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INTRODUCTION Metabolic Syndrome (MetS) constitutes an important risk factor for Alzheimer's disease (AD); however, the mechanism linking these two disorders has not been completely elucidated. Hence, hypercoagulation may account for the missing hallmark connecting MetS and AD. The present review proposes how hemostatic imbalance triggered in MetS advances in the context of AD. MetS causes interruption of insulin signaling and inflammation, inciting insulin resistance in the brain. Subsequently, neuroinflammation and brain endothelial dysfunction are prompted that further intensify the exorbitant infiltration of circulating lipids and platelet aggregation, thereby causing hypercoagulable state, impairing fibrinolysis and eventually inducing prothrombic state in the brain leading to neurodegeneration. OBJECTIVE This study aims to understand the role of hypercoagulation in triggering the progression of neurodegeneration in MetS. It also offers a few interventions to prevent the progression of AD in MetS targeting hypercoagulation. METHODS Literature studies based on MetS related neurodegeneration, the impact of coagulation on aggravating obesity and AD via the mechanisms of BBB disruption, neuroinflammation, and hypofibrinolysis. CONCLUSION The present paper proposes the hypothesis that hypercoagulation might amplify MetS associated insulin resistance, neuroinflammation, BBB disruption, and amyloid beta accumulation which eventually leads to AD.

This study’s aim is to investigate the role of e-governance in combating COVID-19 by integrating the implications of the China–Pakistan Economic Corridor (CPEC). We discuss and analyze the E-Government Development Index (EGDI) reports and rankings issued by the United Nations and big data implications during the COVID-19 pandemic. We used the Origin-pro 2018 application for the analysis and discussion. Overall, China’s EGDI ranking has improved from 74 to 65 out of 193 countries, while Pakistan’s ranking has gradually declined from 137 to 148. 5G and other big data technology and e-governance implications have helped to combat the COVID-19 pandemic. In this pandemic scenario, sustainable socioeconomic development in Pakistan needs significant improvement, similar to what has been done by China. We conclude that CPEC can help combat the COVID-19 pandemic because both countries are working together to mitigate social and economic problems. Pakistan should adapt and learn from the Government of China’s experience of successful and proficient e-governance model of technological advancement. This effort will ensure successful CPEC regional extension and help combat the COVID-19 pandemic to ensure Pakistan’s sustainable development.

Chlorpyrifos (CPF) is an extensively used organophosphate pesticide for crop protection. However, there are concerns of it contaminating the environment and human health with estimated three lakh deaths annually. Detection of CPF in blood samples holds significance to avoid severe health outcomes due to continuous exposure. The most common techniques for CPF detection are Gas chromatography (GC) and high-performance liquid chromatography (HPLC). However, these techniques might not be feasible at the community healthcare level due to high-cost instrumentation, time-consuming sample preparation protocol and skilled analysts. Therefore, rapid, effective and economical methods such as immunoassay would be imperative for CPF detection in biological samples. The vital step in immunoassay development is the design of a potent immunogen from non-immunogenic molecules. The molecular modelling protocol could assist in redesigning known CPF linkers and inserting them at different substitutable positions of CPF to get distinctive CPF derivatives. Molecular docking and binding free energy analysis can be used to identify the CPF derivatives having a better binding affinity with carrier protein compared to CPF. The top-ranked CPF derivatives based on docking score and binding energy could be ideal for synthesis and immunogen development. The present review will comprehend technological trends in immunoassay kits for detecting chlorpyrifos from biological samples.

Protein–protein interactions of Interleukin-17 (IL17) play vital role in the autoimmune and inflammatory diseases, such as rheumatoid arthritis, multiple sclerosis, and psoriasis. Potent therapeutics for these diseases could be developed by blocking or modulating these interactions through biologics, peptide inhibitors and small molecule inhibitors. Unlike biologics, peptide inhibitors are cost effective and can be orally available. Peptide inhibitors do not require a binding groove as that of small molecules either. Therefore, crystal structure of IL17A in complex with a high affinity peptide inhibitor (HAP) (1-IHVTIPADLWDWIN-14) is investigated with an aim to find hot spots that could improve its potency. An in silico mutagenesis strategy was implemented using FoldX PSSM to scan for positions tolerant to amino acid substitution. Three positions T4, A7, and N14 showed improved stability when mutated with ‘F/M/Y’, ‘P’ and ‘F/M/Y’, respectively. A set of 31 mutant peptides are designed through combinations of these tolerant mutations using Build Model application of FoldX. Binding affinity and interactions of 31 peptides are assessed through protein–peptide docking and binding free energy calculations. Two peptides namely, P1 (“1-IHVTIPPDLWDWIY-14”) and P2 (“1-IHVMIPPDLWDWIF-14”) showed better binding affinity to IL17A dimerization site compared to HAP. Interactions of P1, P2 and HAP are also analyzed through 100 ns molecular dynamics simulations using GROMACS v5.0. The results revealed that the P2 peptide likely to offer better potency compared to HAP and P1. Therefore, the P2 peptide can be synthesized to develop oral therapies for autoimmune and inflammatory diseases with further experimental evaluations. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13205-021-02856-y.

The recent outbreaks of Zika virus and the absence of a specific therapy have necessitated to identify T-cell-stimulating antigenic peptides as potential subunit vaccine candidates. The translated ssRNA (+) genome of Zika virus was explored in EMBOSS antigenic and VaxiJen to predict 63 peptides as potential antigens. Three MHC-II binding peptide prediction tools, viz. NetMHCIIpan, PREDIVAC and immune epitope database (IEDB) were employed in consensus on 63 antigenic peptides to propose 14 T-helper cell epitopes. Similarly, analysis on 63 antigenic peptides through NetMHC, NetCTL and IEDB MHC-I binding peptide prediction tool led to identification of 14 CTL epitopes. Seven T-cell epitopes, C:44-66, M:135-149, NS2A:124-144, NS3:421-453, NS3:540-554, NS4B:90-134 and NS4B:171-188, are observed to share overlapping MHC-I and MHC-II binding motifs and hence, are being proposed to constitute minimum T-cell antigens to elicit protective T-cell immune response against Zika. Three of them, C:44-66, NS3:421-453 and NS3:540-554 are identified to be conserved across all the selected strains of Zika virus. Moreover, the 21 T-cell epitopes are non-self to humans and exhibited good coverage in variable populations of 14 geographical locations. Therefore, 21 T-cell epitopes are proposed as potential subunit vaccines against Zika virus. Electronic supplementary material The online version of this article (10.1007/s12539-017-0238-3) contains supplementary material, which is available to authorized users.

Patients with congestive heart failure (CHF) have a high prevalence of cognitive impairment and the association is multifactorial. In general, the burden of anticholinergic drugs has consistently been shown to be a risk factor for cognitive impairment in the elderly. The aim of this study was to assess the cognitive burden of medications in patients with CHF.This was a cross-sectional, retrospective, single-center study.The study was conducted in an outpatient setting.Patients who presented to a comprehensive heart failure clinic during a 1-month period were included.The primary outcomes of interest were mean anticholinergic cognitive burden (ACB) score of all medications and CHF medications (ACB-CHF), calculated based on the ACB Scoring Scale (ACB-SS). The ACB-CHF score was further dichotomized as 0 or 1 (low anticholinergic burden) versus 2 or 3 (high anticholinergic burden).A total of 182 patients were included. The mean ACB and ACB-CHF scores were 2.4 (range 0-13) and 1.0 (range 0-4), respectively, while 25.8 % of patients had an ACB-CHF score of 2 or 3. There was no association found between ejection fraction in patients with systolic heart failure and the ACB (p = 0.28) or ACB-CHF (p = 0.62) score.We conclude that patients with CHF have a substantial exposure to anticholinergic medications with adverse cognitive effects. This may be another important contributor to the increased prevalence of cognitive impairment in these patients.

The present study evaluated the plausible role of circulating biomarkers in immune pathogenesis of chronic hepatitis considered a priority in clinical hepatology. Total viral load of chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) patients was quantified and correlation studies were performed with circulating levels of Th1/Th2 cytokines; C reactive protein and circulating nucleosomes; glutathione reductase (GR) and superoxide dismutase. To our knowledge, the study is first among its kind that validates strong positive correlation of viral load with IL-4, IL-6, GR in HBV and IL-6, IL-10, GR in HCV infections. Although, multi-centric studies including large cohorts are required for translating our findings to clinical practice, however, role of these biomarkers with potential diagnostic or prognostic significance might be helpful in clinical assessment of high-risk individuals, thereby, designing interventional strategies, towards development of personalized medicare. The results of our study also offer valuable insights of immune signaling mediators engaged in development of hepatocellular carcinoma.

The present study was designed to probe the possible role of singlet oxygen and superoxide anion radical modified DNA in the etiopathogenesis of Systemic lupus erythematosus. These species were generated by the exposure of riboflavin to 365 nm UV light. Modified DNA showed single strand breaks, hyperchromicity at 260nm and decrease in Tm. The modified DNA induced high titer antibodies in experimental animals. The antibodies showed reactivity with various nucleic acid polymers, a property commonly associated with Systemic lupus erythematosus anti-DNA autoantibodies. Systemic lupus erythematosus sera showed preferential binding of modified DNA over native DNA in direct binding and competitive binding solid phase immunoassays and band shift assays. The results suggest for the possible involvement of the singlet- superoxide modified DNA as a potential trigger for anti- DNA autoantibody production in SLE and thus in the etiopathogenesis of the disease.

Summary Half of Métis citizens, compared to less than 10 % of the general population of Ontario, reside in northern regions, with little access to bone mineral density (BMD) testing. Métis citizens had lower sex-specific and age-standardized rates of BMD testing, yet similar rates of fracture (both sexes) and pharmacotherapy (women only). Purpose To examine osteoporosis management and common osteoporosis-related fractures among Métis citizens compared to the general population of older adults residing in Ontario. Methods We linked healthcare (medical and pharmacy) utilization and administrative (demographic) databases with the Métis Nation of Ontario citizenship registry to estimate osteoporosis management (bone mineral density [BMD] testing, pharmacotherapy) and fractures (hip, humerus, radius/ulna) among adults aged ≥50 years, from April 1, 2006 to March 31, 2011. Pharmacotherapy data were limited to residents aged ≥65 years. Sex-specific and age-standardized rates were compared between the Métis and the general population. Multivariable logistic regression was used to compare rates of BMD testing after controlling for differences in age and region of residence between the Métis and the general population. Results We studied 4219 Métis citizens (55 % men), and 140 (3 %) experienced a fracture. Half of Métis citizens, compared to less than 10 % of the general population of Ontario, resided in northern regions. We identified significantly lower sex-specific and age-standardized rates of BMD testing among Métis compared to the general population, yet found little difference in fracture rates (both sexes) or pharmacotherapy (women only). Differences in BMD testing disappeared after adjusting for region of residence among women yet remained significant among men. Conclusions Despite finding significantly lower rates of osteoporosis management among men, Métis men and women were found to have similar age-standardized fracture rates to the general population.

Sirtuins are a class of enzymes originally identified as nicotinamide adenine dinucleotide (NAD)-dependent protein lysine deacetylases. Among the seven mammalian sirtuins, SIRT1-7, only SIRT1-3 possess efficient deacetylase activity in vitro, whereas SIRT4-7 possess very weak in vitro deacetylase activity. Several sirtuins that exhibit weak deacetylase activity have recently been shown to possess more efficient activity for the removal other acyl lysine modifications, such as succinyl lysine and palmitoyl lysine. Here, we demonstrate that even the well-known deacetylase SIRT2 possesses efficient activity for the removal of long-chain fatty acyl groups. The catalytic efficiency (kcat/Km) for the removal of a myristoyl group is slightly higher than that for the removal of an acetyl group. The crystal structure of SIRT2 in complex with a thiomyristoyl peptide reveals that SIRT2 possesses a large hydrophobic pocket that can accommodate the myristoyl group. Comparison of the SIRT2 acyl pocket to those of SIRT1, SIRT3 and SIRT6 reveals that the acyl pockets of SIRT1-3 are highly similar and to a lesser degree, similar to that of SIRT6. The efficient in vitro demyristoylase activity of SIRT2 suggests that this activity may be physiologically relevant and warrants future investigative studies.

The human kallikrein gene 10 (KLK10) is a member of the kallikrein gene family on chromosome 19q13.4. This gene was identified by its downregulation in breast cancer, and preliminary evidence suggests that it may act as a tumor suppressor. A computer-based analysis was performed on EST and SAGE clones from the Cancer Genome Anatomy Project and other databases. Experimental verification of differential expression of KLK10 in cancer was performed by PCR using gene-specific primers. The mRNA and EST analysis allowed the construction of the longest transcript of the gene and characterization of a 5' extension of the reported mRNA. In addition, seven new splice variants of KLK10 were identified. One of these variants, named KLK10 splice variant 3 (KLK10-SV3) which starts with a novel first exon, was experimentally verified. This variant is predicted to encode for the same protein as the 'classical' KLK10 mRNA, since the first exon is untranslated. One variant mRNA partially matches with the sequence of KLK10, while the rest of the mRNA matches with a portion of the polycystic kidney disease gene, found on chromosome 15. This variant could not be experimentally verified in either normal or cancerous tissues. There are 39 reported single nucleotide polymorphisms (SNPs) for the gene, in which three result in amino acid substitutions. SAGE analysis shows a clear upregulation of KLK10 in ovarian, pancreatic, colon, and gastric cancers. The gene is, however, downregulated in breast and prostate cancers. A three-fold decrease in expression levels was noted in actinic keratosis, compared to normal skin from the same patient. The differential regulation of KLK10 in ovarian and prostate cancers was experimentally verified by RT-PCR analysis. In addition, a significant number of clones were isolated from carcinomas of the head and neck. Fewer clones were found in carcinomas of the skin, brain and prostate. Orthologues were identified in three other species, with the highest degree of homology observed with the mouse and rat orthologues (42% in each). In conclusion new splice variants of the KLK10 gene were identified. These in silico analyses show a differential expression of the gene in various malignancies and provide the basis for directing experimental efforts to investigate the possible role of the gene as a cancer biomarker.

Kallikreins are a family of 15 serine proteases clustered together on the long arm of chromosome 19. Recent reports have linked kallikreins to malignancy. The human kallikrein gene 6 (KLK6) is a newly characterized member of the human kallikrein gene family. Recent work has focused on the possible role of this gene and its protein product as a tumor marker and its involvement in diseases of the central nervous system. In this study, we performed extensive in silico analyses of KLK6 expression from different databases using various bioinformatic tools. These data enabled us to construct and verify the longest transcript for this kallikrein, to identify several polymorphisms among published sequences and to summarize the 21 single-nucleotide polymorphisms of the gene. Our expressed sequence tag (EST) analyses suggest the existence of seven new splice variants of the gene, in addition to the already reported ones. Most of these variants were identified in libraries from cancerous tissues. KLK6 orthologues were identified from three other species with approximately 86% overall homology with rat and mouse orthologues. We also utilized several databases to compare KLK6 gene expression in normal and cancerous tissues. The serial analysis of gene expression and EST expression profiles showed upregulation of the gene in female genital (ovarian and uterine) and gastrointestinal (gastric, colon, esophageal and pancreatic) cancers. Significant downregulation was observed in breast cancers and brain tumors, in relation to their normal counterparts.