ATP5H&Sol;KCTD2 Locus Is Associated With
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Establishing the Pathogenicity of Novel Mitochondrial DNA Sequence Variations: a Cell and Molecular Biology Approach
Mafalda Rita Avó Bacalhau Establishing the Pathogenicity of Novel Mitochondrial DNA Sequence Variations: a Cell and Molecular Biology Approach Tese de doutoramento do Programa de Doutoramento em Ciências da Saúde, ramo de Ciências Biomédicas, orientada pela Professora Doutora Maria Manuela Monteiro Grazina e co-orientada pelo Professor Doutor Henrique Manuel Paixão dos Santos Girão e pela Professora Doutora Lee-Jun C. Wong e apresentada à Faculdade de Medicina da Universidade de Coimbra Julho 2017 Faculty of Medicine Establishing the pathogenicity of novel mitochondrial DNA sequence variations: a cell and molecular biology approach Mafalda Rita Avó Bacalhau Tese de doutoramento do programa em Ciências da Saúde, ramo de Ciências Biomédicas, realizada sob a orientação científica da Professora Doutora Maria Manuela Monteiro Grazina; e co-orientação do Professor Doutor Henrique Manuel Paixão dos Santos Girão e da Professora Doutora Lee-Jun C. Wong, apresentada à Faculdade de Medicina da Universidade de Coimbra. Julho, 2017 Copyright© Mafalda Bacalhau e Manuela Grazina, 2017 Esta cópia da tese é fornecida na condição de que quem a consulta reconhece que os direitos de autor são pertença do autor da tese e do orientador científico e que nenhuma citação ou informação obtida a partir dela pode ser publicada sem a referência apropriada e autorização. This copy of the thesis has been supplied on the condition that anyone who consults it recognizes that its copyright belongs to its author and scientific supervisor and that no quotation from the -
Linkage Analysis of Candidate Loci for End-Stage Renal Disease Due to Diabetic Nephropathy
J Am Soc Nephrol 14: S195–S201, 2003 Linkage Analysis of Candidate Loci for End-Stage Renal Disease due to Diabetic Nephropathy SUDHA K. IYENGAR,*† KATHERINE A. FOX,*† MARLENE SCHACHERE,*† FAUZIA MANZOOR,*† MARY E. SLAUGHTER,*† ADRIAN M. COVIC,†‡ S. MOHAMMED ORLOFF,*† PATRICK S. HAYDEN,†‡ JANE M. OLSON,*† JEFFREY R. SCHELLING,†‡ and JOHN R. SEDOR†‡ Departments of *Epidemiology and Biostatistics, and ‡Medicine, Case Western Reserve University, and †Rammelkamp Center for Research and Education, MetroHealth Medical Center, Cleveland, Ohio. Abstract. Diabetic nephropathy (DN), a major cause of ESRD, ate in the final linkage analysis. To date, we have collected 212 is undoubtedly multifactorial and is caused by environmental sib pairs from 46 CA and 50 AA families. The average age of and genetic factors. To identify a genetic basis for DN suscep- diabetes onset was 46.8 yr versus 36.2 yr for CA and 39.5 yr tibility, we are collecting multiplex DN families in the Cauca- versus 40.2 yr for AA, in males versus females respectively. sian (CA) and African-American (AA) populations for whole Genotyping data were available for 106 sib pairs (43 CA, 63 genome scanning and candidate gene analysis. A candidate AA) from 27 CA (44% male probands) and 38 AA families gene search of diabetic sibs discordantly affected, concordantly (43% male probands). Average AA and CA sibship size was affected and concordantly unaffected for DN was performed 2.73. Singlepoint and multipoint linkage analyses indicate that with microsatellite markers in genomic regions suspected to marker D10S1654 on chromosome 10p is potentially linked to harbor nephropathy susceptibility loci. -
Table 2. Significant
Table 2. Significant (Q < 0.05 and |d | > 0.5) transcripts from the meta-analysis Gene Chr Mb Gene Name Affy ProbeSet cDNA_IDs d HAP/LAP d HAP/LAP d d IS Average d Ztest P values Q-value Symbol ID (study #5) 1 2 STS B2m 2 122 beta-2 microglobulin 1452428_a_at AI848245 1.75334941 4 3.2 4 3.2316485 1.07398E-09 5.69E-08 Man2b1 8 84.4 mannosidase 2, alpha B1 1416340_a_at H4049B01 3.75722111 3.87309653 2.1 1.6 2.84852656 5.32443E-07 1.58E-05 1110032A03Rik 9 50.9 RIKEN cDNA 1110032A03 gene 1417211_a_at H4035E05 4 1.66015788 4 1.7 2.82772795 2.94266E-05 0.000527 NA 9 48.5 --- 1456111_at 3.43701477 1.85785922 4 2 2.8237185 9.97969E-08 3.48E-06 Scn4b 9 45.3 Sodium channel, type IV, beta 1434008_at AI844796 3.79536664 1.63774235 3.3 2.3 2.75319499 1.48057E-08 6.21E-07 polypeptide Gadd45gip1 8 84.1 RIKEN cDNA 2310040G17 gene 1417619_at 4 3.38875643 1.4 2 2.69163229 8.84279E-06 0.0001904 BC056474 15 12.1 Mus musculus cDNA clone 1424117_at H3030A06 3.95752801 2.42838452 1.9 2.2 2.62132809 1.3344E-08 5.66E-07 MGC:67360 IMAGE:6823629, complete cds NA 4 153 guanine nucleotide binding protein, 1454696_at -3.46081884 -4 -1.3 -1.6 -2.6026947 8.58458E-05 0.0012617 beta 1 Gnb1 4 153 guanine nucleotide binding protein, 1417432_a_at H3094D02 -3.13334396 -4 -1.6 -1.7 -2.5946297 1.04542E-05 0.0002202 beta 1 Gadd45gip1 8 84.1 RAD23a homolog (S. -
NIH Public Access Author Manuscript Pharmacogenet Genomics
NIH Public Access Author Manuscript Pharmacogenet Genomics. Author manuscript; available in PMC 2012 September 01. NIH-PA Author ManuscriptPublished NIH-PA Author Manuscript in final edited NIH-PA Author Manuscript form as: Pharmacogenet Genomics. 2011 September ; 21(9): 607–613. doi:10.1097/FPC.0b013e3283415515. PharmGKB summary: very important pharmacogene information for PTGS2 Caroline F. Thorna, Tilo Grosserc, Teri E. Kleina, and Russ B. Altmana,b aDepartment of Genetics, Stanford University Medical Center, Stanford, California bDepartment of Bioengineering, Stanford University Medical Center, Stanford, California cInstitute for Translational Medicine and Therapeutics, University of Pennsylvania, Pennsylvania, USA Keywords cyclooxygenase-2; coxibs; non-steroidal anti-inflammatory drugs; pharmacogenomics; PTGS2; rs20417; rs5275; rs689466 Very important pharmacogene: PTGS2 This PharmGKB summary briefly discusses the PTGS2 gene and current understanding of its function, structure, regulation, and pharmacogenomic relevance. We also present three variants with pharmacogenomic significance and highlight the gaps in our knowledge of PTGS2-drug interactions. Overview The PTGS2 gene codes for prostaglandin G/H synthase-2, which catalyses the first two steps in the metabolism of arachadonic acid. Prostaglandin G/H synthase-2 has two active sites, a hydroperoxidase and a cyclooxygenase (COX) site, and is colloquially termed COX-2. The bifunctional enzyme performs the bis-dioxygenation and reduction of arachadonic acid to form prostaglandin (PG)G2 and H2. PGH2 is then converted to other PGs that modulate inflammation, including PGD2, PGE2, PGF2α, PGI2, and thromboxane A2 (This pathway is shown in the Lipid maps database at http://www.lipidmaps.org/data/IntegratedPathways Data/SetupIntegratedPathways.pl? imgsize=730&Mode=RAW2647&DataType=FAEicosanoidsMedia). COX-2 is the target for nonsteroidal anti-inflammatory drugs (NSAIDS) including those that were purposefully designed (pd) to be selective for COX-2 (pdNSAIDs or coxibs). -
Leukaemia Section
Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Leukaemia Section Mini Review t(11;11)(q14;q23) KMT2A/PICALM inv(11)(q14q23) KMT2A/PICALM Jean-Loup Huret Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France. jean- [email protected] Published in Atlas Database: March 2017 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t1111q14q23ID1411.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/68879/03-2017-t1111q14q23ID1411.pdf DOI: 10.4267/2042/68879 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2018 Atlas of Genetics and Cytogenetics in Oncology and Haematology Otherwise, in a large study of cases of chromosomal Abstract rearrangements involving the human KMT2A Review on t(11;11)(q14;q23) and inv(11)(q14q23) (MLL) gene, a t(11;11)(q14;q23) or inv(11)(q14q23) KMT2A/PICALM, with data on clinics and the KMT2A/PICALM was found in 1 out of 440 infant genes involved. ALL patients, 1 out of 105 infant AML patients, 1 KEYWORDS out of 205 pediatric ALL patients, 1 out of 272 adult Chromosome 11; KMT2A; PICALM; acute myeloid AML patients, and none in 202 pediatric AML leukemia; acute lymphoblastic leukemia. patients, nor in 333 adult ALL patients (Meyer et al., 2013). Note: the case by Meyer et al., 2006 was Clinics and pathology reused in Meyer et al., 2013. Disease Genes involved and Acute myeloid leukemia (AML) and acute proteins lymphoblastic leukemia (ALL). Clinics PICALM (clathrin assembly lymphoid myeloid leukemia gene) There was the case of a 12-week-old female infant with acute monocytic leukemia (M5b) and Location inv(11)(q14q23), dead at day 11 (Wechsler et al., 11q14.2 2003). -
New Insights from Elucidating the Role of LMP1 in Nasopharyngeal Carcinoma
cancers Review New Insights from Elucidating the Role of LMP1 in Nasopharyngeal Carcinoma Kathy H. Y. Shair 1,2,*, Akhil Reddy 1 and Vaughn S. Cooper 2 ID 1 Cancer Virology Program, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA; [email protected] 2 Department of Microbiology and Molecular Genetics, and Center for Evolutionary Biology and Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA; [email protected] * Correspondence: [email protected]; Tel.: +1-412-623-7717 Received: 3 March 2018; Accepted: 20 March 2018; Published: 21 March 2018 Abstract: Latent membrane protein 1 (LMP1) is an Epstein-Barr virus (EBV) oncogenic protein that has no intrinsic enzymatic activity or sequence homology to cellular or viral proteins. The oncogenic potential of LMP1 has been ascribed to pleiotropic signaling properties initiated through protein-protein interactions in cytosolic membrane compartments, but the effects of LMP1 extend to nuclear and extracellular processes. Although LMP1 is one of the latent genes required for EBV-immortalization of B cells, the biology of LMP1 in the pathogenesis of the epithelial cancer nasopharyngeal carcinoma (NPC) is more complex. NPC is prevalent in specific regions of the world with high incidence in southeast China. The epidemiology and time interval from seroconversion to NPC onset in adults would suggest the involvement of multiple risk factors that complement the establishment of a latent and persistent EBV infection. The contribution of LMP1 to EBV pathogenesis in polarized epithelia has only recently begun to be elucidated. Furthermore, the LMP1 gene has emerged as one of the most divergent sequences in the EBV genome. -
Mitochondrial Reprogramming Via ATP5H Loss Promotes Multimodal Cancer Therapy Resistance
Mitochondrial reprogramming via ATP5H loss promotes multimodal cancer therapy resistance Kwon-Ho Song, … , T.C. Wu, Tae Woo Kim J Clin Invest. 2018;128(9):4098-4114. https://doi.org/10.1172/JCI96804. Research Article Immunology Oncology The host immune system plays a pivotal role in the emergence of tumor cells that are refractory to multiple clinical interventions including immunotherapy, chemotherapy, and radiotherapy. Here, we examined the molecular mechanisms by which the immune system triggers cross-resistance to these interventions. By examining the biological changes in murine and tumor cells subjected to sequential rounds of in vitro or in vivo immune selection via cognate cytotoxic T lymphocytes, we found that multimodality resistance arises through a core metabolic reprogramming pathway instigated by epigenetic loss of the ATP synthase subunit ATP5H, which leads to ROS accumulation and HIF-1α stabilization under normoxia. Furthermore, this pathway confers to tumor cells a stem-like and invasive phenotype. In vivo delivery of antioxidants reverses these phenotypic changes and resensitizes tumor cells to therapy. ATP5H loss in the tumor is strongly linked to failure of therapy, disease progression, and poor survival in patients with cancer. Collectively, our results reveal a mechanism underlying immune-driven multimodality resistance to cancer therapy and demonstrate that rational targeting of mitochondrial metabolic reprogramming in tumor cells may overcome this resistance. We believe these results hold important implications for the clinical management of cancer. Find the latest version: https://jci.me/96804/pdf RESEARCH ARTICLE The Journal of Clinical Investigation Mitochondrial reprogramming via ATP5H loss promotes multimodal cancer therapy resistance Kwon-Ho Song,1,2,3 Jae-Hoon Kim,4 Young-Ho Lee,1,2,3 Hyun Cheol Bae,5 Hyo-Jung Lee,1,2,3 Seon Rang Woo,1,2,3 Se Jin Oh,1,2,3 Kyung-Mi Lee,1,2 Cassian Yee,6 Bo Wook Kim,7 Hanbyoul Cho,4 Eun Joo Chung,8 Joon-Yong Chung,9 Stephen M. -
ATP5H Antibody (Center) Affinity Purified Rabbit Polyclonal Antibody (Pab) Catalog # AW5527
10320 Camino Santa Fe, Suite G San Diego, CA 92121 Tel: 858.875.1900 Fax: 858.622.0609 ATP5H Antibody (Center) Affinity Purified Rabbit Polyclonal Antibody (Pab) Catalog # AW5527 Specification ATP5H Antibody (Center) - Product Information Application WB, IHC-P, FC,E Primary Accession O75947 Reactivity Human Host Rabbit Clonality Polyclonal Calculated MW H=18;M=19;R=19 KDa Isotype Rabbit Ig Antigen Source HUMAN ATP5H Antibody (Center) - Additional Information Gene ID 10476 Antigen Region 68-97 All lanes : Anti-ATP5H Antibody (Center) at 1:1000 dilution Lane 1: MDA-MB-453 whole Other Names cell lysate Lane 2: HepG2 whole cell lysate ATP synthase subunit d, mitochondrial, Lysates/proteins at 20 µg per lane. ATPase subunit d, ATP5H Secondary Goat Anti-Rabbit IgG, (H+L), Peroxidase conjugated at 1/10000 dilution. Dilution Predicted band size : 18 kDa WB~~1:1000 Blocking/Dilution buffer: 5% NFDM/TBST. IHC-P~~1:50~100 FC~~1:10~50 Target/Specificity This ATP5H antibody is generated from rabbits immunized with a KLH conjugated synthetic peptide between 68-97 amino acids from the Central region of human ATP5H. Storage Maintain refrigerated at 2-8°C for up to 2 weeks. For long term storage store at -20°C in small aliquots to prevent freeze-thaw cycles. Precautions ATP5H Antibody (Center) is for research use only and not for use in diagnostic or therapeutic procedures. ATP5H antibody (Center) (Cat. #AW5527) immunohistochemistry analysis in formalin fixed and paraffin embedded human brain Page 1/3 10320 Camino Santa Fe, Suite G San Diego, CA 92121 Tel: 858.875.1900 Fax: 858.622.0609 ATP5H Antibody (Center) - Protein Information tissue followed by peroxidase conjugation of the secondary antibody and DAB staining. -
Expression Pattern of CD2AP in the Intact and Collaterally Sprouting Nervous System
University of Louisville ThinkIR: The University of Louisville's Institutional Repository Electronic Theses and Dissertations 8-2011 Expression pattern of CD2AP in the intact and collaterally sprouting nervous system. Sarah Elizabeth Claypool Couch 1987- University of Louisville Follow this and additional works at: https://ir.library.louisville.edu/etd Recommended Citation Couch, Sarah Elizabeth Claypool 1987-, "Expression pattern of CD2AP in the intact and collaterally sprouting nervous system." (2011). Electronic Theses and Dissertations. Paper 279. https://doi.org/10.18297/etd/279 This Master's Thesis is brought to you for free and open access by ThinkIR: The University of Louisville's Institutional Repository. It has been accepted for inclusion in Electronic Theses and Dissertations by an authorized administrator of ThinkIR: The University of Louisville's Institutional Repository. This title appears here courtesy of the author, who has retained all other copyrights. For more information, please contact [email protected]. EXPRESSION PATTERN OF CD2AP IN THE INTACT AND COLLATERALL Y SPROUTING NERVOUS SYSTEM By Sarah Elizabeth Claypool Couch B.S., Centre College, 2009 A Thesis Submitted to the Faculty of the School of Medicine of the University of Louisville in Fulfillment of the Requirements for the Degree of Master of Science Department of Anatomical Sciences and Neurobiology University of Louisville Louisville, Kentucky August 2011 EXPRESSION PATTERN OF CD2AP IN THE INTACT AND COLLA TERALL Y SPROUTING NERVOUS SYSTEM By Sarah Elizabeth Claypool Couch B.S., Centre College, 2009 A Thesis Approved on July 19,2011 By the following Thesis Committee: Jeffrey Petruska, Ph.D. Theo Hagg, M.D., Ph.D. -
PICALM Modulates Autophagy Activity and Tau Accumulation
ARTICLE Received 13 Dec 2013 | Accepted 14 Aug 2014 | Published 22 Sep 2014 DOI: 10.1038/ncomms5998 OPEN PICALM modulates autophagy activity and tau accumulation Kevin Moreau1,*, Angeleen Fleming1,2,*, Sara Imarisio3, Ana Lopez Ramirez1,2, Jacob L. Mercer4,5, Maria Jimenez-Sanchez1, Carla F. Bento1, Claudia Puri1, Eszter Zavodszky1, Farah Siddiqi1, Catherine P. Lavau4, Maureen Betton1,3, Cahir J. O’Kane3, Daniel S. Wechsler4,5 & David C. Rubinsztein1 Genome-wide association studies have identified several loci associated with Alzheimer’s disease (AD), including proteins involved in endocytic trafficking such as PICALM/CALM (phosphatidylinositol binding clathrin assembly protein). It is unclear how these loci may contribute to AD pathology. Here we show that CALM modulates autophagy and alters clearance of tau, a protein which is a known autophagy substrate and which is causatively linked to AD, both in vitro and in vivo. Furthermore, altered CALM expression exacerbates tau-mediated toxicity in zebrafish transgenic models. CALM influences autophagy by regulating the endocytosis of SNAREs, such as VAMP2, VAMP3 and VAMP8, which have diverse effects on different stages of the autophagy pathway, from autophagosome formation to autophagosome degradation. This study suggests that the AD genetic risk factor CALM modulates autophagy, and this may affect disease in a number of ways including modulation of tau turnover. 1 Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke’s Hospital, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK. 2 Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK. 3 Department of Genetics, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK. -
Molecular Genetic Analysis of Rbm45/Drbp1: Genomic Structure, Expression, and Evolution Lauren E
Journal of Student Research (2018) Volume 7, Issue 2, pp 49-61 Research Article Molecular Genetic Analysis of Rbm45/Drbp1: Genomic Structure, Expression, and Evolution Lauren E. Pricea,f, Abigail B. Loewen Faulb,f, Aleksandra Vuchkovskaa, Kevin J. Lopeza, Katie M. Fastb, Andrew G. Ecka, David W. Hoferera,e, and Jeffrey O. Hendersona,b,c,d,g RNA recognition motif-type RNA-binding domain containing proteins (RBDPs) participate in RNA metabolism including regulating mRNA stability, nuclear-cytoplasmic shuttling, and splicing. Rbm45 is an RBDP first cloned from rat brain and expressed spatiotemporally during rat neural development. More recently, RBM45 has been associated with pathological aggregates in the human neurological disorders amyotrophic lateral sclerosis, frontotemporal lobar degeneration, and Alzheimer’s. Rbm45 and the neural developmental protein musashi-1 are in the same family of RDBPs and have similar expression patterns. In contrast to Musashi-1, which is upregulated during colorectal carcinogenesis, we found no association of RBM45 overexpression in human colon cancer tissue. In order to begin characterizing RNA-binding partners of Rbm45, we have successfully cloned and expressed human RBM45 in an Intein fusion-protein expression system. Furthermore, to gain a better understanding of the molecular genetics and evolution of Rbm45, we used an in silico approach to analyze the gene structure of the human and mouse Rbm45 homologues and explored the evolutionary conservation of Rbm45 in metazoans. Human RBM45 and mouse Rbm45 span ~17 kb and 13 kb, respectively, and contain 10 exons, one of which is non-coding. Both genes have TATA-less promoters with an initiator and a GC-rich element. -
Paternal Finasteride Treatment Can Influence the Testicular
Article Paternal Finasteride Treatment Can Influence the Testicular Transcriptome Profile of Male Offspring—Preliminary Study Agnieszka Kolasa 1,* , Dorota Rogi ´nska 2 , Sylwia Rzeszotek 1 , Bogusław Machali ´nski 2 and Barbara Wiszniewska 1 1 Department of Histology and Embryology, Pomeranian Medical University (PMU), Powsta´nców Wlkp. 72 Avene, 70-111 Szczecin, Poland; [email protected] (S.R.); [email protected] (B.W.) 2 Department of General Pathology, Pomeranian Medical University, Powsta´nców Wlkp. 72 Avene, 70-111 Szczecin, Poland; [email protected] (D.R.); [email protected] (B.M.) * Correspondence: [email protected]; Tel.: +48-91-466-16-77 Abstract: (1) Background: Hormone-dependent events that occur throughout spermatogenesis during postnatal testis maturation are significant for adult male fertility. Any disturbances in the T/DHT ratio in male progeny born from females fertilized by finasteride-treated male rats (F0:Fin) can result in the impairment of testicular physiology. The goal of this work was to profile the testicular transcriptome in the male filial generation (F1:Fin) from paternal F0:Fin rats. (2) Methods: The subject material for the study were testis from immature and mature male rats born from females fertilized by finasteride-treated rats. Testicular tissues from the offspring were used in microarray analyses. (3) Results: The top 10 genes having the highest and lowest fold change values were mainly those that encoded odoriferous (Olfr: 31, 331, 365, 633, 774, 814, 890, 935, 1109, 1112, 1173, 1251, 1259, 1253, 1383) Citation: Kolasa, A.; Rogi´nska,D.; Vmn1r 50 103 210 211 Vmn2r 3 23 99 RIKEN cDNA 5430402E10 Rzeszotek, S.; Machali´nski,B.; and vomeronasal ( : , , , ; : , , ) receptors and , Wiszniewska, B.