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Samuel D. Jordan, Shuhua Fu, Abigail Fulkerson, Donghua Hu, Sherwin Ng, David M. Zhang, Sneha Manikandan, Jeffrey Szymanski, Nan Hu, Yuqian Xie, Anish Bedi, James Tabor, Lauren Boggs-Bailey, Lori Strong, Stephanie Hicks, Lavanya Aryan, Nishanth Gabriel, Geoffrey D. Hugo, Kuo-Chan Weng, Nathaniel Huebsch, Julie K. Schwarz, Bo Zhang, Stacey L. Rentschler, Samuel D. Jordan, Shuhua Fu, Abigail Fulkerson, Donghua Hu, Sherwin Ng, David M. Zhang, Sneha Manikandan, Jeffrey Szymanski, Nan Hu, Yuqian Xie, Anish Bedi, James Tabor, Lauren Boggs-Bailey, Lori Strong, Stephanie Hicks, Lavanya Aryan, Nishanth Gabriel, Geoffrey D. Hugo, Kuo-Chan Weng, Nathaniel Huebsch, Julie K. Schwarz, Bo Zhang, Stacey L. Rentschler
Stereotactic arrhythmia radiotherapy (STAR) is emerging as a highly effective treatment for ventricular tachycardia (VT). Growing evidence indicates that STAR favorably reprograms the electrical substrate by speeding conduction and/or prolonging repolarization via modulation of ion channel expression, although the mechanisms by which single-fraction radiation mediates durable changes in gene expression are incompletely understood. Here, we identify dynamic changes in the cardiomyocyte epigenome and transcriptome after irradiation (IR) in vivo and in vitro, including durably increased expression and chromatin accessibility of Scn5a (encodes the α subunit of the sodium channel, NaV1.5), demonstrating a role for epigenetic memory in conduction velocity (CV) increases observed after STAR. Transcriptomic and epigenetic sequencing further identified dynamic changes in gene expression and regulatory regions involved in cellular repolarization, calcium handling, and metabolism after IR. These changes were mirrored by dose-dependent and cell-autonomous changes in repolarization, calcium flux, and mitochondrial respiration, highlighting important cellular processes that may mediate the therapeutic effects of STAR. Overall, we found that cardiomyocytes exposed to a single fraction of high-dose IR exhibited epigenetic reprogramming that mediated broad and dynamic physiologic responses.
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Sarah K. Royse, Rajesh Narendran, Sarah K. Royse, Rajesh Narendran
Alcohol use disorder (AUD) is linked with changes in brain structure and function, with robust evidence for neurodegenerative changes, including synaptic loss in preclinical models. Developing therapeutic strategies to target synaptic loss will require human studies that clarify their clinical relevance of these changes. In the current issue, Zakiniaeiz et al. demonstrate that AUD and alcohol consumption are associated with lower synaptic vesicle glycoprotein 2a (SV2A) expression, indexed by regional [11C]UCB-J PET. This is, to our knowledge, the first in vivo evidence of relationships between synaptic density and alcohol use, and, as such, it represents an important step toward understanding how AUD influences brain structure and function. Here, we describe two longstanding clinical issues in the AUD population — relapse and dementia risk — and how the results of the present study may guide future investigations of these issues.
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Abhijit S. Naik, Fadhl M. Alakwaa, Viji Nair, Phillip J. McCown, Jennifer A. Schaub, Edgar A. Otto, Rajasree Menon, Francesca Annese, Ye Ji Choi, Hailey E. Hampson, Thomas H. Inge, John Hartman, Sean Eddy, Cathy Smith, Jeffrey B. Hodgin, Ken Inoki, Swayam Prakash Srivastava, Kareem Al-Fagih, Shota Yoshida, Jesse A. Goodrich, Melanie G. Cree, Phoom Narongkiatikhun, Long Yuan, Kalie L. Tommerdahl, Pottumarthi Prasad, Daniël H. van Raalte, Megan M. Kelsey, Justin R. Ryder, Tyler J. Dobbs, Patricia Ladd, Subramaniam Pennathur, Robert G. Nelson, Yusuke Okabayashi, Victor G. Puelles, Jenna Ferrence-Salo, Jeffrey A. Beamish, Frank C. Brosius, Kristen J. Nadeau, Laura Pyle, Matthias Kretzler, Petter Bjornstad, Abhijit S. Naik, Fadhl M. Alakwaa, Viji Nair, Phillip J. McCown, Jennifer A. Schaub, Edgar A. Otto, Rajasree Menon, Francesca Annese, Ye Ji Choi, Hailey E. Hampson, Thomas H. Inge, John Hartman, Sean Eddy, Cathy Smith, Jeffrey B. Hodgin, Ken Inoki, Swayam Prakash Srivastava, Kareem Al-Fagih, Shota Yoshida, Jesse A. Goodrich, Melanie G. Cree, Phoom Narongkiatikhun, Long Yuan, Kalie L. Tommerdahl, Pottumarthi Prasad, Daniël H. van Raalte, Megan M. Kelsey, Justin R. Ryder, Tyler J. Dobbs, Patricia Ladd, Subramaniam Pennathur, Robert G. Nelson, Yusuke Okabayashi, Victor G. Puelles, Jenna Ferrence-Salo, Jeffrey A. Beamish, Frank C. Brosius, Kristen J. Nadeau, Laura Pyle, Matthias Kretzler, Petter Bjornstad
BACKGROUND Youth with type 2 diabetes (T2D) and severe obesity face high risk of diabetic kidney disease, which metabolic bariatric surgery (MBS) can mitigate. This study explores structural and molecular changes in kidneys after vertical sleeve gastrectomy (VSG), a form of MBS.METHODS We performed paired analyses, including metabolic profiling, kidney volume assessment, histological evaluation, and single-cell RNA sequencing (scRNA-seq), on kidney biopsies from 5 youth with T2D and obesity pre- and 12 months post-VSG in the IMPROVE-T2D (Impact of Metabolic surgery on Pancreatic, Renal and cardiOVascular hEalth in youth with T2D) cohort. Circulating proteomics with kidney transcriptomics were linked using data from an independent cohort of youth with obesity, with or without T2D, undergoing MBS in Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS, n = 64).RESULTS After VSG, participants lost weight and had improvements in insulin sensitivity and metabolic parameters. Kidney changes included reduced renal hyperfiltration, total kidney volume, mesangial matrix area, and microalbuminuria. scRNA-seq in proximal tubule (PT) and thick ascending limb cells indicated repression of glycolysis, gluconeogenesis, and tricarboxylic acid (TCA) cycle genes, with upregulation of AMP-activated protein kinase (AMPK) and forkhead box O3 (FOXO3). Decreased metabolic signaling aligned with reduced ribosomal phosphorylated S6K (pS6K), suggesting attenuated mTORC1 activity. Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway activation in PT was diminished, correlating with lower circulating ligands from Teen-LABS proteomic data.CONCLUSION MBS/VSG prompts kidney molecular adaptations, providing potential targets for nonsurgical interventions against obesity- and diabetes-associated kidney disease.FUNDING University of Washington with the American Diabetes Association, University of Michigan with Chan Zuckerberg Initiative, and Breakthrough T1D.
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Declan F. McCole, Declan F. McCole
Crohn’s disease can occur anywhere along the small and/or large intestines, but most commonly occurs in the terminal ileum or ascending colon. Factors governing this region-specific inflammation are poorly understood. In this issue of the JCI, Spencer et al. used a TNF-driven mouse model of small intestinal Crohn’s disease to identify a specific bacterial pathobiont, Chlamydia muridarum, as a necessary and sufficient driver of region-restricted inflammation. C. muridarum triggered increased goblet cell expression of indoleamine 2,3-dioxygenase 1 (IDO1) in the mouse proximal colon, analogous to the human ascending colon. IDO1 metabolism of tryptophan stimulated increased levels of kyneurine, and suppression of this IDO1/kyneurine axis alleviated C. muridarum–provoked inflammation in the proximal colon but not the terminal ileum. Analysis of scRNA-seq datasets from patients with Crohn’s disease with ascending colon involvement also supported increased IDO1 expression in a subpopulation of crypt surface epithelial cells. The study highlights a process by which bacterial pathobionts promote region-specific intestinal inflammation.
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Tao Li, Sergio Castro-Gomez, Pablo Botella Lucena, Ana Vieira-Saecker, Stephanie Schwartz, Yingying Ding, Yushuang Deng, Maling Gou, Valentin Stein, Douglas T. Golenbock, Eicke Latz, Michael T. Heneka, Tao Li, Sergio Castro-Gomez, Pablo Botella Lucena, Ana Vieira-Saecker, Stephanie Schwartz, Yingying Ding, Yushuang Deng, Maling Gou, Valentin Stein, Douglas T. Golenbock, Eicke Latz, Michael T. Heneka
Mild traumatic brain injury (mTBI) from a closed-head injury (CHI) can lead to prevalent neuropsychiatric disorders, including mood disorders and an increased risk for neurodegenerative diseases and dementia. Inflammasomes are molecular complexes crucial for neuroinflammation and secondary damage after trauma, however their role in mild CHI (mCHI) is poorly understood. In this study, we investigate the cellular expression of inflammasome-related genes and their functional significance in CHI models. Single-cell RNA-seq analysis of cortical tissue after trauma revealed selective expression of Asc (also known as Pycard), which encodes the inflammasome adaptor apoptosis-associated Speck-like protein containing a caspase recruitment domain (ASC), predominantly in microglial clusters. Sustained upregulation of inflammasome-related proteins, microglia activation, and astrocyte reactivity persisted up to 21 days in a model for mTBI, with significant reduction of this pattern in Asc–/– mice. Importantly, mild cognitive impairment induced after mCHI was largely abrogated in Asc–/– mice. These findings suggest that ASC, as the primary inflammasome adaptor, plays a critical role in sustaining neuroinflammation and contributes to cognitive deficits after mCHI. This study provides insights into the molecular neuroinflammatory mechanisms underlying CHI, potentially informing future therapeutic strategies.
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Shin-ichi Oka, Eun-Ah Sung, Peiyong Zhai, Kevin B. Schesing, Santosh Bhat, Adave Chin, Jiyeon Park, Yeun-Jun Chung, Akihiro Shirakabe, Takanobu Yamamoto, Yoshiyuki Ikeda, Wataru Mizushima, Shohei Ikeda, Mingming Tong, Jaemin Byun, Michinari Nakamura, Samuel I. Kim, Jamie Francisco, Dominic P. Del Re, Junichi Sadoshima, Shin-ichi Oka, Eun-Ah Sung, Peiyong Zhai, Kevin B. Schesing, Santosh Bhat, Adave Chin, Jiyeon Park, Yeun-Jun Chung, Akihiro Shirakabe, Takanobu Yamamoto, Yoshiyuki Ikeda, Wataru Mizushima, Shohei Ikeda, Mingming Tong, Jaemin Byun, Michinari Nakamura, Samuel I. Kim, Jamie Francisco, Dominic P. Del Re, Junichi Sadoshima
Obesity is accompanied by increases in free fatty acids (FFAs) in the systemic circulation, and patients with obesity often develop cardiac hypertrophy and diastolic dysfunction, termed obesity cardiomyopathy. Proinflammatory cytokines, including IL-6, have been implicated in the pathogenesis of the cardiac dysfunction associated with obesity cardiomyopathy. Elevation of FFAs induced by high-fat diet (HFD) consumption induced diastolic dysfunction in the heart as early as after 1 month. HFD consumption directly stimulated IL-6 production in cardiomyocytes before local inflammation developed and induced diastolic dysfunction even in the presence of macrophage depletion with clodronate in the heart. PPARα played an essential role in mediating Il6 transcription in response to HFD consumption by forming a heterodimer with p50/RelA and binding to the NF-κB element in cardiomyocytes. Local production of IL-6 in cardiomyocytes, in turn, mediated the development of diastolic cardiac dysfunction. HFD-induced diastolic dysfunction was attenuated by cardiac-specific deletion of either Pparα or Il6, as well as by interference with the PPARα–NF-κB heterodimer formation by a molecular decoy. These results suggest elevated FFA levels directly upregulate Il6 through the PPARα–NF-κB heterodimer in cardiomyocytes and highlight autocrine production of IL-6 as a key downstream mechanism in the initial development of diastolic dysfunction.
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Satoshi Konishi, Khaliun Enkhbayar, Shuyu Liu, Naoya Miyashita, Yoshihiko Kobayashi, Vera Hutchison, Ashna Sai, Pankaj Agarwal, Jonathan Witonsky, Nathan D. Jackson, Max A. Seibold, Jichao Chen, Aleksandra Tata, Purushothama Rao Tata, Satoshi Konishi, Khaliun Enkhbayar, Shuyu Liu, Naoya Miyashita, Yoshihiko Kobayashi, Vera Hutchison, Ashna Sai, Pankaj Agarwal, Jonathan Witonsky, Nathan D. Jackson, Max A. Seibold, Jichao Chen, Aleksandra Tata, Purushothama Rao Tata
Cells exhibit diverse sizes and shapes, tailored for functional needs of tissues. Lung alveoli are lined by large, extremely thin epithelial alveolar type 1 cells (AT1s). Their characteristic morphology is essential for lung function and must be restored after injury. The mechanisms underlying small, cuboidal alveolar type 2 cell (AT2) differentiation into thin AT1s remain elusive. Here, we demonstrated that AT2s undergo a stepwise morphological transformation characterized by the development of a unique thick microtubule (MT) bundle organization, critical for AT1 morphology. Using AT2 cultures and in vivo genetic loss-of-function models, we found that MT bundling occurred in a transitional cell state during AT2 differentiation and was regulated by the TP53/TAU (encoded by the microtubule-associated protein tau [MAPT] gene) signaling axis. Notably, TAU underwent a linear clustering process, forming beads-on-a-string-like pattern that preceded thick MT bundle formation. Genetic gain or loss of function of TAU in mouse or human models prevented the formation of thick MT bundles, highlighting the critical role of precise TAU levels in generating ultrathin AT1s. This defect was associated with increased tissue fibrosis following bleomycin-induced injury in vivo. GWAS analysis revealed risk variants in the MAPT locus in lung diseases. Moreover, TP53 controlled TAU expression and its loss phenocopied TAU deficiency. This work revealed an unexpected role for TAU in organizing MT bundles during AT2 differentiation.
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Kaori Oshima, Bailu Yan, Ran Tao, Gustavo Amorim, Chiara Di Gravio, Sarah A. McMurtry, Ryan C. Burke, Yunbi Nam, Ina Nikolli, Max S. Kravitz, Daniel Stephenson, Aaron Issaian, Kirk C. Hansen, Angelo D’Alessandro, Ivor S. Douglas, Wesley H. Self, Christopher J. Lindsell, Carolyn Leroux, Angelika Ringor, Michael A. Matthay, Jonathan S. Schildcrout, Nathan I. Shapiro, Eric P. Schmidt, Kaori Oshima, Bailu Yan, Ran Tao, Gustavo Amorim, Chiara Di Gravio, Sarah A. McMurtry, Ryan C. Burke, Yunbi Nam, Ina Nikolli, Max S. Kravitz, Daniel Stephenson, Aaron Issaian, Kirk C. Hansen, Angelo D’Alessandro, Ivor S. Douglas, Wesley H. Self, Christopher J. Lindsell, Carolyn Leroux, Angelika Ringor, Michael A. Matthay, Jonathan S. Schildcrout, Nathan I. Shapiro, Eric P. Schmidt
BACKGROUND Plasma heparan sulfate, a glycosaminoglycan released during endothelial glycocalyx degradation, predicts sepsis mortality. Chondroitin sulfate is a circulating glycosaminoglycan not specific to glycocalyx degradation; its relevance to sepsis is unknown.METHODS We studied the associations of plasma chondroitin sulfate with (a) mortality in patients with sepsis-associated hypotension and (b) the relative effectiveness of a randomly assigned liberal versus restrictive intravenous fluid resuscitation strategy. We selected 574 patients enrolled in the Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis trial using an outcome-enriched sampling strategy. We used liquid chromatography–mass spectrometry to quantify plasma chondroitin sulfate. In comparison, we measured hyaluronic acid as a glycocalyx degradation marker and IL-6 as an inflammatory biomarker. We conducted Cox proportional hazards regression analyses to examine associations of baseline biomarker concentrations with mortality and resuscitation strategy effectiveness. We used inverse probability of selection weights and generalized raking to account for the nonrepresentative sampling design.RESULTS Plasma chondroitin sulfate, hyaluronic acid, and IL-6 were associated with mortality within 90 days. As baseline chondroitin sulfate increased, subsequent randomization to a restrictive strategy was increasingly beneficial (P = 0.022): treatment effect hazard ratio (restrictive versus liberal) for mortality was estimated as 1.49 (95% CI, 0.98–2.27), 1.30 (95% CI, 1.00–1.69), 1.09 (95% CI, 0.82–1.44), 0.88 (95% CI, 0.66–1.16), and 0.71 (95% CI, 0.52–0.97) for 10th, 25th, 50th, 75th, and 90th percentiles of baseline chondroitin sulfate.CONCLUSION Plasma chondroitin sulfate predicts sepsis mortality and may modify the response to a subsequent liberal versus restrictive intravenous fluid resuscitation strategy.TRIAL REGISTRATION ClinicalTrials.gov NCT03434028.FUNDING NIH grants R01HL149422 and R01HL094786.
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Xun Tian, Mansheng Li, Zhi Wang, Tian Fang, Yi Liu, Jin Fang, Lejing Wang, Zhichao Jiang, Xingyu Zhao, Chen Cao, Zhiqiang Yu, Meiying Yang, Songfeng Wu, Yifan Wu, Rui Tian, Hui Wang, Yunping Zhu, Zheng Hu, Xun Tian, Mansheng Li, Zhi Wang, Tian Fang, Yi Liu, Jin Fang, Lejing Wang, Zhichao Jiang, Xingyu Zhao, Chen Cao, Zhiqiang Yu, Meiying Yang, Songfeng Wu, Yifan Wu, Rui Tian, Hui Wang, Yunping Zhu, Zheng Hu
BACKGROUND Cervical cancer (CC) remains the fourth leading cause of cancer-related deaths in women globally, with poor prognosis for metastatic and recurrent cases. Although genomic alterations have been extensively characterized, global proteogenomic landscape of the disease is largely under explored.METHODS Here, we present the first genome-wide proteogenomic characterization of CC, analyzing 139 tumor-normal tissue pairs using whole-genome sequencing, transcriptomics, proteomics, and phosphoproteomics.RESULTS We identified 4 distinct molecular subtypes with unique clinical outcomes: epithelial-mesenchymal transition (EMT, C1), proliferation (C2), immune response (C3), and epithelial differentiation (C4). A 4-protein classifier (CDH13, TP53BP1, NNMT, HSPB1) was developed with strong prognostic and predictive value, particularly for immunotherapy response in subtype C3. Phosphoproteomic profiling uncovered subtype-specific kinase activity, identifying actionable therapeutic targets.CONCLUSION Our findings further revealed previously uncharacterized somatic copy number alterations, extrachromosomal DNA landscape, and human-HPV fusion peptides, with implications for genetic heterogeneity and therapeutic targets. This study enhances the understanding of cervical cancer through deeper proteogenomic insights and facilitates the development of personalized therapeutic strategies to improve patient outcomes.FUNDING Noncommunicable Chronic Diseases-National Science and Technology Major Project (2025ZD0544102);The National Natural Science Foundation of China (82172584); Key Technology R&D Program of Hubei (2024BCB057 and 2025BCB053); National Natural Science Foundation of China (82373260); the “4+X” clinical trial programs of Women’s Hospital, School of Medicine, Zhejiang University (LY2022004); and the programs of Zhejiang Traditional Chinese Medicine Innovation Team (CZ2024009); and Guangxi Natural Science Foundation (2024GXNSFBA010045).