The transforming growth factor-β1 (TGF-β1)/Smad3 pathway drives DNA damage, necrosis, and ventricular remodeling following acute myocardial infarction (AMI); however, effective therapies targeting this cascade remain limited. Here, we investigated the role of the deubiquitinating enzyme BRCA1/BRCA2-containing complex subunit 3 (BRCC3) in postinfarction cardiac remodeling and dysfunction using a mouse AMI model established via left coronary artery ligation. The cardiac structure and function were evaluated by echocardiography, Western blotting, and histomorphometry. We found that cardiac BRCC3 expression was markedly down-regulated after AMI. Cardiac-specific BRCC3 overexpression inhibited TGF-β1/Smad3 activation, reduced the infarct size, attenuated adverse remodeling and DNA double-strand breaks, improved cardiac function, and enhanced survival, whereas cardiac-specific Brcc3 gene knockout exacerbated these phenotypes. In vitro, BRCC3 suppressed TGF-β1-induced hypertrophic gene expression and DNA damage in cardiomyocytes, as well as profibrotic responses in cardiac fibroblasts. Mechanistically, BRCC3 bound to the MH2 domain of Smad3 and removed K63-linked polyubiquitination at lysine 333 (K333), thereby inhibiting Smad3 phosphorylation at Ser423/425. Collectively, these findings demonstrate that BRCC3 protects against ischemic injury and pathological remodeling by deubiquitinating Smad3 at K333 to antagonize TGF-β1/Smad3 signaling, identifying BRCC3 as a potential therapeutic target for preventing post-AMI heart failure.
Current space transportation employs a multistage rocket system to deliver the payload to its destination in a single launch, and this integrated model significantly constrains payload capacity for medium-high earth orbits and deep-space missions. However, the medium-high earth orbits and deep-space domains are anticipated to become the next exploration and utilization frontier, which needs large payload capacity and low-cost transportation as support. This study proposes a decoupled design for space access and in-space transfer in a medium-high earth orbit or a deep-space mission. This design introduces a novel in-space transfer transportation system enabled by cryogenic propellant refueling in orbit. In the proposed model, Earth-to-orbit vehicles are responsible for space access, while in-space transfer vehicles handle orbital transfer. This separation allows for independent optimization of vehicle designs according to their specific flight environments. Additionally, on-orbit refueling enables long-term, reusable operations for in-space transfer vehicles. The advantages of the new model are analyzed, demonstrating significant improvements in payload capacity for medium and high earth orbits, as well as substantial reducing transportation costs, holding great practical significance. Relevant design challenges associated are also given, providing a reference for subsequent in-depth researches.
Vulnerable atherosclerotic plaques represent a critical pathological basis of acute cardiocerebrovascular events. Previous studies indicate that atherosclerotic plaques are more vulnerable under chronic kidney disease (CKD) milieus. Emerging evidence highlights that vascular smooth muscle cells (VSMCs) play a pivotal role in maintaining plaque stability, but the underlying mechanisms remain incompletely elucidated. Here, single-cell sequencing and functional enrichment analysis of arterial tissues from patients with CKD are performed, identifying lipid metabolism disorders in VSMCs. Further utilizing spatial and targeted lipidomics, apolipoprotein-E-deficient (ApoE−/−) mouse with CKD (CKD/ApoE−/− mouse) and bioinformatics analysis, we investigate the lipidomic profile of VSMCs and find that VSMCs in CKD-associated vulnerable plaques exhibit significant accumulation of polyunsaturated fatty acids (PUFAs), which induces VSMC ferroptosis and exacerbates plaque vulnerability. Mechanistically, the deficiency of ECH1 leads to the accumulation of PUFA in VSMCs, thereby inducing ferroptosis in fibrous cap VSMCs and fibrous cap thinning. Meanwhile, low expression of mRNA binding protein human antigen R (HuR) resulting from CKD milieus mediates the lack of ECH1 in VSMCs. In contrast, VSMC-specific overexpression of ECH1, inhibition of PUFA release using giripladib or suppression of PUFA lipid peroxidation with PRGL493 significantly alleviate VSMC ferroptosis and CKD-associated plaque vulnerability. These findings reveal that ECH1-deficiency-driven PUFA accumulation is responsible for VSMC ferroptosis and atherosclerotic plaque vulnerability. Targeted regulation of ECH1-mediated PUFA metabolism may be a promising preventive and therapeutic strategy for CKD-associated plaque vulnerability.
D-peptides are attractive therapeutic modalities because they are generally more resistant to proteolysis than their L-counterparts, yet systematic design of target-binding D-peptides remains nontrivial. Here, we report Mirror-Peptidizer, an end-to-end in silico mirror-image screening workflow that generates D-peptide binders without requiring chemical synthesis of D-protein targets. The workflow mirrors an L-protein structure to a virtual D-protein, designs L-peptide backbones in the presence of the mirrored target using a diffusion-based backbone generator, selects sequences with a neural sequence design model, and explores local sequence neighborhoods via Bayesian multi-objective optimization balancing sequence-backbone compatibility and a solubility heuristic. Mirroring the resulting complex yields the corresponding D-peptide predicted to bind the native L-target. Using MDM2, PD-L1, and interleukin-23 receptor (IL-23R) as test cases, we identified D-peptides spanning α-helical, β-rich, and mixed conformations with affinity from 11.9 nM to sub-μM. For the MDM2 system, the 1H-15N HSQC (heteronuclear single quantum coherence) perturbations and protein mutagenesis support the designed interface, and cell-penetrating conjugates show p53-dependent cancer growth inhibition. Similarly, PD-L1-targeting D-peptides potently inhibited PD-1/PD-L1 interactions in competitive binding assays in vitro, and IL-23R-targeting D-peptides inhibited IL-2/IL-12/IL-23-induced interferon-γ production in human peripheral blood mononuclear cells. Mirror-Peptidizer is provided as an open-source implementation to facilitate rapid generation of experimentally testable D-peptide starting points.
While critical for human–machine interfaces, on-skin touch sensors struggle to replicate human skin’s curved deformation mechanics and achieve simultaneous high sensitivity, linearity, robustness, and stability. Existing capacitive, piezoresistive, piezoelectric, or triboelectric mechanisms cannot effectively harness touch-induced curved indentation. We introduce a skin-inspired flexoelectret touch sensor that exploits flexoelectricity—converting strain gradients into electricity—to mimic skin’s curved deformation geometry. This enables self-powered, self-calibrated tactile imaging through a novel mechanism establishing linear correlation between inhomogeneous deformation and electrical signal. The sensor achieves high sensitivity (the highest sensitivity up to ~835 mV/N), good linearity, exceptional robustness (>80,000 s continuous operation; >8,000 cycles), and immunity to temperature fluctuations, ultraviolet light illumination, and humidity interference. A 7 × 7-pixel array demonstrates shape-adaptive and touch-trajectory imaging capabilities. This technology unlocks transformative potential for wearable electronics and advanced human–machine interactions.
Plasma p-tau217/Aβ42 accurately captures the systemic molecular risk of Alzheimer’s disease (AD) but lacks the spatial resolution necessary to predict individualized clinical trajectories. Here, we combined plasma biomarker stratification with normative connectome mapping to identify macroscale neurodegenerative epicenters and developed a personalized prognostic tool, the Network Vulnerability Index (NVI). Across the Alzheimer’s Disease Neuroimaging Initiative and independent China ADNI cohorts, plasma p-tau217/Aβ42-positive individuals exhibited highly reproducible epicenters tightly anchored to the default mode network and limbic axis. Multiscale analyses revealed that this spatial vulnerability aligned with transcriptomic signatures of synaptic and mitochondrial dysfunction, monoaminergic receptor density gradients, and memory-related cognitive domains. Longitudinally, baseline epicenter centrality strictly dictated future localized atrophy rates. To translate these group-level topological constraints into a personalized prognostic metric, we utilized least absolute shrinkage and selection operator regression to formulate the NVI. Cross-sectionally, the NVI robustly tracked progressive tau-positron emission tomography accumulation (meta-temporal r = 0.547) and hippocampal atrophy (r = −0.455). Crucially, the NVI demonstrated robust, stage-dependent prognostic utility. When evaluated across the continuous disease spectrum, incorporating the NVI into a fully adjusted baseline model comprising plasma p-tau217/Aβ42 and APOE-ε4, and clinical scores significantly improved the prediction of conversion from mild cognitive impairment to dementia (hazard ratio = 1.47, P = 0.004), providing essential incremental prognostic value. Collectively, our spatially contextualized framework demonstrates that mapping systemic molecular risk onto structural network vulnerability supports a highly scalable “plasma pre-screen plus standard MRI” triage pathway for precision staging in Alzheimer’s disease.
Deep learning models are increasingly used to analyze medical images, but their “black box” nature makes it hard to understand the underlying biology and slows down the development of targeted treatments. To tackle this, we built a multi-step approach that combines deep learning analysis of breast magnetic resonance imaging (MRI) with several types of molecular data, including gene activity, protein levels, and genetic information, along with laboratory experiments. Our MRI-based deep learning model accurately predicted whether breast cancer had spread to lymph nodes, and it performed consistently across 3 separate groups of patients. Causal inference using double least absolute shrinkage and selection operator (LASSO) and causal forest double machine learning established a significant effect of NBPF4 expression on the imaging-defined high-risk phenotype, independent of genomic confounders. When we looked at which genes were linked to the imaging-defined high-risk pattern, one gene called NBPF4 stood out because it was supported by all 4 kinds of evidence: imaging features, gene expression, protein data, and genetic association studies. Follow-up experiments in cells and animals showed that boosting NBPF4 activity made tumor cells grow faster, move more, form new lymphatic vessels, and spread to lymph nodes. Mechanistically, NBPF4 worked by activating the mitogen-activated protein kinase (MAPK) signaling pathway and triggering a process known as epithelial mesenchymal transition (EMT). Interestingly, tumors with high NBPF4 were sensitive to drugs that block one part of the MAPK pathway (JNK/p38) but resistant to another part (ERK), suggesting that the pathway had been rewired. Using this insight, computer-based drug screening and further testing identified MK-886 as a promising compound that could suppress NBPF4-promoted MAPK activation and tumor growth. Together, this work traces a complete path from a noninvasive imaging finding to a specific gene (NBPF4) and a potential treatment (MK-886). It establishes the NBPF4–MAPK–EMT axis as a key player in breast cancer metastasis and provides a general framework for turning imaging-based risk predictions into biological understanding and possible therapies.
Sepsis frequently leaves patients with persistent immune impairment that contributes to late mortality, yet the anatomical routes that transmit this response to the lung remain poorly defined. Here, we identify the spleen as a key extramedullary hub orchestrating pulmonary immune paralysis through a spleen–lung axis. Mechanistically, splenic programmed death-ligand 1 (PD-L1)+ polymorphonuclear myeloid-derived suppressor cells undergo TFDP1-driven expansion and migrate to the lungs via CXCL2/CXCR2 signaling, establishing an interorgan immunosuppressive circuit. In the lung, these cells reprogram alveolar macrophages through programmed death-1 (PD-1)-dependent checkpoint signaling, inducing a dysfunctional state characterized by impaired antibacterial responses and enrichment of complement and immune checkpoint pathways. Genetic or pharmacologic disruption of the PD-L1–PD-1 axis restores macrophage function and improves pulmonary host defense in experimental sepsis. Together, these findings define a mechanistic link between splenic myelopoiesis and distal lung immune paralysis.
Imbalances between osteoblastogenesis and osteoclastogenesis represent the fundamental pathological feature of primary osteoporosis; however, safe and cost-effective therapies that simultaneously promote bone formation and suppress bone resorption are lacking. Given the central roles of runt-related transcription factor 2 and the nuclear factor κB pathway in bone remodeling, we performed a phenotypic screen of a Food and Drug Administration-approved drug library to identify dual-acting regulators of bone homeostasis and identified the orally approved anticoagulant dabigatran (DAB) as a novel candidate. In vivo, DAB administration markedly attenuated bone loss and preserved bone microarchitecture in both ovariectomized and aged mouse models of osteoporosis. In vitro, DAB not only inhibited receptor activator of nuclear factor κB ligand-induced osteoclastogenesis from bone-marrow-derived macrophages but also directly enhanced the osteogenic differentiation of bone marrow mesenchymal stem cells. Mechanistically, using limited proteolysis-coupled mass spectrometry, we identified protein kinase adenosine-monophosphate-activated noncatalytic subunit β1 and v-Rel reticuloendotheliosis viral oncogene homolog A as direct targets of DAB. In bone marrow mesenchymal stem cells, DAB binds to protein kinase adenosine-monophosphate-activated noncatalytic subunit β1 via the alanine-77 residue, leading to adenosine-monophosphate-activated protein kinase activation, subsequent mechanistic target of rapamycin complex 1 inhibition, enhanced autophagic flux, and ultimately promoted osteogenesis; in osteoclast precursors, DAB interacts with v-Rel reticuloendotheliosis viral oncogene homolog A at arginine-50, resulting in suppression of the nuclear factor κB pathway and attenuated osteoclast differentiation. Collectively, our findings reposition DAB as a promising therapeutic candidate for restoring osteoblast–osteoclast balance and maintaining skeletal homeostasis while establishing a novel single-molecule, dual-target pharmacological strategy and providing novel mechanistic insights for bone metabolic disease treatment.
The ANK2 gene mutations are marked risk factors for autism spectrum disorder, one of the neurodevelopmental disorders (NDDs) that often extends into adulthood and has a complex etiology involving genetic and environmental factors. ANK2 encodes 2 major isoforms, AnkB-220 (220-kDa isoform of ankyrin-B) and giant AnkB-440. We previously generated a targeted knockout (KO) of giant AnkB-440 in 2 cynomolgus and 2 rhesus monkeys. While no autism-spectrum-disorder-like phenotypes were observed during infancy, we found marked brain volume loss. In this study, we conducted a longitudinal multimodal study in these giant ANK2 KO monkeys during adolescent and young adulthood. Behavioral results from these giant ANK2 KO monkeys revealed increased locomotor activity, deficient cognition (including working memory, cognitive flexibility, and operant lever-press learning), and impaired emotional regulation and social interaction. Furthermore, the giant ANK2 KO monkeys exhibited persistent structural and functional brain abnormalities, up-regulation of brain triglyceride and glycerophospholipids, and peripheral blood transcriptome signatures of immune dysregulation, which may be related to their behavioral alternations. These observations suggest that giant ANK2 depletion in non-human primates phenocopies aspects of behavioral, neural, and molecular features characteristic of NDDs. This study provides an in-depth exploratory longitudinal characterization of giant ANK2 functions in primate brains, which may contribute to translational research on NDDs.
Intestinal epithelial injury is increasingly linked to ferroptosis, yet how dietary bioactives engage the gut microbiota to restrain this process remains largely unresolved. Here, astaxanthin (ASTA) was identified as a microbiota-engaged regulator of intestinal ferroptosis and lipid peroxidation. ASTA markedly ameliorated dexamethasone-induced intestinal injury, and this protection was closely associated with the attenuation of epithelial ferroptosis. Depletion of the gut microbiota largely abolished the protective effect of ASTA, establishing the gut microbiota as an essential mediator of its intestinal bioactivity. Microbiome and metabolome profiling further revealed that ASTA reshaped the microbial metabolic landscape, with retinol metabolism emerging as a dominant pathway linked to ferroptosis resistance. Among the altered metabolites, retinoic acid was identified as a pivotal ASTA-associated metabolite that connected microbial remodeling with the restoration of epithelial anti-ferroptosis capacity. Metagenomics combined with in vitro bacterial metabolic assays identified Lepagella muris as a candidate ASTA-responsive bacterium capable of contributing to retinoic acid production. Mechanistically, retinoic acid protected intestinal epithelial cells from ferroptosis and barrier disruption through activation of SLC7A11, thereby reinforcing the anti-ferroptosis defense system. This study moves beyond the conventional view of ASTA as a direct antioxidant and reveals a microbiota-enabled redox metabolic mechanism that may be therapeutically exploited for ferroptosis-associated diseases.
