Power Generation through Hybrid Micro wind Turbine Generator & Solar Module using Tracking Mechanism

In advancement of solar & wind power sector there are different types of research has been done in both large & small scale for power generation. In this paper we have focused on power generation to charge the battery of capacity 26Ah 12V, so we need 10% (2.6A) rated current to the battery and we are charging the battery through hybrid solar-wind system at micro level using tracking mechanism to capture more power from solar and wind. This experiment consist of 24 micro windmill with 6 bladed fan which consist of 3-3 dynamos each connected in series firstly and then output of 24 groups of series connected dynamos i.e. output of 72 dynamos taken in parallel finally and there are 10 solar panel of 3 watt each connected in series-parallel combination which are mounted on the top of panel structure also at the slope angle of 280 and tracking of solar started from 10 am to 3 pm & after 3 pm solar panel kept at home position or wind panel kept in west direction, after power generation from hybrid micro solar-wind system we store the energy in battery of 26Ah 12V using MPPT charger and lastly we compared the average efficiencies of hybrid solar-wind system separately i.e. with & without tracking mechanism and battery charging time also and found that the average efficiency of hybrid micro solar-wind system is higher and less charging time of battery in tracking mechanism in compare to without tracking mechanism

Recent scenario on psychotropic drug usage pattern among patients attending psychiatric outpatient department of a tertiary care teaching hospital in Nepal

Background: Due to increasing burden of psychiatric illnesses, it is essential to study the psychotropic drug utilization pattern in actual clinical practice. The objective of the study was to study the psychotropic drug usage pattern among patients attending psychiatric OPD of a tertiary care teaching hospital in Nepal.Methods: This observational retrospective study was conducted in Nepal Gunj Medical College, Nepal for a period of 6 months from January 2016 to June 2016. A total of 282 prescriptions from Psychiatric OPD were analysed for drug usage pattern. Prescriptions containing at least one psychotropic drug were included. Data was measured for number and percentage of prescriptions or drugs, using selected World Health Organization (WHO) drug use indicators.Results: A total of 282 prescriptions from Psychiatric OPD were analysed. Patients had a mean age of 35.01±1.17 years. Male and Female %age was 41.49% and 58.51% respectively. Majority of the patients (47.52%) were in 31-45 years age group. 70.57% patients were literate. Depression was the leading psychiatric illness seen in 144 (51.06%) patients followed by Anxiety disorders which were seen in 60 (21.28%) patients. A total of 2463 drugs were prescribed which included 591 (23.99%) antipsychotic drugs followed by 462 (18.76%) antidepressants, 390 (15.83%) antiepileptics, 312 (12.67%) supplements, 276 (11.21%) antianxiety, 171 (6.94%) antacids, 165 (6.7%) anticholinergics, 96 (3.9%) drugs in miscellaneous category. Drugs prescribed per prescription were 8.73 and psychotropic drugs per prescription were 6.09. Number of oral and injectable drugs were 2313 (93.91%) and 150 (6.09%) respectively. 87 fixed dose combinations (FDCs) of psychotropic drugs were prescribed. 903 (36.66%) drugs were prescribed from WHO’s 18th List of Essential Medicines.Conclusions: Depression was the most common psychiatric illness and antipsychotics were the most commonly prescribed medicines in psychiatry OPD. Majority of the prescriptions revealed polypharmacy

Bark Extract of Lantana camara in 1M HCl as Green Corrosion Inhibitor for Mild Steel

Lantana camara, an invasive species that adversely affects habitant, bioregions and environment has been studied as corrosion inhibitor. Methanolic extract of barks of Lantana camara in 1 M hydrochloric acid was tested as corrosion inhibitor on mild steel using potentiodynamic polarization technique. The corrosion inhibition efficiency of extract varied with concentration of extract and immersion of time. The inhibition was found to increase with increase in concentration of the extract. The polarization behavior of mild steel revealed that maximum inhibition efficiency is 97.33 % and 89.93 % respectively in the 1000 and 200 ppm concentration of the inhibitor respectively. The results showed that the extract of the barks of Lantana camara served as a mixed type inhibitor

Evaluation of Antitumor Efficacy of Chitosan-Tamarind Gum Polysaccharide Polyelectrolyte Complex Stabilized Nanoparticles of Simvastatin

Purpose: The present study was intended to fabricate chitosan (Ch)-tamarind gum polysaccharide (TGP) polyelectrolyte complex stabilized cubic nanoparticles of simvastatin and evaluate their potential against human breast cancer cell lines. Materials and Methods: The antisolvent precipitation method was used for formulation of nanoparticles. Factorial design (32 ) was utilized as a tool to analyze the effect of Ch and TGP concentration on particle size and entrapment efficiency of nanoparticles. Results: Formulated nanoparticles showed high entrapment efficiency (67.19±0.42–83.36 ±0.23%) and small size (53.3–383.1 nm). The present investigation involved utilization of two biological membranes (egg and tomato) as biological barriers for drug release. The study revealed that drug release from tomato membranes was retarded (as compared to egg membranes) but the release pattern matched that of egg membranes. All formulations followed the Baker–Lansdale model of drug release irrespective of the two different biological barriers. Stability studies were carried out for 45 days and exhibited less variation in particle size as well as a reduction in entrapment efficiency. Simvastatin loaded PEC stabilized nanoparticles exhibited better control on growth of human breast cancer cell lines than simple simvastatin. An unusual anticancer effect of simvastatin nanoparticles is also supported by several other research studies. Conclusion: The present study involves first-time synthesis of Ch-TGP polyelectrolyte complex stabilized nanoparticles of simvastatin against MCF-7 cells. It recommends that, in future, theoretical modeling and IVIVC should be carried out for perfect designing of delivery systems

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Allosteric activation mechanism of a human oncogenic chromatin remodeler ALC1

The packaging of the genetic material in the form of chromatin is the fundamental level of regulation for genome-templated processes. Chromatin folding acts as a crucial platform for nuclear processes by regulating the spatio-temporal access to the underlying DNA sequence, thereby regulating DNA transcription, replication, recombination, repair and genome maintenance. Many mechanisms exist to establish this regulation, one of which is via the regulated recruitment and activation of ATP-dependent chromatin-remodelling enzymes. These remodelers use the energy of ATP to remodel, space and/or disrupt nucleosomes or other DNA–protein complexes. One such previously described chromatin remodeler is ALC1 (Amplified in Liver Cancer 1), which is implicated in human cancers, and requires the activity of NAD+-dependent enzyme poly-ADP-ribose (PAR) polymerase 1 (PARP1) for its remodelling activity. ALC1 has a C- terminal poly-ADPr binding macrodomain and an N-terminal Snf2-like ATPase motor domain separated by a linker. This modular architecture provides a way to couple DNA damage induced PARP1-mediated poly-ADP-ribosylation with ATP-dependent remodelling. ALC1’s ATPase activity is strictly dependent on its intact ADPr-binding pocket of the macrodomain, suggesting the existence of a currently unique, post-translationally regulated allosteric activation mechanisms for this chromatin remodeler. However, how PAR regulates ALC1 structure and function was not known. In my core PhD project, I was able to establish that the macrodomain interacts with the ATPase domain and mediates auto-inhibition. DNA damage-induced PARP1 activation suppresses the inhibitory interaction. Poly-ADPr binding to the macrodomain releases auto-inhibition. We identified tri-ADPr as the minimal ligand acting as a potent allosteric effector, capable of disrupting ATPase-macrodomain interaction. The loss of interaction triggers an ungated, active conformation. Consistently, ALC1 fragments lacking the macrodomain decompact chromatin without requiring PARP1 activation. Further, the ATPase restricts the macrodomain’s interaction with PARP1 unless DNA damage is induced. In addition, I found that somatic cancer mutants disrupt ALC1’s auto-inhibition and promote chromatin remodeling. Our data show that the NAD+-metabolite PAR induces a conformational switch in the ALC1 that releases auto-inhibition to drive chromatin relaxation. Modular allostery in this chromatin remodeling oncogene triggers its robust, DNA-damage-dependent activation. My research may catalyze the development of small molecule therapeutics using ALC1 as potential target of clinical relevance. During my PhD, I also worked on many other projects out of which two are part of published results and therefore are also included in this cumulative dissertation; 1. The NASP histone chaperone - histone H3 interactions and the histone chaperoning mechanism thereof, 2. Circadian rhythm protein-protein interaction i.e Cry 1 interaction surface with the FBXL3 and PER2 and insights into the circadian function thereof.Die Verpackung des genetischen Materials in Form von Chromatin ist ein grundlegender Mechanismus für die Regulierung genomgestützter Prozesse. Die Chromatinstruktur dient hierbei als wichtige Plattform für nukleär e Vorgänge. Durch die spezifische Steuerung des räumlichen und zeitlichen Zugangs der zugrundeliegenden DNA-Sequenz werden genomgestützte Prozesse wie Transkription, Replikation, Rekombination, Reparatur und Genom-Engineering reguliert. Es existieren unterschiedliche Mechanismen, um diese Regulation zu gewährleisten. Einer dieser Mechanismen erfolgt über die Rekrutierung und Aktivierung ATP-abhängiger Chromatin-Remodeling-Enzyme. Diese sogenannten Remodeler nutzen die Energie von ATP, um Nukleosomen oder andere DNA- Protein-Komplexe zu verschieben, umzugestalten, deren Strukturen aufzulockern oder ganz aufzulösen, und hierdurch die genomassoziierten Prozesse zu steuern. Ein solcher kürzlich beschriebener Chromatin-Remodeler ist ALC1 (Amplified in Liver Cancer 1), von dem vielfach gezeigt werden konnte, dass er bei der Entstehung verschiedener Krebsarten beteiligt ist. ALC1 benötigt für seine Remodeling-Aktivität das NAD+-abhängige Enzym Poly-ADP-Ribose-Polymerase 1 (PARP1). ALC1 besteht aus einer C-terminalen ADP-Ribose-bindende Makrodomäne und einer N- terminale Snf2-ähnlichen ATPase-Motordomäne, die über eine Linkerregion miteinander verbunden sind. Diese modulare Struktur ermöglicht es, die durch DNA-Schäden induzierte PARP1-vermittelte Poly-ADP-Ribosylierung mit ATP- abhängigem Chromatin-Remodeling zu koppeln. Es konnte weiterhin gezeigt werden, dass die ATPase-Aktivität von ALC1 strikt von seiner intakten ADP- Ribose-Bindungstasche der Makrodomäne abhängig ist. Dies weist auf eine einzigartige allosterische Regulation dieses Chromatin-Remodelers durch post- translationale Modifikationen hin. Allerdings ist der detaillierte Struktur- Funktionsmechanismus noch nicht bekannt. Im Hauptteil meiner Doktorarbeit zeige ich, dass die Makrodomäne mit der ATPase-Domäne interagiert und Autoinhibition vermittelt. Die durch DNA- Schädigung induzierte PARP1-Aktivierung und die Bindung von Poly-ADP-Ribose (PAR) an die Makrodomäne beendet diese inhibitorische Interaktion. Wir konnten Tri-ADP-Ribose als den minimalen Liganden identifizieren, der als ein potenter allosterischer Effektor die ATPase-Makrodomänen-Wechselwirkung aufbricht, aus der eine Konformationsänderung in eine offene, aktive Form resultiert. Hiermit übereinstimmend dekomprimieren ALC1-Fragmente, denen die Makrodomäne fehlt, Chromatin, ohne dass eine PARP1-Aktivierung erforderlich ist. Des Weiteren unterbindet die ATPase-Domäne die Interaktion der Makrodomäne mit PARP1, sofern keine DNA-Schädigung induziert wird. Ich konnte außerdem zeigen, dass somatische Krebsmutationen dieses Chromatin-Remodelers die Auto-Inhibition unterbrechen und die Chromatin-Remodellierung aktivieren. Unsere Daten zeigen, dass der NAD+-Metabolit PAR einen Konformationswechsel in ALC1 induziert, hierdurch die Autoinhibition aufgehoben wird und letztendlich Chromatinrelaxation resultiert. Eine modulare Allosterie in diesem onkogenen Chromatin-Remodeler löst eine stabile DNA-Schadens-abhängige Aktivierung aus. Diese Arbeit könnte die Entwicklung von niedermolekularen Therapeutika unterstützen, die ALC1 als potentielles Wirkstoffziel für eine klinischen Anwendung haben. Während meiner Doktorarbeit habe ich an zwei weiteren Projekten gearbeitet, von denen Teile meiner Ergebnisse in Publikationen eingeflossen sind: 1. Die Histonchaperon NASP-Histon H3 Interaktion und der zugrundeliegende Histonchaperon-Mechanismus, 2. Protein-Protein Interaktionen des circadianen Rythmus, u.a. die Interaktion von Cry 1 mit FBXL3 und PER2, und der Einfluss dieser Interaktion auf den circadianen Rythmus