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Disrupted Ca^(2+) h homeostasis and immunodeficiency in patients with functional IP_(3) receptor subtype 3 defects

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Cellular & Molecular Immunology 2023年第1期20卷 11-25页

作者： Julika Neumann Erika Van Nieuwenhove Lara E.terry Frederik Staels taylor R.Knebel Kirsten Welkenhuyzen Kourosh Ahmadzadeh Mariah R.Baker Margaux Gerbaux Mathijs Willemsen John S.Barber Irina I.Serysheva Liesbeth De Waele François Vermeulen Susan Schlenner Isabelle Meyts David IYule Geert Bultynck Rik Schrijvers Stephanie Humblet-Baron adrian Liston VIB Center for Brain and Disease Research LeuvenBelgium Department of Microbiology and Immunology KU LeuvenLeuvenBelgium UZ Leuven LeuvenBelgium Department of Pharmacology and Physiology University of RochesterRochesterNY14526USA Laboratory of Molecular and Cellular Signaling Department of Cellular and Molecular MedicineLeuven KankerinstituutKU LeuvenLeuvenBelgium Laboratory of Immunobiology Department Microbiology and ImmunologyRega InstituteKU LeuvenLeuvenBelgium Department of Biochemistry and Molecular Biology Structural Biology Imaging CenterMcGovern Medical School at The University of Texas Health Science Center at HoustonHoustonTX77030USA Pediatric Department Academic Children Hospital Queen FabiolaUniversitéLibre de BruxellesBrusselsBelgium Department of Pediatric Neurology University Hospitals LeuvenLeuvenBelgium Department of Pulmonology University Hospitals LeuvenLeuvenBelgium Laboratory for Inborn Errors of Immunity Department of Immunology and MicrobiologyKU LeuvenLeuvenBelgium Laboratory for Allergy and Clinical Immunology and Immunogenetics Research Group Department of MicrobiologyImmunology and TransplantationKU LeuvenLeuvenBelgium Immunology Programme The Babraham InstituteBabraham Research CampusCambridgeCB223ATUK

Calcium signaling is essential for lymphocyte activation, with genetic disruptions of store-operated calcium (Ca^(2+)) entry resulting in severe immunodeficiency. the inositol 1,4,5-trisphosphate receptor (IP_(3)R), a homo- or heterotetramer of the IP_(3)R1-3 isoforms, amplifies lymphocyte signaling by releasing Ca^(2+) from endoplasmic reticulum stores following antigen stimulation. Although knockout of all IP_(3)R isoforms in mice causes immunodeficiency, the seeming redundancy of the isoforms is thought to explain the absence of variants in human immunodeficiency. In this study, we identified compound heterozygous variants of ItPR3 (a gene encoding IP_(3)R subtype 3) in two unrelated Caucasian patients presenting with immunodeficiency. to determine whether ItPR3 variants act in a nonredundant manner and disrupt human immune responses, we characterized the Ca^(2+) signaling capacity, the lymphocyte response, and the clinical phenotype of these patients. We observed disrupted Ca^(2+) signaling in patient-derived fibroblasts and immune cells, with abnormal proliferation and activation responses following t-cell receptor stimulation. Reconstitution of IP_(3)R3 in IP_(3)R knockout cell lines led to the identification of variants as functional hypomorphs that showed reduced ability to discriminate between homeostatic and induced states, validating a genotype–phenotype link. these results demonstrate a functional link between defective endoplasmic reticulum Ca^(2+) channels and immunodeficiency and identify IP_(3)Rs as diagnostic targets for patients with specific inborn errors of immunity. these results also extend the known cause of Ca^(2+)-associated immunodeficiency from store-operated entry to impaired Ca^(2+) mobilization from the endoplasmic reticulum, revealing a broad sensitivity of lymphocytes to genetic defects in Ca^(2+) signaling.

关键词： Primary immunodeficiency Calcium signalling Whole exome sequencing

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奥古斯都

Daclatasvir vs telaprevir plus peginterferon alfa/ribavirin for hepatitis C virus genotype 1

2016年

作者： (英)阿德里安·戈兹沃西(adrian Goldsworthy)[]

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World Journal of Gastroenterology 2016年第12期22卷 3418-3431页

作者： Ira Jacobson Stefan Zeuzem Robert Flisiak Brygida Knysz Stefan Lueth Dorota Zarebska-Michaluk Ewa Janczewska Peter Ferenci Moises Diago Anna Linda Zignego Rifaat Safadi Yaacov Baruch Dzhamal Abdurakhmanov Stephen Shafran Dominique thabut Rafael Bruck adrian Gadano Alexander James thompson Justin Kopit Fiona Mc Phee tracy Michener Eric A Hughes Philip D Yin Stephanie Noviello Weill Cornell Medical College New YorkNY 10029United States Icahn School of Medicine at Mount Sinai New YorkNY 10029United States JW Goethe University Hospital 60323 FrankfurtGermany Uniwersytet Medyczny w Bialymstoku 15-089 BialystokPoland EMC and Medical University 50-220 WroclawPoland Universitatsklinikum Hamburg-Eppendorf 20246 HamburgGermany Wojewodzki Szpital Zespolony w Kielcach 25-736 KielcePoland ID Clinic 41-400 MyslowicePoland Medizinische Universitat Wien 1090 ViennaAustria Clinica Quiron 46010 ValenciaSpain Universita degli Studi di Firenze 50121 FlorenceItaly Holy Family Hospital Nazareth 6004Israel Rambam Medical Center Haifa 31096Israel 1st Moscow State Medical University N.A.I.M.Sechenov 119991 MoscowRussia University of Alberta Hospital EdmontonAlberta T6G 2B7Canada Groupe Hospitalier Pitie-Salpetriere 75013 ParisFrance tel Aviv Sourasky Medical Center and tel Aviv University Tel Aviv 64239Israel Hospital Italiano de Buenos Aires Buenos Aires C1181ACHArgentina St.Vincents Hospital and the University of Melbourne Melbourne 3065Australia Fiona McPhee Bristol-Myers Squibb Research and DevelopmentWallingfordCT 06492United States Bristol-Myers Squibb Research and Development PrincetonNJ 08450United States

AIM: to evaluate daclatasvir vs telaprevir, each combined with peginterferon alfa-2a/ribavirin(peg IFN/RBV), in treatment-naive hepatitis C virus(HCV) genotype(Gt) 1-infected ***: In this phase 3, randomized, open-label, noninferiority study, 602 patients were randomly assigned(2:1) to daclatasvir vs telaprevir, stratified by IL28 B rs12979860 host genotype(CC vs non-CC), cirrhosis status(compensated cirrhosis vs no cirrhosis), and HCV Gt1 subtype(Gt1a vs Gt1b). Patients were selected by study inclusion criteria from a total of 793 enrolled patients. Patients received daclatasvir 60 mg once daily or telaprevir 750 mg 3 times daily plus peg IFN/RBV. Daclatasvir recipients received 24 wk of daclatasvir plus peg IFN/RBV; those without an extended rapid virologic response(e RVR; undetectable HCV-RNA at weeks 4 and 12) received an additional 24 wk of peg IFN/RBV. telaprevir-treated patients received 12 wk of telaprevir plus peg IFN/RBV followed by 12(with e RVR) or 36(no e RVR) wk of peg IFN/RBV. the primary objective was to compare for noninferiority of sustained virologic response rates at posttreatment week 12(SVR12) in Gt1b-infected patients. Key secondary objectives were to demonstrate that the rates of anemia(hemoglobin ted events, through week 12, were lower with daclatasvir + peg IFN/RBV than with telaprevir + peg IFN/RBV among Gt1b-infected patients. Resistance testing was performed using population-based sequencing of the NS5 A region for all patients at baseline, and for patients with virologic failure or relapse and HCV-RNA ≥ 1000 IU/m L, to investigate any link between NS5 A polymorphisms associated with daclatasvir resistance and virologic outcome. RESULtS: Patient demographics and disease characteristics were generally balanced across treatment arms; however, there was a higher proportion of black/African Americans in the daclatasvir groups(6.0% and 8.2% in the Gt1 b and Gt1 a groups, respectively) than in the telaprevi

关键词： Direct-acting antiviral Chronic hepatitis C Daclatasvir Genotype 1b NS5A inhibitor Liver disease

Bacteria in cancer therapy: beyond immunostimulation

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Journal of Cancer Metastasis and treatment 2018年第1期4卷 44-68页

作者： Wheeler torres Victor Lameda Luis Carlos Olivar Carla Navarro Jorge Fuenmayor adrian Perez Andres Mindiola Milagros Rojas Maria Sofia Martinez Manuel Velasco Joselyn Rojas Valmore Bermudez Endocrine and Metabolic Diseases Research Center the University of ZuliaMaracaibo 4001Venezuela Miami Veterans Affairs Medical Center Geriatric Research Education and Clinical Center(GRECC)Miami 33125FLUSA Departme nt of Pharmacology "JM Vargas"Medical SchoolCentral University of VenezuelaCaracas 1050Venezuela Division of Pulmonary and Critical Care Medicine Brigham and Women's HospitalHarvard Medical SchoolBoston 02115MAUSA Advaneed Frontier Studies Research Group(ALEF) Simon Bolivar UniversityCucuta 540006Colombia

Currently,conventional therapies in cancer are improving;chemotherapy,radiotherapy and surgery have increased survival *** therapies have arisen with the same goal;immunotherapy has appeared as a promising option in the fight against cancer stimulating the immune system by inducing innate and adaptive *** responses include release of pro-inflammatory cytokines,making the immune system capable to eliminate or protect against multiple ***,many of these therapies are being used in clinical settings,such as checkpoint inhibitors,monoclonal anti cytotoxic t-Lymphocyte associated protein 4(CtL-4)and programmed death protein 1(PD1),with inspiring results;however,they may decrease immunotolerance,limiting their *** the same time,chemotherapy works by passive transport across the cell membrane,limiting its capacity to penetrate in tumor *** these reasons,bacteria employment represents one of the best candidates for cancer *** can surpass these barriers with their selective colonization which also has an oncolytic effect by increasing proliferation and immunostimulation in the tumor *** strains,such as Mycobacterium bovis,Clostridium,Salmonella typhimirium and Listeria monocytogenes have been studied showing promising results in experimental ***,their application in clinical trials has shown the need to maximize their therapeutic *** engineering and synthetic biology are necessary to prove the scope that this novel approach has against cancer due to implications of cancer therapy and public health.

关键词： Bacterium cancer selective colonization salmonella clostridium listeria

Rock Engineering Risk

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Journal of Rock Mechanics and Geotechnical Engineering 2015年第4期7卷 479-480页

作者： John A.Hudson Xia-ting Feng E.t.Brown Golder Associates Pty Ltd

the invaluable book reports the outcome of the work of the Commission on Design Methodology of the International Society for Rock Mechanics （ISRM） in the ISRM＇s 2011-2015 term of office during which Professor John Hudson acted as Commission Presi- dent while Professor Xia-ting Feng served as ISRM President. It pro- vides a sequel to the authors＇ previous book, Rock Engineering Design （Feng and Hudson, 2011）, which reported the work of the Commission in the ISRM＇s 2007-2011 term of office when Profes- sor Feng acted as Commission President and Professor Hudson served as ISRM President. It is also the first volume in the newly established ISRM Book Series published by CRC press/Balkema of the taylor ＆ Francis Group, an initiative taken during Professor Feng＇s recent term of office as ISRM President.

关键词： rock Rock Engineering Risk

Goldman, Andrea S., Opera and the City： the Politics of Culture in Beijing, 1770-1900. Stanford： Stanford University press, 2012. ISBN 978-0-804-77831-2. 386pp. $55.00 （hardcover）.

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Frontiers of History in China 2013年第3期8卷 455-457页

作者： William t. Rowe Johns Hopkins University

the great D＇Oyly Carte star John Reed routinely substituted sly references to current politicians and events for the classic Gilbert and Sullivan lyrics he was supposed to be singing. When his audience responded with applause to a particular scene he had performed, he would sometimes tum to them and announce：＂You liked that, did you？ Let＇s do it again!＂ And he did. Similar liberties in performance of classic scripts have been taken for centuries with Shakespeare and other canonical playwrights. As Andrea Goldman demonstrates to great effect in this marvelous new book, the gap ＂from page to stage＂ was particularly wide, and the innovations particularly significant, in opera performances in Qing Beijing.

关键词：歌剧院斯坦福大学 ISBN 北京政治出版社城市文化

Rock Engineering Design by Xiating Feng and JohnA Hudson

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Journal of Rock Mechanics and Geotechnical Engineering 2012年第1期4卷 I0004-I0005页

作者： E.t.Brown Goder Associates Pty Ltd.

CRC press/Balkema, taylor ＆ FrancisGroup （2011）. 488 pages. ISBN： 978-0-415-60356-0（Hbk）, 978-0-203-09337-5 （eBook） this highly original and innovative book is theoutcome of the work of the Commission on .

关键词： rock Design

Acoustic Myography in Assessment of Isokinetic and Isometric Muscle Strength in a Healthy Danish Population

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Journal of Biomedical Science and Engineering 2020年第12期13卷 235-253页

作者： Else Marie Bartels Waqas Ahmed Jack Kvistgaard Olsen Eva Littrup Andersen Bente Danneskiold-Samsøe Lars-Erik Kristensen Henning Bliddal Cecilie Rødgaard Bartholdy adrian P. Harrison the Parker Institute Copenhagen University Hospital Bispebjerg and Frederiksberg Denmark Department of Neurology Copenhagen University Hospital Bispebjerg and Frederiksberg Denmark Department of Veterinary and Animal Sciences Faculty of Health Science University of Copenhagen Copenhagen Denmark

Isokinetic and isometric force measurements involving a dynamometer setup are widely used in training and in muscle assessment. For further understanding of the method, we investigated the activation of key functional muscles during isokinetic and isometric movements. During force measurements in an isokinetic Biodex System 3 ProtM, acoustic myography (AMG) was applied. ten healthy subjects (5 men/5 women) in each decade from 20 to 69 years of age participated in the study. Measurements were carried out during extension and flexion of the ankle, knee and elbow joints. Muscle fibre use was measured by efficiency (E-score) and fibre recruitment (temporal (t-score) and spatial (S-score) summation). AMG measurements showed good reproducibility, and the recruitment pattern of muscle fibres did not change with gender or age. Overall, a significantly higher E-score (P t the lower angular velocities than at the higher ones, indicating a lower level of muscle efficiency at higher velocities. Muscles used for knee movement exhibited higher scores than muscles associated with the ankle and elbow joints, most likely related to the greater degree of force production at this joint compared to the ankle and elbow. the ability to activate and inactivate muscle fibres during periods of isokinetic activity becomes increasingly more difficult as the velocity increases. When assessing training effects in sports or rehabilitation, AMG in parallel with isokinetic measurements adds important additional information by giving a measure of possible improvements in efficiency and fibre use.

关键词： Muscle Strength Acoustic Myography Range of Motion Muscle Fibre Use

Hexachlorobenzene Episode in turkey

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Biomedical and Environmental Sciences 1989年第1期2卷 36-43页

作者： AYHAN GOCMEN HENRY A.PEtERS DEREK J.CRIPPS GEORGE t.BRYAN CARL R.MORRIS Department of Pediatrics School of Medicine University of Hacettepe 06100 Ankara Turkey Center for Health Sciences University of Wisconsin Madison Wisconsin 53706 International Chemical Consultants Alexandria Virginia 22312

During the period 1955-1959, approximately 4000 people in southeast Anatolia developed porphyria due to the ingestion of hexachlorobenzene (HCB), a fungicide added to wheat seedlings. these HCB exposures subsequently led to the development of bullae on sun-exposed areas, hyperpigmentation, hypertrichosis, and porphyrinuria. the condition was called kara yara or 'black sore.' Many of the breast-fed children under the age of 2 years whose mothers had ingested HCB-treated grain died from a disease known as pembe yara or 'pink sore.' In this follow-up study of 252 patients, 20-30 years postexposure, there were 162 males and 90 females, with an average current age of 35.7 years, an average of onset of 7.6 years, and a duration of 2.2 years. Many patients had dermatologic, neurologic, and orthopedic symptoms and signs. the observed clinical findings include scarring of the face and hands (83.7％), hyperpigmentation (65％), hypertrichosis (44.8％), pinched facies (40.1％), painless arthritis (70.2％), small hands (66.6％), sensory shading (60.6％), myotonia (37.9％), cogwheeling (41.9％), enlarged thyroid (34.9％), and enlarged liver (4.8％). Urine and stool porphyrin levels were determined in all patients, and 17 have at least one of the porphyrins elevated. A total of 56 specimens of human milk obtained from mothers with porphyria were analyzed for HCB. the average value was 0.51 ppm in HCB-exposed patients compared to 0.07 ppm in unexposed controls. Offspring of mothers with three decades of HCB-induced porphyria appear normal. 1989 Academic press, Inc.

关键词： Hexachlorobenzene Episode in turkey HCB