2,839,263 results match your criteria Molecular Targets in the Treatment of Head and Neck Squamous Cell Carcinoma


Factor cooperation for chromosome discrimination in Drosophila.

Nucleic Acids Res 2018 Dec 12. Epub 2018 Dec 12.

Molecular Biology Division, Biomedical Center, Faculty of Medicine and Center for Integrated Protein Science Munich (CIPSM), Ludwig-Maximilians-Universität Munich, 82151 Martinsried, Germany.

Transcription regulators select their genomic binding sites from a large pool of similar, non-functional sequences. Although general principles that allow such discrimination are known, the complexity of DNA elements often precludes a prediction of functional sites. The process of dosage compensation in Drosophila allows exploring the rules underlying binding site selectivity. Read More

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December 2018

Regulation of ATR activity via the RNA polymerase II associated factors CDC73 and PNUTS-PP1.

Nucleic Acids Res 2018 Dec 12. Epub 2018 Dec 12.

Department of Radiation Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.

Ataxia telangiectasia mutated and Rad3-related (ATR) kinase is a key factor activated by DNA damage and replication stress. An alternative pathway for ATR activation has been proposed to occur via stalled RNA polymerase II (RNAPII). However, how RNAPII might signal to activate ATR remains unknown. Read More

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December 2018

Functional expansion of a TCA cycle operon mRNA by a 3' end-derived small RNA.

Nucleic Acids Res 2018 Dec 12. Epub 2018 Dec 12.

RNA Biology Group, Institute for Molecular Infection Biology, University of Würzburg, D-97080 Würzburg, Germany.

Global RNA profiling studies in bacteria have predicted the existence of many of small noncoding RNAs (sRNAs) that are processed off mRNA 3' ends to regulate other mRNAs via the RNA chaperones Hfq and ProQ. Here, we present targets of SdhX (RybD), an Hfq-dependent sRNA that is generated by RNase E mediated 3' processing of the ∼10 000-nt mRNA of the TCA cycle operon sdhCDAB-sucABCD in enteric bacteria. An in silico search predicted ackA mRNA, which encodes acetate kinase, as a conserved primary target of SdhX. Read More

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December 2018

A coronary artery disease-associated tRNAThr mutation altered mitochondrial function, apoptosis and angiogenesis.

Nucleic Acids Res 2018 Dec 12. Epub 2018 Dec 12.

Division of Medical Genetics and Genomics, The Children's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.

The tissue specificity of mitochondrial tRNA mutations remains largely elusive. In this study, we demonstrated the deleterious effects of tRNAThr 15927G>A mutation that contributed to pathogenesis of coronary artery disease. The m. Read More

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December 2018

The Gly385(388)Arg Polymorphism of the FGFR4 Receptor regulates Hepatic Lipogenesis under healthy Diet.

J Clin Endocrinol Metab 2018 Dec 12. Epub 2018 Dec 12.

Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Disease, Nephrology and Clinical Chemistry, University of Tübingen, Germany.

Context: The effect of a lifestyle intervention to reduce liver fat content in nonalcoholic fatty liver disease in humans is influenced by genetics. We hypothesized that the functionally active amino acid exchange in humans Gly388Arg (mouse homologue: Gly385Arg) in the fibroblast growth factor receptor 4 (FGFR4), which regulates bile acid, lipid and glucose metabolism, may determine the dynamics of hepatic lipid accumulation and insulin sensitivity in humans. Mechanisms of this substitution were studied in mice under normal chow and high-fat diet. Read More

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December 2018
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Intrinsically disordered regions regulate both catalytic and non-catalytic activities of the MutLα mismatch repair complex.

Nucleic Acids Res 2018 Dec 12. Epub 2018 Dec 12.

Department of Molecular Biosciences and Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, TX 78712, USA.

Intrinsically disordered regions (IDRs) are present in at least 30% of the eukaryotic proteome and are enriched in chromatin-associated proteins. Using a combination of genetics, biochemistry and single-molecule biophysics, we characterize how IDRs regulate the functions of the yeast MutLα (Mlh1-Pms1) mismatch repair (MMR) complex. Shortening or scrambling the IDRs in both subunits ablates MMR in vivo. Read More

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December 2018

Expression of GHR and downstream signaling genes in human adipose tissue - relation to obesity and weight-change.

J Clin Endocrinol Metab 2018 Dec 12. Epub 2018 Dec 12.

Department of Molecular and Clinical Medicine, Institute of Medicine at the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Context: Growth hormone (GH) is a strong regulator of metabolism. In obesity, both GH secretion and adipose tissue GHR gene expression are decreased. More detailed information on the regulation of GHR, STAT3/5 and downstream-regulated genes in human adipose tissue during diet-induced weight loss and weight gain is lacking. Read More

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December 2018

Evidence that a catalytic glutamate and an 'Arginine Toggle' act in concert to mediate ATP hydrolysis and mechanochemical coupling in a viral DNA packaging motor.

Nucleic Acids Res 2018 Dec 12. Epub 2018 Dec 12.

Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195, USA.

ASCE ATPases include ring-translocases such as cellular helicases and viral DNA packaging motors (terminases). These motors have conserved Walker A and B motifs that bind Mg2+-ATP and a catalytic carboxylate that activates water for hydrolysis. Here we demonstrate that Glu179 serves as the catalytic carboxylate in bacteriophage λ terminase and probe its mechanistic role. Read More

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December 2018

Plasmid-based gap-repair recombineered transgenes reveal a central role for introns in mutually exclusive alternative splicing in Down Syndrome Cell Adhesion Molecule exon 4.

Nucleic Acids Res 2018 Dec 12. Epub 2018 Dec 12.

School of Biosciences, College of Life and Environmental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.

Alternative splicing is a key feature of human genes, yet studying its regulation is often complicated by large introns. The Down Syndrome Cell Adhesion Molecule (Dscam) gene from Drosophila is one of the most complex genes generating vast molecular diversity by mutually exclusive alternative splicing. To resolve how alternative splicing in Dscam is regulated, we first developed plasmid-based UAS reporter genes for the Dscam variable exon 4 cluster and show that its alternative splicing is recapitulated by GAL4-mediated expression in neurons. Read More

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December 2018

Allosteric DNAzyme-based DNA logic circuit: operations and dynamic analysis.

Nucleic Acids Res 2018 Dec 12. Epub 2018 Dec 12.

Key Laboratory of Advanced Design and Intelligent Computing, Dalian University, Ministry of Education, Dalian 116622, China.

Recently, due to the dual roles of DNA and enzyme, DNAzyme has been widely used in the field of DNA circuit, which has a wide range of applications in bio-engineered system, information processing and biocomputing. In fact, the activity of DNAzymes was regulated by subunits assembly, pH control and metal ions triggers. However, those regulations required to change the sequences of whole DNAzyme, as separating parts and inserting extra DNA sequence. Read More

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December 2018

Diurnal distribution of carbohydrates and fat affects substrate oxidation and adipokine secretion in humans.

Am J Clin Nutr 2018 Dec;108(6):1209-1219

Departments of Clinical Nutrition.

Background: A diet in which fat is mainly eaten in the morning and carbohydrates mainly in the evening (compared with the reverse order) was recently shown to worsen glycemic control in people with prediabetes.

Objective: We investigated the effects of these dietary patterns on energy metabolism, and on the daily profiles of circulating lipids, adipokines, and inflammatory markers.

Design: In a randomized controlled crossover trial, 29 nonobese men (with normal glucose tolerance, n = 18; or impaired fasting glucose/glucose tolerance, n = 11) underwent 2 isocaloric 4-wk diets: 1) carbohydrate-rich meals until 1330 and fat-rich meals between 1630 and 2200 (HC/HF); or 2) the inverse sequence of meals (HF/HC). Read More

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December 2018

Structural insights into nucleotide and protein sequence of Ageritin: a novel prototype of fungal ribotoxin.

J Biochem 2018 Dec 12. Epub 2018 Dec 12.

Department of Environmental, Biological and Pharmaceutical Sciences and Technologies (DISTABIF), University of Campania 'Luigi Vanvitelli', Via Vivaldi 43, Caserta, Italy.

Here, we report the amino acid sequence of Ageritin, the first ribotoxin-like protein from basidiomycetes (Agrocybe aegerita). This protein consists of 135 amino acid residues with a theoretical molecular mass of 14801.80 Da (experimental mass 14802. Read More

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December 2018
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Archaeal NSUN6 catalyzes m5C72 modification on a wide-range of specific tRNAs.

Nucleic Acids Res 2018 Dec 12. Epub 2018 Dec 12.

State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences; University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, P.R. China.

Human NOL1/NOP2/Sun RNA methyltransferase family member 6 (hNSun6) generates 5-methylcytosine (m5C) at C72 of four specific tRNAs, and its homologs are present only in higher eukaryotes and hyperthermophilic archaea. Archaeal NSun6 homologs possess conserved catalytic residues, but have distinct differences in their RNA recognition motifs from eukaryotic NSun6s. Until now, the biochemical properties and functions of archaeal NSun6 homologs were unknown. Read More

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December 2018
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Galapagos Islands Endemic Vertebrates: A Population Genetics Perspective.

Authors:
Philip W Hedrick

J Hered 2018 Dec 12. Epub 2018 Dec 12.

School of Life Sciences, Arizona State University, Tempe, AZ.

The organisms of the Galapagos Islands played a central role in the development of the theory of evolution by Charles Darwin. Examination of the population genetics factors of many of these organisms with modern molecular methods have expanded our understanding of their evolution. Here I provide a perspective on how selection, gene flow, genetic drift, mutation, and inbreeding have contributed to the evolution of six of the iconic Galapagos species; flightless cormorant, pink iguana, marine iguana, Galapagos hawk, giant tortoises, and Darwin's finches. Read More

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December 2018

In Vivo Imaging With Confirmation by Histopathology for Increased Rigor and Reproducibility in Translational Research: A Review of Examples, Options, and Resources.

ILAR J 2018 Dec 12. Epub 2018 Dec 12.

Department of Radiology, Miller Research Building Molecular Imaging Service Center, Johns Hopkins University, Baltimore, Maryland.

Preclinical noninvasive imaging can be an indispensable tool for studying animal models of disease. In vivo imaging to assess anatomical, functional, and molecular features requires verification by a comparison to the macroscopic and microscopic morphological features, since all noninvasive in vivo imaging methods have much lower resolution than standard histopathology. Comprehensive pathological evaluation of the animal model is underutilized; yet, many institutions have veterinary or human pathologists with necessary comparative pathology expertise. Read More

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December 2018

Lateral hypothalamic Mc3R-expressing neurons modulate locomotor activity, energy expenditure and adiposity in male mice.

Endocrinology 2018 Dec 11. Epub 2018 Dec 11.

Dept. of Pediatrics, Division of Endocrinology, Michigan Medicine, Ann Arbor, MI.

The central melanocortin (Mc) system plays a crucial role in the control of energy balance. While the decreased energy expenditure and increased adiposity of Mc-3 receptor (Mc3R)-null mice suggest the importance of Mc3R-regulated neurons in energy homeostasis, the roles for specific subsets of Mc3R neurons in energy balance have yet to be determined. Because the lateral hypothalamic area (LHA) contributes to the control of energy expenditure and feeding, we generated Mc3rcre mice to determine the roles of LHA Mc3R (Mc3RLHA) neurons in energy homeostasis. Read More

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December 2018
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ModL: exploring and restoring regularity when testing for positive selection.

Bioinformatics 2018 Dec 12. Epub 2018 Dec 12.

Department of Mathematics and Statistics, Dalhousie University, Halifax, NS, Canada.

Motivation: Likelihood ratio tests are commonly used to test for positive selection acting on proteins. They are usually applied with thresholds for declaring a protein under positive selection determined from a chi-square or mixture of chi-square distributions. While it is known that such distributions are not strictly justified due to the statistical irregularity of the problem, the hope has been that the resulting tests are conservative and do not lose much power in comparison with the same test using the unknown, correct threshold. Read More

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December 2018

Commonly misunderstood parameters of NCBI BLAST and important considerations for users.

Bioinformatics 2018 Dec 12. Epub 2018 Dec 12.

Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia.

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December 2018

Molecular phylogenomics of the tribe Shoreeae (Dipterocarpaceae) using whole plastid genomes.

Ann Bot 2018 Dec 12. Epub 2018 Dec 12.

University of Vienna, Department of Botany and Biodiversity Research, Rennweg, Vienna, Austria.

Background And Aims: Phylogenetic relationships within tribe Shoreeae, containing the main elements of tropical forests in Southeast Asia, present a long-standing problem in the systematics of Dipterocarpaceae. Sequencing whole plastomes using next-generation sequencing- (NGS) based genome skimming is increasingly employed for investigating phylogenetic relationships of plants. Here, the usefulness of complete plastid genome sequences in resolving phylogenetic relationships within Shoreeae is evaluated. Read More

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December 2018
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Gene expression models based on transcription factor binding events confer insight into functional cis-regulatory variants.

Bioinformatics 2018 Dec 12. Epub 2018 Dec 12.

Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, BC Children's Hospital Research Institute, University of British Columbia, Vancouver, Canada.

Motivation: Deciphering the functional roles of cis-regulatory variants is a critical challenge in genome analysis and interpretation. It has been hypothesized that altered transcription factor (TF) binding events are a central mechanism by which cis-regulatory variants impact gene expression levels. However, we lack a computational framework to understand and quantify such mechanistic contributions. Read More

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December 2018

RNAi of Sterol Methyl Transferase1 Reveals its Direct Role in Diverting Intermediates Towards Withanolide/ Phytosterol Biosynthesis in Withania somnifera.

Plant Cell Physiol 2018 Dec 12. Epub 2018 Dec 12.

Laboratory of Aromatic Plants and Chiral Separation, Chemical Sciences Division, CSIR-Central Institute of Medicinal and Aromatic Plants (CIMAP), India.

The medicinal properties of Ashwagandha (Withania somnifera) are accredited to a group of compounds called as withanolides. 24-methylene cholesterol is the intermediate for sterol biosynthesis and a proposed precursor of withanolides biogenesis. But, conversion of 24-methylene cholesterol to withaferin A and other withanolides has not yet been biochemically dissected. Read More

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December 2018

Agnostic Pathway/Gene Set Analysis of Genome-Wide Association Data Identifies Associations for Pancreatic Cancer.

Authors:
Naomi Walsh Han Zhang Paula L Hyland Qi Yang Evelina Mocci Mingfeng Zhang Erica J Childs Irene Collins Zhaoming Wang Alan A Arslan Laura Beane-Freeman Paige M Bracci Paul Brennan Federico Canzian Eric J Duell Steven Gallinger Graham G Giles Michael Goggins Gary E Goodman Phyllis J Goodman Rayjean J Hung Charles Kooperberg Robert C Kurtz Núria Malats Loic LeMarchand Rachel E Neale Sara H Olson Ghislaine Scelo Xiao O Shu Stephen K Van Den Eeden Kala Visvanathan Emily White Wei Zheng Demetrius Albanes Gabriella Andreotti Ana Babic William R Bamlet Sonja I Berndt Ayelet Borgida Marie-Christine Boutron-Ruault Lauren Brais Paul Brennan Bas Bueno-de-Mesquita Julie Buring Kari G Chaffee Stephen Chanock Sean Cleary Michelle Cotterchio Lenka Foretova Charles Fuchs J Michael M Gaziano Edward Giovannucci Michael Goggins Thilo Hackert Christopher Haiman Patricia Hartge Manal Hasan Kathy J Helzlsouer Joseph Herman Ivana Holcatova Elizabeth A Holly Robert Hoover Rayjean J Hung Vladimir Janout Eric A Klein Robert C Kurtz Daniel Laheru I-Min Lee Lingeng Lu Núria Malats Satu Mannisto Roger L Milne Ann L Oberg Irene Orlow Alpa V Patel Ulrike Peters Miquel Porta Francisco X Real Nathaniel Rothman Howard D Sesso Gianluca Severi Debra Silverman Oliver Strobel Malin Sund Mark D Thornquist Geoffrey S Tobias Jean Wactawski-Wende Nick Wareham Elisabete Weiderpass Nicolas Wentzensen William Wheeler Herbert Yu Anne Zeleniuch-Jacquotte Peter Kraft Donghui Li Eric J Jacobs Gloria M Petersen Brian M Wolpin Harvey A Risch Laufey T Amundadottir Kai Yu Alison P Klein Rachael Z Stolzenberg-Solomon

J Natl Cancer Inst 2018 Dec 12. Epub 2018 Dec 12.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD.

Background: Genome-wide association studies (GWAS) identify associations of individual single-nucleotide polymorphisms (SNPs) with cancer risk but usually only explain a fraction of the inherited variability. Pathway analysis of genetic variants is a powerful tool to identify networks of susceptibility genes.

Methods: We conducted a large agnostic pathway-based meta-analysis of GWAS data using the summary-based adaptive rank truncated product method to identify gene sets and pathways associated with pancreatic ductal adenocarcinoma (PDAC) in 9040 cases and 12 496 controls. Read More

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December 2018

Predicting Ames Mutagenicity Using Conformal Prediction in the Ames/QSAR International Challenge Project.

Mutagenesis 2018 Dec 12. Epub 2018 Dec 12.

Computer Learning Research Centre, Royal Holloway, University of London Egham, Surrey, UK.

Valid and predictive models for classifying Ames mutagenicity have been developed using conformal prediction. The models are Random Forest models using signature molecular descriptors. The investigation indicates, on excluding not-strongly mutagenic compounds (class B), that the validity for mutagenic compounds is increased for the predictions based on both public and the Division of Genetics and Mutagenesis, National Institute of Health Sciences of Japan (DGM/NIHS) data while less so when using only the latter data source. Read More

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December 2018

How methyl-sugar interactions determine DNA structure and flexibility.

Nucleic Acids Res 2018 Dec 12. Epub 2018 Dec 12.

Physics Department T38, Technical University of Munich, James-Franck-Str. 1, 85748 Garching, Germany.

The sequence dependent structure and flexibility of the DNA double helix is of key importance for gene expression and DNA packing and it can be modulated by DNA modifications. The presence of a C5'-methyl group in thymine or the frequent C5'-methylated-cytosine affects the DNA fine structure, however, the underlying mechanism and steric origins have remained largely unexplained. Employing Molecular Dynamics free energy simulations that allow switching on or off interactions with the methyl groups in several DNA sequences, we systematically identified the physical origin of the coupling between methyl groups and DNA backbone fine structure. Read More

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December 2018

The Na+/H+ Exchanger Nhe1 Modulates Network Excitability via GABA Release.

Cereb Cortex 2018 Dec 12. Epub 2018 Dec 12.

Institute of Human Genetics, Jena University Hospital, Jena, Germany.

Brain functions are extremely sensitive to pH changes because of the pH-dependence of proteins involved in neuronal excitability and synaptic transmission. Here, we show that the Na+/H+ exchanger Nhe1, which uses the Na+ gradient to extrude H+, is expressed at both inhibitory and excitatory presynapses. We disrupted Nhe1 specifically in mice either in Emx1-positive glutamatergic neurons or in parvalbumin-positive cells, mainly GABAergic interneurons. Read More

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December 2018
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Molecular point-of-care testing for influenza to improve early neuraminidase inhibitor treatment and outcomes in hospitalised adults.

Clin Infect Dis 2018 Dec 9. Epub 2018 Dec 9.

Academic Unit of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.

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December 2018

Mucosal healing and bacterial composition in response to enteral nutrition versus steroid based induction therapy - a randomized prospective clinical trial in children with Crohn's disease.

J Crohns Colitis 2018 Dec 12. Epub 2018 Dec 12.

Hôpital Necker Enfants Malades Université Sorbonne Paris Cité, Paris, APHP.

Exclusive Enteral Nutrition (EEN) is as efficacious as corticosteroids (CS) to induce remission in Crohn's disease (CD), without their adverse effects. EEN seems to be more efficient than steroids to induce mucosal healing, but the underlying molecular mechanisms are only sparsely understood. We aimed in the present work to study the anti-inflammatory effects of EEN with Modulen IBD® versus CS in active pediatric CD and to assess its modulatory effects on the intestinal microbiota as compared to steroids. Read More

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December 2018

Elevated Levels of Urinary Extracellular Vesicle Fibroblast-Specific Protein 1 in Patients with Active Crescentic Glomerulonephritis.

Nephron 2018 Dec 12:1-11. Epub 2018 Dec 12.

Department of Nephrology, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.

Background/aims: Extracellular vesicles (EVs), including exosomes, are present in various bodily fluids, including urine. We and others previously reported that cells expressing fibroblast-specific protein 1 (FSP1) accumulate within damaged glomeruli, and that urinary FSP1, as well as urinary soluble CD163, could potentially serve as a biomarker of ongoing glomerular injury.

Methods: To test that idea, we collected urine samples from 37 patients with glomerular disease; purified the urinary EVs; characterized them using Nanosight, western blotting, and immunoelectron microscopy; and determined FSP1 and soluble CD163 levels using enzyme-linked immunosorbent assays. Read More

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December 2018

Electrical transport and gas sensing characteristics of dielectrophoretically aligned MBE grown catalyst free InAs nanowires.

Nanotechnology 2018 Dec 12. Epub 2018 Dec 12.

DRDO Solid State Physics Laboratory, Lucknow Road, Timarpur, Delhi, Delhi, 110054, INDIA.

In this report, the precise alignment of catalyst free InAs nanowires (NWs) on pre-patterned Au microelectrodes by dielectrophoresis (DEP) technique for gas sensing applications is presented. The catalyst free InAs NWs have been grown on Si (111) substrate by molecular beam epitaxy (MBE) technique. The effect of dispersing solvents, electrode geometries and gaps, magnitude, frequency and duration of applied voltage etc. Read More

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December 2018

Effect of the anchoring strength on the phase behaviour of discotic liquid crystals under face-on confinement.

J Phys Condens Matter 2018 Dec 12. Epub 2018 Dec 12.

Universidad Nacional Autonoma de Mexico Instituto de Investigaciones en Materiales, Mexico D.F., Coyoacan, MEXICO.

In this study we have performed molecular dynamics simulations to study a Gay-Berne discotic fluid confined in a slab geometry for a fixed confinement length. Four different anchoring strengths with a homeotropic (face-on) configuration were studied. We found that changing the anchoring strength changes the normal component of the stress tensor, which in turn changes de density of the system's bulk. Read More

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December 2018

Self-assembled CpG oligodeoxynucleotides conjugated hollow gold nanospheres to enhance cancer-associated immunostimulation.

Colloids Surf B Biointerfaces 2018 Dec 3;175:248-255. Epub 2018 Dec 3.

Key Laboratory of Coal Conversion & New Carbon Materials of Hubei Province, School of Chemistry and Chemical Engineering, Wuhan University of Science and Technology, Wuhan 430081, PR China. Electronic address:

To realize efficiently cellular uptake and enhance the immunostimulation, thiolated cytosine-phosphate-guanine (CpG) oligodeoxynucleotides (ODNs) were self-assembled on hollow gold nanospheres (HGNs) to form CpG-HGNs. The cellular uptake of CpG-HGNs in immune cells was studied in RAW 264.7 cells. Read More

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December 2018

Screening-Based Chemical Approaches to Unravel Stem Cell Biology.

Authors:
Shuibing Chen

Stem Cell Reports 2018 Dec;11(6):1312-1323

Department of Surgery and Biochemistry, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA. Electronic address:

Cell-permeable compounds provide a convenient and efficient approach to manipulate biological processes. A number of compounds controlling stem cell self-renewal, survival, differentiation, and reprogramming have been identified through high-throughput/content screens. Using these powerful chemical tools, strategies have been developed to direct human pluripotent stem cell (hPSC) differentiation to functional cells. Read More

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December 2018

A Renewable Source of Human Beige Adipocytes for Development of Therapies to Treat Metabolic Syndrome.

Cell Rep 2018 Dec;25(11):3215-3228.e9

Center for Molecular Medicine, Maine Medical Center Research Institute, 81 Research Drive, Scarborough, ME 04074, USA; School of Biomedical Sciences and Engineering, The University of Maine, Orono, ME 04469, USA; Tufts University School of Medicine, 145 Harrison Avenue, Boston, MA 02111, USA. Electronic address:

Molecular- and cellular-based therapies have the potential to reduce obesity-associated disease. In response to cold, beige adipocytes form in subcutaneous white adipose tissue and convert energy stored in metabolic substrates to heat, making them an attractive therapeutic target. We developed a robust method to generate a renewable source of human beige adipocytes from induced pluripotent stem cells (iPSCs). Read More

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December 2018
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CDK Phosphorylation of Translation Initiation Factors Couples Protein Translation with Cell-Cycle Transition.

Cell Rep 2018 Dec;25(11):3204-3214.e5

Department of Microbiology and Molecular Genetics, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA. Electronic address:

Protein translation in eukaryotes is cell-cycle dependent, with translation rates more robust in G1 phase of the cell cycle than in mitosis. However, whether the fundamental cell-cycle control machinery directly activates protein translation during the G1/S cell-cycle transition remains unknown. Using the early divergent eukaryote Trypanosoma brucei as a model organism, we report that the G1 cyclin-dependent kinase CRK1 phosphorylates two translation initiation factors, eIF4E4 and PABP1, to promote the G1/S cell-cycle transition and global protein translation. Read More

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December 2018

Importin α5 Regulates Anxiety through MeCP2 and Sphingosine Kinase 1.

Cell Rep 2018 Dec;25(11):3169-3179.e7

Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 76100, Israel. Electronic address:

Importins mediate transport from synapse to soma and from cytoplasm to nucleus, suggesting that perturbation of importin-dependent pathways should have significant neuronal consequences. A behavioral screen on five importin α knockout lines revealed that reduced expression of importin α5 (KPNA1) in hippocampal neurons specifically decreases anxiety in mice. Re-expression of importin α5 in ventral hippocampus of knockout animals increased anxiety behaviors to wild-type levels. Read More

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December 2018

Cryo-EM Structures of Eastern Equine Encephalitis Virus Reveal Mechanisms of Virus Disassembly and Antibody Neutralization.

Cell Rep 2018 Dec;25(11):3136-3147.e5

Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA. Electronic address:

Alphaviruses are enveloped pathogens that cause arthritis and encephalitis. Here, we report a 4.4-Å cryoelectron microscopy (cryo-EM) structure of eastern equine encephalitis virus (EEEV), an alphavirus that causes fatal encephalitis in humans. Read More

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December 2018
3 Reads

V2-Directed Vaccine-like Antibodies from HIV-1 Infection Identify an Additional K169-Binding Light Chain Motif with Broad ADCC Activity.

Cell Rep 2018 Dec;25(11):3123-3135.e6

National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg 2131, South Africa; Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2000, South Africa; Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu Natal, Durban 4041, South Africa. Electronic address:

Antibodies that bind residue K169 in the V2 region of the HIV-1 envelope correlated with reduced risk of infection in the RV144 vaccine trial but were restricted to two ED-motif-encoding light chain genes. Here, we identify an HIV-infected donor with high-titer V2 peptide-binding antibodies and isolate two antibody lineages (CAP228-16H/19F and CAP228-3D) that mediate potent antibody-dependent cell-mediated cytotoxicity (ADCC). Both lineages use the IGHV5-51 heavy chain germline gene, similar to the RV144 antibody CH58, but one lineage (CAP228-16H/19F) uses a light chain without the ED motif. Read More

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December 2018

Galectin-8 Favors the Presentation of Surface-Tethered Antigens by Stabilizing the B Cell Immune Synapse.

Cell Rep 2018 Dec;25(11):3110-3122.e6

Departamento de Biologia Celular y Molecular, Facultad de Ciencias Biologicas, Pontificia Universidad Católica de Chile, Region Metropolitana, Santiago 8331150, Chile. Electronic address:

Complete activation of B cells relies on their capacity to extract tethered antigens from immune synapses by either exerting mechanical forces or promoting their proteolytic degradation through lysosome secretion. Whether antigen extraction can also be tuned by local cues originating from the lymphoid microenvironment has not been investigated. We here show that the expression of Galectin-8-a glycan-binding protein found in the extracellular milieu, which regulates interactions between cells and matrix proteins-is increased within lymph nodes under inflammatory conditions where it enhances B cell arrest phases upon antigen recognition in vivo and promotes synapse formation during BCR recognition of immobilized antigens. Read More

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December 2018
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Organ-Specific Fate, Recruitment, and Refilling Dynamics of Tissue-Resident Macrophages during Blood-Stage Malaria.

Cell Rep 2018 Dec;25(11):3099-3109.e3

Nanyang Technological University, School of Biological Sciences, 60 Nanyang Drive, Singapore 637551, Singapore. Electronic address:

Inflammation-induced disappearance of tissue-resident macrophages represents a key pathogen defense mechanism. Using a model of systemic blood-stage malaria, we studied the dynamics of tissue-resident macrophages in multiple organs to determine how they are depleted and refilled during the course of disease. We show that Plasmodium infection results in a transient loss of embryonically established resident macrophages prior to the parasitemia peak. Read More

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December 2018

Drp1 Controls Effective T Cell Immune-Surveillance by Regulating T Cell Migration, Proliferation, and cMyc-Dependent Metabolic Reprogramming.

Cell Rep 2018 Dec;25(11):3059-3073.e10

Department of Biology, University of Rome Tor Vergata, Rome, Italy; IRCCS, Fondazione Santa Lucia, Rome, Italy. Electronic address:

Mitochondria are key players in the regulation of T cell biology by dynamically responding to cell needs, but how these dynamics integrate in T cells is still poorly understood. We show here that the mitochondrial pro-fission protein Drp1 fosters migration and expansion of developing thymocytes both in vitro and in vivo. In addition, we find that Drp1 sustains in vitro clonal expansion and cMyc-dependent metabolic reprogramming upon activation, also regulating effector T cell numbers in vivo. Read More

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December 2018
2 Reads

Myeloid-Derived Suppressor Cells Produce IL-10 to Elicit DNMT3b-Dependent IRF8 Silencing to Promote Colitis-Associated Colon Tumorigenesis.

Cell Rep 2018 Dec;25(11):3036-3046.e6

Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, USA; Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA; Charlie Norwood VA Medical Center, Augusta, GA 30904, USA. Electronic address:

IL-10 functions as a suppressor of colitis and colitis-associated colon cancer, but it is also a risk locus associated with ulcerative colitis. The mechanism underlying the contrasting roles of IL-10 in inflammation and colon cancer is unknown. We report here that inflammation induces the accumulation of CD11bGr1 myeloid-derived suppressor cells (MDSCs) that express high levels of IL-10 in colon tissue. Read More

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December 2018

KLF4, A Gene Regulating Prostate Stem Cell Homeostasis, Is a Barrier to Malignant Progression and Predictor of Good Prognosis in Prostate Cancer.

Cell Rep 2018 Dec;25(11):3006-3020.e7

Department of Cell Biology, NYU School of Medicine, New York, NY 10016, USA; Department of Urology, NYU School of Medicine, New York, NY 10016, USA. Electronic address:

There is a considerable need to identify those individuals with prostate cancer who have indolent disease. We propose that genes that control adult stem cell homeostasis in organs with slow turnover, such as the prostate, control cancer fate. One such gene, KLF4, overexpressed in murine prostate stem cells, regulates their homeostasis, blocks malignant transformation, and controls the self-renewal of tumor-initiating cells. Read More

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December 2018

PARP Inhibition Elicits STING-Dependent Antitumor Immunity in Brca1-Deficient Ovarian Cancer.

Cell Rep 2018 Dec;25(11):2972-2980.e5

Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Electronic address:

PARP inhibitors have shown promising clinical activities for patients with BRCA mutations and are changing the landscape of ovarian cancer treatment. However, the therapeutic mechanisms of action for PARP inhibition in the interaction of tumors with the tumor microenvironment and the host immune system remain unclear. We find that PARP inhibition by olaparib triggers robust local and systemic antitumor immunity involving both adaptive and innate immune responses through a STING-dependent antitumor immune response in mice bearing Brca1-deficient ovarian tumors. Read More

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December 2018
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Sh3rf2 Haploinsufficiency Leads to Unilateral Neuronal Development Deficits and Autistic-Like Behaviors in Mice.

Cell Rep 2018 Dec;25(11):2963-2971.e6

State Key Laboratory of Molecular Developmental Biology, CAS Center for Excellence in Brain Science and Intelligence Technology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China; Parkinson's Disease Center, Beijing Institute for Brain Disorders, Beijing 100101, China. Electronic address:

Autism spectrum disorders (ASDs) include a variety of developmental brain disorders with clinical findings implicating the dysfunction of the left hemisphere. Here, we generate mice lacking one copy of Sh3rf2, which was detected in ASD patients, to determine whether Sh3rf2 is involved in brain development and whether mutation of SH3RF2 is causative for ASD and the mechanisms linking it to ASD traits. We find that mice with Sh3rf2 haploinsufficiency display significant deficits in social interaction and communication, as well as stereotyped or repetitive behaviors and hyperactivity and seizures. Read More

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December 2018

Crystal Structure of the Double Homeodomain of DUX4 in Complex with DNA.

Cell Rep 2018 Dec;25(11):2955-2962.e3

Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA. Electronic address:

Double homeobox (DUX) transcription factors are unique to eutherian mammals. DUX4 regulates expression of repetitive elements during early embryogenesis, but misexpression of DUX4 causes facioscapulohumeral muscular dystrophy (FSHD) and translocations overexpressing the DUX4 double homeodomain cause B cell leukemia. Here, we report the crystal structure of the tandem homeodomains of DUX4 bound to DNA. Read More

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December 2018
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SIRT7-Dependent Deacetylation of Fibrillarin Controls Histone H2A Methylation and rRNA Synthesis during the Cell Cycle.

Cell Rep 2018 Dec;25(11):2946-2954.e5

Molecular Biology of the Cell II, German Cancer Research Centre (DKFZ), DKFZ-Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH) Alliance, 69120 Heidelberg, Germany. Electronic address:

Fibrillarin (FBL) is a dual-function nucleolar protein that catalyzes 2'-O methylation of pre-rRNA and methylation of histone H2A at glutamine 104 (H2AQ104me). The mechanisms that regulate FBL activity are unexplored. Here, we show that FBL is acetylated at several lysine residues by the acetyltransferase CBP and deacetylated by SIRT7. Read More

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December 2018

An RpaA-Dependent Sigma Factor Cascade Sets the Timing of Circadian Transcriptional Rhythms in Synechococcus elongatus.

Cell Rep 2018 Dec;25(11):2937-2945.e3

Howard Hughes Medical Institute, Harvard University Faculty of Arts and Sciences Center for Systems Biology, Cambridge, MA 02138, USA; Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA. Electronic address:

The circadian clock of the cyanobacterium Synechococcus elongatus PCC 7942 drives oscillations in global mRNA abundances with 24-hr periodicity under constant light conditions. The circadian clock-regulated transcription factor RpaA controls the timing of circadian gene expression, but the mechanisms underlying this control are not well understood. Here, we show that four RpaA-dependent sigma factors-RpoD2, RpoD6, RpoD5, and SigF2-are sequentially activated downstream of active RpaA and are required for proper expression of circadian mRNAs. Read More

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December 2018

Conformational stability and dynamics of the cancer-associated isoform Δ133p53β are modulated by p53 peptides and p53-specific DNA.

FASEB J 2018 Dec 12:fj201801973R. Epub 2018 Dec 12.

Basic Science Program, Leidos Biomedical Research, Inc., Cancer and Inflammation Program, National Cancer Institute, Frederick, Maryland, USA; and.

p53 is a tumor suppressor protein that maintains genome stability, but its Δ133p53β and Δ160p53β isoforms promote breast cancer cell invasion. The sequence truncations in the p53 core domain raise key questions related to their physicochemical properties, including structural stabilities, interaction mechanisms, and DNA-binding abilities. Herein, we investigated the conformational dynamics of Δ133p53β and Δ160p53β with and without binding to p53-specific DNA by using molecular dynamics simulations. Read More

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December 2018
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