Citations

The discovery of genes encoding the volume-regulated anion channel (VRAC) has enabled detailed exploration of its cell type–specific roles in the brain. LRRC8A (SWELL1) is the essential VRAC subunit. We observed seizure-induced, subunit-specific changes in microglial VRAC expression and investigated its function using conditional KO (cKO) of LRRC8A in microglia. SWELL1 cKO mice exhibited a male-specific increase in kainate-induced seizure severity, yet showed paradoxical neuroprotection against seizure-associated neuronal loss. Mechanistically, SWELL1 deletion led to a cell-autonomous reduction in microglial density and decreased release of VRAC-permeable neuroactive metabolites, including taurine, GABA, and glutamate in culture. Additionally, impaired phagocytic kinetics and reduced lysosomal biogenesis contributed to the observed neuroprotection. These findings reveal potentially novel roles for microglial VRAC in regulating seizure outcomes and microglia-neuron interactions.

Objective: Endotracheal intubation can cause laryngeal injury, with clinical presentation ranging from transient hoarseness to persistent vocal cord immobility. This study examines the incidence, clinical features, and outcomes of post-intubation laryngeal injuries following procedures traditionally considered low risk for such complications. Methods: We conducted a retrospective review of adult patients who underwent tracheal intubation for surgical procedures between May 1, 2018, and December 31, 2024, and subsequently presented with postoperative laryngeal injury–related symptoms. Patients who underwent cardiothoracic, thyroid, parathyroid, or anterior cervical spine procedures were excluded. We reviewed patient demographics, airway and intubation characteristics, treatments, and clinical outcomes. Results: Among 267 824 patients undergoing 454 924 general anesthetics, 30 developed postoperative laryngeal injury (6.6/100 000; 95% CI 4.5–9.4) which did not resolve spontaneously and required laryngology evaluation. Of these 22 (67%) had well defined movement abnormalities : unilateral (n = 15) and bilateral vocal cord immobility (n = 1), unilateral hypomobility (n = 4), bilateral hypomobility (n = 1), combined unilateral vocal cord immobility with contralateral hypomobility (n = 1), and 11 (33%) had no movement abnormality . Twenty-one (64%) were intubated via video laryngoscopy. Follow-up was available for 21 patients (70%) with a median [IQR] duration of 12 [9-35] months; 15 (72%) showed partial improvement without complete resolution, while 6 showed no improvement. Conclusion: Laryngeal injury following general anesthesia with tracheal intubation is a uncommon complication. In our series, approximately two-thirds of patients had identifiable injuries, while one-third exhibited no structural abnormality. While 75% of patients demonstrated partial symptomatic improvement, however, complete resolution was not observed in any of the patients who received follow-up in our institution, underscoring the severity of this complication.

ABSTRACT Enteroendocrine cells (EECs) are specialized sensors of the gastrointestinal (GI) epithelium that regulate gut function and systemic metabolism through hormone secretion. The molecular pathways directing intestinal stem cell (ISC) differentiation into EECs are incompletely understood due, in part, to their rarity. We sought to identify novel regulators of human EEC differentiation using a high-throughput screen of FDA-approved drugs and human duodenal organoids. Two epidermal growth factor receptor inhibitors (EGFRi) commonly used in cancer therapy and known to cause GI side effects, erlotinib and lapatinib, emerged as strong inducers of EEC differentiation, dramatically increasing chromogranin A (CHGA) expression compared to controls, while maintaining ISC function and organoid growth. EGFRi-treated organoids revealed robust and broad upregulation of EEC hormones, including serotonin (5HT), motilin (MLN), and somatostatin (SST), among others. In agreement with these findings, analysis of a patient cohort with lung cancer revealed an association with erlotinib use and increased circulating levels of the above EEC hormones compared to matched controls. Supporting a direct effect of EGFRi on EEC differentiation, mice treated with erlotinib demonstrated increased EEC numbers and hormones and showed EGFRi-associated diarrhea (EAD), a limiting side effect of these medications. Mechanistically, EGFRi induced upregulation of interferon (IFN) signaling targets during early ISC-to-EEC differentiation. Consistent with this, inhibition of Signal Transducer and Activator of Transcription 1 (STAT1) attenuated EGFRi-induced EEC differentiation. These findings provide important insight into EEC differentiation that could inform treatment strategies for EAD, metabolic diseases, and GI diseases. Brief Summary Inhibition of EGFR signaling promotes human ISC-to-EEC differentiation through activation of STAT1 signaling.

BACKGROUND: Atherothrombosis, which underlies most acute coronary syndromes and is driven by intraplaque thrombosis, preferentially occurs in regions of disturbed blood flow (d-flow). Although LATS1/2 (large tumor suppressor kinases 1 and 2) are known regulators of endothelial mechanotransduction, the mechanisms by which d-flow connects endothelial senescence, proliferation, and intraplaque thrombosis remain poorly understood. METHODS: We investigated endothelial cell (EC)-specific roles of Lats1/2 using inducible EC-specific knockout mice in a partial carotid ligation model. Spatial multiomics of human and mouse plaques was performed using imaging mass cytometry, COMET sequential immunofluorescence, and spatial metabolomics. RESULTS: Tamoxifen-induced deletion of both Lats1 and Lats2 (homozygous) in ECs caused fatal edema and increased vascular permeability. In contrast, Lats1 het ( ± ) / Lats2 homo ( −/−) -EC-specific knockout mice survived and developed spontaneous atherothrombotic plaques with neovascularization. Spatial proteomics revealed that LATS1/2 loss induced a senescence-associated stemness phenotype driven by CD38 upregulation. Spatial metabolomics showed sulfite and taurine accumulation, indicating SUOX (sulfite oxidase) deficiency. CD38 suppressed SUOX, demonstrated a switch into the reverse mode of mitochondrial complex V, increased succinate dehydrogenase activity, and promoted ATP consumption. Despite ATP depletion, glutamate metabolism and the citric acid cycle flux increased, sustaining EC proliferation under energetic stress. This senescence-associated stemness state promoted both proliferation and senescence, leading to fragile, leaky neovessels and intraplaque thrombotic lesions. Pharmacological CD38 inhibition attenuated these phenotypes. Similar EC states were observed in human plaques. CONCLUSIONS: Loss of Lats1/2 in ECs induces a CD38-associated senescence-associated stemness-like phenotype that promotes intraplaque thrombosis through mitochondrial metabolic reprogramming, including changes consistent with reverse-mode operation of mitochondrial complex V. These findings define a mechanistic link between disturbed flow, endothelial metabolic reprogramming, and intraplaque thrombosis and hemorrhage.

BACKGROUND: Hemorrhagic risk in dural arteriovenous fistulas (dAVFs) is largely determined by venous anatomy, but the contribution of systemic cardiovascular factors and their medical therapy remains poorly defined. This study examined associations between cardiovascular risk factors and antithrombotic use and hemorrhagic presentation, angiographic obliteration, and early functional outcomes after treatment. METHODS: We analyzed 1350 adults with intracranial dAVFs from the international Consortium for Dural Arteriovenous Fistula Outcomes Research registry, which retrospectively accrued cases across 14 centers in 4 countries between 1990 and 2017. Demographics, cardiovascular comorbidities, antithrombotic use, angioarchitectural features, treatment strategies, and follow-up outcomes were collected from prospectively maintained databases. Primary end points were hemorrhagic presentation, angiographic obliteration, and 90-day functional status after treatment. Univariable and multivariable logistic regressions were performed with model-specific adjustments. RESULTS: Hemorrhage occurred in 375 patients (27.8%) and was most strongly associated with high-grade dAVF classification and male sex; antithrombotic therapy was associated with lower odds of hemorrhagic presentation. Other cardiovascular risk factors showed no independent relationship with bleeding. Angiographic obliteration was achieved in 621 of 845 patients (73.5%). Hemorrhagic onset, high dAVF grade, and surgical treatment were independently associated with angiographic obliteration, whereas smoking and embolization demonstrated only nonsignificant trends after adjustment. At 90 days, 934 patients (88.9%) were functionally independent. Baseline modified Rankin Scale score was the strongest factor associated with 90-day functional outcome, while neither cardiovascular comorbidities nor treatment modality independently influenced functional status. CONCLUSIONS: In this large multicenter dAVF cohort, hemorrhagic presentation was most strongly associated with venous angioarchitecture. Male sex and antithrombotic therapy were also independently associated with hemorrhagic presentation. Angiographic obliteration was common, particularly among surgically treated lesions, and 90-day functional outcome was most strongly associated with baseline functional status.

Biparietal osteodystrophy, also known as bilateral parietal calvarium bone thinning, is a rare calvarial condition characterized by loss of diploic bone within the parietal region. Although historically described in anthropologic and radiologic literature, current understanding of its epidemiology, pathogenesis, clinical relevance, and management remains fragmented. This review synthesizes current evidence and highlights emerging studies on biparietal osteodystrophy. Epidemiologic reports indicate that biparietal osteodystrophy affects a broad age range but appears most frequently in older adults, with several series suggesting a slight female predominance. Prevalence is difficult to estimate due to incidental detection, though modern imaging has increased recognition of the condition. Histologically and anatomically, biparietal osteodystrophy is marked by thinning of the outer table and loss of the diploic space, with little osteoblastic or osteoclastic remodeling. Proposed pathogenic mechanisms include chronic degenerative change, impaired vascular supply to the diploë, and other theories, although no single explanation fully accounts for its complete presentation. Clinically, most patients remain asymptomatic, with complications such as calvarial fractures and traumatic brain injury being rare but highlighting the structural vulnerability associated with severe thinning. Management strategies are not standardized, and the use of anti-osteoporotic drugs and cranioplasty has been reported to offer benefit in select cases, although no treatment has been formally validated for biparietal osteodystrophy. As the understanding of biparietal osteodystrophy continues to evolve, future research is needed to clarify its natural history, identify potential etiologic pathways, and establish evidence-based management guidelines.

Abstract Background Progressive supranuclear palsy (PSP) is a tauopathy for which there is limited understanding of epidemiological risk factors. Objective The objective of this study was to identify premorbid nonmedical and medical risk factors for PSP diagnosis in a large prospective population‐based cohort. Methods We performed a matched nested case–control study using the UK Biobank (UKB) cohort consisting of >500,000 adults aged 37 to 73 years. PSP diagnoses were identified from 2007 to censor date (August 2025) and matched 1:10 by age and sex to control subjects without parkinsonism or dementia diagnoses. We derived risk factors using an iterative logistic regression approach. Results There were 240 incident PSP diagnoses in the UKB. In the fully adjusted model, premorbid depression (odds ratio [OR], 3.22; 95% confidence interval [CI], 2.30–4.50; P < 0.001), delirium (OR, 6.76; 95% CI, 4.08–11.19; P < 0.001), and functional gastrointestinal disorders (OR, 1.91; 95% CI, 1.39–2.63; P < 0.001) were associated with increased risk. Heavy alcohol consumption was associated with higher risk compared with moderate consumption (OR, 1.65; 95% CI: 1.21–2.26; P = 0.0017). Body mass index (BMI) and alcohol consumption had nonlinear risk profiles. Cancer diagnosis was inversely associated with PSP (OR, 0.56; 95% CI, 0.40–0.79; P < 0.001). Depression and delirium diagnoses remained significant 5 to 10 years before diagnosis. Conclusions In this large prospective cohort, PSP was associated with premorbid lifestyle practices and neuropsychiatric diagnoses years before diagnosis. This suggests a long premotor phase and highlights opportunities for earlier diagnosis and further mechanistic investigation. The inverse association with cancer mirrors the relationship seen in other neurodegenerative conditions and may point toward shared mechanisms. © 2026 International Parkinson and Movement Disorder Society.

ABSTRACT Microbial colonization of plant roots involves strong selective pressures that shape the structure and function of root-associated communities. In particular, the endosphere represents a highly selective environment requiring host entry and in planta persistence. However, strain-specific microbial traits that enable endosphere colonization remain poorly understood. Here, we use a defined, genome-resolved community of 28 Variovorax strains isolated from the roots of Populus deltoides and Populus trichocarpa (poplar trees) to determine which strains partition between rhizosphere and endosphere compartments and to identify the genomic traits associated with endosphere specialization. By combining strain-resolved metagenomic profiling, comparative genomics, and functional assays, we demonstrate that dominant endosphere colonizers are enriched in genes related to nutrient metabolism, redox balance, transcriptional regulation, and a conserved L-fucose utilization pathway experimentally shown to enhance root colonization. Not all strains succeed through the same strategy. Community-wide functional profiling revealed a distinct and reduced set of traits in the endosphere, including orthogroups associated with low-abundance strains that were overlooked in strain-level analyses. These findings reveal that multiple ecological strategies, such as metabolic competition, regulatory adaptation, and niche specialization, can support endosphere colonization. Our results advance the understanding of how bacterial colonization traits are distributed and deployed within a plant microbiome and suggest that host filtering selects for distinct, and sometimes complementary, microbial strategies. This work supports a shift toward mechanistic, genome-resolved models of microbiome assembly and offers a framework for linking microbial function to host colonization success. IMPORTANCE Plants often depend on diverse microbial partners to support their growth, resilience, and adaptation to changing environments. Among these microbes, some bacteria inhabit the rhizosphere (the narrow zone around roots where microbes interact with the plant) while others are able to enter and persist within root tissues. The traits that distinguish these two lifestyles remain poorly understood. In this study, we examined a group of related Variovorax strains from poplar tree root microbiomes to ask why some rhizosphere-associated strains also become successful endosphere colonizers. We found that strains appear to succeed through different strategies: some may benefit from rapid growth on plant-derived carbon sources, while others may rely on stress tolerance or fine-tuned regulation. These results suggest that there is no single path from the rhizosphere into the root interior, but rather multiple strategies shaped by the host environment. Understanding this diversity can inform efforts to design resilient plant-microbe communities.