Ligand based pharmacophore modelling of anticancer histone deacetylase inhibitors

Histone deacetylases have emerged as an important therapeutic target for the treatment of cancer. Genome-wide histone hypoacetylation causes many cancers. Recently, inhibitors of histone deacetylases (HDAC) have emerged as an important class of anticancer agents. Various side effectslike myocardium damage and bone marrow depression even leading to cell death have been observed in the treatment of caner cells using HDAC inhibitors. The discovery and development of type-specific HDAC inhibitors is of both research and clinical interests. Ligand based pharmacophore modelling is playing a key role for the identification of ligand features for the particular targets. We present a model for designing the pharmacophore onto the set of 70 compounds of three different classes and two subclasses. The ligand based pharmacophore model has been identified in order to facilitate the discovery of type specific anticancer HDAC inhibitors. The result indicates that the in silico methodsare useful in predicting the biological activity of the compound or compound library by screening it against a predicted pharmacophore. Ligand Scout 2.02 has been used to predict the pharmacophorefeatures for anticancer HDAC inhibitors and the distances between pharmacophore features have been calculated through the software Jmol. The proposed model has been validated by docking the MS275compound into the binding pocket of Human HDAC8. Our discovery will help in the identification of more specific anticancer human HDAC inhibitors

Women’s perception and attitude towards male dominancy and controlling behaviors

Introduction/Background: The study was conducted in urban Karachi, Pakistan to investigate women’s perceptions and attitudes towards male dominancy, female autonomy, and controlling behavior of husbands. Method: This was investigated in a population based study with a cross-sectional design, involving married women aged 25 to 60 years. A Structured questionnaire developed by World Health Organisation (WHO) on violence was used. Community midwives interviewed these married women living in pre-selected low, middle and upper socio-economic areas of urban Karachi, Pakistan.Findings: This study revealed women’s overall perception regarding male dominancy and controlling behavior and highlighted this attitude, as being acceptable to women. It was found that 96.7% (n=734) of females perceived their husband as authority figure in the family and 99.2% (n=753) consider themselves as good wives by being obedient to their husbands. Not only this, 88.9% (n=675) females perceived performing sex unwillingly with their husbands as an obligation. Conclusion: Perceptions of women regarding gender discrimination and male dominancy play a vital role in accepting gender discrimination. This study identified the declining status of women as compared to men in marital life due to various socio-cultural and religious beliefs, which promote controlling behaviour by the male partner. This is the result of learned behaviour and social norms in a patriarchal society adapted by women

Novel variants underlying autosomal recessive intellectual disability in Pakistani consanguineous families

Background: Intellectual disability (ID) is both a clinically diverse and genetically heterogeneous group of disorder, with an onset of cognitive impairment before the age of 18 years. ID is characterized by significant limitations in intellectual functioning and adaptive behaviour. The identification of genetic variants causing ID and neurodevelopmental disorders using whole-exome sequencing (WES) has proven to be successful. So far more than 1222 primary and 1127 candidate genes are associated with ID. Methods: To determine pathogenic variants causative of ID in three unrelated consanguineous Pakistani families, we used a combination of WES, homozygosity-by-descent mapping, de-deoxy sequencing and bioinformatics analysis. Results: Rare pathogenic single nucleotide variants identified by WES which passed our filtering strategy were confirmed by traditional Sanger sequencing and segregation analysis. Novel and deleterious variants in VPS53, GLB1, and MLC1, genes previously associated with variable neurodevelopmental anomalies, were found to segregate with the disease in the three families. Conclusions: This study expands our knowledge on the molecular basis of ID as well as the clinical heterogeneity associated to different rare genetic causes of neurodevelopmental disorders. This genetic study could also provide additional knowledge to help genetic assessment as well as clinical and social management of ID in Pakistani familie

Histopathological changes and antioxidant responses in common carp (Cyprinus carpio) exposed to copper nanoparticles

This is the author accepted manuscript. The final version is available from Taylor & Francis via the DOI in this recordDespite the rapid increase of nanotechnology in a wide array of industrial sectors, the biosafety profile of nanomaterials remains undefined. The accelerated use of nanomaterials has increased the potential discharge of nanomaterials into the environment in different ways. The aquatic environment is mainly susceptible as it is likely to act as an ultimate sink for all contaminants. Therefore, this study assessed the toxicological impacts of waterborne engineered copper nanoparticles (Cu-NPs) on histology, lipid peroxidation (LPO), catalase (CAT), and glutathione (GSH) levels in the gills of common carp (Cyprinus carpio). Nanoparticles were characterized by XRD and SEM techniques. Before starting the sub-acute toxicity testing, 96 h LC50 of Cu-NPs for C. carpio was calculated as 4.44 mg/l. Then based on LC50, C. carpio of 40–45 g in weight were exposed to three sub-lethal doses of waterborne engineered Cu-NPs (0 or 0.5 or 1 or 1.5 mg/l) for a period of 14 days. The waterborne Cu-NPs have appeared to induce alterations in gill histology and oxidative stress parameters in a dose-dependent manner. The gill tissues showed degenerative secondary lamellae, necrotic lamella, fused lamella, necrosis of the primary and secondary lamella, edema, complete degeneration, epithelial lifting, degenerative epithelium, and hyperplasia in a dose-dependent manner. In the gill tissues, waterborne Cu-NPs caused a decreased level of CAT and elevated levels of LPO, and GSH in the fish exposed to the highest dose of 1.5 mg Cu-NPs/l of water. Our results indicate that the exposure to waterborne Cu-NPs was toxic to the aquatic organisms as shown by the oxidative stresses and histological alterations in C. carpio, a freshwater fish of good economic value

Isothermal Plasma Wave Properties of the Schwarzschild de-Sitter Black Hole in a Veselago Medium

In this paper, we study wave properties of isothermal plasma for the Schwarzschild de-Sitter black hole in a Veselago medium. We use ADM 3+1 formalism to formulate general relativistic magnetohydrodynamical (GRMHD) equations for the Schwarzschild de-Sitter spacetime in Rindler coordinates. Further, Fourier analysis of the linearly perturbed GRMHD equations for the rotating (non-magnetized and magnetized) background is taken whose determinant leads to a dispersion relation. We investigate wave properties by using graphical representation of the wave vector, the refractive index, change in refractive index, phase and group velocities. Also, the modes of wave dispersion are explored. The results indicate the existence of the Veselago medium.Comment: 24 pages, 12 figures, accepted for publication in Astrophys. Space Sci. arXiv admin note: text overlap with arXiv:1101.0884 and arxiv:1007.285

Youth Culturally adapted Manual Assisted Problem Solving Training (YCMAP) in Pakistani adolescent with a history of self-harm: protocol for multicentre clinical and cost-effectiveness randomised controlled trial

Introduction: Suicide is a global health concern. Sociocultural factors have an impact on self-harm and suicide rates. In Pakistan, both self-harm and suicide are considered as criminal offence’s and are condemned on both religious and social grounds. The proposed intervention ‘Youth Culturally Adapted Manual Assisted Problem Solving Training (YCMAP)’ is based on principles of problem-solving and cognitive–behavioural therapy. YCMAP is a brief, culturally relevant, scalable intervention that can be implemented in routine clinical practice if found to be effective. Method and analysis: A multicentre rater blind randomised controlled trial to evaluate the clinical and cost-effectiveness of YCMAP including a sample of 652 participants, aged 12–18 years, presenting to general physicians/clinicians, emergency room after self harm or self referrals. We will test the effectiveness of 8–10 individual sessions of YCMAP delivered over 3 months compared with treatment as usual. Primary outcome measure is repetition of self-harm at 12 months. The seconday outcomes include reduction in suicidal ideation, hopelessness and distress and improvement in health related quality of life. Assessments will be completed at baseline, 3, 6, 9 and 12 months postrandomisation. The nested qualitative component will explore perceptions about management of self-harm and suicide prevention among adolescents and investigate participants’ experiences with YCMAP. The study will be guided by the theory of change approach to ensure that the whole trial is centred around needs of the end beneficiaries as key stakeholders in the process. Ethics and dissemination: Ethics approval has been obtained from the Ethics Committee of University of Manchester, the National Bioethics Committee in Pakistan. The findings of this study will be disseminated through community workshops, social media, conference presentations and peer-reviewed journals. Trial registration number: NCT04131179

Lack of association of rs3798220 with small apolipoprotein(a) isoforms and high lipoprotein(a) levels in East and Southeast Asians

OBJECTIVE : The variant allele of rs3798220 in the apolipoprotein(a) gene (LPA) is used to assess the risk for coronary artery disease (CAD) in Europeans, where it is associated with short alleles of the Kringle IV-2 (KIV-2) copy number variation (CNV) and high lipoprotein(a) (Lp(a)) concentrations. No association of rs3798220 with CAD was detected in a GWAS of East Asians. Our study investigated the association of rs3798220 with Lp(a) concentrations and KIV-2 CNV size in non-European populations to explain the missing association of the variant with CAD in Asians. METHODS : We screened three populations from Africa and seven from Asia by TaqMan Assay for rs3798220 and determined KIV-2 CNV sizes of LPA alleles by pulsed-field gel electrophoresis (PFGE). Additionally, CAD cases from India were analysed. To investigate the phylogenetic origin of rs3798220, 40 LPA alleles from Chinese individuals were separated by PFGE and haplotyped for further SNPs. RESULTS : The variant was not found in Africans. Allele frequencies in East and Southeast Asians ranged from 2.9% to 11.6%, and were very low (0.15%) in CAD cases and controls from India. The variant was neither associated with short KIV-2 CNV alleles nor elevated Lp(a) concentrations in Asians. CONCLUSION : Our study shows that rs3798220 is no marker for short KIV-2 CNV alleles and high Lp(a) in East and Southeast Asians, although the haplotype background is shared with Europeans. It appears unlikely that this SNP confers atherogenic potential on its own. Furthermore, this SNP does not explain Lp(a) attributed risk for CAD in Asian Indians.http://www.elsevier.com/locate/atherosclerosis2016-10-31hb2016Chemical Patholog

Human papillomavirus and Epstein-Barr virus infections in breast cancer from chile

<p>Abstract</p> <p>Background</p> <p>Human papillomavirus (HPV) and Epstein Barr virus (EBV) have been found in breast carcinomas (BCs) around the world. In this study, fifty-five BCs from Chile were analyzed for HPV and EBV presence. In addition, HPV-16 viral load/physical status and E6/E7 expressions were determined.</p> <p>Results</p> <p>The amplification of a housekeeping gene showed that 46/55 samples (84%) had amplifiable DNA. HPV-16 was detected in 4/46 BCs (8.7%) and EBV was detected in 3/46 (6.5%) BCs. The analysis of HPV-16 physical status showed that this virus was integrated in all of the tumors with a relatively low viral load (range: 0.14 to 33.8 copies/cell). E6 and E7 transcripts, however, were not detected in any HPV-16 positive specimens. Using a Cox-regression model, we found a statistically significant association between EBV presence and poor survival (p = 0.013).</p> <p>Conclusions</p> <p>The findings in this study suggest that it is unlikely that HPV and/or EBV play a direct role in the etiology of BC.</p