Journal of Clinical Investigation最新文献_第10页

Mucins protect against Streptococcus pneumoniae virulence by suppressing pneumolysin expression. 粘蛋白通过抑制肺炎溶蛋白的表达来保护肺炎链球菌的毒力。

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2024-08-22 DOI: 10.1172/JCI182769

Jade Bath, Elisabet Bjånes, Cengiz Goekeri, Jeff Hsiao, Deniz Uzun, Geraldine Nouailles, Victor Nizet, Katharina Ribbeck

引用次数: 0

It's good to know what to BACE the specificity of your inhibitors on. 知道抑制剂的特异性取决于什么很有好处。

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2024-08-15 DOI: 10.1172/JCI183677

Aoife Murray, Ana Muñiz-García, Ivan Alić, Dean Nižetić

引用次数: 0

CBFA2T3-GLIS2 model of pediatric acute megakaryoblastic leukemia identifies FOLR1 as a CAR T cell target. CBFA2T3-GLIS2小儿急性巨核细胞白血病模型确定FOLR1为CAR T细胞靶点。

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2024-08-15 DOI: 10.1172/JCI184305

Quy Le, Brandon Hadland, Jenny L Smith, Amanda Leonti, Benjamin J Huang, Rhonda Ries, Tiffany A Hylkema, Sommer Castro, Thao T Tang, Cyd N McKay, LaKeisha Perkins, Laura Pardo, Jay Sarthy, Amy K Beckman, Robin Williams, Rhonda Idemmili, Scott Furlan, Takashi Ishida, Lindsey Call, Shivani Srivastava, Anisha M Loeb, Filippo Milano, Suzan Imren, Shelli M Morris, Fiona Pakiam, Jim M Olson, Michael R Loken, Lisa Brodersen, Stanley R Riddell, Katherine Tarlock, Irwin D Bernstein, Keith R Loeb, Soheil Meshinchi

引用次数: 0

Improving radiotherapy in immunosuppressive microenvironments by targeting complement receptor C5aR1. 通过靶向补体受体 C5aR1 改善免疫抑制微环境中的放射治疗。

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2024-08-15 DOI: 10.1172/JCI185067

Callum Beach, David MacLean, Dominika Majorova, Stavros Melemenidis, Dhanya K Nambiar, Ryan K Kim, Gabriel N Valbuena, Silvia Guglietta, Carsten Krieg, Mahnaz Darvish-Damavandi, Tatsuya Suwa, Alistair Easton, Lily Vs Hillson, Ashley K McCulloch, Ross K McMahon, Kathryn Pennel, Joanne Edwards, Sean M O'Cathail, Campbell S Roxburgh, Enric Domingo, Eui Jung Moon, Dadi Jiang, Yanyan Jiang, Qingyang Zhang, Albert C Koong, Trent M Woodruff, Edward E Graves, Tim Maughan, Simon Ja Buczacki, Manuel Stucki, Quynh-Thu Le, Simon J Leedham, Amato J Giaccia, Monica M Olcina

引用次数: 0

Posttranslationally modified self-peptides promote hypertension in mouse models. 翻译后修饰的自身肽可促进小鼠模型中的高血压。

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2024-08-15 DOI: 10.1172/JCI174374

Nathaniel Bloodworth, Wei Chen, Kuniko Hunter, David Patrick, Amy Palubinsky, Elizabeth Phillips, Daniel Roeth, Markus Kalkum, Simon Mallal, Sean Davies, Mingfang Ao, Rocco Moretti, Jens Meiler, David G Harrison

{"title":"Posttranslationally modified self-peptides promote hypertension in mouse models.","authors":"Nathaniel Bloodworth, Wei Chen, Kuniko Hunter, David Patrick, Amy Palubinsky, Elizabeth Phillips, Daniel Roeth, Markus Kalkum, Simon Mallal, Sean Davies, Mingfang Ao, Rocco Moretti, Jens Meiler, David G Harrison","doi":"10.1172/JCI174374","DOIUrl":"10.1172/JCI174374","url":null,"abstract":"Posttranslational modifications can enhance immunogenicity of self-proteins. In several conditions, including hypertension, systemic lupus erythematosus, and heart failure, isolevuglandins (IsoLGs) are formed by lipid peroxidation and covalently bond with protein lysine residues. Here, we show that the murine class I major histocompatibility complex (MHC-I) variant H-2Db uniquely presents isoLG-modified peptides and developed a computational pipeline that identifies structural features for MHC-I accommodation of such peptides. We identified isoLG-adducted peptides from renal proteins, including sodium glucose transporter 2, cadherin 16, Kelch domain-containing protein 7A, and solute carrier family 23, that are recognized by CD8+ T cells in tissues of hypertensive mice, induce T cell proliferation in vitro, and prime hypertension after adoptive transfer. Finally, we find patterns of isoLG-adducted antigen restriction in class I human leukocyte antigens that are similar to those in murine analogs. Thus, we have used a combined computational and experimental approach to define likely antigenic peptides in hypertension.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":null,"pages":null},"PeriodicalIF":13.3,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11324298/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141982446","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Decoding the decline: unveiling drivers of sarcopenia. 解码衰退：揭示肌肉疏松症的驱动因素。

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2024-08-15 DOI: 10.1172/JCI183302

Allison M Owen, Christopher S Fry

引用次数: 0

MNK-driven eIF4E phosphorylation regulates the fibrogenic transformation of mesenchymal cells and chronic lung allograft dysfunction. MNK 驱动的 eIF4E 磷酸化调控间充质细胞的纤维化转化和慢性肺移植功能障碍。

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2024-08-15 DOI: 10.1172/JCI168393

Natalie M Walker, Yuta Ibuki, A Patrick McLinden, Keizo Misumi, Dylan C Mitchell, Gabriel G Kleer, Alison M Lock, Ragini Vittal, Nahum Sonenberg, Amanda L Garner, Vibha N Lama

{"title":"MNK-driven eIF4E phosphorylation regulates the fibrogenic transformation of mesenchymal cells and chronic lung allograft dysfunction.","authors":"Natalie M Walker, Yuta Ibuki, A Patrick McLinden, Keizo Misumi, Dylan C Mitchell, Gabriel G Kleer, Alison M Lock, Ragini Vittal, Nahum Sonenberg, Amanda L Garner, Vibha N Lama","doi":"10.1172/JCI168393","DOIUrl":"10.1172/JCI168393","url":null,"abstract":"Tissue fibrosis remains unamenable to meaningful therapeutic interventions and is the primary cause of chronic graft failure after organ transplantation. Eukaryotic translation initiation factor (eIF4E), a key translational regulator, serves as convergent target of multiple upstream profibrotic signaling pathways that contribute to mesenchymal cell (MC) activation. Here, we investigate the role of MAP kinase-interacting serine/threonine kinase-induced (MNK-induced) direct phosphorylation of eIF4E at serine 209 (Ser209) in maintaining fibrotic transformation of MCs and determine the contribution of the MNK/eIF4E pathway to the pathogenesis of chronic lung allograft dysfunction (CLAD). MCs from patients with CLAD demonstrated constitutively higher eIF4E phosphorylation at Ser209, and eIF4E phospho-Ser209 was found to be critical in regulating key fibrogenic protein autotaxin, leading to sustained β-catenin activation and profibrotic functions of CLAD MCs. MNK1 signaling was upregulated in CLAD MCs, and genetic or pharmacologic targeting of MNK1 activity inhibited eIF4E phospho-Ser209 and profibrotic functions of CLAD MCs in vitro. Treatment with an MNK1/2 inhibitor (eFT-508) abrogated allograft fibrosis in an orthotopic murine lung-transplant model. Together these studies identify what we believe is a previously unrecognized MNK/eIF4E/ATX/β-catenin signaling pathway of fibrotic transformation of MCs and present the first evidence, to our knowledge, for the utility of MNK inhibitors in fibrosis.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":null,"pages":null},"PeriodicalIF":13.3,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11324311/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141982444","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Rare genetic variants provide a mechanistic basis for immune imbalance in IgG4-related disease. 罕见基因变异为 IgG4 相关疾病的免疫失衡提供了机理基础。

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2024-08-15 DOI: 10.1172/JCI183396

Dominic J Ciavatta

引用次数: 0

Stress and substance use disorders: risk, relapse, and treatment outcomes. 压力与药物使用障碍：风险、复发和治疗结果。

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2024-08-15 DOI: 10.1172/JCI172883

Rajita Sinha

{"title":"Stress and substance use disorders: risk, relapse, and treatment outcomes.","authors":"Rajita Sinha","doi":"10.1172/JCI172883","DOIUrl":"10.1172/JCI172883","url":null,"abstract":"Stress has long been associated with substance misuse and substance use disorders (SUDs). The past two decades have seen a surge in research aimed at understanding the underlying mechanisms driving this association. This Review introduces a multilevel \"adaptive stress response\" framework, encompassing a stress baseline, acute reaction, and recovery with return-to-homeostasis phase that occurs at varying response times and across domains of analysis. It also discusses evidence showing the disruption of this adaptive stress response in the context of chronic and repeated stressors, trauma, adverse social and drug-related environments, as well as with acute and chronic drug misuse and with drug withdrawal and abstinence sequelae. Subjective, cognitive, peripheral, and neurobiological disruptions in the adaptive stress response phases and their link to inflexible, maladaptive coping; increased craving; relapse risk; and maintenance of drug intake are also presented. Finally, the prevention and treatment implications of targeting this \"stress pathophysiology of addiction\" are discussed, along with specific aspects that may be targeted in intervention development to rescue stress-related alterations in drug motivation and to improve SUD treatment outcomes.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":null,"pages":null},"PeriodicalIF":13.3,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11324296/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141982449","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Modulation of NOX2 causes obesity-mediated atrial fibrillation. 调节 NOX2 会导致肥胖介导的心房颤动。

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2024-08-15 DOI: 10.1172/JCI175447

Arvind Sridhar, Jaime DeSantiago, Hanna Chen, Mahmud Arif Pavel, Olivia Ly, Asia Owais, Miles Barney, Jordan Jousma, Sarath Babu Nukala, Khaled Abdelhady, Malek Massad, Lona Ernst Rizkallah, Sang-Ging Ong, Jalees Rehman, Dawood Darbar

{"title":"Modulation of NOX2 causes obesity-mediated atrial fibrillation.","authors":"Arvind Sridhar, Jaime DeSantiago, Hanna Chen, Mahmud Arif Pavel, Olivia Ly, Asia Owais, Miles Barney, Jordan Jousma, Sarath Babu Nukala, Khaled Abdelhady, Malek Massad, Lona Ernst Rizkallah, Sang-Ging Ong, Jalees Rehman, Dawood Darbar","doi":"10.1172/JCI175447","DOIUrl":"10.1172/JCI175447","url":null,"abstract":"Obesity is linked to an increased risk of atrial fibrillation (AF) via increased oxidative stress. While NADPH oxidase 2 (NOX2), a major source of oxidative stress and reactive oxygen species (ROS) in the heart, predisposes to AF, the underlying mechanisms remain unclear. Here, we studied NOX2-mediated ROS production in obesity-mediated AF using Nox2-knockout mice and mature human induced pluripotent stem cell-derived atrial cardiomyocytes (hiPSC-aCMs). Diet-induced obesity (DIO) mice and hiPSC-aCMs treated with palmitic acid (PA) were infused with a NOX blocker (apocynin) and a NOX2-specific inhibitor, respectively. We showed that NOX2 inhibition normalized atrial action potential duration and abrogated obesity-mediated ion channel remodeling with reduced AF burden. Unbiased transcriptomics analysis revealed that NOX2 mediates atrial remodeling in obesity-mediated AF in DIO mice, PA-treated hiPSC-aCMs, and human atrial tissue from obese individuals by upregulation of paired-like homeodomain transcription factor 2 (PITX2). Furthermore, hiPSC-aCMs treated with hydrogen peroxide, a NOX2 surrogate, displayed increased PITX2 expression, establishing a mechanistic link between increased NOX2-mediated ROS production and modulation of PITX2. Our findings offer insights into possible mechanisms through which obesity triggers AF and support NOX2 inhibition as a potential novel prophylactic or adjunctive therapy for patients with obesity-mediated AF.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":null,"pages":null},"PeriodicalIF":13.3,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11405042/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141988094","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0