The Journal of Clinical Investigation最新文献_第2页

Pathogenic SIV infection is associated with acceleration of epigenetic age in rhesus macaques. 致病性SIV感染与恒河猴表观遗传年龄的加速有关。

The Journal of Clinical Investigation Pub Date : 2025-07-15 DOI: 10.1172/jci189574

Anna J Jasinska,Ranjit Sivanandham,Sindhuja Sivanandham,Cuiling Xu,Juozas Gordevicius,Milda Milčiūtė,Robert T Brooke,Paola Sette,Tianyu He,Egidio Brocca-Cofano,Benjamin B Policicchio,Krishna Nayak,Saharsh Talwar,Haritha Annapureddy,Dongzhu Ma,Ruy M Ribeiro,Cristian Apetrei,Ivona Pandrea

{"title":"Pathogenic SIV infection is associated with acceleration of epigenetic age in rhesus macaques.","authors":"Anna J Jasinska,Ranjit Sivanandham,Sindhuja Sivanandham,Cuiling Xu,Juozas Gordevicius,Milda Milčiūtė,Robert T Brooke,Paola Sette,Tianyu He,Egidio Brocca-Cofano,Benjamin B Policicchio,Krishna Nayak,Saharsh Talwar,Haritha Annapureddy,Dongzhu Ma,Ruy M Ribeiro,Cristian Apetrei,Ivona Pandrea","doi":"10.1172/jci189574","DOIUrl":"https://doi.org/10.1172/jci189574","url":null,"abstract":"HIV infection accelerates biological aging, but the contribution of the host's age to this process is unknown. We investigated the influence of SIV infection in macaques (SIVmac) on the risk of comorbidities and aging in young and old rhesus macaques (RMs) by assessing pathogenesis markers, DNA methylation-based epigenetic age (EA), and EA acceleration (EAA) in blood and tissues. Initially, upon SIV infection, the young RMs showed greater resilience to CD4+ T cell depletion, better control of T cell activation, hypercoagulation, and excessive inflammation, yet this resilience was progressively lost in the advanced stages of infection. During the late stages of infection, the young RMs, but not the aged ones, showed an increase in EA in PBMCs; also, EAA in the cerebellum and heart of young RMs was higher compared with old RMs. SIV infection was more pathogenic in aged animals in early stages, leading to a more rapid disease progression; however, accelerated aging mostly affected young animals, so that the levels of multiple key pathogenesis markers in the young RMs converged toward those specific to aged ones in the late stages of infection. We conclude that SIV infection-driven age acceleration is tissue specific, and that host age influences the susceptibility of different tissues to enhanced aging.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"52 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144630039","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Integrative mapping of pre-existing influenza immune landscapes predicts vaccine response. 预先存在的流感免疫景观的综合制图预测疫苗反应。

The Journal of Clinical Investigation Pub Date : 2025-07-15 DOI: 10.1172/jci189300

Stephanie Hao,Ivan Tomic,Benjamin B Lindsey,Ya Jankey Jagne,Katja Hoschler,Adam Meijer,Juan Manuel Carreño Quiroz,Philip Meade,Kaori Sano,Chikondi Peno,André G Costa-Martins,Debby Bogaert,Beate Kampmann,Helder Nakaya,Florian Krammer,Thushan I de Silva,Adriana Tomic

{"title":"Integrative mapping of pre-existing influenza immune landscapes predicts vaccine response.","authors":"Stephanie Hao,Ivan Tomic,Benjamin B Lindsey,Ya Jankey Jagne,Katja Hoschler,Adam Meijer,Juan Manuel Carreño Quiroz,Philip Meade,Kaori Sano,Chikondi Peno,André G Costa-Martins,Debby Bogaert,Beate Kampmann,Helder Nakaya,Florian Krammer,Thushan I de Silva,Adriana Tomic","doi":"10.1172/jci189300","DOIUrl":"https://doi.org/10.1172/jci189300","url":null,"abstract":"BACKGROUNDPredicting individual vaccine responses is a substantial public health challenge. We developed immunaut, an open-source, data-driven framework for systems vaccinologists to analyze and predict immunological outcomes across diverse vaccination settings, beyond traditional assessments.METHODSUsing a comprehensive live attenuated influenza vaccine (LAIV) dataset from 244 Gambian children, immunaut integrated pre- and post-vaccination humoral, mucosal, cellular, and transcriptomic data. Through advanced modeling, our framework provided a holistic, systems-level view of LAIV-induced immunity.RESULTSThe analysis identified three distinct immunophenotypic profiles driven by baseline immunity: (1) CD8 T-cell responders with strong pre-existing immunity boosting memory T-cell responses; (2) Mucosal responders with prior influenza A virus immunity developing robust mucosal IgA and subsequent influenza B virus seroconversion; and (3) Systemic, broad influenza A virus responders starting from immune naivety who mounted broad systemic antibody responses. Pathway analysis revealed how pre-existing immune landscapes and baseline features, such as mucosal preparedness and cellular support, quantitatively dictate vaccine outcomes.CONCLUSIONOur findings emphasize the power of integrative, predictive frameworks for advancing precision vaccinology. The immunaut framework is a valuable resource for deciphering vaccine response heterogeneity and can be applied to optimize immunization strategies across diverse populations and vaccine platforms.FUNDINGWellcome Trust (110058/Z/15/Z); Bill & Melinda Gates Foundation (INV-004222); HIC-Vac consortium; NIAID (R21 AI151917); NIAID CEIRR Network (75N93021C00045).","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"16 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144639844","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Age-dependent brain responses to mechanical stress determine resilience in a chronic lymphatic drainage impairment model. 年龄依赖的大脑对机械应力的反应决定了慢性淋巴排水损伤模型的恢复能力。

The Journal of Clinical Investigation Pub Date : 2025-07-15 DOI: 10.1172/jci182555

Zachary H Gursky,Zohaib Nisar Khan,Sunil Koundal,Ankita Bhardwaj,Joaquin Caceres Melgarejo,Kaiming Xu,Xinan Chen,Hung-Mo Lin,Xianfeng Gu,Hedok Lee,Jonathan Kipnis,Yoav Dori,Allen Tannenbaum,Laura Santambrogio,Helene Benveniste

{"title":"Age-dependent brain responses to mechanical stress determine resilience in a chronic lymphatic drainage impairment model.","authors":"Zachary H Gursky,Zohaib Nisar Khan,Sunil Koundal,Ankita Bhardwaj,Joaquin Caceres Melgarejo,Kaiming Xu,Xinan Chen,Hung-Mo Lin,Xianfeng Gu,Hedok Lee,Jonathan Kipnis,Yoav Dori,Allen Tannenbaum,Laura Santambrogio,Helene Benveniste","doi":"10.1172/jci182555","DOIUrl":"https://doi.org/10.1172/jci182555","url":null,"abstract":"The outflow of 'dirty' brain fluids from the glymphatic system drains via the meningeal lymphatic vessels to the lymph nodes in the neck, primarily the deep cervical lymph nodes (dcLN). However, it is unclear whether dcLN drainage is essential for normal cerebral homeostasis. Using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and computational fluid dynamics, we studied the impact of long-term mechanical stress from compromised dcLN drainage on brain solute and fluid outflow in anesthetized rats. We found that in young, but not middle-aged rats, impairment of dcLN drainage was linked to moderately increased intracranial pressure and the emergence of extracranial peri-venous drainage, with no evidence of hydrocephalus at any age. Surprisingly, both age groups showed enhanced brain solute clearance despite reduced glymphatic influx. CSF proteomic analysis revealed cellular stress in the form of low-grade inflammation, and up-regulation of pathways associated with neurodegeneration and blood brain barrier leakage in the rats with impaired lymphatic drainage. Our findings highlight that dcLN drainage is indeed a prerequisite for normal cerebral homeostasis in the rat and reveal the brain's age-dependent compensatory responses to chronic impairment of its lymphatic drainage pathways.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"205 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144639847","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Corrigendum to Targeting apoptotic pathways for cancer therapy. 靶向细胞凋亡通路用于癌症治疗的勘误表。

The Journal of Clinical Investigation Pub Date : 2025-07-15 DOI: 10.1172/jci196275

Xiaobing Tian,Praveen R Srinivasan,Vida Tajiknia,Ashley F Sanchez Sevilla Uruchurtu,Attila A Seyhan,Benedito A Carneiro,Arielle De La Cruz,Maximilian Pinho-Schwermann,Andrew George,Shuai Zhao,Jillian Strandberg,Francesca Di Cristofano,Shengliang Zhang,Lanlan Zhou,Alexander G Raufi,Arunasalam Navaraj,Yiqun Zhang,Nataliia Verovkina,Maryam Ghandali,Dinara Ryspayeva,Wafik S El-Deiry

引用次数: 0

The NUDIX hydrolase NUDT5 influences purine nucleotide metabolism and thiopurine pharmacology. NUDIX水解酶NUDT5影响嘌呤核苷酸代谢和硫嘌呤药理学。

The Journal of Clinical Investigation Pub Date : 2025-07-15 DOI: 10.1172/jci194434

Leo Kager,Kaan Boztug

引用次数: 0

Metastatic heterogeneity in pancreatic cancer: mechanisms and opportunities for targeted intervention. 胰腺癌转移异质性：靶向干预的机制和机会。

The Journal of Clinical Investigation Pub Date : 2025-07-15 DOI: 10.1172/jci191943

Ravikanth Maddipati

{"title":"Metastatic heterogeneity in pancreatic cancer: mechanisms and opportunities for targeted intervention.","authors":"Ravikanth Maddipati","doi":"10.1172/jci191943","DOIUrl":"https://doi.org/10.1172/jci191943","url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDAC) remains among the most lethal cancers, with metastasis as the primary driver of mortality. While metastatic mechanisms are shared across malignancies, PDAC metastasis poses unique therapeutic challenges due to the presence of extensive tumor heterogeneity, desmoplasia, and immunosuppression - features that enable diverse migratory behaviors and therapeutic resistance. Recent advances have shown that metastatic progression in PDAC emerges from dynamic interactions between tumor cell-intrinsic and microenvironmental factors, each adapting to evolving stressors throughout the metastatic cascade. In the primary tumor, genomic instability and epigenetic reprogramming generate subclones with heightened invasive potential, while dense stromal reactions and myeloid-dominated immune suppression facilitate escape. During circulation, PDAC cells employ distinctive survival strategies through homotypic clustering and heterotypic interactions with blood components. At distant sites, PDAC cells adapt to organ-specific microenvironments through context-dependent metabolic and immune modulation, resulting in phenotypes that diverge from the primary tumor. In this Review, we examine how tumor-stroma crosstalk mechanisms shape metastatic progression in PDAC, provide a framework for understanding why conventional therapies often fail against metastatic disease, and highlight emerging opportunities for stage- and site-specific therapeutic interventions that target these unique adaptations.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"84 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144629983","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The NUDIX hydrolase NUDT5 regulates thiopurine metabolism and cytotoxicity. NUDIX水解酶NUDT5调节硫嘌呤代谢和细胞毒性。

The Journal of Clinical Investigation Pub Date : 2025-07-15 DOI: 10.1172/jci190443

Maud Maillard,Rina Nishii,Hieu S Vu,Kashi R Bhattarai,Wenjian Yang,Jing Li,Ute Hofmann,Daniel Savic,Smita Bhatia,Matthias Schwab,Min Ni,Jun J Yang

{"title":"The NUDIX hydrolase NUDT5 regulates thiopurine metabolism and cytotoxicity.","authors":"Maud Maillard,Rina Nishii,Hieu S Vu,Kashi R Bhattarai,Wenjian Yang,Jing Li,Ute Hofmann,Daniel Savic,Smita Bhatia,Matthias Schwab,Min Ni,Jun J Yang","doi":"10.1172/jci190443","DOIUrl":"https://doi.org/10.1172/jci190443","url":null,"abstract":"Thiopurines are anticancer agents used for the treatment of leukemia and autoimmune diseases. These purine analogs are characterized by a narrow therapeutic index because of the risk of myelosuppression. With the discovery of NUDIX hydrolase 15 (NUDT15) as a major modulator of thiopurine metabolism and toxicity, we sought to comprehensively examine all members of the NUDIX hydrolase family for their effect on the pharmacologic effects of thiopurine. By performing a NUDIX-targeted CRISPR/Cas9 screen in leukemia cells, we identified NUDT5, whose depletion led to drastic thiopurine resistance. NUDT5 deficiency resulted in a nearly complete depletion of active metabolites of thiopurine and the loss of thioguanine incorporation into DNA. Mechanistically, NUDT5 deletion resulted in substantial alteration in purine nucleotide biosynthesis, as determined by steady-state metabolomics profiling. Stable isotope tracing demonstrated that the loss of NUDT5 was linked to a marked suppression of the purine salvage pathway but with minimal effects on purine de novo synthesis. Finally, we comprehensively identified germline genetic variants in NUDT5 associated with thiopurine-induced myelosuppression in 582 children with acute lymphoblastic leukemia. Collectively, these results pointed to NUDT5 as a key regulator of the thiopurine response primarily through its effects on purine homeostasis, highlighting its potential to inform individualized thiopurine therapy.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"9 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144630038","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

cGAS activation converges with intracellular acidification to promote STING aggregation and pyroptosis in tumor models. 在肿瘤模型中，cGAS的激活与细胞内酸化相结合，促进STING聚集和焦亡。

The Journal of Clinical Investigation Pub Date : 2025-07-15 DOI: 10.1172/jci188872

Li Xiao,Yuan-Li Ai,Xiang-Yu Mi,Han Liang,Xiang Zhi,Liu-Zheng Wu,Qi-Tao Chen,Tong Gou,Chao Chen,Bo Zhou,Wen-Bin Hong,Lu-Ming Yao,Jun-Jie Chen,Xianming Deng,Fu-Nan Li,Qiao Wu,Hang-Zi Chen

{"title":"cGAS activation converges with intracellular acidification to promote STING aggregation and pyroptosis in tumor models.","authors":"Li Xiao,Yuan-Li Ai,Xiang-Yu Mi,Han Liang,Xiang Zhi,Liu-Zheng Wu,Qi-Tao Chen,Tong Gou,Chao Chen,Bo Zhou,Wen-Bin Hong,Lu-Ming Yao,Jun-Jie Chen,Xianming Deng,Fu-Nan Li,Qiao Wu,Hang-Zi Chen","doi":"10.1172/jci188872","DOIUrl":"https://doi.org/10.1172/jci188872","url":null,"abstract":"The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is intimately associated with anti-tumoral immunity; however, the direct involvement of this pathway in tumor cell demise remains elusive. Here, we identified a compound dodecyl 6-hydroxy-2-naphthoate (DHN) that induces pyroptosis in melanoma cells through activating the non-canonical cGAS-STING signaling. DHN targets mitochondrial protein cyclophilin D (CypD) to induce the release of mitochondrial DNA, leading to cGAS activation and cyclic GMP-AMP (cGAMP) generation. Meanwhile, DHN-caused intracellular acidification induces PRKR-like endoplasmic reticulum kinase (PERK) activation, which promotes STING phosphorylation and polymerization in the presence of cGAMP, thereby facilitating the aggregation of STING in the endoplasmic reticulum, which serves as a platform to recruit Fas associated via death domain (FADD) and caspase-8, leading to caspase-8 activation and subsequent gasdermin E (GSDME) cleavage, which ultimately results in pyroptosis of tumor cells and tumor regression in mouse models. The occurrence of this non-canonical cGAS-STING pathway-associated pyroptosis is also observed when both cGAS is activated and intracellular pH declines. Collectively, our findings reveal a pathway that links non-canonical cGAS-STING signaling to GSDME-mediated pyroptosis, thereby offering valuable insights for tumor therapy.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"10 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144639846","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Organ-specific features of human kidney lymphatics are disrupted in chronic transplant rejection. 慢性移植排斥反应破坏了人肾淋巴的器官特异性特征。

The Journal of Clinical Investigation Pub Date : 2025-07-15 DOI: 10.1172/jci168962

Daniyal J Jafree,Benjamin J Stewart,Karen L Price,Maria Kolatsi-Joannou,Camille Laroche,Barian Mohidin,Benjamin Davis,Hannah Mitchell,Lauren G Russell,Lucía Marinas Del Rey,Chun Jing Wang,William J Mason,Byung Il Lee,Lauren Heptinstall,Ayshwarya Subramanian,Gideon Pomeranz,Dale Moulding,Laura Wilson,Tahmina Wickenden,Saif N Malik,Natalie Holroyd,Claire L Walsh,Jennifer C Chandler,Kevin X Cao,Paul Jd Winyard,Adrian S Woolf,Marc Aurel Busche,Simon Walker-Samuel,Lucy Sk Walker,Tessa Crompton,Peter J Scambler,Reza Motallebzadeh,Menna R Clatworthy,David A Long

{"title":"Organ-specific features of human kidney lymphatics are disrupted in chronic transplant rejection.","authors":"Daniyal J Jafree,Benjamin J Stewart,Karen L Price,Maria Kolatsi-Joannou,Camille Laroche,Barian Mohidin,Benjamin Davis,Hannah Mitchell,Lauren G Russell,Lucía Marinas Del Rey,Chun Jing Wang,William J Mason,Byung Il Lee,Lauren Heptinstall,Ayshwarya Subramanian,Gideon Pomeranz,Dale Moulding,Laura Wilson,Tahmina Wickenden,Saif N Malik,Natalie Holroyd,Claire L Walsh,Jennifer C Chandler,Kevin X Cao,Paul Jd Winyard,Adrian S Woolf,Marc Aurel Busche,Simon Walker-Samuel,Lucy Sk Walker,Tessa Crompton,Peter J Scambler,Reza Motallebzadeh,Menna R Clatworthy,David A Long","doi":"10.1172/jci168962","DOIUrl":"https://doi.org/10.1172/jci168962","url":null,"abstract":"Lymphatic vessels maintain tissue fluid homeostasis and modulate inflammation, yet their spatial organisation and molecular identity in the healthy human kidney, and how these change during chronic transplant rejection, remain poorly defined. Here, we show that lymphatic capillaries initiate adjacent to cortical kidney tubules and lack smooth muscle coverage. These vessels exhibit an organ-specific molecular signature, enriched for CCL14, DNASE1L3, and MDK, with limited expression of canonical immune-trafficking markers found in other organ lymphatics, such as LYVE1 and CXCL8. In allografts with chronic mixed rejection, lymphatics become disorganised and infiltrate the medulla, with their endothelial junctions remodelling from a button-like to a continuous, zipper-like architecture. Lymphatics in rejecting kidneys localise around and interconnect tertiary lymphoid structures at different maturation stages, with altered intra- and peri-lymphatic CD4⁺ T cell distribution. The infiltrating T cells express IFNγ, which upregulates co-inhibitory ligands in lymphatic endothelial cells, including PVR and LGALS9. Simultaneously, lymphatics acquire HLA class II expression and exhibit C4d deposition, consistent with alloantibody binding and complement activation. Together, these findings define the spatial and molecular features of human kidney lymphatics, revealing tolerogenic reprogramming, accompanied by structural perturbations, during chronic transplant rejection.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"15 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144639841","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Biomedical education in the era of large language models: a paradigm shift. 大语言模式时代的生物医学教育：一种范式转变。

The Journal of Clinical Investigation Pub Date : 2025-07-15 DOI: 10.1172/jci196863

Shen-Han Lee

引用次数: 0