The Role of Gastrointestinal Dysbiosis and Fecal Transplantation in Various Neurocognitive Disorders.

This review explores the critical role of the human microbiome in neurological and neurodegenerative disorders, focusing on gut-brain axis dysfunction caused by dysbiosis, an imbalance in gut bacteria. Dysbiosis has been linked to diseases such as Alzheimer's disease, Parkinson's disease (PD), multiple sclerosis (MS), and stroke. The gut microbiome influences the central nervous system (CNS) through signaling molecules, including short-chain fatty acids, neurotransmitters, and metabolites, impacting brain health and disease progression.

Population and conservation threats to the vulnerable Sarus crane in Nepal.

Globally, biodiversity is declining due to habitat loss and degradation, over-exploitation, climate change, invasive species, pollution, and infrastructure development. These threats affect the populations of large waterbird species, such as Sarus crane (), which inhabits agricultural-wetland ecosystems. Despite the burgeoning built-up areas and diminishing agricultural and wetland spaces, scant research investigates the impact of these changing land uses on the globally vulnerable Sarus crane in Nepal.

Thrombomodulin: a multifunctional receptor modulating the endothelial quiescence.

Thrombomodulin (TM) is a type 1 receptor best known for its function as an anticoagulant cofactor for thrombin activation of protein C on the surface of vascular endothelial cells. In addition to its anticoagulant cofactor function, TM also regulates fibrinolysis, complement, and inflammatory pathways. TM is a multidomain receptor protein with a lectin-like domain at its N-terminus that has been shown to exhibit direct anti-inflammatory functions.

Thrombomodulin Switches Signaling and Protease-Activated Receptor 1 Cleavage Specificity of Thrombin.

Background: Cleavage of the extracellular domain of PAR1 (protease-activated receptor 1) by thrombin at Arg41 and by APC (activated protein C) at Arg46 initiates paradoxical cytopathic and cytoprotective signaling in endothelial cells. In the latter case, the ligand-dependent coreceptor signaling by EPCR (endothelial protein C receptor) is required for the protective PAR1 signaling by APC. Here, we investigated the role of thrombomodulin in determining the specificity of PAR1 signaling by thrombin.

Thrombomodulin Regulates PTEN/AKT Signaling Axis in Endothelial Cells.

Background: We recently demonstrated that deletion of thrombomodulin gene from endothelial cells results in upregulation of proinflammatory phenotype. In this study, we investigated the molecular basis for the altered phenotype in thrombomodulin-deficient (TM) cells.

Methods: Different constructs containing deletions or mutations in the cytoplasmic domain of thrombomodulin were prepared and introduced to TM cells.

Isolation and Culture of Human Umbilical Vein Endothelial Cells (HUVECs).

This protocol describes a simple and an economical method for isolation of endothelial cells from human umbilical vein. Umbilical cord is easily available postpartum following informed consent, and the method for its collection is noninvasive with few ethical concerns. Thus, umbilical vein is an ideal source for isolation of endothelial cells of human origin.

Determination of Endothelial Barrier Resistance by Electric Cell-Substrate Impedance Sensing (ECIS) System.

Endothelial cells lining the inner surface of blood vessels and lymphatic vessels play an indispensable role in vascular homeostasis. Apart from regulating vessel tone and forming an anti-thrombotic and anti-atherosclerotic surface, the dynamic endothelial barrier controls transport of solutes and fluid in and out of tissues at the capillary bed. Transit of circulating leukocytes into and out of circulation during inflammation and tissue repair is also regulated by the endothelium.

Activated protein C inhibits mesothelial-to-mesenchymal transition in experimental peritoneal fibrosis.

Background: In addition to its anticoagulant function in downregulating thrombin generation, activated protein C (APC) evokes pleiotropic cytoprotective signaling activities when it binds to endothelial protein C receptor (EPCR) to activate protease-activated receptor 1 (PAR1) in endothelial cells.

Objectives: To investigate the protective effect of APC in a chlorhexidine gluconate (CG)-induced peritoneal fibrosis model.

Methods: Peritoneal fibrosis was induced in wild-type as well as EPCR- and PAR1-deficient mice via daily injection of CG (0.

Endoscopic Versus Microscopic Stapedotomy: Our Experience.

With technological improvements leading to enhanced image resolution, as well as recognized acceptance of endoscopes within the field of rhinology, there has been greater implementation of endoscopes in otologic and neurotologic procedures. Surgeons now use endoscopes for a wide range of otological procedure, one such procedure is endoscopic stapedotomy for otosclerosis. This study is done to compare merits and demerits of endoscopic stapedotomy with microscopic stapedotomy.

Apoptosis signal-regulating kinase-1 regulates thrombin-induced endothelial permeability.

Thrombin-induced endothelial permeability is associated with various pathological conditions. Apoptosis signal-regulating kinase-1 (ASK1), one of the upstream MAP3K, has been reported to be an important regulator of endothelial stress and apoptosis. Despite this, its role in endothelial permeability is unknown.

Antithrombin protects against Plasmodium falciparum histidine-rich protein II-mediated inflammation and coagulation.

Plasmodium falciparum-derived histidine-rich protein II (HRPII) has been shown to inhibit heparin-dependent anticoagulant activity of antithrombin (AT) and induce inflammation in vitro and in vivo. In a recent study, we showed that HRPII interacts with the AT-binding vascular glycosaminoglycans (GAGs) not only to disrupt the barrier-permeability function of endothelial cells but also to inhibit the antiinflammatory signaling function of AT. Here we investigated the mechanisms of the proinflammatory function of HRPII and the protective activity of AT in cellular and animal models.

Extracellular Histones Bind Vascular Glycosaminoglycans and Inhibit the Anti-Inflammatory Function of Antithrombin.

Background/aims: Binding of histones to molecular pattern recognition receptors on endothelial cells and leukocytes provokes proinflammatory responses and promotes activation of coagulation. Histones also bind therapeutic heparins, thereby neutralizing their anticoagulant functions. The aim of this study was to test the hypothesis that histones can interact with the antithrombin (AT)-binding vascular glycosaminoglycans (GAGs) to induce inflammation and inhibit the anti-inflammatory function of AT.

Thrombomodulin is essential for maintaining quiescence in vascular endothelial cells.

Thrombomodulin (TM) is a thrombin receptor on endothelial cells that is involved in promoting activation of the anticoagulant protein C pathway during blood coagulation. TM also exerts protective anti-inflammatory properties through a poorly understood mechanism. In this study, we investigated the importance of TM signaling to cellular functions by deleting it from endothelial cells by CRISPR-Cas9 technology and analyzed the resultant phenotype of TM-deficient ( ) cells.

Protective Role of Activated Protein C against Viral Mimetic Poly(I:C)-Induced Inflammation.

Activated protein C (APC) is an anticoagulant plasma serine protease which exhibits potent cytoprotective and anti-inflammatory activities. Here, we studied protective effects of APC on the proinflammatory function of polyinosinic:polycytidylic acid [poly(I:C)], a synthetic analog of viral double-stranded RNA, in cellular and animal models. Poly(I:C) induced histone H3 extranuclear translocation via interaction with toll-like receptor 3 in two established endothelial cell lines.

Anticoagulant and signaling functions of antithrombin.

Antithrombin (AT) is a major plasma glycoprotein of the serpin superfamily that regulates the proteolytic activity of the procoagulant proteases of both intrinsic and extrinsic pathways. Two important structural features that participate in the regulatory function of AT include a mobile reactive center loop that binds to active site of coagulation proteases, trapping them in the form of inactive covalent complexes, and a basic D-helix that binds to therapeutic heparins and heparan sulfate proteoglycans (HSPGs) on vascular endothelial cells. The binding of D-helix of AT by therapeutic heparins promotes the reactivity of the serpin with coagulation proteases by several orders of magnitude by both a conformational activation of the serpin and a template (bridging) mechanism.

Hyperinsulinemia promotes endothelial inflammation via increased expression and release of Angiopoietin-2.

Background And Aims: Angiopoietin-2 (ANG-2) mediates endothelial inflammation to initiate atherosclerosis and angiogenesis. Here we determined the serum levels of ANG-2 in hyperinsulinemic subjects and whether insulin increases its expression and release.

Methods: Healthy male subjects were recruited from the D-CLIP and CURES studies and, based on their fasting insulin levels, were classified as normoinsulinemic (n = 228) and hyperinsulinemic (n = 32).

PKC (Protein Kinase C)-δ Modulates AT (Antithrombin) Signaling in Vascular Endothelial Cells.

Objective: Native and latent conformers of AT (antithrombin) induce anti-inflammatory and proapoptotic signaling activities, respectively, in vascular endothelial cells by unknown mechanisms. Synd-4 (syndecan-4) has been identified as a receptor that is involved in transmitting signaling activities of AT in endothelial cells. Approach and Results: In this study, we used flow cytometry, signaling assays, immunoblotting and confocal immunofluorescence microscopy to investigate the mechanism of the paradoxical signaling activities of high-affinity heparin (native) and low-affinity heparin (latent) conformers of AT in endothelial cells.

Gly197Arg mutation in protein C causes recurrent thrombosis in a heterozygous carrier.

Background: Activated protein C (APC) downregulates thrombin generation by inactivating procoagulant cofactors Va and VIIIa by limited proteolysis. We identified two protein C-deficient patients both of whom carry a heterozygous Gly197 to Arg (G197R) mutation in PROC and experience venous thrombosis.

Objective: The objective of this study was to determine the molecular basis of the clotting defect in patients carrying the G197R mutation.

Plasmodium falciparum histidine rich protein HRPII inhibits the anti-inflammatory function of antithrombin.

Background: It has been reported that histidine-rich protein II (HRPII), secreted by the malaria parasite, Plasmodium falciparum (Pf), inhibits the heparin-dependent anticoagulant activity of antithrombin (AT) in vitro and in plasma-based assay systems.

Objective: The objective of this study was to test the hypothesis that HRPII may also interact with the AT-binding vascular glycosaminoglycans (GAGs), thereby inhibiting the anti-inflammatory signaling function of the serpin.

Methods: We expressed HRPII in bacteria, purified it to homogeneity and studied its effect on endothelial cell signaling in the absence and presence of AT employing established signaling assays.

Thrombomodulin Regulation of Mitogen-Activated Protein Kinases.

The multifaceted role of mitogen-activated protein kinases (MAPKs) in modulating signal transduction pathways in inflammatory conditions such as infection, cardiovascular disease, and cancer has been well established. Recently, coagulation factors have also emerged as key players in regulating intracellular signaling pathways during inflammation. Among coagulation factors, thrombomodulin, as a high affinity receptor for thrombin on vascular endothelial cells, has been discovered to be a potent anti-inflammatory and anti-tumorigenic signaling molecule.

The Cardioprotective Signaling Activity of Activated Protein C in Heart Failure and Ischemic Heart Diseases.

Activated protein C (APC) is a vitamin-K dependent plasma serine protease, which functions as a natural anticoagulant to downregulate thrombin generation in the clotting cascade. APC also modulates cellular homeostasis by exhibiting potent cytoprotective and anti-inflammatory signaling activities. The beneficial cytoprotective effects of APC have been extensively studied and confirmed in a number of preclinical disease and injury models including sepsis, type-1 diabetes and various ischemia/reperfusion diseases.

Activated protein C inhibits lipopolysaccharide-mediated acetylation and secretion of high-mobility group box 1 in endothelial cells.

Essentials APC elicits cytoprotective responses in endothelial cells via EPCR-dependent cleavage of PAR1. APC inhibits LPS-mediated translocation and extracellular secretion of HMGB1 in endothelial cells. Signaling activity of APC inhibits LPS-mediated acetylation of HMGB1 by epigenetic mechanisms.

Perception of District Judges and Lawyers Towards Medico-legal Reports, Medical Certificates and Medical Expert Opinion.

Introduction: The medico legal reports and certificates prepared by doctors can be used as valuable documentary evidence in the court of law. The study was designed with objectives to explore the perception of judges and lawyers about the quality of medico legal reports prepared by the doctors and their competence in providing the expert evidence in the court.

Methods: It is a questionnaire based cross sectional study conducted among the district judges and government attorneys of 75 districts of Nepal from March to May 2016.

Combining bottleneck analysis and quality improvement as a novel methodology to improve the quality of neonatal care in a northeastern state of India: a feasibility study.

Background: The State of Meghalaya, India, has some of the worst newborn health outcomes in the country. State health authorities commissioned an assessment of newborn service delivery to improve services. This study proposes bottleneck analysis (BNA) and quality improvement (QI) methods as a combined method to improve compliance with evidence-based neonatal interventions in newborn health facilities.