The ventral tegmental area (VTA) is a dopaminergic brain area that is critical in the development and maintenance of addiction. During withdrawal from chronic ethanol exposure, the response of VTA ...neurons to GABA (gamma-aminobutyric acid) is reduced through an epigenetically regulated mechanism. In the current study, a whole-genome transcriptomic approach was used to investigate the underlying molecular mechanism of GABA hyposensitivity in the VTA during withdrawal after chronic ethanol exposure.
We performed RNA sequencing of the VTA of Sprague Dawley male rats withdrawn for 24 hours from a chronic ethanol diet as well as sequencing of the VTA of control rats fed the Lieber-DeCarli diet. RNA sequencing data were analyzed using weighted gene coexpression network analysis to identify modules that contained coexpressed genes. Validation was performed with quantitative polymerase chain reaction, gas chromatography–mass spectrometry, and electrophysiological assays.
Pathway and network analysis of weighted gene coexpression network analysis module 1 revealed a significant downregulation of genes associated with the cholesterol synthesis pathway. Consistent with this association, VTA cholesterol levels were significantly decreased during withdrawal. Chromatin immunoprecipitation indicated a decrease in levels of acetylated H3K27 at the transcriptional control regions of these genes. Electrophysiological studies in VTA slices demonstrated that GABA hyposensitivity during withdrawal was normalized by addition of exogenous cholesterol. In addition, inhibition of cholesterol synthesis produced GABA hyposensitivity, which was reversed by adding exogenous cholesterol to VTA slices.
These results suggest that decreased expression of cholesterol synthesis genes may regulate GABA hyposensitivity of VTA neurons during alcohol withdrawal. Increasing cholesterol levels in the brain may be a novel avenue for therapeutic intervention to reverse detrimental effects of chronic alcohol exposure.
Extensive research has been conducted by the manufacturing industry to enhance the efficiency of drilling processes by focusing on the utilization of nanoenhanced cutting fluids that possess ...excellent heat conductivity. Due to their eco-friendliness and adaptability of physical and chemical properties, ionic fluids offer enormous potential for application as cutting fluids. This study investigates the computational fluid dynamics analysis of the heat transfer performance of various ionanofluid pairs dispersed with nanoparticles as cutting fluids in the drilling process using Ansys Fluent software. For this purpose, 1-Hexyl-3-methyl-imidazolium-tetrafluoroborate is considered the ionic fluid, and its thermal behavior is examined by dispersing it with nanoparticles of copper, silver, and multiwalled carbon nanotubes (MWCNT) at different particle volume fractions and Reynolds numbers. The workpiece is composed of an alloy of titanium Ti–6Al–4V, while the drill bit is made of tungsten carbide-cobalt. It is observed that the ionic nanocoolant mist emanates from the spray tip and moves towards the drill bit-workpiece interface. Initially, the coolant's velocity is greatest close to the orifice, and as time passes, it approaches the drilling space. The data indicates that the spraying velocity of the coolant augments over time and that it disperses heat at the tool-chip interface. The results help us validate the flow and interaction of ionanocoolant with the drilling zone. With a rise in the volume fraction of added nanoparticles and Reynolds number, the results indicated a significant decrease in the drilling temperature. With a higher particle volume fraction, the MWCNT-ionic coolant combination decreases the drilling temperature of pure ionic liquid by 25.64 %. The copper, silver, and MWCNT ionanofluids enhance the average heat transfer coefficient of pure ionic coolant by 35.14 %, 47.42 %, and 62.75 %, respectively. In addition, MWCNT nanocoolants demonstrated improved thermal performance and heat removal rate in comparison to copper and silver ionanocoolants.
Sustained or repeated exposure to sedating drugs, such as alcohol, triggers homeostatic adaptations in the brain that lead to the development of drug tolerance and dependence. These adaptations ...involve long-term changes in the transcription of drug-responsive genes as well as an epigenetic restructuring of chromosomal regions that is thought to signal and maintain the altered transcriptional state. Alcohol-induced epigenetic changes have been shown to be important in the long-term adaptation that leads to alcohol tolerance and dependence endophenotypes. A major constraint impeding progress is that alcohol produces a surfeit of changes in gene expression, most of which may not make any meaningful contribution to the ethanol response under study. Here we used a novel genomic epigenetic approach to find genes relevant for functional alcohol tolerance by exploiting the commonalities of two chemically distinct alcohols. In Drosophila melanogaster, ethanol and benzyl alcohol induce mutual cross-tolerance, indicating that they share a common mechanism for producing tolerance. We surveyed the genome-wide changes in histone acetylation that occur in response to these drugs. Each drug induces modifications in a large number of genes. The genes that respond similarly to either treatment, however, represent a subgroup enriched for genes important for the common tolerance response. Genes were functionally tested for behavioral tolerance to the sedative effects of ethanol and benzyl alcohol using mutant and inducible RNAi stocks. We identified a network of genes that are essential for the development of tolerance to sedation by alcohol.
,
, and
are traditionally used to treat diarrheal diseases in India and were reported to show anti-Cholera toxin activity from our earlier studies. As polyphenols are reported to neutralize Cholera ...toxin (CT), the present study investigated the inhibitory activity of selected polyphenols from these plants against CTB binding to GM1 receptor using
,
, and
approaches.
Molecular modelling approach was used to investigate the intermolecular interactions of selected 20 polyphenolic compounds from three plants with CT using DOCK6. Based on intermolecular interactions, two phenolic acids, Ellagic acid (EA) and Chlorogenic acid (CHL); two flavonoids, Rutin (RTN) and Phloridzin (PHD) were selected along with their respective standards, Gallic acid (GA) and Quercetrin (QRTN). The stability of docked complexes was corroborated using molecular dynamics simulation. Furthermore, in vitro inhibitory activity of six compounds against CT was assessed using GM1 ELISA and cAMP assay. EA and CHL that showed prominent activity against CT in
assays were investigated for their neutralizing activity against CT-induced fluid accumulation and histopathological changes in adult mouse.
The molecular modelling study revealed significant structural stability of the CT-EA, CT-CHL, and CT-PHD complexes compared to their respective controls. All the selected six compounds significantly reduced CT-induced cAMP levels, whereas EA, CHL, and PHD exhibited > 50% binding inhibition of CT to GM1. The EA and CHL that showed prominent neutralization activity against CT from
studies, also significantly decreased CT-induced fluid accumulation and histopathological changes in adult mouse. Our study identified bioactive compounds from these three plants against CT-induced diarrhea.
Hepatitis B infection caused by the hepatitis B virus is a life-threatening cause of liver fibrosis, cirrhosis, and hepatocellular carcinoma. Researchers have produced multiple in vivo models for ...hepatitis B virus (HBV) and, currently, there are no specific laboratory animal models available to study HBV pathogenesis or immune response; nonetheless, their limitations prevent them from being used to study HBV pathogenesis, immune response, or therapeutic methods because HBV can only infect humans and chimpanzees. The current study is the first of its kind to identify a suitable chemically induced liver cirrhosis/HCC model that parallels HBV pathophysiology. Initially, data from the peer-reviewed literature and the GeneCards database were compiled to identify the genes that HBV and seven drugs (acetaminophen, isoniazid, alcohol, D-galactosamine, lipopolysaccharide, thioacetamide, and rifampicin) regulate. Functional enrichment analysis was performed in the STRING server. The network HBV/Chemical, genes, and pathways were constructed by Cytoscape 3.6.1. About 1546 genes were modulated by HBV, of which 25.2% and 17.6% of the genes were common for alcohol and lipopolysaccharide-induced hepatitis. In accordance with the enrichment analysis, HBV activates the signaling pathways for apoptosis, cell cycle, PI3K-Akt, TNF, JAK-STAT, MAPK, chemokines, NF-kappa B, and TGF-beta. In addition, alcohol and lipopolysaccharide significantly activated these pathways more than other chemicals, with higher gene counts and lower FDR scores. In conclusion, alcohol-induced hepatitis could be a suitable model to study chronic HBV infection and lipopolysaccharide-induced hepatitis for an acute inflammatory response to HBV.
Repeated binge-like exposure to alcohol during adolescence has been reported to perturb prefrontal cortical development, yet the mechanisms underlying these effects are unknown. Here we report that ...adolescent intermittent ethanol exposure induces cellular and dopaminergic abnormalities in the adult prelimbic cortex (PrL-C). Exposing rats to alcohol during early-mid adolescence (PD28-42) increased the density of long/thin dendritic spines of layer 5 pyramidal neurons in the adult PrL-C. Interestingly, although AIE exposure did not alter the expression of glutamatergic proteins in the adult PrL-C, there was a pronounced reduction in dopamine (DA) D
receptor modulation of both intrinsic firing and evoked NMDA currents in pyramidal cells, whereas D
receptor function was unaltered. Recordings from fast-spiking interneurons also revealed that AIE reduced intrinsic excitability, glutamatergic signaling, and D
receptor modulation of these cells. Analysis of PrL-C tissue of AIE-exposed rats further revealed persistent changes in the expression of DA-related proteins, including reductions in the expression of tyrosine hydroxylase and catechol-O-methyltransferase (COMT). AIE exposure was associated with hypermethylation of the COMT promoter at a conserved CpG site in exon II. Taken together, these findings demonstrate that AIE exposure disrupts DA and GABAergic transmission in the adult medial prefrontal cortex (mPFC). As DA and GABA work in concert to shape and synchronize neuronal ensembles in the PFC, these alterations could contribute to deficits in behavioral control and decision-making in adults who abused alcohol during adolescence.
Introduction: In India, even with planned health services, it is difficult to reach the health goals without community participation. While Community needs assessment approach (CNAA) tools like ...Focussed group Discussion (FGD), Village mapping and matrix ranking have been effective in quickly gathering information, surveys have been conventionally preferred. Aim & Objective: The present study compares qualitative and quantitative methods to understand feasibility of using CNAA tools in place of survey as an alternative tool Methodology: Mixed Method research employing Survey and CNAA methods of FGD, Village Mapping, transect walk and Matrix ranking score was carried out as a part of academic activity of National Service Scheme(NSS). Data was represented in form of percentages and frequency tables. Association was measured using Chi Square using Epi Info TM version 7.2.1software. Results: Using quantitative survey, we found that 71% used piped supply and 93.1% of the households used toilets. But 6.9% of them still preferred open fields for defecation. Amongst the participants of FGD, it was found that 90% participants preferred going to government hospitals. Comparable data found for variables like Maternal and child health indicators, Sanitation practices and burden of Non communicable diseases. Partially comparable results were found for burden of communicable diseases. Conclusion: CNAA research tools demonstrated comparability with survey in most areas of health concern and reduced the time required for conducting research without compromising the quality of results
The enantiomers of diquats (DQs), a new class of functional organic molecules, were recently separated by capillary electrophoresis (CE) with high resolution up to 11.4 within 5–7 min using randomly ...sulfated α‐, β‐, and γ‐cyclodextrins (CDs) as chiral selectors. These results indicated strong interactions between dicationic diquats and multiply negatively charged sulfated CDs (S‐CDs). However, the binding strength of these interactions was not quantified. For that reason, in this study, affinity CE was applied for the determination of the binding constants and ionic mobilities of the complexes of DQ P‐ and M‐enantiomers with CD chiral selectors in an aqueous medium. The non‐covalent interactions of 10 pairs of DQ enantiomers with the above CDs were investigated in a background electrolyte (BGE) composed of 22 mM NaOH, 35 mM H3PO4, pH 2.5, and 0.0–1.0 mM concentrations of CDs. The average apparent binding constant and the average actual ionic mobility of the DQ‐CD complexes were determined by nonlinear regression analysis of the dependence of the effective mobility of DQ enantiomers on the concentration of CDs in the BGE. The complexes were found to be relatively strong with the averaged apparent binding constants in the range 13 600–547 400 L/mol.
Surface integrity parameters are the major aspect in the extension of the fatigue life of aero- engine components. In this study, a modified burnishing surface treatment (low plasticity burnishing) ...with reduced cold work was proposed to improve surface integrity characteristics such as surface finish and hardness, and to induce stable, advantageous compressive residual stress in a cylindrical Ti-6Al-4 V specimen (as-received). In this process, a rolling rigid spherical tungsten carbide ball is pressed across a Ti-6Al-4 V specimen at an appropriate fluid pressure generated by the hydraulic unit. The low plasticity ball burnishing tooling system supported by a hydraulic unit of capacity 30 MPa is designed and developed in this study. By using a suitable specimen holding fixture, the ball burnishing with a small amount of plastic strain was carried out on the Ti-6Al-4 V cylindrical specimen. This research examined the effect of burnishing process variables namely tool pass and burnishing fluid pressure on compressive residual stresses, surface roughness, and hardness in Ti-6Al-4 V. The explicit dynamic analysis was carried out by using FE-Analysis software ABAQUS 6.17 as a part of numerical simulation. Hydraulic burnishing pressure and burnishing passes are the most influential parameters in generating favourable compressive residual stress, qualitative surface finish with less cold work in Ti-6Al-4 V turned specimen.
Abstract
The Angle of Attack (AOA) in a Vertical Axis Wind Turbine (VAWT) plays an important role in determining the forces and the power generated by the wind turbine. It is difficult to find the ...suitable AOA due to the complex and constantly changing wind flow patterns. In this paper, we have performed CFD simulations using Ansys Fluent software, based on the constantly changing AOA. The CFD simulations were conducted by selecting a suitable range of AOA and the velocity of the wind. The selected range of AOA varied from 5 degrees to 25 degrees with increments of 5 degrees and the range of the air velocities varied from 7m/s to 21m/s with increments of 7m/s. The tests were also performed using the X-Foil software. The results obtained from the CFD simulations, done by using the Ansys Fluent Software and from the X-Foil software, were then compared to give a more accurate and optimized AOA and velocity value. This optimization of the AOA could enhance the overall performance of the Vertical Axis Wind turbine.
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