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https://www.readbyqxmd.com/read/28445521/next-generation-sequencing-to-dissect-the-genetic-architecture-of-kng1-and-f11-loci-using-factor-xi-levels-as-an-intermediate-phenotype-of-thrombosis
#1
Laura Martin-Fernandez, Giovana Gavidia-Bovadilla, Irene Corrales, Helena Brunel, Lorena Ramírez, Sonia López, Juan Carlos Souto, Francisco Vidal, José Manuel Soria
Venous thromboembolism is a complex disease with a high heritability. There are significant associations among Factor XI (FXI) levels and SNPs in the KNG1 and F11 loci. Our aim was to identify the genetic variation of KNG1 and F11 that might account for the variability of FXI levels. The KNG1 and F11 loci were sequenced completely in 110 unrelated individuals from the GAIT-2 (Genetic Analysis of Idiopathic Thrombophilia 2) Project using Next Generation Sequencing on an Illumina MiSeq. The GAIT-2 Project is a study of 935 individuals in 35 extended Spanish families selected through a proband with idiopathic thrombophilia...
2017: PloS One
https://www.readbyqxmd.com/read/28445411/discovery-of-farnesoid-x-receptor-antagonists-based-on-a-library-of-oleanolic-acid-3-o-esters-through-diverse-substituent-design-and-molecular-docking-methods
#2
Shao-Rong Wang, Tingting Xu, Kai Deng, Chi-Wai Wong, Jinsong Liu, Wei-Shuo Fang
The pentacyclic triterpene oleanolic acid (OA, 1) with known farnesoid X receptor (FXR) modulatory activity was modified at its C-3 position to find new FXR-interacting agents. A diverse substitution library of OA derivatives was constructed in silico through a 2D fingerprint similarity cluster strategy. With further docking analysis, four top-scored OA 3-O-ester derivatives were selected for synthesis. The bioassay results indicated that all four compounds 3 inhibited chenodeoxycholic acid (CDCA)-induced FXR transactivation in a concentration-dependent mode...
April 26, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28444748/identification-of-coagulation-gene-3-utr-variants-that-are-potentially-regulated-by-micrornas
#3
Carla Y Vossen, Astrid van Hylckama Vlieg, Raúl Teruel-Montoya, Salam Salloum-Asfar, Hugoline de Haan, Javier Corral, Pieter Reitsma, Bobby P C Koeleman, Constantino Martínez
MicroRNAs have been recognized as critical regulators of gene expression and might affect the risk of venous thrombosis. We aimed to identify 3' untranslated region (UTR) variants in coagulation genes that influence coagulation factor levels and venous thrombosis risk. The 3'UTR of coagulation genes were sequenced in subjects with extremely high or low plasma levels of these factors in two case-control studies. In total, 28 variants were identified. Five single nucleotide polymorphisms (SNPs) were predominantly present in one extreme level group (F2 rs1799963, F8 rs1050705 and F11 rs4253429, rs4253430 and rs1062547)...
April 26, 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/28444595/cloning-and-characterization-of-auxin-efflux-carrier-genes-ecpin1a-and-ecpin1b-from-finger-millet-eleusine-coracana-l
#4
Tapan Kumar Mohanta, Hanhong Bae
Auxin signaling events in plants play important role in developmental regulation as well as gravitropic responses and plays crucial role in the development of root, lateral root and root hairs. The gene that is known to be most important in the development of root, lateral root and root hairs is commonly known as auxin efflux carrier (PIN). Being commonly known as orphan plant, the genome sequence of Eleusine coracana is not known yet, and hence it was very difficult to conduct advanced research in root development in this plant...
May 2017: 3 Biotech
https://www.readbyqxmd.com/read/28444562/infliximab-maintenance-dosing-in-inflammatory-bowel-disease-an-example-for-in-silico-assessment-of-adaptive-dosing-strategies
#5
Jessica Wojciechowski, Richard N Upton, Diane R Mould, Michael D Wiese, David J R Foster
Infliximab is an anti-tumour necrosis factor alpha monoclonal antibody used to treat inflammatory diseases. Many patients fail during induction and others respond initially but relapse during maintenance therapy. Although anti-drug antibodies (ADA) are associated with some clinical failures, there is evidence that some failures may be due to subtherapeutic exposure. Adapting doses based on clinical outcomes and trough concentrations can improve response and reduce the proportion that develop ADA, but identification of appropriate doses in the presence of time-varying patient factors is complicated...
April 25, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28444482/synthesis-pharmacological-evaluation-and-molecular-docking-of-pyranopyrazole-linked-1-4-dihydropyridines-as-potent-positive-inotropes
#6
Rakesh Kumar, Neha Yadav, Rodolfo Lavilla, Daniel Blasi, Jordi Quintana, José Manuel Brea, María Isabel Loza, Jordi Mestres, Mamta Bhandari, Ritu Arora, Rita Kakkar, Ashok K Prasad
1,4-Dihydropyridines are well-known calcium channel blockers, but variations in the substituents attached to the ring have resulted in their role reversal making them calcium channel activators in some cases. We describe the microwave-assisted eco-friendly approach for the synthesis of pyranopyrazole-1,4-dihydropyridines, a new class of 1,4-DHPs, under solvent-free conditions in good yield, and screen them for various in silico, in vitro and in vivo activities. The in vivo experimentation results show that the compounds possess positive inotropic effect, and the docking results validate their good binding with calcium channels...
April 25, 2017: Molecular Diversity
https://www.readbyqxmd.com/read/28443248/shiga-toxin-subtypes-of-non-o157-escherichia-coli-serogroups-isolated-from-cattle-feces
#7
Pragathi B Shridhar, Chris Siepker, Lance W Noll, Xiaorong Shi, T G Nagaraja, Jianfa Bai
Shiga toxin producing Escherichia coli (STEC) are important foodborne pathogens responsible for human illnesses. Cattle are a major reservoir that harbor the organism in the hindgut and shed in the feces. Shiga toxins (Stx) are the primary virulence factors associated with STEC illnesses. The two antigenically distinct Stx types, Stx1 and Stx2, encoded by stx1 and stx2 genes, share approximately 56% amino acid sequence identity. Genetic variants exist within Stx1 and Stx2 based on differences in amino acid composition and in cytotoxicity...
2017: Frontiers in Cellular and Infection Microbiology
https://www.readbyqxmd.com/read/28442890/justification-of-disintegration-testing-beyond-current-fda-criteria-using-in-vitro-and-in-silico-models
#8
Lukas Uebbing, Lukas Klumpp, Gregory K Webster, Raimar Löbenberg
Drug product performance testing is an important part of quality-by-design approaches, but this process often lacks the underlying mechanistic understanding of the complex interactions between the disintegration and dissolution processes involved. Whereas a recent draft guideline by the US Food and Drug Administration (FDA) has allowed the replacement of dissolution testing with disintegration testing, the mentioned criteria are not globally accepted. This study provides scientific justification for using disintegration testing rather than dissolution testing as a quality control method for certain immediate release (IR) formulations...
2017: Drug Design, Development and Therapy
https://www.readbyqxmd.com/read/28442497/an-in-silico-model-of-retinal-cholesterol-dynamics-rcd-model-insights-into-the-pathophysiology-of-dry-age-related-macular-degeneration
#9
Seyedeh Maryam Zekavat, James Lu, Cyrille Maugeais, Norman A Mazer
We developed an in-silico mathematical model of retinal cholesterol (Ch) dynamics (RCD) to quantify the physiological rate of Ch turnover in the rod outer segment (ROS), the lipoprotein transport mechanisms by which Ch enters and leaves the outer retina, and the rates of drusen growth and macrophage-mediated clearance in dry Age-Related Macular Degeneration (AMD). Based on existing experimental data and mechanistic hypotheses, we estimate the Ch turnover rate in the ROS to be 1-6 pg/mm2/min, dependent on the rate of Ch recycling in the outer retina, and find comparable rates for LDL receptor-mediated endocytosis of Ch by the retinal pigment epithelium (RPE), ABCA1-mediated Ch transport from the RPE to outer retina, ABCA1-mediated Ch efflux from the RPE to choroid, and the secretion of 70 nm ApoB-Ch particles from the RPE...
April 25, 2017: Journal of Lipid Research
https://www.readbyqxmd.com/read/28442386/arginine-deiminase-pathway-provides-atp-and-boosts-growth-of-the-gas-fermenting-acetogen-clostridium-autoethanogenum
#10
Kaspar Valgepea, Kim Q Loi, James B Behrendorff, Renato de S P Lemgruber, Manuel Plan, Mark P Hodson, Michael Köpke, Lars K Nielsen, Esteban Marcellin
Acetogens are attractive organisms for the production of chemicals and fuels from inexpensive and non-food feedstocks such as syngas (CO, CO2 and H2). Expanding their product spectrum beyond native compounds is dictated by energetics, particularly ATP availability. Acetogens have evolved sophisticated strategies to conserve energy from reduction potential differences between major redox couples, however, this coupling is sensitive to small changes in thermodynamic equilibria. To accelerate the development of strains for energy-intensive products from gases, we used a genome-scale metabolic model (GEM) to explore alternative ATP-generating pathways in the gas-fermenting acetogen Clostridium autoethanogenum...
April 22, 2017: Metabolic Engineering
https://www.readbyqxmd.com/read/28442262/an-integrated-chemical-biology-approach-reveals-the-mechanism-of-action-of-hiv-replication-inhibitors
#11
Nicholas Pagano, Peter Teriete, Margrith E Mattmann, Li Yang, Beth A Snyder, Zhaohui Cai, Marintha L Heil, Nicholas D P Cosford
Continuous flow (microfluidic) chemistry was employed to prepare a small focused library of dihydropyrimidinone (DHPM) derivatives. Compounds in this class have been reported to exhibit activity against the human immunodeficiency virus (HIV), but their molecular target had not been identified. We tested the initial set of DHPMs in phenotypic assays providing a hit (1i) that inhibited the replication of the human immunodeficiency virus HIV in cells. Flow chemistry-driven optimization of 1i led to the identification of HIV replication inhibitors such as 1l with cellular potency comparable with the clinical drug nevirapine (NVP)...
April 8, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28442062/retinoic-acid-triggers-c-kit-gene-expression-in-spermatogonial-stem-cells-through-an-enhanceosome-constituted-between-transcription-factor-binding-sites-for-retinoic-acid-response-element-rare-spleen-focus-forming-virus-proviral-integration-oncogene-spfi1-pu
#12
Swanand Koli, Ayan Mukherjee, Kudumula Venkata Rami Reddy
Restricted availability of retinoic acid (RA) in the testicular milieu regulates transcriptional activity of c-kit (KIT, CD117), which aids in the determination of spermatogonial stem-cell differentiation. The effect of RA on c-kit has been reported previously, but its mode of genomic action remains unresolved. We studied the molecular machinery guiding RA responsiveness to the c-kit gene using spermatogonial stem-cell line C18-4 and primary spermatogonial cells. A novel retinoic acid response element (RARE) positioned at -989 nucleotides upstream of the transcription start site (TSS) was identified, providing a binding site for a dimeric RA receptor (i...
March 2017: Reproduction, Fertility, and Development
https://www.readbyqxmd.com/read/28441890/rosuvastatin-ameliorates-cognitive-impairment-in-rats-fed-with-high-salt-and-cholesterol-diet-via-inhibiting-acetylcholinesterase-activity-and-amyloid-beta-peptide-aggregation
#13
I Husain, M Akhtar, M Zainul Abdin, M Islamuddin, M Shaharyar, A K Najmi
Amyloid beta (Aβ) peptide aggregation and cholinergic neurodegeneration are involved in the development of cognitive impairment. Therefore, in this article, we examined rosuvastatin (RSV), an oral hypolipidemic drug, to determine its potential as a dual inhibitor of acetylcholinesterase (AChE) and Aβ peptide aggregation for the treatment of cognitive impairment. Molecular docking study was done to examine the affinity of RSV with Aβ1-42 and AChE in silico. We also employed neurobehavioral activity tests, biochemical estimation, and histopathology to study the anti-Aβ1-42 aggregation capability of RSV in vivo...
January 1, 2017: Human & Experimental Toxicology
https://www.readbyqxmd.com/read/28441762/replication-and-oncolytic-activity-of-an-avian-orthoreovirus-in-human-hepatocellular-carcinoma-cells
#14
Robert A Kozak, Larissa Hattin, Mia J Biondi, Juan C Corredor, Scott Walsh, Max Xue-Zhong, Justin Manuel, Ian D McGilvray, Jason Morgenstern, Evan Lusty, Vera Cherepanov, Betty-Anne McBey, David Leishman, Jordan J Feld, Byram Bridle, Éva Nagy
Oncolytic viruses are cancer therapeutics with promising outcomes in pre-clinical and clinical settings. Animal viruses have the possibility to avoid pre-existing immunity in humans, while being safe and immunostimulatory. We isolated an avian orthoreovirus (ARV-PB1), and tested it against a panel of hepatocellular carcinoma cells. We found that ARV-PB1 replicated well and induced strong cytopathic effects. It was determined that one mechanism of cell death was through syncytia formation, resulting in apoptosis and induction of interferon stimulated genes (ISGs)...
April 24, 2017: Viruses
https://www.readbyqxmd.com/read/28441541/molecular-interaction-of-2-4-diacetylphloroglucinol-dapg-with-human-serum-albumin-hsa-the-spectroscopic-calorimetric-and-computational-investigation
#15
Pragna Lakshmi T, Moumita Mondal, Krishna Ramadas, Sakthivel Natarajan
Drug molecule interaction with human serum albumin (HSA) affects the distribution and elimination of the drug. The compound, 2,4-diacetylphloroglucinol (DAPG) has been known for its antimicrobial, antiviral, antihelminthic and anticancer properties. However, its interaction with HSA is not yet reported. In this study, the interaction between HSA and DAPG was investigated through steady-state fluorescence, time-resolved fluorescence (TRF), circular dichroism (CD), Fourier transform infrared (FT-IR) spectroscopy, isothermal titration calorimetry (ITC), molecular docking and molecular dynamics simulation (MDS)...
April 18, 2017: Spectrochimica Acta. Part A, Molecular and Biomolecular Spectroscopy
https://www.readbyqxmd.com/read/28441029/variable-susceptibility-to-cigarette-smoke-induced-emphysema-in-34-inbred-strains-of-mice-implicates-abi3bp-in-emphysema-susceptibility
#16
Josiah E Radder, Alyssa D Gregory, Adriana S Leme, Michael H Cho, Yanxia Chu, Neil J Kelly, Per Bakke, Amund Gulsvik, Augusto A Litonjua, David Sparrow, Terri H Beaty, James D Crapo, Edwin K Silverman, Yingze Zhang, Annerose Berndt, Steven D Shapiro
RATIONALE: Chronic obstructive pulmonary disease (COPD) is caused by a complex interaction of environmental exposures, most commonly cigarette smoke, and genetic factors. Chronic cigarette smoke exposure in the mouse is a commonly used animal model of COPD. We aimed to expand our knowledge of the variable susceptibility of inbred strains to this model and test for genetic variants associated with this trait. OBJECTIVE: To measure differential susceptibility to cigarette smoke-induced emphysema in the mouse, identify genetic loci associated with this quantitative trait, and find homologous human genes associated with COPD...
April 25, 2017: American Journal of Respiratory Cell and Molecular Biology
https://www.readbyqxmd.com/read/28440912/performance-of-in-silico-tools-for-the-evaluation-of-p16ink4a-cdkn2a-variants-in-cagi
#17
Marco Carraro, Giovanni Minervini, Manuel Giollo, Yana Bromberg, Emidio Capriotti, Rita Casadio, Roland Dunbrack, Lisa Elefanti, Pietro Fariselli, Carlo Ferrari, Julian Gough, Panagiotis Katsonis, Emanuela Leonardi, Olivier Lichtarge, Chiara Menin, Pier Luigi Martelli, Abhishek Niroula, Lipika R Pal, Susanna Repo, Maria Chiara Scaini, Mauno Vihinen, Qiong Wei, Qifang Xu, Yuedong Yang, Yizhou Yin, Jan Zaucha, Huiying Zhao, Yaoqi Zhou, Steven E Brenner, John Moult, Silvio C E Tosatto
Correct phenotypic interpretation of variants of unknown significance for cancer-associated genes is a diagnostic challenge as genetic screenings gain in popularity in the next-generation sequencing era. The Critical Assessment of Genome Interpretation (CAGI) experiment aims to test and define the state of the art of genotype-phenotype interpretation. Here, we present the assessment of the CAGI p16INK4a challenge. Participants were asked to predict the effect on cellular proliferation of ten variants for the p16INK4a tumor suppressor, a cyclin-dependent kinase inhibitor encoded by the CDKN2A gene...
April 25, 2017: Human Mutation
https://www.readbyqxmd.com/read/28440667/camelus-dromedarius-glucose-transporter-4-in-silico-analysis-cloning-expression-purification-and-characterisation-in-e-coli
#18
Anwar Ahmed, Mohammed Arshad, Ajamaluddin Malik, Shama Parveen, Abdulrahman M Alsenaidy
Camels have exceptional carbohydrate metabolism as their plasma glucose level is high and have low whole body insulin sensitivity, similar to that observed in type 2 diabetes patients. We aimed at studing an important component of insulin signalling pathway, the GLUT4, in camel. Camelus dromedarius GLUT4 (CdGLUT4) CDS is 1530 nucleotide in length that encodes for a 55KDa protein. CdGLUT4 has 23 amino acid substitutions and 3N-glycosylation sites, compared to 2 in Human GLUT4. 3 D structures of CdGLUT4 and HsGLUT4 generated by homology modelling revealed conservation of characteristic signature motifs...
April 25, 2017: Archives of Physiology and Biochemistry
https://www.readbyqxmd.com/read/28440410/a-novel-notch3-mutation-identified-in-patients-with-oral-cancer-by-whole-exome-sequencing
#19
Yanjun Yi, Zhuowei Tian, Houyu Ju, Guoxin Ren, Jingzhou Hu
Oral cancer is a serious disease caused by environmental factors and/or susceptible genes. In the present study, in order to identify useful genetic biomarkers for cancer prediction and prevention, and for personalized treatment, we detected somatic mutations in 5 pairs of oral cancer tissues and blood samples using whole exome sequencing (WES). Finally, we confirmed a novel nonsense single-nucleotide polymorphism (SNP; chr19:15288426A>C) in the NOTCH3 gene with sanger sequencing, which resulted in a N1438T mutation in the protein sequence...
April 25, 2017: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/28440310/klf5-mediates-odontoblastic-differentiation-through-regulating-dentin-specific-extracellular-matrix-gene-expression-during-mouse-tooth-development
#20
Zhuo Chen, Qi Zhang, Han Wang, Wentong Li, Feng Wang, Chunyan Wan, Shuli Deng, Hui Chen, Yixin Yin, Xiaoyan Li, Zhijian Xie, Shuo Chen
Klf5, a member of the Krüppel-like transcription factor family, has essential roles during embryonic development, cell proliferation, differentiation, migration and apoptosis. This study was to define molecular mechanism of Klf5 during the odontoblastic differentiation. The expression of Klf5, odontoblast-differentiation markers, Dspp and Dmp1 was co-localized in odontoblastic cells at different stages of mouse tooth development and mouse dental papilla mesenchymal cells. Klf5 was able to promote odontoblastic differentiation and enhance mineral formation of mouse dental papilla mesenchymal cells...
April 25, 2017: Scientific Reports
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