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Retinoic acid signaling acts as a rheostat to balance Treg function

Cellular & Molecular Immunology 2022年第7期19卷 820-833页

作者： Govindarajan Thangavelu Gabriela Andrejeva Sara Bolivar-Wagers Sujeong Jin Michael C.Zaiken Michael Loschi Ethan G.Aguilar scott n.furlan Chrysothemis C.Brown Yu-Chi Lee Cameron McDonald Hyman Colby J.Feser Angela Panoskaltsis-Mortari Keli L.Hippen Kelli P.MacDonald William J.Murphy Ivan Maillard Geoffrey R.Hill David H.Munn Robert Zeiser Leslie S.Kean Jeffrey C.Rathmell Hongbo Chi Randolph J.noelle Bruce R.Blazar Department of Pediatrics Center for ImmunologyUniversity of MinnesotaMinneapolisMNUSA Center for Immunobiology Vanderbilt University Medical CenterNashville TNUSA Department of Pediatrics University of WashingtonSeattleWAUSA Fred Hutchinson Cancer Research Center SeattleWAUSA Howard Hughes Medical Institute Immunology Program and Ludwig CenterSloan Kettering InstituteMemorial Sloan Kettering Cancer CenterNew YorkNYUSA Department of Microbiology and Immunology.Geisel School of Medicine at Dartmouth Norris Cotton Cancer CenterLebanonUSA Department of Immunology Queensland Institute of Medical Research(QIMR)Berghofer Medical Research Institute and School of MedicineUniversity of QueenslandBrisbaneQLDAustralia Departmentof Dermatology School of MedicineUniversity of California DavisSacramentoCAUSA Division of Hematology/Oncology Department of MedicineUniversity of Pennsylvania Perelman School of MedicinePhiladelphiaPAUSA Georgia Cancer Center Augusta UniversityAugustaGAUSA Department of Haematology Oncology and Stem Cell TransplantationFaculty of MedicineFreiburg University Medical CentreFreiburgGermany Boston Children's Hospital and the Dana-Farber Cancer Institute BostonMAUSA Department of Immunology St.Jude Children's ResearchHospitalMemphisTNUSA

Regulatory T cells(Tregs)promote immune homeostasis by maintaining self-tolerance and regulating inflammatory *** certain inflammatory conditions,Tregs can lose their lineage stability and *** studies have reported that ex vivo exposure to retinoic acid(RA)enhances Treg function and ***,it is unknown how RA receptor signaling in Tregs influences these processes in ***,we employed mouse models in which RA signaling is silenced by the expression of the dominant negative receptor(Dn)RARαin all T *** the fact that DnRARαconventional T cells are hypofunctional,Tregs had increased CD25 expression,STAT5 pathway activation,mTORC1 signaling and supersuppressor ***,DnRARαTregs had increased inhibitory molecule expression,amino acid transporter expression,and metabolic fitness and decreased antiapoptotic *** function was observed when wild-type mice were treated with a pharmacologic pan-RAR ***,Treg-specific expression of DnRARαresulted in distinct phenotypes,such that a single allele of DnRARαin Tregs heightened their suppressive function,and biallelic expression led to loss of suppression and *** loss of Treg function was not cell intrinsic,as Tregs that developed in a noninflammatory milieu in chimeric mice reconstituted with DnRARαand wild-type bone marrow maintained the enhanced suppressive *** mapping suggested that maintaining Treg stability in an inflammatory milieu requires RA *** findings indicate that RA signaling acts as a rheostat to balance Treg function in inflammatory and noninflammatory conditions in a dose-dependent manner.

关键词： Retinoic acid Tregulatory cells Autoimmunity Metabolism mTORC1 STAT5

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Exploring the effects of coronary artery disease as a preexisting comorbidity on mortality in hospitalized septic patients:a retrospective observation study

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Emergency and Critical Care Medicine 2024年第2期4卷 47-51页

作者： Anmol Multani Greg Stahl Kerry Johnson scott Goade Robert D.Arnce College of Osteopathic Medicine Kansas City UniversityJoplinMOUSA Department of Data Improvement Freeman Health SystemJoplinMOUSA Department of Mathematics Missouri Southern State UniversityJoplinMOUSA Department of Pharmacy Freeman Health SystemJoplinMOUSA

Background:Sepsis has high prevalence and mortality rate,and it is imperative to identify populations at risk of poor sepsis *** patients with preexisting chronic comorbidities are shown to have worse sepsis *** identifying comorbidities with greater influence on sepsis progression,we can direct limited resources to septic patients with comorbidities and reduce health care *** comorbidities can impact the risk of developing sepsis and having worse *** artery disease(CAD)is a common comorbidity,especially in the elderly,and a leading cause of death *** wished to investigate the influence of CAD as a comorbidity on sepsis and hypothesized that preexisting CAD would increase mortality in hospitalized septic ***:We conducted retrospective observational study using patient data from Freeman Health System in Joplin,*** analyzed patient records from Freeman Health System database from January 1,2019,to June 30,*** patients were identified using the International Classification of Diseases,Tenth Revision sepsis *** identify septic patients with preexisting CAD,we used International Classification of Diseases,Tenth Revision codes for *** compared mortality rates for septic patients with and without ***:Two-sample proportion test was conducted to test the difference in mortality between septic patients with and without preexisting *** difference in mortality for the total population was−0.016(P=0.553).In the male and female subgroups,the differences in mortality were 0.0122(P=0.739)and−0.0511(P=0.208),*** differences in mortality in patients aged 40 to 64 years and 65 years and older were−0.0077(P=0.870)and 0.0007(P=0.983),*** statistical tests failed to find significant differences when comparing septic patients with and without preexisting *** was no significant difference in the age and sex ***:Our study showed that CAD alone was n

关键词： Comorbidity Coronary artery disease Inflammation Mortality rate in sepsis prognosis Sepsis

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Lean body mass index is a marker of advanced tumor features in patients with hepatocellular carcinoma

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World Journal of Hepatology 2024年第3期16卷 393-404页

作者： Andrew scott deLemos Jing Zhao Milin Patel Banks Kooken Karan Mathur Hieu Minh nguyen Areej Mazhar Maggie McCarter Heather Burney Carla Kettler naga Chalasani Samer Gawrieh Department of Medicine Atrium HealthCharlotteNC 28204United States Center for Outcomes Research and Evaluation Atrium HealthCharlotteNC 28204United States Department of Medicine Indiana University School of MedicineIndianapolisIN 46202United States Center for Health System Sciences(CHASSIS) Atrium HealthCharlotteNC 28204United States Department of Medicine Northwestern University Feinberg School of MedicineChicagoIL 60611United States Department of Biostatistics and Health Data Science Indiana University School of MedicineIndianapolisIN 46202United States Department of Gastroenterology and Hepatology Indiana University School of MedicineIndianapolisIN 46202United States

BACKGROUnD Obesity is an independent risk factor for the development of hepatocellular carcinoma(HCC)and may influence its ***,after diagnosis of HCC,like other malignancies,the obesity paradox may exist where higher body mass index(BMI)may in fact confer a survival *** is frequently observed in patients with advanced HCC and cirrhosis,who often present late with advanced tumor features and cancer related weight *** To explore the relationship between BMI and survival in patients with cirrhosis and *** This is a retrospective cohort study of over 2500 patients diagnosed with HCC between 2009-2019 at two United States academic medical *** and tumor characteristics were extracted manually from medical records of each institutions'cancer *** were stratified according to BMI classes:n),25-29.9 kg/m^(2)(overweight),and>30 kg/m^(2)(obese).Patient and tumor characteristics were compared according to BMI *** performed an overall survival analysis using Kaplan Meier by the three BMI classes and after adjusting for Milan criteria.A multivariable Cox regression model was then used to assess known risk factors for survival in patients with cirrhosis and *** A total of 2548 patients with HCC were included in the analysis of which 11.2%(n=286)were classified as *** three main BMI categories:Lean(n=754),overweight(n=861),and obese(n=933)represented 29.6%,33.8%,and 36.6%of the total population *** each BMI class,the non-cirrhotic patients accounted for 15%(n=100),12%(n=94),and 11%(n=92),*** patients with a BMIn=52)were included in the lean *** the obese cohort,42%(n=396)had a BMI≥35 kg/m^(2).Out of 2262 patients with cirrhosis and HCC,654(29%)were lean,767(34%)were overweight,and 841(37%)were *** three BMI classes did not differ by age,MELD,or Child-Pugh *** hepatitis C was the dominant etiology in lea

关键词： Hepatocellular carcinoma Cirrhosis Obesity Body mass index class Sarcopenia Chronic hepatitis C

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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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How does heterogeneity in dwelling type preferences relate to housing and built environment characteristics?

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International Journal of Digital Earth 2023年第1期16卷 93-112页

作者： Yuanyuan Huang scott n.Lieske Siqin Wang Yan Liu School of Earth and Environmental Sciences The University of QueenslandBrisbaneAustralia Graduate School of Interdisciplinary Information Studies The University of TokyoTokyoJapan

Understanding housing preferences is critical for successful compact city ***,there is limited research on understanding preference heterogeneity in dwelling type *** the Household Income and Labour Dynamics in Australia survey,this paper identifies the key housing and built environment characteristics associated with changes in dwelling type choice from detached houses to high-density.A latent class choice model captures the heterogeneity of dwelling type preferences within a traditionally low-density city,Brisbane,*** reveal six household classes with distinct dwelling preferences:Class 1(senior households without children with other family members)and Class 2(couple families with children)in inner-city areas,Class 3(high-income young households)and Class 4(low-income households without children)in middle-city areas,Class 5(low-income families with children)and Class 6(middle-income young families without children)in outer-city *** environments with better access to educational facilities encourage Classes 3 and 6 to change to high-density *** land use diversity encourages Classes 2,3,and 6 to move towards high-density *** can be used to design and improve high-density housing for targeted population groups across inner-,middle-and outer-city areas.

关键词： Dwelling type middle housing medium-to high-rise residential latent class choice preference heterogeneity

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面向异构集成应用的“片上”嵌入式冷却技术的研究进展

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Engineering 2023年第7期26卷 185-197,I0007,I0008页

作者： Srikanth Rangarajan scott n.Schiffres Bahgat Sammakia Watson School of Engineering Binghamton UniversityBinghamtonNY 13902USA Office of the V.P.for Research Binghamton UniversityBinghamtonNY 13902USA

The electronics packaging community strongly believes that Moore’s law will continue for another few years due to recent technological efforts to build heterogeneously integrated *** integration(HI)can be at the chip level(a single chip with multiple hotspots),in multi-chip modules,or in vertically stacked three-dimensional(3D)integrated *** values have increased exponentially with a simultaneous reduction in chip size and a significant increase in performance,leading to increased heat *** electronics industry and the academic research community have examined various solutions to tackle skyrocketing thermal-management *** cooling eliminates most sequential conduction resistance from the chip to the ambient,unlike separable cold plates/heat *** embedding the cooling solution onto an electronic chip results in a high heat transfer potential,technological risks and complexity are still associated with the implementation of these technologies and with uncertainty regarding which technologies will be *** manuscript discusses recent advances in embedded cooling,fluid selection considerations,and conventional,immersion,and additive manufacturing-based embedded cooling technologies.

关键词： Electronic cooling Embedded cooling Immersion cooling

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The mechanisms of color production in black skin versus red skin on the heads of new World vultures

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Avian Research 2023年第1期14卷 86-92页

作者： nicholas M.Justyn Matthew J.Powers Geoffrey E.Hill Kayla Alexander Adrián naveda-Rodríguez scott A.Rush Department of Biological Sciences Auburn UniversityAuburnALUSA College of Veterinary Medicine Mississippi State UniversityMississippiStateMSUSA Department of Wildlife Fisheriesand AquacultureMississippi State UniversityMississippi StateMSUSA

A determination of how the color of animal integument is produced is a starting point for investigations into the function and evolution of *** mechanisms that give rise to the color of bare skin of new World vultures are largely ***,we investigate the source of color production in the bare skin of Turkey Vultures(Cathartes aura)and Black Vultures(Coragyps atratus).Using UV-vis reflectance spectroscopy,we found evidence that hemoglobin is the primary pigment responsible for the red coloration of the bare skin on the heads of Turkey Vultures,and that eumelanin is responsible for the black coloration of the bare skin on the heads of Black *** microscopy of incisional skin samples further supported these mechanisms of color production by revealing the presence of numerous blood vessels near the surface of the Turkey Vulture skin,and a high concentration of melanosomes in the skin of Black *** high performance liquid chromatography(HPLC),we detected carotenoids within the skin of both species with significantly higher total concentrations of carotenoids in the skin of Turkey Vultures compared to the skin of Black *** carotenoids detected were dietary carotenoids that typically produce yellow coloration when accumulated in integument and were present in low *** hypothesize that the dietary carotenoids present do not contribute to the color of the skin,but rather help to compensate for the lack of melanosomes found in Turkey Vulture *** presence of additional carotenoids may act as an antioxidant to minimize UV damage when the bare Turkey Vulture head skin is exposed to direct sunlight for prolonged periods of time when soaring and scavenging for food.

关键词： Carotenoids Cathartes aura Coragyps atratus Hemoglobin High performance liquid chromatography Melanosomes Skin biopsies

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Inhibition of pancreatic EZH2 restores progenitor insulin in T1D donor

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Signal Transduction and Targeted Therapy 2022年第8期7卷 3045-3053页

作者： Keith Al-Hasani Ishant Khurana Lina Mariana Thomas Loudovaris scott Maxwell K.n.Harikrishnan Jun Okabe Mark ECooper Assam El-Osta Department of Diabetes Central Clinical SchoolMonash UniversityMelbourneVictoria 3004Australia Epigenetics in Human Health and Disease Laboratory Central Clinical SchoolMonash UniversityMelbourneVictoria 3004Australia Immunology and Diabetes Unit St Vincent’s Institute of Medical ResearchFitzroyVictoriaAustralia Department of Clinical Pathology The University of MelbourneParkvilleVictoriaAustralia Department of Medicine and Therapeutics The Chinese University of Hong KongSha TinHong Kong SAR Hong Kong Institute of Diabetes and Obesity Prince of Wales HospitalThe Chinese University of Hong Kong3/F Lui Che Woo Clinical Sciences Building30-32 Ngan Shing StreetSha TinHong Kong SAR Li Ka Shing Institute of Health Sciences The Chinese University of Hong KongSha TinHong Kong SAR Faculty of Health Department of TechnologyBiomedical Laboratory ScienceUniversity College CopenhagenCopenhagenDenmark

Type 1 diabetes(T1D)is an autoimmune disease that selectively destroys insulin-producingβ-cells in the *** unmet need in diabetes management,current therapy is focussed on *** the reprogramming of progenitor cells into functional insulin-producingβ-cells has also been proposed this remains controversial and poorly *** challenge is determining why default transcriptional suppression is refractory to exocrine *** the death of a 13-year-old girl with established insulin-dependent T1D,pancreatic cells were harvested in an effort to restore and understand exocrine *** pancreas showed classic silencing ofβ-cell progenitor genes with barely detectable insulin(Ins)***126,a highly selective inhibitor of EZH2 methyltransferase activity influenced H3K27me3 chromatin content and transcriptional control resulting in the expression of coreβ-cell markers and ductal progenitor ***126 also reinstated Ins gene expression despite absoluteβ-cell *** studies show the refractory nature of chromatin characterises exocrine suppression influencingβ-cell *** regeneration studies are warranted to determine if the approach of this n-of-1 study generalises to a broader T1D population.

关键词： EZH2 progenitor donor

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Targeting whole body metabolism and mitochondrial bioenergetics in the drug development for Alzheimer’s disease

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Acta Pharmaceutica Sinica B 2022年第2期12卷 511-531页

作者： Steven n.Austad scott Ballinger Thomas W.Buford Christy S.Carter Daniel L.Smith Jr Victor Darley-Usmar Jianhua Zhang Department of Biology University of Alabama at BirminghamBirminghamAL 35294USA Department of Pathology University of Alabama at BirminghamBirminghamAL 35294USA Department of Medicine University of Alabama at BirminghamBirminghamAL 35294USA Department of nutrition Sciences University of Alabama at BirminghamBirminghamAL 35294USA

Aging is by far the most prominent risk factor for Alzheimer’s disease(AD),and both aging and AD are associated with apparent metabolic *** developing effective therapeutic interventions to treat AD is clearly in urgent need,the impact of modulating whole-body and intracellular metabolism in preclinical models and in human patients,on disease pathogenesis,have been *** is also an increasing awareness of differential risk and potential targeting strategies related to biological sex,microbiome,and circadian *** a major part of intracellular metabolism,mitochondrial bioenergetics,mitochondrial quality-control mechanisms,and mitochondria-linked inflammatory responses have been considered for AD therapeutic *** review summarizes and highlights these efforts.

关键词： Mitochondrial DnA Mitochondrial electron transport chain Mitochondrial quality control Reactive species DAMPs Hexokinase biosynthesis pathway Diabetes Circadian regulation Microbiome

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Congestive heart failure and sepsis:a retrospective study of hospitalization outcomes from a rural hospital in Southwest Missouri

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Emergency and Critical Care Medicine 2022年第3期2卷 105-108页

作者： Alexandra Skovran Mason Hinke Shelly n.B.Sloan Greg Stahl Kerry Johnson scott Goade Robert Arnce Kansas City University–College of Medicine JoplinMOUSA Freeman Health System JoplinMOUSA Missouri Southern State University JoplinMOUSA

Background:Sepsis is the leading cause of death in hospitalized patients and significant effort has been made to facilitate early diagnosis and ***,aggressive treatment can have negative effects,especially in patients with unstable volume status,such as those with congestive heart ***:We used electronic medical records to perform a retrospective study looking at hospital outcomes in patients from Southwest Missouri who were admitted with sepsis and had a comorbid diagnosis of hypertensive heart *** primary outcome was in-hospital ***:We studied a total of 184 patients with the diagnosis of hypertensive heart failure with sepsis,and 348 patients with the diagnosis of sepsis that served as the baseline *** was a total of 37(20%)deaths in the hypertensive heart failure group and a total of 94(27%)deaths in the baseline ***:Our study showed no significant difference between the baseline group and those with hypertensive heart disease with heart failure.

关键词： Congestive heart failure Hypertension Hypertensive heart disease Sepsis

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