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vere toxicities without evident loss of antitumor activity these findings raise broader questions about the organization of checkpoint induced autoimmunity the emerging concept of immune reset and the compartment specific roles of b cells in antitumor immunity authors chuan yuan li cell state programs offer a potential axis for classifying neuroendocrine tumors parambir s dulai parambir s dulai view text pdf cell state programs offer a potential axis for classifying neuroendocrine tumors text pdf abstract gastroenteropancreatic neuroendocrine tumors gep nets arise from hormone producing cells in the gut and pancreas despite increasing incidence of these tumors therapeutic options remain limited well differentiated gep nets are classified by anatomic site morphology and proliferation indices but this approach offers limited prognostic resolution among phenotypically similar tumors and constrains personalization of treatment decisions in this issue of the jci karam hoffman and colleagues profiled 38 pancreatic and small intestinal nets using joint single nucleus rna and atac sequencing and projected the resulting malignant cell associated programs onto matched spatial transcriptomes two conserved malignant states emerged neuronal like and secretory neuroendocrine these states span a continuum in both organ sites are enriched for largely different transcription factor motifs and occupy distinct microenvironmental niches secretory program scores trended higher in metastatic disease and may carry prognostic value taken together these data describe net heterogeneity as a cell state axis linked to tissue architecture authors parambir s dulai research articles microtubule associated protein 1s phosphorylation regulates dynein driven transport and synaptogenesis in neurons andré t lopes ondine janiv suzanne claxton sila k ultanir andré t lopes ondine janiv suzanne claxton sila k ultanir view text pdf microtubule associated protein 1s phosphorylation regulates dynein driven transport and synaptogenesis in neurons text pdf abstract cyclin dependent kinase like 5 cdkl5 is a serine threonine kinase enriched in the mammalian brain whose loss of function causes a severe developmental and epileptic encephalopathy named cdkl5 deficiency disorder we previously showed that cdkl5 phosphorylates the microtubule associated protein map1s but how this regulates microtubule dependent functions is not well understood to address this question we generated map1s phosphomutant mice in which the cdkl5 phosphorylation sites s786 and s812 were mutated to alanine map1s s786 812a map1s sa using a microtubule cosedimentation assay we found that dynein binding to microtubules was reduced in map1s sa and cdkl5 knockout ko brain lysates and time lapse imaging showed impaired dynein motility in dendrites from both genotypes map1s sa mice also exhibited reduced ampa receptor transport dendritic spine density and excitatory synapses accompanied by anxiety like behavior and motor social and memory deficits relevant to cdd mechanistically map1s sa and cdkl5 ko neurons showed increased microtubule stability and reduced tubulin tyrosination consistent with excessive map1s mediated stabilization restoring tubulin tyrosination by expressing tubulin tyrosine ligase rescued dynein transport defects together these findings identify map1s phosphorylation as a critical regulator of microtubule dynamics and dynein dependent transport authors andré t lopes ondine janiv suzanne claxton sila k ultanir targeting n acetyltransferase 10 reprograms treg function to enhance anti pd 1 immunotherapy sensitivity in murine lung tumors xuewei qi dan cui xiao li wenfan fu handong ma wenting guo jiabao wang jiaxi song jiaxin ma jing yang haoyu yu yuting hong qian wang susu luo jia wang baixing wu shanshan li hao cheng min cheng bin li kaiming zhang jia li fengyin li xuewei qi dan cui xiao li wenfan fu handong ma wenting guo jiabao wang jiaxi song jiaxin ma jing yang haoyu yu yuting hong qian wang susu luo jia wang baixing wu shanshan li hao cheng min cheng bin li kaiming zhang jia li fengyin li view text pdf targeting n acetyltransferase 10 reprograms treg function to enhance anti pd 1 immunotherapy sensitivity in murine lung tumors text pdf abstract a significant challenge for improving the efficacy of immune checkpoint blockade icb therapy is the concurrent activation of tregs which can dampen antitumor responses thus elucidating the mechanisms that maintain treg suppressive function within the tumor microenvironment is critical here we identified an accumulation of n acetyltransferase 10 modified nat10 modified rna particularly in nat10 foxp3 tregs in human non small cell lung cancer genetic ablation of nat10 in tumor infiltrating ti tregs or pharmacological inhibition of nat10 expression significantly reduced the pd 1 treg cd8 t cell ratio these effects were accompanied by an increase in ifn γ tregs a reduction in the immunosuppressive activity of tregs and inhibition of tumor progression mechanistically nat10 promotes ti treg infiltration and activation independently of its rna modifying function by directly interacting with foxp3 and chromatin modulating local 3d chromatin contacts combined administration of anti pd 1 antibodies and a nat10 inhibitor further impaired ti treg mediated immunosuppression leading to enhanced tumor control our findings demonstrate that nat10 is a key regulator of ti treg fragility and function and that its inhibition may enhance the therapeutic efficacy of icb authors xuewei qi dan cui xiao li wenfan fu handong ma wenting guo jiabao wang jiaxi song jiaxin ma jing yang haoyu yu yuting hong qian wang susu luo jia wang baixing wu shanshan li hao cheng min cheng bin li kaiming zhang jia li fengyin li anti pla2r autoantibodies induce complement activation via igg subclass dependent epitope pairings in membranous nephropathy tsai yi wu kun hua tu larissa seifert kung wei lin han po shih yu fang lo jhan jie peng gunther zahner oliver kretz you ning lin chen xuan kang jing ya ding yi ran tu li yi ma ya ting chuang chia chi lo yu huan tsai chih wei yang nicola m tomas cheng lung ku tsai yi wu kun hua tu larissa seifert kung wei lin han po shih yu fang lo jhan jie peng gunther zahner oliver kretz you ning lin chen xuan kang jing ya ding yi ran tu li yi ma ya ting chuang chia chi lo yu huan tsai chih wei yang nicola m tomas cheng lung ku view text pdf anti pla2r autoantibodies induce complement activation via igg subclass dependent epitope pairings in membranous nephropathy text pdf abstract membranous nephropathy mn is an autoimmune kidney disease and a major cause of nephrotic syndrome in adults although autoantibodies against phospholipase a2 receptor 1 pla2r and complement activation are central to disease pathogenesis the mechanisms by which anti pla2r antibodies activate complement at the podocyte surface remain incompletely defined here we cloned 14 patient derived anti pla2r mabs and found that they predominantly recognized the n terminal cysteine rich cysr and c type lectin domain 1 ctld1 regions of pla2r individual anti pla2r mabs induced little or no complement dependent cytotoxicity cdc of pla2r expressing podocytes in vitro in contrast paired mabs targeting distinct epitopes particularly cysr and ctld1 markedly enhanced cdc this effect was strongest for igg1 and igg3 antibodies whereas igg4 alone did not activate complement but modulated cdc in combination with igg1 purified igg from patients with pla2r associated mn similarly induced cdc which was augmented by addition of anti pla2r igg1 and reduced by anti pla2r igg4 or fab fragments targeting cysr or ctld1 in human pla2r expressing mice paired anti pla2r antibodies increased glomerular complement deposition and induced albuminuria these findings identify epitope pairing as a key determinant of complement activation in pla2r associated mn and support epitope specific targeting strategies as a promising avenue for therapeutic intervention authors tsai yi wu kun hua tu larissa seifert kung wei lin han po shih yu fang lo jhan jie peng gunther zahner oliver kretz you ning lin chen xuan kang jing ya ding yi ran tu li yi ma ya ting chuang chia chi lo yu huan tsai chih wei yang nicola m tomas cheng lung ku a single dorsal vagal complex circuit mediates the aversive and anorectic responses to glp1r agonists warren t yacawych yi wang guoxiang zhou shad hassan cagri bodur elisabeth walters john g santinga frederike sass martin devaux stace kernodle iris wu jenny m brown dylan belmont rausch alan c rupp abigail j tomlinson zitian lin emma vantongeren anna secher kirsten raun tune h pers randy j seeley martin g myers jr weiwei qiu warren t yacawych yi wang guoxiang zhou shad hassan cagri bodur elisabeth walters john g santinga frederike sass martin devaux stace kernodle iris wu jenny m brown dylan belmont rausch alan c rupp abigail j tomlinson zitian lin emma vantongeren anna secher kirsten raun tune h pers randy j seeley martin g myers jr weiwei qiu view text pdf a single dorsal vagal complex circuit mediates the aversive and anorectic responses to glp1r agonists text pdf abstract glucagon like peptide 1 glp 1 receptor agonists glp1ras effectively reduce feeding to treat obesity although nausea and other aversive side effects of these drugs can limit their use brainstem circuits that promote satiation and mediate the physiological control of body weight can be distinguished from those that cause aversion it remains unclear however whether brainstem glp1r neurons contribute to the normal regulation of energy balance and whether glp1ras control appetite via circuits distinct from those that mediate aversive responses here we silenced glp1r neurons in the nucleus of the solitary tract nts or area postrema ap ntsglp1r or apglp1r neurons respectively or restored their glp1r signaling on an otherwise glp1r deficient background to determine physiological and pharmacological roles for each neuron population although ntsglp1r neurons contributed to the normal restraint of food intake and body weight they failed to mediate glp1ra dependent weight loss in contrast while we detected no role for apglp1r neurons in physiological feeding they mediated both the weight lowering and aversive effects of glp1ras therefore while nonaversive ntsglp1r neurons controlled physiologic satiation they did not contribute to weight loss during glp1ra treatment rather apglp1r neurons mediated both the weight lowering and aversive effects of glp1ras preventing the separation of their nauseating and weight loss effects at a circuit level authors warren t yacawych yi wang guoxiang zhou shad hassan cagri bodur elisabeth walters john g santinga frederike sass martin devaux stace kernodle iris wu jenny m brown dylan belmont rausch alan c rupp abigail j tomlinson zitian lin emma vantongeren anna secher kirsten raun tune h pers randy j seeley martin g myers jr weiwei qiu cerebellar and frontal lobe alterations in pulmonary hypertension implicate an inflammatory lung vascular brain axis satoshi okawa yinan shi somanshu banerjee yi yin tai jamal nabhanizadeh stefan guenther anisha n shah siyi jiang timothy kim yassmin al aaraj caroline pidro metin aytekin omolara fatukasi nishita kalepalli joseph mettenburg timothy d girard james t becker kathiravan kaliyappan shanshan song sandra breuils bonnet steeve provencher sébastien bonnet theodore huppert lloyd d harvey seyed mehdi nouraie rajkumar savai dandan sun soban umar soni s pullamsetti stephen y chan satoshi okawa yinan shi somanshu banerjee yi yin tai jamal nabhanizadeh stefan guenther anisha n shah siyi jiang timothy kim yassmin al aaraj caroline pidro metin aytekin omolara fatukasi nishita kalepalli joseph mettenburg timothy d girard james t becker kathiravan kaliyappan shanshan song sandra breuils bonnet steeve provencher sébastien bonnet theodore huppert lloyd d harvey seyed mehdi nouraie rajkumar savai dandan sun soban umar soni s pullamsetti stephen y chan view text pdf cerebellar and frontal lobe alterations in pulmonary hypertension implicate an inflammatory lung vascular brain axis text pdf abstract connections between vascular and neurocognitive diseases are emerging but remain poorly defined cognitive impairment is increasingly recognized in pulmonary hypertension ph a disease traditionally viewed as limited to the heart and lungs given that inflammation is shared by ph and neurodegenerative diseases we investigated its role in driving brain and cognitive deficits in ph using structural and functional mri data from uk biobank n 248 ph and a prospective validation cohort we identified reduced cerebellar white matter volume thinner frontal gyri and weakened cerebellar frontal connectivity in patients with ph but not in other heart or lung diseases these changes were accompanied by worsened executive function and processing speed olink proteomics and targeted genomics linked inflammatory plasma proteins and a ph associated nuclear receptor coactivator 7 ncoa7 single nucleotide polymorphism rs11154337 to these deficits ph cerebellum showed increased microglial activation and white matter derangement in ph mice ncoa7 deficiency worsened cerebellar inflammation and atrophy microglial functional assays cerebellar single nucleus rna sequencing and spatial transcriptomic analyses further implicated ncoa7 dependent lysosomal inflammatory and cell specific mechanisms of cerebellar pathobiology these findings identify ncoa7 linked inflammatory dysfunction in the cerebellar frontal axis in ph redefining this disease with neurologic consequences and thus offering neural targets for diagnostic prognostic and therapeutic development authors satoshi okawa yinan shi somanshu banerjee yi yin tai jamal nabhanizadeh stefan guenther anisha n shah siyi jiang timothy kim yassmin al aaraj caroline pidro metin aytekin omolara fatukasi nishita kalepalli joseph mettenburg timothy d girard james t becker kathiravan kaliyappan shanshan song sandra breuils bonnet steeve provencher sébastien bonnet theodore huppert lloyd d harvey seyed mehdi nouraie rajkumar savai dandan sun soban umar soni s pullamsetti stephen y chan neoadjuvant pd l1 tgf β blockade can rapidly disrupt the tumor stroma in head and neck cancer patients caroline hoffmann jan timon werle philémon sirven mamy andrianteranagna jocelyn gal wiem lassoued jerzy klijanienko jeremy mesple benjamin demaille abdenour abbas valentine gauthier kyra j e borgman isabelle puisieux serena janho dit hreich olivier choussy gregoire marret sonia lameiras nathalie badois antoine dubray vautrin gilles dolivet lionnel geoffrois renaud leclère wail zeitouni noemie robil jane merlevede altynbek zhubanchaliyev maud kamal ivan bieche laure monard clotilde simon delphine louis clint t allen arun rajan james l gulley maude guillot delost christophe le tourneau hélène salmon caroline hoffmann jan timon werle philémon sirven mamy andrianteranagna jocelyn gal wiem lassoued ...
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