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CD8+T cell metabolic flexibility elicited by CD28-ARS2 axisdriven alternative splicing of PKM supports antitumor immunity

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Cellular & Molecular Immunology 2024年第3期21卷 260-274页

作者： G.Aaron Holling Colin A.Chavel Anand P.Sharda Mackenzie M.Lieberman Caitlin M.James Shivana M.Lightman Jason H.Tong Guanxi Qiao Tiffany R.Emmons Thejaswini Giridharan Shengqi Hou Andrew M.Intlekofer Richard M.Higashi Teresa W.M.Fan Andrew N.Lane Kevin H.Eng Brahm H.Segal Elizabeth A.Repasky Kelvin P.Lee Scott H.Olejniczak Department of Immunology Roswell Park Comprehensive Cancer CenterBuffaloNY 14263USA Department of Medicine Roswell Park Comprehensive Cancer CenterBuffaloNY 14263USA Human Oncology and Pathogenesis Program Memorial Sloan Kettering Cancer CenterNew YorkNY 10065USA Center for Environmental Systems Biochemistry Department of Toxicology and Cancer Biology and Markey Cancer CenterLexingtonKY 40536USA Department of Cancer Genetics and Genomics Roswell Park Comprehensive Cancer CenterBuffaloNY 14263USA Present address:University of Colorado Boulder BoulderCO 80309USA Present address:Dana Farber Cancer Institute BostonMA 02215USA Present address:Massachusetts Institute of Technology BostonMA 02139USA Present address:Melvin and Bren Simon Comprehensive Cancer Center Indiana University School of MedicineIndianapolisIN 46202USA

Metabolic flexibility has emerged as a critical determinant of CD8+T-cell antitumor activity,yet the mechanisms driving the metabolic flexibility of T cells have not been *** this study,we investigated the influence of the nuclear cap-binding complex(CBC)adaptor protein ARS2 on mature T *** doing so,we discovered a novel signaling axis that endows activated CD8+T cells with flexibility of glucose ***2 upregulation driven by CD28 signaling reinforced splicing factor recruitment to pre-mRNAs and affected approximately one-third of T-cell activation-induced alternative splicing *** these effects,the CD28-ARS2 axis suppressed the expression of the M1 isoform of pyruvate kinase in favor of PKM2,a key determinant of CD8+T-cell glucose utilization,interferon gamma production,and antitumor effector ***,PKM alternative splicing occurred independently of CD28-driven PI3K pathway activation,revealing a novel means by which costimulation reprograms glucose metabolism in CD8+T cells.

关键词： Immunometabolism mRNA splicing CD8 T cells ARS2 PKM2

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RPRD1B/CREPT facilitates the progression of diffuse large B-cell lymphoma by inhibiting apoptosis through the NF-κB signaling pathway

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Asian Pacific Journal of Tropical Biomedicine 2024年第7期14卷 307-318页

作者： Lu Xu Zhi-Hao Xie Jun Li Shi Tao Fang-Li Ren Yin-Yin Wang Zhi-Jie Chang Xin-Bao Hao Department of Hematology The First Affiliated Hospital of Hainan Medical UniversityHaikou570102China State Key Laboratory of Membrane Biology School of MedicineTsinghua UniversityBeijing 100084China Heya Beijing Med-Biotech Inc. Beijing 100084China Department of Hematology Roswell Park Comprehensive Cancer CenterNY 14263USA

Objective:To investigate the role of RPRD1B in the progression of diffuse large B-cell lymphoma(DLBCL)and its potential as a therapeutic ***:This study analyzed RPRD1B expression in DLBCL and normal tissues using public databases and assessed its prognostic impact through survival *** vitro and in vivo experiments were conducted to explore the mechanisms by which RPRD1B influences tumor growth and ***:RPRD1B expression was significantly elevated in DLBCL compared to normal tissues and was associated with poor *** vitro and in vivo experiments demonstrated that RPRD1B promoted lymphoma cell proliferation and inhibited apoptosis through the NF-κB signaling ***:RPRD1B plays a critical role in the progression of DLBCL by modulating apoptosis and cellular *** RPRD1B may offer a novel therapeutic strategy for DLBCL,suggesting its potential as a prognostic marker and therapeutic target in hematological malignancies.

关键词： RPRD1B RNAPⅡ Diffuse large B-cell lymphoma NF-κB Apoptosis

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Enhancing the electrochemical performance of Na metal anodes via local eutectic melting in porous Al-Cu alloy hosts

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Nano Research 2024年第7期17卷 6111-6118页

作者： Tao Hu Qiang Wu Cheng Wang Jialu Chen Fu Su Zibo Chen Yizhou Wang Jianyu Chen Yanwen Ma Jin Zhao State Key Laboratory of Organic Electronics and Information Displays&Institute of Advanced Materials(IAM) Nanjing University of Posts&Telecommunications9 Wenyuan RoadNanjing 210023China Materials Science and Engineering King Abdullah University of Science and Technology(KAUST)Thuwal 23955-6900Saudi Arabia Suzhou Vocational Institute of Industrial Technology 1 Zhineng AvenueSuzhou International Education ParkSuzhou 215104China

Sodium(Na)metal batteries(SMBs)have emerged as promising alternatives to lithium metal batteries for large-scale energy storage applications,owing to their cost-effectiveness,abundance,and favorable redox ***,the practical implementation of SMBs faces several challenges associated with the Na metal anode,including the formation of dendrites,low Coulombic efficiency,and capacity ***,we propose a novel approach to enhance the electrochemical performance of Na metal anodes through a porous Al-Cu alloy host(PAC)fabricated by a local eutectic melting *** local eutectic melting facilitates the development of a conductive network,offering mechanical support,and the porous structure provides abundant channels for the diffusion of Na ions and accommodates volume fluctuations in the Na metal during charge–discharge ***,the PAC exhibits a high average Coulombic efficiency of 99.8%at 1 mA·cm^(−2)for 1 mAh·cm^(−2)and a low voltage polarization of 19 mV during 500 *** study provides valuable insight into the design and fabrication of highperformance Na metal anodes,which hold significant promise for the advancements of next-generation energy storage systems.

关键词： Na metal anode porous Al-Cu alloy porous current collector local eutectic melting

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The birth hour of mammals:insights from intra-specific variation in wild blue monkeys

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Current Zoology 2022年第5期68卷 499-506页

作者： Marina Cords Emma Gometz Department of Ecology Evolution and Environmental BiologyColumbia UniversityNew YorkNY 10027USA New York Consortium in Evolutionary Primatology 695 Park AvenueNew YorkNY 10065USA

While most mammals show birth hour peaks at times of the 24-h cycle when they are less active,there are exceptions to this general *** exceptions have been little explored,but may clarify evolutionary reasons for the diel timing of *** investigated intraspecific variation in birth hour in wild blue monkeys Cercopithecus mitis stuhlmanni,a diurnal primate,to identify factors that differentiated daytime versus nighttime *** and life history data from 14 groups over 14 years revealed that 4%of 484 births occurred during the *** of daytime birth varied with mother’s age,peaking at 15.7 *** whose annual timing deviated most from the population’s peak birth months were 5 times more likely to occur during daytime than those that deviated *** was no evidence that mother’s rank or infant sex influenced birth hour,and mixed evidence that daytime births were more probable in larger *** did not differ significantly for infants born during the day versus ***-aged mothers may be able to handle the consequences of an unusual birth hour more successfully than mothers with less experience or those weakened by *** birth may be more advantageous in the off-season because nights are colder at that time of *** findings are consistent with hypotheses relating birth hour to the risk of losing social protection in group-living animals,but are not consistent with those emphasizing risk of conspecific *** of within-species variation can help in evaluating evolutionary hypotheses for non-random birth hour.

关键词： birth timing Cercopithecus mitis circadian pattern diel cycle guenon parturition

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Graph neural network modeling of grain-scale anisotropic elastic behavior using simulated and measured microscale data

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npj Computational Materials 2022年第1期8卷 2471-2482页

作者： Darren C.Pagan Calvin R.Pash Austin R.Benson Matthew P.Kasemer Pennsylvania State University University ParkPA16802USA Cornell University IthacaNY14853USA University of Alabama TuscaloosaAL35487USA

Here we assess the applicability of graph neural networks(GNNs)for predicting the grain-scale elastic response of polycrystalline metallic *** GNN surrogate models,grain-averaged stresses during uniaxial elastic tension in low solvus high-refractory(LSHR)Ni Superalloy and Ti 7 wt%Al(Ti-7Al)are predicted as example face-centered cubic and hexagonal closed packed alloys,respectively.A transfer learning approach is taken in which GNN surrogate models are trained using crystal elasticity finite element method(CEFEM)simulations and then the trained surrogate models are used to predict the mechanical response of microstructures measured using high-energy X-ray diffraction microscopy(HEDM).The performance of using various microstructural and micromechanical descriptors for input nodal features to the GNNs is explored through comparisons to traditional mean-field theory predictions,reserved full-field CEFEM data,and measured far-field HEDM *** effects of elastic anisotropy on GNN model performance and outlooks for the extension of the framework are discussed.

关键词： grain neural behavior

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Adverse effects of tyrosine kinase inhibitors in cancer therapy:pathophysiology, mechanisms and clinical management

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Signal Transduction and Targeted Therapy 2023年第8期8卷 3622-3648页

作者： Sunitha Shyam Sunder Umesh C.Sharma Saraswati Pokharel Cardio-Oncology Research Group Department of Pathology and Laboratory MedicineRoswell Park Comprehensive Cancer CenterBuffaloNYUSA Division of Cardiovascular Medicine Jacob’s School of Medicine and Biomedical SciencesUniversity at BuffaloBuffaloNYUSA

Since their invention in the early 2000s,tyrosine kinase inhibitors(TKIs)have gained prominence as the most effective pathwaydirected anti-cancer *** have shown significant utility in the treatment of multiple hematological malignancies and solid tumors,including chronic myelogenous leukemia,non-small cell lung cancers,gastrointestinal stromal tumors,and HER2-positive breast *** their widespread applications,an increasing frequency of TKI-induced adverse effects has been *** TKIs are known to affect multiple organs in the body including the lungs,liver,gastrointestinal tract,kidneys,thyroid,blood,and skin,cardiac involvement accounts for some of the most serious *** most frequently reported cardiovascular side effects range from hypertension,atrial fibrillation,reduced cardiac function,and heart failure to sudden *** potential mechanisms of these side effects are unclear,leading to critical knowledge gaps in the development of effective therapy and treatment *** are limited data to infer the best clinical approaches for the early detection and therapeutic modulation of TKI-induced side effects,and universal consensus regarding various management guidelines is yet to be *** this state-of-the-art review,we examine multiple pre-clinical and clinical studies and curate evidence on the pathophysiology,mechanisms,and clinical management of these adverse *** expect that this review will provide researchers and allied healthcare providers with the most up-to-date information on the pathophysiology,natural history,risk stratification,and management of emerging TKI-induced side effects in cancer patients.

关键词： clinical involvement organs

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Imprinting at the KBTBD6 locus involves species-specific m ternal methylation and monoallelic expression in livestock animals

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Journal of Animal Science and Biotechnology 2024年第1期15卷 127-145页

作者： Jinsoo Ahn In-Sul Hwang Mi-Ryung park Seongsoo Hwang Kichoon Lee Department of Animal Sciences The Ohio State UniversityColumbusOH 43210USA Animal Biotechnology Division Rural Development AdministrationNational Institute of Animal ScienceJeonbuk 55365Republic of Korea Columbia Center for Translational Immunology Columbia University Irving Medical CenterColumbia UniversityNew YorkNY 10032USA Animal Welfare Research Team National Institute of Animal ScienceRDA1500Kongjwipatjwi‑roJeollabuk‑do 55365Republic of Korea

Background The primary differentially methylated regions(DMRs) which are maternally hypermethylated serve as imprinting control regions(ICRs) that drive monoallelic gene expression, and these ICRs have been investigated due to their implications in mammalian development. Although a subset of genes has been identified as imprinted, in-depth comparative approach needs to be developed for identification of species-specific imprinted genes. Here, we examined DNA methylation status and allelic expression at the KBTBD6 locus across species and tissues and explored potential mechanisms of *** Using whole-genome bisulfite sequencing and RNA-sequencing on parthenogenetic and normal porcine embryos, we identified a maternally hypermethylated DMR between the embryos at the KBTBD6 promoter Cp G island and paternal monoallelic expression of KBTBD6. Also, in analyzed domesticated mammals but not in humans, non-human primates and mice, the KBTBD6 promoter Cp G islands were methylated in oocytes and/or allelically methyl-ated in tissues, and monoallelic KBTBD6 expression was observed, indicating livestock-specific imprinting. Further analysis revealed that these Cp G islands were embedded within transcripts in porcine and bovine oocytes which coexisted with an active transcription mark and DNA methylation, implying the presence of transcription-dependent *** In this study, our comparative approach revealed an imprinted expression of the KBTBD6 gene in domesticated mammals, but not in humans, non-human primates, and mice which implicates species-specific evolution of genomic imprinting.

关键词： Differentially methylated region Domesticated mammal Imprinting KBTBD6 Parthenogenetic

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Emergency department utilization for gastrointestinal care and patient characteristics associated with hospital admission in a national cohort

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Gastroenterology Report 2023年第1期11卷 566-568页

作者： Kelly Suchman Nina Kohn Arvind J.Trindade Division of Gastroenterology Zucker School of Medicine at Hofstra/NorthwellLong Island Jewish Medical CenterNew Hyde ParkNYUSA Institute of Health Innovations and Outcomes Research Feinstein Institutes for Medical ResearchNorthwell HealthManhassetNYUSA

Introduction Gastrointestinal diseases and care in the USA account for a significant amount of healthcare resources and spending,recently totaling>$119 billion dollars annually[1].In addition to ambulatory sites and clinics,a substantial portion of gastrointestinal care occurs through the emergency department(ED).Though the overall rate of ED visits in the USA has remained stable over the past 10 years[2],the number of visits for gastrointestinal complaints has been increasing[1,3],contributing to rising healthcare costs.

关键词： gastrointestinal diseases ambulatory

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Emerging resistance vs. losing response to immune check point inhibitors in renal cell carcinoma: two differing phenomena

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Cancer Drug Resistance 2023年第3期6卷 642-655页

作者： Arya Mariam Roy Saby George Division of Hematology and Oncology Department of Internal MedicineRoswell Park Comprehensive Cancer CenterBuffaloNY 14203USA

The introduction of immune checkpoint inhibitor (ICI) has revolutionized the treatment of metastatic renal cell carcinoma (mRCC) and has dramatically improved the outcomes of patients. The use of monotherapy or combinations of ICIs targeting PD-1/PD-L1 and CTLA-4, as well as the addition of ICIs with tyrosine kinase inhibitors, has significantly enhanced the overall survival of mRCC patients. Despite these promising results, there remains a subset of patients who either do not respond to treatment (primary resistance) or develop resistance to therapy over time (acquired resistance). Understanding the mechanisms underlying the development of resistance to ICI treatment is crucial in the management of mRCC, as they can be used to identify new targets for innovative therapeutic strategies. Currently, there is an unmet need to develop new predictive and prognostic biomarkers that can aid in the development of personalized treatment options for mRCC patients. In this review, we summarize several mechanisms of ICI resistance in RCC, including alterations in tumor microenvironment, upregulation of alternative immune checkpoint pathways, and genetic and epigenetic changes. Additionally, we highlight potential strategies that can be used to overcome resistance, such as combination therapy, targeted therapy, and immune modulation.

关键词： Renal cell carcinoma immunotherapy immune checkpoint inhibitors primary resistance acquired resistance immune exhaustion markers immunosuppressive tumor microenvironment

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读书 1996年第2期 146-147页

作者：潘互美国rego park

一九九五年十月号《读书》登了一篇燕继荣的文章《政治冷漠是不是坏事?》,读后甚觉惊异。作者断言:“自由主义给我们的启示是:极少数人捣鼓政治机器,绝大多数人过自己的生活,那才是社会良性发展的常态。”不知这是哪一家的自由主义? 燕... 详细信息

一九九五年十月号《读书》登了一篇燕继荣的文章《政治冷漠是不是坏事?》,读后甚觉惊异。作者断言:“自由主义给我们的启示是:极少数人捣鼓政治机器,绝大多数人过自己的生活,那才是社会良性发展的常态。”不知这是哪一家的自由主义? 燕继荣的逻辑是:因为自由主义主张“管得最少的政府就是最好的政府”,所以,“老百姓不大过问的政治,才是最好的政治”。在这里,燕继荣把“政府”和“政治”混为一谈。其实,自由主义所极力反对的

关键词：燕继荣良性发展自由主义政治

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