10.1152/ajplung.00345.2020", "link": "https://www.ncbi.nlm.nih.gov/pubmed/32878480", "sort_key": "2020-10-elevated fio2 increa", "quarter": "q4"}, {"pmid": "32442602", "title": "The elephant in the lung: Integrating lineage-tracing, molecular markers, and single cell sequencing data to identify distinct fibroblast populations during lung development and regeneration.", "authors": ["Riccetti M", "Gokey JJ", "Aronow B", "Perl AT"], "journal": "Matrix Biol", "journal_title": "Matrix biology : journal of the International Society for Matrix Biology", "citation": "Matrix biology : journal of the International Society for Matrix Biology, 09 2020", "abstract": "During lung development, the mesenchyme and epithelium are dependent on each other for instructive morphogenic cues that direct proliferation, cellular differentiation and organogenesis. Specification of epithelial and mesenchymal cell lineages occurs in parallel, forming cellular subtypes that guide the formation of both transitional developmental structures and the permanent architecture of the adult lung. While epithelial cell types and lineages have been relatively well-defined in recent years, the definition of mesenchymal cell types and lineage relationships has been more challenging. Transgenic mouse lines with permanent and inducible lineage tracers have been instrumental in identifying lineage relationships among epithelial progenitor cells and their differentiation into distinct airway and alveolar epithelial cells. Lineage tracing experiments with reporter mice used to identify fibroblast progenitors and their lineage trajectories have been limited by the number of cell specific genes and the developmental timepoint when the lineage trace was activated. In this review, we discuss major developmental mesenchymal lineages, focusing on time of origin, major cell type, and other lineage derivatives, as well as the transgenic tools used to find and define them. We describe lung fibroblasts using function, location, and molecular markers in order to compare and contrast cells with similar functions. The temporal and cell-type specific expression of fourteen \"fibroblast lineage\" genes were identified in single-cell RNA-sequencing data from LungMAP in the LGEA database. Using these lineage signature genes as guides, we clustered murine lung fibroblast populations from embryonic day 16.5 to postnatal day 28 (E16.5-PN28) and generated heatmaps to illustrate expression of transcription factors, signaling receptors and ligands in a temporal and population specific manner.", "year": "2020", "month": "09", "volume": "91-92", "issue": "", "pages": "51-74", "doi": "10.1016/j.matbio.2020.05.002", "link": "https://www.ncbi.nlm.nih.gov/pubmed/32442602", "sort_key": "2020-09-the elephant in the ", "quarter": "q3"}, {"pmid": "32460513", "title": "Glucocorticoid regulates mesenchymal cell differentiation required for perinatal lung morphogenesis and function.", "authors": ["Bridges JP", "Sudha P", "Lipps D", "Wagner A", "Guo M", "Du Y", "Brown K", "Filuta A", "Kitzmiller J", "Stockman C", "Chen X", "Weirauch MT", "Jobe AH", "Whitsett JA", "Xu Y"], "journal": "Am J Physiol Lung Cell Mol Physiol", "journal_title": "American journal of physiology. Lung cellular and molecular physiology", "citation": "American journal of physiology. Lung cellular and molecular physiology, 08 2020", "abstract": "While antenatal glucocorticoids are widely used to enhance lung function in preterm infants, cellular and molecular mechanisms by which glucocorticoid receptor (GR) signaling influences lung maturation remain poorly understood. Deletion of the glucocorticoid receptor gene (Nr3c1) from fetal pulmonary mesenchymal cells phenocopied defects caused by global Nr3c1 deletion, while lung epithelial- or endothelial-specific Nr3c1 deletion did not impair lung function at birth. We integrated genome-wide gene expression profiling, ATAC-seq, and single cell RNA-seq data in mice in which GR was deleted or activated to identify the cellular and molecular mechanisms by which glucocorticoids control prenatal lung maturation. GR enhanced differentiation of a newly defined proliferative mesenchymal progenitor cell (PMP) into matrix fibroblasts (MFBs), in part by directly activating extracellular matrix-associated target genes, including Fn1, Col16a4, and Eln and by modulating VEGF, JAK-STAT, and WNT signaling. Loss of mesenchymal GR signaling blocked fibroblast progenitor differentiation into mature MFBs, which in turn increased proliferation of SOX9+ alveolar epithelial progenitor cells and inhibited differentiation of mature alveolar type II (AT2) and AT1 cells. GR signaling controls genes required for differentiation of a subset of proliferative mesenchymal progenitors into matrix fibroblasts, in turn, regulating signals controlling AT2/AT1 progenitor cell proliferation and differentiation and identifying cells and processes by which glucocorticoid signaling regulates fetal lung maturation.", "year": "2020", "month": "08", "volume": "319", "issue": "2", "pages": "L239-L255", "doi": "10.1152/ajplung.00459.2019", "link": "https://www.ncbi.nlm.nih.gov/pubmed/32460513", "sort_key": "2020-08-glucocorticoid regul", "quarter": "q3"}, {"pmid": "32711747", "title": "Early Neonatal Oxygen Exposure Predicts Pulmonary Morbidity and Functional Deficits at 1\u00a0Year.", "authors": ["Dylag AM", "Kopin HG", "O'Reilly MA", "Wang H", "Davis SD", "Ren CL", "Pryhuber GS"], "journal": "J Pediatr", "journal_title": "The Journal of pediatrics", "citation": "The Journal of pediatrics, 08 2020", "abstract": "OBJECTIVE: To evaluate the predictive value of cumulative oxygen exposure thresholds over the first 2 postnatal weeks, linking them to bronchopulmonary dysplasia (BPD) and 1-year pulmonary morbidity and lung function in extremely low gestational age newborns. STUDY DESIGN: Infants (N = 704) enrolled in the Prematurity and Respiratory Outcomes Program, a multicenter prospective cohort study, that survived to discharge were followed through their neonatal intensive care unit hospitalization to 1-year corrected age. Cumulative oxygen exposure (OxygenAUC14) thresholds were derived from univariate models of BPD, stratifying infants into high-, intermediate-, and low-oxygen exposure groups. These groups were then used in multivariate logistic regressions to prospectively predict post-prematurity respiratory disease (PRD), respiratory morbidity score (RMS) in the entire cohort, and pulmonary function z scores (N = 108 subset of infants) at 1-year corrected age. RESULTS: Over the first 14 postnatal days, infants exposed to high oxygen averaged \u226533.1% oxygen, infants exposed to intermediate oxygen averaged 29.1%-33.1%, and infants exposed to low oxygen were below both cutoffs. In multivariate models, infants exposed to high oxygen showed increased PRD and RMS, whereas infants exposed to intermediate oxygen demonstrated increased moderate/severe RMS. Infants in the high/intermediate groups had decreased forced expiratory volume at 0.5 seconds/forced vital capacity ratio. CONCLUSIONS: OxygenAUC14 establishes 3 thresholds of oxygen exposure that risk stratify infants early in their neonatal course, thereby predicting short-term (BPD) and 1-year (PRD, RMS) respiratory morbidity. Infants with greater OxygenAUC14 have altered pulmonary function tests at 1 year of age, indicating early evidence of obstructive lung disease and flow limitation, which may predispose extremely low gestational age newborns to increased long-term pulmonary morbidity. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01435187.", "year": "2020", "month": "08", "volume": "223", "issue": "", "pages": "20-28.e2", "doi": "10.1016/j.jpeds.2020.04.042", "link": "https://www.ncbi.nlm.nih.gov/pubmed/32711747", "sort_key": "2020-08-early neonatal oxyge", "quarter": "q3"}, {"pmid": "32832599", "title": "Single-cell RNA-seq reveals ectopic and aberrant lung-resident cell populations in idiopathic pulmonary fibrosis.", "authors": ["Adams TS", "Schupp JC", "Poli S", "Ayaub EA", "Neumark N", "Ahangari F", "Chu SG", "Raby BA", "DeIuliis G", "Januszyk M", "Duan Q", "Arnett HA", "Siddiqui A", "Washko GR", "Homer R", "Yan X", "Rosas IO", "Kaminski N"], "journal": "Sci Adv", "journal_title": "Science advances", "citation": "Science advances, 07 2020", "abstract": "We provide a single-cell atlas of idiopathic pulmonary fibrosis (IPF), a fatal interstitial lung disease, by profiling 312,928 cells from 32 IPF, 28 smoker and nonsmoker controls, and 18 chronic obstructive pulmonary disease (COPD) lungs. Among epithelial cells enriched in IPF, we identify a previously unidentified population of aberrant basaloid cells that coexpress basal epithelial, mesenchymal, senescence, and developmental markers and are located at the edge of myofibroblast foci in the IPF lung. Among vascular endothelial cells, we identify an ectopically expanded cell population transcriptomically identical to bronchial restricted vascular endothelial cells in IPF. We confirm the presence of both populations by immunohistochemistry and independent datasets. Among stromal cells, we identify IPF myofibroblasts and invasive fibroblasts with partially overlapping cells in control and COPD lungs. Last, we confirm previous findings of profibrotic macrophage populations in the IPF lung. Our comprehensive catalog reveals the complexity and diversity of aberrant cellular populations in IPF.", "year": "2020", "month": "07", "volume": "6", "issue": "28", "pages": "eaba1983", "doi": "10.1126/sciadv.aba1983", "link": "https://www.ncbi.nlm.nih.gov/pubmed/32832599", "sort_key": "2020-07-single-cell rna-seq ", "quarter": "q3"}, {"pmid": "32633718", "title": "A mechanistic model and therapeutic interventions for COVID-19 involving a RAS-mediated bradykinin storm.", "authors": ["Garvin MR", "Alvarez C", "Miller JI", "Prates ET", "Walker AM", "Amos BK", "Mast AE", "Justice A", "Aronow B", "Jacobson D"], "journal": "Elife", "journal_title": "eLife", "citation": "eLife, 07 2020", "abstract": "Neither the disease mechanism nor treatments for COVID-19 are currently known. Here, we present a novel molecular mechanism for COVID-19 that provides therapeutic intervention points that can be addressed with existing FDA-approved pharmaceuticals. The entry point for the virus is ACE2, which is a component of the counteracting hypotensive axis of RAS. Bradykinin is a potent part of the vasopressor system that induces hypotension and vasodilation and is degraded by ACE and enhanced by the angiotensin1-9 produced by ACE2. Here, we perform a new analysis on gene expression data from cells in bronchoalveolar lavage fluid (BALF) from COVID-19 patients that were used to sequence the virus. Comparison with BALF from controls identifies a critical imbalance in RAS represented by decreased expression of ACE in combination with increases in ACE2, renin, angiotensin, key RAS receptors, kinogen and many kallikrein enzymes that activate it, and both bradykinin receptors. This very atypical pattern of the RAS is predicted to elevate bradykinin levels in multiple tissues and systems that will likely cause increases in vascular dilation, vascular permeability and hypotension. These bradykinin-driven outcomes explain many of the symptoms being observed in COVID-19.", "year": "2020", "month": "07", "volume": "9", "issue": "", "pages": "", "doi": "10.7554/eLife.59177", "link": "https://www.ncbi.nlm.nih.gov/pubmed/32633718", "sort_key": "2020-07-a mechanistic model ", "quarter": "q3"}, {"pmid": "32439709", "title": "TRM integrins CD103 and CD49a differentially support adherence and motility after resolution of influenza virus infection.", "authors": ["Reilly EC", "Lambert Emo K", "Buckley PM", "Reilly NS", "Smith I", "Chaves FA", "Yang H", "Oakes PW", "Topham DJ"], "journal": "Proc Natl Acad Sci U S A", "journal_title": "Proceedings of the National Academy of Sciences of the United States of America", "citation": "Proceedings of the National Academy of Sciences of the United States of America, 06 2020", "abstract": "Tissue-resident memory CD8 T (TRM) cells are a unique immune memory subset that develops and remains in peripheral tissues at the site of infection, providing future host resistance upon reexposure to that pathogen. In the pulmonary system, TRM are identified through S1P antagonist CD69 and expression of integrins CD103/\u03b27 and CD49a/CD29(\u03b21). Contrary to the established role of CD69 on CD8 T cells, the functions of CD103 and CD49a on this population are not well defined. This study examines the expression patterns and functions of CD103 and CD49a with a specific focus on their impact on T cell motility during influenza virus infection. We show that the TRM cell surface phenotype develops by 2 wk postinfection, with the majority of the population expressing CD49a and a subset that is also positive for CD103. Despite a previously established role in retaining TRM in peripheral tissues, CD49a facilitates locomotion of virus-specific CD8 T cells, both in vitro and in vivo. These results demonstrate that CD49a may contribute to local surveillance mechanisms of the TRM population.", "year": "2020", "month": "06", "volume": "117", "issue": "22", "pages": "12306-12314", "doi": "10.1073/pnas.1915681117", "link": "https://www.ncbi.nlm.nih.gov/pubmed/32439709", "sort_key": "2020-06-trm integrins cd103 ", "quarter": "q2"}, {"pmid": "32061334", "title": "Small airways pathology in idiopathic pulmonary fibrosis: a retrospective cohort study.", "authors": ["Verleden SE", "Tanabe N", "McDonough JE", "Vasilescu DM", "Xu F", "Wuyts WA", "Piloni D", "De Sadeleer L", "Willems S", "Mai C", "Hostens J", "Cooper JD", "Verbeken EK", "Verschakelen J", "Galban CJ", "Van Raemdonck DE", "Colby TV", "Decramer M", "Verleden GM", "Kaminski N", "Hackett TL", "Vanaudenaerde BM", "Hogg JC"], "journal": "Lancet Respir Med", "journal_title": "The Lancet. Respiratory medicine", "citation": "The Lancet. Respiratory medicine, 06 2020", "abstract": "BACKGROUND: The observation that patients with idiopathic pulmonary fibrosis (IPF) can have higher than normal expiratory flow rates at low lung volumes led to the conclusion that the airways are spared in IPF. This study aimed to re-examine the hypothesis that airways are spared in IPF using a multiresolution imaging protocol that combines multidetector CT (MDCT), with micro-CT and histology. METHODS: This was a retrospective cohort study comparing explanted lungs from patients with severe IPF treated by lung transplantation with a cohort of unused donor (control) lungs. The donor control lungs had no known lung disease, comorbidities, or structural lung injury, and were deemed appropriate for transplantation on review of the clinical files. The diagnosis of IPF in the lungs from patients was established by a multidisciplinary consensus committee according to existing guidelines, and was confirmed by video-assisted thoracic surgical biopsy or by pathological examination of the contralateral lung. The control and IPF groups were matched for age, sex, height, and bodyweight. Samples of lung tissue were compared using the multiresolution imaging approach: a cascade of clinical MDCT, micro-CT, and histological imaging. We did two experiments: in experiment 1, all the lungs were randomly sampled; in experiment 2, samples were selected from regions of minimal and established fibrosis. The patients and donors were recruited from the Katholieke Universiteit Leuven (Leuven, Belgium) and the University of Pennsylvania Hospital (Philadelphia, PA, USA). The study took place at the Katholieke Universiteit Leuven, and the University of British Columbia (Vancouver, BC, Canada). FINDINGS: Between Oct 5, 2009, and July 22, 2016, explanted lungs from patients with severe IPF (n=11), were compared with a cohort of unused donor (control) lungs (n=10), providing 240 samples of lung tissue for comparison using the multiresolution imaging approach. The MDCT specimen scans show that the number of visible airways located between the ninth generation (control 69 [SD 22] versus patients with IPF 105 [33], p=0\u00b70023) and 14th generation (control 9 [6] versus patients with IPF 49 [28], p<0\u00b70001) of airway branching are increased in patients with IPF, which we show by micro-CT is due to thickening of their walls and distortion of their lumens. The micro-CT analysis showed that compared with healthy (control) lung anatomy (mean 5\u00b76 terminal bronchioles per mL [SD 1\u00b76]), minimal fibrosis in IPF tissue was associated with a 57% loss of the terminal bronchioles (mean 2\u00b74 terminal bronchioles per mL [SD 1\u00b70]; p<0\u00b70001), the appearance of fibroblastic foci, and infiltration of the tissue by inflammatory immune cells capable of forming lymphoid follicles. Established fibrosis in IPF tissue had a similar reduction (66%) in the number of terminal bronchioles (mean 1\u00b79 terminal bronchioles per mL [SD 1\u00b74]; p<0\u00b70001) and was dominated by increased airspace size, Ashcroft fibrosis score, and volume fractions of tissue and collagen. INTERPRETATION: Small airways disease is a feature of IPF, with significant loss of terminal bronchioles occuring within regions of minimal fibrosis. On the basis of these findings, we postulate that the small airways could become a potential therapeutic target in IPF. FUNDING: Katholieke Universiteit Leuven, US National Institutes of Health, BC Lung Association, and Genentech.", "year": "2020", "month": "06", "volume": "8", "issue": "6", "pages": "573-584", "doi": "10.1016/S2213-2600(19)30356-X", "link": "https://www.ncbi.nlm.nih.gov/pubmed/32061334", "sort_key": "2020-06-small airways pathol", "quarter": "q2"}, {"pmid": "32207533", "title": "Resolving single-cell heterogeneity from hundreds of thousands of cells through sequential hybrid clustering and NMF.", "authors": ["Venkatasubramanian M", "Chetal K", "Schnell DJ", "Atluri G", "Salomonis N"], "journal": "Bioinformatics", "journal_title": "Bioinformatics (Oxford, England)", "citation": "Bioinformatics (Oxford, England), 06 2020", "abstract": "MOTIVATION: The rapid proliferation of single-cell RNA-sequencing (scRNA-Seq) technologies has spurred the development of diverse computational approaches to detect transcriptionally coherent populations. While the complexity of the algorithms for detecting heterogeneity has increased, most require significant user-tuning, are heavily reliant on dimension reduction techniques and are not scalable to ultra-large datasets. We previously described a multi-step algorithm, Iterative Clustering and Guide-gene Selection (ICGS), which applies intra-gene correlation and hybrid clustering to uniquely resolve novel transcriptionally coherent cell populations from an intuitive graphical user interface. RESULTS: We describe a new iteration of ICGS that outperforms state-of-the-art scRNA-Seq detection workflows when applied to well-established benchmarks. This approach combines multiple complementary subtype detection methods (HOPACH, sparse non-negative matrix factorization, cluster 'fitness', support vector machine) to resolve rare and common cell-states, while minimizing differences due to donor or batch effects. Using data from multiple cell atlases, we show that the PageRank algorithm effectively downsamples ultra-large scRNA-Seq datasets, without losing extremely rare or transcriptionally similar yet distinct cell types and while recovering novel transcriptionally distinct cell populations. We believe this new approach holds tremendous promise in reproducibly resolving hidden cell populations in complex datasets. AVAILABILITY AND IMPLEMENTATION: ICGS2 is implemented in Python. The source code and documentation are available at http://altanalyze.org. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.", "year": "2020", "month": "06", "volume": "36", "issue": "12", "pages": "3773-3780", "doi": "10.1093/bioinformatics/btaa201", "link": "https://www.ncbi.nlm.nih.gov/pubmed/32207533", "sort_key": "2020-06-resolving single-cel", "quarter": "q2"}, {"pmid": "32023086", "title": "Hyperoxia Injury in the Developing Lung Is Mediated by Mesenchymal Expression of Wnt5A.", "authors": ["Sucre JMS", "Vickers KC", "Benjamin JT", "Plosa EJ", "Jetter CS", "Cutrone A", "Ransom M", "Anderson Z", "Sheng Q", "Fensterheim BA", "Ambalavanan N", "Millis B", "Lee E", "Zijlstra A", "K\u00f6nigshoff M", "Blackwell TS", "Guttentag SH"], "journal": "Am J Respir Crit Care Med", "journal_title": "American journal of respiratory and critical care medicine", "citation": "American journal of respiratory and critical care medicine, 05 2020", "abstract": "Rationale: Bronchopulmonary dysplasia (BPD) is a leading complication of preterm birth that affects infants born in the saccular stage of lung development at <32 weeks of gestation. Although the mechanisms driving BPD remain uncertain, exposure to hyperoxia is thought to contribute to disease pathogenesis.Objectives: To determine the effects of hyperoxia on epithelial-mesenchymal interactions and to define the mediators of activated Wnt/\u03b2-catenin signaling after hyperoxia injury.Methods: Three hyperoxia models were used: A three-dimensional organotypic coculture using primary human lung cells, precision-cut lung slices (PCLS), and a murine in vivo hyperoxia model. Comparisons of normoxia- and hyperoxia-exposed samples were made by real-time quantitative PCR, RNA in situ hybridization, quantitative confocal microscopy, and lung morphometry.Measurements and Main Results: Examination of an array of Wnt ligands in the three-dimensional organotypic coculture revealed increased mesenchymal expression of WNT5A. Inhibition of Wnt5A abrogated the BPD transcriptomic phenotype induced by hyperoxia. In the PCLS model, Wnt5A inhibition improved alveolarization following hyperoxia exposure, and treatment with recombinant Wnt5a reproduced features of the BPD phenotype in PCLS cultured in normoxic conditions. Chemical inhibition of NF-\u03baB with BAY11-7082 reduced Wnt5a expression in the PCLS hyperoxia model and in vivo mouse hyperoxia model, with improved alveolarization in the PCLS model.Conclusions: Increased mesenchymal Wnt5A during saccular-stage hyperoxia injury contributes to the impaired alveolarization and septal thickening observed in BPD. Precise targeting of Wnt5A may represent a potential therapeutic strategy for the treatment of BPD.", "year": "2020", "month": "05", "volume": "201", "issue": "10", "pages": "1249-1262", "doi": "10.1164/rccm.201908-1513OC", "link": "https://www.ncbi.nlm.nih.gov/pubmed/32023086", "sort_key": "2020-05-hyperoxia injury in ", "quarter": "q2"}, {"pmid": "32380423", "title": "Efficient Generation and Transcriptomic Profiling of Human iPSC-Derived Pulmonary Neuroendocrine Cells.", "authors": ["Hor P", "Punj V", "Calvert BA", "Castaldi A", "Miller AJ", "Carraro G", "Stripp BR", "Brody SL", "Spence JR", "Ichida JK", "Ryan Firth AL", "Borok Z"], "journal": "iScience", "journal_title": "iScience", "citation": "iScience, 05 2020", "abstract": "Expansion of pulmonary neuroendocrine cells (PNECs) is a pathological feature of many human lung diseases. Human PNECs are inherently difficult to study due to their rarity (<1% of total lung cells) and a lack of established protocols for their isolation. We used induced pluripotent stem cells (iPSCs) to generate induced PNECs (iPNECs), which express core PNEC markers, including ROBO receptors, and secrete major neuropeptides, recapitulating known functions of primary PNECs. Furthermore, we demonstrate that differentiation efficiency is increased in the presence of an air-liquid interface and inhibition of Notch signaling. Single-cell RNA sequencing (scRNA-seq) revealed a PNEC-associated gene expression profile that is concordant between iPNECs and human fetal PNECs. In addition, pseudotime analysis of scRNA-seq results suggests a basal cell origin of human iPNECs. In conclusion, our model has the potential to provide an unlimited source of human iPNECs to explore PNEC pathophysiology associated with several lung diseases.", "year": "2020", "month": "05", "volume": "23", "issue": "5", "pages": "101083", "doi": "10.1016/j.isci.2020.101083", "link": "https://www.ncbi.nlm.nih.gov/pubmed/32380423", "sort_key": "2020-05-efficient generation", "quarter": "q2"}, {"pmid": "31662342", "title": "Disruption of normal patterns of FOXF1 expression in a lethal disorder of lung development.", "authors": ["Steiner LA", "Getman M", "Schiralli Lester GM", "Iqbal MA", "Katzman P", "Szafranski P", "Stankiewicz P", "Bhattacharya S", "Mariani T", "Pryhuber G", "Lin X", "Young JL", "Dean DA", "Scheible K"], "journal": "J Med Genet", "journal_title": "Journal of medical genetics", "citation": "Journal of medical genetics, 05 2020", "abstract": "BACKGROUND: Alveolar capillary dysplasia with misalignment of the pulmonary veins (ACDMPV) is a lethal disorder of lung development. ACDMPV is associated with haploinsufficiency of the transcription factor FOXF1, which plays an important role in the development of the lung and intestine. CNVs upstream of the FOXF1 gene have also been associated with an ACDMPV phenotype, but mechanism(s) by which these deletions disrupt lung development are not well understood. The objective of our study is to gain insights into the mechanisms by which CNVs contribute to an ACDMPV phenotype. METHODS: We analysed primary lung tissue from an infant with classic clinical and histological findings of ACDMPV and harboured a 340 kb deletion on chromosome 16q24.1 located 250 kb upstream of FOXF1. RESULTS: In RNA generated from paraffin-fixed lung sections, our patient had lower expression of FOXF1 than age-matched controls. He also had an abnormal pattern of FOXF1 protein expression, with a dramatic loss of FOXF1 expression in the lung. To gain insights into the mechanisms underlying these changes, we assessed the epigenetic landscape using chromatin immunoprecipitation, which demonstrated loss of histone H3 lysine 27 acetylation (H3K27Ac), an epigenetic mark of active enhancers, in the region of the deletion. CONCLUSIONS: Together, these data suggest that the deletion disrupts an enhancer responsible for directing FOXF1 expression in the developing lung and provide novel insights into the mechanisms underlying a fatal developmental lung disorder.", "year": "2020", "month": "05", "volume": "57", "issue": "5", "pages": "296-300", "doi": "10.1136/jmedgenet-2019-106095", "link": "https://www.ncbi.nlm.nih.gov/pubmed/31662342", "sort_key": "2020-05-disruption of normal", "quarter": "q2"}, {"pmid": "32405060", "title": "A single-cell and single-nucleus RNA-Seq toolbox for fresh and frozen human tumors.", "authors": ["Slyper M", "Porter CBM", "Ashenberg O", "Waldman J", "Drokhlyansky E", "Wakiro I", "Smillie C", "Smith-Rosario G", "Wu J", "Dionne D", "Vigneau S", "Jan\u00e9-Valbuena J", "Tickle TL", "Napolitano S", "Su MJ", "Patel AG", "Karlstrom A", "Gritsch S", "Nomura M", "Waghray A", "Gohil SH", "Tsankov AM", "Jerby-Arnon L", "Cohen O", "Klughammer J", "Rosen Y", "Gould J", "Nguyen L", "Hofree M", "Tramontozzi PJ", "Li B", "Wu CJ", "Izar B", "Haq R", "Hodi FS", "Yoon CH", "Hata AN", "Baker SJ", "Suv\u00e0 ML", "Bueno R", "Stover EH", "Clay MR", "Dyer MA", "Collins NB", "Matulonis UA", "Wagle N", "Johnson BE", "Rotem A", "Rozenblatt-Rosen O", "Regev A"], "journal": "Nat Med", "journal_title": "Nature medicine", "citation": "Nature medicine, 05 2020", "abstract": "Single-cell genomics is essential to chart tumor ecosystems. Although single-cell RNA-Seq (scRNA-Seq) profiles RNA from cells dissociated from fresh tumors, single-nucleus RNA-Seq (snRNA-Seq) is needed to profile frozen or hard-to-dissociate tumors. Each requires customization to different tissue and tumor types, posing a barrier to adoption. Here, we have developed a systematic toolbox for profiling fresh and frozen clinical tumor samples using scRNA-Seq and snRNA-Seq, respectively. We analyzed 216,490 cells and nuclei from 40 samples across 23 specimens spanning eight tumor types of varying tissue and sample characteristics. We evaluated protocols by cell and nucleus quality, recovery rate and cellular composition. scRNA-Seq and snRNA-Seq from matched samples recovered the same cell types, but at different proportions. Our work provides guidance for studies in a broad range of tumors, including criteria for testing and selecting methods from the toolbox for other tumors, thus paving the way for charting tumor atlases.", "year": "2020", "month": "05", "volume": "26", "issue": "5", "pages": "792-802", "doi": "10.1038/s41591-020-0844-1", "link": "https://www.ncbi.nlm.nih.gov/pubmed/32405060", "sort_key": "2020-05-a single-cell and si", "quarter": "q2"}, {"pmid": "32004478", "title": "Reconstructed Single-Cell Fate Trajectories Define Lineage Plasticity Windows during Differentiation of Human PSC-Derived Distal Lung Progenitors.", "authors": ["Hurley K", "Ding J", "Villacorta-Martin C", "Herriges MJ", "Jacob A", "Vedaie M", "Alysandratos KD", "Sun YL", "Lin C", "Werder RB", "Huang J", "Wilson AA", "Mithal A", "Mostoslavsky G", "Oglesby I", "Caballero IS", "Guttentag SH", "Ahangari F", "Kaminski N", "Rodriguez-Fraticelli A", "Camargo F", "Bar-Joseph Z", "Kotton DN"], "journal": "Cell Stem Cell", "journal_title": "Cell stem cell", "citation": "Cell stem cell, 04 2020", "abstract": "Alveolar epithelial type 2 cells (AEC2s) are the facultative progenitors responsible for maintaining lung alveoli throughout life but are difficult to isolate from patients. Here, we engineer AEC2s from human pluripotent stem cells (PSCs) in vitro and use time-series single-cell RNA sequencing with lentiviral barcoding to profile the kinetics of their differentiation in comparison to primary fetal and adult AEC2 benchmarks. We observe bifurcating cell-fate trajectories as primordial lung progenitors differentiate in vitro, with some progeny reaching their AEC2 fate target, while others diverge to alternative non-lung endodermal fates. We develop a Continuous State Hidden Markov model to identify the timing and type of signals, such as overexuberant Wnt responses, that induce some early multipotent NKX2-1+ progenitors to lose lung fate. Finally, we find that this initial developmental plasticity is regulatable and subsides over time, ultimately resulting in PSC-derived AEC2s that exhibit a stable phenotype and nearly limitless self-renewal capacity.", "year": "2020", "month": "04", "volume": "26", "issue": "4", "pages": "593-608.e8", "doi": "10.1016/j.stem.2019.12.009", "link": "https://www.ncbi.nlm.nih.gov/pubmed/32004478", "sort_key": "2020-04-reconstructed single", "quarter": "q2"}, {"pmid": "31726465", "title": "CX3CR1 as a respiratory syncytial virus receptor in pediatric human lung.", "authors": ["Anderson CS", "Chu CY", "Wang Q", "Mereness JA", "Ren Y", "Donlon K", "Bhattacharya S", "Misra RS", "Walsh EE", "Pryhuber GS", "Mariani TJ"], "journal": "Pediatr Res", "journal_title": "Pediatric research", "citation": "Pediatric research, 04 2020", "abstract": "BACKGROUND: Data on the host factors that contribute to infection of young children by respiratory syncytial virus (RSV) are limited. The human chemokine receptor, CX3CR1, has recently been implicated as an RSV receptor. Here we evaluate a role for CX3CR1 in pediatric lung RSV infections. METHODS: CX3CR1 transcript levels in the upper and lower pediatric airways were assessed. Tissue localization and cell-specific expression was confirmed using in situ hybridization and immunohistochemistry. The role of CX3CR1 in RSV infection was also investigated using a novel physiological model of pediatric epithelial cells. RESULTS: Low levels of CX3CR1 transcript were often, but not always, expressed in both upper (62%) and lower airways (36%) of pediatric subjects. CX3CR1 transcript and protein expression was detected in epithelial cells of normal human pediatric lung tissues. CX3CR1 expression was readily detected on primary cultures of differentiated pediatric/infant human lung epithelial cells. RSV demonstrated preferential infection of CX3CR1-positive cells, and blocking CX3CR1/RSV interaction significantly decreased viral load. CONCLUSION: CX3CR1 is present in the airways of pediatric subjects where it may serve as a receptor for RSV infection. Furthermore, CX3CR1 appears to play a mechanistic role in mediating viral infection of pediatric airway epithelial cells in vitro.", "year": "2020", "month": "04", "volume": "87", "issue": "5", "pages": "862-867", "doi": "10.1038/s41390-019-0677-0", "link": "https://www.ncbi.nlm.nih.gov/pubmed/31726465", "sort_key": "2020-04-cx3cr1 as a respirat", "quarter": "q2"}, {"pmid": "32317643", "title": "Collagen-producing lung cell atlas identifies multiple subsets with distinct localization and relevance to fibrosis.", "authors": ["Tsukui T", "Sun KH", "Wetter JB", "Wilson-Kanamori JR", "Hazelwood LA", "Henderson NC", "Adams TS", "Schupp JC", "Poli SD", "Rosas IO", "Kaminski N", "Matthay MA", "Wolters PJ", "Sheppard D"], "journal": "Nat Commun", "journal_title": "Nature communications", "citation": "Nature communications, 04 2020", "abstract": "Collagen-producing cells maintain the complex architecture of the lung and drive pathologic scarring in pulmonary fibrosis. Here we perform single-cell RNA-sequencing to identify all collagen-producing cells in normal and fibrotic lungs. We characterize multiple collagen-producing subpopulations with distinct anatomical localizations in different compartments of murine lungs. One subpopulation, characterized by expression of Cthrc1 (collagen triple helix repeat containing 1), emerges in fibrotic lungs and expresses the highest levels of collagens. Single-cell RNA-sequencing of human lungs, including those from idiopathic pulmonary fibrosis and scleroderma patients, demonstrate similar heterogeneity and CTHRC1-expressing fibroblasts present uniquely in fibrotic lungs. Immunostaining and in situ hybridization show that these cells are concentrated within fibroblastic foci. We purify collagen-producing subpopulations and find disease-relevant phenotypes of Cthrc1-expressing fibroblasts in in vitro and adoptive transfer experiments. Our atlas of collagen-producing cells provides a roadmap for studying the roles of these unique populations in homeostasis and pathologic fibrosis.", "year": "2020", "month": "04", "volume": "11", "issue": "1", "pages": "1920", "doi": "10.1038/s41467-020-15647-5", "link": "https://www.ncbi.nlm.nih.gov/pubmed/32317643", "sort_key": "2020-04-collagen-producing l", "quarter": "q2"}, {"pmid": "32071223", "title": "AB569, a nontoxic chemical tandem that kills major human pathogenic bacteria.", "authors": ["McDaniel CT", "Panmanee W", "Winsor GL", "Gill E", "Bertelli C", "Schurr MJ", "Dongare P", "Paul AT", "Ko SB", "Lau GW", "Dasgupta N", "Bogue AL", "Miller WE", "Mortensen JE", "Haslam DB", "Dexheimer P", "Muruve DA", "Aronow BJ", "Forbes MDE", "Danilczuk M", "Brinkman FSL", "Hancock REW", "Meyer TJ", "Hassett DJ"], "journal": "Proc Natl Acad Sci U S A", "journal_title": "Proceedings of the National Academy of Sciences of the United States of America", "citation": "Proceedings of the National Academy of Sciences of the United States of America, 03 2020", "abstract": "Antibiotic-resistant superbug bacteria represent a global health problem with no imminent solutions. Here we demonstrate that the combination (termed AB569) of acidified nitrite (A-NO2-) and Na2-EDTA (disodium ethylenediaminetetraacetic acid) inhibited all Gram-negative and Gram-positive bacteria tested. AB569 was also efficacious at killing the model organism Pseudomonas aeruginosa in biofilms and in a murine chronic lung infection model. AB569 was not toxic to human cell lines at bactericidal concentrations using a basic viability assay. RNA-Seq analyses upon treatment of P. aeruginosa with AB569 revealed a catastrophic loss of the ability to support core pathways encompassing DNA, RNA, protein, ATP biosynthesis, and iron metabolism. Electrochemical analyses elucidated that AB569 produced more stable SNO proteins, potentially explaining one mechanism of bacterial killing. Our data implicate that AB569 is a safe and effective means to kill pathogenic bacteria, suggesting that simple strategies could be applied with highly advantageous therapeutic/toxicity index ratios to pathogens associated with a myriad of periepithelial infections and related disease scenarios.", "year": "2020", "month": "03", "volume": "117", "issue": "9", "pages": "4921-4930", "doi": "10.1073/pnas.1911927117", "link": "https://www.ncbi.nlm.nih.gov/pubmed/32071223", "sort_key": "2020-03-ab569, a nontoxic ch", "quarter": "q1"}, {"pmid": "31517510", "title": "YAP and TAZ in Lung Development: The Timing Is Important.", "authors": ["Warburton D"], "journal": "Am J Respir Cell Mol Biol", "journal_title": "American journal of respiratory cell and molecular biology", "citation": "American journal of respiratory cell and molecular biology, 02 2020", "abstract": "", "year": "2020", "month": "02", "volume": "62", "issue": "2", "pages": "141-142", "doi": "10.1165/rcmb.2019-0300ED", "link": "https://www.ncbi.nlm.nih.gov/pubmed/31517510", "sort_key": "2020-02-yap and taz in lung ", "quarter": "q1"}, {"pmid": "32024828", "title": "Pre-processing visualization of hyperspectral fluorescent data with Spectrally Encoded Enhanced Representations.", "authors": ["Shi W", "Koo DES", "Kitano M", "Chiang HJ", "Trinh LA", "Turcatel G", "Steventon B", "Arnesano C", "Warburton D", "Fraser SE", "Cutrale F"], "journal": "Nat Commun", "journal_title": "Nature communications", "citation": "Nature communications, 02 2020", "abstract": "Hyperspectral fluorescence imaging is gaining popularity for it enables multiplexing of spatio-temporal dynamics across scales for molecules, cells and tissues with multiple fluorescent labels. This is made possible by adding the dimension of wavelength to the dataset. The resulting datasets are high in information density and often require lengthy analyses to separate the overlapping fluorescent spectra. Understanding and visualizing these large multi-dimensional datasets during acquisition and pre-processing can be challenging. Here we present Spectrally Encoded Enhanced Representations (SEER), an approach for improved and computationally efficient simultaneous color visualization of multiple spectral components of hyperspectral fluorescence images. Exploiting the mathematical properties of the phasor method, we transform the wavelength space into information-rich color maps for RGB display visualization. We present multiple biological fluorescent samples and highlight SEER's enhancement of specific and subtle spectral differences, providing a fast, intuitive and mathematical way to interpret hyperspectral images during collection, pre-processing and analysis.", "year": "2020", "month": "02", "volume": "11", "issue": "1", "pages": "726", "doi": "10.1038/s41467-020-14486-8", "link": "https://www.ncbi.nlm.nih.gov/pubmed/32024828", "sort_key": "2020-02-pre-processing visua", "quarter": "q1"}, {"pmid": "32075728", "title": "Insulin-like Growth Factor 1 Supports a Pulmonary Niche that Promotes Type 3 Innate Lymphoid Cell Development in Newborn Lungs.", "authors": ["Oherle K", "Acker E", "Bonfield M", "Wang T", "Gray J", "Lang I", "Bridges J", "Lewkowich I", "Xu Y", "Ahlfeld S", "Zacharias W", "Alenghat T", "Deshmukh H"], "journal": "Immunity", "journal_title": "Immunity", "citation": "Immunity, 02 2020", "abstract": "Type 3 innate lymphoid cells (ILC3s) are critical for lung defense against bacterial pneumonia in the neonatal period, but the signals that guide pulmonary ILC3 development remain unclear. Here, we demonstrated that pulmonary ILC3s descended from ILC precursors that populated a niche defined by fibroblasts in the developing lung. Alveolar fibroblasts produced insulin-like growth factor 1 (IGF1), which instructed expansion and maturation of pulmonary ILC precursors. Conditional ablation of IGF1 in alveolar fibroblasts or deletion of the IGF-1 receptor from ILC precursors interrupted ILC3 biogenesis and rendered newborn mice susceptible to pneumonia. Premature infants with bronchopulmonary dysplasia, characterized by interrupted postnatal alveolar development and increased morbidity to respiratory infections, had reduced IGF1 concentrations and pulmonary ILC3 numbers. These findings indicate that the newborn period is a critical window in pulmonary immunity development, and disrupted lung development in prematurely born infants may have enduring effects on host resistance to respiratory infections.", "year": "2020", "month": "02", "volume": "52", "issue": "2", "pages": "275-294.e9", "doi": "10.1016/j.immuni.2020.01.005", "link": "https://www.ncbi.nlm.nih.gov/pubmed/32075728", "sort_key": "2020-02-insulin-like growth ", "quarter": "q1"}, {"pmid": "32069291", "title": "Inferring TF activation order in time series scRNA-Seq studies.", "authors": ["Lin C", "Ding J", "Bar-Joseph Z"], "journal": "PLoS Comput Biol", "journal_title": "PLoS computational biology", "citation": "PLoS computational biology, 02 2020", "abstract": "Methods for the analysis of time series single cell expression data (scRNA-Seq) either do not utilize information about transcription factors (TFs) and their targets or only study these as a post-processing step. Using such information can both, improve the accuracy of the reconstructed model and cell assignments, while at the same time provide information on how and when the process is regulated. We developed the Continuous-State Hidden Markov Models TF (CSHMM-TF) method which integrates probabilistic modeling of scRNA-Seq data with the ability to assign TFs to specific activation points in the model. TFs are assumed to influence the emission probabilities for cells assigned to later time points allowing us to identify not just the TFs controlling each path but also their order of activation. We tested CSHMM-TF on several mouse and human datasets. As we show, the method was able to identify known and novel TFs for all processes, assigned time of activation agrees with both expression information and prior knowledge and combinatorial predictions are supported by known interactions. We also show that CSHMM-TF improves upon prior methods that do not utilize TF-gene interaction.", "year": "2020", "month": "02", "volume": "16", "issue": "2", "pages": "e1007644", "doi": "10.1371/journal.pcbi.1007644", "link": "https://www.ncbi.nlm.nih.gov/pubmed/32069291", "sort_key": "2020-02-inferring tf activat", "quarter": "q1"}, {"pmid": "31837950", "title": "Collagen VI Deficiency Results in Structural Abnormalities in the Mouse Lung.", "authors": ["Mereness JA", "Bhattacharya S", "Ren Y", "Wang Q", "Anderson CS", "Donlon K", "Dylag AM", "Haak J", "Angelin A", "Bonaldo P", "Mariani TJ"], "journal": "Am J Pathol", "journal_title": "The American journal of pathology", "citation": "The American journal of pathology, 02 2020", "abstract": "Collagen VI (COL6) is known for its role in a spectrum of congenital muscular dystrophies, which are often accompanied by respiratory dysfunction. However, little is known regarding the function of COL6 in the lung. We confirmed the presence of COL6 throughout the basement membrane region of mouse lung tissue. Lung structure and organization were studied in a previously described Col6a1-/- mouse, which does not produce detectable COL6 in the lung. The Col6a1-/- mouse displayed histopathologic alveolar and airway abnormalities. The airspaces of Col6a1-/- lungs appeared simplified, with larger (29%; P < 0.01) and fewer (31%; P < 0.001) alveoli. These airspace abnormalities included reduced isolectin B4+ alveolar capillaries and surfactant protein C-positive alveolar epithelial type-II cells. Alterations in lung function consistent with these histopathologic changes were evident. Col6a1-/- mice also displayed multiple airway changes, including increased branching (59%; P < 0.001), increased mucosal thickness (34%; P < 0.001), and increased epithelial cell density (13%; P < 0.001). Comprehensive transcriptome analysis revealed that the loss of COL6 is associated with reductions in integrin-paxillin-phosphatidylinositol 3-kinase signaling in vivo. In vitro, COL6 promoted steady-state phosphorylated paxillin levels and reduced cell density (16% to 28%; P < 0.05) at confluence. Inhibition of phosphatidylinositol 3-kinase, or its downstream effectors, resulted in increased cell density to a level similar to that seen on matrices lacking COL6.", "year": "2020", "month": "02", "volume": "190", "issue": "2", "pages": "426-441", "doi": "10.1016/j.ajpath.2019.10.014", "link": "https://www.ncbi.nlm.nih.gov/pubmed/31837950", "sort_key": "2020-02-collagen vi deficien", "quarter": "q1"}, {"pmid": "30776794", "title": "A novel in vitro model of primary human pediatric lung epithelial cells.", "authors": ["Wang Q", "Bhattacharya S", "Mereness JA", "Anderson C", "Lillis JA", "Misra RS", "Romas S", "Huyck H", "Howell A", "Bandyopadhyay G", "Donlon K", "Myers JR", "Ashton J", "Pryhuber GS", "Mariani TJ"], "journal": "Pediatr Res", "journal_title": "Pediatric research", "citation": "Pediatric research, 02 2020", "abstract": "BACKGROUND: Current in vitro human lung epithelial cell models derived from adult tissues may not accurately represent all attributes that define homeostatic and disease mechanisms relevant to the pediatric lung. METHODS: We report methods for growing and differentiating primary Pediatric Human Lung Epithelial (PHLE) cells from organ donor infant lung tissues. We use immunohistochemistry, flow cytometry, quantitative RT-PCR, and single cell RNA sequencing (scRNAseq) analysis to characterize the cellular and transcriptional heterogeneity of PHLE cells. RESULTS: PHLE cells can be expanded in culture up to passage 6, with a doubling time of ~4 days, and retain attributes of highly enriched epithelial cells. PHLE cells can form resistant monolayers, and undergo differentiation when placed at air-liquid interface. When grown at Air-Liquid Interface (ALI), PHLE cells expressed markers of airway epithelial cell lineages. scRNAseq suggests the cultures contained 4 main sub-phenotypes defined by expression of FOXJ1, KRT5, MUC5B, and SFTPB. These cells are available to the research community through the Developing Lung Molecular Atlas Program Human Tissue Core. CONCLUSION: Our data demonstrate that PHLE cells provide a novel in vitro human cell model that represents the pediatric airway epithelium, which can be used to study perinatal developmental and pediatric disease mechanisms.", "year": "2020", "month": "02", "volume": "87", "issue": "3", "pages": "511-517", "doi": "10.1038/s41390-019-0340-9", "link": "https://www.ncbi.nlm.nih.gov/pubmed/30776794", "sort_key": "2020-02-a novel in vitro mod", "quarter": "q1"}, {"pmid": "33552042", "title": "Lymphocyte-Specific Biomarkers Associated With Preterm Birth and Bronchopulmonary Dysplasia.", "authors": ["Bhattacharya S", "Mereness JA", "Baran AM", "Misra RS", "Peterson DR", "Ryan RM", "Reynolds AM", "Pryhuber GS", "Mariani TJ"], "journal": "Front Immunol", "journal_title": "Frontiers in immunology", "citation": "Frontiers in immunology, 2020", "abstract": "Many premature babies who are born with neonatal respiratory distress syndrome (RDS) go on to develop Bronchopulmonary Dysplasia (BPD) and later Post-Prematurity Respiratory Disease (PRD) at one year corrected age, characterized by persistent or recurrent lower respiratory tract symptoms frequently related to inflammation and viral infection. Transcriptomic profiles were generated from sorted peripheral blood CD8+ T cells of preterm and full-term infants enrolled with consent in the NHLBI Prematurity and Respiratory Outcomes Program (PROP) at the University of Rochester and the University at Buffalo. We identified outcome-related gene expression patterns following standard methods to identify markers for oxygen utilization and BPD as outcomes in extremely premature infants. We further identified predictor gene sets for BPD based on transcriptomic data adjusted for gestational age at birth (GAB). RNA-Seq analysis was completed for CD8+ T cells from 145 subjects. Among the subjects with highest risk for BPD (born at <29 weeks gestational age (GA); n=72), 501 genes were associated with oxygen utilization. In the same set of subjects, 571 genes were differentially expressed in subjects with a diagnosis of BPD and 105 genes were different in BPD subjects as defined by physiologic challenge. A set of 92 genes could predict BPD with a moderately high degree of accuracy. We consistently observed dysregulation of TGFB, NRF2, HIPPO, and CD40-associated pathways in BPD. Using gene expression data from both premature and full-term subjects (n=116), we identified a 28 gene set that predicted the PRD status with a moderately high level of accuracy, which also were involved in TGFB signaling. Transcriptomic data from sort-purified peripheral blood CD8+ T cells from 145 preterm and full-term infants identified sets of molecular markers of inflammation associated with independent development of BPD in extremely premature infants at high risk for the disease and of PRD among the preterm and full-term subjects.", "year": "2020", "month": "", "volume": "11", "issue": "", "pages": "563473", "doi": "10.3389/fimmu.2020.563473", "link": "https://www.ncbi.nlm.nih.gov/pubmed/33552042", "sort_key": "2020-00-lymphocyte-specific ", "quarter": "q0"}, {"pmid": "33176330", "title": "Alveolar Airspace Size in Healthy and Diseased Infant Lungs Measured via Hyperpolarized 3He Gas Diffusion Magnetic Resonance Imaging.", "authors": ["Higano NS", "Thomen RP", "Quirk JD", "Huyck HL", "Hahn AD", "Fain SB", "Pryhuber GS", "Woods JC"], "journal": "Neonatology", "journal_title": "Neonatology", "citation": "Neonatology, 2020", "abstract": "BACKGROUND: Alveolar development and lung parenchymal simplification are not well characterized in vivo in neonatal patients with respiratory morbidities, such as bronchopulmonary dysplasia (BPD). Hyperpolarized (HP) gas diffusion magnetic resonance imaging (MRI) is a sensitive, safe, nonionizing, and noninvasive biomarker for measuring airspace size in vivo but has not yet been implemented in young infants. OBJECTIVE: This work quantified alveolar airspace size via HP gas diffusion MRI in healthy and diseased explanted infant lung specimens, with comparison to histological morphometry. METHODS: Lung specimens from 8 infants were obtained: 7 healthy left upper lobes (0-16 months, post-autopsy) and 1 left lung with filamin-A mutation, closely representing BPD lung disease (11 months, post-transplantation). Specimens were imaged using HP 3He diffusion MRI to generate apparent diffusion coefficients (ADCs) as biomarkers of alveolar airspace size, with comparison to mean linear intercept (Lm) via quantitative histology. RESULTS: Mean ADC and Lm were significantly increased throughout the diseased specimen (ADC = 0.26 \u00b1 0.06 cm2/s, Lm = 587 \u00b1 212 \u00b5m) compared with healthy specimens (ADC = 0.14 \u00b1 0.03 cm2/s, Lm = 133 \u00b1 37 \u00b5m; p < 1 \u00d7 10-7); increased values reflect enlarged airspaces. Mean ADCs in healthy specimens were significantly correlated to Lm (r = 0.69, p = 0.041). CONCLUSIONS: HP gas diffusion MRI is sensitive to healthy and diseased regional alveolar airspace size in infant lungs, with good comparison to quantitative histology in ex vivo specimens. This work demonstrates the translational potential of gas MRI techniques for in vivo assessment of normal and abnormal alveolar development in neonates with pulmonary disease.", "year": "2020", "month": "", "volume": "117", "issue": "6", "pages": "704-712", "doi": "10.1159/000511084", "link": "https://www.ncbi.nlm.nih.gov/pubmed/33176330", "sort_key": "2020-00-alveolar airspace si", "quarter": "q0"}, {"pmid": "31840053", "title": "Single-cell connectomic analysis of adult mammalian lungs.", "authors": ["Raredon MSB", "Adams TS", "Suhail Y", "Schupp JC", "Poli S", "Neumark N", "Leiby KL", "Greaney AM", "Yuan Y", "Horien C", "Linderman G", "Engler AJ", "Boffa DJ", "Kluger Y", "Rosas IO", "Levchenko A", "Kaminski N", "Niklason LE"], "journal": "Sci Adv", "journal_title": "Science advances", "citation": "Science advances, 12 2019", "abstract": "Efforts to decipher chronic lung disease and to reconstitute functional lung tissue through regenerative medicine have been hampered by an incomplete understanding of cell-cell interactions governing tissue homeostasis. Because the structure of mammalian lungs is highly conserved at the histologic level, we hypothesized that there are evolutionarily conserved homeostatic mechanisms that keep the fine architecture of the lung in balance. We have leveraged single-cell RNA sequencing techniques to identify conserved patterns of cell-cell cross-talk in adult mammalian lungs, analyzing mouse, rat, pig, and human pulmonary tissues. Specific stereotyped functional roles for each cell type in the distal lung are observed, with alveolar type I cells having a major role in the regulation of tissue homeostasis. This paper provides a systems-level portrait of signaling between alveolar cell populations. These methods may be applicable to other organs, providing a roadmap for identifying key pathways governing pathophysiology and informing regenerative efforts.", "year": "2019", "month": "12", "volume": "5", "issue": "12", "pages": "eaaw3851", "doi": "10.1126/sciadv.aaw3851", "link": "https://www.ncbi.nlm.nih.gov/pubmed/31840053", "sort_key": "2019-12-single-cell connecto", "quarter": "q4"}, {"pmid": "31529053", "title": "cellHarmony: cell-level matching and holistic comparison of single-cell transcriptomes.", "authors": ["DePasquale EAK", "Schnell D", "Dexheimer P", "Ferchen K", "Hay S", "Chetal K", "Valiente-Aland\u00ed \u00cd", "Blaxall BC", "Grimes HL", "Salomonis N"], "journal": "Nucleic Acids Res", "journal_title": "Nucleic acids research", "citation": "Nucleic acids research, 12 2019", "abstract": "To understand the molecular pathogenesis of human disease, precision analyses to define alterations within and between disease-associated cell populations are desperately needed. Single-cell genomics represents an ideal platform to enable the identification and comparison of normal and diseased transcriptional cell populations. We created cellHarmony, an integrated solution for the unsupervised analysis, classification, and comparison of cell types from diverse single-cell RNA-Seq datasets. cellHarmony efficiently and accurately matches single-cell transcriptomes using a community-clustering and alignment strategy to compute differences in cell-type specific gene expression over potentially dozens of cell populations. Such transcriptional differences are used to automatically identify distinct and shared gene programs among cell-types and identify impacted pathways and transcriptional regulatory networks to understand the impact of perturbations at a systems level. cellHarmony is implemented as a python package and as an integrated workflow within the software AltAnalyze. We demonstrate that cellHarmony has improved or equivalent performance to alternative label projection methods, is able to identify the likely cellular origins of malignant states, stratify patients into clinical disease subtypes from identified gene programs, resolve discrete disease networks impacting specific cell-types, and illuminate therapeutic mechanisms. Thus, this approach holds tremendous promise in revealing the molecular and cellular origins of complex disease.", "year": "2019", "month": "12", "volume": "47", "issue": "21", "pages": "e138", "doi": "10.1093/nar/gkz789", "link": "https://www.ncbi.nlm.nih.gov/pubmed/31529053", "sort_key": "2019-12-cellharmony: cell-le", "quarter": "q4"}, {"pmid": "31600171", "title": "Transcriptional regulatory model of fibrosis progression in the human lung.", "authors": ["McDonough JE", "Ahangari F", "Li Q", "Jain S", "Verleden SE", "Herazo-Maya J", "Vukmirovic M", "DeIuliis G", "Tzouvelekis A", "Tanabe N", "Chu F", "Yan X", "Verschakelen J", "Homer RJ", "Manatakis DV", "Zhang J", "Ding J", "Maes K", "De Sadeleer L", "Vos R", "Neyrinck A", "Benos PV", "Bar-Joseph Z", "Tantin D", "Hogg JC", "Vanaudenaerde BM", "Wuyts WA", "Kaminski N"], "journal": "JCI Insight", "journal_title": "JCI insight", "citation": "JCI insight, 11 2019", "abstract": "To develop a systems biology model of fibrosis progression within the human lung we performed RNA sequencing and microRNA analysis on 95 samples obtained from 10 idiopathic pulmonary fibrosis (IPF) and 6 control lungs. Extent of fibrosis in each sample was assessed by microCT-measured alveolar surface density (ASD) and confirmed by histology. Regulatory gene expression networks were identified using linear mixed-effect models and dynamic regulatory events miner (DREM). Differential gene expression analysis identified a core set of genes increased or decreased before fibrosis was histologically evident that continued to change with advanced fibrosis. DREM generated a systems biology model (www.sb.cs.cmu.edu/IPFReg) that identified progressively divergent gene expression tracks with microRNAs and transcription factors that specifically regulate mild or advanced fibrosis. We confirmed model predictions by demonstrating that expression of POU2AF1, previously unassociated with lung fibrosis but proposed by the model as regulator, is increased in B lymphocytes in IPF lungs and that POU2AF1-knockout mice were protected from bleomycin-induced lung fibrosis. Our results reveal distinct regulation of gene expression changes in IPF tissue that remained structurally normal compared with moderate or advanced fibrosis and suggest distinct regulatory mechanisms for each stage.", "year": "2019", "month": "11", "volume": "4", "issue": "22", "pages": "", "doi": "10.1172/jci.insight.131597", "link": "https://www.ncbi.nlm.nih.gov/pubmed/31600171", "sort_key": "2019-11-transcriptional regu", "quarter": "q4"}, {"pmid": "31233341", "title": "Postnatal Alveologenesis Depends on FOXF1 Signaling in c-KIT+ Endothelial Progenitor Cells.", "authors": ["Ren X", "Ustiyan V", "Guo M", "Wang G", "Bolte C", "Zhang Y", "Xu Y", "Whitsett JA", "Kalin TV", "Kalinichenko VV"], "journal": "Am J Respir Crit Care Med", "journal_title": "American journal of respiratory and critical care medicine", "citation": "American journal of respiratory and critical care medicine, 11 2019", "abstract": "Rationale: Disruption of alveologenesis is associated with severe pediatric lung disorders, including bronchopulmonary dysplasia (BPD). Although c-KIT+ endothelial cell (EC) progenitors are abundant in embryonic and neonatal lungs, their role in alveolar septation and the therapeutic potential of these cells remain unknown.Objectives: To determine whether c-KIT+ EC progenitors stimulate alveologenesis in the neonatal lung.Methods: We used single-cell RNA sequencing of neonatal human and mouse lung tissues, immunostaining, and FACS analysis to identify transcriptional and signaling networks shared by human and mouse pulmonary c-KIT+ EC progenitors. A mouse model of perinatal hyperoxia-induced lung injury was used to identify molecular mechanisms that are critical for the survival, proliferation, and engraftment of c-KIT+ EC progenitors in the neonatal lung.Measurements and Main Results: Pulmonary c-KIT+ EC progenitors expressing PECAM-1, CD34, VE-Cadherin, FLK1, and TIE2 lacked mature arterial, venal, and lymphatic cell-surface markers. The transcriptomic signature of c-KIT+ ECs was conserved in mouse and human lungs and enriched in FOXF1-regulated transcriptional targets. Expression of FOXF1 and c-KIT was decreased in the lungs of infants with BPD. In the mouse, neonatal hyperoxia decreased the number of c-KIT+ EC progenitors. Haploinsufficiency or endothelial-specific deletion of Foxf1 in mice increased apoptosis and decreased proliferation of c-KIT+ ECs. Inactivation of either Foxf1 or c-Kit caused alveolar simplification. Adoptive transfer of c-KIT+ ECs into the neonatal circulation increased lung angiogenesis and prevented alveolar simplification in neonatal mice exposed to hyperoxia.Conclusions: Cell therapy involving c-KIT+ EC progenitors can be beneficial for the treatment of BPD.", "year": "2019", "month": "11", "volume": "200", "issue": "9", "pages": "1164-1176", "doi": "10.1164/rccm.201812-2312OC", "link": "https://www.ncbi.nlm.nih.gov/pubmed/31233341", "sort_key": "2019-11-postnatal alveologen", "quarter": "q4"}, {"pmid": "30977807", "title": "Lipid Mini-On: mining and ontology tool for enrichment analysis of lipidomic data.", "authors": ["Clair G", "Reehl S", "Stratton KG", "Monroe ME", "Tfaily MM", "Ansong C", "Kyle JE"], "journal": "Bioinformatics", "journal_title": "Bioinformatics (Oxford, England)", "citation": "Bioinformatics (Oxford, England), 11 2019", "abstract": "SUMMARY: Here we introduce Lipid Mini-On, an open-source tool that performs lipid enrichment analyses and visualizations of lipidomics data. Lipid Mini-On uses a text-mining process to bin individual lipid names into multiple lipid ontology groups based on the classification (e.g. LipidMaps) and other characteristics, such as chain length. Lipid Mini-On provides users with the capability to conduct enrichment analysis of the lipid ontology terms using a Shiny app with options of five statistical approaches. Lipid classes can be added to customize the user's database and remain updated as new lipid classes are discovered. Visualization of results is available for all classification options (e.g. lipid subclass and individual fatty acid chains). Results are also visualized through an editable network of relationships between the individual lipids and their associated lipid ontology terms. The utility of the tool is demonstrated using biological (e.g. human lung endothelial cells) and environmental (e.g. peat soil) samples. AVAILABILITY AND IMPLEMENTATION: Rodin (R package: https://github.com/PNNL-Comp-Mass-Spec/Rodin), Lipid Mini-On Shiny app (https://github.com/PNNL-Comp-Mass-Spec/LipidMiniOn) and Lipid Mini-On online tool (https://omicstools.pnnl.gov/shiny/lipid-mini-on/). SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.", "year": "2019", "month": "11", "volume": "35", "issue": "21", "pages": "4507-4508", "doi": "10.1093/bioinformatics/btz250", "link": "https://www.ncbi.nlm.nih.gov/pubmed/30977807", "sort_key": "2019-11-lipid mini-on: minin", "quarter": "q4"}, {"pmid": "31432713", "title": "Integrating multiomics longitudinal data to reconstruct networks underlying lung development.", "authors": ["Ding J", "Ahangari F", "Espinoza CR", "Chhabra D", "Nicola T", "Yan X", "Lal CV", "Hagood JS", "Kaminski N", "Bar-Joseph Z", "Ambalavanan N"], "journal": "Am J Physiol Lung Cell Mol Physiol", "journal_title": "American journal of physiology. Lung cellular and molecular physiology", "citation": "American journal of physiology. Lung cellular and molecular physiology, 11 2019", "abstract": "A comprehensive understanding of the dynamic regulatory networks that govern postnatal alveolar lung development is still lacking. To construct such a model, we profiled mRNA, microRNA, DNA methylation, and proteomics of developing murine alveoli isolated by laser capture microdissection at 14 predetermined time points. We developed a detailed comprehensive and interactive model that provides information about the major expression trajectories, the regulators of specific key events, and the impact of epigenetic changes. Intersecting the model with single-cell RNA-Seq data led to the identification of active pathways in multiple or individual cell types. We then constructed a similar model for human lung development by profiling time-series human omics data sets. Several key pathways and regulators are shared between the reconstructed models. We experimentally validated the activity of a number of predicted regulators, leading to new insights about the regulation of innate immunity during lung development.", "year": "2019", "month": "11", "volume": "317", "issue": "5", "pages": "L556-L568", "doi": "10.1152/ajplung.00554.2018", "link": "https://www.ncbi.nlm.nih.gov/pubmed/31432713", "sort_key": "2019-11-integrating multiomi", "quarter": "q4"}, {"pmid": "31693907", "title": "DoubletDecon: Deconvoluting Doublets from Single-Cell RNA-Sequencing Data.", "authors": ["DePasquale EAK", "Schnell DJ", "Van Camp PJ", "Valiente-Aland\u00ed \u00cd", "Blaxall BC", "Grimes HL", "Singh H", "Salomonis N"], "journal": "Cell Rep", "journal_title": "Cell reports", "citation": "Cell reports, 11 2019", "abstract": "Methods for single-cell RNA sequencing (scRNA-seq) have greatly advanced in recent years. While droplet- and well-based methods have increased the capture frequency of cells for scRNA-seq, these technologies readily produce technical artifacts, such as doublet cell captures. Doublets occurring between distinct cell types can appear as hybrid scRNA-seq profiles, but do not have distinct transcriptomes from individual cell states. We introduce DoubletDecon, an approach that detects doublets with a combination of deconvolution analyses and the identification of unique cell-state gene expression. We demonstrate the ability of DoubletDecon to identify synthetic, mixed-species, genetic, and cell-hashing cell doublets from scRNA-seq datasets of varying cellular complexity with a high sensitivity relative to alternative approaches. Importantly, this algorithm prevents the prediction of valid mixed-lineage and transitional cell states as doublets by considering their unique gene expression. DoubletDecon has an easy-to-use graphical user interface and is compatible with diverse species and unsupervised population detection algorithms.", "year": "2019", "month": "11", "volume": "29", "issue": "6", "pages": "1718-1727.e8", "doi": "10.1016/j.celrep.2019.09.082", "link": "https://www.ncbi.nlm.nih.gov/pubmed/31693907", "sort_key": "2019-11-doubletdecon: deconv", "quarter": "q4"}, {"pmid": "31215789", "title": "Complete Tracheal Ring Deformity. A Translational Genomics Approach to Pathogenesis.", "authors": ["Sinner DI", "Carey B", "Zgherea D", "Kaufman KM", "Leesman L", "Wood RE", "Rutter MJ", "de Alarcon A", "Elluru RG", "Harley JB", "Whitsett JA", "Trapnell BC"], "journal": "Am J Respir Crit Care Med", "journal_title": "American journal of respiratory and critical care medicine", "citation": "American journal of respiratory and critical care medicine, 11 2019", "abstract": "Rationale: Complete tracheal ring deformity (CTRD) is a rare congenital abnormality of unknown etiology characterized by circumferentially continuous or nearly continuous cartilaginous tracheal rings, variable degrees of tracheal stenosis and/or shortening, and/or pulmonary arterial sling anomaly.Objectives: To test the hypothesis that CTRD is caused by inherited or de novo mutations in genes required for normal tracheal development.Methods: CTRD and normal tracheal tissues were examined microscopically to define the tracheal abnormalities present in CTRD. Whole-exome sequencing was performed in children with CTRD and their biological parents (\"trio analysis\") to identify gene variants in patients with CTRD. Mutations were confirmed by Sanger sequencing, and their potential impact on structure and/or function of encoded proteins was examined using human gene mutation databases. Relevance was further examined by comparison with the effects of targeted deletion of murine homologs important to tracheal development in mice.Measurements and Main Results: The trachealis muscle was absent in all of five patients with CTRD. Exome analysis identified six de novo, three recessive, and multiple compound-heterozygous or rare hemizygous variants in children with CTRD. De novo variants were identified in SHH (Sonic Hedgehog), and inherited variants were identified in HSPG2 (perlecan), ROR2 (receptor tyrosine kinase-like orphan receptor 2), and WLS (Wntless), genes involved in morphogenetic pathways known to mediate tracheoesophageal development in mice.Conclusions: The results of the present study demonstrate that absence of the trachealis muscle is associated with CTRD. Variants predicted to cause disease were identified in genes encoding Hedgehog and Wnt signaling pathway molecules, which are critical to cartilage formation and normal upper airway development in mice.", "year": "2019", "month": "11", "volume": "200", "issue": "10", "pages": "1267-1281", "doi": "10.1164/rccm.201809-1626OC", "link": "https://www.ncbi.nlm.nih.gov/pubmed/31215789", "sort_key": "2019-11-complete tracheal ri", "quarter": "q4"}, {"pmid": "31727986", "title": "Bronchopulmonary dysplasia.", "authors": ["Th\u00e9baud B", "Goss KN", "Laughon M", "Whitsett JA", "Abman SH", "Steinhorn RH", "Aschner JL", "Davis PG", "McGrath-Morrow SA", "Soll RF", "Jobe AH"], "journal": "Nat Rev Dis Primers", "journal_title": "Nature reviews. Disease primers", "citation": "Nature reviews. Disease primers, 11 2019", "abstract": "In the absence of effective interventions to prevent preterm births, improved survival of infants who are born at the biological limits of viability has relied on advances in perinatal care over the past 50 years. Except for extremely preterm infants with suboptimal perinatal care or major antenatal events that cause severe respiratory failure at birth, most extremely preterm infants now survive, but they often develop chronic lung dysfunction termed bronchopulmonary dysplasia (BPD; also known as chronic lung disease). Despite major efforts to minimize injurious but often life-saving postnatal interventions (such as oxygen, mechanical ventilation and corticosteroids), BPD remains the most frequent complication of extreme preterm birth. BPD is now recognized as the result of an aberrant reparative response to both antenatal injury and repetitive postnatal injury to the developing lungs. Consequently, lung development is markedly impaired, which leads to persistent airway and pulmonary vascular disease that can affect adult lung function. Greater insights into the pathobiology of BPD will provide a better understanding of disease mechanisms and lung repair and regeneration, which will enable the discovery of novel therapeutic targets. In parallel, clinical and translational studies that improve the classification of disease phenotypes and enable early identification of at-risk preterm infants should improve trial design and individualized care to enhance outcomes in preterm infants.", "year": "2019", "month": "11", "volume": "5", "issue": "1", "pages": "78", "doi": "10.1038/s41572-019-0127-7", "link": "https://www.ncbi.nlm.nih.gov/pubmed/31727986", "sort_key": "2019-11-bronchopulmonary dys", "quarter": "q4"}, {"pmid": "31272105", "title": "Loss of FLCN inhibits canonical WNT signaling via TFE3.", "authors": ["Kennedy JC", "Khabibullin D", "Hougard T", "Nijmeh J", "Shi W", "Henske EP"], "journal": "Hum Mol Genet", "journal_title": "Human molecular genetics", "citation": "Human molecular genetics, 10 2019", "abstract": "Lower lobe predominant pulmonary cysts occur in up to 90% of patients with Birt-Hogg-Dub\u00e9 (BHD) syndrome, but the key pathologic cell type and signaling events driving this distinct phenotype remain elusive. Through examination of the LungMAP database, we found that folliculin (FLCN) is highly expressed in neonatal lung mesenchymal cells. Using RNA-Seq, we found that inactivation of Flcn in mouse embryonic fibroblasts leads to changes in multiple Wnt ligands, including a 2.8-fold decrease in Wnt2. This was associated with decreased TCF/LEF activity, a readout of canonical WNT activity, after treatment with a GSK3-\u03b1/\u03b2 inhibitor. Similarly, FLCN deficiency in HEK293T cells decreased WNT pathway activity by 76% post-GSK3-\u03b1/\u03b2 inhibition. Inactivation of FLCN in human fetal lung fibroblasts (MRC-5) led to ~ 100-fold decrease in Wnt2 expression and a 33-fold decrease in Wnt7b expression-two ligands known to be necessary for lung development. Furthermore, canonical WNT activity was decreased by 60%. Classic WNT targets such as AXIN2 and BMP4, and WNT enhanceosome members including TCF4, LEF1 and BCL9 were also decreased after GSK3-\u03b1/\u03b2 inhibition. FLCN-deficient MRC-5 cells failed to upregulate LEF1 in response to GSK3-\u03b1/\u03b2 inhibition. Finally, we found that a constitutively active \u03b2-catenin could only partially rescue the decreased WNT activity phenotype seen in FLCN-deficient cells, whereas silencing the transcription factor TFE3 completely reversed this phenotype. In summary, our data establish FLCN as a critical regulator of the WNT pathway via TFE3 and suggest that FLCN-dependent defects in WNT pathway developmental cues may contribute to lung cyst pathogenesis in BHD.", "year": "2019", "month": "10", "volume": "28", "issue": "19", "pages": "3270-3281", "doi": "10.1093/hmg/ddz158", "link": "https://www.ncbi.nlm.nih.gov/pubmed/31272105", "sort_key": "2019-10-loss of flcn inhibit", "quarter": "q4"}, {"pmid": "31509397", "title": "High-Throughput Single Cell Proteomics Enabled by Multiplex Isobaric Labeling in a Nanodroplet Sample Preparation Platform.", "authors": ["Dou M", "Clair G", "Tsai CF", "Xu K", "Chrisler WB", "Sontag RL", "Zhao R", "Moore RJ", "Liu T", "Pasa-Tolic L", "Smith RD", "Shi T", "Adkins JN", "Qian WJ", "Kelly RT", "Ansong C", "Zhu Y"], "journal": "Anal Chem", "journal_title": "Analytical chemistry", "citation": "Analytical chemistry, 10 2019", "abstract": "Effective extension of mass spectrometry-based proteomics to single cells remains challenging. Herein we combined microfluidic nanodroplet technology with tandem mass tag (TMT) isobaric labeling to significantly improve analysis throughput and proteome coverage for single mammalian cells. Isobaric labeling facilitated multiplex analysis of single cell-sized protein quantities to a depth of \u223c1 600 proteins with a median CV of 10.9% and correlation coefficient of 0.98. To demonstrate in-depth high throughput single cell analysis, the platform was applied to measure protein expression in 72 single cells from three murine cell populations (epithelial, immune, and endothelial cells) in <2 days instrument time with over 2 300 proteins identified. Principal component analysis grouped the single cells into three distinct populations based on protein expression with each population characterized by well-known cell-type specific markers. Our platform enables high throughput and unbiased characterization of single cell heterogeneity at the proteome level.", "year": "2019", "month": "10", "volume": "91", "issue": "20", "pages": "13119-13127", "doi": "10.1021/acs.analchem.9b03349", "link": "https://www.ncbi.nlm.nih.gov/pubmed/31509397", "sort_key": "2019-10-high-throughput sing", "quarter": "q4"}, {"pmid": "31651362", "title": "Comprehensive anatomic ontologies for lung development: A comparison of alveolar formation and maturation within mouse and human lung.", "authors": ["Pan H", "Deutsch GH", "Wert SE", "Ontology Subcommittee", "NHLBI Molecular Atlas of Lung Development Program Consortium"], "journal": "J Biomed Semantics", "journal_title": "Journal of biomedical semantics", "citation": "Journal of biomedical semantics, 10 2019", "abstract": "BACKGROUND: Although the mouse is widely used to model human lung development, function, and disease, our understanding of the molecular mechanisms involved in alveolarization of the peripheral lung is incomplete. Recently, the Molecular Atlas of Lung Development Program (LungMAP) was funded by the National Heart, Lung, and Blood Institute to develop an integrated open access database (known as BREATH) to characterize the molecular and cellular anatomy of the developing lung. To support this effort, we designed detailed anatomic and cellular ontologies describing alveolar formation and maturation in both mouse and human lung. DESCRIPTION: While the general anatomic organization of the lung is similar for these two species, there are significant variations in the lung's architectural organization, distribution of connective tissue, and cellular composition along the respiratory tract. Anatomic ontologies for both species were constructed as partonomic hierarchies and organized along the lung's proximal-distal axis into respiratory, vascular, neural, and immunologic components. Terms for developmental and adult lung structures, tissues, and cells were included, providing comprehensive ontologies for application at varying levels of resolution. Using established scientific resources, multiple rounds of comparison were performed to identify common, analogous, and unique terms that describe the lungs of these two species. Existing biological and biomedical ontologies were examined and cross-referenced to facilitate integration at a later time, while additional terms were drawn from the scientific literature as needed. This comparative approach eliminated redundancy and inconsistent terminology, enabling us to differentiate true anatomic variations between mouse and human lungs. As a result, approximately 300 terms for fetal and postnatal lung structures, tissues, and cells were identified for each species. CONCLUSION: These ontologies standardize and expand current terminology for fetal and adult lungs, providing a qualitative framework for data annotation, retrieval, and integration across a wide variety of datasets in the BREATH database. To our knowledge, these are the first ontologies designed to include terminology specific for developmental structures in the lung, as well as to compare common anatomic features and variations between mouse and human lungs. These ontologies provide a unique resource for the LungMAP, as well as for the broader scientific community.", "year": "2019", "month": "10", "volume": "10", "issue": "1", "pages": "18", "doi": "10.1186/s13326-019-0209-1", "link": "https://www.ncbi.nlm.nih.gov/pubmed/31651362", "sort_key": "2019-10-comprehensive anatom", "quarter": "q4"}, {"pmid": "31028279", "title": "Mesenchyme-specific deletion of Tgf-\u03b21 in the embryonic lung disrupts branching morphogenesis and induces lung hypoplasia.", "authors": ["Noe N", "Shim A", "Millette K", "Luo Y", "Azhar M", "Shi W", "Warburton D", "Turcatel G"], "journal": "Lab Invest", "journal_title": "Laboratory investigation; a journal of technical methods and pathology", "citation": "Laboratory investigation; a journal of technical methods and pathology, 09 2019", "abstract": "Proper lung development depends on the precise temporal and spatial expression of several morphogenic factors, including Fgf10, Fgf9, Shh, Bmp4, and Tgf-\u03b2. Over- or under-expression of these molecules often leads to aberrant embryonic or postnatal lung development. Herein, we deleted the Tgf-\u03b21 gene specifically within the lung embryonic mesenchymal compartment at specific gestational stages to determine the contribution of this cytokine to lung development. Mutant embryos developed severe lung hypoplasia and died at birth due to the inability to breathe. Despite the markedly reduced lung size, proliferation and differentiation of the lung epithelium was not affected by the lack of mesenchymal expression of the Tgf-\u03b21 gene, while apoptosis was significantly increased in the mutant lung parenchyma. Lack of mesenchymal expression of the Tgf-\u03b21 gene was also associated with reduced lung branching morphogenesis, with accompanying inhibition of the local FGF10 signaling pathway as well as abnormal development of the vascular system. To shed light on the mechanism of lung hypoplasia, we quantified the phosphorylation of 226 proteins in the mutant E12.5 lung compared with control. We identified five proteins, Hrs, Vav2, c-Kit, the regulatory subunit of Pi3k (P85), and Fgfr1, that were over- or under-phosphorylated in the mutant lung, suggesting that they could be indispensable effectors of the TGF-\u03b2 signaling program during embryonic lung development. In conclusion, we have uncovered novel roles of the mesenchyme-specific Tgf-\u03b21 ligand in embryonic mouse lung development and generated a mouse model that may prove helpful to identify some of the key pathogenic mechanisms underlying lung hypoplasia in humans.", "year": "2019", "month": "09", "volume": "99", "issue": "9", "pages": "1363-1375", "doi": "10.1038/s41374-019-0256-3", "link": "https://www.ncbi.nlm.nih.gov/pubmed/31028279", "sort_key": "2019-09-mesenchyme-specific ", "quarter": "q3"}, {"pmid": "31412198", "title": "Lipid Coverage in Nanospray Desorption Electrospray Ionization Mass Spectrometry Imaging of Mouse Lung Tissues.", "authors": ["Nguyen SN", "Kyle JE", "Dautel SE", "Sontag R", "Luders T", "Corley R", "Ansong C", "Carson J", "Laskin J"], "journal": "Anal Chem", "journal_title": "Analytical chemistry", "citation": "Analytical chemistry, 09 2019", "abstract": "Lipids are a naturally occurring group of molecules that not only contribute to the structural integrity of the lung preventing alveolar collapse but also play important roles in the anti-inflammatory responses and antiviral protection. Alteration in the type and spatial localization of lipids in the lung plays a crucial role in various diseases, such as respiratory distress syndrome (RDS) in preterm infants and oxidative stress-influenced diseases, such as pneumonia, emphysema, and lung cancer following exposure to environmental stressors. The ability to accurately measure spatial distributions of lipids and metabolites in lung tissues provides important molecular insights related to lung function, development, and disease states. Nanospray desorption electrospray ionization (nano-DESI) and other ambient ionization mass spectrometry techniques enable label-free imaging of complex samples in their native state with minimal to absolutely no sample preparation. However, lipid coverage obtained in nano-DESI mass spectrometry imaging (MSI) experiments has not been previously characterized. In this work, the depth of lipid coverage in nano-DESI MSI of mouse lung tissues was compared to liquid chromatography tandem mass spectrometry (LC-MS/MS) lipidomics analysis of tissue extracts prepared using two different procedures: standard Folch extraction method of the whole lung samples and extraction into a 90% methanol/10% water mixture used in nano-DESI MSI experiments. A combination of positive and negative ionization mode nano-DESI MSI identified 265 unique lipids across 20 lipids subclasses and 19 metabolites (284 in total) in mouse lung tissues. Except for triacylglycerols (TG) species, nano-DESI MSI provided comparable coverage to LC-MS/MS experiments performed using methanol/water tissue extracts and up to 50% coverage in comparison with the Folch extraction-based whole lung lipidomics analysis. These results demonstrate the utility of nano-DESI MSI for comprehensive spatially resolved analysis of lipids in tissue sections. A combination of nano-DESI MSI and LC-MS/MS lipidomics is particularly useful for exploring changes in lipid distributions during lung development, as well as resulting from disease or exposure to environmental toxicants.", "year": "2019", "month": "09", "volume": "91", "issue": "18", "pages": "11629-11635", "doi": "10.1021/acs.analchem.9b02045", "link": "https://www.ncbi.nlm.nih.gov/pubmed/31412198", "sort_key": "2019-09-lipid coverage in na", "quarter": "q3"}, {"pmid": "31268347", "title": "Integration of transcriptomic and proteomic data identifies biological functions in cell populations from human infant lung.", "authors": ["Du Y", "Clair GC", "Al Alam D", "Danopoulos S", "Schnell D", "Kitzmiller JA", "Misra RS", "Bhattacharya S", "Warburton D", "Mariani TJ", "Pryhuber GS", "Whitsett JA", "Ansong C", "Xu Y"], "journal": "Am J Physiol Lung Cell Mol Physiol", "journal_title": "American journal of physiology. Lung cellular and molecular physiology", "citation": "American journal of physiology. Lung cellular and molecular physiology, 09 2019", "abstract": "Systems biology uses computational approaches to integrate diverse data types to understand cell and organ behavior. Data derived from complementary technologies, for example transcriptomic and proteomic analyses, are providing new insights into development and disease. We compared mRNA and protein profiles from purified endothelial, epithelial, immune, and mesenchymal cells from normal human infant lung tissue. Signatures for each cell type were identified and compared at both mRNA and protein levels. Cell-specific biological processes and pathways were predicted by analysis of concordant and discordant RNA-protein pairs. Cell clustering and gene set enrichment comparisons identified shared versus unique processes associated with transcriptomic and/or proteomic data. Clear cell-cell correlations between mRNA and protein data were obtained from each cell type. Approximately 40% of RNA-protein pairs were coherently expressed. While the correlation between RNA and their protein products was relatively low (Spearman rank coefficient rs ~0.4), cell-specific signature genes involved in functional processes characteristic of each cell type were more highly correlated with their protein products. Consistency of cell-specific RNA-protein signatures indicated an essential framework for the function of each cell type. Visualization and reutilization of the protein and RNA profiles are supported by a new web application, \"LungProteomics,\" which is freely accessible to the public.", "year": "2019", "month": "09", "volume": "317", "issue": "3", "pages": "L347-L360", "doi": "10.1152/ajplung.00475.2018", "link": "https://www.ncbi.nlm.nih.gov/pubmed/31268347", "sort_key": "2019-09-integration of trans", "quarter": "q3"}, {"pmid": "31273041", "title": "Plasma mitochondrial DNA is associated with extrapulmonary sarcoidosis.", "authors": ["Ryu C", "Brandsdorfer C", "Adams T", "Hu B", "Kelleher DW", "Yaggi M", "Manning EP", "Walia A", "Reeves B", "Pan H", "Winkler J", "Minasyan M", "Dela Cruz CS", "Kaminski N", "Gulati M", "Herzog EL"], "journal": "Eur Respir J", "journal_title": "The European respiratory journal", "citation": "The European respiratory journal, 08 2019", "abstract": "Sarcoidosis is an unpredictable granulomatous disease in which African Americans disproportionately experience aggressive phenotypes. Mitochondrial DNA (mtDNA) released by cells in response to various stressors contributes to tissue remodelling and inflammation. While extracellular mtDNA has emerged as a biomarker in multiple diseases, its relevance to sarcoidosis remains unknown. We aimed to define an association between extracellular mtDNA and clinical features of sarcoidosis.Extracellular mtDNA concentrations were measured using quantitative PCR for the human MT-ATP6 gene in bronchoalveolar (BAL) and plasma samples from healthy controls and patients with sarcoidosis from The Yale Lung Repository; associations between MT-ATP6 concentrations and Scadding stage, extrapulmonary disease and demographics were sought. Results were validated in the Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis cohort.Relative to controls, MT-ATP6 concentrations in sarcoidosis subjects were robustly elevated in the BAL fluid and plasma, particularly in the plasma of patients with extrapulmonary disease. Relative to Caucasians, African Americans displayed excessive MT-ATP6 concentrations in the BAL fluid and plasma, for which the latter compartment correlated with significantly higher odds of extrapulmonary disease.Enrichments in extracellular mtDNA in sarcoidosis are associated with extrapulmonary disease and African American descent. Further study into the mechanistic basis of these clinical findings may lead to novel pathophysiologic and therapeutic insights.", "year": "2019", "month": "08", "volume": "54", "issue": "2", "pages": "", "doi": "10.1183/13993003.01762-2018", "link": "https://www.ncbi.nlm.nih.gov/pubmed/31273041", "sort_key": "2019-08-plasma mitochondrial", "quarter": "q3"}, {"pmid": "31085557", "title": "Aging Human Hematopoietic Stem Cells Manifest Profound Epigenetic Reprogramming of Enhancers That May Predispose to Leukemia.", "authors": ["Adelman ER", "Huang HT", "Roisman A", "Olsson A", "Colaprico A", "Qin T", "Lindsley RC", "Bejar R", "Salomonis N", "Grimes HL", "Figueroa ME"], "journal": "Cancer Discov", "journal_title": "Cancer discovery", "citation": "Cancer discovery, 08 2019", "abstract": "Aging is associated with functional decline of hematopoietic stem cells (HSC) as well as an increased risk of myeloid malignancies. We performed an integrative characterization of epigenomic and transcriptomic changes, including single-cell RNA sequencing, during normal human aging. Lineage-CD34+CD38- cells [HSC-enriched (HSCe)] undergo age-associated epigenetic reprogramming consisting of redistribution of DNA methylation and reductions in H3K27ac, H3K4me1, and H3K4me3. This reprogramming of aged HSCe globally targets developmental and cancer pathways that are comparably altered in acute myeloid leukemia (AML) of all ages, encompassing loss of 4,646 active enhancers, 3,091 bivalent promoters, and deregulation of several epigenetic modifiers and key hematopoietic transcription factors, such as KLF6, BCL6, and RUNX3. Notably, in vitro downregulation of KLF6 results in impaired differentiation, increased colony-forming potential, and changes in expression that recapitulate aging and leukemia signatures. Thus, age-associated epigenetic reprogramming may form a predisposing condition for the development of age-related AML. SIGNIFICANCE: AML, which is more frequent in the elderly, is characterized by epigenetic deregulation. We demonstrate that epigenetic reprogramming of human HSCs occurs with age, affecting cancer and developmental pathways. Downregulation of genes epigenetically altered with age leads to impairment in differentiation and partially recapitulates aging phenotypes.This article is highlighted in the In This Issue feature, p. 983.", "year": "2019", "month": "08", "volume": "9", "issue": "8", "pages": "1080-1101", "doi": "10.1158/2159-8290.CD-18-1474", "link": "https://www.ncbi.nlm.nih.gov/pubmed/31085557", "sort_key": "2019-08-aging human hematopo", "quarter": "q3"}, {"pmid": "30995076", "title": "The Human Lung Cell Atlas: A High-Resolution Reference Map of the Human Lung in Health and Disease.", "authors": ["Schiller HB", "Montoro DT", "Simon LM", "Rawlins EL", "Meyer KB", "Strunz M", "Vieira Braga FA", "Timens W", "Koppelman GH", "Budinger GRS", "Burgess JK", "Waghray A", "van den Berge M", "Theis FJ", "Regev A", "Kaminski N", "Rajagopal J", "Teichmann SA", "Misharin AV", "Nawijn MC"], "journal": "Am J Respir Cell Mol Biol", "journal_title": "American journal of respiratory cell and molecular biology", "citation": "American journal of respiratory cell and molecular biology, 07 2019", "abstract": "Lung disease accounts for every sixth death globally. Profiling the molecular state of all lung cell types in health and disease is currently revolutionizing the identification of disease mechanisms and will aid the design of novel diagnostic and personalized therapeutic regimens. Recent progress in high-throughput techniques for single-cell genomic and transcriptomic analyses has opened up new possibilities to study individual cells within a tissue, classify these into cell types, and characterize variations in their molecular profiles as a function of genetics, environment, cell-cell interactions, developmental processes, aging, or disease. Integration of these cell state definitions with spatial information allows the in-depth molecular description of cellular neighborhoods and tissue microenvironments, including the tissue resident structural and immune cells, the tissue matrix, and the microbiome. The Human Cell Atlas consortium aims to characterize all cells in the healthy human body and has prioritized lung tissue as one of the flagship projects. Here, we present the rationale, the approach, and the expected impact of a Human Lung Cell Atlas.", "year": "2019", "month": "07", "volume": "61", "issue": "1", "pages": "31-41", "doi": "10.1165/rcmb.2018-0416TR", "link": "https://www.ncbi.nlm.nih.gov/pubmed/30995076", "sort_key": "2019-07-the human lung cell ", "quarter": "q3"}, {"pmid": "31162136", "title": "Normal lung development needs self-eating.", "authors": ["Warburton D", "Bellusci S"], "journal": "J Clin Invest", "journal_title": "The Journal of clinical investigation", "citation": "The Journal of clinical investigation, 06 2019", "abstract": "Autophagy is a Greek-derived concept that means \"self-eating\" and is increasingly recognized as an important regulator of homeostasis and disease. In this issue of the JCI, Yeganeh et al. report the important finding that intrinsic autophagy is required for normal progression of lung development. Conditional deletion of the beclin 1-encoding gene (Becn1) specifically within lung epithelial cells of embryonic mice resulted in neonatal lethal respiratory distress that was associated with negative impacts on airway branching and differentiation of airway epithelial cell lineages. The authors draw speculative parallels with the alveolar simplification phenotype of bronchopulmonary dysplasia in premature human infants and suggest that stimulation of autophagy by cAMP-dependent kinase activation might conceivably rescue these phenotypes.", "year": "2019", "month": "06", "volume": "129", "issue": "7", "pages": "2658-2659", "doi": "10.1172/JCI129442", "link": "https://www.ncbi.nlm.nih.gov/pubmed/31162136", "sort_key": "2019-06-normal lung developm", "quarter": "q2"}, {"pmid": "31227752", "title": "Dosing and formulation of antenatal corticosteroids for fetal lung maturation and gene expression in rhesus macaques.", "authors": ["Schmidt AF", "Kannan PS", "Bridges JP", "Filuta A", "Lipps D", "Kemp M", "Miller LA", "Kallapur SG", "Xu Y", "Whitsett JA", "Jobe AH"], "journal": "Sci Rep", "journal_title": "Scientific reports", "citation": "Scientific reports, 06 2019", "abstract": "Antenatal corticosteroids (ANS) are the major intervention to decrease respiratory distress syndrome and mortality from premature birth and are standard of care. The use of ANS is expanding to include new indications and gestational ages, although the recommended dosing was never optimized. The most widely used treatment is two intramuscular doses of a 1:1 mixture of betamethasone-phosphate (Beta-P) and betamethasone-acetate (Beta-Ac) - the clinical drug. We tested in a primate model the efficacy of the slow release Beta-Ac alone for enhancing fetal lung maturation and to reduce fetal corticosteroid exposure and potential toxic effects. Pregnant rhesus macaques at 127 days of gestation (80% of term) were treated with either the clinical drug (0.25 mg/kg) or Beta-Ac (0.125 mg/kg). Beta-Ac alone increased lung compliance and surfactant concentration in the fetal lung equivalently to the clinical drug. By transcriptome analyses the early suppression of genes associated with immune responses and developmental pathways were less affected by Beta-Ac than the clinical drug. Promoter and regulatory analysis prediction identified differentially expressed genes targeted by the glucocorticoid receptor in the lung. At 5 days the clinical drug suppressed genes associated with neuronal development and differentiation in the fetal hippocampus compared to control, while low dose Beta-Ac alone did not. A low dose ANS treatment with Beta-Ac should be assessed for efficacy in human trials.", "year": "2019", "month": "06", "volume": "9", "issue": "1", "pages": "9039", "doi": "10.1038/s41598-019-45171-6", "link": "https://www.ncbi.nlm.nih.gov/pubmed/31227752", "sort_key": "2019-06-dosing and formulati", "quarter": "q2"}, {"pmid": "30930166", "title": "The Pediatric Cell Atlas: Defining the Growth Phase of Human Development at Single-Cell Resolution.", "authors": ["Taylor DM", "Aronow BJ", "Tan K", "Bernt K", "Salomonis N", "Greene CS", "Frolova A", "Henrickson SE", "Wells A", "Pei L", "Jaiswal JK", "Whitsett J", "Hamilton KE", "MacParland SA", "Kelsen J", "Heuckeroth RO", "Potter SS", "Vella LA", "Terry NA", "Ghanem LR", "Kennedy BC", "Helbig I", "Sullivan KE", "Castelo-Soccio L", "Kreigstein A", "Herse F", "Nawijn MC", "Koppelman GH", "Haendel M", "Harris NL", "Rokita JL", "Zhang Y", "Regev A", "Rozenblatt-Rosen O", "Rood JE", "Tickle TL", "Vento-Tormo R", "Alimohamed S", "Lek M", "Mar JC", "Loomes KM", "Barrett DM", "Uapinyoying P", "Beggs AH", "Agrawal PB", "Chen YW", "Muir AB", "Garmire LX", "Snapper SB", "Nazarian J", "Seeholzer SH", "Fazelinia H", "Singh LN", "Faryabi RB", "Raman P", "Dawany N", "Xie HM", "Devkota B", "Diskin SJ", "Anderson SA", "Rappaport EF", "Peranteau W", "Wikenheiser-Brokamp KA", "Teichmann S", "Wallace D", "Peng T", "Ding YY", "Kim MS", "Xing Y", "Kong SW", "B\u00f6nnemann CG", "Mandl KD", "White PS"], "journal": "Dev Cell", "journal_title": "Developmental cell", "citation": "Developmental cell, 04 2019", "abstract": "Single-cell gene expression analyses of mammalian tissues have uncovered profound stage-specific molecular regulatory phenomena that have changed the understanding of unique cell types and signaling pathways critical for lineage determination, morphogenesis, and growth. We discuss here the case for a Pediatric Cell Atlas as part of the Human Cell Atlas consortium to provide single-cell profiles and spatial characterization of gene expression across human tissues and organs. Such data will complement adult and developmentally focused HCA projects to provide a rich cytogenomic framework for understanding not only pediatric health and disease but also environmental and genetic impacts across the human lifespan.", "year": "2019", "month": "04", "volume": "49", "issue": "1", "pages": "10-29", "doi": "10.1016/j.devcel.2019.03.001", "link": "https://www.ncbi.nlm.nih.gov/pubmed/30930166", "sort_key": "2019-04-the pediatric cell a", "quarter": "q2"}, {"pmid": "30178494", "title": "Regularized Latent Class Model for Joint Analysis of High-Dimensional Longitudinal Biomarkers and a Time-to-Event Outcome.", "authors": ["Sun J", "Herazo-Maya JD", "Molyneaux PL", "Maher TM", "Kaminski N", "Zhao H"], "journal": "Biometrics", "journal_title": "Biometrics", "citation": "Biometrics, 03 2019", "abstract": "Although many modeling approaches have been developed to jointly analyze longitudinal biomarkers and a time-to-event outcome, most of these methods can only handle one or a few biomarkers. In this article, we propose a novel joint latent class model to deal with high dimensional longitudinal biomarkers. Our model has three components: a class membership model, a survival submodel, and a longitudinal submodel. In our model, we assume that covariates can potentially affect biomarkers and class membership. We adopt a penalized likelihood approach to infer which covariates have random effects and/or fixed effects on biomarkers, and which covariates are informative for the latent classes. Through extensive simulation studies, we show that our proposed method has improved performance in prediction and assigning subjects to the correct classes over other joint modeling methods and that bootstrap can be used to do inference for our model. We then apply our method to a dataset of patients with idiopathic pulmonary fibrosis, for whom gene expression profiles were measured longitudinally. We are able to identify four interesting latent classes with one class being at much higher risk of death compared to the other classes. We also find that each of the latent classes has unique trajectories in some genes, yielding novel biological insights.", "year": "2019", "month": "03", "volume": "75", "issue": "1", "pages": "69-77", "doi": "10.1111/biom.12964", "link": "https://www.ncbi.nlm.nih.gov/pubmed/30178494", "sort_key": "2019-03-regularized latent c", "quarter": "q1"}, {"pmid": "30413314", "title": "Neonatal Lung Disease Associated with TBX4 Mutations.", "authors": ["Suhrie K", "Pajor NM", "Ahlfeld SK", "Dawson DB", "Dufendach KR", "Kitzmiller JA", "Leino D", "Lombardo RC", "Smolarek TA", "Rathbun PA", "Whitsett JA", "Towe C", "Wikenheiser-Brokamp KA"], "journal": "J Pediatr", "journal_title": "The Journal of pediatrics", "citation": "The Journal of pediatrics, 03 2019", "abstract": "Variable lung disease was documented in 2 infants with heterozygous TBX4 mutations; their clinical presentations, pathology, and outcomes were distinct. These findings demonstrate that TBX4 gene mutations are associated with neonatal respiratory failure and highlight the wide spectrum of clinicopathological outcomes that have implications for patient diagnosis and management.", "year": "2019", "month": "03", "volume": "206", "issue": "", "pages": "286-292.e1", "doi": "10.1016/j.jpeds.2018.10.018", "link": "https://www.ncbi.nlm.nih.gov/pubmed/30413314", "sort_key": "2019-03-neonatal lung diseas", "quarter": "q1"}, {"pmid": "30141961", "title": "BAL Cell Gene Expression Is Indicative of Outcome and Airway Basal Cell Involvement in Idiopathic Pulmonary Fibrosis.", "authors": ["Prasse A", "Binder H", "Schupp JC", "Kayser G", "Bargagli E", "Jaeger B", "Hess M", "Rittinghausen S", "Vuga L", "Lynn H", "Violette S", "Jung B", "Quast K", "Vanaudenaerde B", "Xu Y", "Hohlfeld JM", "Krug N", "Herazo-Maya JD", "Rottoli P", "Wuyts WA", "Kaminski N"], "journal": "Am J Respir Crit Care Med", "journal_title": "American journal of respiratory and critical care medicine", "citation": "American journal of respiratory and critical care medicine, 03 2019", "abstract": "RATIONALE: Idiopathic pulmonary fibrosis (IPF) is a fatal disease with a variable and unpredictable course. OBJECTIVES: To determine whether BAL cell gene expression is predictive of survival in IPF. METHODS: This retrospective study analyzed the BAL transcriptome of three independent IPF cohorts: Freiburg (Germany), Siena (Italy), and Leuven (Belgium) including 212 patients. BAL cells from 20 healthy volunteers, 26 patients with sarcoidosis stage III and IV, and 29 patients with chronic obstructive pulmonary disease were used as control subjects. Survival analysis was performed by Cox models and component-wise boosting. Presence of airway basal cells was tested by immunohistochemistry and flow cytometry. MEASUREMENTS AND MAIN RESULTS: A total of 1,582 genes were predictive of mortality in the IPF derivation cohort in univariate analyses adjusted for age and sex at false discovery rate less than 0.05. A nine-gene signature, derived from the discovery cohort (Freiburg), performed well in both replication cohorts, Siena (P < 0.0032) and Leuven (P = 0.0033). nCounter expression analysis confirmed the array results (P < 0.0001). The genes associated with mortality in BAL cells were significantly enriched for genes expressed in airway basal cells. Further analyses by gene expression, flow cytometry, and immunohistochemistry showed an increase in airway basal cells in BAL and tissues of IPF compared with control subjects, but not in chronic obstructive pulmonary disease or sarcoidosis. CONCLUSIONS: Our results identify and validate a BAL signature that predicts mortality in IPF and improves the accuracy of outcome prediction based on clinical parameters. The BAL signature associated with mortality unmasks a potential role for airway basal cells in IPF.", "year": "2019", "month": "03", "volume": "199", "issue": "5", "pages": "622-630", "doi": "10.1164/rccm.201712-2551OC", "link": "https://www.ncbi.nlm.nih.gov/pubmed/30141961", "sort_key": "2019-03-bal cell gene expres", "quarter": "q1"}, {"pmid": "30923323", "title": "Alteration of cystic airway mesenchyme in congenital pulmonary airway malformation.", "authors": ["Jiang Y", "Luo Y", "Tang Y", "Moats R", "Warburton D", "Zhou S", "Lou J", "Pryhuber GS", "Shi W", "Wang LL"], "journal": "Sci Rep", "journal_title": "Scientific reports", "citation": "Scientific reports, 03 2019", "abstract": "Congenital pulmonary airway malformation (CPAM) is the most common congenital lesion detected in the neonatal lung, which may lead to respiratory distress, infection, and pneumothorax. CPAM is thought to result from abnormal branching morphogenesis during fetal lung development, arising from different locations within the developing respiratory tract. However, the pathogenic mechanisms are unknown, and previous studies have focused on abnormalities in airway epithelial cells. We have analyzed 13 excised lung specimens from infants (age < 1 year) with a confirmed diagnosis of type 2 CPAM, which is supposed to be derived from abnormal growth of intrapulmonary distal airways. By examining the mesenchymal components including smooth muscle cells, laminin, and elastin in airway and cystic walls using immunofluorescence staining, we found that the thickness and area of the smooth muscle layer underlining the airway cysts in these CPAM tissue sections were significantly decreased compared with those in bronchiolar walls of normal controls. Extracellular elastin fibers were also visually reduced or absent in airway cystic walls. In particular, a layer of elastin fibers seen in normal lung between airway epithelia and underlying smooth muscle cells was missing in type 2 CPAM samples. Thus, our data demonstrate for the first time that airway cystic lesions in type 2 CPAM occur not only in airway epithelial cells, but also in adjacent mesenchymal tissues, including airway smooth muscle cells and their extracellular protein products. This provides a new direction to study the molecular and cellular mechanisms of CPAM pathogenesis in human.", "year": "2019", "month": "03", "volume": "9", "issue": "1", "pages": "5296", "doi": "10.1038/s41598-019-41777-y", "link": "https://www.ncbi.nlm.nih.gov/pubmed/30923323", "sort_key": "2019-03-alteration of cystic", "quarter": "q1"}, {"pmid": "30596133", "title": "Spatial distribution of marker gene activity in the mouse lung during alveolarization.", "authors": ["Ljungberg MC", "Sadi M", "Wang Y", "Aronow BJ", "Xu Y", "Kao RJ", "Liu Y", "Gaddis N", "Ardini-Poleske ME", "Umrod T", "Ambalavanan N", "Nicola T", "Kaminski N", "Ahangari F", "Sontag R", "Corley RA", "Ansong C", "Carson JP"], "journal": "Data Brief", "journal_title": "Data in brief", "citation": "Data in brief, 02 2019", "abstract": "This data is a curated collection of visual images of gene expression patterns from the pre- and post-natal mouse lung, accompanied by associated mRNA probe sequences and RNA-Seq expression profiles. Mammalian lungs undergo significant growth and cellular differentiation before and after the transition to breathing air. Documenting normal lung development is an important step in understanding abnormal lung development, as well as the challenges faced during a preterm birth. Images in this dataset indicate the spatial distribution of mRNA transcripts for over 500 different genes that are active during lung development, as initially determined via RNA-Seq. Images were systematically acquired using high-throughput in situ hybridization with non-radioactive digoxigenin-labeled mRNA probes across mouse lungs from developmental time points E16.5, E18.5, P7, and P28. The dataset was produced as part of The Molecular Atlas of Lung Development Program (LungMAP) and is hosted at https://lungmap.net. This manuscript describes the nature of the data and the protocols for generating the dataset.", "year": "2019", "month": "02", "volume": "22", "issue": "", "pages": "365-372", "doi": "10.1016/j.dib.2018.10.150", "link": "https://www.ncbi.nlm.nih.gov/pubmed/30596133", "sort_key": "2019-02-spatial distribution", "quarter": "q1"}, {"pmid": "30357827", "title": "Discordant roles for FGF ligands in lung branching morphogenesis between human and mouse.", "authors": ["Danopoulos S", "Thornton ME", "Grubbs BH", "Frey MR", "Warburton D", "Bellusci S", "Al Alam D"], "journal": "J Pathol", "journal_title": "The Journal of pathology", "citation": "The Journal of pathology, 02 2019", "abstract": "Fibroblast growth factor (FGF) signaling plays an important role in lung organogenesis. Over recent decades, FGF signaling in lung development has been extensively studied in animal models. However, little is known about the expression, localization, and functional roles of FGF ligands during human fetal lung development. Therefore, we aimed to determine the expression and function of several FGF ligands and receptors in human lung development. Using in situ hybridization (ISH) and RNA sequencing, we assessed their expression and distribution in native human fetal lung. Human fetal lung explants were treated with recombinant FGF7, FGF9, or FGF10 in air-liquid interface culture. Explants were analyzed grossly to observe differences in branching pattern as well as at the cellular and molecular level. ISH demonstrated that FGF7 is expressed in both the epithelium and mesenchyme; FGF9 is mainly localized in the distal epithelium, whereas FGF10 demonstrated diffuse expression throughout the parenchyma, with some expression in the smooth muscle cells (SMCs). FGFR2 expression was high in both proximal and distal epithelial cells as well as the SMCs. FGFR3 was expressed mostly in the epithelial cells, with lower expression in the mesenchyme, while FGFR4 was highly expressed throughout the mesenchyme and in the distal epithelium. Using recombinant FGFs, we demonstrated that FGF7 and FGF9 had similar effects on human fetal lung as on mouse fetal lung; however, FGF10 caused the human explants to expand and form cysts as opposed to inducing epithelial branching as seen in the mouse. In conjunction with decreased branching, treatment with recombinant FGF7, FGF9, and FGF10 also resulted in decreased double-positive SOX2/SOX9 progenitor cells, which are exclusively present in the distal epithelial tips in early human fetal lung. Although FGF ligand localization may be somewhat comparable between developing mouse and human lungs, their functional roles may differ substantially. Copyright \u00a9 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.", "year": "2019", "month": "02", "volume": "247", "issue": "2", "pages": "254-265", "doi": "10.1002/path.5188", "link": "https://www.ncbi.nlm.nih.gov/pubmed/30357827", "sort_key": "2019-02-discordant roles for", "quarter": "q1"}, {"pmid": "30806029", "title": "CFTR dysfunction increases endoglin and TGF-\u03b2 signaling in airway epithelia.", "authors": ["Nicola T", "Kabir FL", "Coric T", "Wall SB", "Zhang W", "James M", "MacEwen M", "Ren C", "Halloran B", "Ambalavanan N", "Harris WT"], "journal": "Physiol Rep", "journal_title": "Physiological reports", "citation": "Physiological reports, 02 2019", "abstract": "Endoglin (ENG) regulates signaling by transforming growth factor-\u03b2 (TGF-\u03b2), a genetic modifier of cystic fibrosis (CF) lung disease severity. We hypothesized that ENG mediates TGF-\u03b2 pathobiology in CF airway epithelia. Comparing CF and non-CF human lungs, we measured ENG by qPCR, immunoblotting and ELISA. In human bronchial epithelial cell lines (16HBE), we used CFTR siRNA knockdown and functional inhibition (CFTRINH -172) to connect loss of CFTR to ENG synthesis. Plasmid overexpression of ENG assessed the direct effect of ENG on TGF-\u03b2 transcription and signal amplification in 16HBE cells. We found ENG protein to be increased more than fivefold both in human CF bronchoalveolar fluid (BALF) and human CF lung homogenates. ENG transcripts were increased threefold in CF, with a twofold increase in TGF-\u03b2 signaling. CFTR knockdown in 16HBE cells tripled ENG transcription and doubled protein levels with corresponding increases in TGF-\u03b2 signaling. Plasmid overexpression of ENG alone nearly doubled TGF-\u03b21 mRNA and increased TGF-\u03b2 signaling in 16HBE cells. These experiments identify that loss of CFTR function increases ENG expression in CF epithelia and amplifies TGF-\u03b2 signaling. Targeting ENG may offer a novel therapeutic opportunity to address TGF-\u03b2 associated pathobiology in CF.", "year": "2019", "month": "02", "volume": "7", "issue": "4", "pages": "e13977", "doi": "10.14814/phy2.13977", "link": "https://www.ncbi.nlm.nih.gov/pubmed/30806029", "sort_key": "2019-02-cftr dysfunction inc", "quarter": "q1"}, {"pmid": "30604742", "title": "Single cell RNA analysis identifies cellular heterogeneity and adaptive responses of the lung at birth.", "authors": ["Guo M", "Du Y", "Gokey JJ", "Ray S", "Bell SM", "Adam M", "Sudha P", "Perl AK", "Deshmukh H", "Potter SS", "Whitsett JA", "Xu Y"], "journal": "Nat Commun", "journal_title": "Nature communications", "citation": "Nature communications, 01 2019", "abstract": "The respiratory system undergoes a diversity of structural, biochemical, and functional changes necessary for adaptation to air breathing at birth. To identify the heterogeneity of pulmonary cell types and dynamic changes in gene expression mediating adaptation to respiration, here we perform single cell RNA analyses of mouse lung on postnatal day 1. Using an iterative cell type identification strategy we unbiasedly identify the heterogeneity of murine pulmonary cell types. We identify distinct populations of epithelial, endothelial, mesenchymal, and immune cells, each containing distinct subpopulations. Furthermore we compare temporal changes in RNA expression patterns before and after birth to identify signaling pathways selectively activated in specific pulmonary cell types, including activation of cell stress and the unfolded protein response during perinatal adaptation of the lung. The present data provide a single cell view of the adaptation to air breathing after birth.", "year": "2019", "month": "01", "volume": "10", "issue": "1", "pages": "37", "doi": "10.1038/s41467-018-07770-1", "link": "https://www.ncbi.nlm.nih.gov/pubmed/30604742", "sort_key": "2019-01-single cell rna anal", "quarter": "q1"}, {"pmid": "30507980", "title": "New mass spectrometry technologies contributing towards comprehensive and high throughput omics analyses of single cells.", "authors": ["Couvillion SP", "Zhu Y", "Nagy G", "Adkins JN", "Ansong C", "Renslow RS", "Piehowski PD", "Ibrahim YM", "Kelly RT", "Metz TO"], "journal": "Analyst", "journal_title": "The Analyst", "citation": "The Analyst, 01 2019", "abstract": "Mass-spectrometry based omics technologies - namely proteomics, metabolomics and lipidomics - have enabled the molecular level systems biology investigation of organisms in unprecedented detail. There has been increasing interest for gaining a thorough, functional understanding of the biological consequences associated with cellular heterogeneity in a wide variety of research areas such as developmental biology, precision medicine, cancer research and microbiome science. Recent advances in mass spectrometry (MS) instrumentation and sample handling strategies are quickly making comprehensive omics analyses of single cells feasible, but key breakthroughs are still required to push through remaining bottlenecks. In this review, we discuss the challenges faced by single cell MS-based omics analyses and highlight recent technological advances that collectively can contribute to comprehensive and high throughput omics analyses in single cells. We provide a vision of the potential of integrating pioneering technologies such as Structures for Lossless Ion Manipulations (SLIM) for improved sensitivity and resolution, novel peptide identification tactics and standards free metabolomics approaches for future applications in single cell analysis.", "year": "2019", "month": "01", "volume": "144", "issue": "3", "pages": "794-807", "doi": "10.1039/c8an01574k", "link": "https://www.ncbi.nlm.nih.gov/pubmed/30507980", "sort_key": "2019-01-new mass spectrometr", "quarter": "q1"}, {"pmid": "30427276", "title": "Building and Regenerating the Lung Cell by Cell.", "authors": ["Whitsett JA", "Kalin TV", "Xu Y", "Kalinichenko VV"], "journal": "Physiol Rev", "journal_title": "Physiological reviews", "citation": "Physiological reviews, 01 2019", "abstract": "The unique architecture of the mammalian lung is required for adaptation to air breathing at birth and thereafter. Understanding the cellular and molecular mechanisms controlling its morphogenesis provides the framework for understanding the pathogenesis of acute and chronic lung diseases. Recent single-cell RNA sequencing data and high-resolution imaging identify the remarkable heterogeneity of pulmonary cell types and provides cell selective gene expression underlying lung development. We will address fundamental issues related to the diversity of pulmonary cells, to the formation and function of the mammalian lung, and will review recent advances regarding the cellular and molecular pathways involved in lung organogenesis. What cells form the lung in the early embryo? How are cell proliferation, migration, and differentiation regulated during lung morphogenesis? How do cells interact during lung formation and repair? How do signaling and transcriptional programs determine cell-cell interactions necessary for lung morphogenesis and function?", "year": "2019", "month": "01", "volume": "99", "issue": "1", "pages": "513-554", "doi": "10.1152/physrev.00001.2018", "link": "https://www.ncbi.nlm.nih.gov/pubmed/30427276", "sort_key": "2019-01-building and regener", "quarter": "q1"}, {"pmid": "30487069", "title": "Genomics, microbiomics, proteomics, and metabolomics in bronchopulmonary dysplasia.", "authors": ["Lal CV", "Bhandari V", "Ambalavanan N"], "journal": "Semin Perinatol", "journal_title": "Seminars in perinatology", "citation": "Seminars in perinatology, 11 2018", "abstract": "Bronchopulmonary Dysplasia (BPD) is a disorder with a multifactorial etiology and highly variable clinical phenotype. Several traditional biomarkers have been identified, but due to the complex disease phenotype, these biomarkers have low predictive accuracy for BPD. In recent years, newer technologies have facilitated the in-depth and unbiased analysis of 'big data' in delineating the diagnosis, pathogenesis, and mechanisms of diseases. Novel systems-biology based 'omic' approaches, including but not limited to genomics, microbiomics, proteomics, and metabolomics may help define the multiple cellular and humoral interactions that regulate normal as well as abnormal lung development and response to injury that are the hallmarks of BPD.", "year": "2018", "month": "11", "volume": "42", "issue": "7", "pages": "425-431", "doi": "10.1053/j.semperi.2018.09.004", "link": "https://www.ncbi.nlm.nih.gov/pubmed/30487069", "sort_key": "2018-11-genomics, microbiomi", "quarter": "q4"}, {"pmid": "30153454", "title": "FOXF1 transcription factor promotes lung morphogenesis by inducing cellular proliferation in fetal lung mesenchyme.", "authors": ["Ustiyan V", "Bolte C", "Zhang Y", "Han L", "Xu Y", "Yutzey KE", "Zorn AM", "Kalin TV", "Shannon JM", "Kalinichenko VV"], "journal": "Dev Biol", "journal_title": "Developmental biology", "citation": "Developmental biology, 11 2018", "abstract": "Organogenesis is regulated by mesenchymal-epithelial signaling events that induce expression of cell-type specific transcription factors critical for cellular proliferation, differentiation and appropriate tissue patterning. While mesenchymal transcription factors play a key role in mesenchymal-epithelial interactions, transcriptional networks in septum transversum and splanchnic mesenchyme remain poorly characterized. Forkhead Box F1 (FOXF1) transcription factor is expressed in mesenchymal cell lineages; however, its role in organogenesis remains uncharacterized due to early embryonic lethality of Foxf1-/- mice. In the present study, we generated mesenchyme-specific Foxf1 knockout mice (Dermo1-Cre Foxf1-/-) and demonstrated that FOXF1 is required for development of respiratory, cardiovascular and gastrointestinal organ systems. Deletion of Foxf1 from mesenchyme caused embryonic lethality in the middle of gestation due to multiple developmental defects in the heart, lung, liver and esophagus. Deletion of Foxf1 inhibited mesenchyme proliferation and delayed branching lung morphogenesis. Gene expression profiling of micro-dissected distal lung mesenchyme and ChIP sequencing of fetal lung tissue identified multiple target genes activated by FOXF1, including Wnt2, Wnt11, Wnt5A and Hoxb7. FOXF1 decreased expression of the Wnt inhibitor Wif1 through direct transcriptional repression. Furthermore, using a global Foxf1 knockout mouse line (Foxf1-/-) we demonstrated that FOXF1-deficiency disrupts the formation of the lung bud in foregut tissue explants. Finally, deletion of Foxf1 from smooth muscle cell lineage (smMHC-Cre Foxf1-/-) caused hyper-extension of esophagus and trachea, loss of tracheal and esophageal muscle, mispatterning of esophageal epithelium and decreased proliferation of smooth muscle cells. Altogether, FOXF1 promotes lung morphogenesis by regulating mesenchymal-epithelial signaling and stimulating cellular proliferation in fetal lung mesenchyme.", "year": "2018", "month": "11", "volume": "443", "issue": "1", "pages": "50-63", "doi": "10.1016/j.ydbio.2018.08.011", "link": "https://www.ncbi.nlm.nih.gov/pubmed/30153454", "sort_key": "2018-11-foxf1 transcription ", "quarter": "q4"}, {"pmid": "30431340", "title": "Airway Epithelial Differentiation and Mucociliary Clearance.", "authors": ["Whitsett JA"], "journal": "Ann Am Thorac Soc", "journal_title": "Annals of the American Thoracic Society", "citation": "Annals of the American Thoracic Society, 11 2018", "abstract": "The lung is continuously exposed to particles, toxicants, and microbial pathogens that are cleared by a complex mechanical, innate, and acquired immune system. Mucociliary clearance, mediated by the actions of diverse conducting airway and submucosal gland epithelial cells, plays a critical role in a multilayered defense system by secreting fluids, electrolytes, antimicrobial and antiinflammatory proteins, and mucus onto airway surfaces. The mucociliary escalator removes particles and pathogens by the mechanical actions of cilia and cough. Abnormalities in mucociliary clearance, whether related to impaired fluid secretion, ciliary dysfunction, lack of cough, or the disruption of epithelial cells lining the respiratory tract, contribute to the pathogenesis of common chronic pulmonary disorders. Although mucus and other airway epithelial secretions play a critical role in protecting the lung during acute injury, impaired mucus clearance after chronic mucus hyperproduction causes airway obstruction and infection, which contribute to morbidity in common pulmonary disorders, including chronic obstructive pulmonary disease, asthma, idiopathic pulmonary fibrosis, cystic fibrosis, bronchiectasis, and primary ciliary dyskinesia. In this summary, the molecular and cellular mechanisms mediating airway mucociliary clearance, as well as the role of goblet cell metaplasia and mucus hyperproduction, in the pathogenesis of chronic respiratory diseases are considered.", "year": "2018", "month": "11", "volume": "15", "issue": "Suppl 3", "pages": "S143-S148", "doi": "10.1513/AnnalsATS.201802-128AW", "link": "https://www.ncbi.nlm.nih.gov/pubmed/30431340", "sort_key": "2018-11-airway epithelial di", "quarter": "q4"}, {"pmid": "29952221", "title": "Iloprost attenuates hyperoxia-mediated impairment of lung development in newborn mice.", "authors": ["Olave N", "Lal CV", "Halloran B", "Bhandari V", "Ambalavanan N"], "journal": "Am J Physiol Lung Cell Mol Physiol", "journal_title": "American journal of physiology. Lung cellular and molecular physiology", "citation": "American journal of physiology. Lung cellular and molecular physiology, 10 2018", "abstract": "Cyclooxygenase-2 (COX-2/PTGS2) mediates hyperoxia-induced impairment of lung development in newborn animals and is increased in the lungs of human infants with bronchopulmonary dysplasia (BPD). COX-2 catalyzes the production of cytoprotective prostaglandins, such as prostacyclin (PGI2), as well as proinflammatory mediators, such as thromboxane A2. Our objective was to determine whether iloprost, a synthetic analog of PGI2, would attenuate hyperoxia effects in the newborn mouse lung. To test this hypothesis, newborn C57BL/6 mice along with their dams were exposed to normoxia (21% O2) or hyperoxia (85% O2) from 4 to 14 days of age in combination with daily intraperitoneal injections of either iloprost 200 \u00b5g\u00b7kg-1\u00b7day-1, nimesulide (selective COX-2 antagonist) 100 mg\u00b7kg-1\u00b7day-1, or vehicle. Alveolar development was estimated by radial alveolar counts and mean linear intercepts. Lung function was determined on a flexiVent, and multiple cytokines and myeloperoxidase (MPO) were quantitated in lung homogenates. Lung vascular and microvascular morphometry was performed, and right ventricle/left ventricle ratios were determined. We determined that iloprost (but not nimesulide) administration attenuated hyperoxia-induced inhibition of alveolar development and microvascular density in newborn mice. Iloprost and nimesulide both attenuated hyperoxia-induced, increased lung resistance but did not improve lung compliance that was reduced by hyperoxia. Iloprost and nimesulide reduced hyperoxia-induced increases in MPO and some cytokines (IL-1\u03b2 and TNF-\u03b1) but not others (IL-6 and KC/Gro). There were no changes in pulmonary arterial wall thickness or right ventricle/left ventricle ratios. We conclude that iloprost improves lung development and reduces lung inflammation in a newborn mouse model of BPD.", "year": "2018", "month": "10", "volume": "315", "issue": "4", "pages": "L535-L544", "doi": "10.1152/ajplung.00125.2017", "link": "https://www.ncbi.nlm.nih.gov/pubmed/29952221", "sort_key": "2018-10-iloprost attenuates ", "quarter": "q4"}, {"pmid": "29975103", "title": "Dissociation, cellular isolation, and initial molecular characterization of neonatal and pediatric human lung tissues.", "authors": ["Bandyopadhyay G", "Huyck HL", "Misra RS", "Bhattacharya S", "Wang Q", "Mereness J", "Lillis J", "Myers JR", "Ashton J", "Bushnell T", "Cochran M", "Holden-Wiltse J", "Katzman P", "Deutsch G", "Whitsett JA", "Xu Y", "Mariani TJ", "Pryhuber GS"], "journal": "Am J Physiol Lung Cell Mol Physiol", "journal_title": "American journal of physiology. Lung cellular and molecular physiology", "citation": "American journal of physiology. Lung cellular and molecular physiology, 10 2018", "abstract": "Human lung morphogenesis begins by embryonic life and continues after birth into early childhood to form a complex organ with numerous morphologically and functionally distinct cell types. Pulmonary organogenesis involves dynamic changes in cell proliferation, differentiation, and migration of specialized cells derived from diverse embryonic lineages. Studying the molecular and cellular processes underlying formation of the fully functional lung requires isolating distinct pulmonary cell populations during development. We now report novel methods to isolate four major pulmonary cell populations from pediatric human lung simultaneously. Cells were dissociated by protease digestion of neonatal and pediatric lung and isolated on the basis of unique cell membrane protein expression patterns. Epithelial, endothelial, nonendothelial mesenchymal, and immune cells were enriched by fluorescence-activated cell sorting. Dead cells and erythrocytes were excluded by 7-aminoactinomycin D uptake and glycophorin-A (CD235a) expression, respectively. Leukocytes were identified by membrane CD45 (protein tyrosine phosphatase, receptor type C), endothelial cells by platelet endothelial cell adhesion molecule-1 (CD31) and vascular endothelial cadherin (CD144), and both were isolated. Thereafter, epithelial cell adhesion molecule (CD326)-expressing cells were isolated from the endothelial- and immune cell-depleted population to enrich epithelial cells. Cells lacking these membrane markers were collected as \"nonendothelial mesenchymal\" cells. Quantitative RT-PCR and RNA sequencing analyses of population specific transcriptomes demonstrate the purity of the subpopulations of isolated cells. The method efficiently isolates major human lung cell populations that we announce are now available through the National Heart, Lung, and Blood Institute Lung Molecular Atlas Program (LungMAP) for their further study.", "year": "2018", "month": "10", "volume": "315", "issue": "4", "pages": "L576-L583", "doi": "10.1152/ajplung.00041.2018", "link": "https://www.ncbi.nlm.nih.gov/pubmed/29975103", "sort_key": "2018-10-dissociation, cellul", "quarter": "q4"}, {"pmid": "29797682", "title": "Proteomic Analysis of Single Mammalian Cells Enabled by Microfluidic Nanodroplet Sample Preparation and Ultrasensitive NanoLC-MS.", "authors": ["Zhu Y", "Clair G", "Chrisler WB", "Shen Y", "Zhao R", "Shukla AK", "Moore RJ", "Misra RS", "Pryhuber GS", "Smith RD", "Ansong C", "Kelly RT"], "journal": "Angew Chem Int Ed Engl", "journal_title": "Angewandte Chemie (International ed. in English)", "citation": "Angewandte Chemie (International ed. in English), 09 2018", "abstract": "We report on the quantitative proteomic analysis of single mammalian cells. Fluorescence-activated cell sorting was employed to deposit cells into a newly developed nanodroplet sample processing chip, after which samples were analyzed by ultrasensitive nanoLC-MS. An average of circa 670 protein groups were confidently identified from single HeLa cells, which is a far greater level of proteome coverage for single cells than has been previously reported. We demonstrate that the single-cell proteomics platform can be used to differentiate cell types from enzyme-dissociated human lung primary cells and identify specific protein markers for epithelial and mesenchymal cells.", "year": "2018", "month": "09", "volume": "57", "issue": "38", "pages": "12370-12374", "doi": "10.1002/anie.201802843", "link": "https://www.ncbi.nlm.nih.gov/pubmed/29797682", "sort_key": "2018-09-proteomic analysis o", "quarter": "q3"}, {"pmid": "30185671", "title": "MEG3 is increased in idiopathic pulmonary fibrosis and regulates epithelial cell differentiation.", "authors": ["Gokey JJ", "Snowball J", "Sridharan A", "Speth JP", "Black KE", "Hariri LP", "Perl AT", "Xu Y", "Whitsett JA"], "journal": "JCI Insight", "journal_title": "JCI insight", "citation": "JCI insight, 09 2018", "abstract": "Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial lung disease causing fibrotic remodeling of the peripheral lung, leading to respiratory failure. Peripheral pulmonary epithelial cells lose normal alveolar epithelial gene expression patterns and variably express genes associated with diverse conducting airway epithelial cells, including basal cells. Single-cell RNA sequencing of pulmonary epithelial cells isolated from IPF lung tissue demonstrated altered expression of LncRNAs, including increased MEG3. MEG3 RNA was highly expressed in subsets of the atypical IPF epithelial cells and correlated with conducting airway epithelial gene expression patterns. Expression of MEG3 in human pulmonary epithelial cell lines increased basal cell-associated RNAs, including TP63, KRT14, STAT3, and YAP1, and enhanced cell migration, consistent with a role for MEG3 in regulating basal cell identity. MEG3 reduced expression of TP73, SOX2, and Notch-associated RNAs HES1 and HEY1, in primary human bronchial epithelial cells, demonstrating a role for MEG3 in the inhibition of genes influencing basal cell differentiation into club, ciliated, or goblet cells. MEG3 induced basal cell genes and suppressed genes associated with terminal differentiation of airway cells, supporting a role for MEG3 in regulation of basal progenitor cell functions, which may contribute to tissue remodeling in IPF.", "year": "2018", "month": "09", "volume": "3", "issue": "17", "pages": "", "doi": "10.1172/jci.insight.122490", "link": "https://www.ncbi.nlm.nih.gov/pubmed/30185671", "sort_key": "2018-09-meg3 is increased in", "quarter": "q3"}, {"pmid": "30194354", "title": "Cell type-resolved human lung lipidome reveals cellular cooperation in lung function.", "authors": ["Kyle JE", "Clair G", "Bandyopadhyay G", "Misra RS", "Zink EM", "Bloodsworth KJ", "Shukla AK", "Du Y", "Lillis J", "Myers JR", "Ashton J", "Bushnell T", "Cochran M", "Deutsch G", "Baker ES", "Carson JP", "Mariani TJ", "Xu Y", "Whitsett JA", "Pryhuber G", "Ansong C"], "journal": "Sci Rep", "journal_title": "Scientific reports", "citation": "Scientific reports, 09 2018", "abstract": "Cell type-resolved proteome analyses of the brain, heart and liver have been reported, however a similar effort on the lipidome is currently lacking. Here we applied liquid chromatography-tandem mass spectrometry to characterize the lipidome of major lung cell types isolated from human donors, representing the first lipidome map of any organ. We coupled this with cell type-resolved proteomics of the same samples (available at Lungmap.net). Complementary proteomics analyses substantiated the functional identity of the isolated cells. Lipidomics analyses showed significant variations in the lipidome across major human lung cell types, with differences most evident at the subclass and intra-subclass (i.e. total carbon length of the fatty acid chains) level. Further, lipidomic signatures revealed an overarching posture of high cellular cooperation within the human lung to support critical functions. Our complementary cell type-resolved lipid and protein datasets serve as a rich resource for analyses of human lung function.", "year": "2018", "month": "09", "volume": "8", "issue": "1", "pages": "13455", "doi": "10.1038/s41598-018-31640-x", "link": "https://www.ncbi.nlm.nih.gov/pubmed/30194354", "sort_key": "2018-09-cell type-resolved h", "quarter": "q3"}, {"pmid": "29789704", "title": "Single-cell RNA sequencing for the study of development, physiology and disease.", "authors": ["Potter SS"], "journal": "Nat Rev Nephrol", "journal_title": "Nature reviews. Nephrology", "citation": "Nature reviews. Nephrology, 08 2018", "abstract": "An ongoing technological revolution is continually improving our ability to carry out very high-resolution studies of gene expression patterns. Current technology enables the global gene expression profiles of single cells to be defined, facilitating dissection of heterogeneity in cell populations that was previously hidden. In contrast to gene expression studies that use bulk RNA samples and provide only a virtual average of the diverse constituent cells, single-cell studies enable the molecular distinction of all cell types within a complex population mix, such as a tumour or developing organ. For instance, single-cell gene expression profiling has contributed to improved understanding of how histologically identical, adjacent cells make different differentiation decisions during development. Beyond development, single-cell gene expression studies have enabled the characteristics of previously known cell types to be more fully defined and facilitated the identification of novel categories of cells, contributing to improvements in our understanding of both normal and disease-related physiological processes and leading to the identification of new treatment approaches. Although limitations remain to be overcome, technology for the analysis of single-cell gene expression patterns is improving rapidly and beginning to provide a detailed atlas of the gene expression patterns of all cell types in the human body.", "year": "2018", "month": "08", "volume": "14", "issue": "8", "pages": "479-492", "doi": "10.1038/s41581-018-0021-7", "link": "https://www.ncbi.nlm.nih.gov/pubmed/29789704", "sort_key": "2018-08-single-cell rna sequ", "quarter": "q3"}, {"pmid": "29972024", "title": "Multifunctional Activity-Based Protein Profiling of the Developing Lung.", "authors": ["Stoddard EG", "Volk RF", "Carson JP", "Ljungberg CM", "Murphree TA", "Smith JN", "Sadler NC", "Shukla AK", "Ansong C", "Wright AT"], "journal": "J Proteome Res", "journal_title": "Journal of proteome research", "citation": "Journal of proteome research, 08 2018", "abstract": "Lung diseases and disorders are a leading cause of death among infants. Many of these diseases and disorders are caused by premature birth and underdeveloped lungs. In addition to developmentally related disorders, the lungs are exposed to a variety of environmental contaminants and xenobiotics upon birth that can cause breathing issues and are progenitors of cancer. In order to gain a deeper understanding of the developing lung, we applied an activity-based chemoproteomics approach for the functional characterization of the xenometabolizing cytochrome P450 enzymes, active ATP and nucleotide binding enzymes, and serine hydrolases using a suite of activity-based probes (ABPs). We detected P450 activity primarily in the postnatal lung; using our ATP-ABP, we characterized a wide range of ATPases and other active nucleotide- and nucleic acid-binding enzymes involved in multiple facets of cellular metabolism throughout development. ATP-ABP targets include kinases, phosphatases, NAD- and FAD-dependent enzymes, RNA/DNA helicases, and others. The serine hydrolase-targeting probe detected changes in the activities of several proteases during the course of lung development, yielding insights into protein turnover at different stages of development. Select activity-based probe targets were then correlated with RNA in situ hybridization analyses of lung tissue sections.", "year": "2018", "month": "08", "volume": "17", "issue": "8", "pages": "2623-2634", "doi": "10.1021/acs.jproteome.8b00086", "link": "https://www.ncbi.nlm.nih.gov/pubmed/29972024", "sort_key": "2018-08-multifunctional acti", "quarter": "q3"}, {"pmid": "29567123", "title": "Fibrosis: Lessons from OMICS analyses of the human lung.", "authors": ["Yu G", "Ibarra GH", "Kaminski N"], "journal": "Matrix Biol", "journal_title": "Matrix biology : journal of the International Society for Matrix Biology", "citation": "Matrix biology : journal of the International Society for Matrix Biology, 08 2018", "abstract": "In recent decades there has been a significant shift in our understanding of idiopathic pulmonary fibrosis (IPF), a progressive and lethal disorder. While initially much of the mechanistic understanding was derived from hypotheses generated from animal models of disease, in recent decades new insights derived from humans with IPF have taken precedence. This is mainly because of the establishment of large collections of IPF lung tissues and patient cohorts, and the emergence of high throughput profiling technologies collectively termed 'omics' technologies based on their shared suffix. In this review we describe impacts of 'omics' analyses of human IPF samples on our understanding of the disease. In particular, we discuss the results of genomics and transcriptomics studies, as well as proteomics, epigenomics and metabolomics. We then describe how these findings can be integrated in a modified paradigm of human idiopathic pulmonary fibrosis, that introduces the 'hallmarks of aging' as a central theme in the IPF lung. This allows resolution of all the disparate cellular and molecular features in IPF, from the central role of epithelial cells, through the dramatic phenotypic alterations observed in fibroblasts and the numerous aberrations that inflammatory cells exhibit. We end with reiterating a call for renewed efforts to collect and analyze carefully characterized human tissues, in ways that would facilitate implementation of novel technologies for high resolution single cell omics profiling.", "year": "2018", "month": "08", "volume": "68-69", "issue": "", "pages": "422-434", "doi": "10.1016/j.matbio.2018.03.014", "link": "https://www.ncbi.nlm.nih.gov/pubmed/29567123", "sort_key": "2018-08-fibrosis: lessons fr", "quarter": "q3"}, {"pmid": "29516783", "title": "Time-resolved proteome profiling of normal lung development.", "authors": ["Moghieb A", "Clair G", "Mitchell HD", "Kitzmiller J", "Zink EM", "Kim YM", "Petyuk V", "Shukla A", "Moore RJ", "Metz TO", "Carson J", "McDermott JE", "Corley RA", "Whitsett JA", "Ansong C"], "journal": "Am J Physiol Lung Cell Mol Physiol", "journal_title": "American journal of physiology. Lung cellular and molecular physiology", "citation": "American journal of physiology. Lung cellular and molecular physiology, 07 2018", "abstract": "Biochemical networks mediating normal lung morphogenesis and function have important implications for ameliorating morbidity and mortality in premature infants. Although several transcript-level studies have examined normal lung development, corresponding protein-level analyses are lacking. Here we performed proteomics analysis of murine lungs from embryonic to early adult ages to identify the molecular networks mediating normal lung development. We identified 8,932 proteins, providing a deep and comprehensive view of the lung proteome. Analysis of the proteomics data revealed discrete modules and the underlying regulatory and signaling network modulating their expression during development. Our data support the cell proliferation that characterizes early lung development and highlight responses of the lung to exposure to a nonsterile oxygen-rich ambient environment and the important role of lipid (surfactant) metabolism in lung development. Comparison of dynamic regulation of proteomic and recent transcriptomic analyses identified biological processes under posttranscriptional control. Our study provides a unique proteomic resource for understanding normal lung formation and function and can be freely accessed at Lungmap.net.", "year": "2018", "month": "07", "volume": "315", "issue": "1", "pages": "L11-L24", "doi": "10.1152/ajplung.00316.2017", "link": "https://www.ncbi.nlm.nih.gov/pubmed/29516783", "sort_key": "2018-07-time-resolved proteo", "quarter": "q3"}, {"pmid": "29844468", "title": "Spatial and temporal changes in extracellular elastin and laminin distribution during lung alveolar development.", "authors": ["Luo Y", "Li N", "Chen H", "Fernandez GE", "Warburton D", "Moats R", "Mecham RP", "Krenitsky D", "Pryhuber GS", "Shi W"], "journal": "Sci Rep", "journal_title": "Scientific reports", "citation": "Scientific reports, 05 2018", "abstract": "Lung alveolarization requires precise coordination of cell growth with extracellular matrix (ECM) synthesis and deposition. The role of extracellular matrices in alveogenesis is not fully understood, because prior knowledge is largely extrapolated from two-dimensional structural analysis. Herein, we studied temporospatial changes of two important ECM proteins, laminin and elastin that are tightly associated with alveolar capillary growth and lung elastic recoil respectively, during both mouse and human lung alveolarization. By combining protein immunofluorescence staining with two- and three-dimensional imaging, we found that the laminin network was simplified along with the thinning of septal walls during alveogenesis, and more tightly associated with alveolar endothelial cells in matured lung. In contrast, elastin fibers were initially localized to the saccular openings of nascent alveoli, forming a ring-like structure. Then, throughout alveolar growth, the number of such alveolar mouth ring-like structures increased, while the relative ring size decreased. These rings were interconnected via additional elastin fibers. The apparent patches and dots of elastin at the tips of alveolar septae found in two-dimensional images were cross sections of elastin ring fibers in the three-dimension. Thus, the previous concept that deposition of elastin at alveolar tips drives septal inward growth may potentially be conceptually challenged by our data.", "year": "2018", "month": "05", "volume": "8", "issue": "1", "pages": "8334", "doi": "10.1038/s41598-018-26673-1", "link": "https://www.ncbi.nlm.nih.gov/pubmed/29844468", "sort_key": "2018-05-spatial and temporal", "quarter": "q2"}, {"pmid": "29642003", "title": "FOXF1 Inhibits Pulmonary Fibrosis by Preventing CDH2-CDH11 Cadherin Switch in Myofibroblasts.", "authors": ["Black M", "Milewski D", "Le T", "Ren X", "Xu Y", "Kalinichenko VV", "Kalin TV"], "journal": "Cell Rep", "journal_title": "Cell reports", "citation": "Cell reports, 04 2018", "abstract": "Idiopathic pulmonary fibrosis (IPF) is characterized by aberrant accumulation of collagen-secreting myofibroblasts. Development of effective therapies is limited due to incomplete understanding of molecular mechanisms regulating myofibroblast expansion. FOXF1 transcription factor is expressed in resident lung fibroblasts, but its role in lung fibrosis remains unknown due to the lack of genetic mouse models. Through comprehensive analysis of human IPF genomics data, lung biopsies, and transgenic mice with fibroblast-specific inactivation of FOXF1, we show that FOXF1 inhibits pulmonary fibrosis. FOXF1 deletion increases myofibroblast invasion and collagen secretion and promotes a switch from N-cadherin (CDH2) to Cadherin-11 (CDH11), which is a critical step in the acquisition of the pro-fibrotic phenotype. FOXF1 directly binds to Cdh2 and Cdh11 promoters and differentially regulates transcription of these genes. Re-expression of CDH2 or inhibition of CDH11 in FOXF1-deficient cells reduces myofibroblast invasion in vitro. FOXF1 inhibits pulmonary fibrosis by regulating a switch from CDH2 to CDH11 in lung myofibroblasts.", "year": "2018", "month": "04", "volume": "23", "issue": "2", "pages": "442-458", "doi": "10.1016/j.celrep.2018.03.067", "link": "https://www.ncbi.nlm.nih.gov/pubmed/29642003", "sort_key": "2018-04-foxf1 inhibits pulmo", "quarter": "q2"}, {"pmid": "29317474", "title": "Reconstructing differentiation networks and their regulation from time series single-cell expression data.", "authors": ["Ding J", "Aronow BJ", "Kaminski N", "Kitzmiller J", "Whitsett JA", "Bar-Joseph Z"], "journal": "Genome Res", "journal_title": "Genome research", "citation": "Genome research, 03 2018", "abstract": "Generating detailed and accurate organogenesis models using single-cell RNA-seq data remains a major challenge. Current methods have relied primarily on the assumption that descendant cells are similar to their parents in terms of gene expression levels. These assumptions do not always hold for in vivo studies, which often include infrequently sampled, unsynchronized, and diverse cell populations. Thus, additional information may be needed to determine the correct ordering and branching of progenitor cells and the set of transcription factors (TFs) that are active during advancing stages of organogenesis. To enable such modeling, we have developed a method that learns a probabilistic model that integrates expression similarity with regulatory information to reconstruct the dynamic developmental cell trajectories. When applied to mouse lung developmental data, the method accurately distinguished different cell types and lineages. Existing and new experimental data validated the ability of the method to identify key regulators of cell fate.", "year": "2018", "month": "03", "volume": "28", "issue": "3", "pages": "383-395", "doi": "10.1101/gr.225979.117", "link": "https://www.ncbi.nlm.nih.gov/pubmed/29317474", "sort_key": "2018-03-reconstructing diffe", "quarter": "q1"}, {"pmid": "29232160", "title": "MicroRNA-145 Antagonism Reverses TGF-\u03b2 Inhibition of F508del CFTR Correction in Airway Epithelia.", "authors": ["Lutful Kabir F", "Ambalavanan N", "Liu G", "Li P", "Solomon GM", "Lal CV", "Mazur M", "Halloran B", "Szul T", "Gerthoffer WT", "Rowe SM", "Harris WT"], "journal": "Am J Respir Crit Care Med", "journal_title": "American journal of respiratory and critical care medicine", "citation": "American journal of respiratory and critical care medicine, 03 2018", "abstract": "RATIONALE: MicroRNAs (miRNAs) destabilize mRNA transcripts and inhibit protein translation. miR-145 is of particular interest in cystic fibrosis (CF) as it has a direct binding site in the 3'-untranslated region of CFTR (cystic fibrosis transmembrane conductance regulator) and is upregulated by the CF genetic modifier TGF (transforming growth factor)-\u03b2. OBJECTIVES: To demonstrate that miR-145 mediates TGF-\u03b2 inhibition of CFTR synthesis and function in airway epithelia. METHODS: Primary human CF (F508del homozygous) and non-CF airway epithelial cells were grown to terminal differentiation at the air-liquid interface on permeable supports. TGF-\u03b2 (5 ng/ml), a miR-145 mimic (20 nM), and a miR-145 antagonist (20 nM) were used to manipulate CFTR function. In CF cells, lumacaftor (3 \u03bcM) and ivacaftor (10 \u03bcM) corrected mutant F508del CFTR. Quantification of CFTR mRNA, protein, and function was done by standard techniques. MEASUREMENTS AND MAIN RESULTS: miR-145 is increased fourfold in CF BAL fluid compared with non-CF (P < 0.01) and increased 10-fold in CF primary airway epithelial cells (P < 0.01). Exogenous TGF-\u03b2 doubles miR-145 expression (P < 0.05), halves wild-type CFTR mRNA and protein levels (P < 0.01), and nullifies lumacaftor/ivacaftor F508del CFTR correction. miR-145 overexpression similarly decreases wild-type CFTR protein synthesis (P < 0.01) and function (P < 0.05), and eliminates F508del corrector benefit. miR-145 antagonism blocks TGF-\u03b2 suppression of CFTR and enhances lumacaftor correction of F508del CFTR. CONCLUSIONS: miR-145 mediates TGF-\u03b2 inhibition of CFTR synthesis and function in airway epithelia. Specific antagonists to miR-145 interrupt TGF-\u03b2 signaling to restore F508del CFTR modulation. miR-145 antagonism may offer a novel therapeutic opportunity to enhance therapeutic benefit of F508del CFTR correction in CF epithelia.", "year": "2018", "month": "03", "volume": "197", "issue": "5", "pages": "632-643", "doi": "10.1164/rccm.201704-0732OC", "link": "https://www.ncbi.nlm.nih.gov/pubmed/29232160", "sort_key": "2018-03-microrna-145 antagon", "quarter": "q1"}, {"pmid": "29538379", "title": "iDREM: Interactive visualization of dynamic regulatory networks.", "authors": ["Ding J", "Hagood JS", "Ambalavanan N", "Kaminski N", "Bar-Joseph Z"], "journal": "PLoS Comput Biol", "journal_title": "PLoS computational biology", "citation": "PLoS computational biology, 03 2018", "abstract": "The Dynamic Regulatory Events Miner (DREM) software reconstructs dynamic regulatory networks by integrating static protein-DNA interaction data with time series gene expression data. In recent years, several additional types of high-throughput time series data have been profiled when studying biological processes including time series miRNA expression, proteomics, epigenomics and single cell RNA-Seq. Combining all available time series and static datasets in a unified model remains an important challenge and goal. To address this challenge we have developed a new version of DREM termed interactive DREM (iDREM). iDREM provides support for all data types mentioned above and combines them with existing interaction data to reconstruct networks that can lead to novel hypotheses on the function and timing of regulators. Users can interactively visualize and query the resulting model. We showcase the functionality of the new tool by applying it to microglia developmental data from multiple labs.", "year": "2018", "month": "03", "volume": "14", "issue": "3", "pages": "e1006019", "doi": "10.1371/journal.pcbi.1006019", "link": "https://www.ncbi.nlm.nih.gov/pubmed/29538379", "sort_key": "2018-03-idrem: interactive v", "quarter": "q1"}, {"pmid": "30271681", "title": "Epigenetic Regulation of Myofibroblast Phenotypes in Fibrosis.", "authors": ["Duong TE", "Hagood JS"], "journal": "Curr Pathobiol Rep", "journal_title": "Current pathobiology reports", "citation": "Current pathobiology reports, 03 2018", "abstract": "PURPOSE OF REVIEW: Myofibroblasts are the fundamental drivers of fibrosing disorders; there is great value in better defining epigenetic networks involved in myofibroblast behavior. Complex epigenetic paradigms, which are likely organ and/or disease specific, direct pathologic myofibroblast phenotypes. In this review, we highlight epigenetic regulators and the mechanisms through which they shape myofibroblast phenotype in fibrotic diseases of different organs. RECENT FINDINGS: Hundreds of genes and their expression contribute to the myofibroblast transcriptional regime influencing myofibroblast phenotype. An increasingly large number of epigenetic modifications have been identified in the regulation of these signaling pathways driving myofibroblast activation and disease progression. Drugs that inhibit or reverse profibrotic epigenetic modifications have shown promise in vitro and in vivo; however, no current epigenetic therapies have been approved to treat fibrosis. Newly described epigenetic mechanisms will be mentioned, along with potential therapeutic targets and innovative strategies to further understand myofibroblast-directed fibrosis. SUMMARY: Epigenetic regulators that direct myofibroblast behavior and differentiation into pathologic myofibroblast phenotypes in fibrotic disorders comprise both overlapping and organ-specific epigenetic mechanisms.", "year": "2018", "month": "03", "volume": "6", "issue": "1", "pages": "79-96", "doi": "10.1007/s40139-018-0155-0", "link": "https://www.ncbi.nlm.nih.gov/pubmed/30271681", "sort_key": "2018-03-epigenetic regulatio", "quarter": "q1"}, {"pmid": "29563341", "title": "Active epithelial Hippo signaling in idiopathic pulmonary fibrosis.", "authors": ["Gokey JJ", "Sridharan A", "Xu Y", "Green J", "Carraro G", "Stripp BR", "Perl AT", "Whitsett JA"], "journal": "JCI Insight", "journal_title": "JCI insight", "citation": "JCI insight, 03 2018", "abstract": "Hippo/YAP signaling plays pleiotropic roles in the regulation of cell proliferation and differentiation during organogenesis and tissue repair. Herein we demonstrate increased YAP activity in respiratory epithelial cells in lungs of patients with idiopathic pulmonary fibrosis (IPF), a common, lethal form of interstitial lung disease (ILD). Immunofluorescence staining in IPF epithelial cells demonstrated increased nuclear YAP and loss of MST1/2. Bioinformatic analyses of epithelial cell RNA profiles predicted increased activity of YAP and increased canonical mTOR/PI3K/AKT signaling in IPF. Phospho-S6 (p-S6) and p-PTEN were increased in IPF epithelial cells, consistent with activation of mTOR signaling. Expression of YAP (S127A), a constitutively active form of YAP, in human bronchial epithelial cells (HBEC3s) increased p-S6 and p-PI3K, cell proliferation and migration, processes that were inhibited by the YAP-TEAD inhibitor verteporfin. Activation of p-S6 was required for enhancing and stabilizing YAP, and the p-S6 inhibitor temsirolimus blocked nuclear YAP localization and suppressed expression of YAP target genes CTGF, AXL, and AJUBA (JUB). YAP and mTOR/p-S6 signaling pathways interact to induce cell proliferation and migration, and inhibit epithelial cell differentiation that may contribute to the pathogenesis of IPF.", "year": "2018", "month": "03", "volume": "3", "issue": "6", "pages": "", "doi": "10.1172/jci.insight.98738", "link": "https://www.ncbi.nlm.nih.gov/pubmed/29563341", "sort_key": "2018-03-active epithelial hi", "quarter": "q1"}, {"pmid": "28755258", "title": "Towards High-Resolution Tissue Imaging Using Nanospray Desorption Electrospray Ionization Mass Spectrometry Coupled to Shear Force Microscopy.", "authors": ["Nguyen SN", "Sontag RL", "Carson JP", "Corley RA", "Ansong C", "Laskin J"], "journal": "J Am Soc Mass Spectrom", "journal_title": "Journal of the American Society for Mass Spectrometry", "citation": "Journal of the American Society for Mass Spectrometry, 02 2018", "abstract": "Constant mode ambient mass spectrometry imaging (MSI) of tissue sections with high lateral resolution of better than 10 \u03bcm was performed by combining shear force microscopy with nanospray desorption electrospray ionization (nano-DESI). Shear force microscopy enabled precise control of the distance between the sample and nano-DESI probe during MSI experiments and provided information on sample topography. Proof-of-concept experiments were performed using lung and brain tissue sections representing spongy and dense tissues, respectively. Topography images obtained using shear force microscopy were comparable to the results obtained using contact profilometry over the same region of the tissue section. Variations in tissue height were found to be dependent on the tissue type and were in the range of 0-5 \u03bcm for lung tissue and 0-3 \u03bcm for brain tissue sections. Ion images of phospholipids obtained in this study are in good agreement with literature data. Normalization of nano-DESI MSI images to the signal of the internal standard added to the extraction solvent allowed us to construct high-resolution ion images free of matrix effects. Graphical Abstract \u115f.", "year": "2018", "month": "02", "volume": "29", "issue": "2", "pages": "316-322", "doi": "10.1007/s13361-017-1750-8", "link": "https://www.ncbi.nlm.nih.gov/pubmed/28755258", "sort_key": "2018-02-towards high-resolut", "quarter": "q1"}, {"pmid": "29552412", "title": "Fiber pattern removal and image reconstruction method for snapshot mosaic hyperspectral endoscopic images.", "authors": ["Wang P", "Turcatel G", "Arnesano C", "Warburton D", "Fraser SE", "Cutrale F"], "journal": "Biomed Opt Express", "journal_title": "Biomedical optics express", "citation": "Biomedical optics express, 02 2018", "abstract": "Hyperspectral endoscopic imaging has the potential to enhance clinical diagnostics and outcome. Most commercial endoscopes utilize imaging fiber bundles to transmit the collected signal from the patient to the medical operator. These bundles consist of several fiber cores surrounded by a cladding layer creating comb structure-like artifacts, which complicate further analysis, both spatially and spectrally. Here we present an optical fiber pattern removal algorithm which we applied to hyperspectral bronchoscopic images robustly and quantitatively without the need for specific optical or electrical hardware. We validate the performance of the pattern removal by using a novel hyperspectral phasor approach. This algorithm can be generalized to all forms of fiber bundle hyperspectral endoscopy.", "year": "2018", "month": "02", "volume": "9", "issue": "2", "pages": "780-790", "doi": "10.1364/BOE.9.000780", "link": "https://www.ncbi.nlm.nih.gov/pubmed/29552412", "sort_key": "2018-02-fiber pattern remova", "quarter": "q1"}, {"pmid": "30550606", "title": "Type VI collagen promotes lung epithelial cell spreading and wound-closure.", "authors": ["Mereness JA", "Bhattacharya S", "Wang Q", "Ren Y", "Pryhuber GS", "Mariani TJ"], "journal": "PLoS One", "journal_title": "PloS one", "citation": "PloS one, 2018", "abstract": "Basement membrane (BM) is an essential part of the extracellular matrix (ECM) that plays a crucial role in mechanical support and signaling to epithelial cells during lung development, homeostasis and repair. Abnormal composition and remodeling of the lung ECM have been associated with developmental abnormalities observed in multiple pediatric and adult respiratory diseases. Collagen VI (COL6) is a well-studied muscle BM component, but its role in the lung and its effect on pulmonary epithelium is largely undetermined. We report the presence of COLVI immediately subjacent to human airway and alveolar epithelium in the pediatric lung, in a location where it is likely to interact with epithelial cells. In vitro, both primary human lung epithelial cells and human lung epithelial cell lines displayed an increased rate of \"wound healing\" in response to a scratch injury when plated on COL6 as compared to other matrices. For the 16HBE cell line, wounds remained >5-fold larger for cells on COL1 (p<0.001) and >6-fold larger on matrigel (p<0.001), a prototypical basement membrane, when compared to COL6 (>96% closure at 10 hr). The effect of COL6 upon lung epithelial cell phenotype was associated with an increase in cell spreading. Three hours after initial plating, 16HBE cells showed >7-fold less spreading on matrigel (p<0.01), and >4-fold less spreading on COL1 (p<0.01) when compared to COL6. Importantly, the addition of COL6 to other matrices also enhanced cell spreading. Similar responses were observed for primary cells. Inhibitor studies indicated both integrin \u03b21 activity and activation of multiple signaling pathways was required for enhanced spreading on all matrices, with the PI3K/AKT pathway (PI3K, CDC42, RAC1) showing both significant and specific effects for spreading on COL6. Genetic gain-of-function experiments demonstrated enhanced PI3K/AKT pathway activity was sufficient to confer equivalent cell spreading on other matrices as compared to COL6. We conclude that COL6 has significant and specific effects upon human lung epithelial cell-autonomous functions.", "year": "2018", "month": "", "volume": "13", "issue": "12", "pages": "e0209095", "doi": "10.1371/journal.pone.0209095", "link": "https://www.ncbi.nlm.nih.gov/pubmed/30550606", "sort_key": "2018-00-type vi collagen pro", "quarter": "q0"}, {"pmid": "29508300", "title": "Single-Cell Transcriptome Analysis Using SINCERA Pipeline.", "authors": ["Guo M", "Xu Y"], "journal": "Methods Mol Biol", "journal_title": "Methods in molecular biology (Clifton, N.J.)", "citation": "Methods in molecular biology (Clifton, N.J.), 2018", "abstract": "Genome-scale single-cell biology has recently emerged as a powerful technology with important implications for both basic and medical research. There are urgent needs for the development of computational methods or analytic pipelines to facilitate large amounts of single-cell RNA-Seq data analysis. Here, we present a detailed protocol for SINCERA (SINgle CEll RNA-Seq profiling Analysis), a generally applicable analytic pipeline for processing single-cell data from a whole organ or sorted cells. The pipeline supports the analysis for the identification of major cell types, cell type-specific gene signatures, and driving forces of given cell types. In this chapter, we provide step-by-step instructions for the functions and features of SINCERA together with application examples to provide a practical guide for the research community. SINCERA is implemented in R, licensed under the GNU General Public License v3, and freely available from CCHMC PBGE website, https://research.cchmc.org/pbge/sincera.html .", "year": "2018", "month": "", "volume": "1751", "issue": "", "pages": "209-222", "doi": "10.1007/978-1-4939-7710-9_15", "link": "https://www.ncbi.nlm.nih.gov/pubmed/29508300", "sort_key": "2018-00-single-cell transcri", "quarter": "q0"}, {"pmid": "28980276", "title": "Quantitative Proteomic Analysis of Mass Limited Tissue Samples for Spatially Resolved Tissue Profiling.", "authors": ["Piehowski PD", "Zhao R", "Moore RJ", "Clair G", "Ansong C"], "journal": "Methods Mol Biol", "journal_title": "Methods in molecular biology (Clifton, N.J.)", "citation": "Methods in molecular biology (Clifton, N.J.), 2018", "abstract": "Traditionally, proteomic studies have been carried out on whole tissues or organs enabling the profiling of thousands of proteins within a single LC-MS analysis. A disadvantage of this approach is that proteomes generated from whole tissues are an \"average\" that represents a blend of cell types and distinct anatomical regions which can obscure important biological phenomena. Laser capture microdissection (LCM) is an elegant method that allows tissue features of interest, as small as a single cell, to be identified and isolated for downstream analysis. Herein we describe an approach that utilizes an immobilized enzyme reactor (IMER) coupled directly to nanoLC-MS/MS for highly sensitive, automated, quantitative proteomic analysis of the microscopic tissue specimens generated by LCM.", "year": "2018", "month": "", "volume": "1788", "issue": "", "pages": "269-277", "doi": "10.1007/7651_2017_78", "link": "https://www.ncbi.nlm.nih.gov/pubmed/28980276", "sort_key": "2018-00-quantitative proteom", "quarter": "q0"}, {"pmid": "29273797", "title": "Thy-1 dependent uptake of mesenchymal stem cell-derived extracellular vesicles blocks myofibroblastic differentiation.", "authors": ["Shentu TP", "Huang TS", "Cernelc-Kohan M", "Chan J", "Wong SS", "Espinoza CR", "Tan C", "Gramaglia I", "van der Heyde H", "Chien S", "Hagood JS"], "journal": "Sci Rep", "journal_title": "Scientific reports", "citation": "Scientific reports, 12 2017", "abstract": "Bone marrow-derived mesenchymal stem cells (MSC) have been promoted for multiple therapeutic applications. Many beneficial effects of MSCs are paracrine, dependent on extracellular vesicles (EVs). Although MSC-derived EVs (mEVs) are beneficial for acute lung injury and pulmonary fibrosis, mechanisms of mEV uptake by lung fibroblasts and their effects on myofibroblastic differentiation have not been established. We demonstrate that mEVs, but not fibroblast EVs (fEVs), suppress TGF\u03b21-induced myofibroblastic differentiation of normal and idiopathic pulmonary fibrosis (IPF) lung fibroblasts. MEVs display increased time- and dose-dependent cellular uptake compared to fEVs. Removal or blocking of Thy-1, or blocking Thy-1-beta integrin interactions, decreased mEV uptake and prevented suppression of myofibroblastic differentiation. MicroRNAs (miRs) 199a/b-3p, 21-5p, 630, 22-3p, 196a-5p, 199b-5p, 34a-5p and 148a-3p are selectively packaged in mEVs. In silico analyses indicated that IPF lung fibroblasts have increased expression of genes that are targets of mEV-enriched miRs. MiR-630 mimics blocked TGF\u03b21 induction of CDH2 in normal and IPF fibroblasts, and antagomiR-630 abrogated the effect of mEV on CDH2 expression. These data suggest that the interaction of Thy-1 with beta integrins mediates mEV uptake by lung fibroblasts, which blocks myofibroblastic differentiation, and that mEVs are enriched for miRs that target profibrotic genes up-regulated in IPF fibroblasts.", "year": "2017", "month": "12", "volume": "7", "issue": "1", "pages": "18052", "doi": "10.1038/s41598-017-18288-9", "link": "https://www.ncbi.nlm.nih.gov/pubmed/29273797", "sort_key": "2017-12-thy-1 dependent upta", "quarter": "q4"}, {"pmid": "29270905", "title": "The Oxygen Paradox, the French Paradox, and age-related diseases.", "authors": ["Davies JMS", "Cillard J", "Friguet B", "Cadenas E", "Cadet J", "Cayce R", "Fishmann A", "Liao D", "Bulteau AL", "Derbr\u00e9 F", "R\u00e9billard A", "Burstein S", "Hirsch E", "Kloner RA", "Jakowec M", "Petzinger G", "Sauce D", "Sennlaub F", "Limon I", "Ursini F", "Maiorino M", "Economides C", "Pike CJ", "Cohen P", "Salvayre AN", "Halliday MR", "Lundquist AJ", "Jakowec NA", "Mechta-Grigoriou F", "Mericskay M", "Mariani J", "Li Z", "Huang D", "Grant E", "Forman HJ", "Finch CE", "Sun PY", "Pomatto LCD", "Agbulut O", "Warburton D", "Neri C", "Rouis M", "Cillard P", "Capeau J", "Rosenbaum J", "Davies KJA"], "journal": "Geroscience", "journal_title": "GeroScience", "citation": "GeroScience, 12 2017", "abstract": "A paradox is a seemingly absurd or impossible concept, proposition, or theory that is often difficult to understand or explain, sometimes apparently self-contradictory, and yet ultimately correct or true. How is it possible, for example, that oxygen \"a toxic environmental poison\" could be also indispensable for life (Beckman and Ames Physiol Rev 78(2):547-81, 1998; Stadtman and Berlett Chem Res Toxicol 10(5):485-94, 1997)?: the so-called Oxygen Paradox (Davies and Ursini 1995; Davies Biochem Soc Symp 61:1-31, 1995). How can French people apparently disregard the rule that high dietary intakes of cholesterol and saturated fats (e.g., cheese and pat\u00e9) will result in an early death from cardiovascular diseases (Renaud and de Lorgeril Lancet 339(8808):1523-6, 1992; Catalgol et al. Front Pharmacol 3:141, 2012; Eisenberg et al. Nat Med 22(12):1428-1438, 2016)?: the so-called, French Paradox. Doubtless, the truth is not a duality and epistemological bias probably generates apparently self-contradictory conclusions. Perhaps nowhere in biology are there so many apparently contradictory views, and even experimental results, affecting human physiology and pathology as in the fields of free radicals and oxidative stress, antioxidants, foods and drinks, and dietary recommendations; this is particularly true when issues such as disease-susceptibility or avoidance, \"healthspan,\" \"lifespan,\" and ageing are involved. Consider, for example, the apparently paradoxical observation that treatment with low doses of a substance that is toxic at high concentrations may actually induce transient adaptations that protect against a subsequent exposure to the same (or similar) toxin. This particular paradox is now mechanistically explained as \"Adaptive Homeostasis\" (Davies Mol Asp Med 49:1-7, 2016; Pomatto et al. 2017a; Lomeli et al. Clin Sci (Lond) 131(21):2573-2599, 2017; Pomatto and Davies 2017); the non-damaging process by which an apparent toxicant can activate biological signal transduction pathways to increase expression of protective genes, by mechanisms that are completely different from those by which the same agent induces toxicity at high concentrations. In this review, we explore the influences and effects of paradoxes such as the Oxygen Paradox and the French Paradox on the etiology, progression, and outcomes of many of the major human age-related diseases, as well as the basic biological phenomenon of ageing itself.", "year": "2017", "month": "12", "volume": "39", "issue": "5-6", "pages": "499-550", "doi": "10.1007/s11357-017-0002-y", "link": "https://www.ncbi.nlm.nih.gov/pubmed/29270905", "sort_key": "2017-12-the oxygen paradox, ", "quarter": "q4"}, {"pmid": "28783377", "title": "Extracellular Mitochondrial DNA Is Generated by Fibroblasts and Predicts Death in Idiopathic Pulmonary Fibrosis.", "authors": ["Ryu C", "Sun H", "Gulati M", "Herazo-Maya JD", "Chen Y", "Osafo-Addo A", "Brandsdorfer C", "Winkler J", "Blaul C", "Faunce J", "Pan H", "Woolard T", "Tzouvelekis A", "Antin-Ozerkis DE", "Puchalski JT", "Slade M", "Gonzalez AL", "Bogenhagen DF", "Kirillov V", "Feghali-Bostwick C", "Gibson K", "Lindell K", "Herzog RI", "Dela Cruz CS", "Mehal W", "Kaminski N", "Herzog EL", "Trujillo G"], "journal": "Am J Respir Crit Care Med", "journal_title": "American journal of respiratory and critical care medicine", "citation": "American journal of respiratory and critical care medicine, 12 2017", "abstract": "RATIONALE: Idiopathic pulmonary fibrosis (IPF) involves the accumulation of \u03b1-smooth muscle actin-expressing myofibroblasts arising from interactions with soluble mediators such as transforming growth factor-\u03b21 (TGF-\u03b21) and mechanical influences such as local tissue stiffness. Whereas IPF fibroblasts are enriched for aerobic glycolysis and innate immune receptor activation, innate immune ligands related to mitochondrial injury, such as extracellular mitochondrial DNA (mtDNA), have not been identified in IPF. OBJECTIVES: We aimed to define an association between mtDNA and fibroblast responses in IPF. METHODS: We evaluated the response of normal human lung fibroblasts (NHLFs) to stimulation with mtDNA and determined whether the glycolytic reprogramming that occurs in response to TGF-\u03b21 stimulation and direct contact with stiff substrates, and spontaneously in IPF fibroblasts, is associated with excessive levels of mtDNA. We measured mtDNA concentrations in bronchoalveolar lavage (BAL) from subjects with and without IPF, as well as in plasma samples from two longitudinal IPF cohorts and demographically matched control subjects. MEASUREMENTS AND MAIN RESULTS: Exposure to mtDNA augments \u03b1-smooth muscle actin expression in NHLFs. The metabolic changes in NHLFs that are induced by interactions with TGF-\u03b21 or stiff hydrogels are accompanied by the accumulation of extracellular mtDNA. These findings replicate the spontaneous phenotype of IPF fibroblasts. mtDNA concentrations are increased in IPF BAL and plasma, and in the latter compartment, they display robust associations with disease progression and reduced event-free survival. CONCLUSIONS: These findings demonstrate a previously unrecognized and highly novel connection between metabolic reprogramming, mtDNA, fibroblast activation, and clinical outcomes that provides new insight into IPF.", "year": "2017", "month": "12", "volume": "196", "issue": "12", "pages": "1571-1581", "doi": "10.1164/rccm.201612-2480OC", "link": "https://www.ncbi.nlm.nih.gov/pubmed/28783377", "sort_key": "2017-12-extracellular mitoch", "quarter": "q4"}, {"pmid": "29083321", "title": "EMC3 coordinates surfactant protein and lipid homeostasis required for respiration.", "authors": ["Tang X", "Snowball JM", "Xu Y", "Na CL", "Weaver TE", "Clair G", "Kyle JE", "Zink EM", "Ansong C", "Wei W", "Huang M", "Lin X", "Whitsett JA"], "journal": "J Clin Invest", "journal_title": "The Journal of clinical investigation", "citation": "The Journal of clinical investigation, 12 2017", "abstract": "Adaptation to respiration at birth depends upon the synthesis of pulmonary surfactant, a lipid-protein complex that reduces surface tension at the air-liquid interface in the alveoli and prevents lung collapse during the ventilatory cycle. Herein, we demonstrated that the gene encoding a subunit of the endoplasmic reticulum membrane complex, EMC3, also known as TMEM111 (Emc3/Tmem111), was required for murine pulmonary surfactant synthesis and lung function at birth. Conditional deletion of Emc3 in murine embryonic lung epithelial cells disrupted the synthesis and packaging of surfactant lipids and proteins, impaired the formation of lamellar bodies, and induced the unfolded protein response in alveolar type 2 (AT2) cells. EMC3 was essential for the processing and routing of surfactant proteins, SP-B and SP-C, and the biogenesis of the phospholipid transport protein ABCA3. Transcriptomic, lipidomic, and proteomic analyses demonstrated that EMC3 coordinates the assembly of lipids and proteins in AT2 cells that is necessary for surfactant synthesis and function at birth.", "year": "2017", "month": "12", "volume": "127", "issue": "12", "pages": "4314-4325", "doi": "10.1172/JCI94152", "link": "https://www.ncbi.nlm.nih.gov/pubmed/29083321", "sort_key": "2017-12-emc3 coordinates sur", "quarter": "q4"}, {"pmid": "29263307", "title": "Alveolar injury and regeneration following deletion of ABCA3.", "authors": ["Rindler TN", "Stockman CA", "Filuta AL", "Brown KM", "Snowball JM", "Zhou W", "Veldhuizen R", "Zink EM", "Dautel SE", "Clair G", "Ansong C", "Xu Y", "Bridges JP", "Whitsett JA"], "journal": "JCI Insight", "journal_title": "JCI insight", "citation": "JCI insight, 12 2017", "abstract": "Adaptation to air breathing after birth is dependent upon the synthesis and secretion of pulmonary surfactant by alveolar type 2 (AT2) cells. Surfactant, a complex mixture of phospholipids and proteins, is secreted into the alveolus, where it reduces collapsing forces at the air-liquid interface to maintain lung volumes during the ventilatory cycle. ABCA3, an ATP-dependent Walker domain containing transport protein, is required for surfactant synthesis and lung function at birth. Mutations in ABCA3 cause severe surfactant deficiency and respiratory failure in newborn infants. We conditionally deleted the Abca3 gene in AT2 cells in the mature mouse lung. Loss of ABCA3 caused alveolar cell injury and respiratory failure. ABCA3-related lung dysfunction was associated with surfactant deficiency, inflammation, and alveolar-capillary leak. Extensive but incomplete deletion of ABCA3 caused alveolar injury and inflammation, and it initiated proliferation of progenitor cells, restoring ABCA3 expression, lung structure, and function. M2-like macrophages were recruited to sites of AT2 cell proliferation during the regenerative process and were present in lung tissue from patients with severe lung disease caused by mutations in ABCA3. The remarkable and selective regeneration of ABCA3-sufficient AT2 progenitor cells provides plausible approaches for future correction of ABCA3 and other genetic disorders associated with surfactant deficiency and acute interstitial lung disease.", "year": "2017", "month": "12", "volume": "2", "issue": "24", "pages": "", "doi": "10.1172/jci.insight.97381", "link": "https://www.ncbi.nlm.nih.gov/pubmed/29263307", "sort_key": "2017-12-alveolar injury and ", "quarter": "q4"}, {"pmid": "28947536", "title": "Pluripotent stem cell differentiation reveals distinct developmental pathways regulating lung- versus thyroid-lineage specification.", "authors": ["Serra M", "Alysandratos KD", "Hawkins F", "McCauley KB", "Jacob A", "Choi J", "Caballero IS", "Vedaie M", "Kurmann AA", "Ikonomou L", "Hollenberg AN", "Shannon JM", "Kotton DN"], "journal": "Development", "journal_title": "Development (Cambridge, England)", "citation": "Development (Cambridge, England), 11 2017", "abstract": "The in vitro-directed differentiation of pluripotent stem cells (PSCs) through stimulation of developmental signaling pathways can generate mature somatic cell types for basic laboratory studies or regenerative therapies. However, there has been significant uncertainty regarding a method to separately derive lung versus thyroid epithelial lineages, as these two cell types each originate from Nkx2-1+ foregut progenitors and the minimal pathways claimed to regulate their distinct lineage specification in vivo or in vitro have varied in previous reports. Here, we employ PSCs to identify the key minimal signaling pathways (Wnt+BMP versus BMP+FGF) that regulate distinct lung- versus thyroid-lineage specification, respectively, from foregut endoderm. In contrast to most previous reports, these minimal pathways appear to be evolutionarily conserved between mice and humans, and FGF signaling, although required for thyroid specification, unexpectedly appears to be dispensable for lung specification. Once specified, distinct Nkx2-1+ lung or thyroid progenitor pools can now be independently derived for functional 3D culture maturation, basic developmental studies or future regenerative therapies.", "year": "2017", "month": "11", "volume": "144", "issue": "21", "pages": "3879-3893", "doi": "10.1242/dev.150193", "link": "https://www.ncbi.nlm.nih.gov/pubmed/28947536", "sort_key": "2017-11-pluripotent stem cel", "quarter": "q4"}, {"pmid": "28798251", "title": "LungMAP: The Molecular Atlas of Lung Development Program.", "authors": ["Ardini-Poleske ME", "Clark RF", "Ansong C", "Carson JP", "Corley RA", "Deutsch GH", "Hagood JS", "Kaminski N", "Mariani TJ", "Potter SS", "Pryhuber GS", "Warburton D", "Whitsett JA", "Palmer SM", "Ambalavanan N", "LungMAP Consortium"], "journal": "Am J Physiol Lung Cell Mol Physiol", "journal_title": "American journal of physiology. Lung cellular and molecular physiology", "citation": "American journal of physiology. Lung cellular and molecular physiology, 11 2017", "abstract": "The National Heart, Lung, and Blood Institute is funding an effort to create a molecular atlas of the developing lung (LungMAP) to serve as a research resource and public education tool. The lung is a complex organ with lengthy development time driven by interactive gene networks and dynamic cross talk among multiple cell types to control and coordinate lineage specification, cell proliferation, differentiation, migration, morphogenesis, and injury repair. A better understanding of the processes that regulate lung development, particularly alveologenesis, will have a significant impact on survival rates for premature infants born with incomplete lung development and will facilitate lung injury repair and regeneration in adults. A consortium of four research centers, a data coordinating center, and a human tissue repository provides high-quality molecular data of developing human and mouse lungs. LungMAP includes mouse and human data for cross correlation of developmental processes across species. LungMAP is generating foundational data and analysis, creating a web portal for presentation of results and public sharing of data sets, establishing a repository of young human lung tissues obtained through organ donor organizations, and developing a comprehensive lung ontology that incorporates the latest findings of the consortium. The LungMAP website (www.lungmap.net) currently contains more than 6,000 high-resolution lung images and transcriptomic, proteomic, and lipidomic human and mouse data and provides scientific information to stimulate interest in research careers for young audiences. This paper presents a brief description of research conducted by the consortium, database, and portal development and upcoming features that will enhance the LungMAP experience for a community of users.", "year": "2017", "month": "11", "volume": "313", "issue": "5", "pages": "L733-L740", "doi": "10.1152/ajplung.00139.2017", "link": "https://www.ncbi.nlm.nih.gov/pubmed/28798251", "sort_key": "2017-11-lungmap: the molecul", "quarter": "q4"}, {"pmid": "28862507", "title": "A \"GLI-tch\" in Alveolar Myofibroblast Differentiation.", "authors": ["Ahlfeld SK", "Perl AK"], "journal": "Am J Respir Cell Mol Biol", "journal_title": "American journal of respiratory cell and molecular biology", "citation": "American journal of respiratory cell and molecular biology, 09 2017", "abstract": "", "year": "2017", "month": "09", "volume": "57", "issue": "3", "pages": "261-262", "doi": "10.1165/rcmb.2017-0148ED", "link": "https://www.ncbi.nlm.nih.gov/pubmed/28862507", "sort_key": "2017-09-a \"gli-tch\" in alveo", "quarter": "q3"}, {"pmid": "28702480", "title": "Dataset on transcriptional profiles and the developmental characteristics of PDGFR\u03b1 expressing lung fibroblasts.", "authors": ["Endale M", "Ahlfeld S", "Bao E", "Chen X", "Green J", "Bess Z", "Weirauch M", "Xu Y", "Perl AK"], "journal": "Data Brief", "journal_title": "Data in brief", "citation": "Data in brief, 08 2017", "abstract": "The following data are derived from key stages of acinar lung development and define the developmental role of lung interstitial fibroblasts expressing platelet-derived growth factor alpha (PDGFR\u03b1). This dataset is related to the research article entitled \"Temporal, spatial, and phenotypical changes of PDGFR\u03b1 expressing fibroblasts during late lung development\" (Endale et al., 2017) [1]. At E16.5 (canalicular), E18.5 (saccular), P7 (early alveolar) and P28 (late alveolar), PDGFR\u03b1GFP mice, in conjunction with immunohistochemical markers, were utilized to define the spatiotemporal relationship of PDGFR\u03b1+ fibroblasts to endothelial, stromal and epithelial cells in both the proximal and distal acinar lung. Complimentary analysis with flow cytometry was employed to determine changes in cellular proliferation, define lipofibroblast and myofibroblast populations via the presence of intracellular lipid or alpha smooth muscle actin (\u03b1SMA), and evaluate the expression of CD34, CD29, and Sca-1. Finally, PDGFR\u03b1+ cells isolated at each stage of acinar lung development were subjected to RNA-Seq analysis, data was subjected to Bayesian timeline analysis and transcriptional factor promoter enrichment analysis.", "year": "2017", "month": "08", "volume": "13", "issue": "", "pages": "415-431", "doi": "10.1016/j.dib.2017.06.001", "link": "https://www.ncbi.nlm.nih.gov/pubmed/28702480", "sort_key": "2017-08-dataset on transcrip", "quarter": "q3"}, {"pmid": "28408205", "title": "Temporal, spatial, and phenotypical changes of PDGFR\u03b1 expressing fibroblasts during late lung development.", "authors": ["Endale M", "Ahlfeld S", "Bao E", "Chen X", "Green J", "Bess Z", "Weirauch MT", "Xu Y", "Perl AK"], "journal": "Dev Biol", "journal_title": "Developmental biology", "citation": "Developmental biology, 05 2017", "abstract": "Many studies have investigated the source and role of epithelial progenitors during lung development; such information is limited for fibroblast populations and their complex role in the developing lung. In this study, we characterized the spatial location, mRNA expression and Immunophenotyping of PDGFR\u03b1+ fibroblasts during sacculation and alveolarization. Confocal microscopy identified spatial association of PDGFR\u03b1 expressing fibroblasts with proximal epithelial cells of the branching bronchioles and the dilating acinar tubules at E16.5; with distal terminal saccules at E18.5; and with alveolar epithelial cells at PN7 and PN28. Immunohistochemistry for alpha smooth muscle actin revealed that PDGFR\u03b1+ fibroblasts contribute to proximal peribronchiolar smooth muscle at E16.5 and to transient distal alveolar myofibroblasts at PN7. Time series RNA-Seq analyses of PDGFR\u03b1+ fibroblasts identified differentially expressed genes that, based on gene expression similarity were clustered into 7 major gene expression profile patterns. The presence of myofibroblast and smooth muscle precursors at E16.5 and PN7 was reflected by a two-peak gene expression profile on these days and gene ontology enrichment in muscle contraction. Additional molecular and functional differences between peribronchiolar smooth muscle cells at E16.5 and transient intraseptal myofibroblasts at PN7 were suggested by a single peak in gene expression at PN7 with functional enrichment in cell projection and muscle cell differentiation. Immunophenotyping of subsets of PDGFR\u03b1+ fibroblasts by flow cytometry confirmed the predicted increase in proliferation at E16.5 and PN7, and identified subsets of CD29+ myofibroblasts and CD34+ lipofibroblasts. These data can be further mined to develop novel hypotheses and valuable understanding of the molecular and cellular basis of alveolarization.", "year": "2017", "month": "05", "volume": "425", "issue": "2", "pages": "161-175", "doi": "10.1016/j.ydbio.2017.03.020", "link": "https://www.ncbi.nlm.nih.gov/pubmed/28408205", "sort_key": "2017-05-temporal, spatial, a", "quarter": "q2"}, {"pmid": "28070014", "title": "Lung Gene Expression Analysis (LGEA): an integrative web portal for comprehensive gene expression data analysis in lung development.", "authors": ["Du Y", "Kitzmiller JA", "Sridharan A", "Perl AK", "Bridges JP", "Misra RS", "Pryhuber GS", "Mariani TJ", "Bhattacharya S", "Guo M", "Potter SS", "Dexheimer P", "Aronow B", "Jobe AH", "Whitsett JA", "Xu Y"], "journal": "Thorax", "journal_title": "Thorax", "citation": "Thorax, 05 2017", "abstract": "'LungGENS', our previously developed web tool for mapping single-cell gene expression in the developing lung, has been well received by the pulmonary research community. With continued support from the 'LungMAP' consortium, we extended the scope of the LungGENS database to accommodate transcriptomics data from pulmonary tissues and cells from human and mouse at different stages of lung development. Lung Gene Expression Analysis (LGEA) web portal is an extended version of LungGENS useful for the analysis, display and interpretation of gene expression patterns obtained from single cells, sorted cell populations and whole lung tissues. The LGEA web portal is freely available at http://research.cchmc.org/pbge/lunggens/mainportal.html.", "year": "2017", "month": "05", "volume": "72", "issue": "5", "pages": "481-484", "doi": "10.1136/thoraxjnl-2016-209598", "link": "https://www.ncbi.nlm.nih.gov/pubmed/28070014", "sort_key": "2017-05-lung gene expression", "quarter": "q2"}, {"pmid": "27998929", "title": "SLICE: determining cell differentiation and lineage based on single cell entropy.", "authors": ["Guo M", "Bao EL", "Wagner M", "Whitsett JA", "Xu Y"], "journal": "Nucleic Acids Res", "journal_title": "Nucleic acids research", "citation": "Nucleic acids research, 04 2017", "abstract": "A complex organ contains a variety of cell types, each with its own distinct lineage and function. Understanding the lineage and differentiation state of each cell is fundamentally important for the ultimate delineation of organ formation and function. We developed SLICE, a novel algorithm that utilizes single-cell RNA-seq (scRNA-seq) to quantitatively measure cellular differentiation states based on single cell entropy and predict cell differentiation lineages via the construction of entropy directed cell trajectories. We validated our approach using three independent data sets with known lineage and developmental time information from both Homo sapiens and Mus musculus. SLICE successfully measured the differentiation states of single cells and reconstructed cell differentiation trajectories that have been previously experimentally validated. We then applied SLICE to scRNA-seq of embryonic mouse lung at E16.5 to identify lung mesenchymal cell lineage relationships that currently remain poorly defined. A two-branched differentiation pathway of five fibroblastic subtypes was predicted using SLICE. The present study demonstrated the general applicability and high predictive accuracy of SLICE in determining cellular differentiation states and reconstructing cell differentiation lineages in scRNA-seq analysis.", "year": "2017", "month": "04", "volume": "45", "issue": "7", "pages": "e54", "doi": "10.1093/nar/gkw1278", "link": "https://www.ncbi.nlm.nih.gov/pubmed/27998929", "sort_key": "2017-04-slice: determining c", "quarter": "q2"}, {"pmid": "27870560", "title": "Effect of Prenatal versus Postnatal Vitamin D Deficiency on Pulmonary Structure and Function in Mice.", "authors": ["Saadoon A", "Ambalavanan N", "Zinn K", "Ashraf AP", "MacEwen M", "Nicola T", "Fanucchi MV", "Harris WT"], "journal": "Am J Respir Cell Mol Biol", "journal_title": "American journal of respiratory cell and molecular biology", "citation": "American journal of respiratory cell and molecular biology, 03 2017", "abstract": "Epidemiologic studies have linked gestational vitamin D deficiency to respiratory diseases, although mechanisms have not been defined. We hypothesized that antenatal vitamin D deficiency would impair airway development and alveolarization in a mouse model. We studied the effect of antenatal vitamin D deficiency by inducing it in pregnant mice and then compared lung development and function in their offspring to littermate controls. Postnatal vitamin D deficiency and sufficiency models from each group were also studied. We developed a novel tracheal ultrasound imaging technique to measure tracheal diameter in vivo. Histological analysis estimated tracheal cartilage total area and thickness. We found that vitamin D-deficient pups had reduced tracheal diameter with decreased tracheal cartilage minimal width. Vitamin D deficiency increased airway resistance and reduced lung compliance, and led to alveolar simplification. Postnatal vitamin D supplementation improved lung function and radial alveolar count, a parameter of alveolar development, but did not correct tracheal narrowing. We conclude that antenatal vitamin D deficiency impairs airway and alveolar development and limits lung function. Reduced tracheal diameter, cartilage irregularity, and alveolar simplification in vitamin D-deficient mice may contribute to increased airways resistance and diminished lung compliance. Vitamin D supplementation after birth improved lung function and, potentially, alveolar simplification, but did not improve defective tracheal structure. This mouse model offers insight into the mechanisms of vitamin D deficiency-associated lung disease and provides an in vivo model for investigating preclinical preventive and therapeutic strategies.", "year": "2017", "month": "03", "volume": "56", "issue": "3", "pages": "383-392", "doi": "10.1165/rcmb.2014-0482OC", "link": "https://www.ncbi.nlm.nih.gov/pubmed/27870560", "sort_key": "2017-03-effect of prenatal v", "quarter": "q1"}, {"pmid": "27893721", "title": "Biomarkers associated with bronchopulmonary dysplasia/mortality in premature infants.", "authors": ["Balena-Borneman J", "Ambalavanan N", "Tiwari HK", "Griffin RL", "Halloran B", "Askenazi D"], "journal": "Pediatr Res", "journal_title": "Pediatric research", "citation": "Pediatric research, 03 2017", "abstract": "BACKGROUND: Bronchopulmonary dysplasia (BPD) portends lifelong organ impairment and death. Our ability to predict BPD in first days of life is limited, but could be enhanced using novel biomarkers. METHODS: Using an available clinical and urine biomarker database obtained from a prospective 113 infant cohort (birth weight \u22641,200 g and/or gestational age \u226431 wk), we evaluated the independent association of 14 urine biomarkers with BPD/mortality. RESULTS: Two of the 14 urine biomarkers were independently associated with BPD/mortality after controlling for gestational age (GA), small for gestational age (SGA), and intubation status. The best performing protein was clusterin, a ubiquitously expressed protein and potential sensor of oxidative stress associated with lung function in asthma patients. When modeling for BPD/mortality, the independent odds ratio for maximum adjusted urine clusterin was 9.2 (95% CI: 3.3-32.8, P < 0.0001). In this model, clinical variables (GA, intubation status, and SGA) explained 38.3% of variance; clusterin explained an additional 9.2%, while albumin explained an additional 3.4%. The area under the curve incorporating clinical factors and biomarkers was 0.941. CONCLUSION: Urine clusterin and albumin may improve our ability to predict BPD/mortality. Future studies are needed to validate these findings and determine their clinical usefulness.", "year": "2017", "month": "03", "volume": "81", "issue": "3", "pages": "519-525", "doi": "10.1038/pr.2016.259", "link": "https://www.ncbi.nlm.nih.gov/pubmed/27893721", "sort_key": "2017-03-biomarkers associate", "quarter": "q1"}, {"pmid": "27736153", "title": "SH2 Domain-Containing Phosphatase-2 Is a Novel Antifibrotic Regulator in Pulmonary Fibrosis.", "authors": ["Tzouvelekis A", "Yu G", "Lino Cardenas CL", "Herazo-Maya JD", "Wang R", "Woolard T", "Zhang Y", "Sakamoto K", "Lee H", "Yi JS", "DeIuliis G", "Xylourgidis N", "Ahangari F", "Lee PJ", "Aidinis V", "Herzog EL", "Homer R", "Bennett AM", "Kaminski N"], "journal": "Am J Respir Crit Care Med", "journal_title": "American journal of respiratory and critical care medicine", "citation": "American journal of respiratory and critical care medicine, 02 2017", "abstract": "RATIONALE: Idiopathic pulmonary fibrosis (IPF) is a chronic fatal lung disease with dismal prognosis and no cure. The potential role of the ubiquitously expressed SH2 domain-containing tyrosine phosphatase-2 (SHP2) as a therapeutic target has not been studied in IPF. OBJECTIVES: To determine the expression, mechanistic role, and potential therapeutic usefulness of SHP2 in pulmonary fibrosis. METHODS: The effects of SHP2 overexpression and inhibition on fibroblast response to profibrotic stimuli were analyzed in vitro in primary human and mouse lung fibroblasts. In vivo therapeutic effects were assessed in the bleomycin model of lung fibrosis by SHP2-lentiviral administration and transgenic mice carrying a constitutively active SHP2 mutation. MEASUREMENTS AND MAIN RESULTS: SHP2 was down-regulated in lungs and lung fibroblasts obtained from patients with IPF. Immunolocalization studies revealed that SHP2 was absent within fibroblastic foci. Loss of SHP2 expression or activity was sufficient to induce fibroblast-to-myofibroblast differentiation in primary human lung fibroblasts. Overexpression of constitutively active SHP2 reduced the responsiveness of fibroblasts to profibrotic stimuli, including significant reductions in cell survival and myofibroblast differentiation. SHP2 effects were mediated through deactivation of fibrosis-relevant tyrosine kinase and serine/threonine kinase signaling pathways. Mice carrying the Noonan syndrome-associated gain-of-function SHP2 mutation (SHP2D61G/+) were resistant to bleomycin-induced pulmonary fibrosis. Restoration of SHP2 levels in vivo through lentiviral delivery blunted bleomycin-induced pulmonary fibrosis. CONCLUSIONS: Our data suggest that SHP2 is an important regulator of fibroblast differentiation, and its loss as observed in IPF facilitates profibrotic phenotypic changes. Augmentation of SHP2 activity or expression should be investigated as a novel therapeutic strategy for IPF.", "year": "2017", "month": "02", "volume": "195", "issue": "4", "pages": "500-514", "doi": "10.1164/rccm.201602-0329OC", "link": "https://www.ncbi.nlm.nih.gov/pubmed/27736153", "sort_key": "2017-02-sh2 domain-containin", "quarter": "q1"}, {"pmid": "28145528", "title": "Lipidomics reveals dramatic lipid compositional changes in the maturing postnatal lung.", "authors": ["Dautel SE", "Kyle JE", "Clair G", "Sontag RL", "Weitz KK", "Shukla AK", "Nguyen SN", "Kim YM", "Zink EM", "Luders T", "Frevert CW", "Gharib SA", "Laskin J", "Carson JP", "Metz TO", "Corley RA", "Ansong C"], "journal": "Sci Rep", "journal_title": "Scientific reports", "citation": "Scientific reports, 02 2017", "abstract": "Lung immaturity is a major cause of morbidity and mortality in premature infants. Understanding the molecular mechanisms driving normal lung development could provide insights on how to ameliorate disrupted development. While transcriptomic and proteomic analyses of normal lung development have been previously reported, characterization of changes in the lipidome is lacking. Lipids play significant roles in the lung, such as dipalmitoylphosphatidylcholine in pulmonary surfactant; however, many of the roles of specific lipid species in normal lung development, as well as in disease states, are not well defined. In this study, we used liquid chromatography-mass spectrometry (LC-MS/MS) to investigate the murine lipidome during normal postnatal lung development. Lipidomics analysis of lungs from post-natal day 7, day 14 and 6-8 week mice (adult) identified 924 unique lipids across 21 lipid subclasses, with dramatic alterations in the lipidome across developmental stages. Our data confirmed previously recognized aspects of post-natal lung development and revealed several insights, including in sphingolipid-mediated apoptosis, inflammation and energy storage/usage. Complementary proteomics, metabolomics and chemical imaging corroborated these observations. This multi-omic view provides a unique resource and deeper insight into normal pulmonary development.", "year": "2017", "month": "02", "volume": "7", "issue": "", "pages": "40555", "doi": "10.1038/srep40555", "link": "https://www.ncbi.nlm.nih.gov/pubmed/28145528", "sort_key": "2017-02-lipidomics reveals d", "quarter": "q1"}, {"pmid": "28179507", "title": "Intestinal commensal bacteria mediate lung mucosal immunity and promote resistance of newborn mice to infection.", "authors": ["Gray J", "Oehrle K", "Worthen G", "Alenghat T", "Whitsett J", "Deshmukh H"], "journal": "Sci Transl Med", "journal_title": "Science translational medicine", "citation": "Science translational medicine, 02 2017", "abstract": "Immature mucosal defenses contribute to increased susceptibility of newborn infants to pathogens. Sparse knowledge of age-dependent changes in mucosal immunity has hampered improvements in neonatal morbidity because of infections. We report that exposure of neonatal mice to commensal bacteria immediately after birth is required for a robust host defense against bacterial pneumonia, the leading cause of death in newborn infants. This crucial window was characterized by an abrupt influx of interleukin-22 (IL-22)-producing group 3 innate lymphoid cells (IL-22+ILC3) into the lungs of newborn mice. This influx was dependent on sensing of commensal bacteria by intestinal mucosal dendritic cells. Disruption of postnatal commensal colonization or selective depletion of dendritic cells interrupted the migratory program of lung IL-22+ILC3 and made the newborn mice more susceptible to pneumonia, which was reversed by transfer of commensal bacteria after birth. Thus, the resistance of newborn mice to pneumonia relied on commensal bacteria-directed ILC3 influx into the lungs, which mediated IL-22-dependent host resistance to pneumonia during this developmental window. These data establish that postnatal colonization by intestinal commensal bacteria is pivotal in the development of the lung defenses of newborns.", "year": "2017", "month": "02", "volume": "9", "issue": "376", "pages": "", "doi": "10.1126/scitranslmed.aaf9412", "link": "https://www.ncbi.nlm.nih.gov/pubmed/28179507", "sort_key": "2017-02-intestinal commensal", "quarter": "q1"}, {"pmid": "28124972", "title": "Selecting the most appropriate time points to profile in high-throughput studies.", "authors": ["Kleyman M", "Sefer E", "Nicola T", "Espinoza C", "Chhabra D", "Hagood JS", "Kaminski N", "Ambalavanan N", "Bar-Joseph Z"], "journal": "Elife", "journal_title": "eLife", "citation": "eLife, 01 2017", "abstract": "Biological systems are increasingly being studied by high throughput profiling of molecular data over time. Determining the set of time points to sample in studies that profile several different types of molecular data is still challenging. Here we present the Time Point Selection (TPS) method that solves this combinatorial problem in a principled and practical way. TPS utilizes expression data from a small set of genes sampled at a high rate. As we show by applying TPS to study mouse lung development, the points selected by TPS can be used to reconstruct an accurate representation for the expression values of the non selected points. Further, even though the selection is only based on gene expression, these points are also appropriate for representing a much larger set of protein, miRNA and DNA methylation changes over time. TPS can thus serve as a key design strategy for high throughput time series experiments. Supporting Website: www.sb.cs.cmu.edu/TPS.", "year": "2017", "month": "01", "volume": "6", "issue": "", "pages": "", "doi": "10.7554/eLife.18541", "link": "https://www.ncbi.nlm.nih.gov/pubmed/28124972", "sort_key": "2017-01-selecting the most a", "quarter": "q1"}, {"pmid": "28538234", "title": "Overview of Lung Development in the Newborn Human.", "authors": ["Warburton D"], "journal": "Neonatology", "journal_title": "Neonatology", "citation": "Neonatology, 2017", "abstract": "In human neonates rapid adaptation from an aqueous intrauterine environment to permanent air breathing is the rate-limiting step for extrauterine life, failure of which justifies the existence of neonatal intensive care units. The lung develops at about 4-6 weeks' gestation in humans as a ventral outpouching of the primitive foregut into the surrounding ventral mesenchyme, termed the laryngotracheal groove. At its posterior end lie progenitor cells that form a pair of bronchial tubes, from which arise all the distal epithelial structures of the lung. In humans, formation of the distal gas exchange surfaces begins in utero at about 20 weeks' gestation and is substantially established by term. Stereotypic branching of the proximal airway ends relatively early at 16-18 weeks at the bronchoalveolar duct junctions. Distally, about 5 finger-like alveolar ducts arise from each bronchoalveolar duct junction and ramify outwards towards the pleura. The majority of alveolar air sacs arise from the sides of the alveolar ducts and each of these alveoli can have up to 5 daughter alveoli arising from the outer surface as subsequent buds. At the end of each alveolar duct lie the mouths of 5 interconnected alveoli. Each family of alveoli arising from each bronchoalveolar duct junction has a different shape depending upon the limitations imposed by the pleural surface as well as the interstitial fascial planes.", "year": "2017", "month": "", "volume": "111", "issue": "4", "pages": "398-401", "doi": "10.1159/000458465", "link": "https://www.ncbi.nlm.nih.gov/pubmed/28538234", "sort_key": "2017-00-overview of lung dev", "quarter": "q0"}, {"pmid": "28347618", "title": "Implementation of Hysterectomy Pathway: Impact on Complications.", "authors": ["Linkov F", "Sanei-Moghaddam A", "Edwards RP", "Lounder PJ", "Ismail N", "Goughnour SL", "Kang C", "Mansuria SM", "Comerci JT"], "journal": "Womens Health Issues", "journal_title": "Women's health issues : official publication of the Jacobs Institute of Women's Health", "citation": "Women's health issues : official publication of the Jacobs Institute of Women's Health, 2017", "abstract": "OBJECTIVE: Hysterectomy is one of the most common surgical procedures in the United States. For women who need hysterectomy, it is important to ensure that minimally invasive hysterectomy procedures are used appropriately to reduce surgical complications and improve value of care. Although we previously demonstrated a reduction in total abdominal hysterectomy rates after the implementation of hysterectomy pathway treatment algorithm in 2012, this study focuses on exploring the effect of pathways implementation on surgical outcomes. METHODS: All retrospective medical records for hysterectomy surgeries performed for benign indications at University of Pittsburgh Medical Center hospitals between the fiscal years (FY) 2012 and 2014 were identified. We analyzed the health care outcomes by route of surgery and year using \u03a72 test for categorical data, and non-parametric approaches for non-normal continuous variables. RESULTS: A total of 6,569 hysterectomies for benign indications were performed between FY 2012 and 2014. In FY 2012, 1,154 patients (59.15%) had a length of stay of 1 day or less, whereas in FY 2014 this number increased to 1,791 (74.53%; p < .0001). Within 3 years of implementing the pathway, surgical site infections had a reduction of 47%, with a considerable trend toward significance (p = .067). CONCLUSIONS: Implementation of hysterectomy pathway has been associated with reduction of surgical complications in benign hysterectomy settings. Implementation of clinical pathways offers an opportunity for improving patient outcomes that should be investigated in various health care settings and across procedures.", "year": "2017", "month": "", "volume": "27", "issue": "4", "pages": "493-498", "doi": "10.1016/j.whi.2017.02.004", "link": "https://www.ncbi.nlm.nih.gov/pubmed/28347618", "sort_key": "2017-00-implementation of hy", "quarter": "q0"}, {"pmid": "28004771", "title": "Spatially-Resolved Proteomics: Rapid Quantitative Analysis of Laser Capture Microdissected Alveolar Tissue Samples.", "authors": ["Clair G", "Piehowski PD", "Nicola T", "Kitzmiller JA", "Huang EL", "Zink EM", "Sontag RL", "Orton DJ", "Moore RJ", "Carson JP", "Smith RD", "Whitsett JA", "Corley RA", "Ambalavanan N", "Ansong C"], "journal": "Sci Rep", "journal_title": "Scientific reports", "citation": "Scientific reports, 12 2016", "abstract": "Laser capture microdissection (LCM)-enabled region-specific tissue analyses are critical to better understand complex multicellular processes. However, current proteomics workflows entail several manual sample preparation steps and are challenged by the microscopic mass-limited samples generated by LCM, impacting measurement robustness, quantification and throughput. Here, we coupled LCM with a proteomics workflow that provides fully automated analysis of proteomes from microdissected tissues. Benchmarking against the current state-of-the-art in ultrasensitive global proteomics (FASP workflow), our approach demonstrated significant improvements in quantification (~2-fold lower variance) and throughput (>5 times faster). Using our approach we for the first time characterized, to a depth of >3,400 proteins, the ontogeny of protein changes during normal lung development in microdissected alveolar tissue containing only 4,000 cells. Our analysis revealed seven defined modules of coordinated transcription factor-signaling molecule expression patterns, suggesting a complex network of temporal regulatory control directs normal lung development with epigenetic regulation fine-tuning pre-natal developmental processes.", "year": "2016", "month": "12", "volume": "6", "issue": "", "pages": "39223", "doi": "10.1038/srep39223", "link": "https://www.ncbi.nlm.nih.gov/pubmed/28004771", "sort_key": "2016-12-spatially-resolved p", "quarter": "q4"}, {"pmid": "27942595", "title": "Single-cell RNA sequencing identifies diverse roles of epithelial cells in idiopathic pulmonary fibrosis.", "authors": ["Xu Y", "Mizuno T", "Sridharan A", "Du Y", "Guo M", "Tang J", "Wikenheiser-Brokamp KA", "Perl AT", "Funari VA", "Gokey JJ", "Stripp BR", "Whitsett JA"], "journal": "JCI Insight", "journal_title": "JCI insight", "citation": "JCI insight, 12 2016", "abstract": "Idiopathic pulmonary fibrosis (IPF) is a lethal interstitial lung disease characterized by airway remodeling, inflammation, alveolar destruction, and fibrosis. We utilized single-cell RNA sequencing (scRNA-seq) to identify epithelial cell types and associated biological processes involved in the pathogenesis of IPF. Transcriptomic analysis of normal human lung epithelial cells defined gene expression patterns associated with highly differentiated alveolar type 2 (AT2) cells, indicated by enrichment of RNAs critical for surfactant homeostasis. In contrast, scRNA-seq of IPF cells identified 3 distinct subsets of epithelial cell types with characteristics of conducting airway basal and goblet cells and an additional atypical transitional cell that contributes to pathological processes in IPF. Individual IPF cells frequently coexpressed alveolar type 1 (AT1), AT2, and conducting airway selective markers, demonstrating \"indeterminate\" states of differentiation not seen in normal lung development. Pathway analysis predicted aberrant activation of canonical signaling via TGF-\u03b2, HIPPO/YAP, P53, WNT, and AKT/PI3K. Immunofluorescence confocal microscopy identified the disruption of alveolar structure and loss of the normal proximal-peripheral differentiation of pulmonary epithelial cells. scRNA-seq analyses identified loss of normal epithelial cell identities and unique contributions of epithelial cells to the pathogenesis of IPF. The present study provides a rich data source to further explore lung health and disease.", "year": "2016", "month": "12", "volume": "1", "issue": "20", "pages": "e90558", "doi": "10.1172/jci.insight.90558", "link": "https://www.ncbi.nlm.nih.gov/pubmed/27942595", "sort_key": "2016-12-single-cell rna sequ", "quarter": "q4"}, {"pmid": "27768862", "title": "Inactivation of Tsc2 in Mesoderm-Derived Cells Causes Polycystic Kidney Lesions and Impairs Lung Alveolarization.", "authors": ["Ren S", "Luo Y", "Chen H", "Warburton D", "Lam HC", "Wang LL", "Chen P", "Henske EP", "Shi W"], "journal": "Am J Pathol", "journal_title": "The American journal of pathology", "citation": "The American journal of pathology, 12 2016", "abstract": "The tuberous sclerosis complex (TSC) proteins are critical negative regulators of the mammalian/mechanistic target of rapamycin complex 1 pathway. Germline mutations of TSC1 or TSC2 cause TSC, affecting multiple organs, including the kidney and lung, and causing substantial morbidity and mortality. The mechanisms of organ-specific disease in TSC remain incompletely understood, and the impact of TSC inactivation on mesenchymal lineage cells has not been specifically studied. We deleted Tsc2 specifically in mesoderm-derived mesenchymal cells of multiple organs in mice using the Dermo1-Cre driver. The Dermo1-Cre-driven Tsc2 conditional knockout mice had body growth retardation and died approximately 3 weeks after birth. Significant phenotypes were observed in the postnatal kidney and lung. Inactivation of Tsc2 in kidney mesenchyme caused polycystic lesions starting from the second week of age, with increased cell proliferation, tubular epithelial hyperplasia, and epithelial-mesenchymal transition. In contrast, Tsc2 deletion in lung mesenchyme led to decreased cell proliferation, reduced postnatal alveolarization, and decreased differentiation with reduced numbers of alveolar myofibroblast and type II alveolar epithelial cells. Two major findings thus result from this model: inactivation of Tsc2 in mesoderm-derived cells causes increased cell proliferation in the kidneys but reduced proliferation in the lungs, and inactivation of Tsc2 in mesoderm-derived cells causes epithelial-lined renal cysts. Therefore, Tsc2-mTOR signaling in mesenchyme is essential for the maintenance of renal structure and for lung alveolarization.", "year": "2016", "month": "12", "volume": "186", "issue": "12", "pages": "3261-3272", "doi": "10.1016/j.ajpath.2016.08.013", "link": "https://www.ncbi.nlm.nih.gov/pubmed/27768862", "sort_key": "2016-12-inactivation of tsc2", "quarter": "q4"}, {"pmid": "27663992", "title": "Searching for better animal models of BPD: a perspective.", "authors": ["Ambalavanan N", "Morty RE"], "journal": "Am J Physiol Lung Cell Mol Physiol", "journal_title": "American journal of physiology. Lung cellular and molecular physiology", "citation": "American journal of physiology. Lung cellular and molecular physiology, 11 2016", "abstract": "There have been many efforts to develop good animal models of bronchopulmonary dysplasia (BPD) to better understand the pathophysiology and mechanisms underlying development of BPD as well as to test potential strategies for its prevention and treatment. This Perspectives summarizes the features of common animal models of BPD and the strengths and limitations of such models. Potential optimal approaches to development of animal models are indicated, with the underlying concepts that require emphasis.", "year": "2016", "month": "11", "volume": "311", "issue": "5", "pages": "L924-L927", "doi": "10.1152/ajplung.00355.2016", "link": "https://www.ncbi.nlm.nih.gov/pubmed/27663992", "sort_key": "2016-11-searching for better", "quarter": "q4"}, {"pmid": "27374190", "title": "Inhibition of Regulatory-Associated Protein of Mechanistic Target of Rapamycin Prevents Hyperoxia-Induced Lung Injury by Enhancing Autophagy and Reducing Apoptosis in Neonatal Mice.", "authors": ["Sureshbabu A", "Syed M", "Das P", "Jan\u00e9r C", "Pryhuber G", "Rahman A", "Andersson S", "Homer RJ", "Bhandari V"], "journal": "Am J Respir Cell Mol Biol", "journal_title": "American journal of respiratory cell and molecular biology", "citation": "American journal of respiratory cell and molecular biology, 11 2016", "abstract": "Administration of supplemental oxygen remains a critical clinical intervention for survival of preterm infants with respiratory failure. However, prolonged exposure to hyperoxia can augment pulmonary damage, resulting in developmental lung diseases embodied as hyperoxia-induced acute lung injury and bronchopulmonary dysplasia (BPD). We sought to investigate the role of autophagy in hyperoxia-induced apoptotic cell death in developing lungs. We identified increased autophagy signaling in hyperoxia-exposed mouse lung epithelial-12 cells, freshly isolated fetal type II alveolar epithelial cells, lungs of newborn wild-type mice, and human newborns with respiratory distress syndrome and evolving and established BPD. We found that hyperoxia exposure induces autophagy in a Trp53-dependent manner in mouse lung epithelial-12 cells and in neonatal mouse lungs. Using pharmacological inhibitors and gene silencing techniques, we found that the activation of autophagy, upon hyperoxia exposure, demonstrated a protective role with an antiapoptotic response. Specifically, inhibiting regulatory-associated protein of mechanistic target of rapamycin (RPTOR) in hyperoxia settings, as evidenced by wild-type mice treated with torin2 or mice administered (Rptor) silencing RNA via intranasal delivery or Rptor+/-, limited lung injury by increased autophagy, decreased apoptosis, improved lung architecture, and increased survival. Furthermore, we identified increased protein expression of phospho-beclin1, light chain-3-II and lysosomal-associated membrane protein 1, suggesting altered autophagic flux in the lungs of human neonates with established BPD. Collectively, our study unveils a novel demonstration of enhancing autophagy and antiapoptotic effects, specifically through the inhibition of RPTOR as a potentially useful therapeutic target for the treatment of hyperoxia-induced acute lung injury and BPD in developing lungs.", "year": "2016", "month": "11", "volume": "55", "issue": "5", "pages": "722-735", "doi": "10.1165/rcmb.2015-0349OC", "link": "https://www.ncbi.nlm.nih.gov/pubmed/27374190", "sort_key": "2016-11-inhibition of regula", "quarter": "q4"}, {"pmid": "27811239", "title": "A transcription factor hierarchy defines an environmental stress response network.", "authors": ["Song L", "Huang SC", "Wise A", "Castanon R", "Nery JR", "Chen H", "Watanabe M", "Thomas J", "Bar-Joseph Z", "Ecker JR"], "journal": "Science", "journal_title": "Science (New York, N.Y.)", "citation": "Science (New York, N.Y.), 11 2016", "abstract": "Environmental stresses are universally encountered by microbes, plants, and animals. Yet systematic studies of stress-responsive transcription factor (TF) networks in multicellular organisms have been limited. The phytohormone abscisic acid (ABA) influences the expression of thousands of genes, allowing us to characterize complex stress-responsive regulatory networks. Using chromatin immunoprecipitation sequencing, we identified genome-wide targets of 21 ABA-related TFs to construct a comprehensive regulatory network in Arabidopsis thaliana Determinants of dynamic TF binding and a hierarchy among TFs were defined, illuminating the relationship between differential gene expression patterns and ABA pathway feedback regulation. By extrapolating regulatory characteristics of observed canonical ABA pathway components, we identified a new family of transcriptional regulators modulating ABA and salt responsiveness and demonstrated their utility to modulate plant resilience to osmotic stress.", "year": "2016", "month": "11", "volume": "354", "issue": "6312", "pages": "", "doi": "10.1126/science.aag1550", "link": "https://www.ncbi.nlm.nih.gov/pubmed/27811239", "sort_key": "2016-11-a transcription fact", "quarter": "q4"}, {"pmid": "27438473", "title": "Flow-based sorting of neonatal lymphocyte populations for transcriptomics analysis.", "authors": ["Misra RS", "Bhattacharya S", "Huyck HL", "Wang JC", "Slaunwhite CG", "Slaunwhite SL", "Wightman TR", "Secor-Socha S", "Misra SK", "Bushnell TP", "Reynolds AM", "Ryan RM", "Quataert SA", "Pryhuber GS", "Mariani TJ"], "journal": "J Immunol Methods", "journal_title": "Journal of immunological methods", "citation": "Journal of immunological methods, 10 2016", "abstract": "RATIONALE: Emerging data suggest an important role for T lymphocytes in the pathogenesis of chronic lung disease in preterm infants. Comprehensive assessment of the lymphocyte transcriptome may identify biomarkers and mechanisms of disease. METHODS: Small volume peripheral blood samples were collected from premature infants enrolled with consent in the Prematurity and Respiratory Outcomes Program (PROP), at the time of discharge from the hospital. Blood samples were collected at two sites and shipped to a central laboratory for processing. Peripheral blood mononuclear cells (PBMCs) were isolated by Ficoll-Hypaque gradient centrifugation and separated into individual lymphocyte cell types by fluorescence-activated cell sorting. Gating strategies were optimized to ensure reproducible recovery of highly purified lymphocyte populations over a multi-year recruitment period. RNA was isolated from sorted cells and characterized by high-throughput sequencing (RNASeq). RESULTS: Blood volumes averaged 2.5ml, and sufficient PBMCs were collected from 165 of the 246 samples obtained (67%) from the 277 recruited subjects to complete sorting and RNASeq analysis on the resulting sorted cells. The number of total lymphocytes per ml of blood in the neonatal subjects was approximately 4 million/ml. Total lymphocyte frequencies recovered following sort varied widely among subjects, as did the frequency of individual lymphocyte and NK cell sub-populations. RNA yield from sorted cells varied according to cell type, but RNA of sufficient quantity and quality was recovered to enable RNASeq. SUMMARY: Our results describe a validated procedure for the generation of genome-wide expression data from isolated lymphocyte sub-populations obtained from newborn blood.", "year": "2016", "month": "10", "volume": "437", "issue": "", "pages": "13-20", "doi": "10.1016/j.jim.2016.07.001", "link": "https://www.ncbi.nlm.nih.gov/pubmed/27438473", "sort_key": "2016-10-flow-based sorting o", "quarter": "q4"}, {"pmid": "27471253", "title": "Acute Kidney Injury Urine Biomarkers in Very Low-Birth-Weight Infants.", "authors": ["Askenazi DJ", "Koralkar R", "Patil N", "Halloran B", "Ambalavanan N", "Griffin R"], "journal": "Clin J Am Soc Nephrol", "journal_title": "Clinical journal of the American Society of Nephrology : CJASN", "citation": "Clinical journal of the American Society of Nephrology : CJASN, 09 2016", "abstract": "BACKGROUND AND OBJECTIVES: Serum creatinine (SCr)-based AKI definitions have important limitations, particularly in very low-birth-weight (VLBW) neonates. Urine biomarkers may improve our ability to detect kidney damage. We assessed the association between 14 different urine biomarkers and AKI in VLBW infants. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We performed a prospective cohort study on 113 VLBW infants (weight \u22641200 g or <31 weeks' gestation) admitted to a regional neonatal intensive care unit at the University of Alabama at Birmingham between February 2012 and June 2013. SCr was measured on postnatal days 1, 2, 3, and 4 and was combined with clinically measured SCr to determine AKI according to Kidney Disease Improving Global Outcomes AKI definition (increase in SCr \u22650.3 mg/dl or \u226550% increase from previous lowest value). Urine was collected on the first 4 days (average number of urine collections, 3; range, 1-4). The maximum urine biomarkers and urine biomarker/creatinine levels were calculated for 12 urine biomarkers, and the minimum urine biomarker and biomarker/creatinine levels were assessed for two urine biomarkers. We compared these values between infants with and those without AKI. Ideal cutoffs, area under the receiver-operating characteristic curve , and area under the curve adjusted for gestational age were calculated. RESULTS: Cumulative incidence of AKI during the first 2 postnatal weeks was 28 of 113 (25%). Infants with AKI had higher maximum levels of urine cystatin C, neutrophil gelatinase-associated lipocalin, osteopontin, clusterin, and \u03b1 glutathione S-transferase (2.0, 1.8, 1.7, 1.7, and 3.7 times higher, respectively) than infants without AKI. In addition, infants with AKI had lower minimum levels of epithelial growth factor and uromodulin than those without AKI (1.4 and 1.6 times lower, respectively). Most but not all participants had their maximum (or minimum) biomarker values preceding AKI. These associations remained after adjustment for gestational age. CONCLUSIONS: Urine biomarkers measured in the first 4 days of life are associated with AKI during the first postnatal weeks. Further evaluations are necessary to determine whether these biomarkers can predict important clinical outcomes. In addition, intervention studies that use biomarkers to stratify enrollment groups are needed before bedside evaluations can be incorporated into care.", "year": "2016", "month": "09", "volume": "11", "issue": "9", "pages": "1527-1535", "doi": "10.2215/CJN.13381215", "link": "https://www.ncbi.nlm.nih.gov/pubmed/27471253", "sort_key": "2016-09-acute kidney injury ", "quarter": "q3"}, {"pmid": "27488092", "title": "The Airway Microbiome at Birth.", "authors": ["Lal CV", "Travers C", "Aghai ZH", "Eipers P", "Jilling T", "Halloran B", "Carlo WA", "Keeley J", "Rezonzew G", "Kumar R", "Morrow C", "Bhandari V", "Ambalavanan N"], "journal": "Sci Rep", "journal_title": "Scientific reports", "citation": "Scientific reports, 08 2016", "abstract": "Alterations of pulmonary microbiome have been recognized in multiple respiratory disorders. It is critically important to ascertain if an airway microbiome exists at birth and if so, whether it is associated with subsequent lung disease. We found an established diverse and similar airway microbiome at birth in both preterm and term infants, which was more diverse and different from that of older preterm infants with established chronic lung disease (bronchopulmonary dysplasia). Consistent temporal dysbiotic changes in the airway microbiome were seen from birth to the development of bronchopulmonary dysplasia in extremely preterm infants. Genus Lactobacillus was decreased at birth in infants with chorioamnionitis and in preterm infants who subsequently went on to develop lung disease. Our results, taken together with previous literature indicating a placental and amniotic fluid microbiome, suggest fetal acquisition of an airway microbiome. We speculate that the early airway microbiome may prime the developing pulmonary immune system, and dysbiosis in its development may set the stage for subsequent lung disease.", "year": "2016", "month": "08", "volume": "6", "issue": "", "pages": "31023", "doi": "10.1038/srep31023", "link": "https://www.ncbi.nlm.nih.gov/pubmed/27488092", "sort_key": "2016-08-the airway microbiom", "quarter": "q3"}, {"pmid": "27453445", "title": "Tradeoffs between Dense and Replicate Sampling Strategies for High-Throughput Time Series Experiments.", "authors": ["Sefer E", "Kleyman M", "Bar-Joseph Z"], "journal": "Cell Syst", "journal_title": "Cell systems", "citation": "Cell systems, 07 2016", "abstract": "An important experimental design question for high-throughput time series studies is the number of replicates required for accurate reconstruction of the profiles. Due to budget and sample availability constraints, more replicates imply fewer time points and vice versa. We analyze the performance of dense and replicate sampling by developing a theoretical framework that focuses on a restricted yet expressive set of possible curves over a wide range of noise levels and by analyzing real expression data. For both the theoretical analysis and experimental data, we observe that, under reasonable noise levels, autocorrelations in the time series data allow dense sampling to better determine the correct levels of non-sampled points when compared to replicate sampling. A Java implementation of our framework can be used to determine the best replicate strategy given the expected noise. These results provide theoretical support to the large number of high-throughput time series experiments that do not use replicates.", "year": "2016", "month": "07", "volume": "3", "issue": "1", "pages": "35-42", "doi": "10.1016/j.cels.2016.06.007", "link": "https://www.ncbi.nlm.nih.gov/pubmed/27453445", "sort_key": "2016-07-tradeoffs between de", "quarter": "q3"}, {"pmid": "27225961", "title": "Management of hypoxemic respiratory failure and pulmonary hypertension in preterm infants.", "authors": ["Ambalavanan N", "Aschner JL"], "journal": "J Perinatol", "journal_title": "Journal of perinatology : official journal of the California Perinatal Association", "citation": "Journal of perinatology : official journal of the California Perinatal Association, 06 2016", "abstract": "While diagnoses of hypoxemic respiratory failure (HRF) and pulmonary hypertension (PH) in preterm infants may be based on criteria similar to those in term infants, management approaches often differ. In preterm infants, HRF can be classified as 'early' or 'late' based on an arbitrary threshold of 28 postnatal days. Among preterm infants with late HRF, the pulmonary vascular abnormalities associated with bronchopulmonary dysplasia (BPD) represent a therapeutic challenge for clinicians. Surfactant, inhaled nitric oxide (iNO), sildenafil, prostacyclin and endothelin receptor blockers have been used to manage infants with both early and late HRF. However, evidence is lacking for most therapies currently in use. Chronic oral sildenafil therapy for BPD-associated PH has demonstrated some preliminary efficacy. A favorable response to iNO has been documented in some preterm infants with early PH following premature prolonged rupture of membranes and oligohydramnios. Management is complicated by a lack of clear demarcation between interventions designed to manage respiratory distress syndrome, prevent BPD and treat HRF. Heterogeneity in clinical phenotype, pathobiology and genomic underpinnings of BPD pose challenges for evidence-based management recommendations. Greater insight into the spectrum of disease phenotypes represented by BPD can optimize existing therapies and promote development of new treatments. In addition, better understanding of an individual's phenotype, genotype and biomarkers may suggest targeted personalized interventions. Initiatives such as the Prematurity and Respiratory Outcomes Program provide a framework to address these challenges using genetic, environmental, physiological and clinical data as well as large repositories of patient samples.", "year": "2016", "month": "06", "volume": "36 Suppl 2", "issue": "", "pages": "S20-7", "doi": "10.1038/jp.2016.45", "link": "https://www.ncbi.nlm.nih.gov/pubmed/27225961", "sort_key": "2016-06-management of hypoxe", "quarter": "q2"}, {"pmid": "27186799", "title": "Greazy: Open-Source Software for Automated Phospholipid Tandem Mass Spectrometry Identification.", "authors": ["Kochen MA", "Chambers MC", "Holman JD", "Nesvizhskii AI", "Weintraub ST", "Belisle JT", "Islam MN", "Griss J", "Tabb DL"], "journal": "Anal Chem", "journal_title": "Analytical chemistry", "citation": "Analytical chemistry, 06 2016", "abstract": "Lipid identification from data produced with high-throughput technologies is essential to the elucidation of the roles played by lipids in cellular function and disease. Software tools for identifying lipids from tandem mass (MS/MS) spectra have been developed, but they are often costly or lack the sophistication of their proteomics counterparts. We have developed Greazy, an open source tool for the automated identification of phospholipids from MS/MS spectra, that utilizes methods similar to those developed for proteomics. From user-supplied parameters, Greazy builds a phospholipid search space and associated theoretical MS/MS spectra. Experimental spectra are scored against search space lipids with similar precursor masses using a peak score based on the hypergeometric distribution and an intensity score utilizing the percentage of total ion intensity residing in matching peaks. The LipidLama component filters the results via mixture modeling and density estimation. We assess Greazy's performance against the NIST 2014 metabolomics library, observing high accuracy in a search of multiple lipid classes. We compare Greazy/LipidLama against the commercial lipid identification software LipidSearch and show that the two platforms differ considerably in the sets of identified spectra while showing good agreement on those spectra identified by both. Lastly, we demonstrate the utility of Greazy/LipidLama with different instruments. We searched data from replicates of alveolar type 2 epithelial cells obtained with an Orbitrap and from human serum replicates generated on a quadrupole-time-of-flight (Q-TOF). These findings substantiate the application of proteomics derived methods to the identification of lipids. The software is available from the ProteoWizard repository: http://tiny.cc/bumbershoot-vc12-bin64 .", "year": "2016", "month": "06", "volume": "88", "issue": "11", "pages": "5733-41", "doi": "10.1021/acs.analchem.6b00021", "link": "https://www.ncbi.nlm.nih.gov/pubmed/27186799", "sort_key": "2016-06-greazy: open-source ", "quarter": "q2"}, {"pmid": "27225964", "title": "Challenges, priorities and novel therapies for hypoxemic respiratory failure and pulmonary hypertension in the neonate.", "authors": ["Aschner JL", "Gien J", "Ambalavanan N", "Kinsella JP", "Konduri GG", "Lakshminrusimha S", "Saugstad OD", "Steinhorn RH"], "journal": "J Perinatol", "journal_title": "Journal of perinatology : official journal of the California Perinatal Association", "citation": "Journal of perinatology : official journal of the California Perinatal Association, 06 2016", "abstract": "Future priorities for the management of hypoxemic respiratory failure (HRF) and pulmonary hypertension include primary prevention of neonatal lung diseases, 'precision medicine' and translating promising clinical and preclinical research into novel therapies. Promising areas of investigation include noninvasive ventilation strategies, emerging pulmonary vasodilators (for example, cinaciguat, intravenous bosentan, rho-kinase inhibitors, peroxisome proliferator-activated receptor-\u03b3 agonists) and hemodynamic support (arginine vasopressin). Research challenges include the optimal timing for primary prevention interventions and development of validated biomarkers that predict later disease or serve as surrogates for long-term respiratory outcomes. Differentiating respiratory disease endotypes using biomarkers and experimental therapies tailored to the underlying pathobiology are central to the concept of 'precision medicine' (that is, prevention and treatment strategies that take individual variability into account). The ideal biomarker should be expressed early in the neonatal course to offer an opportunity for effective and targeted interventions to modify outcomes. The feasibility of this approach will depend on the identification and validation of accurate, rapid and affordable point-of-care biomarker tests. Trials targeting patient-specific pathobiology may involve less risk than traditional randomized controlled trials that enroll all at-risk neonates. Such approaches would reduce trial costs, potentially with fewer negative trials and improved health outcomes. Initiatives such as the Prematurity and Respiratory Outcomes Program, supported by the National Heart, Lung, and Blood Institute, provide a framework to develop refined outcome measures and early biomarkers that will enhance our understanding of novel, mechanistic therapeutic targets that can be tested in clinical trials in neonates with HRF.", "year": "2016", "month": "06", "volume": "36 Suppl 2", "issue": "", "pages": "S32-6", "doi": "10.1038/jp.2016.47", "link": "https://www.ncbi.nlm.nih.gov/pubmed/27225964", "sort_key": "2016-06-challenges, prioriti", "quarter": "q2"}, {"pmid": "26572893", "title": "Acute changes in fluid status affect the incidence, associative clinical outcomes, and urine biomarker performance in premature infants with acute kidney injury.", "authors": ["Askenazi D", "Saeidi B", "Koralkar R", "Ambalavanan N", "Griffin RL"], "journal": "Pediatr Nephrol", "journal_title": "Pediatric nephrology (Berlin, Germany)", "citation": "Pediatric nephrology (Berlin, Germany), 05 2016", "abstract": "BACKGROUND: During the first postnatal weeks, infants have abrupt changes in fluid weight that alter serum creatinine (SCr) concentration, and possibly, the evaluation for acute kidney injury (AKI). METHODS: We performed a prospective study on 122 premature infants to determine how fluid adjustment (FA) to SCr alters the incidence of AKI, demographics, outcomes, and performance of candidate urine biomarkers. FA-SCr values were estimated using changes in total body water (TBW) from birth; FA-SCR = SCr \u00d7 [TBW + (current wt. - BW)]/ TBW; where TBW = 0.8 \u00d7 wt in kg). SCr-AKI and FA-SCr AKI were defined if values increased by \u2265 0.3 mg/dl from previous lowest value. RESULTS: AKI incidence was lower using the FA-SCr vs. SCr definition [(23/122 (18.8 %) vs. (34/122 (27.9 %); p < 0.05)], with concordance in 105/122 (86 %) and discordance in 17/122 (14 %). Discordant subjects tended to have similar demographics and outcomes to those who were negative by both definitions. Candidate urine AKI biomarkers performed better under the FA-SCr than SCr definition, especially on day 4 and days 12-14. CONCLUSIONS: Adjusting SCr for acute change in fluid weight may help differentiate SCr rise from true change in renal function from acute concentration due to abrupt weight change.", "year": "2016", "month": "05", "volume": "31", "issue": "5", "pages": "843-51", "doi": "10.1007/s00467-015-3258-4", "link": "https://www.ncbi.nlm.nih.gov/pubmed/26572893", "sort_key": "2016-05-acute changes in flu", "quarter": "q2"}, {"pmid": "26719145", "title": "Regulation of alveolar septation by microRNA-489.", "authors": ["Olave N", "Lal CV", "Halloran B", "Pandit K", "Cuna AC", "Faye-Petersen OM", "Kelly DR", "Nicola T", "Benos PV", "Kaminski N", "Ambalavanan N"], "journal": "Am J Physiol Lung Cell Mol Physiol", "journal_title": "American journal of physiology. Lung cellular and molecular physiology", "citation": "American journal of physiology. Lung cellular and molecular physiology, 03 2016", "abstract": "MicroRNAs (miRs) are small conserved RNA that regulate gene expression. Bioinformatic analysis of miRNA profiles during mouse lung development indicated a role for multiple miRNA, including miRNA-489. miR-489 increased on completion of alveolar septation [postnatal day 42 (P42)], associated with decreases in its conserved target genes insulin-like growth factor-1 (Igf1) and tenascin C (Tnc). We hypothesized that dysregulation of miR-489 and its target genes Igf1 and Tnc contribute to hyperoxia-induced abnormal lung development. C57BL/6 mice were exposed to normoxia (21%) or hyperoxia (85% O2) from P4 to P14, in combination with intranasal locked nucleic acid against miR-489 to inhibit miR-489, cytomegalovirus promoter (pCMV)-miR-489 to overexpress miR-489, or empty vector. Hyperoxia reduced miR-489 and increased Igf1 and Tnc. Locked nucleic acid against miR-489 improved lung development during hyperoxia and did not alter it during normoxia, whereas miR-489 overexpression inhibited lung development during normoxia. The 3' untranslated region in vitro reporter studies confirmed Igf1 and Tnc as targets of miR-489. While miR-489 was of epithelial origin and present in exosomes, its targets Igf1 and Tnc were produced by fibroblasts. Infants with bronchopulmonary dysplasia (BPD) had reduced lung miR-489 and increased Igf1 and Tnc compared with normal preterm or term infants. These results suggest increased miR-489 is an inhibitor of alveolar septation. During hyperoxia or BPD, reduced miR-489 and increased Igf1 and Tnc may be inadequate attempts at compensation. Further inhibition of miR-489 may permit alveolar septation to proceed. The use of specific miRNA antagonists or agonists may be a therapeutic strategy for inhibited alveolarization, such as in BPD.", "year": "2016", "month": "03", "volume": "310", "issue": "5", "pages": "L476-87", "doi": "10.1152/ajplung.00145.2015", "link": "https://www.ncbi.nlm.nih.gov/pubmed/26719145", "sort_key": "2016-03-regulation of alveol", "quarter": "q1"}, {"pmid": "26938952", "title": "Hyperoxia Induces Intracellular Acidification in Neonatal Mouse Lung Fibroblasts: Real-Time Investigation Using Plasmonically Enhanced Raman Spectroscopy.", "authors": ["Panikkanvalappil SR", "James M", "Hira SM", "Mobley J", "Jilling T", "Ambalavanan N", "El-Sayed MA"], "journal": "J Am Chem Soc", "journal_title": "Journal of the American Chemical Society", "citation": "Journal of the American Chemical Society, 03 2016", "abstract": "It is important to understand the molecular mechanisms underlying oxygen toxicity, which contributes to multiple human disorders. The archetype model of oxygen toxicity is neonatal lung injury induced by hyperoxia exposure. Here, we utilized plasmonically enhanced Raman spectroscopy (PERS) in combination with fluorescence and proteomic analysis to provide comprehensive information on hyperoxia-induced biomolecular modifications in neonatal mouse lung fibroblasts (nMLFs). During this study, we made the novel observation that hyperoxia induces intracellular acidification in nMLF, which we probed in real-time using label-free PERS. We found that intracellular acidification induces conformational modifications in proteins followed by significant changes in Raman vibrations corresponding to aromatic amino acids such as phenylalanine and tryptophan as well as cysteine moieties. Hyperoxia-induced intracellular pH changes and subsequent modifications in protein expression and associated post-translational modifications within the cells were further validated by fluorescence and proteomic analysis. These new insights may help identifying unique oxidant stress-induced mechanisms in disease processes and may guide the development of more efficient therapeutic strategies.", "year": "2016", "month": "03", "volume": "138", "issue": "11", "pages": "3779-88", "doi": "10.1021/jacs.5b13177", "link": "https://www.ncbi.nlm.nih.gov/pubmed/26938952", "sort_key": "2016-03-hyperoxia induces in", "quarter": "q1"}, {"pmid": "26593073", "title": "Update on Molecular Biology of Lung Development--Transcriptomics.", "authors": ["Mariani TJ"], "journal": "Clin Perinatol", "journal_title": "Clinics in perinatology", "citation": "Clinics in perinatology, 12 2015", "abstract": "This article highlights some of the significant advances in our understanding of lung developmental biology made over the last few years, which challenge existing paradigms and are relevant to a fundamental understanding of this process. Additional comments address how these new insights may be informative for chronic lung diseases that occur, or initiate, in the neonatal period. This is not meant to be an exhaustive review of the molecular biology of lung development. For a more comprehensive, contemporary review of the cellular and molecular aspects of lung development, readers can refer to recent reviews by others.", "year": "2015", "month": "12", "volume": "42", "issue": "4", "pages": "685-95", "doi": "10.1016/j.clp.2015.08.001", "link": "https://www.ncbi.nlm.nih.gov/pubmed/26593073", "sort_key": "2015-12-update on molecular ", "quarter": "q4"}, {"pmid": "26593074", "title": "Postnatal Infections and Immunology Affecting Chronic Lung Disease of Prematurity.", "authors": ["Pryhuber GS"], "journal": "Clin Perinatol", "journal_title": "Clinics in perinatology", "citation": "Clinics in perinatology, 12 2015", "abstract": "Premature infants suffer significant respiratory morbidity during infancy with long-term negative consequences on health, quality of life, and health care costs. Enhanced susceptibility to a variety of infections and inflammation play a large role in early and prolonged lung disease following premature birth, although the mechanisms of susceptibility and immune dysregulation are active areas of research. This article reviews aspects of host-pathogen interactions and immune responses that are altered by preterm birth and that impact chronic respiratory morbidity in these children.", "year": "2015", "month": "12", "volume": "42", "issue": "4", "pages": "697-718", "doi": "10.1016/j.clp.2015.08.002", "link": "https://www.ncbi.nlm.nih.gov/pubmed/26593074", "sort_key": "2015-12-postnatal infections", "quarter": "q4"}, {"pmid": "26471063", "title": "Genetic predisposition to bronchopulmonary dysplasia.", "authors": ["Lal CV", "Ambalavanan N"], "journal": "Semin Perinatol", "journal_title": "Seminars in perinatology", "citation": "Seminars in perinatology, 12 2015", "abstract": "The objective of this study is to review the candidate gene and genome-wide association studies relevant to bronchopulmonary dysplasia, and to discuss the emerging understanding of the complexities involved in genetic predisposition to bronchopulmonary dysplasia and its outcomes. Genetic factors contribute much of the variance in risk for BPD. Studies to date evaluating single or a few candidate genes have not been successful in yielding results that are replicated in GWAS, perhaps due to more stringent p-value thresholds. GWAS studies have identified only a single gene (SPOCK2) at genome-wide significance in a European White and African cohort, which was not replicated in two North American studies. Pathway gene-set analysis in a North American cohort confirmed involvement of known pathways of lung development and repair (e.g., CD44 and phosphorus oxygen lyase activity) and indicated novel molecules and pathways (e.g., adenosine deaminase and targets of miR-219) involved in genetic predisposition to BPD. The genetic basis of severe BPD is different from that of mild/moderate BPD, and the variants/pathways associated with BPD vary by race/ethnicity. A pilot study of whole exome sequencing identified hundreds of genes of interest, and indicated the overall feasibility as well as complexity of this approach. Better phenotyping of BPD by severity and pathophysiology, and careful analysis of race/ethnicity is required to gain a better understanding of the genetic basis of BPD. Future translational studies are required for the identification of potential genetic predispositions (rare variants and dysregulated pathways) by next-generation sequencing methods in individual infants (personalized genomics).", "year": "2015", "month": "12", "volume": "39", "issue": "8", "pages": "584-91", "doi": "10.1053/j.semperi.2015.09.004", "link": "https://www.ncbi.nlm.nih.gov/pubmed/26471063", "sort_key": "2015-12-genetic predispositi", "quarter": "q4"}, {"pmid": "26593076", "title": "Biomarkers, Early Diagnosis, and Clinical Predictors of Bronchopulmonary Dysplasia.", "authors": ["Lal CV", "Ambalavanan N"], "journal": "Clin Perinatol", "journal_title": "Clinics in perinatology", "citation": "Clinics in perinatology, 12 2015", "abstract": "The pathogenesis of bronchopulmonary dysplasia (BPD) is multifactorial, and the clinical phenotype of BPD is extremely variable. Several clinical and laboratory biomarkers have been proposed for the early identification of infants at higher risk of BPD and for determination of prognosis of infants with a diagnosis of BPD. The authors review available literature on prediction tools and biomarkers of BPD, using clinical variables and biomarkers based on imaging, lung function measures, and measurements of various analytes in different body fluids that have been determined to be associated with BPD either in a targeted manner or by unbiased omic profiling.", "year": "2015", "month": "12", "volume": "42", "issue": "4", "pages": "739-54", "doi": "10.1016/j.clp.2015.08.004", "link": "https://www.ncbi.nlm.nih.gov/pubmed/26593076", "sort_key": "2015-12-biomarkers, early di", "quarter": "q4"}, {"pmid": "26600239", "title": "SINCERA: A Pipeline for Single-Cell RNA-Seq Profiling Analysis.", "authors": ["Guo M", "Wang H", "Potter SS", "Whitsett JA", "Xu Y"], "journal": "PLoS Comput Biol", "journal_title": "PLoS computational biology", "citation": "PLoS computational biology, 11 2015", "abstract": "A major challenge in developmental biology is to understand the genetic and cellular processes/programs driving organ formation and differentiation of the diverse cell types that comprise the embryo. While recent studies using single cell transcriptome analysis illustrate the power to measure and understand cellular heterogeneity in complex biological systems, processing large amounts of RNA-seq data from heterogeneous cell populations creates the need for readily accessible tools for the analysis of single-cell RNA-seq (scRNA-seq) profiles. The present study presents a generally applicable analytic pipeline (SINCERA: a computational pipeline for SINgle CEll RNA-seq profiling Analysis) for processing scRNA-seq data from a whole organ or sorted cells. The pipeline supports the analysis for: 1) the distinction and identification of major cell types; 2) the identification of cell type specific gene signatures; and 3) the determination of driving forces of given cell types. We applied this pipeline to the RNA-seq analysis of single cells isolated from embryonic mouse lung at E16.5. Through the pipeline analysis, we distinguished major cell types of fetal mouse lung, including epithelial, endothelial, smooth muscle, pericyte, and fibroblast-like cell types, and identified cell type specific gene signatures, bioprocesses, and key regulators. SINCERA is implemented in R, licensed under the GNU General Public License v3, and freely available from CCHMC PBGE website, https://research.cchmc.org/pbge/sincera.html.", "year": "2015", "month": "11", "volume": "11", "issue": "11", "pages": "e1004575", "doi": "10.1371/journal.pcbi.1004575", "link": "https://www.ncbi.nlm.nih.gov/pubmed/26600239", "sort_key": "2015-11-sincera: a pipeline ", "quarter": "q4"}, {"pmid": "26160872", "title": "Increased alveolar soluble annexin V promotes lung inflammation and fibrosis.", "authors": ["Buckley S", "Shi W", "Xu W", "Frey MR", "Moats R", "Pardo A", "Selman M", "Warburton D"], "journal": "Eur Respir J", "journal_title": "The European respiratory journal", "citation": "The European respiratory journal, 11 2015", "abstract": "The causes underlying the self-perpetuating nature of idiopathic pulmonary fibrosis (IPF), a progressive and usually lethal disease, remain unknown. We hypothesised that alveolar soluble annexin V contributes to lung fibrosis, based on the observation that human IPF bronchoalveolar lavage fluid (BALF) containing high annexin V levels promoted fibroblast involvement in alveolar epithelial wound healing that was reduced when annexin V was depleted from the BALF. Conditioned medium from annexin V-treated alveolar epithelial type 2 cells (AEC2), but not annexin V per se, induced proliferation of human fibroblasts and contained pro-fibrotic, IPF-associated proteins, as well as pro-inflammatory cytokines that were found to correlate tightly (r>0.95) with annexin V levels in human BALF. ErbB2 receptor tyrosine kinase in AECs was activated by annexin V, and blockade reduced the fibrotic potential of annexin V-treated AEC-conditioned medium. In vivo, aerosol delivery of annexin V to mouse lung induced inflammation, fibrosis and increased hydroxyproline, with activation of Wnt, transforming growth factor-\u03b2, mitogen-activated protein kinase and nuclear factor-\u03baB signalling pathways, as seen in IPF. Chronically increased alveolar annexin V levels, as reflected in increased IPF BALF levels, may contribute to the progression of IPF by inducing the release of pro-fibrotic mediators.", "year": "2015", "month": "11", "volume": "46", "issue": "5", "pages": "1417-29", "doi": "10.1183/09031936.00002115", "link": "https://www.ncbi.nlm.nih.gov/pubmed/26160872", "sort_key": "2015-11-increased alveolar s", "quarter": "q4"}, {"pmid": "26001700", "title": "Impact of gestational age, sex, and postnatal age on urine biomarkers in premature neonates.", "authors": ["Saeidi B", "Koralkar R", "Griffin RL", "Halloran B", "Ambalavanan N", "Askenazi DJ"], "journal": "Pediatr Nephrol", "journal_title": "Pediatric nephrology (Berlin, Germany)", "citation": "Pediatric nephrology (Berlin, Germany), 11 2015", "abstract": "BACKGROUND: Urine proteins may help in understanding physiology and diagnosing disease in premature infants. Determining how urine proteins vary by degree of prematurity, sex, and postnatal day is warranted. METHODS: We performed a prospective cohort study to assess the independent correlation of 14 urine biomarkers (measured on postnatal days 1-4) with gestational age (GA), sex, and postnatal age in 81 premature infants (mean, 1017 g) without acute kidney injury using a random-effects mixed model. RESULTS: Neutrophil gelatinase-associated lipocalin (NGAL) and vascular endothelial growth factor (VEGF) showed significant associations for sex, GA, and postnatal age. Cystatin C, osteopontin (OPN), and trefoil factor 3 (TFF3) were associated with postnatal age and GA, but not sex. Epithelial growth factor (EGF) and uromodulin were associated with GA only. Clusterin was associated with postnatal age and sex. Albumin was associated with sex only. Beta-2-microglbulin (B2M), osteoactivin, kidney injury molecule -1 (KIM-1), and alpha glutathione S-transferase (\u03b1GST) were associated with postnatal age only. CONCLUSIONS: Postnatal age affects B2M, cystatin C, NGAL, OPN, clusterin, Kim-1, osteoactivin, TFF3, VEGF, \u03b1GST. GA affects cystatin C, EGF, NGAL, OPN, UMOD, TFF3, and VEGF. Sex affects albumin, NGAL, and clusterin. Interpretation of urine biomarkers will need to account for these associations.", "year": "2015", "month": "11", "volume": "30", "issue": "11", "pages": "2037-44", "doi": "10.1007/s00467-015-3129-z", "link": "https://www.ncbi.nlm.nih.gov/pubmed/26001700", "sort_key": "2015-11-impact of gestationa", "quarter": "q4"}, {"pmid": "26130332", "title": "'LungGENS': a web-based tool for mapping single-cell gene expression in the developing lung.", "authors": ["Du Y", "Guo M", "Whitsett JA", "Xu Y"], "journal": "Thorax", "journal_title": "Thorax", "citation": "Thorax, 11 2015", "abstract": "We developed LungGENS (Lung Gene Expression iN Single-cell), a web-based bioinformatics resource for querying single-cell gene expression databases by entering a gene symbol or a list of genes or selecting a cell type of their interest. Gene query provides quantitative RNA expression of the gene of interest in each lung cell type. Cell type query returns associated selective gene signatures and genes encoding cell surface markers and transcription factors in interactive heatmap and tables. LungGENS will be broadly applicable in respiratory research, providing a cell-specific RNA expression resource at single-cell resolution. LungGENS is freely available for non-commercial use at https://research.cchmc.org/pbge/lunggens/default.html.", "year": "2015", "month": "11", "volume": "70", "issue": "11", "pages": "1092-4", "doi": "10.1136/thoraxjnl-2015-207035", "link": "https://www.ncbi.nlm.nih.gov/pubmed/26130332", "sort_key": "2015-11-'lunggens': a web-ba", "quarter": "q4"}, {"pmid": "26493725", "title": "Systems biology evaluation of cell-free amniotic fluid transcriptome of term and preterm infants to detect fetal maturity.", "authors": ["Kamath-Rayne BD", "Du Y", "Hughes M", "Wagner EA", "Muglia LJ", "DeFranco EA", "Whitsett JA", "Salomonis N", "Xu Y"], "journal": "BMC Med Genomics", "journal_title": "BMC medical genomics", "citation": "BMC medical genomics, 10 2015", "abstract": "BACKGROUND: Amniotic fluid (AF) is a proximal fluid to the fetus containing higher amounts of cell-free fetal RNA/DNA than maternal serum, thereby making it a promising source for identifying novel biomarkers that predict fetal development and organ maturation. Our aim was to compare AF transcriptomic profiles at different time points in pregnancy to demonstrate unique genetic signatures that would serve as potential biomarkers indicative of fetal maturation. METHODS: We isolated AF RNA from 16 women at different time points in pregnancy: 4 from 18 to 24 weeks, 6 from 34 to 36 weeks, and 6 from 39 to 40 weeks. RNA-sequencing was performed on cell-free RNA. Gene expression and splicing analyses were performed in conjunction with cell-type and pathway predictions. RESULTS: Sample-level analysis at different time points in pregnancy demonstrated a strong correlation with cell types found in the intrauterine environment and fetal respiratory, digestive and external barrier tissues of the fetus, using high-confidence cellular molecular markers. While some RNAs and splice variants were present throughout pregnancy, many transcripts were uniquely expressed at different time points in pregnancy and associated with distinct neonatal co-morbidities (respiratory distress and gavage feeding), indicating fetal immaturity. CONCLUSION: The AF transcriptome exhibits unique cell/organ-selective expression patterns at different time points in pregnancy that can potentially identify fetal organ maturity and predict neonatal morbidity. Developing novel biomarkers indicative of the maturation of multiple organ systems can improve upon our current methods of fetal maturity testing which focus solely on the lung, and will better inform obstetrical decisions regarding delivery timing.", "year": "2015", "month": "10", "volume": "8", "issue": "", "pages": "67", "doi": "10.1186/s12920-015-0138-5", "link": "https://www.ncbi.nlm.nih.gov/pubmed/26493725", "sort_key": "2015-10-systems biology eval", "quarter": "q4"}, {"pmid": "26093309", "title": "Endodermal Wnt signaling is required for tracheal cartilage formation.", "authors": ["Snowball J", "Ambalavanan M", "Whitsett J", "Sinner D"], "journal": "Dev Biol", "journal_title": "Developmental biology", "citation": "Developmental biology, 09 2015", "abstract": "Tracheobronchomalacia is a common congenital defect in which the walls of the trachea and bronchi lack of adequate cartilage required for support of the airways. Deletion of Wls, a cargo receptor mediating Wnt ligand secretion, in the embryonic endoderm using ShhCre mice inhibited formation of tracheal-bronchial cartilaginous rings. The normal dorsal-ventral patterning of tracheal mesenchyme was lost. Smooth muscle cells, identified by Acta2 staining, were aberrantly located in ventral mesenchyme of the trachea, normally the region of Sox9 expression in cartilage progenitors. Wnt/\u03b2-catenin activity, indicated by Axin2 LacZ reporter, was decreased in tracheal mesenchyme of Wls(f/f);Shh(Cre/+) embryos. Proliferation of chondroblasts was decreased and reciprocally, proliferation of smooth muscle cells was increased in Wls(f/f);Shh(Cre/+) tracheal tissue. Expression of Tbx4, Tbx5, Msx1 and Msx2, known to mediate cartilage and muscle patterning, were decreased in tracheal mesenchyme of Wls(f/f);Shh(Cre/+) embryos. Ex vivo studies demonstrated that Wnt7b and Wnt5a, expressed by the epithelium of developing trachea, and active Wnt/\u03b2-catenin signaling are required for tracheal chondrogenesis before formation of mesenchymal condensations. In conclusion, Wnt ligands produced by the tracheal epithelium pattern the tracheal mesenchyme via modulation of gene expression and cell proliferation required for proper tracheal cartilage and smooth muscle differentiation.", "year": "2015", "month": "09", "volume": "405", "issue": "1", "pages": "56-70", "doi": "10.1016/j.ydbio.2015.06.009", "link": "https://www.ncbi.nlm.nih.gov/pubmed/26093309", "sort_key": "2015-09-endodermal wnt signa", "quarter": "q3"}, {"pmid": "26400819", "title": "De novo ChIP-seq analysis.", "authors": ["He X", "Cicek AE", "Wang Y", "Schulz MH", "Le HS", "Bar-Joseph Z"], "journal": "Genome Biol", "journal_title": "Genome biology", "citation": "Genome biology, 09 2015", "abstract": "Methods for the analysis of chromatin immunoprecipitation sequencing (ChIP-seq) data start by aligning the short reads to a reference genome. While often successful, they are not appropriate for cases where a reference genome is not available. Here we develop methods for de novo analysis of ChIP-seq data. Our methods combine de novo assembly with statistical tests enabling motif discovery without the use of a reference genome. We validate the performance of our method using human and mouse data. Analysis of fly data indicates that our method outperforms alignment based methods that utilize closely related species.", "year": "2015", "month": "09", "volume": "16", "issue": "1", "pages": "205", "doi": "10.1186/s13059-015-0756-4", "link": "https://www.ncbi.nlm.nih.gov/pubmed/26400819", "sort_key": "2015-09-de novo chip-seq ana", "quarter": "q3"}, {"pmid": "25808019", "title": "Acute kidney injury is associated with bronchopulmonary dysplasia/mortality in premature infants.", "authors": ["Askenazi D", "Patil NR", "Ambalavanan N", "Balena-Borneman J", "Lozano DJ", "Ramani M", "Collins M", "Griffin RL"], "journal": "Pediatr Nephrol", "journal_title": "Pediatric nephrology (Berlin, Germany)", "citation": "Pediatric nephrology (Berlin, Germany), 09 2015", "abstract": "BACKGROUND: Acute kidney injury (AKI) impairs electrolyte balance, alters fluid homeostasis and decreases toxin excretion. More recent data suggest it also affects the physiology of distant organs. METHODS: We performed a prospective cohort study which invloved 122 premature infants [birth weight (BW) \u22641200 g and/or gestational age (GA) <31 weeks] to determine relationships between AKI and bronchopulmonary dysplasia (BPD)/mortality. Days until oxygen discontinuation was compared between those with and without AKI in survivors who received oxygen for \u226524 h. RESULTS: Acute kidney disease, defined by a rise in serum creatinine (SCr) of \u22650.3 mg/dl or an increase in SCr of \u2265150%, occurred in 36/122 (30%) of the premature infants. Those with AKI had a 70% higher risk of oxygen requirement or of dying at 28 days of life [relative risk (RR) 1.71, 95% confidence interval (CI) 1.22-2.39; p < 0.002]. This association remained after controlling for GA, pre-eclampsia, 5 min Apgar score and percentage maximum weight change (max % weight \u0394) in the first 4 days (RR 1.45, 95% CI 1.07-1.97); p < 0.02). Similar findings were noted for receipt of mechanical ventilation/death by day 28 (adjusted RR 1.53, 95% CI 1.05-2.22; p < 0.03). Those without AKI were 2.5-fold more likely to come off oxygen [hazard ratio (HR) 1.3-5; p < 0.02) than those with AKI, even when controlling for GA, pre-eclampsia, 5 min Apgar and max % weight \u0394 (multivariate HR 2.0, 95% CI 0.9-4.0; p < 0.06). CONCLUSIONS: In premature infants, AKI is associated with BPD/mortality. As AKI could lead to altered lung physiology, interventions to ameliorate AKI could improve long-term BPD.", "year": "2015", "month": "09", "volume": "30", "issue": "9", "pages": "1511-8", "doi": "10.1007/s00467-015-3087-5", "link": "https://www.ncbi.nlm.nih.gov/pubmed/25808019", "sort_key": "2015-09-acute kidney injury ", "quarter": "q3"}, {"pmid": "25932959", "title": "Alveolar development and disease.", "authors": ["Whitsett JA", "Weaver TE"], "journal": "Am J Respir Cell Mol Biol", "journal_title": "American journal of respiratory cell and molecular biology", "citation": "American journal of respiratory cell and molecular biology, 07 2015", "abstract": "Gas exchange after birth is entirely dependent on the remarkable architecture of the alveolus, its formation and function being mediated by the interactions of numerous cell types whose precise positions and activities are controlled by a diversity of signaling and transcriptional networks. In the later stages of gestation, alveolar epithelial cells lining the peripheral lung saccules produce increasing amounts of surfactant lipids and proteins that are secreted into the airspaces at birth. The lack of lung maturation and the associated lack of pulmonary surfactant in preterm infants causes respiratory distress syndrome, a common cause of morbidity and mortality associated with premature birth. At the time of birth, surfactant homeostasis begins to be established by balanced processes involved in surfactant production, storage, secretion, recycling, and catabolism. Insights from physiology and engineering made in the 20th century enabled survival of newborn infants requiring mechanical ventilation for the first time. Thereafter, advances in biochemistry, biophysics, and molecular biology led to an understanding of the pulmonary surfactant system that made possible exogenous surfactant replacement for the treatment of preterm infants. Identification of surfactant proteins, cloning of the genes encoding them, and elucidation of their roles in the regulation of surfactant synthesis, structure, and function have provided increasing understanding of alveolar homeostasis in health and disease. This Perspective seeks to consider developmental aspects of the pulmonary surfactant system and its importance in the pathogenesis of acute and chronic lung diseases related to alveolar homeostasis.", "year": "2015", "month": "07", "volume": "53", "issue": "1", "pages": "1-7", "doi": "10.1165/rcmb.2015-0128PS", "link": "https://www.ncbi.nlm.nih.gov/pubmed/25932959", "sort_key": "2015-07-alveolar development", "quarter": "q3"}, {"pmid": "25387348", "title": "Alterations in gene expression and DNA methylation during murine and human lung alveolar septation.", "authors": ["Cuna A", "Halloran B", "Faye-Petersen O", "Kelly D", "Crossman DK", "Cui X", "Pandit K", "Kaminski N", "Bhattacharya S", "Ahmad A", "Mariani TJ", "Ambalavanan N"], "journal": "Am J Respir Cell Mol Biol", "journal_title": "American journal of respiratory cell and molecular biology", "citation": "American journal of respiratory cell and molecular biology, 07 2015", "abstract": "DNA methylation, a major epigenetic mechanism, may regulate coordinated expression of multiple genes at specific time points during alveolar septation in lung development. The objective of this study was to identify genes regulated by methylation during normal septation in mice and during disordered septation in bronchopulmonary dysplasia. In mice, newborn lungs (preseptation) and adult lungs (postseptation) were evaluated by microarray analysis of gene expression and immunoprecipitation of methylated DNA followed by sequencing (MeDIP-Seq). In humans, microarray gene expression data were integrated with genome-wide DNA methylation data from bronchopulmonary dysplasia versus preterm and term lung. Genes with reciprocal changes in expression and methylation, suggesting regulation by DNA methylation, were identified. In mice, 95 genes with inverse correlation between expression and methylation during normal septation were identified. In addition to genes known to be important in lung development (Wnt signaling, Angpt2, Sox9, etc.) and its extracellular matrix (Tnc, Eln, etc.), genes involved with immune and antioxidant defense (Stat4, Sod3, Prdx6, etc.) were also observed. In humans, 23 genes were differentially methylated with reciprocal changes in expression in bronchopulmonary dysplasia compared with preterm or term lung. Genes of interest included those involved with detoxifying enzymes (Gstm3) and transforming growth factor-\u03b2 signaling (bone morphogenetic protein 7 [Bmp7]). In terms of overlap, 20 genes and three pathways methylated during mouse lung development also demonstrated changes in methylation between preterm and term human lung. Changes in methylation correspond to altered expression of a number of genes associated with lung development, suggesting that DNA methylation of these genes may regulate normal and abnormal alveolar septation.", "year": "2015", "month": "07", "volume": "53", "issue": "1", "pages": "60-73", "doi": "10.1165/rcmb.2014-0160OC", "link": "https://www.ncbi.nlm.nih.gov/pubmed/25387348", "sort_key": "2015-07-alterations in gene ", "quarter": "q3"}, {"pmid": "25839409", "title": "A novel PI3K inhibitor iMDK suppresses non-small cell lung Cancer cooperatively with A MEK inhibitor.", "authors": ["Ishida N", "Fukazawa T", "Maeda Y", "Yamatsuji T", "Kato K", "Matsumoto K", "Shimo T", "Takigawa N", "Whitsett JA", "Naomoto Y"], "journal": "Exp Cell Res", "journal_title": "Experimental cell research", "citation": "Experimental cell research, 07 2015", "abstract": "The PI3K-AKT pathway is expected to be a therapeutic target for non-small cell lung cancer (NSCLC) treatment. We previously reported that a novel PI3K inhibitor iMDK suppressed NSCLC cells in vitro and in vivo without harming normal cells and mice. Unexpectedly, iMDK activated the MAPK pathway, including ERK, in the NSCLC cells. Since iMDK did not eradicate such NSCLC cells completely, it is possible that the activated MAPK pathway confers resistance to the NSCLC cells against cell death induced by iMDK. In the present study, we assessed whether suppressing of iMDK-mediated activation of the MAPK pathway would enhance anti-tumorigenic activity of iMDK. PD0325901, a MAPK inhibitor, suppressed the MAPK pathway induced by iMDK and cooperatively inhibited cell viability and colony formation of NSCLC cells by inducing apoptosis in vitro. HUVEC tube formation, representing angiogenic processes in vitro, was also cooperatively inhibited by the combinatorial treatment of iMDK and PD0325901. The combinatorial treatment of iMDK with PD0325901 cooperatively suppressed tumor growth and tumor-associated angiogenesis in a lung cancer xenograft model in vivo. Here, we demonstrate a novel treatment strategy using iMDK and PD0325901 to eradicate NSCLC.", "year": "2015", "month": "07", "volume": "335", "issue": "2", "pages": "197-206", "doi": "10.1016/j.yexcr.2015.03.019", "link": "https://www.ncbi.nlm.nih.gov/pubmed/25839409", "sort_key": "2015-07-a novel pi3k inhibit", "quarter": "q3"}, {"pmid": "25727890", "title": "Mesenchymal Wnt signaling promotes formation of sternum and thoracic body wall.", "authors": ["Snowball J", "Ambalavanan M", "Cornett B", "Lang R", "Whitsett J", "Sinner D"], "journal": "Dev Biol", "journal_title": "Developmental biology", "citation": "Developmental biology, 05 2015", "abstract": "Midline defects account for approximately 5% of congenital abnormalities observed at birth. However, the molecular mechanisms underlying the formation of the ventral body wall are not well understood. Recent studies linked mutations in Porcupine-an O-acetyl transferase mediating Wnt ligand acylation-with defects in the thoracic body wall. We hypothesized that anomalous Wnt signaling is involved in the pathogenesis of defective closure of the thoracic body wall. We generated a mouse model wherein Wntless (Wls), which encodes a cargo receptor mediating secretion of Wnt ligands, was conditionally deleted from the developing mesenchyme using Dermo1Cre mice. Wls(f/f);Dermo1(Cre/+) embryos died during mid-gestation. At E13.5, skeletal defects were observed in the forelimbs, jaw, and rib cage. At E14.5, midline defects in the thoracic body wall began to emerge: the sternum failed to fuse and the heart protruded through the body wall at the midline (ectopia cordis). To determine the molecular mechanism underlying the phenotype observed in Wls(f/f);Dermo1(Cre/+) embryos, we tested whether Wnt/\u03b2-catenin signaling was operative in developing the embryonic ventral body wall using Axin2(LacZ) and BatGal reporter mice. While Wnt/\u03b2-catenin signaling activity was observed at the midline of the ventral body wall before sternal fusion, this pattern of activity was altered and scattered throughout the body wall after mesenchymal deletion of Wls. Mesenchymal cell migration was disrupted in Wls(f/f);Dermo1(Cre/+) thoracic body wall partially due to anomalous \u03b2-catenin independent Wnt signaling as determined by in vitro assays. Deletion of Lrp5 and Lrp6 receptors, which mediate Wnt/\u03b2-catenin signaling in the mesenchyme, partially recapitulated the phenotype observed in the chest midline of Wls(f/f);Dermo1(Cre/+) embryos supporting a role for Wnt/\u03b2-catenin signaling activity in the normal formation of the ventral body wall mesenchyme. We conclude that Wls-mediated secretion of Wnt ligands from the developing ventral body wall mesenchyme plays a critical role in fusion of the sternum and closure of the secondary body wall. Thus, impaired Wls activity in the ventral body wall mesenchyme is a mechanism underlying ectopia cordis and unfused sternum.", "year": "2015", "month": "05", "volume": "401", "issue": "2", "pages": "264-75", "doi": "10.1016/j.ydbio.2015.02.014", "link": "https://www.ncbi.nlm.nih.gov/pubmed/25727890", "sort_key": "2015-05-mesenchymal wnt sign", "quarter": "q2"}, {"pmid": "25275225", "title": "Foxm1 regulates resolution of hyperoxic lung injury in newborns.", "authors": ["Xia H", "Ren X", "Bolte CS", "Ustiyan V", "Zhang Y", "Shah TA", "Kalin TV", "Whitsett JA", "Kalinichenko VV"], "journal": "Am J Respir Cell Mol Biol", "journal_title": "American journal of respiratory cell and molecular biology", "citation": "American journal of respiratory cell and molecular biology, 05 2015", "abstract": "Current treatments for inflammation associated with bronchopulmonary dysplasia (BPD) fail to show clinical efficacy. Foxm1, a transcription factor of the Forkhead box family, is a critical mediator of lung development and carcinogenesis, but its role in BPD-associated pulmonary inflammation is unknown. Immunohistochemistry and RNA analysis were used to assess Foxm1 in lung tissue from hyperoxia-treated mice and patients with BPD. LysM-Cre/Foxm1(-/-) mice, in which Foxm1 was deleted from myeloid-derived inflammatory cells, including macrophages, monocytes, and neutrophils, were exposed to neonatal hyperoxia, causing lung injury and remodeling. Measurements of lung function and flow cytometry were used to evaluate the effects of Foxm1 deletion on pulmonary inflammation and repair. Increased Foxm1 expression was observed in pulmonary macrophages of hyperoxia-exposed mice and in lung tissue from patients with BPD. After hyperoxia, deletion of Foxm1 from the myeloid cell lineage decreased numbers of interstitial macrophages (CD45(+)CD11b(+)Ly6C(-)Ly6G(-)F4/80(+)CD68(-)) and impaired alveologenesis and lung function. The exaggerated BPD-like phenotype observed in hyperoxia-exposed LysM-Cre/Foxm1(-/-) mice was associated with increased expression of neutrophil-derived myeloperoxidase, proteinase 3, and cathepsin g, all of which are critical for lung remodeling and inflammation. Our data demonstrate that Foxm1 influences pulmonary inflammatory responses to hyperoxia, inhibiting neutrophil-derived enzymes and enhancing monocytic responses that limit alveolar injury and remodeling in neonatal lungs.", "year": "2015", "month": "05", "volume": "52", "issue": "5", "pages": "611-21", "doi": "10.1165/rcmb.2014-0091OC", "link": "https://www.ncbi.nlm.nih.gov/pubmed/25275225", "sort_key": "2015-05-foxm1 regulates reso", "quarter": "q2"}, {"pmid": "25866971", "title": "Airway epithelial SPDEF integrates goblet cell differentiation and pulmonary Th2 inflammation.", "authors": ["Rajavelu P", "Chen G", "Xu Y", "Kitzmiller JA", "Korfhagen TR", "Whitsett JA"], "journal": "J Clin Invest", "journal_title": "The Journal of clinical investigation", "citation": "The Journal of clinical investigation, 05 2015", "abstract": "Epithelial cells that line the conducting airways provide the initial barrier and innate immune responses to the abundant particles, microbes, and allergens that are inhaled throughout life. The transcription factors SPDEF and FOXA3 are both selectively expressed in epithelial cells lining the conducting airways, where they regulate goblet cell differentiation and mucus production. Moreover, these transcription factors are upregulated in chronic lung disorders, including asthma. Here, we show that expression of SPDEF or FOXA3 in airway epithelial cells in neonatal mice caused goblet cell differentiation, spontaneous eosinophilic inflammation, and airway hyperresponsiveness to methacholine. SPDEF expression promoted DC recruitment and activation in association with induction of Il33, Csf2, thymic stromal lymphopoietin (Tslp), and Ccl20 transcripts. Increased Il4, Il13, Ccl17, and Il25 expression was accompanied by recruitment of Th2 lymphocytes, group 2 innate lymphoid cells, and eosinophils to the lung. SPDEF was required for goblet cell differentiation and pulmonary Th2 inflammation in response to house dust mite (HDM) extract, as both were decreased in neonatal and adult Spdef(-/-) mice compared with control animals. Together, our results indicate that SPDEF causes goblet cell differentiation and Th2 inflammation during postnatal development and is required for goblet cell metaplasia and normal Th2 inflammatory responses to HDM aeroallergen.", "year": "2015", "month": "05", "volume": "125", "issue": "5", "pages": "2021-31", "doi": "10.1172/JCI79422", "link": "https://www.ncbi.nlm.nih.gov/pubmed/25866971", "sort_key": "2015-05-airway epithelial sp", "quarter": "q2"}, {"pmid": "25449221", "title": "Integrated genomic analyses in bronchopulmonary dysplasia.", "authors": ["Ambalavanan N", "Cotten CM", "Page GP", "Carlo WA", "Murray JC", "Bhattacharya S", "Mariani TJ", "Cuna AC", "Faye-Petersen OM", "Kelly D", "Higgins RD", "Genomics and Cytokine Subcommittees of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network"], "journal": "J Pediatr", "journal_title": "The Journal of pediatrics", "citation": "The Journal of pediatrics, 03 2015", "abstract": "OBJECTIVE: To identify single-nucleotide polymorphisms (SNPs) and pathways associated with bronchopulmonary dysplasia (BPD) because O2 requirement at 36 weeks' postmenstrual age risk is strongly influenced by heritable factors. STUDY DESIGN: A genome-wide scan was conducted on 1.2 million genotyped SNPs, and an additional 7 million imputed SNPs, using a DNA repository of extremely low birth weight infants. Genome-wide association and gene set analysis was performed for BPD or death, severe BPD or death, and severe BPD in survivors. Specific targets were validated via the use of gene expression in BPD lung tissue and in mouse models. RESULTS: Of 751 infants analyzed, 428 developed BPD or died. No SNPs achieved genome-wide significance (P < 10(-8)), although multiple SNPs in adenosine deaminase, CD44, and other genes were just below P < 10(-6). Of approximately 8000 pathways, 75 were significant at false discovery rate (FDR) <0.1 and P < .001 for BPD/death, 95 for severe BPD/death, and 90 for severe BPD in survivors. The pathway with lowest FDR was miR-219 targets (P = 1.41E-08, FDR 9.5E-05) for BPD/death and phosphorous oxygen lyase activity (includes adenylate and guanylate cyclases) for both severe BPD/death (P = 5.68E-08, FDR 0.00019) and severe BPD in survivors (P = 3.91E-08, FDR 0.00013). Gene expression analysis confirmed significantly increased miR-219 and CD44 in BPD. CONCLUSIONS: Pathway analyses confirmed involvement of known pathways of lung development and repair (CD44, phosphorus oxygen lyase activity) and indicated novel molecules and pathways (adenosine deaminase, targets of miR-219) involved in genetic predisposition to BPD.", "year": "2015", "month": "03", "volume": "166", "issue": "3", "pages": "531-7.e13", "doi": "10.1016/j.jpeds.2014.09.052", "link": "https://www.ncbi.nlm.nih.gov/pubmed/25449221", "sort_key": "2015-03-integrated genomic a", "quarter": "q1"}, {"pmid": "25480985", "title": "Hippo/Yap signaling controls epithelial progenitor cell proliferation and differentiation in the embryonic and adult lung.", "authors": ["Lange AW", "Sridharan A", "Xu Y", "Stripp BR", "Perl AK", "Whitsett JA"], "journal": "J Mol Cell Biol", "journal_title": "Journal of molecular cell biology", "citation": "Journal of molecular cell biology, 02 2015", "abstract": "The Hippo/Yap pathway is a well-conserved signaling cascade that regulates cell proliferation and differentiation to control organ size and stem/progenitor cell behavior. Following airway injury, Yap was dynamically regulated in regenerating airway epithelial cells. To determine the role of Hippo signaling in the lung, the mammalian Hippo kinases, Mst1 and Mst2, were deleted in epithelial cells of the embryonic and mature mouse lung. Mst1/2 deletion in the fetal lung enhanced proliferation and inhibited sacculation and epithelial cell differentiation. The transcriptional inhibition of cell proliferation and activation of differentiation during normal perinatal lung maturation were inversely regulated following embryonic Mst1/2 deletion. Ablation of Mst1/2 from bronchiolar epithelial cells in the adult lung caused airway hyperplasia and altered differentiation. Inhibitory Yap phosphorylation was decreased and Yap nuclear localization and transcriptional targets were increased after Mst1/2 deletion, consistent with canonical Hippo/Yap signaling. YAP potentiated cell proliferation and inhibited differentiation of human bronchial epithelial cells in vitro. Loss of Mst1/2 and expression of YAP regulated transcriptional targets controlling cell proliferation and differentiation, including Ajuba LIM protein. Ajuba was required for the effects of YAP on cell proliferation in vitro. Hippo/Yap signaling regulates Ajuba and controls proliferation and differentiation of lung epithelial progenitor cells.", "year": "2015", "month": "02", "volume": "7", "issue": "1", "pages": "35-47", "doi": "10.1093/jmcb/mju046", "link": "https://www.ncbi.nlm.nih.gov/pubmed/25480985", "sort_key": "2015-02-hippo/yap signaling ", "quarter": "q1"}, {"pmid": "25521682", "title": "Respiratory epithelial cells orchestrate pulmonary innate immunity.", "authors": ["Whitsett JA", "Alenghat T"], "journal": "Nat Immunol", "journal_title": "Nature immunology", "citation": "Nature immunology, 01 2015", "abstract": "The epithelial surfaces of the lungs are in direct contact with the environment and are subjected to dynamic physical forces as airway tubes and alveoli are stretched and compressed during ventilation. Mucociliary clearance in conducting airways, reduction of surface tension in the alveoli, and maintenance of near sterility have been accommodated by the evolution of a multi-tiered innate host-defense system. The biophysical nature of pulmonary host defenses are integrated with the ability of respiratory epithelial cells to respond to and 'instruct' the professional immune system to protect the lungs from infection and injury.", "year": "2015", "month": "01", "volume": "16", "issue": "1", "pages": "27-35", "doi": "10.1038/ni.3045", "link": "https://www.ncbi.nlm.nih.gov/pubmed/25521682", "sort_key": "2015-01-respiratory epitheli", "quarter": "q1"}, {"pmid": "25621661", "title": "Diseases of pulmonary surfactant homeostasis.", "authors": ["Whitsett JA", "Wert SE", "Weaver TE"], "journal": "Annu Rev Pathol", "journal_title": "Annual review of pathology", "citation": "Annual review of pathology, 2015", "abstract": "Advances in physiology and biochemistry have provided fundamental insights into the role of pulmonary surfactant in the pathogenesis and treatment of preterm infants with respiratory distress syndrome. Identification of the surfactant proteins, lipid transporters, and transcriptional networks regulating their expression has provided the tools and insights needed to discern the molecular and cellular processes regulating the production and function of pulmonary surfactant prior to and after birth. Mutations in genes regulating surfactant homeostasis have been associated with severe lung disease in neonates and older infants. Biophysical and transgenic mouse models have provided insight into the mechanisms underlying surfactant protein and alveolar homeostasis. These studies have provided the framework for understanding the structure and function of pulmonary surfactant, which has informed understanding of the pathogenesis of diverse pulmonary disorders previously considered idiopathic. This review considers the pulmonary surfactant system and the genetic causes of acute and chronic lung disease caused by disruption of alveolar homeostasis.", "year": "2015", "month": "", "volume": "10", "issue": "", "pages": "371-93", "doi": "10.1146/annurev-pathol-012513-104644", "link": "https://www.ncbi.nlm.nih.gov/pubmed/25621661", "sort_key": "2015-00-diseases of pulmonar", "quarter": "q0"}, {"pmid": "25522349", "title": "Multitask learning of signaling and regulatory networks with application to studying human response to flu.", "authors": ["Jain S", "Gitter A", "Bar-Joseph Z"], "journal": "PLoS Comput Biol", "journal_title": "PLoS computational biology", "citation": "PLoS computational biology, 12 2014", "abstract": "Reconstructing regulatory and signaling response networks is one of the major goals of systems biology. While several successful methods have been suggested for this task, some integrating large and diverse datasets, these methods have so far been applied to reconstruct a single response network at a time, even when studying and modeling related conditions. To improve network reconstruction we developed MT-SDREM, a multi-task learning method which jointly models networks for several related conditions. In MT-SDREM, parameters are jointly constrained across the networks while still allowing for condition-specific pathways and regulation. We formulate the multi-task learning problem and discuss methods for optimizing the joint target function. We applied MT-SDREM to reconstruct dynamic human response networks for three flu strains: H1N1, H5N1 and H3N2. Our multi-task learning method was able to identify known and novel factors and genes, improving upon prior methods that model each condition independently. The MT-SDREM networks were also better at identifying proteins whose removal affects viral load indicating that joint learning can still lead to accurate, condition-specific, networks. Supporting website with MT-SDREM implementation: http://sb.cs.cmu.edu/mtsdrem.", "year": "2014", "month": "12", "volume": "10", "issue": "12", "pages": "e1003943", "doi": "10.1371/journal.pcbi.1003943", "link": "https://www.ncbi.nlm.nih.gov/pubmed/25522349", "sort_key": "2014-12-multitask learning o", "quarter": "q4"}]

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