Chronic primary pain conditions (CPPCs), such as fibromyalgia and vestibulodynia, affect over 100 million Americans, predominantly women, and pose a substantial healthcare challenge. CPPCs arise from genetic and environmental factors that enhance catecholamine tone, potentially through miRNA dysregulation following catecholamine activation of β-adrenergic receptors. Here, we identified miR-133a-3p
A subset of people living with HIV (PLWH) can produce broadly neutralizing antibodies (bNAbs) against HIV, but the lymph node (LN) dynamics that promote the generation of these Abs are poorly understood. Here, we explored LN-associated histological, immunological, and virological determinants of bNAb generation in a cohort of antiretroviral therapy–naive PLWH. We found that participants who produc
Epilepsy affects approximately 50 million people worldwide, yet more than half of individuals with a presumed genetic cause still lack a molecular diagnosis despite the identification of over 1,000 monogenic epilepsy genes. This diagnostic gap is unlikely to be resolved by improved variant detection alone, suggesting that variants affecting the same biological pathway may combine to cause disease.
Opioids are essential analgesics for managing severe pain but can paradoxically increase pain sensitivity (hyperalgesia) and diminish analgesic efficacy (tolerance). Hyperactivity of NMDA-type glutamate receptors (NMDARs) at primary afferent terminals in the spinal cord contributes to both phenomena; however, the underlying signaling mechanisms remain unclear. Here, we report that morphine adminis
Obesity is associated with impaired wound healing, but the mechanisms linking excess adiposity to aberrant tissue repair remain unresolved. Heterotopic ossification (HO) is a severe example of pathologic tissue repair in which mesenchymal progenitor cells (MPCs) undergo aberrant osteochondral differentiation within soft tissue, leading to joint contractures and pain. Here, we show that accumulatio
Regulation of mitochondrial health is critical for maintaining cellular homeostasis in the nervous system. Damaged mitochondria can have detrimental effects on neuronal health and are thought to be key contributors to the progression of neurodegenerative disorders including Parkinson’s disease and amyotrophic lateral sclerosis. To mitigate this damage, multiple quality control mechanisms have evol
The methionine cycle plays critical roles in cell fate determination by shaping epigenetic landscape, yet its function in human erythropoiesis remains undefined. Here, we show that disruption of methionine metabolism by compromising the key enzyme adenosylhomocysteinase (AHCY) reshapes H3K4me3 landscape, causing erythroid cell fate reprogramming. AHCY deficiency severely impaired erythroid differe
Bone formation in soft tissues, known as heterotopic ossification (HO), can occur as a complication of trauma or burn injury and can cause pain and functional limitations in the affected site. HO remains an unmet clinical challenge due to a general lack of specific medical therapies. In this issue of the JCI, a study by Moye et al. identified obesity as a risk factor for HO and further found that
Mechanosensitive feedback between tissue stiffness and cellular contractile forces instructs cell identity. To characterize phosphorylation-mediated mechanosensing, we charted the global phosphoproteome dynamics of primary human lung fibroblasts on fibronectin-coated polydimethylsiloxane substrates of defined stiffness. We identified a key signaling threshold at 2–8 kPa, above which cells activate
Fibrosis is driven by the activation of quiescent fibroblasts into contractile, matrix-secreting myofibroblasts, a transition governed jointly by biochemical signals and by the mechanical properties of the ECM. How the physical stiffness of tissue is converted into a durable transcriptional cell fate decision has remained poorly understood. In this issue of the JCI, Kadri et al. used global phosph
Heterogeneous degeneration of the retinal pigment epithelium (RPE) leads to irreversible blindness in diseases associated with macular atrophy. However, the underlying mechanisms of regional RPE degeneration remain poorly understood. To address this gap, this study identified a peripheral RPE subpopulation through spatial, transcriptomic, and functional analyses, thereby contributing to the unders
Cerebral malaria (CM) from Plasmodium falciparum is a major cause of death in African children. Since bradykinin (BK) is a mediator of vasogenic edema, we hypothesized that it contributes to the pathogenesis of CM in Kenyan children and Plasmodium berghei ANKA–infected (PbA-infected) C57BL/6J mice in experimental CM (ECM). Cleaved plasma high-molecular-weight kininogen (cHK) is a marker for BK rel
Tregs maintain immune tolerance through mechanisms tightly coupled to cellular metabolism. Whereas glycolysis supports migration of Tregs, lipid metabolism sustains their suppressive phenotype. Here, we identify SREBP1c as a central regulator of Treg immunobiology. Tregs from Srebp1c-deficient mice displayed impaired suppressive function, reduced frequencies in circulation and lymphoid tissues, an
Defective endometrial decidualization is one major cause of female infertility, yet the underlying mechanisms remain elusive. Here, we identified that protein arginine methyltransferase 5 (PRMT5), which was upregulated during decidualization and by progesterone stimulation, was markedly downregulated in the endometria of patients with recurrent implantation failure (RIF), along with a global reduc
Gut microbiota–derived trimethylamine N-oxide (TMAO) plays a role in the pathogenesis of cardiovascular disease, but its role in the pathogenesis of atrial fibrillation (AF) remains uncertain. TMAO levels were quantified in plasma from serial subjects undergoing elective cardiac catheterizations and shown to independently associate with prevalent AF following adjustment for risk factors. Human cAM
CD20+ T cells are increasingly recognized as drivers of autoimmune and inflammatory diseases. However, their origin, development, and specific role in autoimmune skin diseases remain poorly understood. In this study, we observed an expansion of CD20+ T cells in the peripheral blood and skin lesions of patients with bullous pemphigoid (BP), which correlated with the levels of pathogenic autoantibod
BACKGROUND In female murine models, one source of inflammation is a menopause-related increase in gut permeability. We examined whether the menopause transition (MT) in women is associated with an increase in markers of gut epithelial dysfunction and gut microbial product translocation, signals of compromised gut epithelial barrier integrity.METHODS In 964 women, we measured markers of gut epithel
Fibrosis remains a major driver of organ dysfunction, yet the metabolic programs that sustain extracellular matrix production are incompletely understood. In this issue of the JCI, Takizawa and colleagues identified branched-chain amino acid transaminase 1 (BCAT1) as a crucial metabolic regulator of fibroblast activation and fibrosis in a model of cardiac fibrosis. Their observations were corrobor
Monocytes and macrophages promote tissue repair following myocardial infarction, but the mechanisms tuning their effector functions remain elusive. While macrophages are essential in clearing debris and resolving inflammation, they can also contribute to uncontrolled inflammation and provoke additional damage. Thus, factors that influence macrophage differentiation trajectories and phenotypes play
Sarcopenia is the age-related loss of muscle strength and size that leads to mobility limitations and loss of independence in older adults. The underlying cellular mechanisms remain unclear, and treatments are limited. As the critical interface between the nervous system and muscle, the neuromuscular junction (NMJ) is essential for muscle activation and force production. Here, we demonstrate that
Menopause may have important consequences for gut barrier health. The roles of estradiol and progesterone in immune and mucosal barrier homeostasis have been well studied in the female reproductive tract. However, few human studies have described these hormones’ corresponding regulation in the gastrointestinal tract or how the menopausal transition affects gut barrier integrity. In this issue of t
Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), key effectors of the Hippo pathway, are often hyperactivated in cancer, promoting tumor progression and therapy resistance. Their oncogenic role depends on interaction with TEA domain (TEAD) transcription factors, making the TEAD-YAP/TAZ complex a promising therapeutic target. Using translational mouse model
Myofibroblasts are the cells responsible for collagen production, leading to tissue fibrosis. Because 20.5% of the total amino acids in collagen are proline, myofibroblasts must acquire a well-developed proline-producing mechanism during their differentiation. However, the detailed mechanism for myofibroblasts to acquire and keep the developed proline biosynthesis machinery remains obscure. Here,
γδ T cells are a subset of lymphoid cells that, unlike their αβ lineage counterparts, express a heterodimeric TCR that mostly operates in an MHC-independent manner. γδ T cells are abundant in barrier tissues, where they continuously monitor epithelial cells for signs of stress or damage. Thus, γδ T cells are among the first responders to pathophysiological conditions, including viral infection and
Inflammation contributes to the pathogenesis of myocardial infarction and heart failure and represents a viable therapeutic target. Monocytes and their progeny are highly abundant and display striking functional diversity, serving as key determinants of myocardial inflammation and tissue repair. Much remains to be learned regarding mechanisms and signaling events that instruct monocyte fate decisi
Allergen-specific monoclonal antibodies (mAbs) that block IgE binding to allergens are emerging as new therapeutics for treating allergies to pollen, peanuts, and cats. Alpha-Gal syndrome (AGS) is an allergy to galactose-α-1,3-Galactose (α-Gal), which is present in mammalian meat and tissue-derived products. Initially aiming to identify mAbs targeting α-Gal on malaria parasites, we isolated 42 α-G
Trigeminal neuralgia (TN) is a severe orofacial pain disorder accompanied by anxiety, yet its central mechanisms remain elusive. Analysis of human functional MRI data identified the parafascicular nucleus (PF) as a candidate region. Using a TN mouse model, we uncovered 2 spatially and functionally distinct PF neuronal ensembles that separately encoded sensory and affective dimensions of pain. One