Thiazolidinone CFTR inhibitor identified by high-throughput screening blocks cholera toxin–induced intestinal fluid secretion

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Bridge Monitoring System Using IOT

In countries like India there is powerful focus on national infrastructure. New bridges are built each year and the maintenance of those bridges is frequently ignored. The present structures uses very complex and excessive fee wired network and it additionally required high upkeep for optical fiber machine. So the primary objective of this task is to build a cheap bridge tracking machine for developing international locations like India. This project aim to simplify the system for selecting bridge tracking devices. Many bridges within the India are obsolete or structurally deficient to safely increase the life of those bridges, inspection would be vital. Bridge engineers have many duties and it's far not possible to expect one to know. Our device will sense the crack inside the bridge and signal might be given to govern room immediately to stop cars

Assessment of Population-Based HIV RNA Levels in a Rural East African Setting Using a Fingerprick-Based Blood Collection Method

Background. Population-based human immunodeficiency virus type 1 (HIV-1) RNA levels (viral load [VL]) are proposed metrics for antiretroviral therapy (ART) program effectiveness. We estimated population-based HIV RNA levels using a fingerprick-based approach in a rural Ugandan community implementing rapid ART scale-up

Small-Molecule CFTR Inhibitors Slow Cyst Growth in Polycystic Kidney Disease

Cyst expansion in polycystic kidney disease (PKD) involves progressive fluid accumulation, which is believed to require chloride transport by the cystic fibrosis transmembrane conductance regulator (CFTR) protein. Herein is reported that small-molecule CFTR inhibitors of the thiazolidinone and glycine hydrazide classes slow cyst expansion in in vitro and in vivo models of PKD. More than 30 CFTR inhibitor analogs were screened in an MDCK cell model, and near-complete suppression of cyst growth was found by tetrazolo-CFTRinh-172, a tetrazolo-derived thiazolidinone, and Ph-GlyH-101, a phenyl-derived glycine hydrazide, without an effect on cell proliferation. These compounds also inhibited cyst number and growth by >80% in an embryonic kidney cyst model involving 4-d organ culture of embryonic day 13.5 mouse kidneys in 8-Br-cAMP–containing medium. Subcutaneous delivery of tetrazolo-CFTRinh-172 and Ph-GlyH-101 to neonatal, kidney-specific PKD1 knockout mice produced stable, therapeutic inhibitor concentrations of >3 μM in urine and kidney tissue. Treatment of mice for up to 7 d remarkably slowed kidney enlargement and cyst expansion and preserved renal function. These results implicate CFTR in renal cyst growth and suggest that CFTR inhibitors may hold therapeutic potential to reduce cyst growth in PKD

Thiazolidinone CFTR inhibitor identified by high-throughput screening blocks cholera toxin–induced intestinal fluid secretion

Secretory diarrhea is the leading cause of infant death in developing countries and a major cause of morbidity in adults. The cystic fibrosis transmembrane conductance regulator (CFTR) protein is required for fluid secretion in the intestine and airways and, when defective, causes the lethal genetic disease cystic fibrosis. We screened 50,000 chemically diverse compounds for inhibition of cAMP/flavone–stimulated Cl(–) transport in epithelial cells expressing CFTR. Six CFTR inhibitors of the 2-thioxo-4-thiazolidinone chemical class were identified. The most potent compound discovered by screening of structural analogs, CFTR(inh)-172, reversibly inhibited CFTR short-circuit current in less than 2 minutes in a voltage-independent manner with K(I) approximately 300 nM. CFTR(inh)-172 was nontoxic at high concentrations in cell culture and mouse models. At concentrations fully inhibiting CFTR, CFTR(inh)-172 did not prevent elevation of cellular cAMP or inhibit non-CFTR Cl(–) channels, multidrug resistance protein-1 (MDR-1), ATP-sensitive K(+) channels, or a series of other transporters. A single intraperitoneal injection of CFTR(inh)-172 (250 μg/kg) in mice reduced by more than 90% cholera toxin–induced fluid secretion in the small intestine over 6 hours. Thiazolidinone CFTR inhibitors may be useful in developing large-animal models of cystic fibrosis and in reducing intestinal fluid loss in cholera and other secretory diarrheas

New triazole-based Schiff base ligands and their Co(II) and Ni(II) complexes as biological potent molecules: Chemical preparation, structural elucidation and biological studies

Preparation of sequence of Co(II) and Ni(II) metal complexes (C1a - C3a and C1b - C3b) of bidentate ligands (L1 - L3) has been resulted from the condensation of substituted 1,2,4-triazole with various substituted 1,3-diphenyl-1H-pyrazole-4-carbaldehyde are described in the present study. The structures of synthesized complexes were established by elemental investigation, IR, mass spectroscopy and TGA examinations. The data confirmed that bonding through the nitrogen atom from imine group and sulfur atom of triazole, ligand get integrated with the metal ions in a bidentate nature, gave an octahedral geometry to the complexes. The antibacterial activities have been tested against S. aureus Gram-positive bacteria and E. coli Gram-negative bacteria. Further, through DPPH radical scavenging capacity assay the antioxidant activity values were quantified; all the compounds demonstrate outstanding antioxidant activities. Using molecular docking and highest binding affinities for biological targets, the ligand and complex interactions have been studied. The in vitro anti-proliferative nature of synthesized ligands and their Ni(II) and Co(II) complexes were appraised with the help of SRB assay against Human hepato carcinoma cell (Hep-G2), Lung cells (A-549), Breast cell (MCF-7), Prostate cell (PC-3). Anti-tubercular studies revealed that the complex demonstrates a greater anti-tubercular activity than the analogous ligands

Structural insights and inhibition mechanism of TMPRSS2 by experimentally known inhibitors Camostat mesylate, Nafamostat and Bromhexine hydrochloride to control SARS-coronavirus-2: A molecular modeling approach

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) has been responsible for the cause of global pandemic Covid-19 and to date, there is no effective treatment available. The spike ‘S’ protein of SARS-CoV-2 and ACE2 of the host cell are being targeted to design new drugs to control Covid-19. Similarly, a transmembrane serine protease, TMPRSS2 of the host cell plays a significant role in the proteolytic cleavage of viral ‘S’ protein helpful for the priming of ACE2 receptors and viral entry into human cells. However, three-dimensional structural information and the inhibition mechanism of TMPRSS2 is yet to be explored experimentally. Hence, we have used a molecular dynamics (MD) simulated homology model of TMPRSS2 to study the inhibition mechanism of experimentally known inhibitors Camostat mesylate, Nafamostat and Bromhexine hydrochloride (BHH) using molecular modeling techniques. Prior to docking, all three inhibitors were geometry optimized by semi-empirical quantum chemical RM1 method. Molecular docking analysis revealed that Camostat mesylate and its structural analogue Nafamostat interact strongly with residues His296 and Ser441 present in the catalytic triad of TMPRSS2, whereas BHH binds with Ala386 along with other residues. Comparative molecular dynamics simulations revealed the stable behavior of all the docked complexes. MM-PBSA calculations also revealed the stronger binding of Camostat mesylate to TMPRSS2 active site residues as compared to Nafamostat and BHH. Thus, this structural information could be useful to understand the mechanistic approach of TMPRSS2 inhibition, which may be helpful to design new lead compounds to prevent the entry of SARS-Coronavirus 2 in human cells

Assessment of Population-Based HIV RNA Levels in a Rural East African Setting Using a Fingerprick-Based Blood Collection Method

Background. Population-based human immunodeficiency virus type 1 (HIV-1) RNA levels (viral load [VL]) are proposed metrics for antiretroviral therapy (ART) program effectiveness. We estimated population-based HIV RNA levels using a fingerprick-based approach in a rural Ugandan community implementing rapid ART scale-up. Methods. A fingerprick-based HIV RNA measurement technique was validated against standard phlebotomy. This technique was deployed during a 5-day community-wide health campaign in a 6300-person community. Assessments included rapid HIV antibody testing, VL, and CD4+ T-cell count via fingerprick. We estimated population HIV RNA levels and the prevalence of undetectable RNA, assessed predictors of VL via linear regression, and mapped RNA levels within community geographic units. Results. During the community-wide health campaign, 179 of 2282 adults (7.8%) and 10 of 1826 children (0.5%) tested seropositive for HIV. Fingerprick VL was determined in 174 of 189 HIV-positive persons (92%). The mean log(VL) was 3.67 log (95% confidence interval [CI], 3.50–3.83 log copies/mL), median VL was 2720 copies/mL (interquartile range, <486–38 120 copies/mL), and arithmetic mean VL was 64 064 copies/mL. Overall, 64 of 174 of individuals had undetectable RNA (37% [95% CI, 30%–44%]), 24% had VL 486–10 000; 25% had VL 10 001–100 000; and 15% had VL>100 000 copies/mL. Among participants taking ART, 83% had undetectable VL. Conclusions. We developed and implemented a fingerprick VL testing method and provide the first report of population HIV RNA levels in Africa. In a rural Ugandan community experiencing ART scale-up, we found evidence of population-level ART effectiveness, but found a substantial population to be viremic, in need of ART, and at risk for transmission