The Hrd1-Hrd3 complex is a central component of the endoplasmic reticulum-associated degradation (ERAD) pathway; however, its conformational states during substrate recognition and retrotranslocation remain poorly characterized at the structural level. Conventional cryo-EM data processing pipelines typically aim to obtain a single high-resolution reconstruction, during which low-abundance or subtly distinct conformational states may be averaged out or lost. To explore potential structural heterogeneity in publicly available data, we reanalyzed the cryo-EM dataset of the Hrd1-Hrd3 complex (EMPIAR-10099). A side-view particle enrichment strategy combined with iterative 2D reclassification was applied to re-sort particles and reconstruct distinct subsets. Three density classes were obtained from the side-view-focused classification workflow, with overall resolutions of 7.24 Å, 6.80 Å, and 6.93 Å, respectively. Comparative analysis revealed consistent differences in the position of the Hrd3 luminal region relative to the Hrd1 transmembrane core, showing distinguishable Hrd3-associated density distributions among the classified particle subsets. These results indicate that, even at moderate resolution, a classification strategy focused on side-view particles and iterative 2D sorting can identify domain-level density variability among selected particle subsets from publicly available cryo-EM datasets. This study does not rely on new algorithm development and is fully implemented using existing cryo-EM analysis tools, providing a practical workflow for reanalysis of publicly available cryo-EM data.

Gastric antral web (GAW) is a rare congenital or acquired mucosal anomaly characterized by a membranous septum within the gastric antrum and represents an uncommon cause of gastric outlet obstruction (GOO), particularly in adults. Due to its nonspecific clinical presentation, it is often underdiagnosed and may lead to delayed management. We report the case of a previously healthy adult female patient who presented with progressive epigastric pain and early postprandial fullness. Physical examination and laboratory findings were unremarkable. Upper gastrointestinal endoscopy revealed a membranous structure in the antral region causing significant luminal narrowing, consistent with a GAW. A contrast study demonstrated delayed gastric emptying with passage of contrast through a narrowed aperture. Given the severity of the obstruction, the patient underwent subtotal gastrectomy with gastrojejunostomy. The procedure was uneventful, and postoperative imaging confirmed normal contrast passage without leakage or obstruction. The patient was discharged on postoperative day 2 and remained asymptomatic at the two-month follow-up. GAW remains a rare etiology of GOO, with clinical manifestations varying according to the degree of luminal narrowing. Diagnosis relies primarily on endoscopy and imaging, though a high index of suspicion is essential. Management options range from conservative measures to endoscopic and surgical interventions, with surgery remaining the definitive treatment in cases of significant obstruction. GAW should therefore be considered in the differential diagnosis of GOO in adults, as early recognition and appropriate management are crucial to prevent complications and ensure favorable outcomes, given the rarity of this condition.

Mechanical deformation is integral to intestinal physiology, linking luminal transit to epithelial adaptation and motor control. These physical cues engage multiple mechanotransduction pathways that coordinate cellular adaptation and help preserve intestinal homeostasis. Inflammation, obstruction and matrix remodelling alter both the physical input and the state of the responding cell, allowing normally transient signals to persist or acquire pathological consequences. Ion channels act at several levels of this process. PIEZO1 and PIEZO2 provide a direct route for force-gated cation entry; mechanically gated two-pore-domain potassium channels can oppose depolarisation, and other conductances shape the conversion of mechanical signals into tissue responses. This review synthesises the current understanding of ion-channel mechanotransduction in intestinal physiology and disease. Studies have established the physiological importance of these pathways and are increasingly defining their contribution to disease, although their regulation in diseased tissue remains poorly understood.

Androgens inhibit breast cancer (BC) growth in estrogen receptor (ER)-positive BC and promote growth in ER-negative BC. Correlating intratumoral androgens, instead of circulating androgens, and their downstream transcriptome, a measure of free unbound androgen function, may offer a direct assessment of androgen action in BC. Intratumoral androgen androstenedione (A4) levels in BC specimens correlated with 1388 genes, which classified patients into low, intermediate, and high A4 levels. This A4-high patients' transcriptome was associated with lower tumor cell proliferation, earlier stage and grade, and longer survival, while A4-low patients' transcriptome was associated with the triple-negative subtype. We developed a 90-gene A4-associated transcriptional classifier that captures intratumoral A4-associated biology. The signature requires independent validation. snRNAseq analysis indicated that high A4 specimens were enriched for favorable cell lineage, while low A4 specimens were enriched for aggressive cell lineage and cancer hallmarks. Supporting in vitro evidence suggests that A4 can inhibit ER-positive AR-positive BC cells. Collectively, these data show that intratumoral A4 levels are associated with a transcriptional state linked to lower proliferation, more luminal features, and better BC outcome.

The endothelial glycocalyx depends on Exostosin-1 (Ext1)-mediated heparan sulfate synthesis; however, its endothelial cell-autonomous role in acute inflammation remains unclear. Therefore, we examined the role of Ext1 during acute inflammation. In this study, endothelial-specific Ext1-deficient mice (Ext1[flox/flox] and VE-cadherin-Cre) were generated, and their response to endotoxin challenge was investigated using transcriptomics and imaging. Transcriptomic profiling revealed downregulation of heparan sulfate- and glycocalyx-related genes, with upregulation of genes associated with immune activation. Fluorescence imaging demonstrated lectin- and heparan sulfate-defined glycocalyx depletion; dextran extravasation confirmed impaired barrier integrity. Ultrastructural analyses demonstrated a near-complete absence of the luminal glycocalyx at baseline in Ext1-deficient lungs. Following lipopolysaccharide administration, Ext1-deficient mice exhibited altered cytokine kinetics, delayed clearance of neutrophils and CD11b[+] myeloid cells, increased late-phase macrophage accumulation, and prolonged pulmonary edema, indicating impaired resolution of inflammation. Gene set enrichment analysis revealed upregulated leukocyte transendothelial migration, chemokine signaling, and vascular endothelial growth factor pathways, consistent with a persistently activated endothelial phenotype. Endothelial Ext1 is indispensable for heparan sulfate biosynthesis, endothelial glycocalyx integrity, and timely inflammation resolution. Loss of Ext1 leads to an intrinsically pro-inflammatory endothelial state characterized by impaired heparan sulfate-dependent signaling and dysregulated leukocyte-endothelial interactions, heightened vascular permeability, and prolonged tissue injury. Our findings support glycocalyx-targeted therapy in sepsis, acute respiratory distress syndrome, diabetes-associated inflammation, and other conditions of endothelial vulnerability.

A drug-coated balloon (DCB) strategy has become an established option for de novo coronary lesions, offering the advantage of avoiding permanent implants. However, very long-term vascular changes after stentless percutaneous coronary intervention (PCI) remain insufficiently characterized. We report a case of chronic total occlusion that developed eight years after DCB angioplasty for a diffuse long right coronary artery lesion in a patient with unstable angina. A 65-year-old man developed exertional chest discomfort approximately seven years after the index procedure, and cardiac computed tomography demonstrated severe calcification and suspected occlusion of the previously treated segment. At the index procedure, we selected a DCB-only strategy because intravascular ultrasound (IVUS) revealed a long, diffuse lesion requiring multiple stents and extensive drug-eluting stent (DES) implantation carries increased long-term risks. During repeat PCI, IVUS demonstrated dense calcification and high-echoic crescentic neointimal tissue without imaging features suggestive of thrombus. The imaging findings suggested atherosclerotic progression, potentially compounded by the limited acute luminal gain achieved at the index procedure, the cumulative burden of cardiovascular risk factors, and chronic inflammatory cell infiltration. Although the pharmacological effect of paclitaxel diminishes within months, preclinical studies have suggested that low residual tissue concentrations might contribute to late fibrotic or calcific remodeling. Device-related neoatherosclerosis appears unlikely because of the absence of a metallic scaffold. This case illustrates the multifactorial nature of very late vascular changes after stentless PCI and demonstrates how multimodality imaging, including cardiac computed tomography and IVUS, can describe late lesion morphology and healing patterns. The findings highlight the complex late-phase vascular morphology that may emerge in patients with diffuse disease and multiple risk factors and underscore the clinical value of comprehensive imaging assessment at very late follow-up.

Epicardial coronary disease includes dynamic disorders capable of causing myocardial ischaemia without fixed obstructive stenosis. Vasospastic angina (VSA) and myocardial bridging (MB) are paradigmatic entities characterized by transient luminal narrowing and reversible flow impairment. Although traditionally viewed as distinct, they frequently overlap, sharing mechanisms such as endothelial dysfunction, smooth muscle hyperreactivity, altered shear stress, and autonomic imbalance. VSA results from episodic coronary constriction, whereas MB involves systolic compression of an intramyocardial segment with possible diastolic flow limitation. The aim of this article is to provide a mechanistic appraisal of these conditions and their clinical implications within chronic coronary syndromes.

Large B-cell lymphoma (LBCL) can show luminal growth in lymph nodes and extranodal sites, but nodal cases with intrasinusoidal growth may be difficult to distinguish from intravascular LBCL (IVLBCL). We retrospectively reviewed 19 LBCLs with luminal growth and classified them as nodal LBCL with intrasinusoidal growth (LBCL-IS; n = 5), extranodal LBCL with intravascular growth without hemophagocytic lymphohistiocytosis (HLH; n = 9), or extranodal LBCL with intravascular growth and HLH (n = 5). Compared with combined extranodal cases, nodal LBCL-IS was associated with older age (>75 years, 80.0% vs 14.3%; P = .024), fewer B symptoms (2/5 vs 12/13 evaluable cases; P = .044), absence of bone marrow involvement (0% vs 64.3%; P = .033), and lower serum lactate dehydrogenase levels (median, 327 vs 826 IU/L; P = .006). Limited-stage disease and low or low-intermediate International Prognostic Index scores occurred only in nodal LBCL-IS. Nodal cases largely shared a non-germinal center B-cell phenotype with extranodal cases, whereas Epstein-Barr virus positivity was confined to nodal LBCL-IS (2/5, 40.0%). Among extranodal cases, CD5 expression was associated with a higher complete response rate after initial chemotherapy (7/7 vs 1/5; P = .010). All five patients with nodal LBCL-IS achieved complete response after initial rituximab-based chemotherapy. Nodal LBCL-IS also showed longer progression-free and overall survival than HLH-associated extranodal LBCL (P = .021 and P = .049, respectively), although the small cohort size warrants cautious interpretation. These findings suggest that, despite its histologic resemblance to IVLBCL, nodal LBCL-IS represents a distinctive nodal growth pattern whose recognition may be clinically important.

The intestinal epithelial surface is protected by a multilayered barrier system that includes secreted mucus and a membrane-bound glycocalyx. While gel-forming mucins have been extensively studied, the transmembrane mucins that form the enterocyte glycocalyx remain less well understood. MUC17 has emerged as a dominant and functionally important transmembrane mucin of the small intestinal brush border, where its large, extensively O-glycosylated extracellular domain forms a dense, hydrated barrier between luminal microbes and the epithelial membrane. This review summarizes current knowledge of MUC17 biology, from genomic organization and protein architecture to glycosylation, trafficking, developmental regulation, and barrier function. Particular emphasis is placed on how MUC17 contributes to size-selective exclusion, bacterial segregation, and host-microbe homeostasis. This review further discusses the developmental establishment of the MUC17-rich enterocyte glycocalyx during the suckling-weaning transition and covers the mechanisms that regulate MUC17 localization and dynamics in epithelial cells, including apical targeting, membrane retention, recycling, turnover, and responses to inflammatory cues. Finally, the review examines the consequences of altered MUC17 expression or function, with particular emphasis on glycocalyx barrier defects, host-microbe interactions, bacterial access to the epithelium, and the relevance of MUC17 dysfunction to Crohn's disease and experimental models of intestinal infection. Together, the review positions MUC17 as a central structural and functional component of the intestinal glycocalyx and an underexplored therapeutic axis for restoring epithelial barrier integrity in intestinal disease.

The synaptic vesicle protein 2 (SV2) family is a highly conserved group of transmembrane glycoproteins sharing approximately 70% sequence identity. SV2A and SV2B are broadly distributed throughout the brain, while SV2C, the evolutionarily oldest member of the family, is primarily found in dopaminergic brain regions in the basal ganglia. Genome-wide association studies have linked SV2C to Parkinson's disease, and SV2C appears to enhance dopamine storage in synaptic vesicles, but the basis for this effect is unknown. SV2s are the target of the racetam class of antiseizure medications, and SV2A-specific ligands are widely used to treat seizures. Recently several SV2C-specific ligands have been developed, but the structural basis for ligand specificity is unclear. A better understanding of SV2C structure, function, and pharmacology could lead to better targeted therapies for epilepsy, Parkinson's disease, and other dopamine-related conditions. Here we present cryo-EM structures of apo SV2C, SV2C bound to the high affinity non-selective SV2 ligand padsevonil, SV2C bound to the SV2C-selective ligand UCB-F, and SV2A bound to the SV2A-selective ligand plosaracetam (also known as ABBV-552/SDI-118). We find that SV2C has a wider luminal opening than SV2A and SV2B, which allows for UCB-F to bind to the primary site and form favorable interactions that are not possible in the narrower primary binding site of SV2A and SV2B. We also demonstrate that UCB-F and padsevonil, but not plosaracetam, reduce dopamine release in striatal sections of mouse brain. Our biochemical experiments and structures provide insights into SV2 ligand specificity and offer a template for the rational development of therapeutics targeting SV2C.