Journal of Clinical Investigation最新文献_第5页

Endothelial YAP/TAZ activation promotes atherosclerosis in a mouse model of Hutchinson-Gilford progeria syndrome. 内皮 YAP/TAZ 激活促进 Hutchinson-Gilford progeria 综合征小鼠模型的动脉粥样硬化。

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2024-10-01 DOI: 10.1172/JCI173448

Ana Barettino, Cristina González-Gómez, Pilar Gonzalo, María J Andrés-Manzano, Carlos R Guerrero, Francisco M Espinosa, Rosa M Carmona, Yaazan Blanco, Beatriz Dorado, Carlos Torroja, Fátima Sánchez-Cabo, Ana Quintas, Alberto Benguría, Ana Dopazo, Ricardo García, Ignacio Benedicto, Vicente Andrés

{"title":"Endothelial YAP/TAZ activation promotes atherosclerosis in a mouse model of Hutchinson-Gilford progeria syndrome.","authors":"Ana Barettino, Cristina González-Gómez, Pilar Gonzalo, María J Andrés-Manzano, Carlos R Guerrero, Francisco M Espinosa, Rosa M Carmona, Yaazan Blanco, Beatriz Dorado, Carlos Torroja, Fátima Sánchez-Cabo, Ana Quintas, Alberto Benguría, Ana Dopazo, Ricardo García, Ignacio Benedicto, Vicente Andrés","doi":"10.1172/JCI173448","DOIUrl":"https://doi.org/10.1172/JCI173448","url":null,"abstract":"Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare disease caused by the expression of progerin, an aberrant protein produced by a point mutation in the LMNA gene. HGPS patients show accelerated aging and die prematurely mainly from complications of atherosclerosis such as myocardial infarction, heart failure, or stroke. However, the mechanisms underlying HGPS vascular pathology remain ill defined. We used single-cell RNA sequencing to characterize the aorta in progerin-expressing LmnaG609G/G609G mice and wild-type controls, with a special focus on endothelial cells (ECs). HGPS ECs showed gene expression changes associated with extracellular matrix alterations, increased leukocyte extravasation, and activation of the yes-associated protein 1/transcriptional activator with PDZ-binding domain (YAP/TAZ) mechanosensing pathway, all validated by different techniques. Atomic force microscopy experiments demonstrated stiffer subendothelial extracellular matrix in progeroid aortas, and ultrasound assessment of live HGPS mice revealed disturbed aortic blood flow, both key inducers of the YAP/TAZ pathway in ECs. YAP/TAZ inhibition with verteporfin reduced leukocyte accumulation in the aortic intimal layer and decreased atherosclerosis burden in progeroid mice. Our findings identify endothelial YAP/TAZ signaling as a key mechanism of HGPS vascular disease and open a new avenue for the development of YAP/TAZ targeting drugs to ameliorate progerin-induced atherosclerosis.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":null,"pages":null},"PeriodicalIF":13.3,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142365424","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Ciliary localization of GPR75 promotes fat accumulation in mice. GPR75 的纤毛定位促进了小鼠的脂肪积累。

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2024-10-01 DOI: 10.1172/JCI185059

Marcelo Chávez, Anushweta Asthana, Peter K Jackson

引用次数: 0

Sleepless nights and social plights: medial septum GABAergic hyperactivity in a neuroligin 3-deficient autism model. 不眠之夜与社交困境：神经胶质蛋白 3 缺陷自闭症模型的内侧隔 GABA 能亢进。

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2024-10-01 DOI: 10.1172/JCI184795

Claire E Cho, Dahee Jung, Reesha R Patel

引用次数: 0

The first century of JCI and beyond. 青年商会的第一个世纪及其后。

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2024-10-01 DOI: 10.1172/JCI186113

Elizabeth M McNally

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2024 Lasker Award Recipient Zhijian Chen elucidates how DNA stimulates immunity. 2024 年拉斯克奖获得者陈志坚阐明了 DNA 如何刺激免疫力。

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2024-09-19 DOI: 10.1172/JCI186104

Amy B Heimberger

引用次数: 0

Joel Habener, Svetlana Mojsov, and Lotte Bjerre Knudsen awarded Lasker prize for pioneering work on GLP-1. Joel Habener、Svetlana Mojsov 和 Lotte Bjerre Knudsen 因在 GLP-1 方面的开创性工作而荣获拉斯克奖。

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2024-09-19 DOI: 10.1172/JCI186225

Hossein Ardehali

引用次数: 0

Connecting the dots: sex, depression, and musculoskeletal health. 连接点：性别、抑郁和肌肉骨骼健康。

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2024-09-17 DOI: 10.1172/JCI180072

Mackenzie Newman, Henry J Donahue, Gretchen N Neigh

{"title":"Connecting the dots: sex, depression, and musculoskeletal health.","authors":"Mackenzie Newman, Henry J Donahue, Gretchen N Neigh","doi":"10.1172/JCI180072","DOIUrl":"https://doi.org/10.1172/JCI180072","url":null,"abstract":"Depression and multiple musculoskeletal disorders are overrepresented in women compared with men. Given that depression is a modifiable risk factor and improvement of depressive symptoms increases positive outcomes following orthopedic intervention, efforts to improve clinical recognition of depressive symptoms and increased action toward ameliorating depressive symptoms among orthopedic patients are positioned to reduce complications and positively affect patient-reported outcomes. Although psychosocial factors play a role in the manifestation and remittance of depression, it is also well appreciated that primary biochemical changes are capable of causing and perpetuating depression. Unique insight for novel treatments of depression may be facilitated by query of the bidirectional relationship between musculoskeletal health and depression. This Review aims to synthesize the diverse literature on sex, depression, and orthopedics and emphasize the potential for common underlying biological substrates. Given the overrepresentation of depression and musculoskeletal disorders among women, increased emphasis on the biological drivers of the co-occurrence of these disorders is positioned to improve women's health.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":null,"pages":null},"PeriodicalIF":13.3,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11405046/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142288343","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

Pericyte phenotype switching alleviates immunosuppression and sensitizes vascularized tumors to immunotherapy in preclinical models. 在临床前模型中，周细胞表型转换可减轻免疫抑制，并使血管化肿瘤对免疫疗法敏感。

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2024-09-17 DOI: 10.1172/JCI179860

Zhi-Jie Li, Bo He, Alice Domenichini, Jiulia Satiaputra, Kira H Wood, Devina D Lakhiani, Abate A Bashaw, Lisa M Nilsson, Ji Li, Edward R Bastow, Anna Johansson-Percival, Elena Denisenko, Alistair Rr Forrest, Suraj Sakaram, Rafael Carretero, Günter J Hämmerling, Jonas A Nilsson, Gabriel Yf Lee, Ruth Ganss

{"title":"Pericyte phenotype switching alleviates immunosuppression and sensitizes vascularized tumors to immunotherapy in preclinical models.","authors":"Zhi-Jie Li, Bo He, Alice Domenichini, Jiulia Satiaputra, Kira H Wood, Devina D Lakhiani, Abate A Bashaw, Lisa M Nilsson, Ji Li, Edward R Bastow, Anna Johansson-Percival, Elena Denisenko, Alistair Rr Forrest, Suraj Sakaram, Rafael Carretero, Günter J Hämmerling, Jonas A Nilsson, Gabriel Yf Lee, Ruth Ganss","doi":"10.1172/JCI179860","DOIUrl":"https://doi.org/10.1172/JCI179860","url":null,"abstract":"T cell-based immunotherapies are a promising therapeutic approach for multiple malignancies, but their efficacy is limited by tumor hypoxia arising from dysfunctional blood vessels. Here, we report that cell-intrinsic properties of a single vascular component, namely the pericyte, contribute to the control of tumor oxygenation, macrophage polarization, vessel inflammation, and T cell infiltration. Switching pericyte phenotype from a synthetic to a differentiated state reverses immune suppression and sensitizes tumors to adoptive T cell therapy, leading to regression of melanoma in mice. In melanoma patients, improved survival is correlated with enhanced pericyte maturity. Importantly, pericyte plasticity is regulated by signaling pathways converging on Rho kinase activity, with pericyte maturity being inducible by selective low-dose therapeutics that suppress pericyte MEK, AKT, or notch signaling. We also show that low-dose targeted anticancer therapy can durably change the tumor microenvironment without inducing adaptive resistance, creating a highly translatable pathway for redosing anticancer targeted therapies in combination with immunotherapy to improve outcome.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":null,"pages":null},"PeriodicalIF":13.3,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11405053/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142288356","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

Mechanisms underlying sex differences in autoimmunity. 自身免疫性别差异的内在机制

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2024-09-17 DOI: 10.1172/JCI180076

DeLisa Fairweather, Danielle J Beetler, Elizabeth J McCabe, Scott M Lieberman

引用次数: 0

SARS-CoV-2 Delta and Omicron variants resist spike cleavage by human airway trypsin-like protease. SARS-CoV-2 Delta 和 Omicron 变体可抵抗人类气道胰蛋白酶样蛋白酶的尖峰切割。

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2024-09-17 DOI: 10.1172/JCI174304

Wenyan Ren, Weiqi Hong, Jingyun Yang, Jun Zou, Li Chen, Yanan Zhou, Hong Lei, Aqu Alu, Haiying Que, Yanqiu Gong, Zhenfei Bi, Cai He, Minyang Fu, Dandan Peng, Yun Yang, Wenhai Yu, Cong Tang, Qing Huang, Mengli Yang, Bai Li, Jingmei Li, Junbin Wang, Xuelei Ma, Hongbo Hu, Wei Cheng, Haohao Dong, Jian Lei, Lu Chen, Xikun Zhou, Jiong Li, Wei Wang, Guangwen Lu, Guobo Shen, Li Yang, Jinliang Yang, Zhenling Wang, Guowen Jia, Zhaoming Su, Bin Shao, Hanpei Miao, Johnson Yiu-Nam Lau, Yuquan Wei, Kang Zhang, Lunzhi Dai, Shuaiyao Lu, Xiawei Wei

{"title":"SARS-CoV-2 Delta and Omicron variants resist spike cleavage by human airway trypsin-like protease.","authors":"Wenyan Ren, Weiqi Hong, Jingyun Yang, Jun Zou, Li Chen, Yanan Zhou, Hong Lei, Aqu Alu, Haiying Que, Yanqiu Gong, Zhenfei Bi, Cai He, Minyang Fu, Dandan Peng, Yun Yang, Wenhai Yu, Cong Tang, Qing Huang, Mengli Yang, Bai Li, Jingmei Li, Junbin Wang, Xuelei Ma, Hongbo Hu, Wei Cheng, Haohao Dong, Jian Lei, Lu Chen, Xikun Zhou, Jiong Li, Wei Wang, Guangwen Lu, Guobo Shen, Li Yang, Jinliang Yang, Zhenling Wang, Guowen Jia, Zhaoming Su, Bin Shao, Hanpei Miao, Johnson Yiu-Nam Lau, Yuquan Wei, Kang Zhang, Lunzhi Dai, Shuaiyao Lu, Xiawei Wei","doi":"10.1172/JCI174304","DOIUrl":"https://doi.org/10.1172/JCI174304","url":null,"abstract":"Soluble host factors in the upper respiratory tract can serve as the first line of defense against SARS-CoV-2 infection. In this study, we described the identification and function of a human airway trypsin-like protease (HAT), capable of reducing the infectivity of ancestral SARS-CoV-2. Further, in mouse models, HAT analogue expression was upregulated by SARS-CoV-2 infection. The antiviral activity of HAT functioned through the cleavage of the SARS-CoV-2 spike glycoprotein at R682. This cleavage resulted in inhibition of the attachment of ancestral spike proteins to host cells, which inhibited the cell-cell membrane fusion process. Importantly, exogenous addition of HAT notably reduced the infectivity of ancestral SARS-CoV-2 in vivo. However, HAT was ineffective against the Delta variant and most circulating Omicron variants, including the BQ.1.1 and XBB.1.5 subvariants. We demonstrate that the P681R mutation in Delta and P681H mutation in the Omicron variants, adjacent to the R682 cleavage site, contributed to HAT resistance. Our study reports what we believe to be a novel soluble defense factor against SARS-CoV-2 and resistance of its actions in the Delta and Omicron variants.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":null,"pages":null},"PeriodicalIF":13.3,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11405045/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142288359","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