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.
