JCI insight最新文献_第9页

D801N in ATP1A3-encoded Na/K-ATPase alpha 3 causes cardiac arrhythmogenesis through sodium-calcium exchanger-mediated calcium overload. atp1a3编码Na/ k - atp酶α 3中的D801N通过钠钙交换器介导的钙超载导致心律失常。

IF 6.1 1区医学

JCI insight Pub Date : 2026-04-08 DOI: 10.1172/jci.insight.197721

Minu-Tshyeto K Bidzimou, Padmapriya Muralidharan, Zhushan Zhang, Danyal Raza, Daniel Needs, Bo Sun, Robin M Perelli, Mary E Moya-Mendez, P K Rakesh Manivannan, Arsen S Hunanyan, Abbigail Helfer, Christine Q Simmons, Alfred L George, Donald M Bers, Nenad Bursac, Mohamad A Mikati, Andrew P Landstrom

{"title":"D801N in ATP1A3-encoded Na/K-ATPase alpha 3 causes cardiac arrhythmogenesis through sodium-calcium exchanger-mediated calcium overload.","authors":"Minu-Tshyeto K Bidzimou, Padmapriya Muralidharan, Zhushan Zhang, Danyal Raza, Daniel Needs, Bo Sun, Robin M Perelli, Mary E Moya-Mendez, P K Rakesh Manivannan, Arsen S Hunanyan, Abbigail Helfer, Christine Q Simmons, Alfred L George, Donald M Bers, Nenad Bursac, Mohamad A Mikati, Andrew P Landstrom","doi":"10.1172/jci.insight.197721","DOIUrl":"10.1172/jci.insight.197721","url":null,"abstract":"Short QT syndrome is a heritable arrhythmia disorder linked to sudden cardiac death. We recently identified that individuals with alternating hemiplegia of childhood (AHC), a rare neurodevelopmental disorder, can exhibit shortened corrected QT intervals and elevated risk for ventricular fibrillation. This is especially true for patients with AHC heterozygous for the recurrent ATP1A3-D801N variant, though the underlying cardiac mechanism remains unclear. We hypothesized that the D801N missense impairs Na+/K+-ATPase function, causing Ca2+ overload, shortened action potential duration (APD), and arrhythmias. Using in silico modeling and patient-derived induced pluripotent stem cell cardiomyocytes (iPSC-CMsD801N), we observed shorter APD, elevated intracellular and sarcoplasmic reticulum Ca2+ levels, and delayed afterdepolarizations (DADs) compared with WT. Additionally, increased Ca²+ influx via the Na+/Ca2+ exchanger (NCX1) during depolarization was observed in iPSC-CMsD801N. Simulations and in vitro experiments suggest that reduced ATPase function accelerated inactivation of L-type Ca2+ channels. Pharmacologic inhibition of NCX1 with ORM-10103 normalized APD and reduced DADs. These findings support a Ca2+-mediated mechanism for arrhythmogenesis in ATP1A3-D801N carriers and identify NCX1 as a potential therapeutic target.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"11 7","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13134723/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147633525","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

Impact of a factor Xa inhibitor (apixaban) on SIV pathogenesis and response to antiretroviral therapy. Xa因子抑制剂（阿哌沙班）对SIV发病机制和抗逆转录病毒治疗反应的影响。

IF 6.1 1区医学

JCI insight Pub Date : 2026-04-08 DOI: 10.1172/jci.insight.202434

Cuiling Xu, Haritha Annapureddy, Lilly Carson, Vansh Khurana, Ranjit Sivanandham, Sindhuja Sivanandham, Tianyu He, Kevin D Raehtz, Janet Kim, Christie Biber, Norma Arbujas-Silva, Mohammed Daira, Sudhapriya Kandasamy, Matthew J Feinstein, Irini Sereti, Cristian Apetrei, Ivona Pandrea

{"title":"Impact of a factor Xa inhibitor (apixaban) on SIV pathogenesis and response to antiretroviral therapy.","authors":"Cuiling Xu, Haritha Annapureddy, Lilly Carson, Vansh Khurana, Ranjit Sivanandham, Sindhuja Sivanandham, Tianyu He, Kevin D Raehtz, Janet Kim, Christie Biber, Norma Arbujas-Silva, Mohammed Daira, Sudhapriya Kandasamy, Matthew J Feinstein, Irini Sereti, Cristian Apetrei, Ivona Pandrea","doi":"10.1172/jci.insight.202434","DOIUrl":"10.1172/jci.insight.202434","url":null,"abstract":"Antiretroviral therapy (ART) has prolonged the life expectancy of persons living with HIV, the majority of whom are now older than 50 years. Aging people with HIV are at increased risk for cardiovascular events driven by HIV-related inflammation and hypercoagulation. Apixaban is a factor Xa inhibitor that reduces cardiovascular risks and treats stroke, deep vein thrombosis, and pulmonary embolism. We assessed apixaban's impact on key parameters of HIV/SIV pathogenesis in SIV-infected, aged rhesus macaques (RMs) receiving ART. Inflammation, coagulation, T cell subsets, B cells, and macrophages and their immune activation status were monitored throughout the study. We found no significant differences between the apixaban-treated and control groups for virus replication or CD4+ T cell recovery in blood and tissues after ART. Apixaban did not significantly affect D-dimer, immune activation, or inflammation of SIV-infected, ART-treated RMs. Apixaban-treated RMs experienced multiple bleeding episodes, tissue hemorrhages, and myocardial infarctions, as demonstrated by pathological examination of necropsy-collected tissues. Given apixaban's lack of effect on immune activation, CD4+ T cell restoration, and inflammation, along with increased risk of hemorrhage, factor Xa inhibition may not be an efficient or safe option to target and prevent cardiovascular events in aging people with HIV.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"11 7","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13134728/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147633527","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

Spatially controlled tenascin-C accumulation contributes to inflammatory disease persistence in giant cell aortitis. 空间控制的腱蛋白c积累有助于巨细胞性主动脉炎的炎症性疾病持续存在。

IF 6.1 1区医学

JCI insight Pub Date : 2026-04-08 DOI: 10.1172/jci.insight.200255

Hui Shi, Ying Tang, Jing Li, Ora Gewurz-Singer, Bo Yang, Dogukan Mizrak

{"title":"Spatially controlled tenascin-C accumulation contributes to inflammatory disease persistence in giant cell aortitis.","authors":"Hui Shi, Ying Tang, Jing Li, Ora Gewurz-Singer, Bo Yang, Dogukan Mizrak","doi":"10.1172/jci.insight.200255","DOIUrl":"10.1172/jci.insight.200255","url":null,"abstract":"Giant cell aortitis (GCA) is an inflammatory disease of the aortic wall with a characteristic giant cell pattern on pathology and can lead to life-threatening aortic aneurysm and dissection. Pathogenic GCA mechanisms underlying aortic inflammation and persistence remain elusive. Here, we demonstrate the complexity of medial layer destruction and immune cell infiltration in clinical granulomatous GCA and lymphoplasmacytic IgG4-related aortitis samples using imaging-based gene expression profiling. Single-cell spatial profiling revealed aortic wall remodeling in the GCA aortas, highlighting substantial phenotypic modulation in stromal cells, including vascular smooth muscle cells (SMCs) and fibroblasts. Specifically, we observed the expansion of stromal cells expressing Tenascin-C (TNC) mRNA and spatially refined TNC accumulation in lesion areas. We confirmed these findings histologically using diseased aortas resected from individuals with giant cell arteritis and clinically isolated aortitis. Mechanistically, our data suggest that TNC promotes a proinflammatory phenotype in primary human SMCs, elevating IL-6 levels partially through the TLR4/NF-κB pathway. IL-6 signaling propagates the proinflammatory loop by activating STAT3. Pharmacological blockade of the IL-6 receptor using tocilizumab alleviated the TNC-driven proinflammatory phenotype. We propose that TNC acts as a local catalyst of inflammatory disease persistence mainly via IL-6 signaling activation and offers a potential avenue for sustained disease remission.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"11 7","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13134725/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147633492","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

JAK inhibition may prevent drug hypersensitivity reactions. 抑制JAK可预防药物超敏反应。

IF 6.1 1区医学

JCI insight Pub Date : 2026-04-08 DOI: 10.1172/jci.insight.200914

Xiangmei Hua, Pranali N Shah, Gustavo A Velasquez, Lillian Sidky, George A Romar, Lydia W Boer, Natalie Hickerson, Tracy Qiying Cui, Federico Repetto, Abigail Waldman, Marilyn G Liang, J Paul Marcoux, MacLean Sellars, Victor Barrera, Birgitta Ar Schmidt, Arash Mostaghimi, Ruth K Foreman, Christine G Lian, Sherrie J Divito

引用次数: 0

Increased transvascular retention of atherogenic lipoproteins in type 2 diabetes relates to their enhanced proteoglycan-binding. 2型糖尿病致动脉粥样硬化脂蛋白经血管潴留的增加与它们增强的蛋白聚糖结合有关。

IF 6.1 1区医学

JCI insight Pub Date : 2026-04-07 DOI: 10.1172/jci.insight.177849

Pär Björklund, Jennifer Härdfeldt, Lauri Äikäs, Sara Straniero, Minna Holopainen, Katariina Öörni, Mats J Rudling, Bo Angelin

{"title":"Increased transvascular retention of atherogenic lipoproteins in type 2 diabetes relates to their enhanced proteoglycan-binding.","authors":"Pär Björklund, Jennifer Härdfeldt, Lauri Äikäs, Sara Straniero, Minna Holopainen, Katariina Öörni, Mats J Rudling, Bo Angelin","doi":"10.1172/jci.insight.177849","DOIUrl":"https://doi.org/10.1172/jci.insight.177849","url":null,"abstract":"Subendothelial retention of cholesterol-rich apolipoprotein-B-containing lipoproteins drives atherosclerotic arterial disease. In peripheral interstitial fluid from patients with type 2 diabetes (T2D), levels of such particles have been shown to be paradoxically reduced relative to those in serum, presumably reflecting their increased retention within the arterial wall. To identify possible mechanisms involved in lipoprotein retention in T2D, we obtained serum and skin blister fluid from such patients and matched controls, together with skin biopsies in a subset of individuals. In T2D, smaller LDL and VLDL remnant particles were more prominent in serum, but not in interstitial fluid, reflecting their enhanced vascular entrapment. The interstitial-fluid-to-serum ratio of apolipoprotein-B was 58% lower in T2D than in controls (0.14 vs 0.33), concomitant with increased susceptibility for LDL binding to proteoglycans. The most marked differences were seen in patients with clinically evident cardiovascular disease. The degree of transvascular retention was positively related to the propensity of isolated serum LDL to bind aortic proteoglycans, both in T2D and in controls. Skin unesterified cholesterol levels were higher in T2D patients relative to healthy controls. With aging, both proteoglycan binding and apparent vascular retention of LDL increased in controls, but not in T2D, indicating that these mechanisms may also be relevant for atherogenesis in non-diabetic individuals.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147633404","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

Norepinephrinergic projection from locus coeruleus to parafascicular nucleus promotes pain and anxiety-like behaviors in mice. 从蓝斑到束旁核的去甲肾上腺素能投射促进小鼠疼痛和焦虑样行为。

IF 6.1 1区医学

JCI insight Pub Date : 2026-04-07 DOI: 10.1172/jci.insight.198224

Zhong-Yi Liu, Fei Li, Li-Ming Liu, Yao-Hua Liu, Jia Li, Zi-Ang Li, Jin Cheng, Tian-Yu Zhao, Hui-Min Tian, Dong-Ning Li, Sha-Sha Tao, Hui Li, Fen-Sheng Huang, Yun-Qing Li

{"title":"Norepinephrinergic projection from locus coeruleus to parafascicular nucleus promotes pain and anxiety-like behaviors in mice.","authors":"Zhong-Yi Liu, Fei Li, Li-Ming Liu, Yao-Hua Liu, Jia Li, Zi-Ang Li, Jin Cheng, Tian-Yu Zhao, Hui-Min Tian, Dong-Ning Li, Sha-Sha Tao, Hui Li, Fen-Sheng Huang, Yun-Qing Li","doi":"10.1172/jci.insight.198224","DOIUrl":"https://doi.org/10.1172/jci.insight.198224","url":null,"abstract":"Chronic neuropathic pain is frequently comorbid with anxiety disorders, yet the neural circuits underlying this interaction remain poorly defined. The parafascicular nucleus of the thalamus (PF) integrates nociceptive and affective signals, but its specific regulatory mechanisms in pain-anxiety comorbidity are not well known. Using spared nerve injury (SNI) model mice, we combined viral neural tracing, chemogenetics, pharmacology, and electrophysiology to dissect the locus coeruleus (LC)-PF neural pathway. Viral tracing revealed monosynaptic projections from norepinephrinergic (NEergic) neurons in the dorsal LC to calcium/calmodulin dependent protein kinase IIα (CaMKIIα)- immunopositive neurons within the PF. Chemogenetic inhibition/activation of this pathway were performed in naïve and SNI mice, alongside intra-PF microinjection of the alpha-2 adrenergic receptor (ADRA2) antagonist yohimbine. Behavioral tests assessed mechanical/thermal hypersensitivity and anxiety-like behaviors. Results showed that 92.1% of PF-projecting LC neurons were NEergic, with 70.1% localized dorsally. Chemogenetic inhibition of LCNE-PFCaMKIIα neural pathway significantly alleviated both acute-phase mechanical hypersensitivity (< 7 days post-surgery) and chronic-phase anxiety-like behaviors in SNI mice, while activation of this pathway induced pain sensitization and anxiety-like behaviors in naïve mice. Intra-PF yohimbine reversed SNI-induced allodynia and anxiety-like behaviors. Electrophysiology confirmed yohimbine increased PF neuronal intrinsic excitability. These results suggest that the LCNE-PFCaMKIIα neural pathway promotes neuropathic pain and comorbid anxiety via ADRA2-mediated suppression of PF neuronal activity. Targeted inhibition of this circuit may represent a therapeutic strategy for pain-related affective disorders.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147633462","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

Targeting eIF4A-dependent translation in genetically complex sarcoma. 靶向基因复杂肉瘤中eif4a依赖的翻译。

IF 6.1 1区医学

JCI insight Pub Date : 2026-04-07 DOI: 10.1172/jci.insight.192936

Young-Mi Kim, Prathibha Mohan, Urmila Sehrawat, Evan Seffar, Rafaela Muniz De Queiroz, Kalyani Chadalavada, Nikita Persaud, Tomoyo Okada, Anirudh Kulkarni, Jianan Lin, Nathalie Lailler, Shaleigh Smith, Bhumika Jadeja, Nicholas D Socci, Zhengqing Ouyang, Hans-Guido Wendel, Samuel Singer

{"title":"Targeting eIF4A-dependent translation in genetically complex sarcoma.","authors":"Young-Mi Kim, Prathibha Mohan, Urmila Sehrawat, Evan Seffar, Rafaela Muniz De Queiroz, Kalyani Chadalavada, Nikita Persaud, Tomoyo Okada, Anirudh Kulkarni, Jianan Lin, Nathalie Lailler, Shaleigh Smith, Bhumika Jadeja, Nicholas D Socci, Zhengqing Ouyang, Hans-Guido Wendel, Samuel Singer","doi":"10.1172/jci.insight.192936","DOIUrl":"10.1172/jci.insight.192936","url":null,"abstract":"Dedifferentiated liposarcoma (DDLS), myxofibrosarcoma (MFS), and undifferentiated pleomorphic sarcoma (UPS) are the most common types of genetically complex sarcoma. There is an urgent need to develop effective targeted therapy for these deadly sarcoma types. Despite their genetic complexity, these sarcomas share genomic alterations causing PI3K/Akt/mTOR and MAPK pathway activation, and both pathways control translation mediated by the RNA helicase eIF4A. We therefore investigated eIF4A inhibition as a therapeutic strategy. The eIF4A inhibitor CR-1-31B effectively suppressed tumor growth and induced apoptosis in DDLS, MFS, and UPS patient-derived cell lines and mouse xenografts. Transcriptome-scale ribosome footprinting identified eIF4A-dependent mRNAs such as the Hippo pathway transcriptional coactivators YAP1 (YAP) and WWTR1 (TAZ). Combined knockdown of YAP and TAZ induced apoptosis in DDLS, MFS, and UPS cell lines, and their ectopic expression partially rescued cells from apoptosis induced by CR-1-31B. Genomic analysis of patient tumors revealed that YAP and WWTR1 were frequently amplified or gained in DDLS, MFS, and UPS and were associated with worse clinical outcomes. Together, our findings identify a new strategy for targeting the Hippo pathway in incurable forms of sarcoma based on inhibition of eIF4A-dependent translation of the key oncogenic transcription factors YAP and TAZ.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147633501","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

Ultrasound-targeted microbubble cavitation enhances anti-PD-L1 therapy in TNBC via eNOS-mediated reoxygenation. 超声靶向微泡空化通过enos介导的再氧化增强TNBC抗pd - l1治疗。

IF 6.1 1区医学

JCI insight Pub Date : 2026-04-07 DOI: 10.1172/jci.insight.198349

Zhiyu Zhao, Li Ba, Siwei Li, Jianxin Wang, Yuzhou Luo, Sihan Wang, Yan Jin, Changjun Wu

{"title":"Ultrasound-targeted microbubble cavitation enhances anti-PD-L1 therapy in TNBC via eNOS-mediated reoxygenation.","authors":"Zhiyu Zhao, Li Ba, Siwei Li, Jianxin Wang, Yuzhou Luo, Sihan Wang, Yan Jin, Changjun Wu","doi":"10.1172/jci.insight.198349","DOIUrl":"https://doi.org/10.1172/jci.insight.198349","url":null,"abstract":"Hypoxia critically restricts the effectiveness of immunotherapy in triple-negative breast cancer (TNBC). Comprehensive bioinformatics analyses demonstrated that highly hypoxic TNBC tumors exhibited elevated T cell exhaustion, increased immune checkpoint molecule expression, and diminished responsiveness to immune checkpoint blockade (ICB). Consequently, strategies aimed at alleviating tumor hypoxia may effectively augment ICB therapy. Although ultrasound-targeted microbubble cavitation (UTMC) has been shown to reduce tumor hypoxia, the precise molecular mechanisms remain unclear. Here, we provided evidence that UTMC activated endothelial nitric oxide synthase (eNOS) through G protein-coupled signaling, resembling pathways induced by fluid shear stress. UTMC-induced eNOS activation was largely Ca²⁺-dependent and resulted in increased nitric oxide production. Enhanced nitric oxide generation was associated with improved tumor perfusion and reduced hypoxia. Combining UTMC with anti-PD-L1 therapy markedly improved the tumor immune microenvironment, characterized by increased CD8+ T cell infiltration, reduced T cell exhaustion, diminished regulatory T cell infiltration, increased macrophage polarization from an M2 to M1 phenotype, and elevated production of pro-inflammatory cytokines. Collectively, our findings identified UTMC as a promising adjunctive therapeutic approach to mitigate hypoxia and enhance the efficacy of anti-PD-L1 immunotherapy in TNBC. These results support further translational evaluation of UTMC-based combination strategies in hypoxic TNBC.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147633551","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

Comparing MD-PhD trainee experiences by disciplinary background. 按学科背景比较医学博士实习生的经历。

IF 6.1 1区医学

JCI insight Pub Date : 2026-04-07 DOI: 10.1172/jci.insight.199316

Cambray Smith, Evans K Lodge, C Ray Cheever, Seth M Holmes, Anna R Kahkoska

{"title":"Comparing MD-PhD trainee experiences by disciplinary background.","authors":"Cambray Smith, Evans K Lodge, C Ray Cheever, Seth M Holmes, Anna R Kahkoska","doi":"10.1172/jci.insight.199316","DOIUrl":"https://doi.org/10.1172/jci.insight.199316","url":null,"abstract":"MD-PhD trainees increasingly pursue PhDs in humanities, social sciences, and public health (SSHPH). We characterized SSHPH trainee experiences and compared them to peers in traditional biomedical disciplines. From March-July 2023, a nationwide survey was sent to United States MD-PhD programs that accept SSHPH trainees. Both SSHPH and non-SSHPH trainees participated in a survey focused on belonging, challenges and barriers, funding, and leadership recommendations. Quantitative data were analyzed using Fisher's exact tests, Student's t-tests, and Wilcoxon rank sum tests. Qualitative comments were analyzed using a hybrid deductive-inductive approach. 234 MD-PhD trainees across the U.S. participated, with 111 (47.4%) in SSHPH and 123 (52.6%) in non-SSHPH disciplines. Overall, there were many similarities between trainees across disciplinary groups, but small and consistent differences were noted among SSHPH trainees, including decreased belonging, difficulty identifying role models, and increased work requirements during graduate school. Respondents had 5 recommendations for MD-PhD leaders and 3 recommendations for the National Institutes of Health, such as integrating SSHPH scholars into speaker series and incentivizing funding parity. Limitations include high percentages of missing responses. This exploratory study provides insights into SSHPH MD-PhD trainee experiences, highlighting similarities and unique needs that can be addressed within and across MD-PhD programs.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147633398","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

Dietary Indoles Influence the AHR-RORγt Axis and Mucosal Immune Homeostasis in ART-Treated SIV Infection. 膳食吲哚对抗逆转录病毒治疗SIV感染ahr - r - γ - t轴和黏膜免疫稳态的影响

IF 6.1 1区医学

JCI insight Pub Date : 2026-04-02 DOI: 10.1172/jci.insight.201258

Siva Thirugnanam, Alison R Van Zandt, Alexandra B McNally, Victoria A Hart, Isabelle Berthelot, Cecily C Midkiff, Lara A Doyle-Meyers, David A Welsh, Robert V Blair, Andrew G MacLean, Namita Rout

{"title":"Dietary Indoles Influence the AHR-RORγt Axis and Mucosal Immune Homeostasis in ART-Treated SIV Infection.","authors":"Siva Thirugnanam, Alison R Van Zandt, Alexandra B McNally, Victoria A Hart, Isabelle Berthelot, Cecily C Midkiff, Lara A Doyle-Meyers, David A Welsh, Robert V Blair, Andrew G MacLean, Namita Rout","doi":"10.1172/jci.insight.201258","DOIUrl":"10.1172/jci.insight.201258","url":null,"abstract":"HIV infection rapidly impairs the gastrointestinal (GI) barrier, contributing to persistent mucosal immune dysfunction, microbial translocation, and systemic inflammation despite antiretroviral therapy (ART). Using SIV-infected rhesus macaques on long-term ART, we investigated mechanisms underlying impairment in gut barrier-protective IL-17/IL-22 responses and the potential modulation of this pathway by dietary indoles. Longitudinal profiling of colonic epithelial and lamina propria cells revealed a selective loss of IL-17/IL-22-producing γδT cells and type 3 innate lymphoid cells (ILC3s). This loss correlated with reduced expression of the transcription factors AHR and RORγt and was associated with elevated plasma markers of intestinal epithelial barrier disruption (IEBD), including intestinal fatty acid-binding protein (iFABP), zonulin, and LPS-binding protein (LBP). Targeting this transcriptional deficiency, dietary indole supplementation for one month restored colonic AHR⁺IL-22-producing γδ T cells, RORγt⁺ ILC3s, and Vδ1 T cells, and was associated with reduced iFABP and zonulin levels. Immunohistochemical analyses further demonstrated enrichment of AHR/RORγt-co-expressing cells in the colon of indole-supplemented animals during chronic SIV infection on ART. Collectively, these findings indicate that disruption of the AHR-RORγt axis is a key pathogenic mechanism underlying persistent IEBD in chronic SIV/HIV infection. Modulation of AHR and RORγt signaling pathways in the gut may therefore represent a promising therapeutic strategy to reinforce mucosal barrier function and mitigate chronic inflammation in people living with HIV.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147608864","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