Copyright © 2025| www.jci.org
| The Journal of Clinical Investigation -- New Articles
| The Journal of Clinical Investigation -- New Articles
Cytoplasmic transactive response DNA-binding protein 43 (TDP43) mislocalization and aggregation are pathological hallmarks of amyotrophic lateral sclerosis (ALS). However, the initial cellular insults that lead to TDP43 mislocalization remain unclear. In this study, we demonstrate that nemo-like kinase (NLK) — a proline-directed serine-threonine kinase — promotes the mislocalization of TDP43 and other RNA-binding proteins by disrupting nuclear import. NLK levels were selectively elevated ...| The Journal of Clinical Investigation -- New Articles
Coatomer protein complex subunit α (COPA) syndrome is a monogenic disorder of immune dysregulation that leads to interstitial lung disease and high-titer autoantibodies. Constitutive activation of the innate immune molecule stimulator of interferon genes (STING) is centrally involved in disease. However, the mechanisms by which STING results in autoimmunity are not well understood in COPA syndrome and other STING-associated diseases. Prior studies showed a cell autonomous role for STING in t...| The Journal of Clinical Investigation -- New Articles
Trained immunity (TRIM) is a form of long-lasting functional reprogramming of innate immune cells and their progenitors that enhances responsiveness to subsequent stimuli. Although first characterized in myeloid cells, TRIM was recently extended to nonmyeloid cell types, including endothelial and glial cells, which also exhibit stimulus-driven, memory-like behavior. While initially recognized as a protective mechanism, particularly in the context of vaccines and acute infections, TRIM can als...| The Journal of Clinical Investigation -- New Articles
SPNS1 is a lysosomal transporter that mediates the salvage of lysoglycerophospholipids, the degradative products of lysosomal phospholipid catabolism. However, an understanding of the role of lysolipid transport and salvage in regulating cellular lipid homeostasis and in disease is lacking. Here, we identified members of 2 families with biallelic SPNS1 loss-of-function variants, who presented primarily with progressive liver and striated muscle injury. Patients’ fibroblasts accumulated lyso...| The Journal of Clinical Investigation -- New Articles
Metabolic dysfunction–associated steatohepatitis (MASH) is a globally prevalent but intractable disease lacking effective pharmacotherapies. Here, we performed an integrated multilayered screening for pathogenic genes and druggable targets for MASH. We identified the subclass of metabolite-sensing G protein–coupled receptors, specifically GPR31, a critical contributor to MASH occurrence, which, to our knowledge, was previously uncharacterized. Mechanistically, Gαi3 is the essential downs...| The Journal of Clinical Investigation -- New Articles
Congenital hydrocephalus is a life-threatening condition that might affect brain development by increasing the pressure on the brain parenchyma. Here, we describe 6 male patients from 1 family, all presenting with an isolated X-linked congenital hydrocephalus. Exome sequencing identified a likely pathogenic variant of angiomotin (AMOT) that segregated with the phenotype in the extended family. We show that the variant, affecting the first methionine, translated into a shorter AMOT protein lac...| The Journal of Clinical Investigation -- New Articles
Inflammatory bowel diseases (IBDs) are complex immune disorders that arise at the intersection of genetic susceptibility, environmental exposures, and dysbiosis of the gut microbiota. Our understanding of the role of the microbiome in IBD has greatly expanded over the past few decades, although efforts to translate this knowledge into precision microbiome-based interventions for the prevention and management of disease have thus far met limited success. Here we survey and synthesize recent pr...| The Journal of Clinical Investigation -- New Articles
The balance of hematopoietic stem cell (HSC) self-renewal versus differentiation is essential to ensure long-term repopulation capacity while allowing response to events that require increased hematopoietic output. Proliferation and differentiation of HSCs and their progeny are controlled by the JAK/STAT pathway downstream of cytokine signaling. E3 ubiquitin ligases, like Cullin 5 (CUL5), can regulate JAK/STAT signaling by degrading signaling intermediates. Here we report that mice lacking CU...| The Journal of Clinical Investigation -- New Articles
Bloodstream bacterial infections cause one-third of deaths from bacterial infections, and eradication of circulating bacteria is essential to prevent disseminated infections. Here, we found that hepcidin, the master regulator of systemic iron homeostasis, affected Kupffer cell (KC) immune defense against bloodstream bacterial infections by modulating the gut commensal bacteria–derived tryptophan derivative indole-3-propionic acid (IPA). Hepcidin deficiency impaired bacterial capture by KCs ...| The Journal of Clinical Investigation -- New Articles
Because the lung is a mucosal barrier organ with a unique immunologic environment, mechanisms of immunoregulation in lung cancer may differ from those of other malignancies. Consistent with this notion, we found that CD8+ T cells played a paradoxical role in facilitating, rather than ameliorating, the growth of multiple lung adenocarcinoma models. These included spontaneous, carcinogen-induced, and transplantable tumor cell line models. Specifically, we found that CD8+ T cells promoted homing...| The Journal of Clinical Investigation -- New Articles
The outflow of ‘dirty’ brain fluids from the glymphatic system drains via the meningeal lymphatic vessels to the lymph nodes in the neck, primarily the deep cervical lymph nodes (dcLN). However, it is unclear whether dcLN drainage is essential for normal cerebral homeostasis. Using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and computational fluid dynamics, we studied the impact of long-term mechanical stress from compromised dcLN drainage on brain solute and fluid out...| The Journal of Clinical Investigation -- New Articles
| The Journal of Clinical Investigation -- New Articles
The search for transformative medicines has continuously uncovered select diseases associated with the disruption of the endocannabinoid (eCB) signaling system in the brain and emphasized the therapeutic value of small molecules that rescue this signaling system. In this issue of JCI, Wang et al. report that genetic disruption of PPP2R1A function in mouse forebrain, a preclinical mouse model of neurodevelopmental disorders, resulted in pronounced impairment of eCB signaling. Notably, small-mo...| The Journal of Clinical Investigation -- New Articles
Air pollution comprises a complex mixture of gaseous and particulate components. Particulate matter (PM) air pollution is associated with 4.7 million premature deaths per year. Among modifiable risk factors, air pollution exposure contributes to 8% of disability adjusted life years and ranks above factors such as high blood pressure, smoking, and high fasting plasma glucose. As the site of entry, exposure to PM air pollution causes respiratory symptoms and is a significant cause of respirator...| The Journal of Clinical Investigation -- New Articles
| The Journal of Clinical Investigation -- New Articles
Elevated cholesterol poses cardiovascular risks. The glucocorticoid receptor (GR) harbors a still undefined role in cholesterol regulation. Here, we report that a coding SNP in the gene encoding the GR, rs6190, is associated with increased cholesterol in women according to UK Biobank and All of Us (NIH) datasets. In SNP-genocopying mice, we found that the SNP enhanced hepatic GR activity to transactivate Pcsk9 and Bhlhe40, negative regulators of LDL and HDL receptors, respectively. In mice, t...| The Journal of Clinical Investigation -- New Articles
Neuropathic pain is often comorbid with affective disorders. Synaptic plasticity in anterior cingulate cortex (ACC) is assumed to be a crucial interface for pain perception and emotion. Laminin 1 (LAMB1), a key element of extracellular matrix (ECM) in ACC was recently revealed to convey extracellular alterations to intracellular synaptic plasticity and underlie neuropathic pain and aversive emotion. However, it remains elusive what triggers activity-dependent changes of LAMB1 and ECM remodeli...| The Journal of Clinical Investigation -- New Articles
BACKGROUND Reversal reactions (RRs) in leprosy are acute immune episodes marked by inflammation and bacterial clearance, offering a model to study the dynamics of host responses to Mycobacterium leprae. These episodes are often severe and difficult to treat, frequently progressing to permanent disabilities. We aimed to characterize the immune mechanisms and identify antimicrobial effectors during RRs.METHODS We performed RNA-Seq on paired skin biopsy specimens collected from 9 patients with l...| The Journal of Clinical Investigation -- New Articles
| The Journal of Clinical Investigation -- New Articles
| The Journal of Clinical Investigation -- New Articles
Oncogene expression can cause replication stress (RS), leading to DNA double-strand breaks (DSBs) that require repair through pathways such as homologous recombination, nonhomologous end-joining, and microhomology-mediated end-joining (MMEJ). Cyclin D1 (encoded by CCND1) is a well-known oncoprotein overexpressed in cancer; however, its role in RS is unknown. Using mantle cell lymphoma (MCL) as a naturally occurring model of cyclin D1 overexpression, we examined the impact of cyclin D1 on RS a...| The Journal of Clinical Investigation -- New Articles
Although virus-like particle (VLP) vaccines were shown to be effective against several viruses, their advantage over vaccines that include envelope protein only is not completely clear, particularly for mRNA-encoded VLPs. We conducted a side-by-side comparison of the immunogenicity and protective efficacy of mRNA vaccines encoding the Marburg virus (MARV) full-length glycoprotein (GP) delivered alone or as a VLP. Electron microscopy confirmed VLP formation when MARV GP and matrix protein VP40...| The Journal of Clinical Investigation -- New Articles
| The Journal of Clinical Investigation -- New Articles
There is growing evidence for direct actions of follicle-stimulating hormone (FSH) on tissues other than the ovaries and testes. Blocking FSH action, either genetically or pharmacologically, protects against bone loss, fat gain, and memory loss in mice. We thus developed a humanized FSH-blocking antibody, MS-Hu6, as a lead therapeutic for 3 diseases of public health magnitude — osteoporosis, obesity, and Alzheimer’s disease (AD) — that track together in postmenopausal women. Here, we re...| The Journal of Clinical Investigation -- New Articles
A20, encoded by the TNFAIP3 gene, is a protein linked to Crohn’s disease and celiac disease in humans. We now find that mice expressing point mutations in A20’s M1-ubiquitin–binding zinc finger 7 (ZF7) motif spontaneously develop proximal enteritis that requires both luminal microbes and T cells. Cellular and transcriptomic profiling reveals expansion of Th17 cells and exuberant expression of IL-17A and IL-22 in intestinal lamina propria of A20ZF7 mice. While deletion of IL-17A from A20...| The Journal of Clinical Investigation -- New Articles
Cerebrospinal fluid dynamics play an important role in maintaining brain health and clearing metabolic waste from the brain. In this issue of the JCI, Gursky et al. investigate how CSF distribution is affected when its primary efflux pathway — the deep cervical lymph nodes — is disrupted by cauterization. This timely study reveals compensatory fluid drainage routes from the skull, age-dependent adaptations in CSF homeostasis, and the emergence of neuroinflammation when an efflux pathway i...| The Journal of Clinical Investigation -- New Articles
| The Journal of Clinical Investigation -- New Articles
The dystrophin-glycoprotein complex (DGC) is composed of peripheral and integral membrane proteins at the muscle cell membrane that link the extracellular matrix with the intracellular cytoskeleton. While it is well established that genetic mutations that disrupt the structural integrity of the DGC result in numerous muscular dystrophies, the 3D structure of the complex has remained elusive. Two recent elegant cryoEM structures of the DGC illuminate its molecular architecture and reveal the u...| The Journal of Clinical Investigation -- New Articles
Facioscapulohumeral muscular dystrophy (FSHD) is a genetic muscle disease caused by ectopic expression of the toxic protein DUX4, resulting in muscle weakness. However, the mechanism by which DUX4 exerts its toxicity remains unclear. In this study, we observed abnormal iron accumulation in muscles of patients with FSHD and in mice with muscle-specific DUX4 expression (DUX4-Tg mice). Treatment with iron chelators, an iron-deficient diet, and genetic modifications inhibiting intracellular uptak...| The Journal of Clinical Investigation -- New Articles
| The Journal of Clinical Investigation -- New Articles
| The Journal of Clinical Investigation -- New Articles
Protein phosphatase 2A (PP2A) is a serine/threonine phosphatase in the brain. Mutations in PPP2R1A, encoding the scaffolding subunit, are linked to intellectual disability, although the underlying mechanisms remain unclear. This study examined mice with heterozygous deletion of Ppp2r1a in forebrain excitatory neurons (NEX-het-conditional knockout [NEX-het-cKO]). These mice exhibited impaired spatial learning and memory, resembling Ppp2r1a-associated intellectual disability. Ppp2r1a haploinsuf...| The Journal of Clinical Investigation -- New Articles
| The Journal of Clinical Investigation -- New Articles
Over a century since its routine introduction into medical practice (1), blood transfusion remains one of the most common medical procedures, with over 11 million RBC units collected annually in the United States alone (2). RBC units can be stored in the refrigerator for up to 42 days, providing critical logistical advantages. However, extended storage induces progressive biochemical, metabolic, and morphological changes collectively termed the “storage lesion” (3). These storage-associat...| www.jci.org
Direct interaction of RAS with the PI3K p110α subunit mediates RAS-driven tumor development: however, it is not clear how p110α/RAS-dependant signaling mediates interactions between tumors and host tissues. Here, using a murine tumor cell transfer model, we demonstrated that disruption of the interaction between RAS and p110α within host tissue reduced tumor growth and tumor-induced angiogenesis, leading to improved survival of tumor-bearing mice, even when this interaction was intact in t...| www.jci.org
Pancreatic cancer has a 5-year survival rate of approximately 13% and is projected to become the second-leading cause of cancer-related deaths by 2040. Despite advances in preclinical research, clinical translation remains challenging, and combination chemotherapy remains the standard of care. The intrinsic heterogeneity of pancreas cancer underscores the potential of precision medicine approaches to improve patient outcomes. However, clinical implementation faces substantial challenges, incl...| www.jci.org
To the Editor: Following SARS-CoV-2 infection, approximately 5% of individuals develop long COVID (LC), defined as ongoing symptoms present at least 3 months after infection that are disruptive to everyday functioning. There is growing evidence that SARS-CoV-2 persistence is associated with LC and that people with LC have dysregulated adaptive immune function that may originate from or potentiate viral persistence (1). NK cells, a critical component of the viral innate immune response, can ex...| www.jci.org
The discovery that a protein alone could be infectious, proposed by Stanley Prusiner of the University of California San Francisco (UCSF), was considered heretical in 1982. Now considered orthodoxy, at that time, scientists thought that the only infectious agents were bacteria, viruses, fungi, and parasites. We now know that these proteins, termed prions, which acquire an alternative shape and coax their neighboring proteins to do the same, undergird a variety of neurodegenerative diseases. F...| www.jci.org