Evaluation of α,β-unsaturated ketones as antileishmanial agents

In this study, we assessed the antileishmanial activity of 126 α,β-unsaturated ketones. The compounds NC901, NC884, and NC2459 showed high leishmanicidal activity for both the extracellular (50% effective concentration [EC(50)], 456 nM, 1,122 nM, and 20 nM, respectively) and intracellular (EC(50), 1,870 nM, 937 nM, and 625 nM, respectively) forms of Leishmania major propagated in macrophages, with little or no toxicity to mammalian cells. Bioluminescent imaging of parasite replication showed that all three compounds reduced the parasite burden in the murine model, with no apparent toxicity

Learner engagement in virtual learning environments: a qualitative case study among English teacher trainees

Purpose: The objective of this research is to examine the learner engagement in virtual learning environments and challenges face by the learners. Design/methodology/approach: This reach is a qualitative case study adopts semi structured personal interviews and focus group discussions (FGDs). 20 personal interviews and 8 focus group discussions were conducted among Diploma in TESL English teacher trainees in two private colleges. Findings: This research found that though students prefer virtual learning, most of the students skip online classes than physical lectures. However, they find virtual learning is tedious and not motivating and they feel that face-to-face physical classroom is much more effective than virtual since physical classes improve very positive teacher- students’ rapport. This research also found that the students prefer blended mode due to many Practical implications: Most of the research conducted so far has focused on emergency remote teaching and online learning during the pandemic and post pandemic. Insignificant research has been done on exploring learner engagement in virtual teaching and learning environment. This research finding may be an eye opener for the institutes and teachers to think more about Lerner engagement in virtual teaching and learning. Originality value: This research is a one of the cutting edge research which highlights the new perspectives on virtual learning context

A High Gain DC-DC Converter with Grey Wolf Optimizer Based MPPT Algorithm for PV Fed BLDC Motor Drive

Photovoltaic (PV) water pumping systems are becoming popular these days. In PV water pumping, the role of the converter is most important, especially in the renewable energy-based PV systems case. This study focuses on one such application. In this proposed work, direct current (DC) based intermediate DC-DC power converter, i.e., a modified LUO (M-LUO) converter is used to extricate the availability of power in the high range from the PV array. The M-LUO converter is controlled efficiently by utilizing the Grey Wolf Optimizer (GWO)-based maximum power point tracking algorithm, which aids the smooth starting of a brushless DC (BLDC) motor. The voltage source inverter’s (VSI) fundamental switching frequency is achieved in the BLDC motor by electronic commutation. Hence, the occurrence of VSI losses due to a high switching frequency is eliminated. The GWO optimized algorithm is compared with the perturb and observe (P&O) and fuzzy logic based maximum power point tracking (MPPT) algorithms. However, by sensing the position of the rotor and comparing the reference speed with the actual speed, the speed of the BLDC motor is controlled by the proportional-integral (PI) controller. The recent advancement in motor drives based on distributed sources generates more demand for highly efficient permanent magnet (PM) motor drives, and this was the beginning of interest in BLDC motors. Thus, in this paper, the design of a high-gain boost converter optimized by a GWO algorithm is proposed to drive the BLDC-based pumping motor. The proposed work is simulated in MATLAB-SIMULINK, and the experimental results are verified using the dsPIC30F2010 controller

Human cytomegalovirus immediate-early 1 protein rewires upstream STAT3 to downstream STAT1 signaling switching an IL6-type to an IFNγ-like response

MN and CP were supported by the Wellcome Trust (www.wellcome.ac.uk) Institutional Strategic Support Fund and CP was supported by the Deutsche Forschungsgemeinschaft (PA 815/2-1; www.dfg.de).The human cytomegalovirus (hCMV) major immediate-early 1 protein (IE1) is best known for activating transcription to facilitate viral replication. Here we present transcriptome data indicating that IE1 is as significant a repressor as it is an activator of host gene expression. Human cells induced to express IE1 exhibit global repression of IL6- and oncostatin M-responsive STAT3 target genes. This repression is followed by STAT1 phosphorylation and activation of STAT1 target genes normally induced by IFNγ. The observed repression and subsequent activation are both mediated through the same region (amino acids 410 to 445) in the C-terminal domain of IE1, and this region serves as a binding site for STAT3. Depletion of STAT3 phenocopies the STAT1-dependent IFNγ-like response to IE1. In contrast, depletion of the IL6 receptor (IL6ST) or the STAT kinase JAK1 prevents this response. Accordingly, treatment with IL6 leads to prolonged STAT1 instead of STAT3 activation in wild-type IE1 expressing cells, but not in cells expressing a mutant protein (IE1dl410-420) deficient for STAT3 binding. A very similar STAT1-directed response to IL6 is also present in cells infected with a wild-type or revertant hCMV, but not an IE1dl410-420 mutant virus, and this response results in restricted viral replication. We conclude that IE1 is sufficient and necessary to rewire upstream IL6-type to downstream IFNγ-like signaling, two pathways linked to opposing actions, resulting in repressed STAT3- and activated STAT1-responsive genes. These findings relate transcriptional repressor and activator functions of IE1 and suggest unexpected outcomes relevant to viral pathogenesis in response to cytokines or growth factors that signal through the IL6ST-JAK1-STAT3 axis in hCMV-infected cells. Our results also reveal that IE1, a protein considered to be a key activator of the hCMV productive cycle, has an unanticipated role in tempering viral replication.Publisher PDFPeer reviewe

National culture and tourist destination choice in the UK and Venezuela: an exploratory and preliminary study

National culture determines consumer attitudes and behaviour. While this holds true for tourism consumption, little research has sought to better understand the effect of culture on tourist destination choice. The geographical scope of analysis has also been restricted. This study employs the Hofstede’s cultural dimensions framework to conduct an exploratory, qualitative evaluation of the influence of the tourist cultural background on destination choice. It focuses on the UK and Venezuela, the two countries with significant cultural differences and forecast growth in outbound tourism. The study shows the distinct role of culture in tourist preferences for destination choice and structure of travel groups. The effect of culture is also recorded in how tourists research destinations prior to visit and perceive travel risks, thus ultimately influencing their motivation to travel. Recommendations are developed on how to integrate knowledge on the cultural background of tourists into tourism management and policy-making practices

Chikungunya virus adaptation to Aedes albopictus mosquitoes does not correlate with acquisition of cholesterol dependence or decreased pH threshold for fusion reaction

<p>Abstract</p> <p>Background</p> <p>Chikungunya virus (CHIKV) is a mosquito transmitted alphavirus that recently caused several large scale outbreaks/epidemics of arthritic disease in tropics of Africa, Indian Ocean basin and South-East Asia. This re-emergence event was facilitated by genetic adaptation (E1-A226V substitution) of CHIKV to a newly significant mosquito vector for this virus; <it>Aedes albopictus</it>. However, the molecular mechanism explaining the positive effect of the E1-A226V mutation on CHIKV fitness in this vector remains largely unknown. Previously we demonstrated that the E1-A226V substitution is also associated with attenuated CHIKV growth in cells depleted by cholesterol.</p> <p>Methods</p> <p>In this study, using a panel of CHIKV clones that varies in sensitivity to cholesterol, we investigated the possible relationship between cholesterol dependence and <it>Ae. albopictus </it>infectivity.</p> <p>Results</p> <p>We demonstrated that there is no clear mechanistic correlation between these two phenotypes. We also showed that the E1-A226V mutation increases the pH dependence of the CHIKV fusion reaction; however, subsequent genetic analysis failed to support an association between CHIKV dependency on lower pH, and mosquito infectivity phenotypes.</p> <p>Conclusion</p> <p>the E1-A226V mutation probably acts at different steps of the CHIKV life cycle, affecting multiple functions of the virus.</p

In Vitro and In Vivo Studies Identify Important Features of Dengue Virus pr-E Protein Interactions

Flaviviruses bud into the endoplasmic reticulum and are transported through the secretory pathway, where the mildly acidic environment triggers particle rearrangement and allows furin processing of the prM protein to pr and M. The peripheral pr peptide remains bound to virus at low pH and inhibits virus-membrane interaction. Upon exocytosis, the release of pr at neutral pH completes virus maturation to an infectious particle. Together this evidence suggests that pr may shield the flavivirus fusion protein E from the low pH environment of the exocytic pathway. Here we developed an in vitro system to reconstitute the interaction of dengue virus (DENV) pr with soluble truncated E proteins. At low pH recombinant pr bound to both monomeric and dimeric forms of E and blocked their membrane insertion. Exogenous pr interacted with mature infectious DENV and specifically inhibited virus fusion and infection. Alanine substitution of E H244, a highly conserved histidine residue in the pr-E interface, blocked pr-E interaction and reduced release of DENV virus-like particles. Folding, membrane insertion and trimerization of the H244A mutant E protein were preserved, and particle release could be partially rescued by neutralization of the low pH of the secretory pathway. Thus, pr acts to silence flavivirus fusion activity during virus secretion, and this function can be separated from the chaperone activity of prM. The sequence conservation of key residues involved in the flavivirus pr-E interaction suggests that this protein-protein interface may be a useful target for broad-spectrum inhibitors

Pericardial Patch Angioplasty Heals via an Ephrin-B2 and CD34 Positive Cell Mediated Mechanism

Pericardial patches are commonly used in vascular surgery to close arteriotomies. The mechanism of early healing after patch implantation is still not well defined. We used a rat aortic patch model to assess pericardial patch healing and examined Ephrin-B2, a marker of arterial identity, expression within the post-implantation patch. We also determined whether endothelial progenitor cells (EPC) are associated with early patch healing in the arterial environment.Wistar rats (200-250 grams) underwent infrarenal aortic arteriotomy and then closure via bovine or porcine pericardial patch angioplasty. Control groups included subcutaneously implanted patches. Patches were harvested at 0-30 days and analyzed by histology, immunohistochemistry, immunofluorescence and Western blot as well as quantitative PCR.Prior to implantation, pericardial patches are largely composed of collagen and are acellular. Following arterial implantation, increasing numbers of CD68-positive cells as well as Ephrin-B2 and CD34 dual-positive cells are found within both bovine and porcine pericardial patches, whereas the infiltrating cells are negative for vWF and α-actin. Porcine patches have a luminal monolayer of cells at day 7, compared to bovine patches that have fewer luminal cells. Subcutaneously implanted patches do not attract Ephrin-B2/CD34-positive cells. By day 30, both bovine and porcine pericardial patches develop a neointima that contains Ephrin-B2, CD34, and VEGFR2-positive cells.Both CD68-positive and Ephrin-B2 and CD34 dual-positive cells infiltrate the pericardial patch early after implantation. Arteriotomy closure via pericardial patch angioplasty shows patch adaptation to the arterial environment that may involve a foreign body response as well as localization of EPC. Arterial remodeling of pericardial patches support endothelialization and may represent a paradigm of healing of scaffolds used for tissue engineering