Background: Emerging evidence suggests that autoantibodies targeting podocytes are potential contributors to idiopathic nephrotic syndrome (INS); however, the specific mechanisms remain unclear. This study aims to explore the pathogenic role and underlying mechanisms of anti-vinculin autoantibodies in INS. Methods: Serum anti-vinculin autoantibody levels detected by protein microarray and clinical data were compared among INS patients (n = 147), healthy individuals (n = 84), and patients with other kidney or immune diseases (n = 100 of each disease). Immune-mediated mouse models were established to verify the pathogenicity of anti-vinculin autoantibodies. Mouse urine was monitored for urine protein levels, while immunofluorescence, pathological staining, and electron microscopy assessed kidney pathological and ultrastructural changes. Transcriptome sequencing of mouse kidney tissues was performed to investigate the key molecular mechanisms and signaling pathways involved in kidney injury post-immunization. Results: Anti-vinculin autoantibody levels were specifically elevated in INS patients, with a 54.42% positivity rate, correlating with urinary albumin, serum albumin, cholesterol, and CD19 levels. The average anti-vinculin autoantibody levels dropped markedly in pediatric INS patients during remission. Mouse experiments revealed that injecting anti-vinculin antibodies or recombinant vinculin protein induced proteinuria and podocyte injury in the immunized mice, and the renal phenotype closely resembled the pathological characteristics of minimal change disease. Transcriptome sequencing of renal tissues revealed up-regulation of inflammation, immune responses, cytokine activities, and B cell activation pathways in the immunized mice, while cytoskeleton-related functions were down-regulated. Conclusions: Autoantibodies targeting vinculin act as pathogenic autoantibodies in INS and hold potential value for diagnosing and monitoring INS progression.

Bedside monitoring of brain function in severely brain-injured patients remains a critical clinical challenge. We demonstrate the translational potential of functional ultrasound (fUS) imaging for this purpose. In 6 comatose patients (Glasgow coma scale ≤ 8) with cranial windows after decompressive craniectomy, we used a 7.8-MHz transducer optimized for cortical depths of 1.5 to 4 cm to perform real-time fUS during auditory stimulation. We observed task-related increases in regional cerebral blood flow (rCBF) in relevant brain regions (P < 0.001, t test), which correlated with subsequent neurological recovery at 9-month follow-up. These findings establish fUS as a sensitive and portable tool for bedside brain function assessment, offering potential for improved prognostication, treatment guidance, and development of targeted rehabilitative strategies.

Type 2 diabetes mellitus (T2DM), a prevalent metabolic disorder marked by insulin resistance and hyperglycemia, has been linked to volumetric changes in subcortical regions, yet the genetic basis of this relationship remains unclear. We analyzed genome-wide association study summary data for T2DM and 14 subcortical volumetric traits, using MiXeR to quantify shared genetic architecture and applying conditional/conjunctional false discovery rate analyses to detect novel and shared genomic loci. Enrichment and gene expression analyses were subsequently performed to explore the biological functions and mechanisms of genes associated with these loci. We observed a substantial proportion of trait-influencing variants shared between T2DM and subcortical structures, with Dice coefficients ranging from 22.4% to 49.6%. Additionally, 70 distinct loci were identified as being jointly associated with T2DM and subcortical volumes, 5 and 22 of which were novel for T2DM and subcortical volumes, respectively. The 769 protein-coding genes mapped to these shared loci are enriched in metabolic and neurodevelopmental pathways and exhibit specific developmental trajectories, with 117 genes showing expression levels linked to both T2DM and subcortical structures. This study uncovered polygenic overlap between T2DM and subcortical structures, deepening our comprehension of the genetic factors linking metabolic disorders and brain health.

Although omics and multi-omics approaches are the most used methods to create signature arrays for liquid biopsy, the high cost of omics technologies still largely limits their wide applications for point-of-care. Inspired by the bat echolocation mechanism, we propose an “echoes” approach for creating chemiluminescence signatures via screening of a compound library, and serum samples of Alzheimer's disease (AD) were used for our proof-of-concept study. We first demonstrated the discrepancy in physicochemical properties between AD and healthy control serums. On this basis, we developed a simple, cost-effective, and versatile platform termed UNICODE (UNiversal Interaction of Chemiluminescence echOes for Disease Evaluation). The UNICODE platform consists of a “bat” probe, which generates different chemiluminescence intensities upon interacting with various substrates, and a panel/array of “flag” molecules that are selected from library screening. The UNICODE array could enable the reflecting/“echoing” of the signatures of various serum components and intact physicochemical interactions between serum substrates. In this study, we screened a library of over 1,000 small molecules and identified 12 “flag” molecules (top 12) that optimally depict the differences between AD and healthy control serums. Finally, we employed the top 12 array to conduct tests on serum samples and utilized machine learning methods to optimize detection performance. We successfully distinguished AD serums, achieving the highest area under the curve of 90.24% with the random forest method. Our strategy could provide new insights into biofluid abnormality and prototype tools for developing liquid biopsy diagnoses for AD and other diseases.

Arsenic trioxide (ATO) is able to selectively target and degrade the disease-causing PML::RARα (P/R) oncoprotein in acute promyelocytic leukemia (APL) for curing the disease. However, some relapsed patients develop resistance to ATO due to mutations in the promyelocytic leukemia (PML) part of the PML::RARα fusion gene. A relapsed APL patient had shown resistance to ATO and chemotherapy and was identified to harbor a point mutation (A216V) in the unrearranged PML allele rather than the PML::RARα fusion gene. Here, we report that mutations in the unrearranged PML allele impede the ATO-induced destabilization and degradation of the wild-type P/R oncoprotein. Deletion of the coiled-coil domain in a PML mutant completely reversed wild-type P/R protein resistance to ATO by abolishing the interaction between PML and P/R proteins. Collectively, our findings reveal that a point mutation in the unrearranged PML allele can confer ATO resistance through a protein–protein interaction. Therefore, the unrearranged PML allele should also be screened for drug-resistant mutations in relapsed APL patients.

Supplementation with short-chain fatty acids (SCFAs) is a potential therapeutic approach for inflammatory bowel disease (IBD). However, the therapeutic effects and mechanisms of action of isobutyrate in IBD remain unclear. Clinical data indicate that the fecal levels of isobutyrate are markedly lower in patients with Crohn's disease than in healthy controls. Compared with healthy mice and healthy pigs, mice and pigs with colitis presented significantly lower isobutyrate levels. Furthermore, the level of isobutyrate in pigs was significantly negatively correlated with the disease activity index. We speculate that isobutyrate may play a crucial role in regulating host gut homeostasis. We established a model of dextran sulfate sodium-induced colitis in pigs, which have gastrointestinal structure and function similar to those of humans; we performed multiomic analysis to investigate the therapeutic effects and potential mechanisms of isobutyrate on IBD at both the animal and cellular levels and validated the results. Phenotypically, isobutyrate can significantly alleviate diarrhea, bloody stools, weight loss, and colon shortening caused by colitis in pigs. Mechanistically, isobutyrate can increase the relative abundance of Lactobacillus reuteri, thereby increasing the production of indole-3-lactic acid, regulating aryl hydrocarbon receptor expression and downstream signaling pathways, and regulating Foxp3⁺ CD4⁺ T cell recruitment to alleviate colitis. Isobutyrate can directly activate G protein-coupled receptor 109A, promote the expression of Claudin-1, and improve intestinal barrier function. In addition, isobutyrate can increase the production of intestinal SCFAs and 3-hydroxybutyric acid and inhibit the TLR4/MyD88/NF-κB signaling pathway to suppress intestinal inflammation. In conclusion, our findings demonstrate that isobutyrate confers resistance to IBD through host–microbiota interactions, providing a theoretical basis for the use of isobutyrate in alleviating colitis.

The disruption of ferroptosis, an emerging form of programmed cell death, is crucial in the development and aggressiveness of tumors. Meanwhile, the mechanisms and treatments that control ferroptosis in neuroblastoma (NB), a prevalent extracranial cancer in children, are still unknown. In this study, forkhead box C1 (FOXC1) and O-GlcNAc transferase (OGT) are identified as regulators of asparagine- and alanine-mediated ferroptosis repression in NB. Mechanistically, OGT facilitates FOXC1 stabilization via inducing O-GlcNAcylation in liquid condensates to increase the expression of asparagine synthetase (ASNS) and glutamate pyruvate transaminase 2 (GPT2), resulting in asparagine and alanine biogenesis, and subsequent synthesis of cystathionine β-synthase (CBS) or ferritin heavy chain 1 (FTH1). Meanwhile, exonic circular OGT RNA (ecircOGT) is able to encode a novel protein (OGT-570aa) containing domain essential for binding of OGT to FOXC1, which competitively decreases the OGT–FOXC1 interaction. Preclinically, miconazole nitrate facilitates the interaction of OGT-570aa with FOXC1, suppresses ferroptosis resistance of NB cells, and inhibits their growth, invasion, and metastasis. In clinical NB cases, higher OGT, FOXC1, ASNS, GPT2, CBS, or FTH1 levels are correlated with worse survival, while lower ecircOGT or OGT-570aa expression is associated with tumor progression. These results indicate that targeting the ecircOGT/OGT/FOXC1 axis inhibits asparagine- and alanine-mediated ferroptosis repression in NB progression.

Although equivalent in the infinite-momentum limit, large-momentum effective theory (LaMET) and short-distance operator product expansion (SDE) are 2 very different approaches to obtain parton distribution functions (PDFs) from coordinate-space correlation functions computed in a large-momentum proton through lattice quantum chromodynamics (QCD). LaMET implements a momentum-space expansion in {\mathrm{\Lambda }}_{\mathrm{QCD}} / \left[x\left(1-x\right)P^z\right] to directly calculate PDFs f \left(x\right) in a middle region of Bjorken x \in \left[x_{\min }\sim {\mathrm{\Lambda }}_{\mathrm{QCD}}/{\mathit{xP}}^z,x_{\max }\sim 1-x_{\min }\right]. SDE applies perturbative QCD at small Euclidean distances z to extract a range \left[0,{\lambda }_{\max }\right] of leading-twist correlations, h \left(\lambda ={\mathit{zP}}^z\right), corresponding to the Fourier transformation of PDFs. An incomplete leading-twist correlation from SDE cannot be readily converted to a momentum-space distribution, and solving its constraints on the PDFs (or the so-called “inverse problem”) involves phenomenological modeling of the missing information beyond {\lambda }_{\max } and has no systematic control of errors. I argue that the best use of short-distance correlations is to constrain the PDFs in the LaMET-complementary regions: x \in \left[0,x_{\min }\right] and \left[x_{\max },1\right] through expected end-point asymptotics, and use the results of the pion valence quark distribution from the ANL/BNL collaboration to demonstrate how this can be done.

Malignant and premalignant ocular surface tumors (OSTs) can be sight-threatening or even life-threatening if not diagnosed and treated promptly. Artificial intelligence holds great promise for the early detection of these diseases. However, training traditional convolutional neural networks (CNNs) for this task presents challenges due to the lack of large, well-annotated datasets containing OST images labeled according to histopathological results. Here, we introduce the ocular surface pretrained model (OSPM), a domain-specific pretrained model designed to address the scarcity of labeled data. OSPM is constructed utilizing self-supervised learning on approximately 0.76 million unlabeled ocular surface images from 10 clinical centers across China and can be readily adapted to the OST classification task. We then develop and evaluate an OSPM-enhanced classification model (OECM) using 1,455 OST images labeled with histopathological diagnoses to differentiate between malignant, premalignant, and benign OSTs. OECM achieves excellent performance with AUROCs ranging from 0.891 to 0.993 on internal, external, and prospective test datasets, significantly outperforming the traditional CNN models. OECM demonstrated performance comparable to that of senior ophthalmologists and increased the diagnostic accuracy of junior ophthalmologists. Greater label efficiency was observed in OECM compared to CNN models. Our proposed model has high potential to enhance the early detection and treatment of malignant and premalignant OSTs, thereby reducing cancer-related mortality and optimizing functional outcomes.

Antiangiogenesis gene therapy based on adeno-associated virus (AAV) vectors represents a promising advancement in the treatment of neovascular age-related macular degeneration (nAMD), providing an alternative to antibody-based therapies. However, the development of a safe and effective AAV vector capable of precisely targeting neovascularization and choroidal leakage remains a critical unmet need. In the present study, we engineered a novel intravitreally administered AAV vector with retinal-pigment-epithelium (RPE)-specific tropism. This vector demonstrated robust and localized gene expression in RPE cells while maintaining a favorable safety profile. The RPE-tropic AAV vector delivered a dual-acting antibody against vascular endothelial growth factor (VEGF) and angiopoietin-2 (ANG-2), exhibiting strong therapeutic efficacy and tolerability in both rodent and nonhuman primate choroidal neovascularization models. Based on the promising preclinical data, a single-center, single-arm, investigator-initiated trial (ChiCTR2400085329) was conducted to assess its safety and efficacy in patients with nAMD. The RPE-tropic AAV vector expressing anti-VEGF-A and anti-ANG-2 effectively alleviated disease progression and was well tolerated in the clinical setting. These findings highlight the potential of this engineered AAV-RPE capsid as a versatile platform for gene therapy, not only for nAMD but also for other ocular diseases involving RPE cells.