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Genetics of hemostasis: from bedside to bench and back again. 止血遗传学：从床边到工作台，再从工作台到床边。
IF 13.3 1区 医学
Journal of Clinical Investigation Pub Date : 2024-11-15 DOI: 10.1172/JCI183500
David Ginsburg
{"title":"Genetics of hemostasis: from bedside to bench and back again.","authors":"David Ginsburg","doi":"10.1172/JCI183500","DOIUrl":"10.1172/JCI183500","url":null,"abstract":"","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"134 22","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11563663/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638910","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
Super chickens, givers, and collective intelligence: the importance of collaboration, teamwork, and mentorship in science. 超级鸡、奉献者和集体智慧：科学中合作、团队和导师的重要性。
IF 13.3 1区 医学
Journal of Clinical Investigation Pub Date : 2024-11-15 DOI: 10.1172/JCI187403
Benjamin D Humphreys
{"title":"Super chickens, givers, and collective intelligence: the importance of collaboration, teamwork, and mentorship in science.","authors":"Benjamin D Humphreys","doi":"10.1172/JCI187403","DOIUrl":"10.1172/JCI187403","url":null,"abstract":"","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"134 22","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11563665/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638945","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
Parkin paves the path to antitumor immunity: Expanding Parkin's role as a tumor suppressor. Parkin为抗肿瘤免疫铺平了道路：拓展Parkin作为肿瘤抑制因子的作用
IF 13.3 1区 医学
Journal of Clinical Investigation Pub Date : 2024-11-15 DOI: 10.1172/JCI185838
Hyungsoo Kim, Ze'ev A Ronai
{"title":"Parkin paves the path to antitumor immunity: Expanding Parkin's role as a tumor suppressor.","authors":"Hyungsoo Kim, Ze'ev A Ronai","doi":"10.1172/JCI185838","DOIUrl":"10.1172/JCI185838","url":null,"abstract":"<p><p>Parkin, a ring-between-ring-type E3 ubiquitin ligase, first shown to play a critical role in autosomal recessive juvenile Parkinsonism, has recently emerged as a key player in cancer biology. Parkin is now known to serve as a tumor suppressor, and its deregulation frequently promotes tumorigenesis. In this issue of the JCI, Perego et al. expand that role by showing that Parkin expression stimulated an interferon (IFN) response to modulate CD8+ T cell activity. These findings suggest that, in addition to directly inhibiting tumor progression, Parkin enhances antitumor immune responses, highlighting it as a promising therapeutic target for cancer treatment.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"134 22","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11563666/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638940","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
Cell-cycle machinery is critical in regulating uterine steroid hormone for embryo implantation and development. 细胞周期机制是调节子宫类固醇激素以促进胚胎植入和发育的关键。
IF 13.3 1区 医学
Journal of Clinical Investigation Pub Date : 2024-11-15 DOI: 10.1172/JCI186194
Francesco J DeMayo
{"title":"Cell-cycle machinery is critical in regulating uterine steroid hormone for embryo implantation and development.","authors":"Francesco J DeMayo","doi":"10.1172/JCI186194","DOIUrl":"10.1172/JCI186194","url":null,"abstract":"<p><p>Proper embryo implantation is necessary for a successful pregnancy. In this issue of the JCI, Aljubran et al. identified the cell cycle regulatory protein cyclin A2 (CCNA2) as a factor in supporting embryo implantation and embryo development. Endometrial stromal cells showed higher levels of CCNA2 in patients undergoing assisted reproductive technology who had successful pregnancies. CCNA2 expression correlated with stromal cell proliferation and the expression of steroid hormone receptors for estrogen (ESR1, also known as ERα) and progesterone (PGR). Notably, loss of Ccna2 in mouse models resulted in infertility. The uteri of these mice were hypoplastic with reduced estrogen sensitivity, resulting in the disruption of stroma cell decidualization and loss of embryo viability after implantation. These findings demonstrate the importance of stroma cell proliferation in preparing the uterus for embryo implantation. They also identify CCNA2 as a coregulator of steroid hormone receptor signaling and suggest that impaired uterine stroma can underly early pregnancy loss.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"134 22","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11563671/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638901","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
Defects in meiosis I contribute to the genesis of androgenetic hydatidiform moles. 减数分裂 I 的缺陷是雄激素性水滴形痣的成因之一。
IF 13.3 1区 医学
Journal of Clinical Investigation Pub Date : 2024-11-15 DOI: 10.1172/JCI170669
Maryam Rezaei, Manqi Liang, Zeynep Yalcin, Jacinta H Martin, Parinaz Kazemi, Eric Bareke, Zhao-Jia Ge, Majid Fardaei, Claudio Benadiva, Reda Hemida, Adnan Hassan, Geoffrey J Maher, Ebtesam Abdalla, William Buckett, Pierre-Adrien Bolze, Iqbaljit Sandhu, Onur Duman, Suraksha Agrawal, JianHua Qian, Jalal Vallian Broojeni, Lavi Bhati, Pierre Miron, Fabienne Allias, Amal Selim, Rosemary A Fisher, Michael J Seckl, Philippe Sauthier, Isabelle Touitou, Seang Lin Tan, Jacek Majewski, Teruko Taketo, Rima Slim
{"title":"Defects in meiosis I contribute to the genesis of androgenetic hydatidiform moles.","authors":"Maryam Rezaei, Manqi Liang, Zeynep Yalcin, Jacinta H Martin, Parinaz Kazemi, Eric Bareke, Zhao-Jia Ge, Majid Fardaei, Claudio Benadiva, Reda Hemida, Adnan Hassan, Geoffrey J Maher, Ebtesam Abdalla, William Buckett, Pierre-Adrien Bolze, Iqbaljit Sandhu, Onur Duman, Suraksha Agrawal, JianHua Qian, Jalal Vallian Broojeni, Lavi Bhati, Pierre Miron, Fabienne Allias, Amal Selim, Rosemary A Fisher, Michael J Seckl, Philippe Sauthier, Isabelle Touitou, Seang Lin Tan, Jacek Majewski, Teruko Taketo, Rima Slim","doi":"10.1172/JCI170669","DOIUrl":"10.1172/JCI170669","url":null,"abstract":"<p><p>To identify novel genes responsible for recurrent hydatidiform moles (HMs), we performed exome sequencing on 75 unrelated patients who were negative for mutations in the known genes. We identified biallelic deleterious variants in 6 genes, FOXL2, MAJIN, KASH5, SYCP2, MEIOB, and HFM1, in patients with androgenetic HMs, including a familial case of 3 affected members. Five of these genes are essential for meiosis I, and their deficiencies lead to premature ovarian insufficiency. Advanced maternal age is the strongest risk factor for sporadic androgenetic HM, which affects 1 in every 600 pregnancies. We studied Hfm1-/- female mice and found that these mice lost all their oocytes before puberty but retained some at younger ages. Oocytes from Hfm1-/- mice initiated meiotic maturation and extruded the first polar bodies in culture; however, their meiotic spindles were often positioned parallel, instead of perpendicular, to the ooplasmic membrane at telophase I, and some oocytes extruded the entire spindle with all the chromosomes into the polar bodies at metaphase II, a mechanism we previously reported in Mei1-/- oocytes. The occurrence of a common mechanism in two mouse models argues in favor of its plausibility at the origin of androgenetic HM formation in humans.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"134 22","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11563684/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638907","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
MGA loss-of-function variants cause premature ovarian insufficiency. MGA 功能缺失变体会导致卵巢早衰。
IF 13.3 1区 医学
Journal of Clinical Investigation Pub Date : 2024-11-15 DOI: 10.1172/JCI183758
Shuyan Tang, Ting Guo, Chengcheng Song, Lingbo Wang, Jun Zhang, Aleksandar Rajkovic, Xiaoqi Lin, Shiling Chen, Yujun Liu, Weidong Tian, Bangguo Wu, Shixuan Wang, Wenwen Wang, Yunhui Lai, Ao Wang, Shuhua Xu, Li Jin, Hanni Ke, Shidou Zhao, Yan Li, Yingying Qin, Feng Zhang, Zi-Jiang Chen
{"title":"MGA loss-of-function variants cause premature ovarian insufficiency.","authors":"Shuyan Tang, Ting Guo, Chengcheng Song, Lingbo Wang, Jun Zhang, Aleksandar Rajkovic, Xiaoqi Lin, Shiling Chen, Yujun Liu, Weidong Tian, Bangguo Wu, Shixuan Wang, Wenwen Wang, Yunhui Lai, Ao Wang, Shuhua Xu, Li Jin, Hanni Ke, Shidou Zhao, Yan Li, Yingying Qin, Feng Zhang, Zi-Jiang Chen","doi":"10.1172/JCI183758","DOIUrl":"10.1172/JCI183758","url":null,"abstract":"<p><p>Although premature ovarian insufficiency (POI), a common cause of female infertility and subfertility, has a well-established hereditary component, the genetic factors currently implicated in POI account for only a limited proportion of cases. Here, using an exome-wide, gene-based case-control analysis in a discovery cohort comprising 1,027 POI cases and 2,733 ethnically matched women controls from China, we found that heterozygous loss-of-function (LoF) variants of MAX dimerization protein (MGA) were significantly enriched in the discovery cohort, accounting for 2.6% of POI cases, while no MGA LoF variants were found in the matched control females. Further exome screening was conducted in 4 additional POI cohorts (2 from China and 2 from the United States) for replication studies, and we identified heterozygous MGA LoF variants in 1.0%, 1.4%, 1.0%, and 1.0% of POI cases, respectively. Overall, a total of 37 distinct heterozygous MGA LoF variants were discovered in 38 POI cases, accounting for approximately 2.0% of the total 1,910 POI cases analyzed in this study. Accordingly, Mga+/- female mice were subfertile, exhibiting shorter reproductive lifespan and decreased follicle number compared with WT, mimicking the observed phenotype in humans. Our findings highlight the essential role of MGA deficiency for impaired female reproductive ability.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"134 22","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11563689/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638925","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
Xylazine induces dopamine release and augments the effects of fentanyl. 赛拉嗪可诱导多巴胺释放，并增强芬太尼的作用。
IF 13.3 1区 医学
Journal of Clinical Investigation Pub Date : 2024-11-15 DOI: 10.1172/JCI183354
Joseph R Trinko, Ethan Foscue, Edward M Kong, Aakash Basu, Anouk M Corstens, Summer L Thompson, Alfred P Kaye, Jane R Taylor, Ralph J DiLeone
{"title":"Xylazine induces dopamine release and augments the effects of fentanyl.","authors":"Joseph R Trinko, Ethan Foscue, Edward M Kong, Aakash Basu, Anouk M Corstens, Summer L Thompson, Alfred P Kaye, Jane R Taylor, Ralph J DiLeone","doi":"10.1172/JCI183354","DOIUrl":"10.1172/JCI183354","url":null,"abstract":"","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"134 22","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11563672/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638973","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
It takes a village. 这需要一个村庄。
IF 13.3 1区 医学
Journal of Clinical Investigation Pub Date : 2024-11-15 DOI: 10.1172/JCI188177
Alex D Waldman
{"title":"It takes a village.","authors":"Alex D Waldman","doi":"10.1172/JCI188177","DOIUrl":"10.1172/JCI188177","url":null,"abstract":"","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"134 22","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11563686/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638919","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
Single-nuclei transcriptomics reveals TBX5-dependent targets in a patient with Holt-Oram syndrome. 单核转录组学揭示了一名霍尔特-奥拉姆综合征患者的 TBX5 依赖性靶点。
IF 13.3 1区 医学
Journal of Clinical Investigation Pub Date : 2024-11-14 DOI: 10.1172/JCI180670
Jeffrey D Steimle, Yi Zhao, Fansen Meng, Mikaela E Taylor, Diwakar Turaga, Iki Adachi, Xiao Li, James F Martin
{"title":"Single-nuclei transcriptomics reveals TBX5-dependent targets in a patient with Holt-Oram syndrome.","authors":"Jeffrey D Steimle, Yi Zhao, Fansen Meng, Mikaela E Taylor, Diwakar Turaga, Iki Adachi, Xiao Li, James F Martin","doi":"10.1172/JCI180670","DOIUrl":"https://doi.org/10.1172/JCI180670","url":null,"abstract":"","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142621123","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
Rapid response of lichen planus to baricitinib associated with suppression of cytotoxic CXCL13+ CD8+ T-cells. 扁平苔藓对巴利替尼的快速反应与细胞毒性 CXCL13+ CD8+ T 细胞的抑制有关。
IF 13.3 1区 医学
Journal of Clinical Investigation Pub Date : 2024-11-14 DOI: 10.1172/JCI179436
Angelina S Hwang, Jacob A Kechter, Tran H Do, Alysia N Hughes, Nan Zhang, Xing Li, Rachael Bogle, Caitlin M Brumfiel, Meera H Patel, Blake Boudreaux, Puneet Bhullar, Shams Nassir, Miranda L Yousif, Alyssa L Stockard, Zachary Leibovit-Reiben, Ewoma Ogbaudu, David J DiCaudo, Jennifer Fox, Mehrnaz Gharaee-Kermani, Xianying Xing, Samantha Zunich, Emily Branch, J Michelle Kahlenberg, Allison C Billi, Olesya Plazyo, Lam C Tsoi, Mark R Pittelkow, Johann E Gudjonsson, Aaron R Mangold
{"title":"Rapid response of lichen planus to baricitinib associated with suppression of cytotoxic CXCL13+ CD8+ T-cells.","authors":"Angelina S Hwang, Jacob A Kechter, Tran H Do, Alysia N Hughes, Nan Zhang, Xing Li, Rachael Bogle, Caitlin M Brumfiel, Meera H Patel, Blake Boudreaux, Puneet Bhullar, Shams Nassir, Miranda L Yousif, Alyssa L Stockard, Zachary Leibovit-Reiben, Ewoma Ogbaudu, David J DiCaudo, Jennifer Fox, Mehrnaz Gharaee-Kermani, Xianying Xing, Samantha Zunich, Emily Branch, J Michelle Kahlenberg, Allison C Billi, Olesya Plazyo, Lam C Tsoi, Mark R Pittelkow, Johann E Gudjonsson, Aaron R Mangold","doi":"10.1172/JCI179436","DOIUrl":"https://doi.org/10.1172/JCI179436","url":null,"abstract":"<p><strong>Background: </strong>Cutaneous lichen planus (LP) is a recalcitrant, difficult-to-treat, inflammatory skin disease characterized by pruritic, flat-topped, violaceous papules on the skin. Baricitinib is an oral Janus kinase (JAK) 1/2 inhibitor that interrupts the signaling pathway of interferon gamma (IFN)-γ, a cytokine implicated in the pathogenesis of LP.</p><p><strong>Methods: </strong>In this phase II trial, twelve patients with cutaneous LP received baricitinib 2 mg daily for 16 weeks, accompanied by in-depth spatial, single-cell, and bulk transcriptomic profiling of pre- and post-treatment samples.</p><p><strong>Results: </strong>An early and sustained clinical response was seen, with 83.3% of patients responsive at week 16. Our molecular data identified a unique, oligoclonal IFN-γ, CD8+, CXCL13+ cytotoxic T-cell population in LP skin and demonstrated a rapid decrease in IFN signature within 2 weeks of treatment, most prominently in the basal layer of the epidermis.</p><p><strong>Conclusion: </strong>This study demonstrates the efficacy and molecular mechanisms of JAK inhibition in LP.</p><p><strong>Trial registration: </strong>NCT05188521.ROLE OF FUNDING SOURCE. Eli Lilly, Appignani Benefactor Funds, 5P30AR075043, Mayo Clinic Clinical Trials Stimulus Funds.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142621108","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
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