Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Physician-Scientist Development
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • In-Press Preview
    • Resource and Technical Advances
    • Clinical Research and Public Health
    • Research Letters
    • Editorials
    • Perspectives
    • Physician-Scientist Development
    • Reviews
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Resource and Technical Advances
  • Clinical Research and Public Health
  • Research Letters
  • Editorials
  • Perspectives
  • Physician-Scientist Development
  • Reviews
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Transfers
  • Advertising
  • Job board
  • Contact

Top read articles in the last 30 days

This list is updated daily and reflects the last month of access data. Articles older than two years will not be shown.

  • Research
Human pegivirus alters brain and blood immune and transcriptomic profiles of patients with Parkinson’s disease
Barbara A. Hanson, … , Rudolph J. Castellani, Igor J. Koralnik
Barbara A. Hanson, … , Rudolph J. Castellani, Igor J. Koralnik
Published July 8, 2025
Citation Information: JCI Insight. 2025;10(13):e189988. https://doi.org/10.1172/jci.insight.189988.
View: Text | PDF
Research Article Neuroscience Virology Article has an altmetric score of 792

Human pegivirus alters brain and blood immune and transcriptomic profiles of patients with Parkinson’s disease

  • Text
  • PDF
Abstract

Parkinson’s disease (PD) is a neurodegenerative disorder with both genetic and environmental factors contributing to pathogenesis. Viral infections are potential environmental triggers that influence PD pathology. Using ViroFind, an unbiased platform for whole virome sequencing, along with quantitative PCR (qPCR), we identified human pegivirus (HPgV) in 5 of 10 (50%) of PD brains, confirmed by IHC in 2 of 2 cases, suggesting an association with PD. All 14 age- and sex-matched controls were HPgV negative. HPgV-brain positive patients with PD showed increased neuropathology by Braak stage and Complexin-2 levels, while those positive in the blood had higher IGF-1 and lower pS65-ubiquitin, supporting disruption in metabolism or mitophagy in response to HPgV. RNA-Seq revealed altered immune signaling in HPgV-infected PD samples, including consistent suppression of IL-4 signaling in both the brain and blood. Longitudinal analysis of blood samples showed a genotype-dependent viral response, with HPgV titers correlating directly with IL-4 signaling in a LRRK2 genotype–dependent manner. YWHAB was a key hub gene in the LRRK2 genotypic response, which exhibited an altered relationship with immune-related factors, including NFKB1, ITPR2, and LRRK2 itself, in patients with PD who are positive for HPgV. These results suggest a role for HPgV in shaping PD pathology and highlight the complex interplay between viral infection, immunity, and neuropathogenesis.

Authors

Barbara A. Hanson, Xin Dang, Pouya Jamshidi, Alicia Steffens, Kaleigh Copenhaver, Zachary S. Orban, Bernabe Bustos, Steven J. Lubbe, Rudolph J. Castellani, Igor J. Koralnik

×

Total views: 4228


Tubulin tyrosine ligase variant perturbs microtubule tyrosination, causing hypertrophy in patient-specific and CRISPR gene-edited iPSC-cardiomyocytes
Pratul Kumar Jain, … , Minhajuddin Sirajuddin, Perundurai S. Dhandapany
Pratul Kumar Jain, … , Minhajuddin Sirajuddin, Perundurai S. Dhandapany
Published August 8, 2025
Citation Information: JCI Insight. 2025;10(15):e187942. https://doi.org/10.1172/jci.insight.187942.
View: Text | PDF
Research Article Cardiology Genetics Stem cells Article has an altmetric score of 1

Tubulin tyrosine ligase variant perturbs microtubule tyrosination, causing hypertrophy in patient-specific and CRISPR gene-edited iPSC-cardiomyocytes

  • Text
  • PDF
Abstract

Hypertrophic cardiomyopathy (HCM) is a hereditary heart condition characterized by either preserved or reduced ejection fraction without any underlying secondary causes. The primary cause of HCM is sarcomeric gene mutations, which account for only 40%–50% of the total cases. Here, we identified a pathogenic missense variant in tubulin tyrosine ligase (TTL p.G219S) in a patient with HCM. We used clinical, genetics, computational, and protein biochemistry approaches, as well as patient-specific and CRISPR gene-edited induced pluripotent stem cell–derived cardiomyocytes (iPSC-CMs), to demonstrate that the TTL pathogenic variant results in a reduced enzymatic activity and the accumulation of detyrosinated tubulin leading to the disruption of redox signaling, ultimately leading to HCM. Our findings highlight — for the first time to our knowledge — the crucial roles of the TTL variant in cardiac remodeling resulting in disease.

Authors

Pratul Kumar Jain, Susobhan Mahanty, Harshil Chittora, Veronique Henriot, Carsten Janke, Minhajuddin Sirajuddin, Perundurai S. Dhandapany

×

Total views: 2130


Stimulation of skeletal stem cells in the growth plate promotes linear bone growth
Dana Trompet, … , Maria Kasper, Andrei S. Chagin
Dana Trompet, … , Maria Kasper, Andrei S. Chagin
Published March 22, 2024
Citation Information: JCI Insight. 2024;9(6):e165226. https://doi.org/10.1172/jci.insight.165226.
View: Text | PDF
Research Article Bone biology Stem cells Article has an altmetric score of 2

Stimulation of skeletal stem cells in the growth plate promotes linear bone growth

  • Text
  • PDF
Abstract

Recently, skeletal stem cells were shown to be present in the epiphyseal growth plate (epiphyseal skeletal stem cells, epSSCs), but their function in connection with linear bone growth remains unknown. Here, we explore the possibility that modulating the number of epSSCs can correct differences in leg length. First, we examined regulation of the number and activity of epSSCs by Hedgehog (Hh) signaling. Both systemic activation of Hh pathway with Smoothened agonist (SAG) and genetic activation of Hh pathway by Patched1 (Ptch1) ablation in Pthrp-creER Ptch1fl/fl tdTomato mice promoted proliferation of epSSCs and clonal enlargement. Transient intra-articular administration of SAG also elevated the number of epSSCs. When SAG-containing beads were implanted into the femoral secondary ossification center of 1 leg of rats, this leg was significantly longer 1 month later than the contralateral leg implanted with vehicle-containing beads, an effect that was even more pronounced 2 and 6 months after implantation. We conclude that Hh signaling activates growth plate epSSCs, which effectively leads to increased longitudinal growth of bones. This opens therapeutic possibilities for the treatment of differences in leg length.

Authors

Dana Trompet, Anastasiia D. Kurenkova, Baoyi Zhou, Lei Li, Ostap Dregval, Anna P. Usanova, Tsz Long Chu, Alexandra Are, Andrei A. Nedorubov, Maria Kasper, Andrei S. Chagin

×

Total views: 1294


BCG immunization mitigates SARS-CoV-2 replication in macaques via monocyte efferocytosis and neutrophil recruitment in lungs
Mohammad Arif Rahman, … , Mark G. Lewis, Genoveffa Franchini
Mohammad Arif Rahman, … , Mark G. Lewis, Genoveffa Franchini
Published August 8, 2025
Citation Information: JCI Insight. 2025;10(15):e194633. https://doi.org/10.1172/jci.insight.194633.
View: Text | PDF
Research Article Immunology Infectious disease Article has an altmetric score of 3

BCG immunization mitigates SARS-CoV-2 replication in macaques via monocyte efferocytosis and neutrophil recruitment in lungs

  • Text
  • PDF
Abstract

Exposure to Bacillus Calmette-Guérin (BCG) or Canarypox ALVAC/Alum vaccine elicits pro- or antiinflammatory innate responses, respectively. We tested whether prior exposure of macaques to these immunogens protected against SARS-CoV-2 replication in lungs and found more efficient replication control after the pro-inflammatory immunity elicited by BCG. The decreased virus level in lungs was linked to early infiltrates of classical monocytes producing IL-8 with systemic neutrophils, Th2 cells, and Ki67+CD95+CD4+ T cells producing CCR7. At the time of SARS-CoV-2 exposure, BCG-treated animals had higher frequencies of lung infiltrating neutrophils and higher CD14+ cells expressing efferocytosis marker MERTK, responses correlating with decreased SARS-CoV-2 replication in lung. At the same time point, plasma IL-18, TNF-α, TNFSF-10, and VEGFA levels were also higher in the BCG group and correlated with decreased virus replication. Finally, after SARS-CoV-2 exposure, decreased virus replication correlated with neutrophils producing IL-10 and CCR7 preferentially recruited to the lungs of BCG-vaccinated animals. These data point to the importance of the spatiotemporal distribution of functional monocytes and neutrophils in controlling SARS-CoV-2 levels and suggest a central role of monocyte efferocytosis in curbing replication.

Authors

Mohammad Arif Rahman, Katherine C. Goldfarbmuren, Sarkis Sarkis, Massimiliano Bissa, Anna Gutowska, Luca Schifanella, Ramona Moles, Melvin N. Doster, Hanne Andersen, Yogita Jethmalani, Leonid Serebryannyy, Timothy Cardozo, Mark G. Lewis, Genoveffa Franchini

×

Total views: 1212


A prometabolite strategy inhibits cardiometabolic disease in an ApoE–/– murine model of atherosclerosis
Taryn N. Beckman, … , Eugene B. Chang, Jeffrey A. Hubbell
Taryn N. Beckman, … , Eugene B. Chang, Jeffrey A. Hubbell
Published August 8, 2025
Citation Information: JCI Insight. 2025;10(15):e191090. https://doi.org/10.1172/jci.insight.191090.
View: Text | PDF
Research Article Inflammation Therapeutics Article has an altmetric score of 1

A prometabolite strategy inhibits cardiometabolic disease in an ApoE–/– murine model of atherosclerosis

  • Text
  • PDF
Abstract

Butyrate, a microbiome-derived short-chain fatty acid with pleiotropic effects on inflammation and metabolism, has been shown to significantly reduce atherosclerotic lesions, rectify routine metabolic parameters such as low-density lipoprotein cholesterol (LDL-C), and reduce systemic inflammation in murine models of atherosclerosis. However, its foul odor, rapid metabolism in the gut and thus low systemic bioavailability limit its therapeutic effectiveness. Our laboratory has engineered an ester-linked L-serine conjugate to butyrate (SerBut) to mask its taste and odor and to coopt amino acid transporters in the gut to increase its systemic bioavailability, as determined by tissue measurements of free butyrate, produced by hydrolysis of SerBut. In an apolipoprotein E–knockout (ApoE)–/– mouse model of atherosclerosis, SerBut reduced systemic LDL-C, proinflammatory cytokines, and circulating neutrophils. SerBut enhanced inhibition of plaque progression and reduced monocyte accumulation in the aorta compared with sodium butyrate. SerBut suppressed liver injury biomarkers alanine transaminase and aspartate aminotransferase and suppressed steatosis in the liver. SerBut overcomes several barriers to the translation of butyrate and shows superior promise in slowing atherosclerosis and liver injury compared with equidosed sodium butyrate.

Authors

Taryn N. Beckman, Lisa R. Volpatti, Salvador Norton de Matos, Anna J. Slezak, Joseph W. Reda, Ada Weinstock, Leah Ziolkowski, Alex Turk, Erica Budina, Shijie Cao, Gustavo Borjas, Jung Woo Kwon, Orlando deLeon, Kirsten C. Refvik, Abigail L. Lauterbach, Suzana Gomes, Eugene B. Chang, Jeffrey A. Hubbell

×

Total views: 1157


Impaired AMPK control of alveolar epithelial cell metabolism promotes pulmonary fibrosis
Luis R. Rodríguez, … , Darrell N. Kotton, Michael F. Beers
Luis R. Rodríguez, … , Darrell N. Kotton, Michael F. Beers
Published July 1, 2025
Citation Information: JCI Insight. 2025;10(15):e182578. https://doi.org/10.1172/jci.insight.182578.
View: Text | PDF
Research Article Metabolism Pulmonology Article has an altmetric score of 10

Impaired AMPK control of alveolar epithelial cell metabolism promotes pulmonary fibrosis

  • Text
  • PDF
Abstract

Alveolar epithelial type II (AT2) cell dysfunction is implicated in the pathogenesis of familial and sporadic idiopathic pulmonary fibrosis (IPF). We previously demonstrated that expression of an AT2 cell–exclusive disease-associated protein isoform (SP-CI73T) in murine and patient-specific induced pluripotent stem cell–derived (iPSC-derived) AT2 cells leads to a block in late macroautophagy and promotes time-dependent mitochondrial impairments; however, how a metabolically dysfunctional AT2 cell results in fibrosis remains elusive. Here, using murine and human iPSC-derived AT2 cell models expressing SP-CI73T, we characterize the molecular mechanisms governing alterations in AT2 cell metabolism that lead to increased glycolysis, decreased mitochondrial biogenesis, disrupted fatty acid oxidation, accumulation of impaired mitochondria, and diminished AT2 cell progenitor capacity manifesting as reduced AT2 cell self-renewal and accumulation of transitional epithelial cells. We identify deficient AMPK signaling as a critical component of AT2 cell dysfunction and demonstrate that targeting this druggable signaling hub can rescue the aberrant AT2 cell metabolic phenotype and mitigate lung fibrosis in vivo.

Authors

Luis R. Rodríguez, Konstantinos-Dionysios Alysandratos, Jeremy Katzen, Aditi Murthy, Willy Roque Barboza, Yaniv Tomer, Sarah Bui, Rebeca Acín-Pérez, Anton Petcherski, Kasey Minakin, Paige Carson, Swati Iyer, Katrina Chavez, Charlotte H. Cooper, Apoorva Babu, Aaron I. Weiner, Andrew E. Vaughan, Zoltan Arany, Orian S. Shirihai, Darrell N. Kotton, Michael F. Beers

×

Total views: 1015


Spatial proteomics and transcriptomics reveal early immune cell organization in pancreatic intraepithelial neoplasia
Melissa R. Lyman, … , Won Jin Ho, Neeha Zaidi
Melissa R. Lyman, … , Won Jin Ho, Neeha Zaidi
Published June 26, 2025
Citation Information: JCI Insight. 2025;10(15):e191595. https://doi.org/10.1172/jci.insight.191595.
View: Text | PDF
Research Article Immunology Inflammation Oncology Article has an altmetric score of 18

Spatial proteomics and transcriptomics reveal early immune cell organization in pancreatic intraepithelial neoplasia

  • Text
  • PDF
Abstract

Pancreatic ductal adenocarcinoma (PDAC) has a poor survival rate due to late detection. PDAC arises from precursor microscopic lesions, termed pancreatic intraepithelial neoplasia (PanIN), that develop at least a decade before overt disease; this provides an opportunity to intercept PanIN-to-PDAC progression. However, immune interception strategies require full understanding of PanIN and PDAC cellular architecture. Surgical specimens containing PanIN and PDAC lesions from a unique cohort of 5 treatment-naive patients with PDAC were surveyed using spatial omics (proteomic and transcriptomic). Findings were corroborated by spatial proteomics of PanIN and PDAC from tamoxifen-inducible KPC mice. We uncovered the organization of lymphoid cells into tertiary lymphoid structures (TLSs) adjacent to PanIN lesions. These TLSs lacked CD21+CD23+ B cells compared with more mature TLSs near the PDAC border. PanINs harbored mostly CD4+ T cells, with fewer Tregs and exhausted T cells than PDAC. Peritumoral space was enriched with naive CD4+ and central memory T cells. These observations highlight the opportunity to modulate the immune microenvironment in PanINs before immune exclusion and immunosuppression emerge during progression into PDAC.

Authors

Melissa R. Lyman, Jacob T. Mitchell, Sidharth Raghavan, Luciane T. Kagohara, Amanda L. Huff, Saurav D. Haldar, Sarah M. Shin, Samantha Guinn, Benjamin Barrett, Gabriella Longway, Alexei Hernandez, Erin M. Coyne, Xuan Yuan, Lalitya Andaloori, Jiaying Lai, Yun Zhou Liu, Rachel Karchin, Anuj Gupta, Ashley L. Kiemen, André Forjaz, Denis Wirtz, Pei-Hsun Wu, Atul Deshpande, Jae W. Lee, Todd D. Armstrong, Nilofer S. Azad, Jacquelyn W. Zimmerman, Laura D. Wood, Robert A. Anders, Elizabeth D. Thompson, Elizabeth M. Jaffee, Elana J. Fertig, Won Jin Ho, Neeha Zaidi

×

Total views: 1005


Chimeric antigen receptor macrophages target and resorb amyloid plaques
Alexander B. Kim, … , Jin-Moo Lee, Carl J. DeSelm
Alexander B. Kim, … , Jin-Moo Lee, Carl J. DeSelm
Published March 22, 2024
Citation Information: JCI Insight. 2024;9(6):e175015. https://doi.org/10.1172/jci.insight.175015.
View: Text | PDF
Resource and Technical Advance Aging Therapeutics Article has an altmetric score of 27

Chimeric antigen receptor macrophages target and resorb amyloid plaques

  • Text
  • PDF
Abstract

Substantial evidence suggests a role for immunotherapy in treating Alzheimer’s disease (AD). While the precise pathophysiology of AD is incompletely understood, clinical trials of antibodies targeting aggregated forms of β amyloid (Aβ) have shown that reducing amyloid plaques can mitigate cognitive decline in patients with early-stage AD. Here, we describe what we believe to be a novel approach to target and degrade amyloid plaques by genetically engineering macrophages to express an Aβ-targeting chimeric antigen receptor (CAR-Ms). When injected intrahippocampally, first-generation CAR-Ms have limited persistence and fail to significantly reduce plaque load, which led us to engineer next-generation CAR-Ms that secrete M-CSF and self-maintain without exogenous cytokines. Cytokine secreting “reinforced CAR-Ms” have greater survival in the brain niche and significantly reduce plaque load locally in vivo. These findings support CAR-Ms as a platform to rationally target, resorb, and degrade pathogenic material that accumulates with age, as exemplified by targeting Aβ in AD.

Authors

Alexander B. Kim, Qingli Xiao, Ping Yan, Qiuyun Pan, Gaurav Pandey, Susie Grathwohl, Ernesto Gonzales, Isabella Xu, Yoonho Cho, Hans Haecker, Slava Epelman, Abhinav Diwan, Jin-Moo Lee, Carl J. DeSelm

×

Total views: 893


STAC3 binding to CaV1.1 II-III loop is nonessential but critically supports skeletal muscle excitation-contraction coupling
Wietske E. Tuinte, … , Adele D’Amico, Marta Campiglio
Wietske E. Tuinte, … , Adele D’Amico, Marta Campiglio
Published August 8, 2025
Citation Information: JCI Insight. 2025;10(15):e191053. https://doi.org/10.1172/jci.insight.191053.
View: Text | PDF
Research Article Muscle biology Neuroscience Article has an altmetric score of 1

STAC3 binding to CaV1.1 II-III loop is nonessential but critically supports skeletal muscle excitation-contraction coupling

  • Text
  • PDF
Abstract

Skeletal muscle excitation-contraction (EC) coupling depends on the direct coupling between CaV1.1 on the sarcolemma and ryanodine receptor (RyR1) on the sarcoplasmic reticulum. A key regulator of this process is STAC3, a protein essential for both the functional expression of CaV1.1 and its conformational coupling with RyR1. Mutations in Stac3 cause STAC3 disorder, a congenital myopathy characterized by muscle weakness. STAC3 interacts with CaV1.1 in 2 key regions: the II-III loop and the proximal C-terminus. While the II-III loop has been previously found to be essential for skeletal muscle EC coupling, here we demonstrated that the interaction between STAC3 and the proximal C-terminus is necessary and sufficient for CaV1.1 functional expression and minimal EC coupling. In contrast, the interaction with the II-III loop is not essential for EC coupling, though it plays a facilitating role in enhancing the process. Supporting this finding, we identified a patient with STAC3 disorder carrying a mutation that deletes the domain of STAC3 involved in the II-III loop interaction. Collectively, our results established that STAC3 binding to CaV1.1 C-terminus is essential for its functional expression, whereas STAC3 interaction with the II-III loop serves to enhance the conformational coupling with RyR1.

Authors

Wietske E. Tuinte, Enikő Török, Petronel Tuluc, Fabiana Fattori, Adele D’Amico, Marta Campiglio

×

Total views: 891


NAT10-mediated ac4C modification of Lipin1 mRNA contributes to the pathogenesis of PWMI
Xinyu Li, … , Xiue Wei, Ruiqin Yao
Xinyu Li, … , Xiue Wei, Ruiqin Yao
Published August 8, 2025
Citation Information: JCI Insight. 2025;10(15):e193712. https://doi.org/10.1172/jci.insight.193712.
View: Text | PDF
Research Article Cell biology Neuroscience Article has an altmetric score of 1

NAT10-mediated ac4C modification of Lipin1 mRNA contributes to the pathogenesis of PWMI

  • Text
  • PDF
Abstract

Preterm white matter injury (PWMI) is a leading cause of cerebral palsy and chronic neurological disabilities in premature infants. It is characterized by defects in oligodendrocyte precursor cell (OPC) differentiation and dysmyelination. Currently, there are no effective therapeutic strategies available in clinical practice. Lipid homeostasis plays a crucial role in myelin development, yet the function of Lipin1 — a key phosphatidic acid phosphatase involved in phospholipid synthesis — remains unclear. In this study, we identified a significant downregulation of Lipin1 in OPCs from PWMI mice, which impaired OPC differentiation and myelin formation. Conversely, Lipin1 overexpression in these mice promoted OPC maturation and enhanced myelin development. We found evidence that N-acetyltransferase 10 (NAT10) acts as a regulator of Lipin1 expression through RNA pull-down and mass spectrometry. NAT10-mediated N4-acetylcytidine (ac4C) modification enhanced Lipin1 mRNA stability and translation, and NAT10 knockdown in OPCs impaired myelination, highlighting its crucial role in Lipin1-mediated myelination. Our study revealed that the downregulation of Lipin1 impaired OPC differentiation and myelination in PWMI, with NAT10-mediated ac4C modification playing a critical role in regulating Lipin1 expression. These findings highlight Lipin1 and NAT10 as promising therapeutic targets for treating myelination defects in PWMI, warranting further investigation into their potential in preterm birth–related neurological disorders.

Authors

Xinyu Li, Meng Zhang, Yanan Liu, Chunjie Guo, Yiwei Liu, Lei Han, Zhaowei Feng, Xiue Wei, Ruiqin Yao

×

Total views: 885

Show more results

Advertisement

Copyright © 2025 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts

Referenced by 1 Bluesky users
See more details
Posted by 7 X users
Referenced by 2 Bluesky users
See more details
Posted by 36 X users
Referenced by 1 Bluesky users
8 readers on Mendeley
See more details
Referenced by 1 Bluesky users
See more details
Referenced by 1 Bluesky users
See more details
Referenced by 2 Bluesky users
See more details
Picked up by 73 news outlets
Blogged by 2
Posted by 186 X users
Referenced in 2 Wikipedia pages
Referenced by 151 Bluesky users
5 readers on Mendeley
See more details
Posted by 8 X users
Referenced by 7 Bluesky users
8 readers on Mendeley
See more details
Posted by 2 X users
Reddited by 1
7 readers on Mendeley
See more details
Picked up by 1 news outlets
Posted by 33 X users
27 readers on Mendeley
See more details