Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Resource and Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact

  • 3,186 Articles
  • 0 Posts
  • ← Previous
  • 1
  • 2
  • 3
  • …
  • 318
  • 319
  • Next →
Alleviation of neuropathic pain with neuropeptide Y requires spinal Npy1r interneurons that coexpress Grp
Tyler S. Nelson, … , Andrew J. Todd, Bradley K. Taylor
Tyler S. Nelson, … , Andrew J. Todd, Bradley K. Taylor
Published October 12, 2023
Citation Information: JCI Insight. 2023;8(22):e169554. https://doi.org/10.1172/jci.insight.169554.
View: Text | PDF

Alleviation of neuropathic pain with neuropeptide Y requires spinal Npy1r interneurons that coexpress Grp

  • Text
  • PDF
Abstract

Neuropeptide Y targets the Y1 receptor (Y1) in the spinal dorsal horn (DH) to produce endogenous and exogenous analgesia. DH interneurons that express Y1 (Y1-INs; encoded by Npy1r) are necessary and sufficient for neuropathic hypersensitivity after peripheral nerve injury. However, as Y1-INs are heterogenous in composition in terms of morphology, neurophysiological characteristics, and gene expression, we hypothesized that a more precisely defined subpopulation mediates neuropathic hypersensitivity. Using fluorescence in situ hybridization, we found that Y1-INs segregate into 3 largely nonoverlapping subpopulations defined by the coexpression of Npy1r with gastrin-releasing peptide (Grp/Npy1r), neuropeptide FF (Npff/Npy1r), and cholecystokinin (Cck/Npy1r) in the superficial DH of mice, nonhuman primates, and humans. Next, we analyzed the functional significance of Grp/Npy1r, Npff/Npy1r, and Cck/Npy1r INs to neuropathic pain using a mouse model of peripheral nerve injury. We found that chemogenetic inhibition of Npff/Npy1r-INs did not change the behavioral signs of neuropathic pain. Further, inhibition of Y1-INs with an intrathecal Y1 agonist, [Leu31, Pro34]-NPY, reduced neuropathic hypersensitivity in mice with conditional deletion of Npy1r from CCK-INs and NPFF-INs but not from GRP-INs. We conclude that Grp/Npy1r-INs are conserved in higher order mammalian species and represent a promising and precise pharmacotherapeutic target for the treatment of neuropathic pain.

Authors

Tyler S. Nelson, Heather N. Allen, Paramita Basu, Pranav Prasoon, Eileen Nguyen, Cynthia M. Arokiaraj, Diogo F.S. Santos, Rebecca P. Seal, Sarah E. Ross, Andrew J. Todd, Bradley K. Taylor

×

GADD45A is a mediator of mitochondrial loss, atrophy, and weakness in skeletal muscle
George R. Marcotte, … , Scott M. Ebert, Christopher M. Adams
George R. Marcotte, … , Scott M. Ebert, Christopher M. Adams
Published October 10, 2023
Citation Information: JCI Insight. 2023;8(22):e171772. https://doi.org/10.1172/jci.insight.171772.
View: Text | PDF

GADD45A is a mediator of mitochondrial loss, atrophy, and weakness in skeletal muscle

  • Text
  • PDF
Abstract

Aging and many illnesses and injuries impair skeletal muscle mass and function, but the molecular mechanisms are not well understood. To better understand the mechanisms, we generated and studied transgenic mice with skeletal muscle–specific expression of growth arrest and DNA damage inducible α (GADD45A), a signaling protein whose expression in skeletal muscle rises during aging and a wide range of illnesses and injuries. We found that GADD45A induced several cellular changes that are characteristic of skeletal muscle atrophy, including a reduction in skeletal muscle mitochondria and oxidative capacity, selective atrophy of glycolytic muscle fibers, and paradoxical expression of oxidative myosin heavy chains despite mitochondrial loss. These cellular changes were at least partly mediated by MAP kinase kinase kinase 4, a protein kinase that is directly activated by GADD45A. By inducing these changes, GADD45A decreased the mass of muscles that are enriched in glycolytic fibers, and it impaired strength, specific force, and endurance exercise capacity. Furthermore, as predicted by data from mouse models, we found that GADD45A expression in skeletal muscle was associated with muscle weakness in humans. Collectively, these findings identify GADD45A as a mediator of mitochondrial loss, atrophy, and weakness in mouse skeletal muscle and a potential target for muscle weakness in humans.

Authors

George R. Marcotte, Matthew J. Miller, Hawley E. Kunz, Zachary C. Ryan, Matthew D. Strub, Patrick M. Vanderboom, Carrie J. Heppelmann, Sarah Chau, Zachary D. Von Ruff, Sean P. Kilroe, Andrew T. McKeen, Jason M. Dierdorff, Jennifer I. Stern, Karl A. Nath, Chad E. Grueter, Vitor A. Lira, Andrew R. Judge, Blake B. Rasmussen, K. Sreekumaran Nair, Ian R. Lanza, Scott M. Ebert, Christopher M. Adams

×

Functional Pdgfra fibroblast heterogeneity in normal and fibrotic mouse lung
Carol S. Trempus, … , Anne K. Perl, Stavros Garantziotis
Carol S. Trempus, … , Anne K. Perl, Stavros Garantziotis
Published October 12, 2023
Citation Information: JCI Insight. 2023;8(22):e164380. https://doi.org/10.1172/jci.insight.164380.
View: Text | PDF

Functional Pdgfra fibroblast heterogeneity in normal and fibrotic mouse lung

  • Text
  • PDF
Abstract

Aberrant fibroblast function plays a key role in the pathogenesis of idiopathic pulmonary fibrosis, a devastating disease of unrelenting extracellular matrix deposition in response to lung injury. Platelet-derived growth factor α–positive (Pdgfra+) lipofibroblasts (LipoFBs) are essential for lung injury response and maintenance of a functional alveolar stem cell niche. Little is known about the effects of lung injury on LipoFB function. Here, we used single-cell RNA-Seq (scRNA-Seq) technology and PdgfraGFP lineage tracing to generate a transcriptomic profile of Pdgfra+ fibroblasts in normal and injured mouse lungs 14 days after bleomycin exposure, generating 11 unique transcriptomic clusters that segregated according to treatment. While normal and injured LipoFBs shared a common gene signature, injured LipoFBs acquired fibrogenic pathway activity with an attenuation of lipogenic pathways. In a 3D organoid model, injured Pdgfra+ fibroblast–supported organoids were morphologically distinct from those cultured with normal fibroblasts, and scRNA-Seq analysis suggested distinct transcriptomic changes in alveolar epithelia supported by injured Pdgfra+ fibroblasts. In summary, while LipoFBs in injured lung have not migrated from their niche and retain their lipogenic identity, they acquire a potentially reversible fibrogenic profile, which may alter the kinetics of epithelial regeneration and potentially contribute to dysregulated repair, leading to fibrosis.

Authors

Carol S. Trempus, Brian N. Papas, Maria I. Sifre, Carl D. Bortner, Erica Scappini, Charles J. Tucker, Xin Xu, Katina L. Johnson, Leesa J. Deterding, Jason G. Williams, Dylan J. Johnson, Jian-Liang Li, Deloris Sutton, Charan Ganta, Debabrata Mahapatra, Muhammad Arif, Abhishek Basu, Lenny Pommerolle, Resat Cinar, Anne K. Perl, Stavros Garantziotis

×

Airway surveillance and lung viral control by memory T cells induced by COVID-19 mRNA vaccine
Brock Kingstad-Bakke, … , Yoshihiro Kawaoka, M. Suresh
Brock Kingstad-Bakke, … , Yoshihiro Kawaoka, M. Suresh
Published October 5, 2023
Citation Information: JCI Insight. 2023;8(22):e172510. https://doi.org/10.1172/jci.insight.172510.
View: Text | PDF

Airway surveillance and lung viral control by memory T cells induced by COVID-19 mRNA vaccine

  • Text
  • PDF
Abstract

Although SARS-CoV-2 evolution seeds a continuous stream of antibody-evasive viral variants, COVID-19 mRNA vaccines provide robust protection against severe disease and hospitalization. Here, we asked whether mRNA vaccine–induced memory T cells limit lung SARS-CoV-2 replication and severe disease. We show that mice and humans receiving booster BioNTech mRNA vaccine developed potent CD8 T cell responses and showed similar kinetics of expansion and contraction of granzyme B/perforin-expressing effector CD8 T cells. Both monovalent and bivalent mRNA vaccines elicited strong expansion of a heterogeneous pool of terminal effectors and memory precursor effector CD8 T cells in spleen, inguinal and mediastinal lymph nodes, pulmonary vasculature, and most surprisingly in the airways, suggestive of systemic and regional surveillance. Furthermore, we document that: (a) CD8 T cell memory persists in multiple tissues for > 200 days; (b) following challenge with pathogenic SARS-CoV-2, circulating memory CD8 T cells rapidly extravasate to the lungs and promote expeditious viral clearance, by mechanisms that require CD4 T cell help; and (c) adoptively transferred splenic memory CD8 T cells traffic to the airways and promote lung SARS-CoV-2 clearance. These findings provide insights into the critical role of memory T cells in preventing severe lung disease following breakthrough infections with antibody-evasive SARS-CoV-2 variants.

Authors

Brock Kingstad-Bakke, Thomas Cleven, Hailey Bussan, Boyd L. Yount Jr., Ryuta Uraki, Kiyoko Iwatsuki-Horimoto, Michiko Koga, Shinya Yamamoto, Hiroshi Yotsuyanagi, Hongtae Park, Jay S. Mishra, Sathish Kumar, Ralph S. Baric, Peter J. Halfmann, Yoshihiro Kawaoka, M. Suresh

×

Endothelial transcriptomic analysis identifies biomarkers of severe and cerebral malaria
Cláudia Gomes, … , Quique Bassat, Ana Rodriguez
Cláudia Gomes, … , Quique Bassat, Ana Rodriguez
Published October 3, 2023
Citation Information: JCI Insight. 2023;8(22):e172845. https://doi.org/10.1172/jci.insight.172845.
View: Text | PDF

Endothelial transcriptomic analysis identifies biomarkers of severe and cerebral malaria

  • Text
  • PDF
Abstract

Malaria can quickly progress from an uncomplicated infection into a life-threatening severe disease. However, the unspecificity of early symptoms often makes it difficult to identify patients at high risk of developing severe disease. Additionally, one of the most feared malaria complications — cerebral malaria — is challenging to diagnose, often resulting in treatment delays that can lead to adverse outcomes. To identify candidate biomarkers for the prognosis and/or diagnosis of severe and cerebral malaria, we have analyzed the transcriptomic response of human brain microvascular endothelial cells to erythrocytes infected with Plasmodium falciparum. Candidates were validated in plasma samples from a cohort of pediatric patients with malaria from Mozambique, resulting in the identification of several markers with capacity to distinguish uncomplicated from severe malaria, the most potent being the metallopeptidase ADAMTS18. Two other biomarkers, Angiopoietin-like-4 and Inhibin-βE were able to differentiate children with cerebral malaria within the severe malaria group, showing increased sensitivity after combination in a biomarker signature. The validation of the predicted candidate biomarkers in plasma of children with severe and cerebral malaria underscores the power of this transcriptomic approach and indicates that a specific endothelial response to P. falciparum–infected erythrocytes is linked to the pathophysiology of severe malaria.

Authors

Cláudia Gomes, Rosauro Varo, Miquel Duran-Frigola, Antonio Sitoe, Rubão Bila, Sonia Machevo, Alfredo Mayor, Quique Bassat, Ana Rodriguez

×

Cell-based screen identifies porphyrins as FGFR3 activity inhibitors with therapeutic potential for achondroplasia and cancer
Yun-Wen Lin, … , Yuan-Tsong Chen, Yi-Ching Lee
Yun-Wen Lin, … , Yuan-Tsong Chen, Yi-Ching Lee
Published October 12, 2023
Citation Information: JCI Insight. 2023;8(22):e171257. https://doi.org/10.1172/jci.insight.171257.
View: Text | PDF

Cell-based screen identifies porphyrins as FGFR3 activity inhibitors with therapeutic potential for achondroplasia and cancer

  • Text
  • PDF
Abstract

Overactive fibroblast growth factor receptor 3 (FGFR3) signaling drives pathogenesis in a variety of cancers and a spectrum of short-limbed bone dysplasias, including the most common form of human dwarfism, achondroplasia (ACH). Targeting FGFR3 activity holds great promise as a therapeutic approach for treatment of these diseases. Here, we established a receptor/adaptor translocation assay system that can specifically monitor FGFR3 activation, and we applied it to identify FGFR3 modulators from complex natural mixtures. An FGFR3-suppressing plant extract of Amaranthus viridis was identified from the screen, and 2 bioactive porphyrins, pheophorbide a (Pa) and pyropheophorbide a, were sequentially isolated from the extract and functionally characterized. Further analysis showed that Pa reduced excessive FGFR3 signaling by decreasing its half-life in FGFR3-overactivated multiple myeloma cells and chondrocytes. In an ex vivo culture system, Pa alleviated defective long bone growth in humanized ACH mice (FGFR3ACH mice). Overall, our study presents an approach to discovery and validation of plant extracts or drug candidates that target FGFR3 activation. The compounds identified by this approach may have applications as therapeutics for FGFR3-associated cancers and skeletal dysplasias.

Authors

Yun-Wen Lin, Hsiao-Jung Kao, Wei-Ting Chen, Cheng-Fu Kao, Jer-Yuarn Wu, Yuan-Tsong Chen, Yi-Ching Lee

×

Dormant tumors circumvent tumor-specific adaptive immunity by establishing a Treg-dominated niche via DKK3
Timothy N. Trotter, … , H. Kim Lyerly, Zachary C. Hartman
Timothy N. Trotter, … , H. Kim Lyerly, Zachary C. Hartman
Published October 17, 2023
Citation Information: JCI Insight. 2023;8(22):e174458. https://doi.org/10.1172/jci.insight.174458.
View: Text | PDF

Dormant tumors circumvent tumor-specific adaptive immunity by establishing a Treg-dominated niche via DKK3

  • Text
  • PDF
Abstract

Approximately 30% of breast cancer survivors deemed free of disease will experience locoregional or metastatic recurrence even up to 30 years after initial diagnosis, yet how residual/dormant tumor cells escape immunity elicited by the primary tumor remains unclear. We demonstrate that intrinsically dormant tumor cells are indeed recognized and lysed by antigen-specific T cells in vitro and elicit robust immune responses in vivo. However, despite close proximity to CD8+ killer T cells, dormant tumor cells themselves support early accumulation of protective FoxP3+ T regulatory cells (Tregs), which can be targeted to reduce tumor burden. These intrinsically dormant tumor cells maintain a hybrid epithelial/mesenchymal state that is associated with immune dysfunction, and we find that the tumor-derived, stem cell/basal cell protein Dickkopf WNT signaling pathway inhibitor 3 (DKK3) is critical for Treg inhibition of CD8+ T cells. We also demonstrate that DKK3 promotes immune-mediated progression of proliferative tumors and is significantly associated with poor survival and immunosuppression in human breast cancers. Together, these findings reveal that latent tumors can use fundamental mechanisms of tolerance to alter the T cell microenvironment and subvert immune detection. Thus, targeting these pathways, such as DKK3, may help render dormant tumors susceptible to immunotherapies.

Authors

Timothy N. Trotter, Carina E. Dagotto, Delila Serra, Tao Wang, Xiao Yang, Chaitanya R. Acharya, Junping Wei, Gangjun Lei, H. Kim Lyerly, Zachary C. Hartman

×

Incretin effect determines glucose trajectory and insulin sensitivity in youths with obesity
Alfonso Galderisi, … , Nicola Santoro, Sonia Caprio
Alfonso Galderisi, … , Nicola Santoro, Sonia Caprio
Published October 17, 2023
Citation Information: JCI Insight. 2023;8(22):e165709. https://doi.org/10.1172/jci.insight.165709.
View: Text | PDF

Incretin effect determines glucose trajectory and insulin sensitivity in youths with obesity

  • Text
  • PDF
Abstract

In youths with obesity, the gut hormone potentiation of insulin secretion — the incretin effect — is blunted. We explored the longitudinal impact of the incretin effect during pubertal transition on β cell function and insulin sensitivity. Youths with obesity and 2-hour glucose level ≥ 120 mg/dL underwent a 3-hour oral glucose-tolerance test (OGTT) and an isoglycemic i.v. glucose infusion to quantify the incretin effect. After 2 years, 30 of 39 participants had a repeated OGTT and were stratified into 3 tertiles according to the baseline incretin effect. The high–incretin effect group demonstrated a longitudinal increase in β cell function (disposition index, minimal model [DIMM]), with greater insulin sensitivity at follow-up and stable insulin secretion (φtotal). A lower incretin effect at baseline was associated with higher 1-hour and 2-hour glucose level at follow-up. The high–incretin effect group displayed a greater increase of GLP-17–36 than the moderate- and low-incretin group at baseline, while such a difference did not persist after 2 years. Glucagon suppression was reduced at follow-up in those with low-baseline incretin in respect to the high-incretin group. The incretin effect during pubertal transition affected the longitudinal trajectory of β cell function and weight in youths with obesity.

Authors

Alfonso Galderisi, Domenico Tricò, Jessica Lat, Stephanie Samuels, Ram Weiss, Michelle Van Name, Bridget Pierpont, Nicola Santoro, Sonia Caprio

×

Homeostatic cytokines reciprocally modulate the emergence of prenatal effector PLZF+CD4+ T cells in humans
Veronica Locher, … , Gabriela K. Fragiadakis, Joanna Halkias
Veronica Locher, … , Gabriela K. Fragiadakis, Joanna Halkias
Published October 19, 2023
Citation Information: JCI Insight. 2023;8(22):e164672. https://doi.org/10.1172/jci.insight.164672.
View: Text | PDF

Homeostatic cytokines reciprocally modulate the emergence of prenatal effector PLZF+CD4+ T cells in humans

  • Text
  • PDF
Abstract

The development of human prenatal adaptive immunity progresses faster than previously appreciated, with the emergence of memory CD4+ T cells alongside regulatory T cells by midgestation. We previously identified a prenatal specific population of promyelocytic leukemia zinc finger–positive (PLZF+) CD4+ T cells with heightened effector potential that were enriched in the developing intestine and accumulated in the cord blood of infants exposed to prenatal inflammation. However, the signals that drive their tissue distribution and effector maturation are unknown. Here, we define the transcriptional and functional heterogeneity of human prenatal PLZF+CD4+ T cells and identify the compartmentalization of T helper–like (Th-like) effector function across the small intestine (SI) and mesenteric lymph nodes (MLNs). IL-7 was more abundant in the SI relative to the MLNs and drove the preferential expansion of naive PLZF+CD4+ T cells via enhanced STAT5 and MEK/ERK signaling. Exposure to IL-7 was sufficient to induce the acquisition of CD45RO expression and rapid effector function in a subset of PLZF+CD4+ T cells, identifying a human analog of memory phenotype CD4+ T cells. Further, IL-7 modulated the differentiation of Th1- and Th17-like PLZF+CD4+ T cells and thus likely contributes to the anatomic compartmentalization of human prenatal CD4+ T cell effector function.

Authors

Veronica Locher, Sara Park, Daniel G. Bunis, Stephanie Makredes, Margareta Mayer, Trevor D. Burt, Gabriela K. Fragiadakis, Joanna Halkias

×

Biallelic MAD2L1BP (p31comet) mutation is associated with mosaic aneuploidy and juvenile granulosa cell tumors
Ghada M. H. Abdel-Salam, … , Susanne Strand, Hanno J. Bolz
Ghada M. H. Abdel-Salam, … , Susanne Strand, Hanno J. Bolz
Published October 5, 2023
Citation Information: JCI Insight. 2023;8(22):e170079. https://doi.org/10.1172/jci.insight.170079.
View: Text | PDF

Biallelic MAD2L1BP (p31comet) mutation is associated with mosaic aneuploidy and juvenile granulosa cell tumors

  • Text
  • PDF
Abstract

MAD2L1BP-encoded p31comet mediates Trip13-dependent disassembly of Mad2- and Rev7-containing complexes and, through this antagonism, promotes timely spindle assembly checkpoint (SAC) silencing, faithful chromosome segregation, insulin signaling, and homology-directed repair (HDR) of DNA double-strand breaks. We identified a homozygous MAD2L1BP nonsense variant, R253*, in 2 siblings with microcephaly, epileptic encephalopathy, and juvenile granulosa cell tumors of ovary and testis. Patient-derived cells exhibited high-grade mosaic variegated aneuploidy, slowed-down proliferation, and instability of truncated p31comet mRNA and protein. Corresponding recombinant p31comet was defective in Trip13, Mad2, and Rev7 binding and unable to support SAC silencing or HDR. Furthermore, C-terminal truncation abrogated an identified interaction of p31comet with tp53. Another homozygous truncation, R227*, detected in an early-deceased patient with low-level aneuploidy, severe epileptic encephalopathy, and frequent blood glucose elevations, likely corresponds to complete loss of function, as in Mad2l1bp–/– mice. Thus, human mutations of p31comet are linked to aneuploidy and tumor predisposition.

Authors

Ghada M. H. Abdel-Salam, Susanne Hellmuth, Elise Gradhand, Stephan Käseberg, Jennifer Winter, Ann-Sophie Pabst, Maha M. Eid, Holger Thiele, Peter Nürnberg, Birgit S. Budde, Mohammad Reza Toliat, Ines B. Brecht, Christopher Schroeder, Axel Gschwind, Stephan Ossowski, Friederike Häuser, Heidi Rossmann, Mohamed S. Abdel-Hamid, Ibrahim Hegazy, Ahmed G. Mohamed, Dominik T. Schneider, Aida Bertoli-Avella, Peter Bauer, Jillian N. Pearring, Rolph Pfundt, Alexander Hoischen, Christian Gilissen, Dennis Strand, Ulrich Zechner, Soha A. Tashkandi, Eissa A. Faqeih, Olaf Stemmann, Susanne Strand, Hanno J. Bolz

×
  • ← Previous
  • 1
  • 2
  • 3
  • …
  • 318
  • 319
  • Next →

No posts were found with this tag.

Advertisement

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts