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FOXP3 protects conventional human T cells from premature restimulation-induced cell death

Cellular & molecular Immunology 2021年第1期18卷 194-205页

作者： kelsey Voss Camille Lake Christopher R.Luthers Nathaniel m.Lott Batsukh Dorjbal Swadhinya Arjunaraja Bradly m.Bauman Anthony R.Soltis Gauthaman Sukumar Clifton LDalgard Andrew L.Snow Department of Pharmacology&molecular Therapeutics Uniformed Services University of the Health SciencesBethesdaMD 20817USA The American Genome Center(TAGC) Collaborative Health Initiative Research ProgramUniformed Services University of the Health SciencesBethesdaMDUSA Department of Anatomy Physiology&GeneticsUniformed Services University of the Health SciencesBethesdaMDUSA

The adaptive immune response relies on specific apoptotic programs to maintain *** effector T cell(Tcon)expansion is constrained by both forkhead box P3(FOXP3)^(+)-regulatory T cells(Tregs)and restimulation-induced cell death(RICD),a proprlocidal apoptosis pathway triggered by repeated stimulation through the T-cell receptor(TCR).Constitutive FOXP3 expression protects Tregs from RICD by suppressing SLAm-associated protein(SAP),a key adaptor protein that amplifies TCR signaling *** role of transient FOXP3 induction in activated human CD4 and CD8 Tcons remains unresolved,but its expression is inversely correlated with acquired RICD ***,we describe a novel role for FOXP3 In protecting human Tcons from premature RICD during *** FOXP3-mediated protection from RICD in Tregs,FOXP3 protects Tcons through a distinct mechanism requiring de novo transcription that does not require SAP *** profiling and functional analyses of expanding Tcons revealed that FOXP3 enhances expression of the SLAm family receptor CD48,which in turn sustains basal autophagy and suppresses pro-apoptotic p53 *** CD48 and FOXP3 expression reduced p53 accumulation upon TCR ***,silencing FOXP3 expression or blocking CD48 decreased the mitochondrial membrane potential in expanding Tcons with a concomitant reduction in basal *** findings suggest that FOXP3 governs a distinct transcriptional program in early-stage effector Tcons that maintains RICD resistance via CD48-dependent protective autophagy and p53 suppression.

关键词： conventional T cells RICD FOXP3 autophagy CD48

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Cellular plasticity and metastasis in breast cancer: a pre- and post-malignant problem

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Journal of Cancer metastasis and Treatment 2019年第6期4卷 15-34页

作者： Jacob m.Smigiel Sarah E.Taylor Benjamin L.Bryson Ilaria Tamagno kelsey Polak mark W.Jackson Department of Pathology Case Western Reserve University School of MedicineClevelandOH 44106USA Case Comprehensive Cancer Center Case Western Reserve UniversityClevelandOH 44106USA

As a field we have made tremendous strides in treating breast cancer,with a decline in the past 30 years of overall breast cancer ***,this progress is met with little affect once the disease spreads beyond the primary *** a 5-year survival rate of 22%,10-year of 13%,for those patients with metastatic breast cancer(mBC),our ability to effectively treat wide spread disease is minimal.A major contributing factor to this ineffectiveness is the complex make-up,or heterogeneity,of the primary *** a primary tumor,secreted factors,malignant and pre-malignant epithelial cells,immune cells,stromal fibroblasts and many others all reside alongside each other creating a dynamic environment contributing to ***,heterogeneity contributes to our lack of understanding regarding the cells'remarkable ability to undergo epithelial/non-cancer stem cell(CSC)to mesenchymal/CSC(E-m/CSC)*** enhanced invasion&motility,tumor-initiating potential,and acquired therapeutic resistance which accompanies E-m/CSC plasticity implicates a significant role in *** most work trying to understand E-m/CSC plasticity has been done on malignant cells,recent evidence is emerging concerning the ability for pre-malignant cells to undergo E-m/CSC plasticity and contribute to the metastatic *** we will discuss the importance of E-m/CSC plasticity within malignant and pre-malignant populations of the ***,we will discuss how one may potentially target these populations,ultimately disrupting the metastatic cascade and increasing patient survival for those with mBC.

关键词： Cell plasticity pre-malignant plasticity breast cancer epithelial-mesenchymal transition/cancer stem cell metastasis

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morbidity and mortality of coagulase-negative staphylococcal sepsis in very-low-birth-weight infants

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World Journal of Pediatrics 2018年第3期14卷 269-273页

作者： Joseph B.Cantey kelsey R.Anderson Ram R.Kalagiri Lea H.mallett Department of Pediatrics University of Texas Health Science Center San Antonio7703 Floyd Curl DriveSan AntonioTX 78229USA Texas A&m Health Science Center College of medicine BryanTXUSA Texas A&m Health Science Center Baylor/Scott&White HealthTempleTXUSA

Background Coagulase-negative staphylococci (CoNS) are the most common cause of late-onset sepsis in the neonatal intensive care unit (NICU) and usually require vancomycin treatment. Our objective was to determine whether CoNS are associated with neonatal morbidity and mortality. methods This was a retrospective cohort study of very-low-birth-weight (VLBW, ≤ 1500 g) infants from 1989 to 2015. Exclusion criteria were major congenital anomaly or death within 72 h. CoNS was considered a pathogen if recovered from ≥ 2 cultures, or 1 culture if treated for ≥ 5 days and signs of sepsis were present. Logistic regression was used to exam-ine factors associated with morbidity and mortality. Results Of 2242 VLBW infants, 285 (12.7%) had late-onset sepsis. CoNS (125, 44%),Staphylococcus aureus (52, 18%), and Escherichia coli (36, 13%) were the most commonly recovered organisms. In multivariate analysis, CoNS sepsis was not associated with mortality (OR 0.6 (95% CI 0.2-2.6)), but sepsis with other organisms was (OR 4.5 (95% CI 2.6-8.0))CoNS sepsis was associated with longer hospitalization but not risk for bronchopulmonary dysplasia, intraventricular hem-orrhage, or retinopathy of prematurity. Conclusion CoNS sepsis was not associated with mortality or morbidities other than length of stay. These findings support vancomycin-reduction strategies in the NICU.

关键词： morbidity mortality Neonate Sepsis

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Defining the‘HoneySweet’insertion event utilizing NextGen sequencing and a de novo genome assembly of plum(Prunus domestica)

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Horticulture Research 2021年第1期8卷 25-37页

作者： Ann m.Callahan Tetyana N.Zhebentyayeva Jodi L.Humann Christopher A.Saski kelsey D.Galimba Laura L.Georgi Ralph Scorza Dorrie main Christopher D.Dardick USDA-ARS Appalachian Fruit Research StationKearneysvilleWV 25430USA The Schatz Center for Tree molecular Genetics Department of Ecosystem Science and ManagementThe Pennsylvania State UniversityUniversity ParkPA 16802USA Department of Horticulture Washington State UniversityPullmanWA 99164USA Plant and Environmental Sciences Department Clemson UniversityClemsonSC 29634USA Department of Genetics and Biochemistry Clemson UniversityClemsonSC 29634USA

HoneySweet’plum(Prunus domestica)is resistant to Plum pox potyvirus,through an RNAi-triggered *** the precise nature of the transgene insertion event has been complicated due to the hexaploid genome of *** blots previously indicated an unintended hairpin arrangement of the Plum pox potyvirus coat protein gene as well as a multicopy insertion *** confirm the transgene arrangement of the insertion event,‘HoneySweet’DNA was subjected to whole genome sequencing using Illumina short-read *** indicated two different insertion events,one containing seven partial copies flanked by putative plum DNA sequence and a second with the predicted inverted repeat of the coat protein gene driven by a double 35S promoter on each side,flanked by plum *** determine the locations of the two transgene insertions,a phased plum genome assembly was developed from the commercial plum‘Improved French’.A subset of the scaffolds(2447)that were>10 kb in length and representing,>95%of the genome were annotated and used for alignment against the‘HoneySweet’transgene *** of eight matching scaffolds spanned both insertion sites ranging from 157,704 to 654,883 bp apart,however we were unable to identify which scaffold(s)represented the actual location of the insertion sites due to potential sequence differences between the two plum ***,there was no evidence of any gene(s)being interrupted as a result of the ***,RNA-seq data verified that the insertions created no new transcriptional units and no dramatic expression changes of neighboring genes.

关键词： plum insertion Sweet

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Hepatic Adenoma Secondary to Long-Term Oral Contraception Use in a Young Female

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Open Journal of Internal medicine 2023年第2期13卷 104-113页

作者： kelsey m. Lamb Jessica E. Darden Suresh G. Jayatilaka Edward Via College of Osteopathic medicine in Virginia Blacksburg USA Department of Gastroenterology Southern Gastroenterology Associates St. Georges University School of Medicine St. Georges Grenada

Hepatic adenomas are a rare byproduct of oral contraceptive pill (OCP) use. Laboratory workup is often inconclusive. Diagnosis can be made via mRI;however, select cases may require further testing such as fine needle aspiration or core needle biopsy. We report a case of a 36-year-old female who was referred to gastroenterology for further evaluation of several liver lesions found incidentally on imaging. Due to risk factors, such as age, long-term oral contraceptive use and obesity, adenoma was high on the differential. Although infrequent, this case emphasizes the importance of a detailed history, including medication review, and physical examination.

关键词： Hepatic Adenoma Oral Contraceptives Liver Lesion

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Differences in metabolic Stress Using a Breathing Restrictive mask Compared to Hypobaric Hypoxia During Cycling at a matched Workload

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Journal of Science in Sport and Exercise 2022年第4期4卷 397-404页

作者： Bryanne N.Bellovary Andrew D.Wells Zachary J.Fennel Jonathan m.Houck Desmond J.millender kelsey C.Bourbeau Christine m.mermier Department of Health Exerciseand Sports SciencesUniversity of New MexicoJohnson Center B143 MSC042610AlbuquerqueNM 87131-0001USA

Purpose The Elevation Training mask(ETm)has been assessed for its impact on exercise performance using acute and training *** the ETm is widely available to consumers,little research exists for validation of the ETm mask ***,the purpose of this study was to compare physiological responses during exercise for the ETm mask settings against moderate hypobaric *** Nine participants living at moderate altitude(1600-1650 m)rested(10 min)and cycled in hypobaric hypoxia simulating 2743 m(ALT),in hypobaric hypoxia simulating 1829 m with the ETm set to 914 m(ALT+ETm),and with the ETm set to 2743 m(ETm)in a randomized *** cycled for 20 min at 60%VO_(2max)as determined by a maximal exertion test(VO_(2max))at baseline *** consumption was measured throughout each *** There were no differences between conditions at *** measures ANOVA showed the ALT condition elicited significantly greater VO_(2) compared to the ETm condition and 60%VO_(2max)at baseline altitude(Pmatched workload,the exercising VO_(2) was higher in the ALT condition than at the ETm mask setting of 2743 m and exercising VO2 during the ETm condition was similar to 60%VO_(2max)at baseline *** results of this study indicate that the ETm did not produce additional metabolic stress compared to hypobaric hypoxia during steady-state exercise in moderate-altitude living individuals.

关键词： Intermittent hypoxia Training mask Acute cycling Altitude

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Plastic Additives Decrease Agrin-Induced Acetylcholine Receptor Clusters and myotube Formation in C2C12 Skeletal muscle Cell Culture

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CellBio 2015年第1期4卷 12-22页

作者： kelsey Neufeld Kelly Ezell Wade A. Grow Department of Anatomy Arizona College of Osteopathic Medicine Midwestern University Glendale AZ USA

Common additives in plastics such as bisphenol A (BPA) or phthalates like di-(2-ethylhexyl) phthalate (DEHP) are environmental estrogens that have been shown to be endocrine disruptors in some experimental animal models. This project used the C2C12 cell culture model to examine how exposure to BPA or DEHP affects two aspects of skeletal muscle development, the fusion of myoblasts into myotubes and agrin-induced clustering of acetylcholine receptors (AChRs). During myotube formation AChRs cluster spontaneously. Treatment with motor neuron derived agrin increases the frequency of AChR clusters through an agrin signaling pathway that also clusters other postsynaptic components of the neuromuscular synapse. For this project C2C12 cells were exposed to BPA or DEHP while myoblasts fused into myotubes. After exposure to 10 μm BPA or 100 μm DEHP the frequency of agrin-induced AChR clusters decreased. In addition, myotube formation decreased as a higher percentage of nuclei remained in myoblasts. Furthermore, BPA or DEHP reduced the amount of the myogenic regulatory factor myogenin. This suggests that BPA and DEHP decrease AChR clustering by reducing myogenin. moreover, plastic additives like BPA and DEHP may pose a risk for skeletal muscle development in humans.

关键词： AChR Agrin Bisphenol A (BPA) C2C12 Di-(2-Ethylhexyl) Phthalate (DEHP) myogenin

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Translational research in early neuroscience careers of high school students

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Neural Regeneration Research 2017年第4期12卷 586-587页

作者： Zachary m.Diamandis Nicholas S.Diaco kelsey Duncan marci Crowley m.Grant Liska Cesar V.Borlongan Center of Excellence for Aging and Brain Repair Department of Neurosurgery and Brain RepairUniversity of South Florida Morsani College of Medicine

Essentially, the knowledge of science alone offers little utility. With-out the ability to investigate, apply and communicate, science serves no purpose. That is not to undermine the importance of scientific knowledge, but there currently exists a major flaw in our high school educational system that inhibits meaningful learning experiences for most students. Application of science in local high schools is largely directed at improving performance on multiple-choice exams. Standardized tests taken by high school students are slowly progressing,

关键词： high Translational research in early neuroscience careers of high school students

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Elucidating regulatory processes of intense physical activity by multi-omics analysis

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military medical Research 2024年第4期11卷 479-499页

作者： Ernesto S.Nakayasu marina A.Gritsenko Young-mo Kim Jennifer E.Kyle Kelly G.Stratton Carrie D.Nicora Nathalie munoz Kathleen m.Navarro Daniel Claborne Yuqian Gao Karl K.Weitz Vanessa L.Paurus Kent J.Bloodsworth kelsey A.Allen Lisa m.Bramer Fernando montes Kathleen A.Clark Grant Tietje Justin Teeguarden Kristin E.Burnum-Johnson Biological Sciences Division Pacific Northwest National LaboratoryRichlandWA 99352USA Environmental and molecular Sciences Division Pacific Northwest National LaboratoryRichlandWA 99352USA Centers for Disease Control and Prevention National Institute for Occupational Safety and HealthWestern States DivisionDenverCO 80204USA Computational Analytics Division Pacific Northwest National LaboratoryRichlandWA 99352USA National Security Directorate Pacific Northwest National LaboratoryRichlandWA 99352USA Los Angeles County Fire Department Los AngelesCA 90063USA Centers for Disease Control and Prevention National Institute for Occupational Safety and HealthRespiratory Health DivisionMorgantownWV 26505USA Environmental and molecular Toxicology Oregon State UniversityCorvallisOR 97331USA

Background:Physiological and biochemical processes across tissues of the body are regulated in response to the high demands of intense physical activity in several occupations,such as firefighting,law enforcement,military,and sports.A better understanding of such processes can ultimately help improve human performance and prevent illnesses in the work ***:To study regulatory processes in intense physical activity simulating real-life conditions,we performed a multi-omics analysis of 3 biofluids(blood plasma,urine,and saliva)collected from 11 wildland firefighters before and after a 45 min,intense exercise *** profiles ***-exercise were compared by Student’s t-test followed by pathway analysis and comparison between the different omics ***:Our multi-omics analysis identified and quantified 3835 proteins,730 lipids and 182 metabolites combining the 3 different types of *** blood plasma analysis revealed signatures of tissue damage and acute repair response accompanied by enhanced carbon metabolism to meet energy *** urine analysis showed a strong,concomitant regulation of 6 out of 8 identified proteins from the renin-angiotensin system supporting increased excretion of catabolites,reabsorption of nutrients and maintenance of fluid *** saliva,we observed a decrease in 3 pro-inflammatory cytokines and an increase in 8 antimicrobial peptides.A systematic literature review identified 6 papers that support an altered susceptibility to respiratory ***:This study shows simultaneous regulatory signatures in biofluids indicative of homeostatic maintenance during intense physical activity with possible effects on increased infection susceptibility,suggesting that caution against respiratory diseases could benefit workers on highly physical demanding jobs.

关键词： multi-omics analysis Intense exercise Human performance Biofluids metabolism Immunity

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Weight loss increases skeletal muscle mitochondrial energy efficiency in obese mice

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Life metabolism 2023年第2期2卷 23-34页

作者： Patrick J.Ferrara marisa J.Lang Jordan m.Johnson Shinya Watanabe kelsey L.mcLaughlin John Alan maschek Anthony R.P.Verkerke Piyarat Siripoksup Amandine Chaix James E.Cox kelsey H.Fisher-Wellman Katsuhiko Funai Diabetes&metabolism Research Center University of UtahSalt Lake CityUtah 84112United States Department of Nutrition&Integrative Physiology University of UtahSalt Lake CityUtah 84112United States East Carolina Diabetes&Obesity Institute East Carolina UniversityGreenvilleNorth Carolina 27834United States Department of Physiology East Carolina UniversityGreenvilleNorth Carolina 27834United States metabolomics Core Research Facility University of UtahSalt Lake CityUtah 84112United States molecular medicine Program University of UtahSalt Lake CityUtah 84112United States Department of Biochemistry University of UtahSalt Lake CityUtah 84112United States

Weight loss from an overweight state is associated with a disproportionate decrease in whole-body energy expenditure that may contribute to the heightened risk for weight *** suggests that this energetic mismatch originates from lean *** this phenomenon is well documented,the mechanisms have remained *** hypothesized that increased mitochondrial energy efficiency in skeletal muscle is associated with reduced expenditure under weight ***(WT)male C57BL6/N mice were fed with high-fat diet for 10 weeks,followed by a subset of mice that were maintained on the obesogenic diet(OB)or switched to standard chow to promote weight loss(WL)for additional 6 *** energy efficiency was evaluated using high-resolution respirometry and *** spectrometric analyses were employed to describe the mitochondrial proteome and *** loss promoted~50%increase in the efficiency of oxidative phosphorylation(ATP produced per O_(2) consumed,or P/O)in skeletal ***,Weight loss did not appear to induce significant changes in mitochondrial proteome,nor any changes in respiratory supercomplex ***,it accelerated the remodeling of mitochondrial cardiolipin(CL)acyl-chains to increase tetralinoleoyl CL(TLCL)content,a species of lipids thought to be functionally critical for the respiratory *** further show that lowering TLCL by deleting the CL transacylase tafazzin was sufficient to reduce skeletal muscle P/O and protect mice from diet-induced weight *** findings implicate skeletal muscle mitochondrial efficiency as a novel mechanism by which weight loss reduces energy expenditure in obesity.

关键词： energy efficiency energy expenditure mitochondria oxidative phosphorylation phospholipids weight loss

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