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Hidden Targets in RAF Signalling Pathways to Block Oncogenic RAS Signalling
G C A T T A C G G C A T genes Review Hidden Targets in RAF Signalling Pathways to Block Oncogenic RAS Signalling Aoife A. Nolan 1, Nourhan K. Aboud 1, Walter Kolch 1,2,* and David Matallanas 1,* 1 Systems Biology Ireland, School of Medicine, University College Dublin, Belfield, Dublin 4, Ireland; [email protected] (A.A.N.); [email protected] (N.K.A.) 2 Conway Institute of Biomolecular & Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland * Correspondence: [email protected] (W.K.); [email protected] (D.M.) Abstract: Oncogenic RAS (Rat sarcoma) mutations drive more than half of human cancers, and RAS inhibition is the holy grail of oncology. Thirty years of relentless efforts and harsh disappointments have taught us about the intricacies of oncogenic RAS signalling that allow us to now get a pharma- cological grip on this elusive protein. The inhibition of effector pathways, such as the RAF-MEK-ERK pathway, has largely proven disappointing. Thus far, most of these efforts were aimed at blocking the activation of ERK. Here, we discuss RAF-dependent pathways that are regulated through RAF functions independent of catalytic activity and their potential role as targets to block oncogenic RAS signalling. We focus on the now well documented roles of RAF kinase-independent functions in apoptosis, cell cycle progression and cell migration. Keywords: RAF kinase-independent; RAS; MST2; ASK; PLK; RHO-α; apoptosis; cell cycle; cancer therapy Citation: Nolan, A.A.; Aboud, N.K.; Kolch, W.; Matallanas, D. Hidden Targets in RAF Signalling Pathways to Block Oncogenic RAS Signalling. -
Expression Gene Network Analyses Reveal Molecular Mechanisms And
www.nature.com/scientificreports OPEN Diferential expression and co- expression gene network analyses reveal molecular mechanisms and candidate biomarkers involved in breast muscle myopathies in chicken Eva Pampouille1,2, Christelle Hennequet-Antier1, Christophe Praud1, Amélie Juanchich1, Aurélien Brionne1, Estelle Godet1, Thierry Bordeau1, Fréderic Fagnoul2, Elisabeth Le Bihan-Duval1 & Cécile Berri1* The broiler industry is facing an increasing prevalence of breast myopathies, such as white striping (WS) and wooden breast (WB), and the precise aetiology of these occurrences remains poorly understood. To progress our understanding of the structural changes and molecular pathways involved in these myopathies, a transcriptomic analysis was performed using an 8 × 60 K Agilent chicken microarray and histological study. The study used pectoralis major muscles from three groups: slow-growing animals (n = 8), fast-growing animals visually free from defects (n = 8), or severely afected by both WS and WB (n = 8). In addition, a weighted correlation network analysis was performed to investigate the relationship between modules of co-expressed genes and histological traits. Functional analysis suggested that selection for fast growing and breast meat yield has progressively led to conditions favouring metabolic shifts towards alternative catabolic pathways to produce energy, leading to an adaptive response to oxidative stress and the frst signs of infammatory, regeneration and fbrosis processes. All these processes are intensifed in muscles afected by severe myopathies, in which new mechanisms related to cellular defences and remodelling seem also activated. Furthermore, our study opens new perspectives for myopathy diagnosis by highlighting fne histological phenotypes and genes whose expression was strongly correlated with defects. Te poultry industry relies on the production of fast-growing chickens, which are slaughtered at high weights and intended for cutting and processing. -
A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated. -
Supplementary Materials
1 Supplementary Materials: Supplemental Figure 1. Gene expression profiles of kidneys in the Fcgr2b-/- and Fcgr2b-/-. Stinggt/gt mice. (A) A heat map of microarray data show the genes that significantly changed up to 2 fold compared between Fcgr2b-/- and Fcgr2b-/-. Stinggt/gt mice (N=4 mice per group; p<0.05). Data show in log2 (sample/wild-type). 2 Supplemental Figure 2. Sting signaling is essential for immuno-phenotypes of the Fcgr2b-/-lupus mice. (A-C) Flow cytometry analysis of splenocytes isolated from wild-type, Fcgr2b-/- and Fcgr2b-/-. Stinggt/gt mice at the age of 6-7 months (N= 13-14 per group). Data shown in the percentage of (A) CD4+ ICOS+ cells, (B) B220+ I-Ab+ cells and (C) CD138+ cells. Data show as mean ± SEM (*p < 0.05, **p<0.01 and ***p<0.001). 3 Supplemental Figure 3. Phenotypes of Sting activated dendritic cells. (A) Representative of western blot analysis from immunoprecipitation with Sting of Fcgr2b-/- mice (N= 4). The band was shown in STING protein of activated BMDC with DMXAA at 0, 3 and 6 hr. and phosphorylation of STING at Ser357. (B) Mass spectra of phosphorylation of STING at Ser357 of activated BMDC from Fcgr2b-/- mice after stimulated with DMXAA for 3 hour and followed by immunoprecipitation with STING. (C) Sting-activated BMDC were co-cultured with LYN inhibitor PP2 and analyzed by flow cytometry, which showed the mean fluorescence intensity (MFI) of IAb expressing DC (N = 3 mice per group). 4 Supplemental Table 1. Lists of up and down of regulated proteins Accession No. -
Disrupted Iron Homeostasis Causes Dopaminergic Neurodegeneration in Mice
Disrupted iron homeostasis causes dopaminergic neurodegeneration in mice Pavle Mataka, Andrija Mataka, Sarah Moustafaa, Dipendra K. Aryalb,c,d,e, Eric J. Bennerf, William Wetselb,c,d,e, and Nancy C. Andrewsa,f,1 aDepartment of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27705; bDepartment of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, NC 27705; cDepartment of Cell Biology, Duke University School of Medicine, Durham, NC 27705; dDepartment of Neurobiology, Duke University School of Medicine, Durham, NC 27705; eMouse Behavioral and Neuroendocrine Analysis Core Facility, Duke University School of Medicine, Durham, NC 27705; and fDepartment of Pediatrics, Duke University School of Medicine, Durham, NC 27705 This contribution is part of the special series of Inaugural Articles by members of the National Academy of Sciences elected in 2015. Contributed by Nancy C. Andrews, January 27, 2016 (sent for review September 30, 2015; reviewed by Michael K. Georgieff and Barry H. Paw) Disrupted brain iron homeostasis is a common feature of neuro- offers a very sensitive approach to detect cellular iron deficiency degenerative disease. To begin to understand how neuronal iron and surfeit (12). handling might be involved, we focused on dopaminergic neurons Iron homeostasis is altered locally, in the affected part of the and asked how inactivation of transport proteins affected iron brain, in most human neurodegenerative disorders (13). Iron ac- homeostasis in vivo in mice. Loss of the cellular iron exporter, cumulates in the substantia nigra (SN) in Parkinson’s disease (PD) ferroportin, had no apparent consequences. However, loss of (14–16), although it is unsettled whether increased iron is in neu- transferrin receptor 1, involved in iron uptake, caused neuronal ropil (17) or dopaminergic (DA) neurons (18), or both. -
Novel Driver Strength Index Highlights Important Cancer Genes in TCGA Pancanatlas Patients
medRxiv preprint doi: https://doi.org/10.1101/2021.08.01.21261447; this version posted August 5, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license . Novel Driver Strength Index highlights important cancer genes in TCGA PanCanAtlas patients Aleksey V. Belikov*, Danila V. Otnyukov, Alexey D. Vyatkin and Sergey V. Leonov Laboratory of Innovative Medicine, School of Biological and Medical Physics, Moscow Institute of Physics and Technology, 141701 Dolgoprudny, Moscow Region, Russia *Corresponding author: [email protected] NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice. 1 medRxiv preprint doi: https://doi.org/10.1101/2021.08.01.21261447; this version posted August 5, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license . Abstract Elucidating crucial driver genes is paramount for understanding the cancer origins and mechanisms of progression, as well as selecting targets for molecular therapy. Cancer genes are usually ranked by the frequency of mutation, which, however, does not necessarily reflect their driver strength. Here we hypothesize that driver strength is higher for genes that are preferentially mutated in patients with few driver mutations overall, because these few mutations should be strong enough to initiate cancer. -
Supplementary Table S4. FGA Co-Expressed Gene List in LUAD
Supplementary Table S4. FGA co-expressed gene list in LUAD tumors Symbol R Locus Description FGG 0.919 4q28 fibrinogen gamma chain FGL1 0.635 8p22 fibrinogen-like 1 SLC7A2 0.536 8p22 solute carrier family 7 (cationic amino acid transporter, y+ system), member 2 DUSP4 0.521 8p12-p11 dual specificity phosphatase 4 HAL 0.51 12q22-q24.1histidine ammonia-lyase PDE4D 0.499 5q12 phosphodiesterase 4D, cAMP-specific FURIN 0.497 15q26.1 furin (paired basic amino acid cleaving enzyme) CPS1 0.49 2q35 carbamoyl-phosphate synthase 1, mitochondrial TESC 0.478 12q24.22 tescalcin INHA 0.465 2q35 inhibin, alpha S100P 0.461 4p16 S100 calcium binding protein P VPS37A 0.447 8p22 vacuolar protein sorting 37 homolog A (S. cerevisiae) SLC16A14 0.447 2q36.3 solute carrier family 16, member 14 PPARGC1A 0.443 4p15.1 peroxisome proliferator-activated receptor gamma, coactivator 1 alpha SIK1 0.435 21q22.3 salt-inducible kinase 1 IRS2 0.434 13q34 insulin receptor substrate 2 RND1 0.433 12q12 Rho family GTPase 1 HGD 0.433 3q13.33 homogentisate 1,2-dioxygenase PTP4A1 0.432 6q12 protein tyrosine phosphatase type IVA, member 1 C8orf4 0.428 8p11.2 chromosome 8 open reading frame 4 DDC 0.427 7p12.2 dopa decarboxylase (aromatic L-amino acid decarboxylase) TACC2 0.427 10q26 transforming, acidic coiled-coil containing protein 2 MUC13 0.422 3q21.2 mucin 13, cell surface associated C5 0.412 9q33-q34 complement component 5 NR4A2 0.412 2q22-q23 nuclear receptor subfamily 4, group A, member 2 EYS 0.411 6q12 eyes shut homolog (Drosophila) GPX2 0.406 14q24.1 glutathione peroxidase -
Cardiovascular Diseases and G-Protein B3 Subunit Gene (GNB3) in the Era of Genomewide Scans
Journal of Human Hypertension (2003) 17, 379–380 & 2003 Nature Publishing Group All rights reserved 0950-9240/03 $25.00 www.nature.com/jhh COMMENTARY Cardiovascular diseases and G-protein b3 subunit gene (GNB3) in the era of genomewide scans M Tomaszewski1,2, FJ Charchar1, S Padmanabhan1, E Zukowska-Szczechowska2, W Grzeszczak2 and AF Dominiczak1 1BHF Glasgow Cardiovascular Research Centre, Division of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK; 2Department of Internal Medicine, Diabetology and Nephrology, Medical University of Silesia, Zabrze, Poland Journal of Human Hypertension (2003) 17, 379–380. doi:10.1038/sj.jhh.1001559 The last 4 years were the era of genomewide scans The ability of angiotensin-converting enzyme (ACE) in cardiovascular genetics. Since 1999, after pub- inhibitors to induce the regression of hypertensive lication of the first comprehensive genome linkage LVH and prevent ventricular remodelling after analysis of systolic blood pressure in humans,1 more myocardial infarction provides a clinical correlate than 20 genomewide searches for hypertension to these observations. Thus, insertion/deletion (I/D) genes have been reported. The number of detected polymorphism of the ACE gene has been tested as a cardiovascular quantitative trait loci (QTLs) has potential risk factor of hypertensive LVH in numer- increased rapidly, forming a new dense QTL-map ous studies, and the proportion of negative and within the human genome. At present, a QTL for positive results appears to be roughly equal.2 blood pressure or hypertension exists almost on Studies on association between hypertensive LVH every human chromosome. However, most of the and polymorphisms within the genes encoding detected QTLs do not overlap, even within popula- angiotensinogen and angiotensin II receptors have tions of the same ethnic origin. -
Histone Deacetylase Inhibitors Promote ATP2A3 Gene Expression in Hepatocellular Carcinoma Cells: P300 As a Transcriptional Regulator T
International Journal of Biochemistry and Cell Biology 113 (2019) 8–16 Contents lists available at ScienceDirect International Journal of Biochemistry and Cell Biology journal homepage: www.elsevier.com/locate/biocel Histone deacetylase inhibitors promote ATP2A3 gene expression in hepatocellular carcinoma cells: p300 as a transcriptional regulator T Andrés Hernández-Oliverasa,b, Eduardo Izquierdo-Torresc, Iván Meneses-Moralesd, ⁎ Gabriela Rodríguezc, Ángel Zarain-Herzbergc, Juan Santiago-Garcíab, a Programa de Doctorado en Ciencias de la Salud, Universidad Veracruzana, Veracruz, Mexico b Instituto de Investigaciones Biológicas, Universidad Veracruzana, Xalapa, Veracruz, Mexico c Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico d Facultad de Ciencias Químicas de la Universidad Juárez del Estado de Durango, Mexico ARTICLE INFO ABSTRACT Keywords: Sarco(endo)plasmic reticulum Ca2+-ATPases (SERCA) expression is reduced or absent in several types of cancer SERCA3 and cancer cell lines; however, their expression and regulation in hepatocellular carcinoma (HCC) are unknown. Chromatin remodeling Histone deacetylase inhibitors (HDACi) increase SERCA3 mRNA expression in gastric and breast cancer cell lines Liver cancer by increasing H3K9ac and binding of Sp1 and Sp3 transcription factors to the promoter; however, the molecular Sodium butyrate mechanism is not fully understood. Our results show that ATP2A3 (SERCA3) gene expression is decreased in Trichostatin A human HCC samples and rat HCC AS-30D cells compared to normal liver, and HCC patients with high expression of ATP2A3 had longer overall survival than those with low expression. Sodium butyrate (NaB) and trichostatin A (TSA) increase SERCA3 mRNA expression in AS-30D cells, whereas SERCA2b mRNA expression did not change. -
Supplementary Table 2
Supplementary Table 2. Differentially Expressed Genes following Sham treatment relative to Untreated Controls Fold Change Accession Name Symbol 3 h 12 h NM_013121 CD28 antigen Cd28 12.82 BG665360 FMS-like tyrosine kinase 1 Flt1 9.63 NM_012701 Adrenergic receptor, beta 1 Adrb1 8.24 0.46 U20796 Nuclear receptor subfamily 1, group D, member 2 Nr1d2 7.22 NM_017116 Calpain 2 Capn2 6.41 BE097282 Guanine nucleotide binding protein, alpha 12 Gna12 6.21 NM_053328 Basic helix-loop-helix domain containing, class B2 Bhlhb2 5.79 NM_053831 Guanylate cyclase 2f Gucy2f 5.71 AW251703 Tumor necrosis factor receptor superfamily, member 12a Tnfrsf12a 5.57 NM_021691 Twist homolog 2 (Drosophila) Twist2 5.42 NM_133550 Fc receptor, IgE, low affinity II, alpha polypeptide Fcer2a 4.93 NM_031120 Signal sequence receptor, gamma Ssr3 4.84 NM_053544 Secreted frizzled-related protein 4 Sfrp4 4.73 NM_053910 Pleckstrin homology, Sec7 and coiled/coil domains 1 Pscd1 4.69 BE113233 Suppressor of cytokine signaling 2 Socs2 4.68 NM_053949 Potassium voltage-gated channel, subfamily H (eag- Kcnh2 4.60 related), member 2 NM_017305 Glutamate cysteine ligase, modifier subunit Gclm 4.59 NM_017309 Protein phospatase 3, regulatory subunit B, alpha Ppp3r1 4.54 isoform,type 1 NM_012765 5-hydroxytryptamine (serotonin) receptor 2C Htr2c 4.46 NM_017218 V-erb-b2 erythroblastic leukemia viral oncogene homolog Erbb3 4.42 3 (avian) AW918369 Zinc finger protein 191 Zfp191 4.38 NM_031034 Guanine nucleotide binding protein, alpha 12 Gna12 4.38 NM_017020 Interleukin 6 receptor Il6r 4.37 AJ002942 -
(Continued) Linkage Mapping and Polymorphisms
Inborn Errors of Metabolism (continued) 965 966 Re-institution of dietary treatment in a PKU adult patient: cdinical and MRI Common point mutations in four patients with the late infantile form of improvement after one yer. (( E. Z h, A. Morronel, M.A DonatiI, E. galosialidosis. ((X.Y. Zhoul6, R. Willemsen2, N. Gillemans', A. Morroe3, Psquni', C Fonda2.)) 'Dept. of Pediatrica, University of Florence and 2Unit of P. Strisciuglo', G. Andria4, D.A. Applegarths and A. d'Azlzo.)) 'Dept. of Neuroradlology, Prato, Italy. Intro by: Luciano Felicetti Cell Biology and 2Clinical Genetics, Erasmus University, Rotterdam, The Retrospective and prospective studies Indicate deteroration of cognition and Netherlands; 3Dept. of Pediatrics, University of Florence, Italy; 'Dept. of neurpsyololcal performance in some PKU patients after treatment Pediatrics, University of Naples, Italy; and Dept. of Pediatrics, University of withdrawL. We report the results ofrestitution ofdiet low in pbenylalanine in Britiach Columbia, Vancouver, Canada. Intro. by E.F. Neufeld. a adult PKU patient with progreulve demyelinating clopathy. The dia of classical PKU was made at age of 4 years and d Uatment was Galactosialidosis is a lysosomal storage disorder caused by mutations in the sarted At 11 years the therapy was stopped: he was able to walk alone, to run, gene encoding the protective protein/cathepsin A. Patienta with the late to cycle, to climb stairs, to write. Since the age of 19 years be had seizures. At 21 infantile phenotype differ from early infantile or juvenile/adult types in that yeas he showed weakness, stiffness, dysarthria, difficulty in gait and swallowing. they have a better prognosis and no mental retration We have analyzed four Later ewas wheelchair-bound and his mother noted gradual deterioration in these his perforannce and behaviour. -
Supplemental Digital Content (Sdc) Sdc, Materials
SUPPLEMENTAL DIGITAL CONTENT (SDC) SDC, MATERIALS AND METHODS Animals This study used 9-12 week old male C57BL/6 mice (Jackson Laboratory, Bar Harbor, ME). This study conformed to the National Institutes of Health guidelines and was conducted under animal protocols approved by the University of Virginia’s Institutional Animal Care and Use Committee. Murine DCD Lung Procedure Mice were anesthetized by isoflurane inhalation and euthanized by cervical dislocation followed by a 60-minute period of “no-touch” warm ischemia. Mice then underwent extended median sternotomy and midline cervical exposure followed by intubation for the initiation of mechanical ventilation at 120 strokes/minute with room air. The left atrium was vented via an atriotomy followed by infusion of the lungs with 3 mL 4°C Perfadex® solution (Vitrolife Inc., Denver, CO) supplemented with THAM Solution (Vitrolife, Kungsbacka, Sweden), estimating weight-based volume recommendations for pulmonary artery perfusion (140mL/kg) (1). The chest was then packed with ice and the trachea occluded by silk-suture tie at tidal volume (7µL/g body weight) prior to cold static preservation (CSP) for 60 minutes at 4°C. Mice were then randomized into three experimental groups: 1) CSP alone with no EVLP, 2) EVLP with Steen solution and 3) EVLP with Steen solution supplemented with the highly selective A2AR agonist, ATL1223 (30nM, Lewis and Clark Pharmaceuticals, Charlottesville, VA). Mice treated with ATL1223 during EVLP also received ATL1223 treatment (30nM) during the Perfadex flush prior to CSP whereas the EVLP group received vehicle (DMSO) during the flush. CSP lungs, which did not undergo EVLP, underwent immediate functional assessment after re-intubation as described below.