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The European Respiratory Journal Dec 2022SARS-CoV-2 has caused devastating effects with over 550 million infections by July 2022 and approximately 6.4 million deaths [1]. Societal and economic impacts will...
SARS-CoV-2 has caused devastating effects with over 550 million infections by July 2022 and approximately 6.4 million deaths [1]. Societal and economic impacts will reverberate for years, with continuous evolution of SARS-CoV-2 as it persistently spreads through the human population as exemplified by reduced activity of vaccines and monoclonals against Omicron BA.4 or BA.5 subvariants [2]. A greater understanding of pathogenesis and more tailored therapeutic approaches are therefore essential.
Topics: Humans; SARS-CoV-2; COVID-19; Angiotensin-Converting Enzyme 2; Permissiveness; Lung; Inflammation; Macrophages
PubMed: 36028257
DOI: 10.1183/13993003.01521-2022 -
Science Translational Medicine Dec 2023Tobacco smoking doubles the risk of active tuberculosis (TB) and accounts for up to 20% of all active TB cases globally. How smoking promotes lung microenvironments...
Tobacco smoking doubles the risk of active tuberculosis (TB) and accounts for up to 20% of all active TB cases globally. How smoking promotes lung microenvironments permissive to () growth remains incompletely understood. We investigated primary bronchoalveolar lavage cells from current and never smokers by performing single-cell RNA sequencing (scRNA-seq), flow cytometry, and functional assays. We observed the enrichment of immature inflammatory monocytes in the lungs of smokers compared with nonsmokers. These monocytes exhibited phenotypes consistent with recent recruitment from blood, ongoing differentiation, increased activation, and states similar to those with chronic obstructive pulmonary disease. Using integrative scRNA-seq and flow cytometry, we identified CD93 as a marker for a subset of these newly recruited smoking-associated lung monocytes and further provided evidence that the recruitment of monocytes into the lung was mediated by CCR2-binding chemokines, including CCL11. We also show that these cells exhibit elevated inflammatory responses upon exposure to and accelerated intracellular growth of compared with mature macrophages. This elevated growth could be inhibited by anti-inflammatory small molecules, providing a connection between smoking-induced pro-inflammatory states and permissiveness to growth. Our findings suggest a model in which smoking leads to the recruitment of immature inflammatory monocytes from the periphery to the lung, which results in the accumulation of these -permissive cells in the airway. This work defines how smoking may lead to increased susceptibility to and identifies host-directed therapies to reduce the burden of TB among those who smoke.
Topics: Humans; Monocytes; Mycobacterium tuberculosis; Tobacco Smoke Pollution; Macrophages; Tuberculosis; Lung
PubMed: 38055798
DOI: 10.1126/scitranslmed.adg3451 -
Intensive Care Medicine Jun 2022
Topics: Acidosis; Acidosis, Respiratory; Humans; Hypercapnia
PubMed: 35441850
DOI: 10.1007/s00134-022-06696-z -
Advances in Surgery Sep 2019
Review
Topics: Advanced Trauma Life Support Care; Blood Coagulation Disorders; Emergency Medical Services; Emergency Medical Technicians; Hemostatic Techniques; Humans; Inservice Training; Patient Care Team; Resuscitation; Shock, Hemorrhagic; Time-to-Treatment; Transportation of Patients; Wounds and Injuries
PubMed: 31327449
DOI: 10.1016/j.yasu.2019.04.010 -
Mucosal Immunology Aug 2023Astroviruses cause a spectrum of diseases spanning asymptomatic infections to severe diarrhea, but little is understood about their pathogenesis. We previously...
Astroviruses cause a spectrum of diseases spanning asymptomatic infections to severe diarrhea, but little is understood about their pathogenesis. We previously determined that small intestinal goblet cells were the main cell type infected by murine astrovirus-1. Here, we focused on the host immune response to infection and inadvertently discovered a role for indoleamine 2,3-dioxygenase 1 (Ido1), a host tryptophan catabolizing enzyme, in the cellular tropism of murine and human astroviruses. We identified that Ido1 expression was highly enriched among infected goblet cells, and spatially corresponded to the zonation of infection. Because Ido1 can act as a negative regulator of inflammation, we hypothesized it could dampen host antiviral responses. Despite robust interferon signaling in goblet cells, as well as tuft cell and enterocyte bystanders, we observed delayed cytokine induction and suppressed levels of fecal lipocalin-2. Although we found Ido animals were more resistant to infection, this was not associated with fewer goblet cells nor could it be rescued by knocking out interferon responses, suggesting that IDO1 instead regulates cell permissivity. We characterized IDO1 Caco-2 cells and observed significantly reduced human astrovirus-1 infection. Together this study highlights a role for Ido1 in astrovirus infection and epithelial cell maturation.
Topics: Animals; Humans; Mice; Astroviridae Infections; Caco-2 Cells; Indoleamine-Pyrrole 2,3,-Dioxygenase; Interferons; Tryptophan
PubMed: 37290501
DOI: 10.1016/j.mucimm.2023.05.011 -
Intensive Care Medicine Experimental Jul 2019The biological effects and physiological consequences of hypercapnia are increasingly understood. The literature on hypercapnia is confusing, and at times contradictory.... (Review)
Review
The biological effects and physiological consequences of hypercapnia are increasingly understood. The literature on hypercapnia is confusing, and at times contradictory. On the one hand, it may have protective effects through attenuation of pulmonary inflammation and oxidative stress. On the other hand, it may also have deleterious effects through inhibition of alveolar wound repair, reabsorption of alveolar fluid, and alveolar cell proliferation. Besides, hypercapnia has meaningful effects on lung physiology such as airway resistance, lung oxygenation, diaphragm function, and pulmonary vascular tree.In acute respiratory distress syndrome, lung-protective ventilation strategies using low tidal volume and low airway pressure are strongly advocated as these have strong potential to improve outcome. These strategies may come at a price of hypercapnia and hypercapnic acidosis. One approach is to accept it (permissive hypercapnia); another approach is to treat it through extracorporeal means. At present, it remains uncertain what the best approach is.
PubMed: 31346806
DOI: 10.1186/s40635-019-0239-0 -
Pediatric Research Apr 2022There is no consensus on the optimal pCO levels in the newborn. We reviewed the effects of hypercapnia and hypocapnia and existing carbon dioxide thresholds in neonates.... (Review)
Review
There is no consensus on the optimal pCO levels in the newborn. We reviewed the effects of hypercapnia and hypocapnia and existing carbon dioxide thresholds in neonates. A systematic review was conducted in accordance with the PRISMA statement and MOOSE guidelines. Two hundred and ninety-nine studies were screened and 37 studies included. Covidence online software was employed to streamline relevant articles. Hypocapnia was associated with predominantly neurological side effects while hypercapnia was linked with neurological, respiratory and gastrointestinal outcomes and Retinpathy of prematurity (ROP). Permissive hypercapnia did not decrease periventricular leukomalacia (PVL), ROP, hydrocephalus or air leaks. As safe pCO ranges were not explicitly concluded in the studies chosen, it was indirectly extrapolated with reference to pCO levels that were found to increase the risk of neonatal disease. Although PaCO ranges were reported from 2.6 to 8.7 kPa (19.5-64.3 mmHg) in both term and preterm infants, there are little data on the safety of these ranges. For permissive hypercapnia, parameters described for bronchopulmonary dysplasia (BPD; PaCO 6.0-7.3 kPa: 45.0-54.8 mmHg) and congenital diaphragmatic hernia (CDH; PaCO ≤ 8.7 kPa: ≤65.3 mmHg) were identified. Contradictory findings on the effectiveness of permissive hypercapnia highlight the need for further data on appropriate CO parameters and correlation with outcomes. IMPACT: There is no consensus on the optimal pCO levels in the newborn. There is no consensus on the effectiveness of permissive hypercapnia in neonates. A safe range of pCO of 5-7 kPa was inferred following systematic review.
Topics: Carbon Dioxide; Humans; Hypercapnia; Hypocapnia; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Respiration, Artificial
PubMed: 34230621
DOI: 10.1038/s41390-021-01473-y -
Nucleic Acids Research Oct 2023Arginine methylation, catalyzed by the protein arginine methyltransferases (PRMTs), is a common post-translational protein modification (PTM) that is engaged in a...
Arginine methylation, catalyzed by the protein arginine methyltransferases (PRMTs), is a common post-translational protein modification (PTM) that is engaged in a plethora of biological events. However, little is known about how the methylarginine-directed signaling functions in germline development. In this study, we discover that Prmt1 is predominantly distributed in the nuclei of spermatogonia but weakly in the spermatocytes throughout mouse spermatogenesis. By exploiting a combination of three Cre-mediated Prmt1 knockout mouse lines, we unravel that Prmt1 is essential for spermatogonial establishment and maintenance, and that Prmt1-catalyzed asymmetric methylarginine coordinates inherent transcriptional homeostasis within spermatogonial cells. In conjunction with high-throughput CUT&Tag profiling and modified mini-bulk Smart-seq2 analyses, we unveil that the Prmt1-deposited H4R3me2a mark is permissively enriched at promoter and exon/intron regions, and sculpts a distinctive transcriptomic landscape as well as the alternative splicing pattern, in the mouse spermatogonia. Collectively, our study provides the genetic and mechanistic evidence that connects the Prmt1-deposited methylarginine signaling to the establishment and maintenance of a high-fidelity transcriptomic identity in orchestrating spermatogonial development in the mammalian germline.
Topics: Animals; Male; Mice; Arginine; Epigenome; Fertility; Mammals; Mice, Knockout; Protein-Arginine N-Methyltransferases; Spermatogonia
PubMed: 37739418
DOI: 10.1093/nar/gkad769 -
International Journal of Pharmaceutics Oct 2022In vitro drug release test has become one of the most important tools for drug development and approval process of semisolid dosage forms. In vitro release test (IVRT)... (Review)
Review
In vitro drug release test has become one of the most important tools for drug development and approval process of semisolid dosage forms. In vitro release test (IVRT) has the ability to reflect the combined effects of several physicochemical characteristics, particle or droplet size, viscosity, microstructure arrangement of the matter and state of aggregation of dosage form. Genesis of IVRT, its principles and rank order relationship with pharmacodynamic response such as vasoconstriction or dermatopharmacokinetic (skin stripping) results and the evolution of test requirements for regulatory approval is discussed. IVRT reflects various parameters and is an essential part of the stepwise approach to compare topical formulation and its ability to release active in similar quantity at similar rate. Therefore, it is an essential tool, in addition to similar qualitative and quantitative composition (Q1 Q2), to assess the similarity of microstructural arrangement (Q3) as proposed in the Topical drug Classification System (TCS) approach of classes 1 and 3. The TCS system along with evolving concept for topical dermatological drug products from Q1, Q2, Q3 sameness to Q1, Q2, Q3 similar allowing greater permissiveness in formulation changes is discussed.
Topics: Drug Liberation; In Vitro Techniques
PubMed: 36067919
DOI: 10.1016/j.ijpharm.2022.122159 -
Journal of Virology Sep 2023Oncolytic virus (OV) therapy is a promising virus-based approach against various malignancies, including pancreatic ductal adenocarcinoma (PDAC). Our previous studies...
Oncolytic virus (OV) therapy is a promising virus-based approach against various malignancies, including pancreatic ductal adenocarcinoma (PDAC). Our previous studies demonstrated that human PDAC cell lines are highly variable in their permissiveness to OVs. Mouse PDAC cell lines, which are widely used for examination of the adaptive immune responses during OV and other cancer therapies, have never been examined systematically for the impact of intertumoral heterogeneity (the differences observed between tumors in different patients) on OV virus efficacy. Here, we examined phenotypically and genotypically three commonly used allograftable mouse PDAC cell lines (C57BL6 genetic background): Panc02 (derived from chemically induced PDAC; also known as Pan02), and two cell lines originated from PDACs developed in two different KPC (Kras, Trp53, and PDX-1-Cre) mouse models. Our study (i) characterized the ability of a widely used attenuated oncolytic vesicular stomatitis virus VSV-ΔM51-GFP to infect, replicate in, and kill mouse PDAC cells; (ii) examined their innate antiviral responses; (iii) compared their permissiveness to a non-attenuated VSV-Mwt-GFP and chemotherapeutic drugs; and (iv) analyzed their karyotype and exome. Mouse PDAC cell lines showed high divergence in their permissiveness to VSV-ΔM51-GFP, which negatively correlated with their abilities to mount innate antiviral responses, while all three cell lines were highly permissive to VSV-Mwt-GFP. No correlation was found between resistance to VSV-ΔM51-GFP and chemotherapy. Also, mouse PDAC cell lines showed high divergence in their karyotype and exome. The exome analysis demonstrated that more VSV-ΔM51-GFP-permissive mouse PDAC cell lines harbor mutations in multiple important antiviral genes, such as TYK2, JAK2, and JAK3. IMPORTANCE Oncolytic virus (OV) therapy is a promising virus-based approach against various malignancies, including pancreatic ductal adenocarcinoma (PDAC). Our previous studies using various human PDAC cell lines demonstrated that they are highly variable in their permissiveness to OVs. In this study, we examined phenotypically and genotypically three commonly used allograftable mouse PDAC cell lines, which are widely used for examination of the adaptive immune responses during cancer therapies. Mouse PDAC cell lines showed high divergence in their permissiveness to oncolytic vesicular stomatitis virus (VSV), which negatively correlated with their abilities to mount innate antiviral responses. Also, we discovered that more VSV-permissive mouse PDAC cell lines harbor mutations in multiple important antiviral genes, such as TYK2, JAK2, and JAK3. Our study provides essential information about three model mouse PDAC cell lines and proposes a novel platform to study OV-based therapies against different PDACs in immunocompetent mice.
Topics: Animals; Humans; Mice; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Interferon Type I; Oncolytic Virotherapy; Oncolytic Viruses; Pancreatic Neoplasms; Vesicular stomatitis Indiana virus
PubMed: 37671865
DOI: 10.1128/jvi.01005-23