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Roles of Adipose Tissue-Derived Factors in Adipose Tissue Development and Lipid Metabolism Dissertation Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Jinsoo Ahn, M.S. Graduate Program in Ohio State University Nutrition The Ohio State University 2015 Dissertation Committee: Kichoon Lee, Ph.D., Advisor Earl H. Harrison, Ph.D. Ramesh Selvaraj, Ph.D. Ouliana Ziouzenkova, Ph.D. Copyright by Jinsoo Ahn 2015 Abstract Obesity is a global trend and major risk factor for serious diseases including type 2 diabetes, heart disease, and hypertension. Obesity is characterized by excess fat accumulation, especially in the visceral area. The pathogenic effects related to common obesity are largely attributed to dysregulated secretion of adipokines followed by insulin resistance in peripheral tissues when adipose tissue mass is altered. White adipose tissue serves as a dynamic endocrine organ as well as a major energy reservoir for whole-body energy homeostasis. Adipokines influence various metabolic processes in the body including adipocyte differentiation; however, precise physiological roles of adipokines need to be further investigated. In addition, a large proportion of adipokines still needs to be identified. Information from the gene expression omnibus (GEO) profile, a public repository for microarray data, combined with confirmatory studies on mRNA and protein expression were used to identify a novel adipose tissue-specific gene, chordin-like 1 (Chrdl1). Further analysis showed that Chrdl1 encodes a putative secreted protein which is a new adipokine. Chrdl1 expression increases during 3T3-L1 adipocyte development in vitro and mouse adipose tissue development in vivo. -
Clinical Spectrum and Genetic Landscape for Hereditary Spastic
Dong et al. Molecular Neurodegeneration (2018) 13:36 https://doi.org/10.1186/s13024-018-0269-1 RESEARCH ARTICLE Open Access Clinical spectrum and genetic landscape for hereditary spastic paraplegias in China En-Lin Dong1†, Chong Wang1†, Shuang Wu1†, Ying-Qian Lu1, Xiao-Hong Lin1, Hui-Zhen Su1, Miao Zhao1, Jin He1, Li-Xiang Ma2, Ning Wang1,3, Wan-Jin Chen1,3* and Xiang Lin1* Abstract Background: Hereditary spastic paraplegias (HSP) is a heterogeneous group of rare neurodegenerative disorders affecting the corticospinal tracts. To date, more than 78 HSP loci have been mapped to cause HSP. However, both the clinical and mutational spectrum of Chinese patients with HSP remained unclear. In this study, we aim to perform a comprehensive analysis of clinical phenotypes and genetic distributions in a large cohort of Chinese HSP patients, and to elucidate the primary pathogenesis in this population. Methods: We firstly performed next-generation sequencing targeting 149 genes correlated with HSP in 99 index cases of our cohort. Multiplex ligation-dependent probe amplification testing was further carried out among those patients without known disease-causing gene mutations. We simultaneously performed a retrospective study on the reported patients exhibiting HSP in other Chinese cohorts. All clinical and molecular characterization from above two groups of Chinese HSP patients were analyzed and summarized. Eventually, we further validated the cellular changes in fibroblasts of two major spastic paraplegia (SPG) patients (SPG4 and SPG11) in vitro. Results: Most patients of ADHSP (94%) are pure forms, whereas most patients of ARHSP (78%) tend to be complicated forms. In ADHSP, we found that SPG4 (79%) was the most prevalent, followed by SPG3A (11%), SPG6 (4%) and SPG33 (2%). -
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Crystal Structure of LSD1 in Complex with 4-[5-(Piperidin-4-Ylmethoxy)-2-(P-Tolyl) Pyridin-3-Yl]Benzonitrile
molecules Article Crystal Structure of LSD1 in Complex with 4-[5-(Piperidin-4-ylmethoxy)-2-(p-tolyl) pyridin-3-yl]benzonitrile Hideaki Niwa 1 ID , Shin Sato 1, Tomoko Hashimoto 2, Kenji Matsuno 2 and Takashi Umehara 1,* ID 1 Laboratory for Epigenetics Drug Discovery, RIKEN Center for Biosystems Dynamics Research (BDR), 1-7-22 Suehiro-cho, Tsurumi, Yokohama 230-0045, Japan; [email protected] (H.N.); [email protected] (S.S.) 2 Department of Chemistry and Life Science, School of Advanced Engineering, Kogakuin University, 2665-1 Nakano, Hachioji, Tokyo 192-0015, Japan; [email protected] (T.H.); [email protected] (K.M.) * Correspondence: [email protected]; Tel.: +81-45-503-9457 Received: 28 May 2018; Accepted: 22 June 2018; Published: 26 June 2018 Abstract: Because lysine-specific demethylase 1 (LSD1) regulates the maintenance of cancer stem cell properties, small-molecule inhibitors of LSD1 are expected to be useful for the treatment of several cancers. Reversible inhibitors of LSD1 with submicromolar inhibitory potency have recently been reported, but their exact binding modes are poorly understood. In this study, we synthesized a recently reported reversible inhibitor, 4-[5-(piperidin-4-ylmethoxy)-2-(p-tolyl)pyridin-3- yl]benzonitrile, which bears a 4-piperidinylmethoxy group, a 4-methylphenyl group, and a 4-cyanophenyl group on a pyridine ring, and determined the crystal structure of LSD1 in complex with this inhibitor at 2.96 Å. We observed strong electron density for the compound, showing that its cyano group forms a hydrogen bond with Lys661, which is a critical residue in the lysine demethylation reaction located deep in the catalytic center of LSD1. -
Identification of the Drosophila Melanogaster Homolog of the Human Spastin Gene
View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by RERO DOC Digital Library Dev Genes Evol (2003) 213:412–415 DOI 10.1007/s00427-003-0340-x EXPRESSION NOTE Lars Kammermeier · Jrg Spring · Michael Stierwald · Jean-Marc Burgunder · Heinrich Reichert Identification of the Drosophila melanogaster homolog of the human spastin gene Received: 14 April 2003 / Accepted: 5 May 2003 / Published online: 5 June 2003 Springer-Verlag 2003 Abstract The human SPG4 locus encodes the spastin gene encoding spastin. This gene is expressed ubiqui- gene, which is responsible for the most prevalent form tously in fetal and adult human tissues (Hazan et al. of autosomal dominant hereditary spastic paraplegia 1999). The highest expression levels are found in the (AD-HSP), a neurodegenerative disorder. Here we iden- brain, with selective expression in the cortex and striatum. tify the predicted gene product CG5977 as the Drosophila In the spinal cord, spastin is expressed exclusively in homolog of the human spastin gene, with much higher nuclei of motor neurons, suggesting that the strong sequence similarities than any other related AAA domain neurodegenerative defects observed in patients are caused protein in the fly. Furthermore we report a new potential by a primary defect of spastin in neurons (Charvin et al. transmembrane domain in the N-terminus of the two 2003). The human spastin gene encodes a predicted 616- homologous proteins. During embryogenesis, the expres- amino-acid long protein and is a member of the large sion pattern of Drosophila spastin becomes restricted family of proteins with an AAA domain (ATPases primarily to the central nervous system, in contrast to the Associated with diverse cellular Activities). -
Epithelial Delamination Is Protective During Pharmaceutical-Induced Enteropathy
Epithelial delamination is protective during pharmaceutical-induced enteropathy Scott T. Espenschieda, Mark R. Cronana, Molly A. Mattya, Olaf Muellera, Matthew R. Redinbob,c,d, David M. Tobina,e,f, and John F. Rawlsa,e,1 aDepartment of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC 27710; bDepartment of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599; cDepartment of Biochemistry, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599; dDepartment of Microbiology and Immunology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599; eDepartment of Medicine, Duke University School of Medicine, Durham, NC 27710; and fDepartment of Immunology, Duke University School of Medicine, Durham, NC 27710 Edited by Dennis L. Kasper, Harvard Medical School, Boston, MA, and approved July 15, 2019 (received for review February 12, 2019) Intestinal epithelial cell (IEC) shedding is a fundamental response to in mediating intestinal responses to injury remains poorly un- intestinal damage, yet underlying mechanisms and functions have derstood for most xenobiotics. been difficult to define. Here we model chronic intestinal damage in Gastrointestinal pathology is common in people using phar- zebrafish larvae using the nonsteroidal antiinflammatory drug maceuticals, including nonsteroidal antiinflammatory drugs (NSAID) Glafenine. Glafenine induced the unfolded protein response (NSAIDs) (11). While gastric ulceration has historically been a (UPR) and inflammatory pathways in IECs, leading to delamination. defining clinical presentation of NSAID-induced enteropathy, Glafenine-induced inflammation was augmented by microbial colo- small intestinal pathology has also been observed, although the nizationandassociatedwithchanges in intestinal and environmental incidence may be underreported due to diagnostic limitations microbiotas. -
Global Analysis of Protein Folding Thermodynamics for Disease State Characterization
Global Analysis of Protein Folding Thermodynamics for Disease State Characterization and Biomarker Discovery by Jagat Adhikari Department of Biochemistry Duke University Date:_______________________ Approved: ___________________________ Michael C. Fitzgerald, Supervisor ___________________________ Kenneth Kreuzer ___________________________ Terrence G. Oas ___________________________ Jiyong Hong ___________________________ Seok-Yong Lee Dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Biochemistry in the Graduate School of Duke University 2015 ABSTRACT Global Analysis of Protein Folding Thermodynamics for Disease State Characterization and Biomarker Discovery by Jagat Adhikari Department of Biochemistry Duke University Date:_______________________ Approved: ___________________________ Michael C. Fitzgerald, Supervisor ___________________________ Kenneth Kreuzer ___________________________ Terrence G. Oas ___________________________ Jiyong Hong ___________________________ Seok-Yong Lee An abstract of a dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Biochemistry in the Graduate School of Duke University 2015 Copyright by Jagat Adhikari 2015 Abstract Protein biomarkers can facilitate the diagnosis of many diseases such as cancer and they can be important for the development of effective therapeutic interventions. Current large-scale biomarker discovery and disease state characterization -
RBP2 Belongs to a Family of Demethylases, Specific For
View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector RBP2 Belongs to a Family of Demethylases, Specific for Tri- and Dimethylated Lysine 4 on Histone 3 Jesper Christensen,1,2,4 Karl Agger,1,2,4 Paul A.C. Cloos,1,2,4 Diego Pasini,1,2 Simon Rose,2 Lau Sennels,3 Juri Rappsilber,3 Klaus H. Hansen,1,2 Anna Elisabetta Salcini,2,* and Kristian Helin1,2,* 1 Centre for Epigenetics 2 Biotech Research and Innovation Centre (BRIC) University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen, Denmark 3 Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh, EH9 3JR, UK 4 These authors contributed equally to this work. *Correspondence: [email protected] (K.H.), [email protected] (A.E.S.) DOI 10.1016/j.cell.2007.02.003 SUMMARY activity (Strahl and Allis, 2000; Turner, 2000). Thus, some of these modifications appear to play important roles in Methylation of histones has been regarded as dividing the genome into transcriptionally active and a stable modification defining the epigenetic inactive areas. program of the cell, which regulates chromatin As an example of this, tri- and dimethylation of histone structure and transcription. However, the recent H3 at lysine 4 (H3K4me3/me2) is restricted to euchromatin discovery of histone demethylases has chal- and is generally associated with active transcription (Sims lenged the stable nature of histone methylation. and Reinberg, 2006). The H3K4 tri- and dimethylation marks may facilitate transcription by the recruitment of nu- Here we demonstrate that the JARID1 proteins cleosome remodeling complexes and histone-modifying RBP2, PLU1, and SMCX are histone demethy- enzymes or by preventing transcriptional repressors lases specific for di- and trimethylated histone from binding to chromatin. -
82594016.Pdf
View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Structure Article Molecular Mimicry and Ligand Recognition in Binding and Catalysis by the Histone Demethylase LSD1-CoREST Complex Riccardo Baron,1,* Claudia Binda,2 Marcello Tortorici,2 J. Andrew McCammon,1 and Andrea Mattevi2,* 1Department of Chemistry and Biochemistry, Center for Theoretical Biological Physics, and Department of Pharmacology, Howard Hughes Medical Institute, University of California at San Diego, La Jolla, CA 92093-0365, USA 2Department of Genetics and Microbiology, University of Pavia, Via Ferrata 1, 27100, Pavia, Italy *Correspondence: [email protected] (R.B.), [email protected] (A.M.) DOI 10.1016/j.str.2011.01.001 SUMMARY (LSD1 or KDM1A, according to the newly adopted nomencla- ture) (Shi et al., 2004; Forneris et al., 2005). This enzyme acts Histone demethylases LSD1 and LSD2 (KDM1A/B) on mono- and dimethylated Lys4 of histone H3 through a catalyze the oxidative demethylation of Lys4 of FAD-dependent oxidative process (Figure 1A). LSD1 is often histone H3. We used molecular dynamics simula- associated to the histone deacetylases (HDAC) 1 and 2 and to tions to probe the diffusion of the oxygen substrate. the corepressor protein CoREST, which tightly binds to LSD1 Oxygen can reach the catalytic center independently enhancing both its stability and enzymatic activity. A number of from the presence of a bound histone peptide, studies have indicated that LSD1-CoREST interacts with various protein complexes involved in gene regulation and chromatin implying that LSD1 can complete subsequent deme- modification (Forneris et al., 2008; Mosammaparast and Shi, thylation cycles without detaching from the nucleo- 2010). -
Partial Deletion of Chromosome 6P Causing Developmental Delay and Mild Dysmorphisms in a Child
Vrachnis et al. Mol Cytogenet (2021) 14:39 https://doi.org/10.1186/s13039-021-00557-y CASE REPORT Open Access Partial deletion of chromosome 6p causing developmental delay and mild dysmorphisms in a child: molecular and developmental investigation and literature search Nikolaos Vrachnis1,2,3* , Ioannis Papoulidis4, Dionysios Vrachnis5, Elisavet Siomou4, Nikolaos Antonakopoulos1,2, Stavroula Oikonomou6, Dimitrios Zygouris2, Nikolaos Loukas7, Zoi Iliodromiti8, Efterpi Pavlidou9, Loretta Thomaidis6 and Emmanouil Manolakos4 Abstract Background: The interstitial 6p22.3 deletions concern rare chromosomal events afecting numerous aspects of both physical and mental development. The syndrome is characterized by partial deletion of chromosome 6, which may arise in a number of ways. Case presentation: We report a 2.8-year old boy presenting with developmental delay and mild dysmorphisms. High-resolution oligonucleotide microarray analysis revealed with high precision a 2.5 Mb interstitial 6p deletion in the 6p22.3 region which encompasses 13 genes. Conclusions: Identifcation and in-depth analysis of cases presenting with mild features of the syndrome will sharpen our understanding of the genetic spectrum of the 6p22.3 deletion. Keywords: 6p22.3 deletion, Syndrome, Developmental delay, Intellectual disability, Dysmorphism, Behavioral abnormalities, High-resolution microarray analysis Background dysmorphic features, and structural organ defects, as well Te interstitial deletion of chromosomal region 6p22.3 as intellectual disability. is a rare condition with variable phenotypic expression. We report herein a case of interstitial deletion of chro- To date, more than 30 children and adolescents with this mosome 6p investigated by array-CGH in a 2.8-year old deletion have been reported [1–11]. -
Supplementary Table S1. Prioritization of Candidate FPC Susceptibility Genes by Private Heterozygous Ptvs
Supplementary Table S1. Prioritization of candidate FPC susceptibility genes by private heterozygous PTVs Number of private Number of private Number FPC patient heterozygous PTVs in heterozygous PTVs in tumors with somatic FPC susceptibility Hereditary cancer Hereditary Gene FPC kindred BCCS samples mutation DNA repair gene Cancer driver gene gene gene pancreatitis gene ATM 19 1 - Yes Yes Yes Yes - SSPO 12 8 1 - - - - - DNAH14 10 3 - - - - - - CD36 9 3 - - - - - - TET2 9 1 - - Yes - - - MUC16 8 14 - - - - - - DNHD1 7 4 1 - - - - - DNMT3A 7 1 - - Yes - - - PKHD1L1 7 9 - - - - - - DNAH3 6 5 - - - - - - MYH7B 6 1 - - - - - - PKD1L2 6 6 - - - - - - POLN 6 2 - Yes - - - - POLQ 6 7 - Yes - - - - RP1L1 6 6 - - - - - - TTN 6 5 4 - - - - - WDR87 6 7 - - - - - - ABCA13 5 3 1 - - - - - ASXL1 5 1 - - Yes - - - BBS10 5 0 - - - - - - BRCA2 5 6 1 Yes Yes Yes Yes - CENPJ 5 1 - - - - - - CEP290 5 5 - - - - - - CYP3A5 5 2 - - - - - - DNAH12 5 6 - - - - - - DNAH6 5 1 1 - - - - - EPPK1 5 4 - - - - - - ESYT3 5 1 - - - - - - FRAS1 5 4 - - - - - - HGC6.3 5 0 - - - - - - IGFN1 5 5 - - - - - - KCP 5 4 - - - - - - LRRC43 5 0 - - - - - - MCTP2 5 1 - - - - - - MPO 5 1 - - - - - - MUC4 5 5 - - - - - - OBSCN 5 8 2 - - - - - PALB2 5 0 - Yes - Yes Yes - SLCO1B3 5 2 - - - - - - SYT15 5 3 - - - - - - XIRP2 5 3 1 - - - - - ZNF266 5 2 - - - - - - ZNF530 5 1 - - - - - - ACACB 4 1 1 - - - - - ALS2CL 4 2 - - - - - - AMER3 4 0 2 - - - - - ANKRD35 4 4 - - - - - - ATP10B 4 1 - - - - - - ATP8B3 4 6 - - - - - - C10orf95 4 0 - - - - - - C2orf88 4 0 - - - - - - C5orf42 4 2 - - - - -
Microtubule-Severing Enzymes at the Cutting Edge
Commentary 2561 Microtubule-severing enzymes at the cutting edge David J. Sharp1,* and Jennifer L. Ross2 1Department of Physiology and Biophysics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA 2Department of Physics, University of Massachusetts-Amherst, 302 Hasbrouck Laboratory, Amherst, MA 01003, USA *Author for correspondence ([email protected]) Journal of Cell Science 125, 2561–2569 ß 2012. Published by The Company of Biologists Ltd doi: 10.1242/jcs.101139 Summary ATP-dependent severing of microtubules was first reported in Xenopus laevis egg extracts in 1991. Two years later this observation led to the purification of the first known microtubule-severing enzyme, katanin. Katanin homologs have now been identified throughout the animal kingdom and in plants. Moreover, members of two closely related enzyme subfamilies, spastin and fidgetin, have been found to sever microtubules and might act alongside katanins in some contexts (Roll-Mecak and McNally, 2010; Yu et al., 2008; Zhang et al., 2007). Over the past few years, it has become clear that microtubule-severing enzymes contribute to a wide range of cellular activities including mitosis and meiosis, morphogenesis, cilia biogenesis and disassembly, and migration. Thus, this group of enzymes is revealing itself to be among the most important of the microtubule regulators. This Commentary focuses on our growing understanding of how microtubule-severing enzymes contribute to the organization and dynamics of diverse microtubule arrays, as well as the structural and biophysical characteristics that afford them the unique capacity to catalyze the removal of tubulin from the interior microtubule lattice. Our goal is to provide a broader perspective, focusing on a limited number of particularly informative, representative and/or timely findings. -
ONLINE SUPPLEMENTARY TABLE Table 2. Differentially Expressed
ONLINE SUPPLEMENTARY TABLE Table 2. Differentially Expressed Probe Sets in Livers of GK Rats. A. Immune/Inflammatory (67 probe sets, 63 genes) Age Strain Probe ID Gene Name Symbol Accession Gene Function 5 WKY 1398390_at small inducible cytokine B13 precursor Cxcl13 AA892854 chemokine activity; lymph node development 5 WKY 1389581_at interleukin 33 Il33 BF390510 cytokine activity 5 WKY *1373970_at interleukin 33 Il33 AI716248 cytokine activity 5 WKY 1369171_at macrophage stimulating 1 (hepatocyte growth factor-like) Mst1; E2F2 NM_024352 serine-throenine kinase; tumor suppression 5 WKY 1388071_x_at major histocompatability antigen Mhc M24024 antigen processing and presentation 5 WKY 1385465_at sialic acid binding Ig-like lectin 5 Siglec5 BG379188 sialic acid-recognizing receptor 5 WKY 1393108_at major histocompatability antigen Mhc BM387813 antigen processing and presentation 5 WKY 1388202_at major histocompatability antigen Mhc BI395698 antigen processing and presentation 5 WKY 1371171_at major histocompatability antigen Mhc M10094 antigen processing and presentation 5 WKY 1370382_at major histocompatability antigen Mhc BI279526 antigen processing and presentation 5 WKY 1371033_at major histocompatability antigen Mhc AI715202 antigen processing and presentation 5 WKY 1383991_at leucine rich repeat containing 8 family, member E Lrrc8e BE096426 proliferation and activation of lymphocytes and monocytes. 5 WKY 1383046_at complement component factor H Cfh; Fh AA957258 regulation of complement cascade 4 WKY 1369522_a_at CD244 natural killer