Galectin-3 aggravates microglial activation and tau transmission in tauopathy
Alzheimer’s disease is characterized by the accumulation of amyloid-β plaques, aggregation of hyperphosphorylated tau (pTau), and microglia activation. Galectin-3 (Gal3) is a β-galactoside–binding protein that has been implicated in amyloid pathology. Its role in tauopathy remains enigmatic. Here, we showed that Gal3 was upregulated in the microglia of humans and mice with tauopathy. pTau triggered the release of Gal3 from human induced pluripotent stem cell–derived microglia in both its free and extracellular vesicular–associated (EV-associated) forms. Both forms of Gal3 increased the accumulation of pathogenic ...
Source: Journal of Clinical Investigation - January 16, 2024 Category: Biomedical Science Authors: Jian Jing Siew, Hui-Mei Chen, Feng-Lan Chiu, Chia-Wei Lee, Yao-Ming Chang, Hung-Lin Chen, Thi Ngoc Anh Nguyen, Hung-Ting Liao, Mengyu Liu, Hsiao-Tien Hagar, Yung-Chen Sun, Hsing-Lin Lai, Min-Hao Kuo, David Blum, Luc Buée, Lee-Way Jin, Shih-Yu Chen, Tai-M Source Type: research
Interactions among insulin resistance, epigenetics, and donor sex in gene expression regulation of iPSC-derived myoblasts
About 25% of people in the general population are insulin resistant, increasing the risk for type 2 diabetes (T2D) and metabolic disease. Transcriptomic analysis of induced pluripotent stem cells differentiated into myoblasts (iMyos) from insulin-resistant (I-Res) versus insulin-sensitive (I-Sen) nondiabetic individuals revealed that 306 genes increased and 271 genes decreased in expression in iMyos from I-Res donors with differences of 2-fold or more. Over 30 of the genes changed in I-Res iMyos were associated with T2D by SNPs and were functionally linked to insulin action and control of metabolism. Interestingly, we also...
Source: Journal of Clinical Investigation - January 16, 2024 Category: Biomedical Science Authors: Nida Haider, C. Ronald Kahn Source Type: research
Understanding and therapeutically exploiting cGAS/STING signaling in glioblastoma
Since the discovery that cGAS/STING recognizes endogenous DNA released from dying cancer cells and induces type I interferon and antitumor T cell responses, efforts to understand and therapeutically target the STING pathway in cancer have ensued. Relative to other cancer types, the glioma immune microenvironment harbors few infiltrating T cells, but abundant tumor-associated myeloid cells, possibly explaining disappointing responses to immune checkpoint blockade therapies in cohorts of patients with glioblastoma. Notably, unlike most extracranial tumors, STING expression is absent in the malignant compartment of gliomas, l...
Source: Journal of Clinical Investigation - January 16, 2024 Category: Biomedical Science Authors: Justin T. Low, Michael C. Brown, Zachary J. Reitman, Joshua D. Bernstock, James M. Markert, Gregory K. Friedman, Matthew S. Waitkus, Michelle L. Bowie, David M. Ashley Source Type: research
The pan-microbiome profiling system Taxa4Meta identifies clinical dysbiotic features and classifies diarrheal disease
Targeted metagenomic sequencing is an emerging strategy to survey disease-specific microbiome biomarkers for clinical diagnosis and prognosis. However, this approach often yields inconsistent or conflicting results owing to inadequate study power and sequencing bias. We introduce Taxa4Meta, a bioinformatics pipeline explicitly designed to compensate for technical and demographic bias. We designed and validated Taxa4Meta for accurate taxonomic profiling of 16S rRNA amplicon data acquired from different sequencing strategies. Taxa4Meta offers significant potential in identifying clinical dysbiotic features that can reliably ...
Source: Journal of Clinical Investigation - January 16, 2024 Category: Biomedical Science Authors: Qinglong Wu, Shyam Badu, Sik Yu So, Todd J. Treangen, Tor C. Savidge Source Type: research
Gestational diabetes in mice induces hematopoietic memory that affects the long-term health of the offspring
Gestational diabetes is a common medical complication of pregnancy that is associated with adverse perinatal outcomes and an increased risk of metabolic diseases and atherosclerosis in adult offspring. The mechanisms responsible for this delayed pathological transmission remain unknown. In mouse models, we found that the development of atherosclerosis in adult offspring born to diabetic pregnancy can be in part linked to hematopoietic alterations. Although they do not show any gross metabolic disruptions, the adult offspring maintain hematopoietic features associated with diabetes, indicating the acquisition of a lasting d...
Source: Journal of Clinical Investigation - January 16, 2024 Category: Biomedical Science Authors: Vinothini Govindarajah, Masahide Sakabe, Samantha Good, Michael Solomon, Ashok Arasu, Nong Chen, Xuan Zhang, H. Leighton Grimes, Ady Kendler, Mei Xin, Damien Reynaud Source Type: research
Truncated titin protein in dilated cardiomyopathy incorporates into the sarcomere and transmits force
(Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - January 16, 2024 Category: Biomedical Science Authors: Quentin McAfee, Matthew A. Caporizzo, Keita Uchida, Kenneth C. Bedi Jr., Kenneth B. Margulies, Zolt Arany, Benjamin L. Prosser Source Type: research
TTN truncation variants produce sarcomere-integrating proteins of uncertain functional significance
Titin (TTN) is one of the largest and most complex proteins expressed in humans, and truncation variants are the most prevalent genetic lesion identified in individuals with dilated cardiomyopathy (DCM) or other disorders of impaired cardiac contractility. Two reports in this issue of the JCI shed light on a potential mechanism involving truncated TTN sarcomere integration and the potential for disruption of sarcomere structural integrity. Kellermayer, Tordai, and colleagues confirmed the presence of truncated TTN protein in human DCM samples. McAfee and authors developed a patient-specific TTN antibody to study truncated ...
Source: Journal of Clinical Investigation - January 16, 2024 Category: Biomedical Science Authors: J. Travis Hinson, Stuart G. Campbell Source Type: research
Truncated titin is structurally integrated into the human dilated cardiomyopathic sarcomere
Heterozygous (HET) truncating variant mutations in the TTN gene (TTNtvs), encoding the giant titin protein, are the most common genetic cause of dilated cardiomyopathy (DCM). However, the molecular mechanisms by which TTNtv mutations induce DCM are controversial. Here, we studied 127 clinically identified DCM human cardiac samples with next-generation sequencing (NGS), high-resolution gel electrophoresis, Western blot analysis, and super-resolution microscopy in order to dissect the structural and functional consequences of TTNtv mutations. The occurrence of TTNtv was found to be 15% in the DCM cohort. Truncated titin prot...
Source: Journal of Clinical Investigation - January 16, 2024 Category: Biomedical Science Authors: Dalma Kellermayer, Hedvig Tordai, Balázs Kiss, György Török, Dániel M. Péter, Alex Ali Sayour, Miklós Pólos, István Hartyánszky, Bálint Szilveszter, Siegfried Labeit, Ambrus Gángó, Gábor Bedics, Csaba Bödör, Tamás Radovits, Béla Merkely, Source Type: research
Keeping translational research grounded in human biology
(Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - January 16, 2024 Category: Biomedical Science Authors: Saptarsi M. Haldar Source Type: research
Cell-free DNA reveals distinct pathology of multisystem inflammatory syndrome in children
(Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - January 2, 2024 Category: Biomedical Science Authors: Temesgen E. Andargie, Katerina Roznik, Neelam Redekar, Tom Hill, Weiqiang Zhou, Zainab Apalara, Hyesik Kong, Oren Gordon, Rohan Meda, Woojin Park, Trevor S. Johnston, Yi Wang, Sheila Brady, Hongkai Ji, Jack A. Yanovski, Moon K. Jang, Clarence M. Lee, Andr Source Type: research
The nociceptin/orphanin FQ receptor partial agonist sunobinop promotes non-REM sleep in rodents and patients with insomnia
(Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - January 2, 2024 Category: Biomedical Science Authors: Garth T. Whiteside, Donald J. Kyle, Ram P. Kapil, Alessandra Cipriano, Ellie He, Mingyan Zhou, Manjunath S. Shet, Michele Hummel, Terri Knappenberger, Kazuya Fukumura, Yoshiyuki Matsuo, Masahiro Uehira, Shuichi Hiroyama, Nozomi Takai, Sandra K. Willsie, S Source Type: research
2023 Association of American Physicians Presidential AddressReplenishing the physician-scientist pipeline in the post–late bloomer era
(Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - January 2, 2024 Category: Biomedical Science Authors: Daniel P. Kelly Source Type: research
In situ vaccination via tissue-targeted cDC1 expansion enhances the immunogenicity of chemoradiation and immunotherapy
Even with the prolific clinical use of next-generation cancer therapeutics, many tumors remain unresponsive or become refractory to therapy, creating a medical need. In cancer, DCs are indispensable for T cell activation, so there is a restriction on cytotoxic T cell immunity if DCs are not present in sufficient numbers in the tumor and draining lymph nodes to take up and present relevant cancer antigens. To address this bottleneck, we developed a therapeutic based on albumin fused with FMS-related tyrosine kinase 3 ligand (Alb-Flt3L) that demonstrated superior pharmacokinetic properties compared with Flt3L, including sign...
Source: Journal of Clinical Investigation - January 2, 2024 Category: Biomedical Science Authors: Brandon Lam, Yu Jui Kung, John Lin, Ssu-Hsueh Tseng, Hsin-Fang Tu, Claire Huang, Brandon Lee, Esteban Velarde, Ya Chea Tsai, Rafael Villasmil, Sung Taek Park, Deyin Xing, Chien-Fu Hung, T.-C. Wu Source Type: research
Spliceosome malfunction causes neurodevelopmental disorders with overlapping features
Pre-mRNA splicing is a highly coordinated process. While its dysregulation has been linked to neurological deficits, our understanding of the underlying molecular and cellular mechanisms remains limited. We implicated pathogenic variants in U2AF2 and PRPF19, encoding spliceosome subunits in neurodevelopmental disorders (NDDs), by identifying 46 unrelated individuals with 23 de novo U2AF2 missense variants (including 7 recurrent variants in 30 individuals) and 6 individuals with de novo PRPF19 variants. Eight U2AF2 variants dysregulated splicing of a model substrate. Neuritogenesis was reduced in human neurons differentiate...
Source: Journal of Clinical Investigation - January 2, 2024 Category: Biomedical Science Authors: Dong Li, Qin Wang, Allan Bayat, Mark R. Battig, Yijing Zhou, Daniëlle G.M. Bosch, Gijs van Haaften, Leslie Granger, Andrea K. Petersen, Luis A. Pérez-Jurado, Gemma Aznar-Laín, Anushree Aneja, Miroslava Hancarova, Sarka Bendova, Martin Schwarz, Radka Kr Source Type: research
Immune mechanisms of granuloma formation in sarcoidosis and tuberculosis
Sarcoidosis is a complex immune-mediated disease characterized by clusters of immune cells called granulomas. Despite major steps in understanding the cause of this disease, many questions remain. In this Review, we perform a mechanistic interrogation of the immune activities that contribute to granuloma formation in sarcoidosis and compare these processes with its closest mimic, tuberculosis, highlighting shared and divergent immune activities. We examine how Mycobacterium tuberculosis is sensed by the immune system; how the granuloma is initiated, formed, and perpetuated in tuberculosis compared with sarcoidosis; and the...
Source: Journal of Clinical Investigation - January 2, 2024 Category: Biomedical Science Authors: Praveen Weeratunga, David R. Moller, Ling-Pei Ho Source Type: research
