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.

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.

This commentary highlights the importance and implications of the study “Quadruple-band synglisis enables high thermoelectric efficiency in earth-abundant tin sulfide crystals”, led by C. Chang and L. Zhao, published in Science. They improved the thermoelectric efficiency by activating quadruple-band synglisis and facilitating carrier transport in tin sulfide crystals, and successfully developed an optical pump–terahertz probe technique in reflection mode to diagnose the carrier dynamics for high-conductivity bulk thermoelectric materials. This study inspires mutual promotion and complementary development between the fields of thermoelectrics and terahertz technology.

It has been demonstrated that glutamine is a key player in boosting endothelial cell (EC) proliferation. However, despite its importance, the role of endothelial glutaminolysis in diabetes remains largely unexplored. Our research aimed to investigate the function of glutaminolysis in ECs within the context of diabetes and to evaluate the potential therapeutic effects of salvianolic acid B (SalB) and α-ketoglutarate (α-KG) on diabetic vascular complications. Histological analysis of skin wounds in diabetic patients revealed delayed restoration of vascularization and collagen synthesis during wound healing, accompanied by decreased glutaminase 1 (GLS1) expression and reduced colocalization with the EC marker platelet-endothelial cell adhesion molecule-1 (CD31). Additionally, a significant decline in GLS1 activity and expression was observed in ECs isolated from diabetic hearts. In vitro studies using cultured ECs demonstrated that exposure to high glucose and high fat (HGHF) reduced GLS1 expression and suppressed glutaminolysis, impairing EC proliferation and tube formation. These adverse effects were mitigated by treatment with SalB or supplementation with α-KG plus nonessential amino acids (NEAAs). Among diabetic mice subjected to myocardial ischemia/reperfusion (MI/R), SalB administration or α-KG supplementation promoted myocardial revascularization and improved cardiac dysfunction. Notably, endothelial-specific GLS1 deletion in mice blocked the beneficial effects afforded by SalB but not those afforded by α-KG. Furthermore, SalB administration accelerated angiogenesis and cutaneous wound healing in diabetic mice, and these influences were removed by pharmacological inhibition of GLS1 using bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl) ethyl sulfide (BPTES) or genetic deletion of endothelial GLS1. These findings indicate that defective endothelial glutaminolysis contributes to impaired angiogenesis and poor ischemic tissue repair in diabetes. Improving endothelial glutaminolysis by treatment with SalB or metabolic supplementation with α-KG promotes angiogenesis and ischemic tissue repair in diabetic mice, emphasizing the possibility of GLS1 as a treatment target.

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.

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.

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.

Discrete-modulated coherent-state continuous-variable quantum key distribution (DMCS-CVQKD) is of great value for its simple implementation. However, the traditional DMCS-CVQKD scheme cannot tolerate the high channel excess noise and channel loss, compared to the Gaussian-modulated scheme, and its error correction is still difficult. In this paper, we propose a discrete-modulated coherent-state basis-encoding quantum key distribution (DMCS-BE-QKD) protocol, where the secret keys are encoded in the random choice of 2 measurement bases, i.e., the conjugate quadratures X and P of discrete-modulated coherent states, and it only needs simple binary sequence error correction. We analyze the secret key rate of DMCS-BE-QKD protocol under individual and collective attacks in the linear Gaussian channel. The results show that DMCS-BE-QKD can greatly enhance the ability to tolerate the channel loss and excess noise compared to the original DMCS-CVQKD protocol, which can tolerate approximately 40 dB more channel loss compared to the original DMCS-CVQKD for the realistic value of noise. Finally, a proof-of-principle experiment is conducted under a 50.5-km optical fiber to verify the feasibility of DMCS-BE-QKD. It is based on the consistent physical procedures of the traditional DMCS-CVQKD, which makes it perfectly compatible to deployed terminals and can serve as a multiplier for the practical secure quantum cryptography communication in harsh environments.

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.

Magnetic continuum robots offer flexibility and controllability, making them promising for minimally invasive surgery (MIS). However, the clinical application of these robots is relatively limited due to the difficulty of integrating miniaturized triaxial force sensors and their single functionality. This paper proposes a multifunctional magnetic catheter robot with magnetic actuation steering and triaxial force-sensing capabilities. The robot features 3 channels at its tip that integrate multi-segmented magnets, a novel triaxial force sensor, and various functional instruments. The sensor is calibrated, demonstrating high sensitivity and accuracy. The steering characterization of the robot confirms that the catheter tip exhibits effective flexibility and force sensing. Palpation experiments involving various hard lumps are performed on porcine kidney, with results verifying that the robot can reliably detect abnormal hard lumps within tissues. Additionally, palpation experiments in bronchial phantom demonstrate the robot's imaging and palpation capabilities for lung nodules with an integrated endoscope. Further, the robot, equipped with biopsy forceps, successfully performs palpation and biopsy functions on simulated stomach polyps, demonstrating its capability for effective tissue manipulation. By leveraging force-sensing capabilities and integrating multifunctional instruments, the robot shows potential for expanded applications in MIS, paving the way for important advancements in clinical procedures.