RAB7 deficiency impairs pulmonary artery endothelial function and promotes pulmonary hypertension
In conclusion, we demonstrate for the first time to our knowledge the fundamental impairment of EC function by loss of RAB7, causing PH, and show RAB7 activation to be a potential therapeutic strategy in a preclinical model of PH. (Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - February 1, 2024 Category: Biomedical Science Authors: Bryce Piper, Srimathi Bogamuwa, Tanvir Hossain, Daniela Farkas, Lorena Rosas, Adam C. Green, Geoffrey Newcomb, Nuo Sun, Jose A. Ovando-Ricardez, Jeffrey C. Horowitz, Aneel R. Bhagwani, Hu Yang, Tatiana V. Kudryashova, Mauricio Rojas, Ana L. Mora, Pearlly Source Type: research

Disease-associated AIOLOS variants lead to immune deficiency/dysregulation by haploinsufficiency and redefine AIOLOS functional domains
AIOLOS, also known as IKZF3, is a transcription factor that is highly expressed in the lymphoid lineage and is critical for lymphocyte differentiation and development. Here, we report on 9 individuals from 3 unrelated families carrying AIOLOS variants Q402* or E82K, which led to AIOLOS haploinsufficiency through different mechanisms of action. Nonsense mutant Q402* displayed abnormal DNA binding, pericentromeric targeting, posttranscriptional modification, and transcriptome regulation. Structurally, the mutant lacked the AIOLOS zinc finger (ZF) 5–6 dimerization domain, but was still able to homodimerize with WT AIOLOS an...
Source: Journal of Clinical Investigation - February 1, 2024 Category: Biomedical Science Authors: Hye Sun Kuehn, Inga S. Sakovich, Julie E. Niemela, Agustin A. Gil Silva, Jennifer L. Stoddard, Ekaterina A. Polyakova, Ana Esteve Sole, Svetlana N. Aleshkevich, Tatjana A. Uglova, Mikhail V. Belevtsev, Vladislav R. Vertelko, Tatsiana V. Shman, Aleksandra Source Type: research

Hemorrhage-activated NRF2 in tumor-associated macrophages drives cancer growth, invasion, and immunotherapy resistance
Microscopic hemorrhage is a common aspect of cancers, yet its potential role as an independent factor influencing both cancer progression and therapeutic response is largely ignored. Recognizing the essential function of macrophages in red blood cell disposal, we explored a pathway that connects intratumoral hemorrhage with the formation of cancer-promoting tumor-associated macrophages (TAMs). Using spatial transcriptomics, we found that NRF2-activated myeloid cells possessing characteristics of procancerous TAMs tend to cluster in perinecrotic hemorrhagic tumor regions. These cells resembled antiinflammatory erythrophagoc...
Source: Journal of Clinical Investigation - February 1, 2024 Category: Biomedical Science Authors: Dominik J. Schaer, Nadja Schulthess-Lutz, Livio Baselgia, Kerstin Hansen, Raphael M. Buzzi, Rok Humar, Elena Dürst, Florence Vallelian Source Type: research

Noncoding SNPs decrease expression of FABP5 during COPD exacerbations
(Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - February 1, 2024 Category: Biomedical Science Authors: Manale El Kharbili, Sarah K. Sasse, Lynn Sanford, Sean Jacobson, Katja Aviszus, Arnav Gupta, Claire Guo, Susan M. Majka, Robin D. Dowell, Anthony N. Gerber, Russell P. Bowler, Fabienne Gally Source Type: research

Histone methyltransferase Ezh2 coordinates mammalian axon regeneration via regulation of key regenerative pathways
Current treatments for neurodegenerative diseases and neural injuries face major challenges, primarily due to the diminished regenerative capacity of neurons in the mammalian CNS as they mature. Here, we investigated the role of Ezh2, a histone methyltransferase, in regulating mammalian axon regeneration. We found that Ezh2 declined in the mouse nervous system during maturation but was upregulated in adult dorsal root ganglion neurons following peripheral nerve injury to facilitate spontaneous axon regeneration. In addition, overexpression of Ezh2 in retinal ganglion cells in the CNS promoted optic nerve regeneration via b...
Source: Journal of Clinical Investigation - February 1, 2024 Category: Biomedical Science Authors: Xue-Wei Wang, Shu-Guang Yang, Ming-Wen Hu, Rui-Ying Wang, Chi Zhang, Anish R. Kosanam, Arinze J. Ochuba, Jing-Jing Jiang, Ximei Luo, Yun Guan, Jiang Qian, Chang-Mei Liu, Feng-Quan Zhou Source Type: research

Single-cell sequencing reveals Hippo signaling as a driver of fibrosis in hidradenitis suppurativa
Hidradenitis suppurativa (HS) is a chronic inflammatory disease characterized by abscesses, nodules, dissecting/draining tunnels, and extensive fibrosis. Here, we integrate single-cell RNA sequencing, spatial transcriptomics, and immunostaining to provide an unprecedented view of the pathogenesis of chronic HS, characterizing the main cellular players and defining their interactions. We found a striking layering of the chronic HS infiltrate and identified the contribution of 2 fibroblast subtypes (SFRP4+ and CXCL13+) in orchestrating this compartmentalized immune response. We further demonstrated the central role of the Hi...
Source: Journal of Clinical Investigation - February 1, 2024 Category: Biomedical Science Authors: Kelsey R. van Straalen, Feiyang Ma, Pei-Suen Tsou, Olesya Plazyo, Mehrnaz Gharaee-Kermani, Marta Calbet, Xianying Xing, Mrinal K. Sarkar, Ranjitha Uppala, Paul W. Harms, Rachael Wasikowski, Lina Nahlawi, Mio Nakamura, Milad Eshaq, Cong Wang, Craig Dobry, Source Type: research

KIBRA repairs synaptic plasticity and promotes resilience to tauopathy-related memory loss
Synaptic plasticity is obstructed by pathogenic tau in the brain, representing a key mechanism that underlies memory loss in Alzheimer’s disease (AD) and related tauopathies. Here, we found that reduced levels of the memory-associated protein KIdney/BRAin (KIBRA) in the brain and increased KIBRA protein levels in cerebrospinal fluid are associated with cognitive impairment and pathological tau levels in disease. We next defined a mechanism for plasticity repair in vulnerable neurons using the C-terminus of the KIBRA protein (CT-KIBRA). We showed that CT-KIBRA restored plasticity and memory in transgenic mice expressing p...
Source: Journal of Clinical Investigation - February 1, 2024 Category: Biomedical Science Authors: Grant Kauwe, Kristeen A. Pareja-Navarro, Lei Yao, Jackson H. Chen, Ivy Wong, Rowan Saloner, Helen Cifuentes, Alissa L. Nana, Samah Shah, Yaqiao Li, David Le, Salvatore Spina, Lea T. Grinberg, William W. Seeley, Joel H. Kramer, Todd C. Sacktor, Birgit Schi Source Type: research

Multiomic profiling reveals metabolic alterations mediating aberrant platelet activity and inflammation in myeloproliferative neoplasms
Platelets from patients with myeloproliferative neoplasms (MPNs) exhibit a hyperreactive phenotype. Here, we found elevated P-selectin exposure and platelet-leukocyte aggregates indicating activation of platelets from essential thrombocythemia (ET) patients. Single-cell RNA-seq analysis of primary samples revealed significant enrichment of transcripts related to platelet activation, mTOR, and oxidative phosphorylation in ET patient platelets. These observations were validated via proteomic profiling. Platelet metabolomics revealed distinct metabolic phenotypes consisting of elevated ATP generation accompanied by increases ...
Source: Journal of Clinical Investigation - February 1, 2024 Category: Biomedical Science Authors: Fan He, Angelo B.A. Laranjeira, Tim Kong, Shuyang Lin, Katrina J. Ashworth, Alice Liu, Nina M. Lasky, Daniel A.C. Fisher, Maggie J. Cox, Mary C. Fulbright, Lilian Antunes-Heck, LaYow Yu, Molly Brakhane, Bei Gao, Stephen M. Sykes, Angelo D’Alessandro, Jo Source Type: research

Age-related loss of Notch3 underlies brain vascular contractility deficiencies, glymphatic dysfunction, and neurodegeneration in mice
Vascular aging affects multiple organ systems, including the brain, where it can lead to vascular dementia. However, a concrete understanding of how aging specifically affects the brain vasculature, along with molecular readouts, remains vastly incomplete. Here, we demonstrate that aging is associated with a marked decline in Notch3 signaling in both murine and human brain vessels. To clarify the consequences of Notch3 loss in the brain vasculature, we used single-cell transcriptomics and found that Notch3 inactivation alters regulation of calcium and contractile function and promotes a notable increase in extracellular ma...
Source: Journal of Clinical Investigation - January 16, 2024 Category: Biomedical Science Authors: Milagros C. Romay, Russell H. Knutsen, Feiyang Ma, Ana Mompeón, Gloria E. Hernandez, Jocelynda Salvador, Snezana Mirkov, Ayush Batra, David P. Sullivan, Daniele Procissi, Samuel Buchanan, Elise Kronquist, Elisa A. Ferrante, William A. Muller, Jordain Wal Source Type: research

CAR T cells for hematological malignancies
(Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - January 16, 2024 Category: Biomedical Science Authors: Barbara Savoldo, Natalie Grover, Gianpietro Dotti Source Type: research

A conversation with Olufunmilayo Olopade
(Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - January 16, 2024 Category: Biomedical Science Authors: Ushma S. Neill Source Type: research

Mg2+ supplementation treats secretory diarrhea in mice by activating calcium-sensing receptor in intestinal epithelial cells
Cholera is a global health problem with no targeted therapies. The Ca2+-sensing receptor (CaSR) is a regulator of intestinal ion transport and a therapeutic target for diarrhea, and Ca2+ is considered its main agonist. We found that increasing extracellular Ca2+ had a minimal effect on forskolin-induced Cl– secretion in human intestinal epithelial T84 cells. However, extracellular Mg2+, an often-neglected CaSR agonist, suppressed forskolin-induced Cl– secretion in T84 cells by 65% at physiological levels seen in stool (10 mM). The effect of Mg2+ occurred via the CaSR/Gq signaling that led to cAMP hydrolysis. Mg2+ (10 m...
Source: Journal of Clinical Investigation - January 16, 2024 Category: Biomedical Science Authors: Livia de Souza Goncalves, Tifany Chu, Riya Master, Parth D. Chhetri, Qi Gao, Onur Cil Source Type: research

The GLP-1 journey: from discovery science to therapeutic impact
(Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - January 16, 2024 Category: Biomedical Science Authors: Daniel J. Drucker Source Type: research

A functional mini-GDE transgene corrects impairment in models of glycogen storage disease type III
In conclusion, our results demonstrated the ability of a single rAAV vector expressing a functional mini-GDE transgene to correct the muscle and heart phenotype in multiple models of GSDIII, supporting its clinical translation to patients with GSDIII. (Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - January 16, 2024 Category: Biomedical Science Authors: Antoine Gardin, Jérémy Rouillon, Valle Montalvo-Romeral, Lucille Rossiaud, Patrice Vidal, Romain Launay, Mallaury Vie, Youssef Krimi Benchekroun, Jérémie Cosette, Bérangère Bertin, Tiziana La Bella, Guillaume Dubreuil, Justine Nozi, Louisa Jauze, Ro Source Type: research

Impaired glycine neurotransmission causes adolescent idiopathic scoliosis
Adolescent idiopathic scoliosis (AIS) is the most common form of spinal deformity, affecting millions of adolescents worldwide, but it lacks a defined theory of etiopathogenesis. Because of this, treatment of AIS is limited to bracing and/or invasive surgery after onset. Preonset diagnosis or preventive treatment remains unavailable. Here, we performed a genetic analysis of a large multicenter AIS cohort and identified disease-causing and predisposing variants of SLC6A9 in multigeneration families, trios, and sporadic patients. Variants of SLC6A9, which encodes glycine transporter 1 (GLYT1), reduced glycine-uptake activity...
Source: Journal of Clinical Investigation - January 16, 2024 Category: Biomedical Science Authors: Xiaolu Wang, Ming Yue, Jason Pui Yin Cheung, Prudence Wing Hang Cheung, Yanhui Fan, Meicheng Wu, Xiaojun Wang, Sen Zhao, Anas M. Khanshour, Jonathan J. Rios, Zheyi Chen, Xiwei Wang, Wenwei Tu, Danny Chan, Qiuju Yuan, Dajiang Qin, Guixing Qiu, Zhihong Wu, Source Type: research