JCI insight最新文献

{"title":"Developmental progression of respiratory dysfunction in a mouse model of Dravet syndrome.","authors":"Brenda M Milla, Eliandra Silva, Cleyton R Sobrinho, Monica Strain, Daniel K Mulkey","doi":"10.1172/jci.insight.184231","DOIUrl":"https://doi.org/10.1172/jci.insight.184231","url":null,"abstract":"<p><p>Dravet syndrome (DS) is an early-onset epilepsy caused by loss of function mutations in the SCN1A gene, which encodes Nav1.1 channels that preferentially regulate activity of inhibitory neurons early in development. DS is associated with a high incidence of sudden unexpected death in epilepsy (SUDEP) by a mechanism that may involve respiratory failure. Evidence also shows that loss of Scn1a impaired activity of neurons in the retrotrapezoid nucleus (RTN) that regulate breathing in response to CO2/H+, suggesting breathing problems precede seizures and serve as a biomarker of SUDEP. Consistent with this, we showed that Scn1a+/- mice exhibited a blunted ventilatory response to CO2/H+ prior to overt seizure activity that worsened with disease progression. Later in development, some Scn1a+/- mice also showed a blunted ventilatory response to hypoxia. Importantly, the severity of respiratory problems correlated with mortality. We also found that pharmacological activation of Nav1.1 rescued activity deficits of RTN neurons in Scn1a+/- mice. We conclude that disordered breathing may be an early biomarker of SUDEP in DS, and at the cellular level loss of Scn1a disrupts RTN neurons by mechanisms involving disinhibition and pharmacological activation of Nav1.1 re-establish inhibitory control of RTN neurons and rescue activity deficits.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145029511","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}

{"title":"Bcl6 reactivity is associated with a distinct immune landscape and spatial transcriptome in COVID-19.","authors":"Cloé Brenna, Bernat Bramon Mora, Kalliopi Ioannidou, Julien Bodelet, Mia L Siebmanns, Simon Burgermeister, Spiros Georgakis, Michail Orfanakis, Yannick D Muller, Nazanin Sédille, Matthew J Feinstein, Jon W Lomasney, Oliver Y Chén, Giuseppe Pantaleo, Sabina Berezowska, Laurence de Leval, Raphael Gottardo, Constantinos Petrovas","doi":"10.1172/jci.insight.189134","DOIUrl":"https://doi.org/10.1172/jci.insight.189134","url":null,"abstract":"<p><p>The regulation of follicular (F) and germinal center (GC) immune reactivity in human lymph nodes (LNs), particularly during the acute stages of viral infection, remains poorly understood: We have analyzed lung-draining lymph nodes (LD-LNs) from COVID-19 autopsies using multiplex imaging and spatial transcriptomics to examine the immune landscape with respect to follicular immune reactivity. We identified three groups of donors based on the Bcl6 prevalence of their Reactive Follicles (RFs): RF-Bcl6no/low, RF-Bcl6int, and RF-Bcl6high. A distinct B/TFH immune landscape, associated with increased prevalence of proliferating B-cell and TFH-cell subsets, was found in RF-Bcl6high LD-LNs. The comparison between LD-LNs and subdiaphragmatic (SD) LNs from the same donor revealed a divergent Bcl6 expression between the two anatomical sites. LD-LN Bcl6 expression was also associated with a distinct spatial transcriptomic profile. TH1-associated genes/pathways (e.g., CXCR3, STAT5, TNF-signaling) were significantly up-regulated in RF-Bcl6no/low tissues, while the RF-Bcl6high tissues exhibited significant up-regulation of GC-promoting genes/pathways (e.g., CXCL13, B-cell receptor signaling). Our findings reveal a heterogeneous F/GC landscape in COVID-19 LD-LNs, highlighting specific molecular targets and pathways that could regulate human F/GC immune dynamics during acute viral infections.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145029467","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}

{"title":"Epigenetic dysregulation of energy homeostasis drives aortic valve stenosis that is treatable with metformin.","authors":"Timothy J Cashman, Sherin Saheera, Ashley E Blau, Edith Mensah Otabil, Nouran Y Nagy, Thomas D Samenuk, Timothy P Fitzgibbons, David D McManus, Chinmay M Trivedi","doi":"10.1172/jci.insight.188562","DOIUrl":"10.1172/jci.insight.188562","url":null,"abstract":"<p><p>Aortic valve stenosis is a progressive and increasingly prevalent disease in older adults, with no approved pharmacologic therapies to prevent or slow its progression. Although genetic risk factors have been identified, the contribution of epigenetic regulation remains poorly understood. Here, we demonstrated that histone deacetylase 3 (HDAC3) maintains aortic valve structure by suppressing mitochondrial biogenesis and preserving extracellular matrix integrity in valvular interstitial fibroblasts. Human stenotic valves displayed elevated acetylation of histone H3 at lysine 27 (H3K27ac) and reduced HDAC3 activity in diseased regions. Mice lacking HDAC3 in aortic valves developed aortic valve stenosis, disrupted collagen organization, increased H3K27ac, and premature mortality. Mechanistically, HDAC3 loss led to activation of nuclear hormone receptor-regulated mitochondrial gene programs, increased oxidative phosphorylation, and reactive oxygen species-induced damage. Treatment with metformin, a mitochondrial complex I inhibitor, restored redox balance, preserved collagen structure, and improved valve function in Hdac3-deficient mice. Supporting these experimental findings, retrospective clinical analysis revealed a significantly lower prevalence and slower progression of aortic valve stenosis in patients treated with metformin. These results uncovered a potentially previously unrecognized role for HDAC3 in coordinating epigenetic and metabolic homeostasis in the aortic valve, suggesting that targeting mitochondrial dysfunction may offer a therapeutic strategy for noncalcific aortic valve disease.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 17","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145023381","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}

{"title":"Virologic characteristics of SARS-CoV-2 infection across evolving omicron subvariants.","authors":"Julie Boucau, Owen T Glover, Caitlin Marino, Gregory E Edelstein, Manish C Choudhary, Yijia Li, Brooke M Leeman, Zahra Reynolds, Karry Su, Dessie Tien, Chase B Mandell, Eliza Passell, Andrew Alexandrescu, Emory Abar, Mamadou Barry, Dibya Ghimire, Tammy D Vyas, Jatin M Vyas, Jacob E Lemieux, Jonathan Z Li, Mark J Siedner, Amy K Barczak","doi":"10.1172/jci.insight.192228","DOIUrl":"10.1172/jci.insight.192228","url":null,"abstract":"<p><strong>Background: </strong>The SARS-CoV-2 virus has evolved subvariants since the emergence of the omicron variant in 2021. Whether these changes impact viral shedding and transmissibility is not known.</p><p><strong>Methods: </strong>POSITIVES is a prospective longitudinal cohort of individuals with mild SARS-CoV-2 infection. Ambulatory, immunocompetent participants who did not receive antivirals self-administered 6 anterior nasal swabs over 15 days. Samples were analyzed by qPCR to quantify viral RNA, semi-quantitative viral culture to detect shedding of replication-competent virus, and whole genome sequencing to classify subvariants. Our predictor of interest was omicron subvariant: BA.1x, BA.2x, BA.4/5x, XBB.x and JN.x. Outcomes included RNA levels and duration of shedding replication-competent virus. We additionally explored whether the duration and severity of symptom correlated with duration of viral shedding and whether symptoms are a valid marker for ending isolation.</p><p><strong>Results: </strong>The median peak nasal SARS-CoV-2 RNA (6.0-6.3 log10 RNA copies/mL), median days to peak RNA (4-5 days), median days to undetectable viral RNA (10-12 days) and median days to negative viral culture (3.5-6 days) was similar across omicron subvariants. Number and severity of symptoms were also similar. For all subvariants, a sizeable percentage (range 28.2-52.0%) shed replication-competent virus after fever resolution and improvement of symptoms.</p><p><strong>Conclusion: </strong>Despite ongoing viral evolution, key aspects of viral dynamics of SARS-CoV-2 infection, including the duration of shedding replication-competent virus, have not substantially changed across omicron subvariants. Replication-competent shedding of these subvariants is detected for a large proportion of people who meet criteria for ending isolation.</p><p><strong>Funding: </strong>This work was supported by the National Institutes of Health (NIH), the Massachusetts Consortium on Pathogen Readiness, and the Massachusetts General Hospital Department of Medicine.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145029677","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}

{"title":"Thyroid hormone promotes fetal neurogenesis.","authors":"Federico Salas-Lucia, Sergio Escamilla, Amanda Charest, Hanzi Jiang, Randy Stout, Antonio C Bianco","doi":"10.1172/jci.insight.194445","DOIUrl":"10.1172/jci.insight.194445","url":null,"abstract":"<p><p>Maternal low thyroxine (T4) serum levels during the first trimester of pregnancy correlate with cerebral cortex volume and mental development of the progeny, but why neural cells during early fetal brain development are vulnerable to maternal T4 levels remains unknown. In this study, using iPSCs obtained from a boy with a loss-of-function mutation in MCT8-a transporter previously identified as critical for thyroid hormone uptake and action in neural cells-we demonstrate that thyroid hormones induce transcriptional changes that promote the progression of human neural precursor cells along the dorsal projection trajectory. Consistent with these findings, single-cell, spatial, and bulk transcriptomics from MCT8-deficient cerebral organoids and cultures of human neural precursor cells underscore the necessity for optimal thyroid hormone levels for these cells to differentiate into neurons. The controlled intracellular activation of T4 signaling occurs through the transient expression of the enzyme type 2 deiodinase, which converts T4 into its active form, T3, alongside the coordinated expression of thyroid hormone nuclear receptors. The intracellular activation of T4 in NPCs results in transcriptional changes important for their division mode and cell cycle progression. Thus, T4 is essential for fetal neurogenesis, highlighting the importance of adequate treatment for mothers with hypothyroidism.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144992611","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}

{"title":"Pediatric T cell and B cell responses to SARS-CoV-2 infection.","authors":"L Benjamin Hills, Numana Bhat, Jillian H Hurst, Amber Myers, Thomas W Burke, Micah T McClain, Elizabeth Petzold, Alexandre T Rotta, Nicholas A Turner, Alba Grifoni, Daniela Weiskopf, Yvonne Dogariu, Genevieve G Fouda, Sallie R Permar, Alessandro Sette, Christopher W Woods, Matthew S Kelly, Shane Crotty","doi":"10.1172/jci.insight.196032","DOIUrl":"https://doi.org/10.1172/jci.insight.196032","url":null,"abstract":"<p><strong>Background: </strong>Understanding age-associated differences in acute and memory adaptive immunity to SARS-CoV-2 and how this contributes to more favorable outcomes in children is critically important.</p><p><strong>Methods: </strong>We evaluated SARS-CoV-2-specific T cell, B cell, and antibody responses in 329 peripheral blood samples collected from non-hospitalized children, adolescents, and adults at three timepoints, including acute and memory timepoints.</p><p><strong>Results: </strong>Most children produced robust CD4+ T cell responses during infection and developed memory CD4+ T cells; however, young children <4 years old often had undetectable CD4+ T cell responses compared to older children and adults. Young children also generated reduced frequencies of memory B cells; despite this, they mounted substantial and durable neutralizing antibody responses. CD4+ T cell responses in children were biased towards non-spike epitopes, especially in asymptomatic cases. Memory B cells in children were preferentially classical memory or, paradoxically, CXCR3+.</p><p><strong>Conclusion: </strong>These findings support the concept that the kinetics and composition of T and B cell responses shift across age groups and may be associated with milder COVID-19 outcomes in children.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144992535","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}

{"title":"Co-phagocytosis of VEGFA with HER2-overexpressing cancer cells induced by HER2-VEGFA BsAb improves antitumor responses.","authors":"Yang Lu, Songbo Qiu, Zhen Fan","doi":"10.1172/jci.insight.194494","DOIUrl":"10.1172/jci.insight.194494","url":null,"abstract":"<p><p>We conceived of a type of antitumor mechanism of action by which a soluble target in the tumor microenvironment, such as a tumor-driving growth factor, can be phagocytized along with cancer cells via antibody-dependent cellular phagocytosis (ADCP) using an antibody bispecific for the soluble target and a solid target overexpressed on the cancer cell surface. We explored this concept through engineering bispecific antibodies (BsAbs) co-targeting human epidermal growth factor receptor-2 (HER2) and vascular endothelial growth factor A (VEGFA) in an scFv-IgG format (VHS). We showed that the HER2-VEGFA BsAbs but not the parental antibodies alone or in combination induced co-phagocytosis of VEGFA and HER2-overexpressing cancer cells by tumor-associated macrophages via ADCP. In both immunocompromised and immunocompetent mice with aggressive tumors, the BsAbs demonstrated greater anti-metastasis activity and produced a greater survival benefit than the parental antibodies alone or in combination, in a manner dependent on Fcγ receptors on the macrophages. Our results provide proof of the concept that HER2-VEGFA BsAbs achieve enhanced antitumor activity by leveraging HER2 overexpressed on the cancer cell surface to induce co-phagocytosis of VEGFA. Our findings warrant clinical testing of the strategy to treat metastasis and recurrence of HER2-overexpressing solid tumors that respond to anti-VEGFA therapy.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144992548","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}

{"title":"GPRC5B preserves a mature β-cell state in obesity by controlling MafA expression.","authors":"Tianpeng Wang, Remy Bonnavion, Janett Piesker, Stefan Günther, Nina Wettschureck","doi":"10.1172/jci.insight.194115","DOIUrl":"https://doi.org/10.1172/jci.insight.194115","url":null,"abstract":"<p><p>In vitro studies have implicated orphan receptor GPRC5B in β-cell survival, proliferation and insulin secretion, but its relevance for glucose homeostasis in vivo is largely unknown. Using tamoxifen-inducible, β-cell-specific GPRC5B knockout mice (Ins-G5b-KOs) we show here that loss of GPRC5B does not affect β-cell function in the lean state, but results in strongly reduced insulin secretion and disturbed glucose tolerance in mice subjected to high fat diet for 16 weeks. Flow cytometry and single-cell expression analyses in islets from obese mice show a reduced β-cell abundance and a less mature β-cell phenotype in Ins-G5b-KOs. Expression of β-cell-specific transcription factor MafA is reduced both on the RNA and protein level, as are transcripts of MafA target genes. Mechanistically, we show that phosphorylation of cAMP response element-binding protein (CREB), a major regulator of MafA expression, is reduced in islets of obese Ins-G5b-KOs, and that this phenotype precedes the downregulation of MafA and MafA target genes. Taken together, GPRC5B helps to maintain mature β-cell function in obesity through cAMP/CREB-dependent regulation of MafA expression.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144992497","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}

{"title":"Defective GNAS imprinting due to splice site variants in pseudohypoparathyroidism type 1B.","authors":"Yorihiro Iwasaki, Monica Reyes, Arnaud Molin, Mari Muurinen, Marie-Laure Kottler, Murat Bastepe, Harald Jüppner","doi":"10.1172/jci.insight.194754","DOIUrl":"https://doi.org/10.1172/jci.insight.194754","url":null,"abstract":"","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144954541","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}

{"title":"Conserved interactions with stromal and immune cells coordinate de novo B-cell lymphopoiesis in fetal intestines.","authors":"Kimberly A Carroll, Weihong Gu, Long Phan, Eduardo Gonzalez Santiago, Wenjia Wang, George C Tseng, Liza Konnikova, Shruti Sharma","doi":"10.1172/jci.insight.192550","DOIUrl":"https://doi.org/10.1172/jci.insight.192550","url":null,"abstract":"<p><p>Recent findings suggest that the small intestine (SI) is a novel site for B cell lymphopoiesis during fetal and neonatal life. However, the unique and/or conserved features that enable B cell development at this site remain unclear. To investigate the molecular and cellular scaffolds for B cell lymphopoiesis in mouse and human fetal intestines we leveraged single-cell RNA sequencing, in situ immunofluorescence, spatial transcriptomics and high-dimensional spectral flow cytometry. We found that SI mesenchymal and stromal cells expressed higher levels of chemokines known to recruit common lymphoid progenitors. Importantly, local lymphatic endothelial cells expressed IL7 and TSLP in proximity to IL7R+ precursor B cells, likely promoting their differentiation in the SI. Notably, we found that fetal-derived lymphoid tissue inducer (LTi) cells were required for B cell development and localization in the SI, but not fetal liver. These findings identify a lymphoid tissue development-independent role for this immune cell in B cell development. Collectively, our data reveal a conserved intestinal B cell niche in mice and humans, challenging traditional models of lymphopoiesis. The identification of a requisite cellular/molecular scaffold for fetal B cell development allows future studies to test the importance of this de novo B cell lymphopoiesis to long-term immunity.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144954535","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}