Protein interactions with molecules, such as other proteins, peptides, or small ligands, play a critical role in biological processes, and the identification of protein binding sites is crucial for understanding the mechanisms underlying diseases such as cancer. Traditional protein binding site prediction models usually extract residue features manually and then employ a graph or point-cloud-based architecture borrowed from other fields. Therefore, substantial information loss and limited learning ability cause them to fail to capture residue binding patterns. To solve these challenges, we introduce a general network that predicts the binding residues of proteins, peptides, and metal ions on proteins. SpatConv extracts sequence features from a pretrained large protein language model and structure features from a local coordinate framework. SpatConv learns residue binding patterns through a specially designed, graph-free bio-spatial convolution, which characterizes the complex spatial environments around the residues. After training and testing, SpatConv demonstrates great improvements over the state-of-the-art predictors and reveals novel biological insights into the relationship between binding sites and physicochemical properties. Notably, SpatConv exhibits robust performance across predicted and experimental structures, enhancing its reliability. Additionally, when applying it to the spike protein structure of severe acute respiratory syndrome coronavirus 2, SpatConv successfully identifies antibody binding sites and predicts potential binding regions, providing strong evidence supporting new drug development. A user-friendly online server for SpatConv is freely available at http://liulab.top/SpatConv/server.

T lymphocytes consist of αβ and γδ T cells, which mature and differentiate from the same progenitor cells in the thymus. Cullin-RING ligases (CRLs), the largest family of ubiquitin ligases, require neddylation on the scaffold protein Cullins for their ligase activity. The role of neddylation–CRL system in thymus development and fate determination of αβ/γδ T cells remains elusive. Here, we generated conditional knockout mouse models with thymus individual deletion of Ube2m or Ube2f, 2 neddylation E2-conjugating enzymes, and Rbx1 or Sag, 2 dual neddylation and ubiquitylation E3 ligases. We found that only Rbx1, but not Ube2m/Ube2f, nor Sag, plays an essential role in thymus development and fate determination of αβ/γδ T cells. Specifically, Rbx1 loss causes shrinkage of the thymus, delayed T cell development, increased γδ T cells in the thymus, increased the ratio of immature Gzma⁺ γδ T cells, and decreased the ratio of the proliferative subpopulation. Some of these phenotypes were moderately rescued by simultaneous Bim deletion. Mechanistically, Rbx1 loss alters the Akt, NF-κB, and metabolic pathways in progenitor γδ T cells/DN3a cells. Finally, Rbx1 loss altered the γδ T1/T17 cell population in the thymus, suggesting that Rbx1 controls the fate of γδ T cells.

In orthopedic minimally invasive surgeries (MIS) such as percutaneous vertebroplasty (PVP) and percutaneous kyphoplasty (PKP), calcium phosphate cements (CPCs) are an attractive alternative to bioinert polymethyl methacrylate (PMMA) due to their superior biocompatibility and osteoconductivity. However, the mechanical strength and injectability of CPCs often remain insufficient for load-bearing applications, limiting their broader use in these critical procedures. To address this challenge, we introduce a machine learning-assisted approach to enhance both the mechanical strength and injectability of CPCs by identifying specific polymers as superplasticizers. By optimizing its concentration and the liquid-to-powder (L/P) ratio, we developed an injectable brushite-based cement with an exceptional compressive strength of 79.5 ± 4.3 MPa, surpassing both traditional CPCs and PMMA in orthopedic applications. Zeta potential and adsorption studies reveal that these superplasticizers enhance cement paste dispersion via electrostatic repulsion. In vitro assays demonstrate excellent biocompatibility and osteogenic properties, while in vivo experiments further confirm the cement’s superior osteoinductive capability. The brushite cement regulates cellular metabolism and stem cell differentiation by enhancing energy metabolism and activating key signaling pathways such as phosphatidylinositol 3-kinase–AKT and mitogen-activated protein kinase–extracellular signal–regulated kinase. These findings offer a novel approach to fabricating CPCs with enhanced mechanical strength and osteogenic potential, addressing long-standing challenges in orthopedic MIS.

Chronic mechanical vibrations and endoplasmic reticulum (ER) stress are major contributors to osteoarthritis (OA) progression. This study proposes a novel “cellular shock absorption” approach by developing viscoelastic hydrogel microspheres with tunable stress relaxation properties. By modulating the chemical bonds in the hydrogel network through oxidation and hydrazine coupling reaction, hydrogel microspheres capable of absorbing shock and reducing mechanical stimulus-induced ER stress in chondrocytes are created. Cationic liposomes, modified with the cartilage-targeting peptide Wyrgrl and loaded with tauroursodeoxycholic acid (TUDCA), are encapsulated within these hydrogel microspheres. The microspheres not only dissipate intra-articular impact forces, reducing vibration and pressure transmission, but also provide sustained release of TUDCA, alleviating ER stress and slowing OA progression. In vitro studies showed that the stress relaxation time constant (τ) of the microspheres was tuned to 23.81 s, closely resembling the mechanical properties of the cartilage matrix. This property, combined with targeted TUDCA delivery, reduced Grp78 and CHOP expression, alleviating ER stress and inhibiting chondrocyte apoptosis. In vivo, the microspheres preserved joint cartilage structure, suppressed ER stress responses, and substantially delayed OA progression. This strategy presents a promising approach to mitigating cartilage damage and delaying OA by reducing mechanical stress and alleviating ER stress.

Textiles with intrinsic breathability and mechanical adaptability are revolutionizing wearable electronics by delivering outstanding comfort and integration potentials. However, the expanding functionalities and body coverage of textile electronics necessitate large-scale and distributed driving circuits, which typically compromise the flexibility and permeability of textiles. To overcome the limitations of traditional circuit boards, textile hybrid electronics (THE) have emerged as promising electronic platforms, where both flexible and rigid components are seamlessly integrated into textiles. This route offers a synergy of system-level performance and wearing comfort. The progress report presents a comprehensive overview of the fabrication strategies for fully integrated THE, mainly encompassing the cross-scale production of flexible components and the reliable integration of rigid components. First, typical materials classified in textile electronic components are summarized. Then, various methods for constructing flexible coatings and fibrous structures are elucidated with distinct mechanisms and advantages for textile substrates. Followed by that, the focus shifts to the heterogeneous integration of rigid components, including the layer-by-layer and in-fiber strategies. Both approaches show promise in realizing monolithic and untethered THE systems. Furthermore, representative paradigms of THE are presented for their applications in pervasive health management and human–machine interaction. Finally, future trends of THE toward distributed and intelligent systems are specially emphasized, with key challenges and potential solutions outlined. The combination of various forms of THE is expected to embed advanced electronic functionalities into everyday textiles, bridging the gap between wearable electronics and human life.

Androgenetic alopecia (AGA)—a condition characterized by hair loss due to aging, autoimmune responses, stress, and other factors—results in hair follicle (HF) shrinkage and dermal papilla cell apoptosis. So far, only minoxidil (MXD) and finasteride have been approved for AGA treatment. However, both drugs have serious side effects, including hypersensitivity and sexual dysfunction. Hence, novel treatment agents are required for AGA. Although metformin (Met) is primarily a diabetes drug, it is also known to promote hair growth. However, it shows low transdermal permeability, and the mechanisms underlying its therapeutic effects on AGA remain unclear. Two-dimensional black phosphorus nanosheets (BP NSs) have attracted attention as drug carriers due to their low cytotoxicity, good biocompatibility, and strong antioxidant capacity. However, they are unstable, prone to degradation, and unsuitable for transdermal drug delivery. Fortunately, this limitation can be addressed through modification strategies, such as polyethylene glycol (PEG) addition (PEGylation). Here, we PEGylated BP NSs to improve their stability and loaded them with Met to generate a transdermal system (BP-PEG-Met) for AGA treatment. Compared with topical MXD, BP-PEG-Met markedly promoted hair regeneration while inducing fewer side effects. BP-PEG-Met scavenged excessive reactive oxygen species in skin cells, reducing the oxidative stress around HFs. Moreover, it up-regulated the expression of vascular endothelial growth factor (VEGF) and platelet-endothelial cell adhesion molecule-1 (CD31) in dermal papillae, inducing angiogenesis around HFs and accelerating the hair cycle toward anagen. Overall, this BP-PEG-Met transdermal delivery system showed marked clinical potential as a multifunctional tool for treating alopecia and possibly managing other skin conditions.

Outbreaks and the widespread prevalence of porcine respiratory infectious diseases have led to substantial economic losses worldwide. In this study, epidemiological surveillance revealed lower viral detection in association with an increased abundance of Bacillaceae in pigs with outdoor access; thus, Bacillus subtilis NS12, a strain with enhanced mucosal colonization and superior broad-spectrum antiviral activity, was isolated from the nasal mucosa of these pigs for further investigation. This mechanistic study revealed that the antiviral efficacy of B. subtilis NS12 is primarily attributed to bioactive metabolites, including a novel surfactin with high safety and antiviral activity and piceatannol, a potent antioxidant molecule. These metabolites modify the structure and fluidity of phospholipids within the viral envelope, thereby inhibiting viral entry by impeding membrane fusion. Therefore, with its broad-spectrum antiviral activity, B. subtilis NS12 offers a probiotic-based, environmentally sustainable, and noninvasive antiviral strategy for preventing and controlling respiratory viral infections.

Nonsuicidal self-injury (NSSI) demonstrates escalating prevalence among adolescents as a maladaptive behavior characterized by deliberate self-harm, yet its neurobiological underpinnings remain elusive. Spontaneous self-injurious behavior (SIB) in nonhuman primates (NHPs) emerges as a clinically relevant animal model for investigating NSSI pathogenesis and therapeutic interventions. However, previous studies have yet to comprehensively evaluate the translational value of self-injury in NHPs through integrated behavioral and neuroimaging characterization. In this study, we identified spontaneously self-injurious macaques within our NHP colony and performed multimodal assessments encompassing ethological profiling, neuroendocrine assays, metabolomic analysis, and neuroimaging. Our results revealed that SIB macaques exhibited biological patterns and temporal onset sequences of self-harm, accompanied by a locomotor and social interaction decrease based on 3-dimensional deep-learning recognition, sensory processing deficits, and impairments in emotional and cognitive processing. Biochemical profiling demonstrated reduced plasma concentrations of cortisol, serotonin, and oxytocin, coupled with metabolomic disturbances including up-regulation of digestive-related pathways and down-regulation of dopaminergic synaptic signaling and phosphatidylinositol metabolism. Neuroimaging analyses identified structural abnormalities featuring volumetric enlargement in amygdala and midbrain regions alongside gray matter reduction in the frontal and parietal lobes. Enhanced structural and functional connectivity was observed. Network-based statistics highlighted increased functional connectivity primarily between the frontal and parietal lobes. These alterations demonstrated a partial correlation with observed behavioral deficits in the self-injury macaques. Notably, a series of administration of low-dose ketamine had no effect on SIB and the physical index. Our integrative multi-omic approach elucidates the neurobiological phenotype of spontaneous SIB in macaques, highlighting the value of the SIB model for pathogenetic investigation and therapeutic development in human NSSIs.

Optical microscopy contributes to the ever-increasing progress in biological and biomedical studies, as it allows the implementation of minimally invasive experimental pipelines to translate the data of measured samples into valuable knowledge. Within these pipelines, reliable quality assessment must be ensured to validate the generated results. Image quality assessment is often applied with full-reference methods to estimate the similarity between the ground truth and the output images. However, current methods often show poor agreement with visual perception and lead to the generation of various full-reference metrics tailored to specific applications. Additionally, they rely on pixel-wise comparisons, emphasizing local intensity similarity while often overlooking comprehensive and interpretable image quality assessment. To address these issues, we have developed a multi-marker similarity method that compares standard quality markers, such as resolution, signal-to-noise ratio, contrast, and high-frequency components. The method computes a similarity score between the image and the ground truth for each marker and then combines these scores into an overall similarity estimate. This provides a full-reference estimate of image quality while extracting global quality features and detecting experimental artifacts. Multi-marker similarity provides a reliable and interpretable method for image quality assessment and the generation of quality rankings. By focusing on the comparison of quality markers rather than direct image distances, the method enables reduced-reference implementations, where a single field of view is used as a benchmark for multiple measurements. This opens a way for reliable automatic evaluation of big datasets, typical of large biomedical studies, when manually assessing single images and defining the ground truth for each field of view is not feasible.

A persistently substantial energy demand and metabolic reprogramming endure throughout the entire course of osteoclastogenesis, accompanied by an intensified oxidative stress. Hence, balancing cellular energy metabolism and maintaining redox homeostasis offer potential for coordinating osteoclastogenesis and bone loss in pathological conditions. In the present study, we have discovered Visomitin, a novel antioxidant that specifically targets mitochondria, which efficiently decreases intracellular reactive oxygen species (ROS) levels, inhibits osteoclastogenesis, and impairs the function of bone resorption. Mechanistically, Visomitin directly targets signal transducer and activator of transcription 3 (STAT3), leading to the inhibition of its transcriptional activity and modulation of lactate dehydrogenase B (LDHB) expression levels, consequently triggering metabolic reprogramming and exerting antagonistic effects on osteoclasts. Furthermore, administration of Visomitin demonstrates marked protective effects against pathological bone loss in vivo. Given its established clinical safety profile in ophthalmologic applications, Visomitin emerges as a promising anti-resorptive agent for clinical translation. This study also unveils the STAT3/LDHB axis as a critical nexus linking mitochondrial redox regulation to osteoclast metabolism, providing a novel therapeutic strategy for osteoclast-driven bone diseases.