DOCSLIB.ORG

Theranostics Targeting Lysosomal Cysteine Protease Cathepsin S Reveals Immunomodulatory Therapeutic Strategy for Oxaliplatin-Ind

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Theranostics Targeting Lysosomal Cysteine Protease Cathepsin S Reveals Immunomodulatory Therapeutic Strategy for Oxaliplatin-Ind Theranostics 2021, Vol. 11, Issue 10 4672 Ivyspring International Publisher Theranostics 2021; 11(10): 4672-4687. doi: 10.7150/thno.54793 Research Paper Targeting lysosomal cysteine protease cathepsin S reveals immunomodulatory therapeutic strategy for oxaliplatin-induced peripheral neuropathy Szu-Jung Chen1, Li-Hsien Chen1, Yu-Min Yeh1, Chou-Ching K Lin2, Peng-Chan Lin1, Han-Wei Huang2, Meng-Ru Shen3,4, Bo-Wen Lin5, Jeng-Chang Lee5, Cheng-Che Lee6, Yueh-Feng Lee1, Huai-Chueh Chiang1, Jang-Yang Chang1,7,8 1. Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan. 2. Department of Neurology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan. 3. Department of Obstetrics/Gynecology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan. 4. Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan. Taiwan. 5. Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan. 6. School of Medicine for International students, College of Medicine, I-SHOU University, Kaohsiung, Taiwan. 7. National Institute of Cancer Research, National Health Research Institutes, Zhunan, Taiwan. 8. Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Taiwan. Corresponding author: Dr. Jang-Yang Chang, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan. E-mail: [email protected]. © The author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions. Received: 2020.10.21; Accepted: 2021.02.08; Published: 2021.03.04 Abstract Rationale: Oxaliplatin-induced peripheral neuropathy (OIPN) is a common adverse effect that causes delayed treatment and poor prognosis among colorectal cancer (CRC) patients. However, its mechanism remains elusive, and no effective treatment is available. Methods: We employed a prospective cohort study of adult patients with pathologically confirmed stage III CRC receiving adjuvant chemotherapy with an oxaliplatin-based regimen for investigating OIPN. To further validate the clinical manifestations and identify a potential therapeutic strategy, animal models, and in vitro studies on the mechanism of OIPN were applied. Results: Our work found that (1) consistent with clinical findings, OIPN was observed in animal models. Targeting the enzymatic activity of cathepsin S (CTSS) by pharmacological blockade and gene deficiency strategy alleviates the manifestations of OIPN. (2) Oxaliplatin treatment increases CTSS expression by enhancing cytosol translocation of interferon response factor 1 (IRF1), which then facilitates STIM- dependent store-operated Ca2+ entry homeostasis. (3) The cytokine array demonstrated an increase in anti-inflammatory cytokines and suppression of proinflammatory cytokines in mice treated with RJW-58. (4) Mechanistically, inhibiting CTSS facilitated olfactory receptors transcription factor 1 release from P300/CBP binding, which enhanced binding to the interleukin-10 (IL-10) promoter region, driving IL-10 downstream signaling pathway. (5) Serum CTSS expression is increased in CRC patients with oxaliplatin- induced neurotoxicity. Conclusions: We highlighted the critical role of CTSS in OIPN, which provides a therapeutic strategy for the common adverse side effects of oxaliplatin. Key words: Oxaliplatin-induced peripheral neuropathy; Cathepsin S; olfactory receptor transcription factor 1; IL-10 Introduction Oxaliplatin has exhibited significant efficacy in neuropathy and concurrent sensory and motor the treatment of human cancers, especially colorectal function deficiencies are a common adverse effect of cancer (CRC). However, acute or chronic peripheral oxaliplatin [1], resulting in chemotherapy dose http://www.thno.org Theranostics 2021, Vol. 11, Issue 10 4673 reduction and early discontinuation [2]. Several Increasing evidence indicates that IL-10 is expressed mechanisms of oxaliplatin-induced peripheral by a wide variety of cell types, including neuropathy have been proposed, including direct macrophages, monocytes, dendritic cells, natural damage, ROS generation, and dysfunction of killer cells, and CD4+ and CD8+ T cells and B cells. The voltage-gated ions channels in the dorsal root ganglia immunosuppressive activity of IL-10 is mediated by and axon [3, 4]. Several clinical trials were conducted ligand binding with IL-10 receptor (IL-10R1, IL-10R2), to prevent or treat oxaliplatin-induced peripheral which activates Janus tyrosine kinases (JAKs) and neuropathy based on the aforementioned signal transducers and activators of transcription mechanisms. However, these studies failed to signaling pathways, which inhibit the expression demonstrate significant effectiveness in alleviating profile of immunomodulatory genes [17] and release this side effect [5, 6]. Moreover, increasing evidence proinflammatory cytokines, such as IL-6, IL-1β, and suggests that neuroinflammation also plays a role in TNF-α [18]. However, despite the fact that IL-10 acts the development of neurotoxicity [7]. In animal as a prime drug target for autoimmune disease, tissue studies, inhibiting macrophage infiltration and damage, and even cancer, effective therapies have yet proinflammatory cytokines in the dorsal root to be developed. ganglion (DRG) suppressed the augmentation of Therefore, we investigated whether targeting paclitaxel-induced neuropathic nociception [7, 8]. CTSS can ameliorate oxaliplatin-induced peripheral Milligan et al. reported that intrathecal administration neuropathy (OIPN) by upregulating IL-10 expression of anti-inflammatory cytokine Interleukin-10 (IL-10) and suppressing proinflammatory cytokines. The briefly reversed chronic constriction injury-induced detailed molecular mechanisms are described. mechanical allodynia and thermal hyperalgesia [9, 10]. Furthermore, suppression of IL-20, a Materials and Methods proinflammatory cytokine, with IL-20 neutralizing Clinical cohort antibody alleviated paclitaxel-induced peripheral neuropathy in animal models [11]. Therefore, Patients with CRC enrolled in a clinical study triggering anti-inflammatory cytokines and investigating the CIPN (NCT02481336) were used for suppressing the proinflammatory response may be a analysis. The details of this study are described therapeutic strategy for managing chemotherapy- elsewhere [19]. Briefly, patients with pathologically induced peripheral neuropathy (CIPN). confirmed stage III or high-risk stage II CRC have Cathepsin S (CTSS), a lysosomal cysteine been prospectively recruited from National Cheng protease, is stably present in the cytoplasm of Kung University Hospital (NCKUH) from January immune-related cells, such as antigen-presenting 2015 until the present. All patients received curative cells, B cells, and phagocytic cells (e.g., macrophages surgery followed by 6 months of oxaliplatin and and microglial cells). Several lines of evidence have infusional 5-fluorouracil and leucovorin (modified demonstrated that releasing CTSS from microglial FOLFOX6) as adjuvant chemotherapy. Patients with cells causes neuropathic pain [12] that could be poor performance status (ECOG performance score > reversed by intraspinal injection of CTSS inhibitor, 1), inadequate organ functions, prior treatment with but the mechanisms remain unclear. Furthermore, neurotoxic chemotherapy (such as oxaliplatin, CTSS is reportedly an autocrine factor that stimulates cisplatin, carboplatin, taxanes, or vinca alkaloids), microglial cell activation and subsequently regulates preexisting peripheral neuropathy of any grade, or a the release of proinflammatory cytokines and family history of genetic or familial neuropathy were chemokines [13]. Our studies have indicated that excluded. A complete neurological examination, CTSS plays a vital role in mediating Ca2+ homeostasis patients-reported peripheral neuropathy CIPN20 by disturbing stromal interaction molecule 1 (STIM1) questionnaire (QLQ-CIPN20), and quantitative trafficking, which alters STIM1-Orai1 interaction and examination of the peripheral nerve system affects Ca2+ influx [14]. And, studies have reported (including nerve conduction velocity [NCV], that STIM1 regulates stored-operated Ca2+ entry quantitative sensory test [QST], nerve excitability test (SOCE) by initiating Ca2+ influx and triggering [NET], and total neuropathy score [TNS]) were immune activation in macrophages, chemotaxis, and assessed at baseline, the end of cycles 1 (week 2), 6 neutrophil infiltration, which plays a role in the (week 12), and 12 (week 24) of chemotherapy, and 9 development of inflammatory pain [15]. (week 36) and 12 months (week 48) after the IL-10, a “founding” member of IL-10 family beginning of chemotherapy. The CIPN20 cytokines, was initially described as a cytokine questionnaire contained 20 items evaluating the synthesis inhibitory factor produced by T helper cells severity of neurologic symptoms, including nine with pleiotropic immunosuppressive functions [16]. items for sensory, eight items for motor, and three http://www.thno.org Theranostics 2021, Vol. 11, Issue 10 4674 items for autonomic symptoms. Scores from 1 to 4 (Institutional
Load more

Recommended publications
  • An Evolutionary Based Strategy for Predicting Rational Mutations in G Protein-Coupled Receptors
    Ecology and Evolutionary Biology 2021; 6(3): 53-77 http://www.sciencepublishinggroup.com/j/eeb doi: 10.11648/j.eeb.20210603.11 ISSN: 2575-3789 (Print); ISSN: 2575-3762 (Online) An Evolutionary Based Strategy for Predicting Rational Mutations in G Protein-Coupled Receptors Miguel Angel Fuertes*, Carlos Alonso Department of Microbiology, Centre for Molecular Biology “Severo Ochoa”, Spanish National Research Council and Autonomous University, Madrid, Spain Email address: *Corresponding author To cite this article: Miguel Angel Fuertes, Carlos Alonso. An Evolutionary Based Strategy for Predicting Rational Mutations in G Protein-Coupled Receptors. Ecology and Evolutionary Biology. Vol. 6, No. 3, 2021, pp. 53-77. doi: 10.11648/j.eeb.20210603.11 Received: April 24, 2021; Accepted: May 11, 2021; Published: July 13, 2021 Abstract: Capturing conserved patterns in genes and proteins is important for inferring phenotype prediction and evolutionary analysis. The study is focused on the conserved patterns of the G protein-coupled receptors, an important superfamily of receptors. Olfactory receptors represent more than 2% of our genome and constitute the largest family of G protein-coupled receptors, a key class of drug targets. As no crystallographic structures are available, mechanistic studies rely on the use of molecular dynamic modelling combined with site-directed mutagenesis data. In this paper, we hypothesized that human-mouse orthologs coding for G protein-coupled receptors maintain, at speciation events, shared compositional structures independent, to some extent, of their percent identity as reveals a method based in the categorization of nucleotide triplets by their gross composition. The data support the consistency of the hypothesis, showing in ortholog G protein-coupled receptors the presence of emergent shared compositional structures preserved at speciation events.
    [Show full text]
  • Genome-Wide Transcriptome Analysis of Laminar Tissue During the Early Stages of Experimentally Induced Equine Laminitis
    GENOME-WIDE TRANSCRIPTOME ANALYSIS OF LAMINAR TISSUE DURING THE EARLY STAGES OF EXPERIMENTALLY INDUCED EQUINE LAMINITIS A Dissertation by JIXIN WANG Submitted to the Office of Graduate Studies of Texas A&M University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY December 2010 Major Subject: Biomedical Sciences GENOME-WIDE TRANSCRIPTOME ANALYSIS OF LAMINAR TISSUE DURING THE EARLY STAGES OF EXPERIMENTALLY INDUCED EQUINE LAMINITIS A Dissertation by JIXIN WANG Submitted to the Office of Graduate Studies of Texas A&M University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Approved by: Chair of Committee, Bhanu P. Chowdhary Committee Members, Terje Raudsepp Paul B. Samollow Loren C. Skow Penny K. Riggs Head of Department, Evelyn Tiffany-Castiglioni December 2010 Major Subject: Biomedical Sciences iii ABSTRACT Genome-wide Transcriptome Analysis of Laminar Tissue During the Early Stages of Experimentally Induced Equine Laminitis. (December 2010) Jixin Wang, B.S., Tarim University of Agricultural Reclamation; M.S., South China Agricultural University; M.S., Texas A&M University Chair of Advisory Committee: Dr. Bhanu P. Chowdhary Equine laminitis is a debilitating disease that causes extreme sufferring in afflicted horses and often results in a lifetime of chronic pain. The exact sequence of pathophysiological events culminating in laminitis has not yet been characterized, and this is reflected in the lack of any consistently effective therapeutic strategy. For these reasons, we used a newly developed 21,000 element equine-specific whole-genome oligoarray to perform transcriptomic analysis on laminar tissue from horses with experimentally induced models of laminitis: carbohydrate overload (CHO), hyperinsulinaemia (HI), and oligofructose (OF).
    [Show full text]
  • WO 2019/068007 Al Figure 2
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization I International Bureau (10) International Publication Number (43) International Publication Date WO 2019/068007 Al 04 April 2019 (04.04.2019) W 1P O PCT (51) International Patent Classification: (72) Inventors; and C12N 15/10 (2006.01) C07K 16/28 (2006.01) (71) Applicants: GROSS, Gideon [EVIL]; IE-1-5 Address C12N 5/10 (2006.0 1) C12Q 1/6809 (20 18.0 1) M.P. Korazim, 1292200 Moshav Almagor (IL). GIBSON, C07K 14/705 (2006.01) A61P 35/00 (2006.01) Will [US/US]; c/o ImmPACT-Bio Ltd., 2 Ilian Ramon St., C07K 14/725 (2006.01) P.O. Box 4044, 7403635 Ness Ziona (TL). DAHARY, Dvir [EilL]; c/o ImmPACT-Bio Ltd., 2 Ilian Ramon St., P.O. (21) International Application Number: Box 4044, 7403635 Ness Ziona (IL). BEIMAN, Merav PCT/US2018/053583 [EilL]; c/o ImmPACT-Bio Ltd., 2 Ilian Ramon St., P.O. (22) International Filing Date: Box 4044, 7403635 Ness Ziona (E.). 28 September 2018 (28.09.2018) (74) Agent: MACDOUGALL, Christina, A. et al; Morgan, (25) Filing Language: English Lewis & Bockius LLP, One Market, Spear Tower, SanFran- cisco, CA 94105 (US). (26) Publication Language: English (81) Designated States (unless otherwise indicated, for every (30) Priority Data: kind of national protection available): AE, AG, AL, AM, 62/564,454 28 September 2017 (28.09.2017) US AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, 62/649,429 28 March 2018 (28.03.2018) US CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, (71) Applicant: IMMP ACT-BIO LTD.
    [Show full text]
  • Evaluating Recovery Potential of the Northern White Rhinoceros from Cryopreserved Somatic Cells
    Downloaded from genome.cshlp.org on September 26, 2021 - Published by Cold Spring Harbor Laboratory Press Research Evaluating recovery potential of the northern white rhinoceros from cryopreserved somatic cells Tate Tunstall,1 Richard Kock,2 Jiri Vahala,3 Mark Diekhans,4 Ian Fiddes,4 Joel Armstrong,4 Benedict Paten,4 Oliver A. Ryder,1,5 and Cynthia C. Steiner1,5 1San Diego Zoo Institute for Conservation Research, Escondido, California 92027, USA; 2Royal Veterinary College, University of London, London NW1 0TU, United Kingdom; 3Dvur Krlov Zoo, Dvr Krlov nad Labem 544 01, Czech Republic; 4Jack Baskin School of Engineering, University California Santa Cruz, Santa Cruz, California 95064, USA The critically endangered northern white rhinoceros is believed to be extinct in the wild, with the recent death of the last male leaving only two remaining individuals in captivity. Its extinction would appear inevitable, but the development of advanced cell and reproductive technologies such as cloning by nuclear transfer and the artificial production of gametes via stem cells differentiation offer a second chance for its survival. In this work, we analyzed genome-wide levels of genetic diversity, inbreeding, population history, and demography of the white rhinoceros sequenced from cryopreserved somatic cells, with the goal of informing how genetically valuable individuals could be used in future efforts toward the genetic res- cue of the northern white rhinoceros. We present the first sequenced genomes of the northern white rhinoceros, which show relatively high levels of heterozygosity and an average genetic divergence of 0.1% compared with the southern sub- species. The two white rhinoceros subspecies appear to be closely related, with low genetic admixture and a divergent time <80,000 yr ago.
    [Show full text]
  • Supplementary Table 2
    Supplementary Table 2. Non-synonymous somatic mutations identified in the Discovery set of four NKTCL cases. Gene Sample Transcript Amino Mutation No. Nucleotide (Genomic) Symbol ID Accession ID Acid Type 1 ABCA4 7 CCDS747.1 g.chr1: 94564391 T>C p.T243A Missense 2 ACOX2 7 ENST00000492530 g.chr3: 58517538 C>T p.G7R Missense 3 ACSS3 10 CCDS9022.1 g.chr12: 81503369 C>A p.Y114X Nonsense 4 ADAMTS2 7 CCDS4444.1 g.chr5: 178540908 A>C p.I1199S Missense 5 AKAP8 7 CCDS12329.1 g.chr19: 15483121 C>T p.G300D Missense 6 ANGEL2 7 CCDS1512.1 g.chr1: 213168445 G>A p.P525S Missense 7 ANKZF1 59 CCDS42821.1 g.chr2: 220100475 C>T p.R617W Missense 8 APBA3 59 ENST00000439726 g.chr19: 3751342 insG fs Insertion 9 APLNR 7 CCDS7950.1 g.chr11: 57004458 A>T p.F7L Missense 10 ARMC7 7 CCDS11714.1 g.chr17: 73124795 G>A p.D87N Missense 11 ATM 7 CCDS31669.1 g.chr11: 108192038 G>A p.V2155M Missense 12 ATP6V0A1 7 CCDS45683.1 g.chr17: 40666340 A>T p.H762L Missense 13 BNIP3 7 CCDS7663.1 g.chr10: 133787372 C>T p.G41E Missense 14 BRCA1 10 CCDS11453.1 g.chr17: 41246517 G>A p.A344V Missense 15 BRI3 7 CCDS5656.1 g.chr7: 97911710 G>A p.V64I Missense 16 BSG 7 CCDS12032.1 g.chr19: 571548 A>G p.M1V Missense 17 BTAF1 7 CCDS7419.1 g.chr10: 93713569 A>G p.R214G Missense 18 BTBD11 59 CCDS31893.1 g.chr12: 107914407 G>A p.E427K Missense 19 BTN2A3 10 ENST00000465856 g.chr6: 26423337 G>A p.E86K Missense 20 C13orf23 31 CCDS45041.1 g.chr13: 39587665 delA fs Deletion 21 C2CD3 7 CCDS31636.1 g.chr11: 73753262 T>G p.S1833R Missense 22 C3orf63 31 CCDS46853.1 g.chr3: 56681175 A>C p.F530L Missense
    [Show full text]
  • Contents 1 Northern White Rhinoceros Pedigree
    Contents 1 Northern white rhinoceros pedigree 1 2 Genetic Divergence 2 3 Shared SNP Polymorphism 2 4 Admixture and PCA 4 5 Mitochondrial Tree 5 6 Demographic Inference Using @a@i 7 7 Inbreeding 8 8 Selection 9 9 Identification of the X chromosome 14 1 Northern white rhinoceros pedigree Figure 1: NWR pedigree highlighting individuals sequenced in this study (in blue box) presumably unrelated, with name, studbook number, ID number, and ploidy number 1 Dinka Lucy Angalifu Nola Nadi SB #74 SB #28 SB #348 SB #374 SB #376 KB6571- KB3731- KB9947- KB 8175 KB 5764 1845 618 3803 FZ 2859 FZ 1329 2n = 82 2n = 82 2n = 82 2n = 82 2n = 82 Nasima Saut SB #351 SB #373 KB8174- KB9939- 2872 3799 2n = 82 2n = 82 Nabire Suni SB #789 SB #630 KB8172- KB5765- 2864 2863 2n = 81 2n = 82 2 Genetic Divergence Pair-wise genetic divergence was estimated between all pairs of individuals using sites callable among all individuals, and defined as (2*homs+hets)/(2*callable fraction of genome), as defined in (Prado-Martinez et al., 2013). Divergence values for all individuals are shown in Supplementary Material Table 1. Calcu- lations were performed on the full set of 9.4 million SNPs. 3 Shared SNP Polymorphism In order to calculate shared polymorphism between the NWR and SWR, we took the average polymorphism of all possible combinations of the nine NWR 2 Table 1: Pair-wise genetic divergence for all rhinoceroses included in this study SB 28 SB 377 SB 376 SB 372 SB 156 SB 74 SB 24 SB 147 SB 351 SB 374 SB 373 SB 348 SB 34 SB 28 0 0 0 0 0 0 0 0 0 0 0 0 0 SB 377 0.0020231648
    [Show full text]
  • The University of Bradford Institutional Repository
    An update on genomic-guided therapies for pediatric solid tumors Item Type Article Authors Tsui, P.C.; Lee, Stephanie; Liu, Z.W.Y.; Ip, L.R.H.; Piao, W.; Chiang, A.K.S.; Lui, V.W.Y. Citation Tsui PC, Lee Y-F, Liu ZWY et al (2017) An update on genomic- guided therapies for pediatric solid tumors. Future Oncology. 13(15): 1345-1358. Rights © 2017 Future Medicine Ltd. Reproduced in accordance with the publisher's self-archiving policy. Download date 28/09/2021 00:29:10 Link to Item http://hdl.handle.net/10454/14823 The University of Bradford Institutional Repository http://bradscholars.brad.ac.uk This work is made available online in accordance with publisher policies. Please refer to the repository record for this item and our Policy Document available from the repository home page for further information. To see the final version of this work please visit the publisher’s website. Access to the published online version may require a subscription. Link to publisher’s version: https://doi.org/10.2217/fon-2017-0003 Citation: Tsui PC, Lee Y-F, Liu ZWY et al (2017) An update on genomic-guided therapies for pediatric solid tumors. Future Oncology. 13(15): 1345-1358. Copyright statement: © 2017 Future Medicine Ltd. Reproduced in accordance with the publisher's self-archiving policy. An Update on Genomic-guided Therapies for Pediatric Solid Tumors Pui Chi Tsui1, Yin-Fai Lee2, Zoey Wing Yee Liu3, Laura Ren Huey Ip4, Wenying Piao4, Alan Kwok Shing Chiang5,*, Vivian Wai Yan Lui4,* 1Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR 2 School of Pharmacy and Medical Sciences, University of Bradford, Bradford BD7 1DP, UK 3Department of Anatomical and Cellular Pathology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR 4School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR 5Department of Pediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR *denotes Co-corresponding authors Corresponding Authors: Dr.
    [Show full text]
  • The Hypothalamus As a Hub for SARS-Cov-2 Brain Infection and Pathogenesis
    bioRxiv preprint doi: https://doi.org/10.1101/2020.06.08.139329; this version posted June 19, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. The hypothalamus as a hub for SARS-CoV-2 brain infection and pathogenesis Sreekala Nampoothiri1,2#, Florent Sauve1,2#, Gaëtan Ternier1,2ƒ, Daniela Fernandois1,2 ƒ, Caio Coelho1,2, Monica ImBernon1,2, Eleonora Deligia1,2, Romain PerBet1, Vincent Florent1,2,3, Marc Baroncini1,2, Florence Pasquier1,4, François Trottein5, Claude-Alain Maurage1,2, Virginie Mattot1,2‡, Paolo GiacoBini1,2‡, S. Rasika1,2‡*, Vincent Prevot1,2‡* 1 Univ. Lille, Inserm, CHU Lille, Lille Neuroscience & Cognition, DistAlz, UMR-S 1172, Lille, France 2 LaBoratorY of Development and PlasticitY of the Neuroendocrine Brain, FHU 1000 daYs for health, EGID, School of Medicine, Lille, France 3 Nutrition, Arras General Hospital, Arras, France 4 Centre mémoire ressources et recherche, CHU Lille, LiCEND, Lille, France 5 Univ. Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 8204 - CIIL - Center for Infection and ImmunitY of Lille (CIIL), Lille, France. # and ƒ These authors contriButed equallY to this work. ‡ These authors directed this work *Correspondence to: [email protected] and [email protected] Short title: Covid-19: the hypothalamic hypothesis 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.06.08.139329; this version posted June 19, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.
    [Show full text]
  • Gnomad Lof Supplement
    1 gnomAD supplement gnomAD supplement 1 Data processing 4 Alignment and read processing 4 Variant Calling 4 Coverage information 5 Data processing 5 Sample QC 7 Hard filters 7 Supplementary Table 1 | Sample counts before and after hard and release filters 8 Supplementary Table 2 | Counts by data type and hard filter 9 Platform imputation for exomes 9 Supplementary Table 3 | Exome platform assignments 10 Supplementary Table 4 | Confusion matrix for exome samples with Known platform labels 11 Relatedness filters 11 Supplementary Table 5 | Pair counts by degree of relatedness 12 Supplementary Table 6 | Sample counts by relatedness status 13 Population and subpopulation inference 13 Supplementary Figure 1 | Continental ancestry principal components. 14 Supplementary Table 7 | Population and subpopulation counts 16 Population- and platform-specific filters 16 Supplementary Table 8 | Summary of outliers per population and platform grouping 17 Finalizing samples in the gnomAD v2.1 release 18 Supplementary Table 9 | Sample counts by filtering stage 18 Supplementary Table 10 | Sample counts for genomes and exomes in gnomAD subsets 19 Variant QC 20 Hard filters 20 Random Forest model 20 Features 21 Supplementary Table 11 | Features used in final random forest model 21 Training 22 Supplementary Table 12 | Random forest training examples 22 Evaluation and threshold selection 22 Final variant counts 24 Supplementary Table 13 | Variant counts by filtering status 25 Comparison of whole-exome and whole-genome coverage in coding regions 25 Variant annotation 30 Frequency and context annotation 30 2 Functional annotation 31 Supplementary Table 14 | Variants observed by category in 125,748 exomes 32 Supplementary Figure 5 | Percent observed by methylation.
    [Show full text]
  • Get High-Res Image
    30 20 10 5 52 37 32 69 69 78 # mutations Non syn. Syn. A->T C->(A/T) A->(C/G) C->G indel+null double_null # mutations/Mb 0 1% 2% 1% 2% 1% 1% 1% 4% 1% 2% 1% 1% 2% 2% 1% 1% 1% 2% 1% 1% 1% 2% 2% 1% 2% 1% 3% 1% 1% 2% 2% 1% 2% 2% 2% 1% 1% 2% 1% 2% 1% 1% 2% 4% 2% 2% 1% 1% 2% 2% 1% 1% 2% 2% 1% 2% 2% 2% 2% 2% 1% 3% 2% 6% 3% 2% 1% 2% 2% 3% 3% 2% 2% 3% 2% 2% 2% 2% 2% 2% 2% 2% 2% 6% 2% 2% 2% 12% 2% 2% 3% 2% 3% 2% 3% 2% 7% 2% 2% 3% 5% 8% 3% 4% 3% 8% 3% 9% 9% 5% 9% 7% 11% 23% 20% 21% 0 1 2 3 4 GBM-06-0743-TP GBM-02-0003-TP GBM-32-1970-TP GBM-19-2625-TP GBM-06-2563-TP GBM-06-2567-TP GBM-06-0876-TP GBM-14-0813-TP GBM-28-5207-TP GBM-32-1991-TP GBM-76-4927-TP GBM-06-0157-TP GBM-06-0155-TP GBM-06-0649-TP GBM-06-0749-TP GBM-14-1395-TP GBM-76-6191-TP GBM-28-5209-TP GBM-06-2561-TP GBM-06-1804-TP GBM-06-0881-TP GBM-76-6661-TP GBM-14-1456-TP GBM-14-0790-TP GBM-06-6695-TP GBM-76-6656-TP GBM-26-5139-TP GBM-06-0750-TP GBM-81-5911-TP GBM-14-1034-TP GBM-27-2528-TP GBM-06-5413-TP GBM-06-0879-TP GBM-15-0742-TP GBM-19-1790-TP GBM-06-0154-TP GBM-06-0158-TP GBM-06-0211-TP GBM-06-0650-TP GBM-06-0142-TP GBM-28-1747-TP GBM-06-0137-TP GBM-14-1829-TP GBM-06-2557-TP GBM-14-1823-TP GBM-12-3652-TP GBM-14-0786-TP GBM-06-5856-TP GBM-06-0174-TP GBM-76-4926-TP GBM-27-1831-TP GBM-81-5910-TP GBM-12-3650-TP GBM-14-0789-TP GBM-06-0747-TP GBM-06-6700-TP GBM-19-2624-TP GBM-06-0878-TP GBM-16-1045-TP GBM-06-2565-TP GBM-76-6662-TP GBM-32-2634-TP GBM-06-0184-TP GBM-76-6286-TP GBM-06-5858-TP GBM-76-6283-TP GBM-27-1838-TP GBM-06-0875-TP GBM-06-0195-TP GBM-27-2519-TP GBM-76-4925-TP GBM-16-0846-TP
    [Show full text]
  • Us 2018 / 0305689 A1
    US 20180305689A1 ( 19 ) United States (12 ) Patent Application Publication ( 10) Pub . No. : US 2018 /0305689 A1 Sætrom et al. ( 43 ) Pub . Date: Oct. 25 , 2018 ( 54 ) SARNA COMPOSITIONS AND METHODS OF plication No . 62 /150 , 895 , filed on Apr. 22 , 2015 , USE provisional application No . 62/ 150 ,904 , filed on Apr. 22 , 2015 , provisional application No. 62 / 150 , 908 , (71 ) Applicant: MINA THERAPEUTICS LIMITED , filed on Apr. 22 , 2015 , provisional application No. LONDON (GB ) 62 / 150 , 900 , filed on Apr. 22 , 2015 . (72 ) Inventors : Pål Sætrom , Trondheim (NO ) ; Endre Publication Classification Bakken Stovner , Trondheim (NO ) (51 ) Int . CI. C12N 15 / 113 (2006 .01 ) (21 ) Appl. No. : 15 /568 , 046 (52 ) U . S . CI. (22 ) PCT Filed : Apr. 21 , 2016 CPC .. .. .. C12N 15 / 113 ( 2013 .01 ) ; C12N 2310 / 34 ( 2013. 01 ) ; C12N 2310 /14 (2013 . 01 ) ; C12N ( 86 ) PCT No .: PCT/ GB2016 /051116 2310 / 11 (2013 .01 ) $ 371 ( c ) ( 1 ) , ( 2 ) Date : Oct . 20 , 2017 (57 ) ABSTRACT The invention relates to oligonucleotides , e . g . , saRNAS Related U . S . Application Data useful in upregulating the expression of a target gene and (60 ) Provisional application No . 62 / 150 ,892 , filed on Apr. therapeutic compositions comprising such oligonucleotides . 22 , 2015 , provisional application No . 62 / 150 ,893 , Methods of using the oligonucleotides and the therapeutic filed on Apr. 22 , 2015 , provisional application No . compositions are also provided . 62 / 150 ,897 , filed on Apr. 22 , 2015 , provisional ap Specification includes a Sequence Listing . SARNA sense strand (Fessenger 3 ' SARNA antisense strand (Guide ) Mathew, Si Target antisense RNA transcript, e . g . NAT Target Coding strand Gene Transcription start site ( T55 ) TY{ { ? ? Targeted Target transcript , e .
    [Show full text]
  • Expression Pattern of Olfactory Receptor Genes in Human Cumulus Cells As an Indicator for Competent Oocyte Selection
    Turkish Journal of Biology Turk J Biol (2020) 44: 371-380 http://journals.tubitak.gov.tr/biology/ © TÜBİTAK Research Article doi:10.3906/biy-2003-79 Expression pattern of olfactory receptor genes in human cumulus cells as an indicator for competent oocyte selection 1 2 1,3 4 5 Neda DAEI-FARSHBAF , Reza AFLATOONIAN , Fatemeh-Sadat AMJADI , Sara TALEAHMAD , Mahnaz ASHRAFI , 3,1, Mehrdad BAKHTIYARI * 1 Department of Anatomy, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran 2 Department of Endocrinology and Female Infertility, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, Academic Center for Education, Culture and Research, Tehran, Iran 3 Cellular and Molecular Research Center, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran 4 Department of Molecular Systems Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology (RI-SCBT), Academic Center for Education, Culture and Research, Tehran, Iran 5 Department of Obstetrics and Gynecology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran Received: 26.03.2020 Accepted/Published Online: 09.09.2020 Final Version: 14.12.2020 Abstract: Odorant or olfactory receptors are mainly localized in the olfactory epithelium for the perception of different odors. Interestingly, many ectopic olfactory receptors with low expression levels have recently been found in nonolfactory tissues to involve in local functions. Therefore, we investigated the probable role of the olfactory signaling pathway in the surrounding microenvironment of oocyte. This study included 22 women in intracytoplasmic sperm injection cycle. The expression of olfactory target molecules in cumulus cells surrounding the growing and mature oocytes was evaluated by Western blotting and real-time polymerase chain reaction.
    [Show full text]