Searskring0642

Mucosal surfaces are constantly exposed to a microbiome consisting of microorganisms that heavily influence human immunity and health. In the lung these microorganisms consist of bacteria, viruses, and fungi and exist in a relatively low biomass state. Bacterial communities of the lung modulate local inflammation and correlate with changes in pulmonary physiology and clinical outcomes in patients with lung disease. Instrumental to this progress has been the study of these bacterial communities in the pathogenesis of pulmonary fibrosis, a fatal and progressive disease culminating in respiratory failure. Key pathophysiological mechanisms in pulmonary fibrosis include recurrent idiopathic alveolar epithelial injury, unchecked collagen deposition, mucociliary dysfunction due to muc5b overexpression, hypoxia, and altered host defense. These key mechanisms and their related consequences promote severe progressive architectural lung destruction and loss of local homeostasis. As such, pulmonary fibrosis is an appropriate target disease for the study of the lung microbiome. Herein, we discuss recent advances in our understanding of the role of the lung microbiome in the pathogenesis of pulmonary fibrosis. We highlight fundamental clinical observations and mechanistic insights and identify crucial areas for further discovery science. An improved understanding of how the lung microbiome acts to influence outcomes in patients with pulmonary fibrosis will lead to enhanced therapies for this devastating lung disease.Severe acute pancreatitis (SAP) includes persistent systemic inflammation (SIRS) and multiorgan failure (MOF). The mechanism of transition from SIRS to MOF is unclear. We developed a fluid compartment model and used clinical data to test predictions. The model includes vascular, interstitial and "third-space" compartments with variable permeability of plasma proteins at the capillaries. Consented patients from University of Pittsburgh Medical Center Presbyterian Hospital were studied. Preadmission and daily hematocrit (HCT), blood urea nitrogen (BUN), creatine (Cr), albumin (Alb), and total protein (TP) were collected, and nonalbumin plasma protein (NAPP = TP minus the Alb) was calculated. Subjects served as their own controls for trajectory analysis. Of 57 SAP subjects, 18 developed MOF (5 died), and 39 were non-MOF (0 died). Compared with preadmission levels, admission HCT increased in MOF +5.00 [25%-75% interquartile range, IQR] versus non-MOF -0.10 [-1.55, 1.40] (P +3 distinguishing MOF from non-MOF (oddnew mechanistic model, we compared patients with severe acute pancreatitis with or without multiorgan failure. All biomarkers of capillary leak and clinical features of multiorgan failure were accurately predicted. This provides a new paradigm for understanding and developing new treatments for patients with severe acute pancreatitis.Portal and hepatic circulation can now be safely accessed using endoscopic ultrasound (EUS). EUS-guided needle access of the portal vein is performed clinically at select tertiary centers for measurement of portal pressure gradients in patients with chronic liver disease and sampling of portal venous thrombus to diagnose malignancy. We propose that this novel clinical technique can be applied in research studies to allow blood collection from and profiling of portal and hepatic circulation. In this technical report, we present and highlight the technical aspects, feasibility, and safety of EUS guided portal venous blood collection. As a proof of the concept and the utility of this technique in metabolic research and biomarker assessment and discovery, we present a pilot metabolite profiling study of portal venous blood in a small cohort of patients with cirrhosis and a comparison with a group without cirrhosis. Despite the very small diameter of the endoscopic needle used for the blood collection, the portal nd discovery, we present a pilot metabolite profiling study of portal venous blood in a small cohort of patients with cirrhosis and a comparison with a group without cirrhosis.The first contractile waves in the developing embryonic gut are purely myogenic; they only involve smooth muscle. Here, we provide evidence for a transition from smooth muscle to interstitial cell of Cajal (ICC)-driven contractile waves in the developing chicken gut. In situ hybridization staining for anoctamin-1 (ANO1), a known ICC marker, shows that ICCs are already present throughout the gut, as from embryonic day (E)7. We devised a protocol to reveal ICC oscillatory and propagative calcium activity in embryonic gut whole mount and found that the first steady calcium oscillations in ICCs occur on (E14). We show that the activation of ICCs leads to an increase in contractile wave frequency, regularity, directionality, and velocity between E12 and E14. We finally demonstrate that application of the c-KIT antagonist imatinib mesylate in organ culture specifically depletes the ICC network and inhibits the transition to a regular rhythmic wave pattern. We compare our findings to existing results in the mouse and predict that a similar transition should take place in the human fetus between 12 and 14 wk of development. Together, our results point to an abrupt physiological transition from smooth muscle mesenchyme self-initiating waves to ICC-driven motility in the fetus and clarify the contribution of ICCs to the contractile wave pattern.NEW & NOTEWORTHY We reveal a sharp transition from smooth muscle to interstitial cell of Cajal (ICC)-driven motility in the chicken embryo, leading to higher-frequency, more rhythmic contractile waves. We predict the transition to happen between 12 and 14 embryonic wk in humans. We image for the first time the onset of ICC activity in an embryonic gut by calcium imaging. We show the first KIT and anoctamin-1 (ANO1) in situ hybridization micrographs in the embryonic chicken gut.Tendon is a dense connective tissue that stores and transmits forces between muscles and bones. Cellular heterogeneity is increasingly recognized as an important factor in the biological basis of tissue homeostasis and disease, yet little is known about the diversity of cell types that populate tendon. To address this, we determined the heterogeneity of cell populations within mouse Achilles tendons using single-cell RNA sequencing. In assembling a transcriptomic atlas of Achilles tendons, we identified 11 distinct types of cells, including three previously undescribed populations of tendon fibroblasts. Prior studies have indicated that pericytes, which are found in the vasculature of tendons, could serve as a potential source of progenitor cells for adult tendon fibroblasts. Using trajectory inference analysis, we provide additional support for the notion that pericytes are likely to be at least one of the progenitor cell populations for the fibroblasts that compose adult tendons. Glumetinib in vitro We also modeled cell-cell interactions and identified previously undescribed ligand-receptor signaling interactions involved in tendon homeostasis.