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Qingqing Wei, Ruiqi Li, Liang Zhong, Haiyuan Mu, Shaopeng Zhang, Liang Yue, Jinzhu Xiang, Enhong Li, Minglei Zhi, Suying Cao, Jianyong Han
After zygotic genome activation and lineage specification, zygotes develop into late blastocysts comprising three distinct cell types. The molecular mechanisms underlying this progress are largely unknown in pigs. Here, we intended to analyze an extensive set of regulators at the single-cell level to define the events involved in the development of the porcine blastocysts. Using a quantitative microfluidics approach in single cells, we detected mRNA levels of 96 genes known to function in early embryonic development and maintenance of stem cell pluripotency simultaneously in 480 individual cells derived from porcine preimplantation embryos...
March 13, 2018: Biology of Reproduction
Jan Raska, Lucie Ctverackova, Aneta Dydowiczova, Iva Sovadinova, Ludek Blaha, Pavel Babica
HL1-hT1 cell line represents adult human liver stem cells (LSCs) immortalized with human telomerase reverse transcriptase. In this study, HL1-hT1 cells were found to express mesenchymal markers (vimentin, CD73, CD90/THY-1 and CD105) and an early hepatic endoderm marker FOXA2, while not expressing hepatic progenitor (HNF4A, LGR5, α-fetoprotein) or differentiated hepatocyte markers (albumin, transthyretin, connexin 32). In response to microcystin-LR (MC-LR), a time- and concentration-dependent formation of MC-positive protein bands in HL1-hT1 cells was observed...
March 10, 2018: Toxicology and Applied Pharmacology
Joanna Yuet-Ling Tung, Kara Boodhansingh, Charles A Stanley, Diva D De León
BACKGROUND: Dominant inactivating mutations in HNF1A and HNF4A have been described to cause hyperinsulinism (HI) before evolving to diabetes. However, information available in the literature regarding the clinical phenotype is limited. OBJECTIVE: To report the prevalence of HNF1A and HNF4A mutations in a large cohort of children with HI, and to describe their genotypes and phenotypes. DESIGN: Retrospective descriptive study. METHODS: Medical records were reviewed to extract clinical information...
March 1, 2018: Pediatric Diabetes
Samir Abu Gazala, Elad Horwitz, Rachel Ben-Haroush Schyr, Aya Bardugo, Hadar Israeli, Ayat Hija, Jonathan Schug, Soona Shin, Yuval Dor, Klaus H Kaestner, Danny Ben-Zvi
Bariatric surgery dramatically improves glycemic control, yet the underlying molecular mechanisms remain controversial due to confounding weight loss. We performed sleeve gastrectomy (SG) on obese and diabetic leptin receptor-deficient mice ( db / db ). One week post-surgery, mice weighed 5% less and displayed improved glycemia compared to sham-operated controls and islets from SG mice displayed reduced expression of diabetes markers. One month post-surgery SG mice weighed more than pre-operatively, but remained near-euglycemic and displayed reduced hepatic lipid droplets...
February 23, 2018: Diabetes
Lay Teng Ang, Antson Kiat Yee Tan, Matias I Autio, Su Hua Goh, Siew Hua Choo, Kian Leong Lee, Jianmin Tan, Bangfen Pan, Jane Jia Hui Lee, Jen Jen Lum, Christina Ying Yan Lim, Isabelle Kai Xin Yeo, Chloe Jin Yee Wong, Min Liu, Jueween Ling Li Oh, Cheryl Pei Lynn Chia, Chet Hong Loh, Angela Chen, Qingfeng Chen, Irving L Weissman, Kyle M Loh, Bing Lim
How are closely related lineages, including liver, pancreas, and intestines, diversified from a common endodermal origin? Here, we apply principles learned from developmental biology to rapidly reconstitute liver progenitors from human pluripotent stem cells (hPSCs). Mapping the formation of multiple endodermal lineages revealed how alternate endodermal fates (e.g., pancreas and intestines) are restricted during liver commitment. Human liver fate was encoded by combinations of inductive and repressive extracellular signals at different doses...
February 20, 2018: Cell Reports
Laura T Dickens, Rochelle N Naylor
PURPOSE OF REVIEW: Monogenic diabetes accounts for 1-2% of all diabetes cases, but is frequently misdiagnosed as type 1, type 2, or gestational diabetes. Accurate genetic diagnosis directs management, such as no pharmacologic treatment for GCK-MODY, low-dose sulfonylureas for HNF1A-MODY and HNF4A-MODY, and high-dose sulfonylureas for KATP channel-related diabetes. While diabetes treatment is defined for the most common causes of monogenic diabetes, pregnancy poses a challenge to management...
February 15, 2018: Current Diabetes Reports
S Ben Khelifa, R Martinez, A Dandana, I Khochtali, S Ferchichi, L Castaño
Maturity Onset Diabetes of the Young (MODY) is a monogenic form of diabetes characterized by autosomal dominant inheritance, an early clinical onset and a primary defect in β-cell function. Mutations in the GCK and HNF1A genes are the most common cause of MODY among Caucasians. The etiology of MODY in Tunisia stills a challenge for researchers. The aim of this study was to screen for mutations in GCK, HNF1A, HNF4A and INS genes in North African Tunisians subjects, in whom the clinical profile was very suggestive of MODY...
February 2, 2018: Gene
Jung Eun Park, Mikang Lee, Seong-Chul Kim, Yanqiao Zhang, James P Hardwick, Yoon Kwang Lee
Peroxisome proliferator-activated receptor gamma (PPARγ) is a master regulator for white adipocyte differentiation and lipid storage. The increased level of hepatic PPARγ2 isoform reprograms liver for lipid storage and causes abnormal fat accumulation in certain pathophysiologic conditions. The current study aimed to investigate a role of transcriptional repressor hairy and enhancer of split 6 (HES6) in the regulation of Pparg2 expression and hepatic steatosis induced by diet. Liver-specific overexpression of Hes6 using adenovirus reduced Pparg2 messenger RNA levels by 90% and hepatic triglyceride accumulation by 22% compared to the levels in mice injected with an adenoviral empty vector with Western diet feeding...
December 2017: Hepatology Communications
Yael Haberman, Marina BenShoshan, Ayelet Di Segni, Phillip J Dexheimer, Tzipi Braun, Batia Weiss, Thomas D Walters, Robert N Baldassano, Joshua D Noe, James Markowitz, Joel Rosh, Melvin B Heyman, Anne M Griffiths, Wallace V Crandall, David R Mack, Susan S Baker, Richard Kellermayer, Ashish Patel, Anthony Otley, Steven J Steiner, Ajay S Gulati, Stephen L Guthery, Neal LeLeiko, Dedrick Moulton, Barbara S Kirschner, Scott Snapper, Camila Avivi, Iris Barshack, Maria Oliva-Hemker, Stanley A Cohen, David J Keljo, David Ziring, Yair Anikster, Bruce Aronow, Jeffrey S Hyams, Subra Kugathasan, Lee A Denson
Background: Long noncoding RNAs (lncRNA) are key regulators of gene transcription and many show tissue-specific expression. We previously defined a novel inflammatory and metabolic ileal gene signature in treatment-naive pediatric Crohn disease (CD). We now extend our analyses to include potential regulatory lncRNA. Methods: Using RNAseq, we systematically profiled lncRNAs and protein-coding gene expression in 177 ileal biopsies. Co-expression analysis was used to identify functions and tissue-specific expression...
January 18, 2018: Inflammatory Bowel Diseases
Luyang Zhao, Chenglei Gu, Mingxia Ye, Zhe Zhang, Li'an Li, Wensheng Fan, Yuanguang Meng
BACKGROUND: The etiology and pathophysiology of endometriosis remain unclear. Accumulating evidence suggests that aberrant microRNA (miRNA) and transcription factor (TF) expression may be involved in the pathogenesis and development of endometriosis. This study therefore aims to survey the key miRNAs, TFs and genes and further understand the mechanism of endometriosis. METHODS: Paired expression profiling of miRNA and mRNA in ectopic endometria compared with eutopic endometria were determined by high-throughput sequencing techniques in eight patients with ovarian endometriosis...
January 22, 2018: Reproductive Biology and Endocrinology: RB&E
Cayla A Thompson, Ann DeLaForest, Michele A Battle
The gastrointestinal (GI) tract, in simplest terms, can be described as an epithelial-lined muscular tube extending along the cephalocaudal axis from the oral cavity to the anus. Although the general architecture of the GI tract organs is conserved from end to end, the presence of different epithelial tissue structures and unique epithelial cell types within each organ enables each to perform the distinct digestive functions required for efficient nutrient assimilation. Spatiotemporal regulation of signaling pathways and downstream transcription factors controls GI epithelial morphogenesis during development to confer essential regional-specific epithelial structures and functions...
January 12, 2018: Developmental Biology
Rui Lin, Yufeng Wang, Kun Ji, Zhongyan Liu, Shuai Xiao, Dehua Zhou, Quanning Chen, Baomin Shi
Due to the lack of potential organs, hepatocellular transplantation has been considered for treating end-stage liver disease. Induced pluripotent stem cells (iPSCs) are reverted from somatic cells and are able to differentiate into hepatocytes. The present study aimed to investigate the mechanisms underlying iPSC differentiation to hepatocytes. GSE66076 was downloaded from the Gene Expression Omnibus; this database includes data from 3 undifferentiated (T0), 3 definitive endoderm (T5), and 3 early hepatocyte (T24) samples across hepatic‑directed differentiation of iPSCs...
January 5, 2018: Molecular Medicine Reports
Lijuan Bo, Bo Wei, Zhanfeng Wang, Chaohui Li, Zheng Gao, Zhuang Miao
Intracranial aneurysm (IA) is a severe clinical condition of primary concern and currently, there is no effective therapeutic reagent. The present study aimed to investigate the molecular mechanism of IA via bioinformatic analysis. Various gene expression profiles (GSE26969) were downloaded from the Gene Expression Omnibus database, including 3 IA and 3 normal superficial temporal artery samples. Firstly, the limma package in R language was used to identify differentially expressed genes (DEGs; P‑value <0...
December 29, 2017: Molecular Medicine Reports
Alondra P Harris, Kareem A Ismail, Martha Nunez, Ira Martopullo, Alejandro Lencinas, Ornella I Selmin, Raymond B Runyan
Exposure to trichloroethylene (TCE) is linked to formation of congenital heart defects in humans and animals. Prior interactome analysis identified the transcription factor, Hepatocyte Nuclear Factor 4 alpha (HNF4a), as a potential target of TCE exposure. As a role for HNF4a is unknown in the heart, we examined developing avian hearts for HNF4a expression and for sensitivity to TCE and the HNF4a agonist, Benfluorex. In vitro analysis using a HNF4a reporter construct showed both TCE and HFN4a to be antagonists of HNF4a-mediated transcription at the concentrations tested...
January 3, 2018: Toxicology Letters
Payman Shahabi, Félix Lamothe, Stéphanie Dumas, Étienne Rouleau-Mailloux, Yassamin Feroz Zada, Sylvie Provost, Geraldine Asselin, Ian Mongrain, Diane Valois, Marie-Josée Gaulin Marion, Louis-Philippe Lemieux Perreault, Sylvie Perreault, Marie-Pierre Dubé
Warfarin is primarily metabolized by cytochrome 2C9, encoded by gene CYP2C9. Here, we investigated whether variants in nuclear receptor genes which regulate the expression of CYP2C9 are associated with warfarin response. We used data from 906 warfarin users from the Quebec Warfarin Cohort (QWC) and tested the association of warfarin dose requirement at 3 months following the initiation of therapy in nine nuclear receptor genes: NR1I3, NR1I2, NR3C1, ESR1, GATA4, RXRA, VDR, CEBPA, and HNF4A. Three correlated SNPs in the VDR gene (rs4760658, rs11168292, and rs11168293) were associated with dose requirements of warfarin (P = 2...
January 3, 2018: Pharmacogenomics Journal
Hüseyin Demirbilek, Khalid Hussain
Pancreatic β-cells are finely tuned to secrete insulin so that plasma glucose levels are maintained within a narrow physiological range (3.5-5.5 mmol/L). Hyperinsulinaemic hypoglycaemia (HH) is the inappropriate seretion of insulin in the presence of low plasma glucose levels and leads to severe and persistent hypoglycaemia in neonates and children. Mutations in 12 different key genes (ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, UCP2, HNF4A, HNF1A, HK1, PGM1 and PMM2) that are involved in the regulation of insulin secretion from pancreatic β-cells have been described to be responsible for the underlying molecular mechanisms leading to congenital HH...
December 27, 2017: Journal of Clinical Research in Pediatric Endocrinology
David Martín-Gálvez, Denis Dunoyer de Segonzac, Man Chun John Ma, Anne E Kwitek, David Thybert, Paul Flicek
BACKGROUND: The genomes of laboratory rat strains are characterised by a mosaic haplotype structure caused by their unique breeding history. These mosaic haplotypes have been recently mapped by extensive sequencing of key strains. Comparison of genomic variation between two closely related rat strains with different phenotypes has been proposed as an effective strategy for the discovery of candidate strain-specific regions involved in phenotypic differences. We developed a method to prioritise strain-specific haplotypes by integrating genomic variation and genomic regulatory data predicted to be involved in specific phenotypes...
December 22, 2017: BMC Genomics
Shangdong Guo, Hong Lu
Hepatocyte nuclear factor 4-alpha (HNF4α) is a well established master regulator of liver development and function. We identified the in vitro presence of a stable secondary structure, G-quadruplex (G4) in the 5' UTR of P1-HNF4A, the predominant HNF4α isoform(s) in adult liver. Our data suggest that the cooperation of G4 and the adjacent putative protein-binding sites within the 5' UTR was necessary and sufficient to mediate a strong translational repression. This was supported by analysis of deleted/mutated 5'UTRs and two native regulatory single-nucleotide polymorphisms in the 5'UTR...
December 12, 2017: Scientific Reports
Cristina Baciu, Elisa Pasini, Marc Angeli, Katherine Schwenger, Jenifar Afrin, Atul Humar, Sandra Fischer, Keyur Patel, Johane Allard, Mamatha Bhat
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the Western world, and encompasses a spectrum from simple steatosis to steatohepatitis (NASH). There is currently no approved pharmacologic therapy against NASH, partly due to an incomplete understanding of its molecular basis. The goal of this study was to determine the key differentially expressed genes (DEGs), as well as those genes and pathways central to its pathogenesis. We performed an integrative computational analysis of publicly available gene expression data in NASH from GEO (GSE17470, GSE24807, GSE37031, GSE89632)...
2017: PloS One
Vikas Bansal, Johann Gassenhuber, Tierney Phillips, Glenn Oliveira, Rebecca Harbaugh, Nikki Villarasa, Eric J Topol, Thomas Seufferlein, Bernhard O Boehm
BACKGROUND: Diagnosis of monogenic as well as atypical forms of diabetes mellitus has important clinical implications for their specific diagnosis, prognosis, and targeted treatment. Single gene mutations that affect beta-cell function represent 1-2% of all cases of diabetes. However, phenotypic heterogeneity and lack of family history of diabetes can limit the diagnosis of monogenic forms of diabetes. Next-generation sequencing technologies provide an excellent opportunity to screen large numbers of individuals with a diagnosis of diabetes for mutations in disease-associated genes...
December 6, 2017: BMC Medicine
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