Research最新文献

Fibroblast-myofibroblast transition (FMT) and the resultant renal fibrosis are central pathological features of chronic kidney disease (CKD). Epigenetic suppression of RASAL1 (Ras protein activator like 1), an antifibrotic regulator in fibroblasts, is a key driver of this process. However, the underlying mechanisms are only partially understood. Here, we identify histone deacetylase 3 (HDAC3) as a critical epigenetic suppressor of RASAL1 expression in FMT of renal fibrosis. In mouse models of renal fibrosis induced by unilateral ureteral obstruction and aristolochic acid I, RASAL1 suppression coincided with a preferential increase in HDAC3. Fibroblast-specific Hdac3 knockout mice exhibited preserved RASAL1 expression, attenuated FMT, and reduced renal fibrosis compared to wild-type controls. Consistently, pharmacological inhibition of HDAC3 with RGFP966 similarly restored RASAL1 expression, inhibited FMT, and alleviated renal fibrotic pathology. In cultured renal fibroblasts, HDAC3 overexpression or inhibition by RGFP966 inversely affected RASAL1 abundance and major FMT parameters, which was coregulated by the repressive transcriptional factor YY1 (Yin Yang 1). Notably, targeted silencing of RASAL1 abrogated the antifibrotic effects of HDAC3 inhibition both in vitro and in vivo, underscoring the functional significance of the HDAC3-YY1-RASAL1 axis in FMT and fibrogenesis. Given that FMT is a conserved feature of fibrotic diseases across multiple organs, restoring RASAL1 expression via HDAC3 and YY1 modulation offers promising therapeutic strategies for CKD and potentially broader fibrotic disorders.

In liver ischemia-reperfusion injury (LIRI), macrophage clearance of apoptotic cells via efferocytosis is crucial to prevent excessive inflammation and tissue damage. Here, we investigate the role of nucleotide-binding oligomerization domain-like receptor protein 3/cysteine-aspartate protease-1 (NLRP3/Caspase-1) signaling in modulating macrophage efferocytosis during LIRI. We observed robust activation of the NLRP3/Caspase-1 pathway during the early phase of LIRI. Genetic ablation of Nlrp3 or Caspase-1 substantially reduced LIRI severity. Notably, myeloid-specific Nlrp3 knockout mice exhibited less severe LIRI compared to hepatocyte-specific Nlrp3 knockouts, whereas macrophage-specific overexpression of Caspase-1 exacerbated tissue injury. Mechanistically, NLRP3/Caspase-1 activation enhances a disintegrin and metalloprotease protein-17 (ADAM17)-mediated cleavage of Mer proto-oncogene tyrosine kinase (MerTK), leading to impaired efferocytosis. Pharmacological inhibition of ADAM17 restored macrophage efferocytic capacity and alleviated LIRI. Clinically, elevated serum levels of soluble MerTK (s-Mer) correlated with hepatic injury severity and Caspase-1 activation in patients after partial hepatectomy or liver transplantation. Our findings suggest a potential therapeutic strategy for LIRI prevention and treatment.

Two-dimensional transition metal dichalcogenides (TMDs) are promising candidates for next-generation electronics, but their future application is hindered by the inherently slow growth kinetics of conventional vapor deposition methods, particularly for the synthesis of large-area single-crystal films. Here, we demonstrate a source-confined chemical vapor deposition strategy that enables the fast synthesis of centimeter-scale MoS₂ single-crystal films within just 10 min. An optimized sandwich-structured Mo source was employed to ensure a concentration-balanced metal supply under sodium chloride catalysis, followed by sulfurization to form MoS₂. The films nucleate uniformly and directionally on the miscut C/A sapphire substrate positioned 2 cm upstream of the Mo source, achieving high crystal quality with a low sulfur vacancy density of 8.49 × 10¹² cm^-2. Additionally, these films support the development of high-performance enhancement-mode MoS₂ field-effect transistors, exhibiting excellent transport performances, including a high on-off ratio of 10⁸, an average positive threshold voltage of 1.71 ± 0.32 V, an average mobility of 34.28 ± 0.46 cm² V^-1 s^-1, and an average subthreshold swing of 155.8 ± 33.7 mV dec^-1. Furthermore, high-performance rail-to-rail inverter gates and logic circuits with low power consumption (<0.3 nW) were successfully demonstrated, underscoring the potential of these MoS₂ films for integrated circuit applications. This work offers a scalable and reliable approach for the fast growth of large-scale TMDs single-crystal films, accelerating their future applications in next-generation electronics.

Hepatocellular carcinoma (HCC) is a cancer type that causes a high rate of cancer death in the world. The standard therapy plan of intermediate and advanced stages of the HCC is transarterial chemoembolization (TACE). The treatment effectiveness is, however, limited because of the heterogeneity of tumors and the resistance to drugs. This paper shows that the HCC patients with TACE resistance alter their tumor immune homeostasis by reducing the secretion of exosomal miR-32-5p, which has a negative relationship with the population of CD68⁺ macrophages. Both in-cellular and animal studies show that exosomal miR-32-5p leads to ferroptotic cell death in tumor-associated macrophages (TAMs) characterized by augmented lipid oxidation, iron buildup, depletion of glutathione, and mitochondrial malfunction. At the same time, miR-32-5p increases production of M1-type proinflammatory factors such as CD86, CCL2, tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6), thereby enabling macrophage polarization toward tumor-suppressive phenotype. Mechanistically, miR-32-5p activates the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway through ARID1B down-regulation, ultimately remodeling the tumor immune microenvironment. Experimental murine models indicated that the delivery of exosomal miR-32-5p was a strong tumor suppressor and disseminator, increased the recruitments of CD86 + antigen-presenting cells and CD8 + T lymphocytes, and boosted anti-neoplastic immunity. It should be highlighted that exosomal miR-32-5p also increased the levels of PD-L1, which reflected its complementary value to anti-PD-L1 immunotherapy. Such a combined treatment led to excellent tumor control and enhanced survival without loss of acceptable toxicity profiles. The essential role of ferroptosis was confirmed by the use of Fer-1 to inhibit the chemical reactions, which revealed a new approach by which TACE-resistant exosomal miR-32-5p could inhibit the progression of HCC and complement the anti-PD-L1 therapeutic effects through ferroptosis using TAM, providing insights as well as potential therapeutic objectives in the treatment of HCC.

Traditional solid metal catalysts in organic reaction have been hindered by drawbacks, including limited surface catalytic region, restricted reactant diffusion, catalyst deactivation, low atom utilization efficiency, and harsh reaction condition. To overcome these drawbacks, we introduce liquid metal into organic reaction. An efficient mechano-assisted reaction system was proposed integrating dynamic metal catalyst and liquid metal reaction medium. With a low-energy ball-milling process (at a speed of 270 rad·min^-1), the dynamic metal atoms in liquid state could achieve maximum atomic utilization and fast reaction kinetics compared to solid metal. Furthermore, liquid metal also act as reaction media. It not only offers a homogeneous electron-rich environment for reactants but also continuously disperses active metals to construct a multimetal catalytic system in one step. These would revolutionize the understanding of metal catalysts and reaction media, providing a novel platform for exploration of high-throughput catalysis and discovery of novel chemical reaction in future.

Metabolism-regulating microspheres have evolved from conventional drug carriers into active platforms capable of spatiotemporally reprogramming pathological metabolic networks. Chronic diseases are increasingly understood to be driven by metabolic dysregulation, highlighting the need for therapeutic strategies that enable localized and precise metabolic intervention. This review systematically outlines the core design principles of these microspheres, emphasizing the synergistic integration of engineered chemical properties, such as ionic signaling, metabolite delivery, and pathway modulator release, with tailored physical characteristics, including stiffness, porosity, and size of the microspheres. Together, these features construct "metabolic instruction systems" that correct dysregulated pathways at the tissue level. Their versatile applications include orthopedic diseases, such as osteoporosis, osteoarthritis, and bone defects; ophthalmic conditions, including glaucoma and diabetic retinopathy; and gynecological disorders, such as premature ovarian insufficiency, ovarian cancer, and endometriosis. These systems target key metabolic abnormalities, such as glycolytic dysregulation, mitochondrial dysfunction, and oxidative stress, which are recognized as central drivers of disease pathogenesis across multiple organ systems. Despite considerable progress, clinical translation remains limited by tissue-specific delivery barriers, interindividual metabolic heterogeneity, and long-term safety concerns within dynamic metabolic networks. Emerging strategies, such as personalized formulations, artificial-intelligence-driven designs, and organ-on-a-chip validation platforms, are being developed to address these challenges. With ongoing interdisciplinary innovation, metabolism-regulating microspheres hold great promise as precise therapeutic modalities for a spectrum of chronic diseases rooted in metabolic imbalance, offering targeted and sustained metabolic correction.

Background: Quantifying tumor-stroma architecture on routine hematoxylin and eosin slides may refine risk stratification in bladder cancer (BCa). We developed a convolutional neural network to segment whole-slide images, compute the mixed tumor-stroma ratio (MTSR), evaluate its prognostic value across multicenter cohorts, explore underlying molecular programs through multi-omics analysis, and construct a preoperative multiparametric MRI (mpMRI) radiomics model to estimate MTSR noninvasively. Methods: The ResNet50 convolutional network was customized using The Cancer Genome Atlas BCa slides labeled into 9 histological classes and background, followed by internal validation and multicenter external testing. Whole-slide-image-level segmentation yielded quantitative tissue ratios. The prognostic value was evaluated using Cox regression, Kaplan-Meier analysis, and meta-analysis, with a nomogram constructed by incorporating independent predictors. Prognostic significance was assessed by Cox regression, Kaplan-Meier analysis, and meta-analysis, and a nomogram was developed by integrating independent predictors. Bulk RNA sequencing underwent gene set variation analysis/gene set enrichment analysis, immune deconvolution, and ESTIMATE analyses, while single-cell RNA sequencing of high- vs. low-MTSR tumors profiled cellular heterogeneity, pseudotime trajectories, and regulon activity using SCENIC. An mpMRI-based random forest radiomics model was trained to predict high vs. low MTSR. Results: The convolutional neural network achieved >90% classification accuracy with Cohen's kappa >0.95 in all cohorts. A nomogram combining MTSR and N stage outperformed clinicopathological predictors. Molecular analyses revealed that high-MTSR tumors displayed increased macrophage infiltration and enrichment of pathways related to extracellular matrix remodeling, cell adhesion, and transforming growth factor-β/WNT signaling. Single-cell analysis identified an integrin subunit beta 8 (ITGB8)-high urothelial subtype (cluster 8) with terminal differentiation, enhanced WNT activity, and sender-dominant communication networks. The mpMRI radiomics model achieved accuracies of 0.701 and 0.710 for predicting MTSR status in the training and validation sets, respectively. Conclusions: The deep learning-generated MTSR showed consistent reproducibility and prognostic independence across cohorts, mechanistically connected with an ITGB8-enriched stromal-oncogenic pathway. Its estimation via mpMRI radiomics enables integrative, noninvasive risk stratification for precision management of BCa.

Because of their outstanding weak light detection ability, multiplication-type photodetectors have great application prospects in fields such as environmental detection, biological science, and night vision imaging. Traditional photomultiplication-type organic photodetectors (PM-OPDs) usually achieve a large external quantum efficiency (EQE) through the mechanism of interfacial trap-assisted charge tunneling injection but inevitably produce a large dark current. Here, we demonstrate a novel dual-function photon-regeneration multiplication-type organic photodetector (PRM-OPD) with photocurrent gain by absorbing additional photons generated by an integrated organic light-emitting diode unit. The optimized PRM-OPD exhibits a maximum EQE of 2,484% and maintains a low dark current density (J_d ) of only 10^-8 A/cm². More importantly, the resulting PRM-OPD can not only exhibit efficient detection performance but also directly detect the shape of the light spot, showing a dual-function working mode. Furthermore, by combining optical resonant microcavities, the response spectrum is successfully extended to the near-infrared region and a narrowband PRM-OPD with excellent performance is obtained. This designed device structure provides a new idea for the development of high-performance PM-OPDs.

Highly pathogenic avian influenza H5N1 virus has spread to over 1,080 dairy farms across 18 states in the United States, resulting in 41 human infections and posing serious risks to both animal and public health. To address these risks, a hemagglutinin-based mRNA-lipid nanoparticle vaccine was developed, and its safety, immunogenicity, and protective efficacy in high-yielding lactating dairy cows were evaluated. The vaccine was well tolerated, had no adverse effects on health or milk production, and induced strong antibody responses. Two weeks after the second immunization, all the immunized cattle were fully protected against a high-dose H5N1 virus challenge. Notably, two-thirds of the cattle were still completely protected even at the 19th week after the first vaccination, when their serum antibody levels were very low. These data demonstrate that the mRNA vaccine confers robust, lasting protection against H5N1 virus in lactating dairy cows, providing a foundation for clinical trials.

Triple-negative breast cancer (TNBC) represents a notably aggressive form of breast cancer, distinguished by heightened invasiveness and an important propensity for metastasis. The expression of ubiquitin D (UBD) is significantly increased in lung metastases associated with TNBC, correlating with unfavorable patient outcomes. Functional assays indicate that UBD promotes invasion, migration, and pulmonary colonization of TNBC cells in vivo. At the mechanistic level, UBD preserves matrix metalloproteinase 3 (MMP3) levels by inhibiting proteasomal degradation. A proteomic analysis has identified MMP3 as a crucial downstream mediator of UBD. Concurrently, chromatin immunoprecipitation and luciferase reporter assays demonstrate that the Spi-B transcription factor (SPIB) directly interacts with the UBD promoter, leading to the activation of its transcription. Collectively, these findings identify the SPIB/UBD/MMP3 axis as a pivotal regulator of TNBC metastasis, indicating its value for prognostic evaluation and targeted therapy.