Hypercholesterolemia is one of the most important risk factors for development of cardiovascular diseases. The composition of gut microbiota (total microbes residing in the gut) impacts on cholesterol and lipid metabolism. On the contrary, alterations in gut microbiota in response to hypercholesterolemia or drug treatment with atorvastatin (a cholesterol-lowering agent) are rarely investigated. We performed 16S rDNA amplicon sequencing to evaluate the gut bacterial community of 15 untreated hypercholesterolemic patients (HP) and 27 atorvastatin-treated hypercholesterolemic patients (At-HP) and compared with 19 healthy subjects (HS). In total, 18 different phyla were identified in the study groups. An increase in relative abundance of Proteobacteria was observed in the HP group compared with At-HP and HS groups. The atherosclerosis-associated genus Collinsella was found at relatively higher abundance in the HP group. The anti-inflammation-associated bacteria (Faecalibacterium prausnitzii, Akkermansia muciniphila, and genus Oscillospira) were found in greater abundance, and proinflammatory species Desulfovibrio sp. was observed at decreased abundance in the drug-treated HP group compared with the untreated HP group. Relative abundances of the Bilophila wadsworthia and Bifidobacterium bifidum (bile acid-associated species) were decreased in the At-HP group. The At-HP and HS clustered separately from HP in the principal coordinate analysis. Decreased bacterial diversity was observed in the atorvastatin-treated group. In conclusion, these data suggest that atorvastatin treatment of patients with hypercholesterolemia may selectively restore the relative abundance of several dominant and functionally important taxa that were disrupted in the HP. Further studies are required to investigate the putative modifying effects of hypocholesterolemic drugs on functionality of gut microbiota, and the potential downstream effects on human health.

Genetic mutations in MED12, a subunit of Mediator complex are seen in a broad spectrum of human diseases. However, the underlying basis of how these pathogenic mutations elicit protein phenotype changes in terms of 3D structure, stability and protein binding sites remains unknown. Therefore, we aimed to investigate the structural and functional impacts of MED12 mutations, using computational methods as an alternate to traditional in vivo and in vitro approaches. The MED12 gene mutations details and their corresponding clinical associations were collected from different databases and by text-mining. Initially, diverse computational approaches were applied to categorize the different classes of mutations based on their deleterious impact to MED12. Then, protein structures for wild and mutant types built by integrative modeling were analyzed for structural divergence, solvent accessibility, stability, and functional interaction deformities. Finally, this study was able to identify that genetic mutations mapped to exon-2 region, highly conserved LCEWAV and Catenin domains induce biochemically severe amino acid changes which alters the protein phenotype as well as the stability of MED12-CYCC interactions. To better understand the deleterious nature of FS-IDs and Indels, this study asserts the utility of computational screening based on their propensity towards non-sense mediated decay. Current study findings may help to narrow down the number of MED12 mutations to be screened for mediator complex dysfunction associated genetic diseases. This study supports computational methods as a primary filter to verify the plausible impact of pathogenic mutations based on the perspective of evolution, expression and phenotype of proteins. J. Cell. Biochem. 117: 2023-2035, 2016. © 2016 Wiley Periodicals, Inc.

Table of contents O1 Regulation of genes by telomere length over long distances Jerry W. Shay O2 The microtubule destabilizer KIF2A regulates the postnatal establishment of neuronal circuits in addition to prenatal cell survival, cell migration, and axon elongation, and its loss leading to malformation of cortical development and severe epilepsy Noriko Homma, Ruyun Zhou, Muhammad Imran Naseer, Adeel G. Chaudhary, Mohammed Al-Qahtani, Nobutaka Hirokawa O3 Integration of metagenomics and metabolomics in gut microbiome research Maryam Goudarzi, Albert J. Fornace Jr. O4 A unique integrated system to discern pathogenesis of central nervous system tumors Saleh Baeesa, Deema Hussain, Mohammed Bangash, Fahad Alghamdi, Hans-Juergen Schulten, Angel Carracedo, Ishaq Khan, Hanadi Qashqari, Nawal Madkhali, Mohamad Saka, Kulvinder S. Saini, Awatif Jamal, Jaudah Al-Maghrabi, Adel Abuzenadah, Adeel Chaudhary, Mohammed Al Qahtani, Ghazi Damanhouri O5 RPL27A is a target of miR-595 and deficiency contributes to ribosomal dysgenesis Heba Alkhatabi O6 Next generation DNA sequencing panels for haemostatic and platelet disorders and for Fanconi anaemia in routine diagnostic service Anne Goodeve, Laura Crookes, Nikolas Niksic, Nicholas Beauchamp O7 Targeted sequencing panels and their utilization in personalized medicine Adel M. Abuzenadah O8 International biobanking in the era of precision medicine Jim Vaught O9 Biobank and biodata for clinical and forensic applications Bruce Budowle, Mourad Assidi, Abdelbaset Buhmeida O10 Tissue microarray technique: a powerful adjunct tool for molecular profiling of solid tumors Jaudah Al-Maghrabi O11 The CEGMR biobanking unit: achievements, challenges and future plans Abdelbaset Buhmeida, Mourad Assidi, Leena Merdad O12 Phylomedicine of tumors Sudhir Kumar, Sayaka Miura, Karen Gomez O13 Clinical implementation of pharmacogenomics for colorectal cancer treatment Angel Carracedo, Mahmood Rasool O14 From association to causality: translation of GWAS findings for genomic medicine Ahmed Rebai O15 E-GRASP: an interactive database and web application for efficient analysis of disease-associated genetic information Sajjad Karim, Hend F Nour Eldin, Heba Abusamra, Elham M Alhathli, Nada Salem, Mohammed H Al-Qahtani, Sudhir Kumar O16 The supercomputer facility “AZIZ” at KAU: utility and future prospects Hossam Faheem O17 New research into the causes of male infertility Ashok Agarwa O18 The Klinefelter syndrome: recent progress in pathophysiology and management Eberhard Nieschlag, Joachim Wistuba, Oliver S. Damm, Mohd A. Beg, Taha A. Abdel-Meguid, Hisham A. Mosli, Osama S. Bajouh, Adel M. Abuzenadah, Mohammed H. Al-Q...

The deleterious amino acid substitution mutations in IL-10 receptor alpha gene are most frequently reported in several autoimmune diseases including early onset-inflammatory bowel disease (IBD). Despite the important role of IL-10 RA in maintaining immune homeostasis, the specific structural and functional implications of these mutations on protein phenotype, stability, ligand binding and post translational characteristics is not well explored. Therefore, this study performed the multidimensional computational analysis of IL10RA missense variations causative to pediatric or early onset inflammatory bowel disease (<5 years of age). Our computational algorithmic screening identified the deleterious nature of p. W45G, p. Y57C, p. W69G, p.T84I, p.Y91C, p.R101W, p.R117C, and p.R117H, IBD causative IL10-RA mutations. The sensitivity and specificity analysis of different computational methods showed that CADD outperform SIFT, PolyPhen 2.0, FATHMM, LRT, MetaLR, MetaSVM, PROVEAN and Condel in predicting the pathogenicity of IL10RA mutations. Our three-dimensional protein modeling assays showed that the point mutations cause major drifts in the structural plasticity of IL10 RA molecule and negatively influence its stability. Findings from molecular docking analysis have shown that these point mutations decrease the binding affinity of IL10RA toward IL10 and may likely to disturb the IL10 signaling pathway. This study provides an easy frame work for phenotypic characterization of mutant IL10RA molecule in terms of structure, flexibility and stability aspects. Our approach may also add a new dimension to conventional functional biology assays in quickly studying IL10 RA mutations and also for designing and developing inhibitors for mutant IL10RA molecule.

Insulin-degrading enzyme (IDE) is a key protease involved in degrading insulin and amyloid peptides in human body. Several non-synonymous genetic mutations of IDE gene have been recently associated with susceptibility to both diabetes and Alzheimer's diseases. However, the consequence of these mutations on the structure of IDE protein and its substrate binding characteristics is not well elucidated. The computational investigation of genetic mutation consequences on structural level of protein is recently found to be an effective alternate to traditional in vivo and in vitro approaches. Hence, by using a combination of empirical rule and support vector machine based in silico algorithms, this study was able to identify that the pathogenic nonsynonymous genetic mutations corresponding to p.I54F, p.P122T, p.T533R, p.P581A and p.Y609A have more potential role in structural and functional deviations of IDE activity. Moreover, molecular modeling and secondary structure analysis have also confirmed their impact on the stability and secondary properties of IDE protein. The molecular docking analysis of IDE with combinational substrates has revealed that peptide inhibitors compared to small non-peptide inhibitor molecules possess good inhibitory activity towards mutant IDE. This finding may pave a way to design novel potential small peptide inhibitors for mutant IDE. Additionally by un-translated region (UTR) scanning analysis, two regulatory pathogenic genetic mutations i.e., rs5786997 (3' UTR) and rs4646954 (5' UTR), which can influence the translation pattern of IDE gene through sequence alteration of upstream-Open Reading Frame and Internal Ribosome Entry Site elements were identified. Our findings are expected to help in narrowing down the number of IDE genetic variants to be screened for disease association studies and also to select better competitive inhibitors for IDE related diseases.

Glutaminase (GLS) is an enzyme essential for amino acid metabolism; in particular, it acts as a catalyst in glutaminolysis, a reaction exploited by the malignant cells to meet the nutrient requirements for their accelerated growth and proliferation.

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The present study is designed for the assessment of various pathological changes like immunoglobins, C-reactive protein, vitamin D, sodium, potassium, calcium in stress-induced hypertensive rats. Albino Wistar rats of sex male were grouped into six. Each group consists of six animals. Groups were Group I (normal control), Group II (disease control), Group III (amlodipine control), Group IV (atenolol control), Group V (amlodipine treatment), and Group VI (atenolol treatment). Group II, V, and VI animals exposed to regular stress by placing them in cages individually and giving foot electric shocks (1 mA, 50 ms duration with 0.5-1 min of intervals regulated randomly by a computer) along with forced swimming (30 min) in order to induce hypertension in rats. This stress was given two times daily (morning and evening) for regular 15 days. Induction of hypertension was confirmed by measuring the tail arterial pressure of blood and angiotensin II. For next 1 month, Group III and V animals are treated with amlodipine with 1 mg/kg, s.c. dose while Group IV and VI animals were given 10 mg/kg, s.c. the dose of atenolol once daily. At the end of the experimental work, blood collected, rats sacrificed, and serum separated. Serum sodium, potassium, immunoglobins, C-reactive protein, vitamin D, and calcium were measured by semi-auto-analyzer. Stress-induced hypertension in rats produced altered serum sodium, potassium, immunoglobins, C-reactive protein, vitamin D, and calcium level which is restored by atenolol. Administration of amlodipine in animals without hypertension shows alteration in the level of immunoglobins, calcium, vitamin D, and electrolytes.