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Themis regulates metabolic signaling and effector functions in CD4^(+) T cells by controlling NFAT nuclear translocation

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Cellular & Molecular Immunology 2021年第9期18卷 2249-2261页

作者： Mukul Prasad joanna Brzostek Namrata Gautam renu Balyan Vasily rybakin nicholas r.j.gascoigne Translational Immunology Programme Yong Loo Lin School of MedicineNational University of Singapore5 Science Drive 2Singapore 117545Singapore Department of Microbiology and Immunology Yong Loo Lin School of MedicineNational University of Singapore5 Science Drive 2Singapore 117545Singapore H.Lee Moffitt Cancer Center and research Institute TampaFLUSA Torque Therapeutics CambridgeMAUSA

Themis is a T cell lineage-specific molecule that is involved in TCr signal *** effects of germline Themis deletion on peripheral CD4^(+)T cell function have not been described *** this study,we found that Themis-deficient CD4^(+)T cells had poor proliferative responses,reduced cytokine production in vitro and weaker inflammatory potential,as measured by their ability to cause colitis in *** T cells are quiescent,whereas activated T cells have high metabolic *** of these metabolic demands depends upon nutrient availability and upregulation of nutrient intake channels after efficient TCr signal transduction,which leads to metabolic reprogramming in T *** tested whether defects in effector functions were caused by impaired metabolic shifts in Themis-deficient CD4^(+)T cells due to inefficient TCr signal transduction,in turn caused by the lack of *** found that upon TCr stimulation,Themis-deficient CD4^(+)T cells were unable to upregulate the expression of insulin receptor(Ir),glucose transporter(GLUT1),the neutral amino acid transporter CD98 and the mTOr pathway,as measured by c-Myc and pS6 *** analysis of activated Themis-deficient CD4^(+)T cells showed more oxidative phosphorylation(OXPHOS)than aerobic glycolysis,indicating defective metabolic ***,we found reduced NFAT translocation in Themis-deficient CD4^(+)T cells upon TCr *** previously reported ChIP-seq and rNA-seq data,we found that NFAT nuclear translocation controls Ir gene ***,our results describe an internal circuit between TCr signal transduction,NFAT nuclear translocation,and metabolic signaling in CD4^(+)T cells.

关键词： Immunometabolism NFAT nuclear translocation Insulin receptor mTOr Mitochondria

Themis suppresses the effector function of CD8^(+)T cells in acute viral infection

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Cellular & Molecular Immunology 2023年第5期20卷 512-524页

作者： jian Tang Xian jia jian Li junchen Dong jiayu Wang Wanyun Li Yuzhen Zhu Yanyan Hu Bowen Hou Chunjie Lin Yu Cong Tong ren Changsheng Yan Hongying Yang Qian Lai Haiping Zheng Yuzhou Bao Namrata Gautam Hong-rui Wang Bing Xu Xiao Lei Chen Qing Li nicholas r.j.gascoigne Guo Fu State Key Laboratory of Cellular Stress Biology School of MedicineFaculty of Medicine and Life SciencesXiamen UniversityXiamenChina School of Life Sciences Xiamen UniversityXiamenChina Immunology Translational research Programme Yong Loo Lin School of MedicineNational University of SingaporeSingaporeSingapore Department of Microbiology and Immunology Yong Loo Lin School of MedicineNational University of SingaporeSingaporeSingapore Department of Hematology The First Affiliated Hospital and Institute of HematologySchool of MedicineXiamen UniversityXiamenChina Cancer research Center of Xiamen University XiamenChina

CD8^(+)T cells play a central role in antiviral immune *** infection,naive CD8^(+)T cells differentiate into effector cells to eliminate virus-infected cells,and some of these effector cells further differentiate into memory cells to provide long-term protection after infection is *** extensively investigated,the underlying mechanisms of CD+T-cell differentiation remain incompletely *** is a T-cell-specific protein that plays critical roles in T-cell *** studies using Themis T-cell conditional knockout mice also demonstrated that Themis is required to promote mature CD8^(+)T-cell homeostasis,cytokine responsiveness,and antibacterial *** this study,we used LCMV Armstrong infection as a probe to explore the role of Themis in viral *** found that preexisting CD8^(+)T-cell homeostasis defects and cytokine hyporesponsiveness do not impair viral clearance in Themis T-cell conditional knockout *** analyses showed that in the primary immune response,Themis deficiency promoted the differentiation of CD8^(+)effector cells and increased their TNF and IFNy ***,Themis deficiency impaired memory precursor cell(MPEC)differentiation but promoted short-lived effector cell(SLEC)*** deficiency also enhanced effector cytokine production in memory CD8^(+)T cells while impairing central memory CD8^(+)T-cell ***,we found that Themis mediates PD-1 expression and its signaling in effector CD8^(+)T cells,which explains the elevated cytokine production in these cells when Themis is disrupted.

关键词： Themis Effector T cell CD8 T-cell differentiation Cytokine LCMV

Classical bovine spongiform encephalopathy and chronic wasting disease:two sides of the prion coin

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Animal Diseases 2024年第1期4卷 1-18页

作者： nicholas j.Haley juergen A.richt Department of Microbiology and Immunology College of Graduate StudiesMidwestern UniversityGlendaleAZUSA Department of Diagnostic Medicine/Pathobiology College of Veterinary MedicineKansas State UniversityManhattanKSUSA

Transmissible spongiform encephalopathies(TSEs)are a group of progressive and ultimately fatal neurologic diseases of man and animals,all resulting from the propagated misfolding of the host's normal cellular prion *** diseases can be spontaneous,heritable,anthropogenic/iatrogenic,or in some cases horizontally transmissible,and include such notable TSEs as bovine spongiform encephalopathy(BSE)of cattle and chronic wasting disease(CWD)of *** they are both unequivocally protein misfolding disorders,they differ markedly in their pathogenesis,transmissibility,and zoonotic *** the BSE epidemic has largely abated over the past three decades following global feed bans on ruminant meat and bone meal,CWD,which is readily transmitted through various forms of excreta,has rapidly expanded from its original endemic zone to encompass much of North America,along with recently identified foci in *** importantly,although the classical form of BSE has proven transmissible to humans consuming contaminated beef or beef products,so far there have been no conclusive reports on the zoonotic transmission of cWD to *** underlying basis for these differences-whether host or agent directed-are not well understood,though may be due to inherent differences in the three-dimensional structure of the misfolded BSE or CWD prion proteins or the expression levels and tissue distribution of respective cellular prion *** the uncontrolled geographic spread of CWD,it is imperative that we improve our understanding of the factors governing prion disease pathogenesis,transmission,and zoonotic potential.

关键词： Prion Bovine Spongiform Encephalopathy Chronic Wasting Disease Transmission Pathogenesis Zoonosis

Olympic Games and 24-hour movement behaviors:A match worth making

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journal of Sport and Health Science 2024年第6期13卷 728-731页

作者： Mark S.Tremblay nicholas Kuzik Markus j.Duncan Diego Augusto Santos Silva CHEO research Institute OttawaON K1H 8L1Canada Department of Pediatrics University of OttawaOttawaON K1H 8L1Canada Federal University of Santa Catarina FlorianopolisSanta Catarina 88040-900Brazil

*** The Olympic motto,"Faster,Higher,Stronger-Together",represents the pursuit of athletic excellence,united as a global community."Excellence,respect and friendship"are the Olympic *** the motto and values are multifaceted and holistic in nature,and all-encompassing in their reach while recognizing no single entity rises above the ***,these foundational statements anchor the Olympic movement in its quest to build a better world through sport.

关键词： movement Together pursuit

Towards precision 24-hour movement behavior recommendations—The next new paradigm?

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journal of Sport and Health Science 2024年第6期13卷 743-748页

作者： Mark S.Tremblay Markus j.Duncan nicholas Kuzik Diego Augusto Santos Silva Valerie Carson CHEO research Institute OttawaON K1H 8L1Canada Department of Pediatrics University of OttawaOttawaON K1H 8L1Canada Federal University of Santa Catarina Santa Catarina 88040900Brazil Faculty of Kinesiology Sportand RecreationUniversity of AlbertaEdmontonAB T6G 2H9Canada

*** The importance of physical activity(PA)for health is unequivocal.^(1)Accordingly,population-based recommendations for exercise,and more recently public health guidelines for PA,have been developed and released by authoritative groups for many decades.^(2)Such guidelines emerged with leadership from the exercise physiology discipline and were rooted in,and loyal to,the importance of moderate-to-vigorous intensity PA(MVPA)or exercise.

关键词： movement behavior exercise

HDPairFinder:A data processing platform for hydrogen/deuterium isotopic labeling-based nontargeted analysis of trace-level amino-containing chemicals in environmental water

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journal of Environmental Sciences 2024年第2期136卷 583-593页

作者： Tingting Zhao Kristin Carroll Caley B.Craven nicholas j.P.Wawryk Shipei Xing jian Guo Xing-Fang Li Tao Huan Department of Chemistry Faculty of ScienceUniversity of British ColumbiaVancouver Campus2036 Main MallVancouverBritish ColumbiaV6T 1Z1Canada Division of Analytical and Environmental Toxicology Department of Laboratory Medicine and PathologyFaculty of Medicine and DentistryUniversity of AlbertaEdmontonAlberta T6G 2G3Canada

The combination of hydrogen/deuterium(H/D)formaldehyde-based isotopic methyl labeling with solid-phase extraction and high-performance liquid chromatography–high resolution mass spectrometry(HPLC-HrMS)is a powerful analytical solution for nontargeted analysis of trace-level amino-containing chemicals in water *** the huge amount of chemical information generated in HPLC-HrMS analysis,identifying all possible H/Dlabeled amino chemicals presents a significant challenge in data *** address this,we designed a streamlined data processing pipeline that can automatically extract H/D-labeled amino chemicals from the raw HPLC-HrMS data with high accuracy and ***,we developed a cross-correlation algorithm to correct the retention time shift resulting from deuterium isotopic effects,which enables reliable pairing of H-and D-labeled ***,we implemented several bioinformatic solutions to remove false chemical features generated by in-source fragmentation,salt adduction,and natural13C ***,we used a data mining strategy to construct the AMINES library that consists of over 38,000 structure-disjointed primary and secondary amines to facilitate putative compound ***,we integrated these modules into a freely available r program,*** rationale of each module was justified and its performance tested using experimental H/D-labeled chemical standards and authentic water *** further demonstrated the application of HDPairFinder to effectively extract N-containing contaminants,thus enabling the monitoring of changes of primary and secondary N-compounds in authentic water *** is a reliable bioinformatic tool for rapid processing of H/D isotopic methyl labeling-based nontargeted analysis of water samples,and will facilitate a better understanding of N-containing chemical compounds in water.

关键词： Isotope labeling Nontargeted analysis reactive N-compounds HPLC-HrMS Source water

Morphological traits explain the individual position within resource-consumer networks of a Neotropical marsupial

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Current Zoology 2024年第4期70卷 453-464页

作者： nicholas F.de Camargo Hernani F.M.de Oliveira juliana F.ribeiro Amabilio j.A.de Camargo Emerson M.Vieira Laboratorio de Ecologia de Vertebrados Departamento de EcologiaInstituto de Ciencias BiologicasUniversidade de BrasiliaCP 04457BrasiliaDF70910-900Brazil Departamento de Zoologia Setor de Ciencias BiologicasUniversidade Federal do ParanaAvenida Coronel Francisco Heraclito dos Santos100CuritibaPR81531980Brazil Embrapa Cerrados Rodovia BR020km 18CP 08223PlanaltinaDE73310-970Brazil

Knowledge regarding the influence of individual traits on interaction patterns in nature can help understand the topological role of individuals within a network of intrapopulation *** tested hypotheses on the relationships between individuals'positions within networks(specialization and centrality)of 4 populations of the mouse opossum Gracilinanus agilis and their traits(i.e.,body length,body condition,tail length relative to body length,sex,reproductive condition,and botfly parasitism)and also seasonal effects in the Brazilian *** with lower body length,better body condition,and relatively shorter tail were more specialized(i.e.,less connected within the network).Individuals were also more specialized and less connected during the warm-wet *** relationship between individuals'position in the network and body traits,however,was independent of *** propose that specialization may arise not only as a result of preferred feed-ing strategies by more capable individuals(i.e.,those with better body condition and potentially prone to defend and access high-quality food resources)but alsobecause of morphological ***/younger individuals(consequently with less experience in foraging)and short-tailed individuals(less skilled to explore the vertical strata of the vegetation)would feed only on a subset of the available food resources and consequently become more ***,individuals are more specialized during the warm-wet season because of high competition(population-dense period)and higher ecological opportunities(resource-rich period).Therefore,our study reveals the relevance of individual traits inshaping interactionpatternsandspecialization inpopulations.

关键词： bodytraits centrality Cerrado Gracilinanus agilis seasonality specialization.

Considerations for the use of porcine organ donation models in preclinical organ donor intervention research

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Animal Models and Experimental Medicine 2024年第3期7卷 283-296页

作者： Frazer I.Heinis Shaheed Merani nicholas W.Markin Kim F.Duncan Michael j.Moulton Lance Fristoe William E.Thorell raechel A.Sherrick Tami r.Wells Matthew T.Andrews Marian Urban School of Natural resources Institute of Agriculture and Natural ResourcesUniversity of Nebraska-LincolnLincolnNebraskaUSA Division of Transplantation and Vascular Surgery Department of SurgeryUniversity of Nebraska Medical CenterOmahaNebraskaUSA Department of Anesthesiology University of Nebraska Medical CenterOmahaNebraskaUSA Division of Cardiothoracic Surgery Department of SurgeryUniversity of Nebraska Medical CenterOmahaNebraskaUSA Clinical Perfusion Nebraska Medicine-Nebraska Medical CenterOmahaNebraskaUSA Department of Neurosurgery University of Nebraska Medical CenterOmahaNebraskaUSA Nutrition and Health Sciences College of Education and Human SciencesUniversity of Nebraska-LincolnLincolnNebraskaUSA Department of Comparative Medicine University of Nebraska Medical CenterOmahaNebraskaUSA

Use of animal models in preclinical transplant research is essential to the optimization of human allografts for clinical *** models of organ donation and preservation help to advance and improve technical elements of solid organ recovery and facilitate research of ischemia-reperfusion injury,organ preservation strategies,and future donor-based *** considerations include cost,public opinion regarding the conduct of animal research,translational value,and relevance of the animal model for clinical *** present an overview of two porcine models of organ donation:donation following brain death(DBD)and donation following circulatory death(DCD).The cardiovascular anatomy and physiology of pigs closely resembles those of humans,making this species the most appropriate for pre-clinical *** are also considered a potential source of organs for human heart and kidney *** is imperative to minimize animal loss during procedures that are surgically *** present our experience with these models and describe in detail the use cases,procedural approach,challenges,alternatives,and limitations of each model.

关键词： animal model brain death circulatory death organ transplantation

Heart healthy equals prostate healthy and statins, aspirin, and/or metformin （S.A.M.） are the ideal recommendations for prostate cancer prevention

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Asian journal of Andrology 2015年第5期17卷 783-791,I0008页

作者： Mark A Moyad nicholas j Vogelzang Department of Urology University of Michigan Medical Center Ann Arbor Michigan USA Developmental Therapeutics Committee and Genitourinary Committee for US Oncology research Comprehensive Cancer Centers of Nevada Las Vegas Nevada USA

Cardiovascular disease （CVD） has been the number one cause of death in the U.S. for 114 of the last 115 years. Lifestyle factors that promote CVD also appear to increase prostate cancer risk and those that reduce CVD risk also appear to reduce the risk of prostate cancer. The largest randomized trials utilizing dietary supplements or pharmacologic agents for prostate cancer prevention （Selenium and Vitamin E Cancer Prevention Trial [SELECT]） have also shed light on the problems and future solutions in this area. Dietary supplements that have not been found to be CVD protective, such as selenium and Vitamin E have not been found to be prostate protective. In addition, over exposure to specific anti-oxidants in nutritionally replete populations may be encouraging cancer growth. Futuretrials of dietary supplements to prevent prostate cancer could be problematic because by the time a definitive trial is initiated the participants will no longer be ＂deficient＂ in the nutrient being tested, which arguably occurred in the SELECT trial. It is also interesting that statins, aspirin, and/or metformin （S.A.M.） are 3 generic, low-cost, heart healthy agents derived from natural sources with separate mechanism of actions, which all appear to have the best benefit to risk ratio compared to any other agent available for prostate cancer prevention, especially aggressive disease, or as an ancillary agent （s） to conventional cancer treatment. It is time to focus on the forest over the trees and recommend proven CVD protective measures for men concerned about their risk of prostate cancer.

关键词： aspirin diet lifestyle metformin prostate cancer statins