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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 determined.In this study,we investigated the influence of the nuclear cap-binding complex(CBC)adaptor protein ARS2 on mature T cells.In doing so,we discovered a novel signaling axis that endows activated CD8+T cells with flexibility of glucose catabolism.ARS2 upregulation driven by CD28 signaling reinforced splicing factor recruitment to pre-mRNAs and affected approximately one-third of T-cell activation-induced alternative splicing events.Among 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 function.Importantly,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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Protective effect of Pisonia aculeata on thioacetamide induced hepatotoxicity in rats

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Asian Pacific Journal of Tropical Biomedicine 2012年第7期2卷 511-515页

作者： Anbarasu C Rajkapoor B Bhat KS John giridharan A Arul Amuthan Satish K Department of Pharmacology Karpagam University Department of Pharmacology Dayananda Sagar College of Pharmacy Strides Arcolab Regulatory Affairs Strides Arcolab

Objective:To evaluate the protective effect of Pisonia aculeata(P.aculeata) on thioacetamide induced hepatotoxicity in rats.Methods:Male Wistar rats were administered 250 or 500 mg/kg p.***.of P.aculeata extract for 21 days and simultaneously administered thioacetamide(TAA) 50 mg/kg bw s.c.1 h alter the respective assigned treatments every 72 h.At the end of all experimental methods,all the animals were sacrificed by cervical decapitation.Blood samples were collected.Serum was separated and analyzed for various biochemical parameters.Results:TAA induced a significant rise in aspartate amino transferase(AST),alanine amino transferase(ALT),alkaline phosphatase(ALP),total bilirubin,gamma glutamate transpeptidase(GGTP),lipid peroxidase(LPO)with a reduction of total protein,superoxide dismutase(SOD),catalase,glutathione peroxidase(GPx) and glutathione S-transferase(GST).Treatment of rats with different does of plant extract(250 and 500 mg/kg) significantly(P<0.001) altered serum marker enzymes and antioxidant levels to near normal against TAA treated rats.The activity of the extract at a dose of 300 tug/kg was comparable to the standard drug,silymarin(50 mg/kg.p.o.).Conclusions:It can be concluded that P.aculeata extract possesses a remarkable hepaloprolective and antioxidant activity against TAA induced hepatotoxicitv.Wore research is required lo derive an optimal therapeutic dose.

关键词： Pisonia aculeate Thioacetamide Biochemical parameters Antioxidants Lipid peroxidation Histopathology Protective effect

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An association between mitochondria and microglia effector function: what do we think we know?

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Neuroimmunology and Neuroinflammation 2020年第2期7卷 150-165页

作者： Gaylia Jean Harry Gabrielle Childers Sahana giridharan Irisyunuel Lopez Hernandes National Toxicology Program Laboratory National Institute of Environmental Health SciencesDurhamNC 27709USA (Current affiliation)Gabrielle Childers University of Albama at BirminghamBirminghamAL 35294USA Sahana giridharan Duke UniversityDurhamNC 27708USA

While resident innate immune cells of the central nervous system, the microglia, represent a cell population unique in origin, microenvironment, and longevity, they assume many properties displayed by peripheral macrophages. One prominent shared property is the ability to undergo a metabolic switch towards glycolysis and away from oxidative phosphorylation (OXPHOS) upon activation by the pro-inflammatory stimuli lipopolysaccharide. This shift serves to meet specific cellular demands and allows for cell survival, similar to the Warburg effect demonstrated in cancer cells. In contrast, normal surveillance phenotype or stimulation to a non-proinflammatory phenotype relies primarily on OXPHOS and fatty acid oxidation. Thus, mitochondria appear to function as a pivotal signaling platform linking energy metabolism and macrophage polarization upon activation. These unique shifts in cell bioenergetics in response to different stimuli are essential for proper effector responses at sites of infection, inflammation, or injury. Here, we present a summary of recent developments as to how these dynamics characterized in peripheral macrophages are displayed in microglia. The new insights provided by an increased understanding of metabolic reprogramming in macrophages may allow for translation to the central nervous system and a better understanding of microglia heterogeneity, regulation, and function.

关键词： Mitochondria bioenergetics inflammasome microglia pro-inflammatory anti-inflammatory polarization

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Important relationships between Rab and MICAL proteins in endocytic trafficking

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World Journal of Biological Chemistry 2010年第8期1卷 254-264页

作者： Juliati Rahajeng Sai Srinivas Panapakkam giridharan Naava Naslavsky Steve Caplan Department of Biochemistry and Molecular Biology and Eppley Cancer CenterUniversity of Nebraska Medical CenterOmahaNE 68198-5870United States

The internalization of essential nutrients,lipids and receptors is a crucial process for all eukaryotic cells.Accordingly,endocytosis is highly conserved across cell types and species.Once internalized,small cargocontaining vesicles fuse with early endosomes(also known as sorting endosomes),where they undergo segregation to distinct membrane regions and are sorted and transported on through the endocytic pathway.Although the mechanisms that regulate this sorting are still poorly understood,some receptors are directed to late endosomes and lysosomes for degradation,whereas other receptors are recycled back to the plasma membrane;either directly or through recycling endosomes.The Rab family of small GTP-binding proteins plays crucial roles in regulating these trafficking pathways.Rabs cycle from inactive GDP-bound cytoplasmic proteins to active GTP-bound membraneassociated proteins,as a consequence of the activity of multiple specific GTPase-activating proteins(GAPs) and GTP exchange factors(GEFs).Once bound to GTP,Rabs interact with a multitude of effector proteins that carry out Rab-specific functions.Recent studies have shown that some of these effectors are also interaction partners for the C-terminal Eps15 homology(EHD) proteins,which are also intimately involved in endocytic regulation.A particularly interesting example of common Rab-EHD interaction partners is the MICALlike protein,MICAL-L1.MICAL-L1 and its homolog,MICAL-L2,belong to the larger MICAL family of proteins,and both have been directly implicated in regulating endocytic recycling of cell surface receptors and junctional proteins,as well as controlling cytoskeletal rearrangement and neurite outgrowth.In this review,we summarize the functional roles of MICAL and Rab proteins,and focus on the significance of their interactions and the implications for endocytic transport.

关键词： Rab MICAL Eps15 homology Endosomes Endocytosis Trafficking Cytoskeleton

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Impaired glucose tolerance (IGT) to frank diabetes: Dietary manipulations in WNIN/GR-Ob rats

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Journal of Diabetes Mellitus 2012年第1期2卷 52-58页

作者： Nemani Harishankar Eunni Seshadri Subramaniam Kalyanasundaram Nappanveettil giridharan National Centre for Laboratory Animal Sciences National Institute of Nutrition (ICMR) Hyderabad

Background: Several rodent models are available to study obesity and obesity associated diabetic problems. We developed an obese mutant rat model viz., WNIN/GR-Ob from our existing WNIN (Inbred Wistar) stock of rats, which exhibit hyperglycemia on challenge with oral glucose. Since such impaired glucose tolerance (IGT) is a fore runner to frank diabetes status, we carried out a study to challenge the animals with different purified carbohydrate sources (glucose, sucrose, starch) and see the outcome. Methods: 48 obese rats of both genders and equal number of lean littermates of 35 days of age were taken for the study and were divided in to four groups, A, B, C, and D. A group received purified glucose based diet, B, received purified sucrose, C, received purified starch and the D, served as the control, receiving standard laboratory rat chow developed at our centre, containing roasted bengal gram as the source of carbohydrate. All diets were isocaloric in nature and contained 56 % carbohydrate in principle. Animals were fed for 8 weeks and parameters like food intake, body weights, and plasma glucose and insulin levels were measured in experimental and control rats at initial, 4 weeks and 8 weeks. Results: As expected, food intake, body weight and feed efficiency ratio were significantly higher in obese rats of all groups as compared to their lean littermate controls and also higher in stock diet, compared to purified diets. Both lean and obese animals showed higher values of glucose and insulin on purified diets compared to control diet. But amongst lean and obese animals, the latter showed sexual dimorphism in their response, the situation being worse in starch fed (C) group. Amongst the obese animals, the males seem to suffer more, compared to females, in starch fed group, followed by glucose and sucrose fed in that order. Conclusions: WNIN/ GR-Ob rats thus seem to be a useful animal model, vulnerable to diet manipulations, especially to carbohydrates. This has the potential to be used as a diabetic model, more

关键词： Purified Diets Frank Diabetes Hyperphagia Plasma Glucose Hyperinsulinemia

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基于脉动血流介导血管重塑的旋转式血泵自适应控制研究

基于脉动血流介导血管重塑的旋转式血泵自适应控制研究

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第十二届全国生物力学学术会议暨第十四届全国生物流变学学...

作者：王宇 Guruprasad A.giridharan 覃开蓉大连理工大学电子信息与电气工程学部生物医学工程学院 University of Louisville Department of Bioengineering 大连理工大学光电工程与仪器科学学院

目的旋转式左心室辅助装置是目前治疗终末期心衰的常用手段。临床上通常为装置的辅助血泵设置恒定转速,这种方法不能自适应地满足病人在不同生理条件下的心输出量要求,且不能提高有利于改善血管重塑的血流脉动幅度和血管搏动性。基于脉...

目的旋转式左心室辅助装置是目前治疗终末期心衰的常用手段。临床上通常为装置的辅助血泵设置恒定转速,这种方法不能自适应地满足病人在不同生理条件下的心输出量要求,且不能提高有利于改善血管重塑的血流脉动幅度和血管搏动性。基于脉动血流介导的血管重塑,设计一种用于旋转式血泵的自适应控制方法。方法基于血泵转速最大值与最小值之差(△RPM)这一血泵自身参数设计自适应反馈控制,用于满足病人的血流灌注需要,提高脉动流刺激和血管搏动,在此基础上研究不同脉动流幅度和血管搏动性影响血管重塑的规律,并通过计算机

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塑料袋栽蔗苗对甘蔗生长和产量的影响

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福建甘蔗 2006年第2期 36-38页

作者： Marimuthu．R M．Jayachandran S．Nasir Ahmed S．giridharan 印度泰米尔纳德邦甘蔗研究站库达格尔

1999-2002年进行田间试验探讨塑料袋装蔗苗的适宜苗龄和长势。结果表明，长势好的30-40天苗龄塑料袋装蔗苗移植后的分蘖数、有效茎数和甘蔗产量显著最高。

关键词：塑料袋栽甘蔗产量生长田间试验有效茎数分蘖数长势苗龄

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Smart lighting system using ANN-IMC for personalized lighting control and daylight harvesting

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建筑节能(中英文) 2018年第7期 41-41页

作者： Nandha Kumar Kandasamy giridharan Karunagaran Costas Spanos 侯恩哲

Lighting contributes a significant portion to the overall energy consumption in an office building. It is thus important to reduce the energy consumption of lighting systems especially for Net Zero Energy Buildings( NZEB). Maximizing daylight harvesting can significantly increase the energy savings. With increase in demand for satisfying occupant preferences in visual comfort,the need for personalized lighting in the office space is also rising. In this paper,a novel lighting control system for Net Zero Energy Buildings( NZEB) is proposed which models the lighting system using Artificial Neural Netw ork( ANN) and utili-zes this model with the Internal Model Control( IMC) principle for controller design. Modeling the lighting system using ANN reduces the challenge of modeling a large and complex system with inherent process variability without the need to analyze extensive data-sets. The proposed ANN-IMC controller uses feedback from sensors on the task table to maintain desired illuminance,is easy to tune with just one parameter and is robust to process variability. The proposed control design is applicable to square systems where the number of lights and number of sensors are equal. How ever,the proposed architecture can also be extended for controlling other lighting accessories such as roller blinds. The performance of the proposed lighting control system to harvest the daylight effectively is demonstrated using both simulation results and an experimental setup in test-bed environment. The versatility of the proposed system will allow an operator to deploy personalized lighting in an office space.

关键词： Smart lighting Personalized lighting settings Daylight harvesting Automatic roller-blinds ANN-IMC closed loop control

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