Evolutionary Pattern of Asian HIV-1 Subtype B from 1990 to 2007: In Silico Analysis Based on Envelop Protein

HIV-1 envelop gene is a major target for vaccine development. Envelop protein and its V3 loop is shown to be important determinant of HIV-1 pathogenecity. Herein, the evolutionary pattern of most prevalent HIV-1 subtype B in Asia is determined by analyzing envelop protein and V3 domain based on the 40 randomly selected sequences of HIV-1 from database (Los Alamos), divided into four groups since 1990–2007. Construction of envelop protein phylogeny by using MEGA 5 exhibit the active mutation pattern, increase in potential N-glycosylation sites which were predicted by using online software SignalP-NN. An online available tool Drawgram was used for multiple sequence alignment (MSA) of HIV-1 subtype B envelop region and V3 loop while the alignment was rechecked by using CLUSTAL W and further was analyzed for GPGX motif and conserved region in V3 loop. Variation at fourth position of the GPGX motif and 60% conservation was found in V3 loop. Hence, this diversifying pattern of envelop protein in the Asia formulates the HIV-1 strains more pathogenic during the period of 17 years. These findings might help in understanding significant structural and functional constrains of the mutant viral strains and ultimately in vaccine development

Sporadic early onset colorectal cancer in Pakistan: A case- control analysis of microsatellite instability

Background: Early onset sporadic colorectal cancer (CRC) is a biologically and clinically distinct entity hypothesized to exhibit differences in histological features and microsatellite instability (MSI) as compared to typical onset CRC. This study compared the MSI status, mismatch repair enzyme deficiency and clinicopathological features of early onset (aged ≤45 years) with controls (\u3e45 years).Materials and Methods: A total of 30 cases and 30 controls were analyzed for MSI status using the Bethesda marker panel. Using antibodies against hMLH1, hMSH2 and hMSH6, mismatch repair protein expression was assessed by immunohistochemistry. Molecular characteristics were correlated with clinicopathological features.Results: The early onset sporadic CRCs were significantly more poorly differentiated tumors, with higher N2 nodal involvement and greater frequency of signet ring phenotype than the typical onset cases. MSI was observed in 18/30 cases, with 12/18 designated as MSI-high (MSI-H) and 6/18 designated as MSI-low (MSI-L). In the control group, 14 patients exhibited MSI, with 7 MSI-H and 7 MSI-L. MSI tumors in both cases and controls exhibited loss of hMLH1, hMSH2 and hMSH6. MSS tumors did not exhibit loss of expression of MMR proteins, except hMLH1 protein in 3 controls. No statistically significant difference was noted in MSI status or expression of MMR proteins in cases versus controls.Conclusions: Microsatellite status is comparable between early and typical onset sporadic CRC patients in Pakistan suggesting that differences in clinicopathological features between these two subsets are attributable to other molecular mechanisms

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

Global diversity of HCV: In-silico analysis based on core region

Abstract Hepatitis C virus is a devastating virus, known to mankind since 1989, but circulating in the human blood for centuries. Viral prevalence and incidences rates vary from country to country. This study is basically a computational analysis based on core gene of HCV conducted to understand the pattern of evolution of HCV around the globe. The nucleotide and protein sequences were retrieved from HCV database and were analyzed by using ClustalW for alignment of sequences and MEGA 4 was used for construction of phylogenetic tree to see the evolutionary pattern of HCV in five different continents of world. In-silico analysis of HCV core gene shows that it has undergone various diversifications in core region worldwide showing different evolutionary rates measured by the Neighbour Joining method. The number of chains varies in the core structure without affecting the overall phenotypic expression

Evaluation of biological potential of selected species of family Poaceae from Bahawalpur, Pakistan

Abstract Background Oxidative stress as well as bacterial and fungal infections are common source of diseases while plants are source of medication for curative or protective purposes. Hence, aim of study was to compare the pharmacological potential of seven grass species in two different solvents i.e. ethanol and acetone. Methods Preliminary phytochemical tests were done and antioxidant activities were evaluated using ELISA and their IC50 values and AAI (%) were recorded. ANOVA was used for statistical analyses. DNA damage protection assay was done using p1391Z plasmid DNA and DNA bands were analyzed. Antimicrobial activity was done via disc diffusion method and MIC and Activity Index were determined. Cytotoxic activity was carried out using the brine shrimps’ assay and LC50 values were calculated using probit analysis program. Results Phytochemical studies confirmed the presence of secondary metabolites in most of the plant extracts. Maximum antioxidant potential was revealed in DiAEE, DiAAE (AAI- 54.54% and 43.24%) and DaAEE and DaAAE (AAI- 49.13% and 44.52%). However, PoAEE and PoAAE showed minimum antioxidant potential (AAI- 41.04% and 34.11%). SaSEE, DiAEE and ElIEE showed very little DNA damage protection activity. In antimicrobial assay, DaAEE significantly inhibited the growth of most of the microbial pathogens (nine microbes out of eleven tested microbes) among ethanol extracts while DaAAE and ImCAE showed maximum inhibition (eight microbes out of eleven tested microbes) among acetone plant extracts. However, PoAEE and PoAAE showed least antimicrobial activity. F. oxysporum and A. niger were revealed as the most resistant micro-organisms. ImCEA and ImCAE showed maximum cytotoxic potential (LC50 11.004 ppm and 7.932 ppm) as compared to the other plant extracts. Conclusion Fodder grasses also contains a substantial phenols and flavonoids contents along with other secondary metabolites and, hence, possess a significant medicinal value. Ethanol extracts showed more therapeutic potential as compared to the acetone extracts. This study provides experimental evidence that the selected species contains such valuable natural compounds which can be used as medicinal drugs in future

Natural Products Mediated Targeting of Virally Infected Cancer

The role of viral infection in developing cancer was determined in the start of 20th century. Until now, 8 different virus-associated cancers have been discovered and most of them progressed in immunosuppressed individuals. The aim of the present study is to look into the benefits of natural products in treating virally infected cancers. The study focuses on bioactive compounds derived from natural sources. Numerous pharmaceutical agents have been identified from plants (vincristine, vinblastine, stilbenes, combretastatin, and silymarin), marine organisms (bryostatins, cephalostatin, ecteinascidins, didemnin, and dolastatin), insects (cantharidin, mastoparan, parectadial, and cecropins), and microorganisms (vancomycin, rhizoxin, ansamitocins, mitomycin, and rapamycin). Beside these, various compounds have been observed from fruits and vegetables which can be utilized in anticancer therapy. These include curcumin in turmeric, resveratrol in red grapes, S-allyl cysteine in allium, allicin in garlic, catechins in green tea, and β-carotene in carrots. The present study addresses various types of virally infected cancers, their mechanism of action, and the role of different cell surface molecules elicited during viral binding and entry into the target cell along with the anticancer drugs derived from natural products by targeting screening of bioactive compounds from natural sources

Schemas Mediate the Link Between Procrastination and Depression: Results from the United States and Pakistan

The current study extended the Procrastination-Health model by examining a multiple mediation model, with two cognitive schemas (defectiveness; insufficient self-control) serving as mediators. The models were as follows: procrastination → defectiveness → depression; procrastination → insufficient self-control → depression. Participants included 412 (271 women, 141 men) United States (US) and 240 (107 women, 133 men) Pakistani college students, who responded via self-report questionnaires. In the US sample, results revealed a non-significant direct effect between procrastination and depression after consideration for the two cognitive schemas, suggesting the schemas completely mediated the model. Both defectiveness and insufficient self-control schemas were significant individual mediators. In the Pakistani model, results revealed a significant direct effect and indirect effect through the two cognitive schemas, indicating partial mediation. Only the indirect path through defectiveness schemas was significant in the Pakistani model. Given slight differences in the two models, a moderated-mediation model was analyzed to determine if the strength of the direct and indirect effects varied by nationality. The strength of the direct and indirect effects was not moderated by nationality. Overall, this is the first study to identify cognitive mediators in the procrastination-depression relationship. Such findings represent a significant extension of the Procrastination-Health model and offer some unique cognitive insights into culturally sensitive conceptualizations and treatments for depression

Hepatocellular carcinoma: targeting of oncogenic signaling networks in TRAIL resistant cancer cells

Apoptotic response in hepatocellular carcinoma (HCC) cells is impaired because of interconnectivity of proteins into complexes and signaling networks that are highly divergent in time and space. TNF-related apoptosis-inducing ligand (TRAIL) has emerged as an attractive anticancer agent reported to selectively induce apoptosis in cancer cells. Although diametrically opposed roles of TRAIL are reported both as an inducer of apoptosis and regulator of metastasis, overwhelmingly accumulating experimental evidence highlighting apoptosis inducing activity of TRAIL is directing TRAIL into clinical trials. Insights from TRAIL mediated signaling in HCC research are catalyzing new lines of study that should not only explain molecular mechanisms of disease but also highlight emerging paradigms in restoration of TRAIL mediated apoptosis in resistant cancer cells. It is becoming progressively more understandable that phytochemicals derived from edible plants have shown potential in modelling their interactions with their target proteins. Rapidly accumulating in vitro and in-vivo evidence indicates that phytonutrients have anticancer activity in rodent models of hepatocellular carcinoma. In this review we bring to limelight how phytonutrients restore apoptosis in hepatocellular carcinoma cells by rebalancing pro-apoptotic and anti-apoptotic proteins. Evidence has started to emerge, that reveals how phytonutrients target pharmacologically intractable proteins to suppress cancer. Target-based small-molecule discovery has entered into the mainstream research in the pharmaceutical industry and a better comprehension of the genetics of patients will be essential for identification of responders and non-responders