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and (253), the (158), with (104), cell (67), cells (65), for (61), that (58), pdf (57), text (57), #disease (40), from (34), muscle (33), authors (33), abstract (32), #signaling (32), cd4 (30), these (28), were (28), airway (28), associated (27), view (27), mice (25), research (24), are (22), patients (21), cancer (21), human (21), protein (19), tumor (19), lung (19), this (18), specific (18), clinical (17), immune (17), expression (17), activation (17), here (17), after (17), epithelial (17), changes (16), gene (16), function (16), our (16), increased (16), model (16), induced (16), dependent (15), through (15), tissue (15), estrogen (15), rna (14), genetic (14), role (14), was (14), pathways (13), organ (13), fibrosis (13), not (13), pathway (12), have (12), development (12), transcriptomic (12), single (12), treatment (12), mouse (12), normal (12), analysis (12), findings (12), models (12), lee (12), sarah (12), peter (12), liu (12), olga (12), pulmonary (11), inflammation (11), 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icki do maya e hignite yohan park fariha nusrat bibi maryam sizhao lu xiaoyan li jenny r gipson xiaogang li david a long mary c m weiser evans bradley k yoder benjamin d cowley jr katharina hopp jason r stubbs qin ma anjun ma kurt a zimmerman sarah j miller hua zhong weidong wu audrey m cordova morgan e yashchenko alex yashchenko zhang li daniyal j jafree chelsea n zimmerman christa i devette vicki do maya e hignite yohan park fariha nusrat bibi maryam sizhao lu xiaoyan li jenny r gipson xiaogang li david a long mary c m weiser evans bradley k yoder benjamin d cowley jr katharina hopp jason r stubbs qin ma anjun ma kurt a zimmerman view text pdf a cross model single cell atlas reveals conserved involvement of osteopontin in polycystic kidney disease text pdf abstract polycystic kidney disease pkd arises from mutations in cilia associated genes such as pkd1 and pkd2 expressed in renal epithelial cells leading to progressive kidney dysfunction and end stage kidney disease patients with pkd exhibit significant heterogeneity in disease progression largely due to genetic and environmental modifiers like patients mouse models of pkd also exhibit significant heterogeneity with regards to the gene mutated age of disease onset and rate of disease progression to elucidate the cellular and molecular consequences of these variables we constructed an integrated single cell rna sequencing scrna seq atlas across mouse models of pkd mapping changes in cell type composition gene expression and intercellular signaling networks across the whole atlas and within individual models across models scrna seq data revealed increased spp1 osteopontin expression and signaling from pkd enriched clusters global deletion of spp1 in pkd1rc rc mice resulted in a modest reduction in cyst severity and improved kidney function from these studies we created a freely available searchable website https bmblx bmi osumc edu scpkd that can be used to identify cross and intra model changes in gene expression guiding researchers to new therapeutic targets for treating pkd authors sarah j miller hua zhong weidong wu audrey m cordova morgan e yashchenko alex yashchenko zhang li daniyal j jafree chelsea n zimmerman christa i devette vicki do maya e hignite yohan park fariha nusrat bibi maryam sizhao lu xiaoyan li jenny r gipson xiaogang li david a long mary c m weiser evans bradley k yoder benjamin d cowley jr katharina hopp jason r stubbs qin ma anjun ma kurt a zimmerman progressive hypothalamic neuroinflammation in ovariectomized mice parallels aging related transcriptomic changes in the female human hypothalamus jordana c b bloom encarnación torres sidney a pereira liliana arvizu sanchez audrey n fontes hadine joffe david c page victor m navarro jordana c b bloom encarnación torres sidney a pereira liliana arvizu sanchez audrey n fontes hadine joffe david c page victor m navarro view text pdf progressive hypothalamic neuroinflammation in ovariectomized mice parallels aging related transcriptomic changes in the female human hypothalamus text pdf abstract the hypothalamic changes that occur after the loss of ovarian estrogen remain poorly characterized here we performed a comprehensive temporal characterization of the mouse hypothalamus after ovariectomy ovx combining physiological measurements with bulk rna seq of the posterior hypothalamus ph and preoptic area at 14 days and 4 months after ovx serum luteinizing hormone levels rose progressively and then declined and core temperature peaked early and subsequently normalized recapitulating the endocrine and thermoregulatory dynamics of reproductive aging in humans transcriptomic analysis revealed time dependent activation of inflammatory pathways glial markers and kndy neuron related gene networks with the most pronounced changes emerging at 4 months after ovx particularly in the ph immunofluorescence confirmed increased neurokinin b release declining kndy neuronal activity and heightened astrocytic reactivity in the arcuate nucleus after prolonged estrogen withdrawal to contextualize these findings we analyzed publicly available human hypothalamic rna seq data across chronological age age related transcriptomic patterns including progressive inflammatory signaling glial activation and altered kndy gene expression showed significant correlation with the ovx mouse model particularly at the pathway level these findings establish a temporal framework for hypothalamic molecular changes after estrogen withdrawal identify conserved neuroinflammatory signatures across species and provide a preclinical platform for testing interventions targeting menopause associated hypothalamic dysfunction authors jordana c b bloom encarnación torres sidney a pereira liliana arvizu sanchez audrey n fontes hadine joffe david c page victor m navarro single cell rna sequencing reveals clonally expanded cd4 tissue resident memory t cells in histidyl trna synthetase induced myositis decheng li daniel p reay iago pinal fernandez maria casal dominguez andrew l mammen sarah l gaffen timothy b oriss dana p ascherman decheng li daniel p reay iago pinal fernandez maria casal dominguez andrew l mammen sarah l gaffen timothy b oriss dana p ascherman view text pdf single cell rna sequencing reveals clonally expanded cd4 tissue resident memory t cells in histidyl trna synthetase induced myositis text pdf abstract the precise mechanisms underlying the pathogenesis of idiopathic inflammatory myopathy iim remain undefined however there has been increasing recognition that tissue resident memory t cells trms play an important role in the pathogenesis of systemic autoimmune disease in iim trm associated transcriptional signatures have been reported but on a very limited basis by using multimodal single cell rna sequencing analysis in our established murine model of histidyl trna synthetase induced myositis we identified a prominent population of cd4 trms in inflamed skeletal muscle muscle cd4 trms exhibited high expression of genes encoding cd69 cxcr6 runx3 and prdm1 alongside low expression of klf2 ccr7 sell s1pr1 and tcf7 a profile that is generally consistent with previous reports of trm gene signature and that we validate through comparison with transcriptomic profiles of human muscle tissue detailed pathway analysis in our model indicates that muscle cd4 trms contribute to innate immune regulatory pathways enriched for tnf and ifn γ signaling furthermore analysis of tcr clonotype distribution and cdr3 sequence similarity revealed pronounced clonal expansion of cd4 trms relative to other t cell subsets a pattern that remained stable from 2 to 6 weeks after immunization collectively these results suggest a potential role for cd4 trms in the pathogenesis of autoimmune myositis authors decheng li daniel p reay iago pinal fernandez maria casal dominguez andrew l mammen sarah l gaffen timothy b oriss dana p ascherman plasma proteins associated with chronic graft versus host disease organ involvement stephanie j lee corey cutler ningxin ma timothy w randolph george l chen joseph pidala betty k hamilton carrie l kitko sally arai najla el jurdi lynn onstad motoko koyama catherine j lee sophie paczesny geoffrey r hill stephanie j lee corey cutler ningxin ma timothy w randolph george l chen joseph pidala betty k hamilton carrie l kitko sally arai najla el jurdi lynn onstad motoko koyama catherine j lee sophie paczesny geoffrey r hill view text pdf plasma proteins associated with chronic graft versus host disease organ involvement text pdf abstract background previous studies identified plasma proteins associated with chronic graft versus host disease cgvhd the goal of this cross sectional study was to evaluate whether plasma biomarkers were associated with specific organ manifestations to help guide treatment choice methods plasma proteins were measured in patients with cgvhd n 695 from chronic gvhd consortium studies correlations of plasma protein levels with individual organ involvement were tested with a p value of 0 05 or less considered significant after benjamini hochberg adjustment and adjustment for 5 baseline clinical variables results median time from cgvhd diagnosis to blood draw was 0 9 months iqr 0 1 9 5 donors were 50 hla matched unrelated 32 matched related and the remainder were umbilical cord blood haploidentical or mismatched unrelated donors methotrexate and calcineurin inhibitor prophylaxis for acute gvhd was used in 53 of patients overall 326 47 had moderate and 244 35 had severe cgvhd with the following organ involvement at time of blood draw skin 67 mouth 60 eye 49 joint 34 gi 31 lung 23 and liver 17 after adjustment for batch effects and patient and transplant characteristics 14 plasma proteins were associated with organ involvement with independent aucs of 0 7 0 8 all organs except the eye were associated with at least 1 biomarker however no combination of plasma proteins improved model fit after adjusting for patient and transplant clinical variables conclusion correlations between plasma proteins and organ involvement were identified but are not actionable our future investigations will focus on more granular and immediately proximal determinants of cgvhd biology in both blood and tissue authors stephanie j lee corey cutler ningxin ma timothy w randolph george l chen joseph pidala betty k hamilton carrie l kitko sally arai najla el jurdi lynn onstad motoko koyama catherine j lee sophie paczesny geoffrey r hill in press preview more zinc restrains multicellular remodeling in fibrotic lung disease research letter in press preview immunology pulmonology zinc restrains multicellular remodeling in fibrotic lung disease text pdf abstract authors jianfei ji wenjing you xiaoli sun peng zhao stabilization of the pp2a b56α complex overcomes venetoclax azacitidine resistance by impairing oxphos in aml cell metabolic rewiring is associated with resistance to venetoclax azacitidine ven aza combination therapy and relapse in acute myeloid leukemia aml patients drug resistant cells exhibit an research in press preview cell biology hematology stabilization of the pp2a b56α complex overcomes venetoclax azacitidine resistance by impairing oxphos in aml text pdf abstract cell metabolic rewiring is associated with resistance to venetoclax azacitidine ven aza combination therapy and relapse in acute myeloid leukemia aml patients drug resistant cells exhibit an enhanced reliance on oxidative phosphorylation oxphos for energy production therefore impairing mitochondrial metabolism represents an exciting strategy to face this unmet clinical need we recently demonstrated that the specific activation of the phosphatase pp2a b56α enhances the pro apoptotic efficacy of venetoclax in aml here through leveraging unbiased multi omics based approaches and using both genetic and pharmacological tools we define key roles for the tumor suppressor pp2a b56α complex in oxphos regulation and treatment response in disease relevant aml models from a translational perspective the specific stabilization of pp2a b56α heterocomplex with the novel pp2a molecular glue activator rpt04402 reduces oxphos levels in treatment resistant aml cells and improves treatment response in both ven aza sensitive and resistant aml cell lines primary cells and in vivo models together our work supports further research on targeted combination therapy approaches based on pp2a b56α stabilization to counteract oxphos related treatment resistance and improve aml responses in a patient population with historically poor outcomes authors silvia romero murillo irene peris anna maria lucianò nerea marcotegui carmen vicente brian tran kelsey barrie caitlin m o connor andrea torres lópez maria c mateos maria l cayuela victoriano mulero joaquín fernández irigoyen enrique santamaría maria d odero goutham narla transcriptomic profiling of immune cells in malignant pleural effusions identifies macrophage reprogramming associated with survival despite advances in treatment approaches for lung cancer the morbidity and survival of lung cancer patients with malignant pleural effusions mpe remain poor this is in part due to gaps in research in press preview oncology pulmonology transcriptomic profiling of immune cells in malignant pleural effusions identifies macrophage reprogramming associated with survival text pdf abstract despite advances in treatment approaches for lung cancer the morbidity and survival of lung cancer patients with malignant pleural effusions mpe remain poor this is in part due to gaps in understanding the role of immune cells in the pleural fluid microenvironment we performed single cell analysis with flow cytometry validation of cd45 cells in eight malignant and five benign pleural fluid bpe specimens to identify changes in the transcriptomic landscape of immune cells across disease states we found upregulation of pro inflammatory signaling pathways including interferon and tnf signaling in t cells b cells and macrophages in benign compared to malignant pleural effusions pro inflammatory hla dr macrophages were associated with good survival outcomes while pro tumorigenic hla dr macrophages with upregulation of angiogenesis tgfβ and fibronectin signaling were associated with poor survival outcomes in patients with mpe we also validated these findings with macrophage cell surface expression markers using flow cytometry in 14 mpe and 7 bpe specimens finally we performed multiplex cytokine analysis which showed enrichment of the type 3 inflammatory cytokine il17a in mpe as a putative mechanism for macrophage reprogramming these data provide a rich resource for interrogating the immune cell types and states present across the spectrum of pleural disease they offer not only prognostic value for patient outcomes at the time of pleural fluid collection but also insights into novel immunotherapy targets authors aaditya khatri huimin wang zhicheng ji prekshaben patel smita k nair javid p mohammed beth h shaz andrew b nixon scott m palmer kamran mahmood feeding induced muscle mtorc1 signaling regulates postprandial protein synthesis and endurance but not muscle size activation of the mechanistic target of rapamycin mtor complex1 mtorc1 promotes muscle protein synthesis mass and function muscle mtorc1 can be activated by feeding and contraction here research in press preview endocrinology muscle biology feeding induced muscle mtorc1 signaling regulates postprandial protein synthesis and endurance but not muscle size text pdf abstract activation of the mechanistic target of rapamycin mtor complex1 mtorc1 promotes muscle protein synthesis mass and function muscle mtorc1 can be activated by feeding and contraction here muscle mtorc1 signaling protein synthesis mass and function are characterized in a genetic mouse model that separates these two major modes of muscle mtorc1 regulation akt signaling is required for feeding induced muscle mtorc1 signaling and protein synthesis and mice expressing a mutan...
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