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Research Letter

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Differential BK channel potentiation by vanzacaftor enantiomers enables therapy for modulator-ineligible people with cystic fibrosis
Nathalie Baumlin, … , Frank Horrigan, Matthias Salathe
Nathalie Baumlin, … , Frank Horrigan, Matthias Salathe
Published August 7, 2025
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI191824.
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Differential BK channel potentiation by vanzacaftor enantiomers enables therapy for modulator-ineligible people with cystic fibrosis

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Abstract

Authors

Nathalie Baumlin, Sumedha Gunewardena, Scott H. Randell, Frank Horrigan, Matthias Salathe

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Early CD4+ T-cell proliferative burst and chronic T-cell engagement impact myeloma outcomes following T-cell engager therapy
Alyssa M. Duffy, … , Madhav V. Dhodapkar, Kavita M. Dhodapkar
Alyssa M. Duffy, … , Madhav V. Dhodapkar, Kavita M. Dhodapkar
Published July 31, 2025
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI192927.
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Early CD4+ T-cell proliferative burst and chronic T-cell engagement impact myeloma outcomes following T-cell engager therapy

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Abstract

Authors

Alyssa M. Duffy, Anshika Goenka, Maryam I. Azeem, Azmain Taz, Sayalee V. Potdar, Sara A. Scott, Ellen Marin, Jonathan L. Kaufman, Craig C. Hofmeister, Nisha S. Joseph, Vikas A. Gupta, Sagar Lonial, Ajay K. Nooka, Madhav V. Dhodapkar, Kavita M. Dhodapkar

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Elesclomol-copper therapy improves neurodevelopment in two children with Menkes disease
Elena Godoy-Molina, … , Vishal M. Gohil, Francesc Palau
Elena Godoy-Molina, … , Vishal M. Gohil, Francesc Palau
Published July 29, 2025
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI193107.
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Elesclomol-copper therapy improves neurodevelopment in two children with Menkes disease

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Abstract

Authors

Elena Godoy-Molina, Natalia L. Serrano, Aquilina Jiménez-González, Miquel Villaronga, Rosa M. Marqués Pérez-Bryan, Rubén Varela-Fernández, Stephanie Lotz-Esquivel, Alba Hevia Tuñón, Prachi P. Trivedi, Nina Horn, Joseph F. Standing, Víctor Mangas-Sanjuan, Mercè Capdevila, Aurora Mateos, Denis Broun, Svetlana Lutsenko, Ines Medina-Rivera, Rafael Artuch, Cristina Jou, Mònica Roldán, Pedro Arango-Sancho, Mónica Saez-Villafañe, Juan J. Ortiz-de-Urbina, Angela Pieras-López, Marta Duero, Rosa Farré, Jordi Pijuan, Janet Hoenicka, James C. Sacchettini, Michael J. Petris, Vishal M. Gohil, Francesc Palau

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Type 1 Classical Dendritic Cells Govern Long-term Cardiac Allograft Acceptance
Macee C. Owen, … , Daniel Kreisel, Kory J. Lavine
Macee C. Owen, … , Daniel Kreisel, Kory J. Lavine
Published July 8, 2025
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI192811.
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Type 1 Classical Dendritic Cells Govern Long-term Cardiac Allograft Acceptance

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Abstract

Authors

Macee C. Owen, Vinay R. Penna, Hao Dun, Wenjun Li, Benjamin J. Kopecky, Kenneth M. Murphy, Daniel Kreisel, Kory J. Lavine

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Hyperactivated Interferon-gamma Pathways in Perianal Fistulizing Crohn’s Disease by Single-Cell and Spatial Multi-omics
Siyan Cao, … , Marco Colonna, Parakkal Deepak
Siyan Cao, … , Marco Colonna, Parakkal Deepak
Published July 3, 2025
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI193413.
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Hyperactivated Interferon-gamma Pathways in Perianal Fistulizing Crohn’s Disease by Single-Cell and Spatial Multi-omics

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Abstract

Perianal fistulizing Crohn’s disease (PCD) is a common and debilitating complication with elusive pathophysiology. To define actionable immunologic targets in PCD, we recruited patients with PCD (n = 24), CD without perianal disease (NPCD, n = 10), and idiopathic/cryptoglandular perianal fistulas (IPF, n = 29). Biopsies from fistula tracts, fistula opening, and rectal mucosa were analyzed using single-cell RNA-sequencing (scRNA-seq), mass cytometry (CyTOF), and spatial transcriptomics (ST). Global hyperactivation of IFN-g pathways distinguished PCD from idiopathic perianal fistulas and CD without perianal disease in the fistula tracts and/or intestinal mucosa. IFN-g and TNF-a signaling directly induced genes involved in epithelial-to-mesenchymal transition in PCD rectal epithelial cells. Enhanced IFN-g signaling in PCD was driven by pathogenic Th17 (pTh17) cells, which were recruited and activated by myeloid cells overexpressing LPS signature (LPS_myeloid). pTh17 and LPS_myeloid cells co-localized adjacent to PCD fistula tracts on ST and drove local IFN-g signaling. Anti-TNFs facilitated fistula healing by downregulating T and myeloid cell signatures, while promoting mucosal barrier repair and immunoregulatory processes. Key single-cell findings were validated by bulk RNA-seq data of an independent CD cohort. To summarize, we identified IFN-g-driven mechanisms contributing to pathogenesis and highlighted its blockade as a therapeutic strategy for PCD.

Authors

Siyan Cao, Khai M. Nguyen, Kaiming Ma, Tingyi Tan, Xin Yao, Ta-Chiang Liu, Malek Ayoub, Jalpa Devi, Sami Samaan, Yizhou Liu, Radhika Smith, Matthew L. Silviera, Steven R. Hunt, Paul E. Wise, Matthew G. Mutch, Sean C. Glasgow, William C. Chapman Jr, Michelle L. Cowan, Mathew A. Ciorba, Marco Colonna, Parakkal Deepak

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Targeting the IL-36 receptor with spesolimab mitigates residual inflammation and prevents generalized pustular psoriasis flares
James G. Krueger, … , Christian Thoma, Johann E. Gudjonsson
James G. Krueger, … , Christian Thoma, Johann E. Gudjonsson
Published July 1, 2025
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI188530.
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Targeting the IL-36 receptor with spesolimab mitigates residual inflammation and prevents generalized pustular psoriasis flares

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Abstract

Authors

James G. Krueger, Mrinal K. Sarkar, Mark G. Lebwohl, Akimichi Morita, Kenneth Gordon, Rachael Bogle, Christopher Cole, Anthony Coon, Richard G. Langley, Richard B. Warren, Arash Mostaghimi, Bruce Strober, A. David Burden, Min Zheng, Aaron R. Mangold, Milan J. Anadkat, Jonathan N. Barker, Joseph F. Merola, Lam C. Tsoi, Ming Tang, Kolja Becker, Denis Delic, Christian Thoma, Johann E. Gudjonsson

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Biallelic variants in SREK1 downregulating SNORD115 and SNORD116 cause a Prader-Willi-like syndrome
Sadia Saeed, … , Philippe Froguel, Giles S.H. Yeo
Sadia Saeed, … , Philippe Froguel, Giles S.H. Yeo
Published June 23, 2025
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI191008.
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Biallelic variants in SREK1 downregulating SNORD115 and SNORD116 cause a Prader-Willi-like syndrome

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Abstract

Up to 10% of patients with severe early-onset obesity carry pathogenic variants in known obesity-related genes, mostly affecting the leptin-melanocortin pathway. Studying children with severe obesity from consanguineous populations provides a unique opportunity to uncover novel molecular mechanisms. Using whole-exome sequencing, followed by a rigorous analytical and filtration strategy, we identified three different homozygous missense variants in SREK1 (encoding Splicing Regulatory glutamic acid and lysine rich protein) in Pakistani children with severe obesity, from three unrelated consanguineous pedigrees. The wild type SREK1 gene of human induced pluripotent stem cell (iPSC)-derived hypothalamic neurons was individually replaced by each of the three variants and the impact of these changes on global gene expression was studied. Neurons expressing the two variants in the SREK1 RNA recognition domain p.P95L and p.T194M, but not the C-terminally located p.E601K, had markedly reduced expression of the small nucleolar RNA clusters SNORD115 and SNORD116, deficiency of which has been implicated in Prader-Willi syndrome (PWS). In addition to hyperphagic obesity the carriers of these two variants had other features of PWS, such as neonatal hypotonia. In conclusion, homozygous variants in SREK1 result in a subtype of severe early onset obesity sharing features with PWS.

Authors

Sadia Saeed, Anna-Maria Siegert, YC Loraine Tung, Roohia Khanam, Qasim M. Janjua, Jaida Manzoor, Mehdi Derhourhi, Bénédicte Toussaint, Brian Y. H. Lam, Sherine Awad, Emmanuel Vaillant, Emmanuel Buse Falay, Souhila Amanzougarene, Hina Ayesha, Waqas Imran Khan, Nosheen Ramzan, Vladimir Saudek, Stephen O'Rahilly, Anthony P. Goldstone, Muhammad Arslan, Amélie Bonnefond, Philippe Froguel, Giles S.H. Yeo

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Clonal hematopoiesis detection by simultaneous assessment of peripheral blood mononuclear cells, blood plasma, and saliva
Caitlin M. Stewart, … , Ross L. Levine, Luis A. Diaz, Jr.
Caitlin M. Stewart, … , Ross L. Levine, Luis A. Diaz, Jr.
Published June 19, 2025
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI191256.
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Clonal hematopoiesis detection by simultaneous assessment of peripheral blood mononuclear cells, blood plasma, and saliva

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Abstract

Authors

Caitlin M. Stewart, Sonya Parpart-Li, James R. White, Mitesh Patel, Oliver Artz, Michael B. Foote, Erika Gedvilaite, Michelle F. Lamendola-Essel, Drew Gerber, Rohini Bhattacharya, Justin M. Haseltine, Kety Huberman, Kelly L. Bolton, Ross L. Levine, Luis A. Diaz, Jr.

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Myeloid-mediated cerebral amyloid vasculitis and the potential role of the immune response in brain atrophy
Rudy J. Castellani, … , Amy B. Heimberger, Pouya Jamshidi
Rudy J. Castellani, … , Amy B. Heimberger, Pouya Jamshidi
Published June 19, 2025
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI195137.
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Myeloid-mediated cerebral amyloid vasculitis and the potential role of the immune response in brain atrophy

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Abstract

Authors

Rudy J. Castellani, Hinda Najem, Amy B. Heimberger, Pouya Jamshidi

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Modulation of the Acod1/itaconate pathway differentially affects atherosclerosis severity across genetic models and sexes
Lara Haase, … , Johannes Meiser, Jochen G. Schneider
Lara Haase, … , Johannes Meiser, Jochen G. Schneider
Published June 12, 2025
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI182472.
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Modulation of the Acod1/itaconate pathway differentially affects atherosclerosis severity across genetic models and sexes

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Abstract

Authors

Lara Haase, Anouar Belkacemi, Laura Neises, Nicole Kiweler, Christine Wesely, Rosanna Huchzermeier, Maja Bozic, Arefeh Khakdan, Marta Sánchez, Arnaud Mary, Nadja Sachs, Hanna Winter, Enrico Glaab, Michael T. Heneka, Emiel P.C. van der Vorst, Michel Mittelbronn, Johannes Meiser, Jochen G. Schneider

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