Skeletal muscle myogenesis is a crucial factor influencing meat production in livestock. MicroRNAs (miRNAs) play a significant role in skeletal muscle myogenesis. The objective of this study was to identify key miRNAs involved in the process of goat skeletal muscle satellite cell (MuSC) differentiation into myotubes. We performed miRNA expression profiling analysis during the proliferation phase (cultured in growth medium, GM) and the differentiation phase (cultured in differentiation medium for 1 day and 5 days, classified as DM1 and DM5, respectively) of goat skeletal muscle satellite cells (MuSCs). A total of 1846 miRNAs were identified in MuSC samples, of which 677 differentially expressed miRNAs (DEmiRNAs) were screened through pairwise comparisons across three groups (GM vs. DM1, GM vs. DM5, and DM1 vs. DM5), and the results were further confirmed by a quantitative real-time PCR assay. Time-series expression profiling facilitated the categorization of the DEmiRNAs into eight distinct clusters, one of which demonstrated a significantly downregulated expression pattern (p < 0.05). Functional enrichment analysis revealed that the target genes of DEmiRNAs are involved in several pathways that are critical for myogenesis, including Hippo, TGF-β, MAPK and cell adhesion molecules. Interaction network analysis identified 19 miRNAs and 56 mRNAs associated with muscle cell development. Notably, novel-m0047-5p emerged as a key regulator, exhibiting strong negative correlations (r = -0.88 to -0.89, q < 0.01) with muscle-related target genes FOSB, CPT1B, and MYOZ2. These findings elucidate miRNA-mediated regulatory networks in goat myogenesis and provide candidate molecular targets for genetic improvement of meat production traits.

C-reactive protein (CRP) plays dual roles in influenza infection, contributing to immune protection but potentially exacerbating severe outcomes.

Background: Phylogenetic relationships within Eulipotyphla have long been debated due to their complex evolutionary history and the frequent inconsistency among phylogenetic trees inferred from different data sources. This order comprises both above-ground and subterranean mammals, providing an opportunity to investigate their adaptation to hypoxic, hypercapnic, and dark environments. Methods: In this study, we reconstructed the phylogeny of Eulipotyphla based on whole-genome comparisons and explored the causes of phylogenetic incongruence as well as the genetic basis of underground adaptation. We analyzed the genomes of ten species, including four above-ground species and six subterranean species. We also identified homologous coding sequences through whole-genome alignment and inferred phylogenetic trees based on genome-wide windows of 1000 bases. Divergence times among major lineages were estimated using MCMCtree, and the causes of inconsistent tree topologies were examined using QuIBL to distinguish incomplete lineage sorting from introgression. Finally, we designated the six subterranean species as foreground branches and applied branch-site models to identify genes under positive and negative selection. Results: Whole-genome analyses recovered a clear clustering pattern, in which the six subterranean species formed a monophyletic group, whereas the four above-ground species clustered into a distinct clade. Divergence time estimation suggested that the split between above-ground and subterranean lineages occurred approximately 53.51 to 68.78 million years ago. Gene tree analyses revealed substantial variation in tree topologies at several internal nodes, and QuIBL results indicated that introgression contributed to phylogenetic discordance in addition to incomplete lineage sorting. Positive selection analyses identified genes associated with heart regulation, blood circulation, oxidative stress response, and erythrocyte differentiation, while negatively selected genes were linked to cardiac septum and chamber development. Conclusions: These results clarify the phylogenetic relationships within Eulipotyphla and provide insights into the genomic basis of adaptation to underground environments.

BACKGROUND: The functions of circRNAs in hepatocellular carcinoma (HCC) till needs to be further elucidated. METHODS: We assessed the biological functions of circGDI2 in vitro and in vivo by gain or loss of function experiments. Then, fuorescence in situ hybridization (FISH), immunofluorescence (IF), RNA pull-down, mass spectrometry, and RNA immunoprecipitation (RIP) were applied to explore the interaction between circGDI2 and heterogeneous nuclear ribonucleoprotein C (HNRNPC). Finally, in vitro and in vivo experiments were performed to explore the influence of circGDI2 on the anti-tumor activity of LGK-974, a porcupine O-acyltransferase (PORCN) inhibitor. RESULTS: CircGDI2 was significantly overexpressed in HBV-related HCC, and its high expression was significantly associated with the growth and invasion characteristics of HCC. Functional experiments indicated that circGDI2 promoted the proliferation and metastasis of HCC cells both in vitro and in vivo. Mechanistic investigations revealed that circGDI2 physically binds to HNRNPC, facilitating its interaction with mPORCN, which stabilizes mRNA and promotes PORCN expression, thereby activating the Wnt signaling pathway and driving tumor proliferation and metastasis. Additionally, we found that the PORCN inhibitor LGK-974 effectively suppressed the proliferation and metastasis of HCC cells both in vitro and in vivo, and a series of experiments demonstrated that knocking down circGDI2 could enhance the antitumor effect of LGK-974, thereby maximizing the inhibition of HCC. CONCLUSION: CircGDI2 played a crucial role in the progression of HCC by interacting with HNRNPC to promote the Wnt signaling pathway. Meanwhile, LGK-974 can effectively inhibit HCC and targeting circGDI2 can enhance the antitumor effect of LGK-974.

Some primates are immune to infection by most African trypanosome parasites due to apolipoprotein L-1 (APOL1), a primate-specific ion channel-forming protein. Our long-term objective has been to reduce African trypanosomiasis in livestock by genetic bioengineering of cattle with primate APOL1. To select which primate APOL1, we analyzed Papio ssp. APOL1 proteins and found that Papio hamadryas APOL1 was a strong candidate for transgenic animal production based on its trypanosome-killing capacity, ion channel properties, and stability. We generated seven transgenic murine lines based on the P. hamadryas APOL1 sequence and used these mice to investigate the level of APOL1 expression required for trypanosome immunity in vivo. We challenged the murine lines with three human and four livestock trypanosome isolates. P. hamadryas APOL1 provided protection against all of the human and three of the livestock trypanosome isolates, though not against Trypanosoma vivax despite the logical hypothesis that APOL1 plays a role in primate immunity to that parasite. Occasionally, lower APOL1 expression in heterozygote mice selected for the emergence of APOL1 resistant parasites in several trypanosome spp. Alarmingly, these resistant parasites were also resistant to high levels of APOL1 in homozygous mice, indicating an increase in virulence. A more-highly expressed chimeric APOL1 transgene encoding Homo sapiens APOL1 with the P. hamadryas APOL1 C-terminus was more effectively protective in heterozygote mice; however, we could not produce homozygous mice, suggesting endogenous toxicity to the mice. Together, these data bear relevance to our long-term objective to generate transgenic APOL1 cattle, the feasibility of which is discussed.

The self-renewal capacity of intestinal stem cells (ISCs) declines with aging, leading to a loss of homeostasis and an increased susceptibility to intestinal diseases. Despite the established significance of lipid metabolism and epigenetic regulation in ISC function, the molecular mechanisms that connect these processes to aging-related ISC dysfunction remain elusive. Here, we hypothesize that histone 3 lysine 36 trimethylation (H3K36me3) might act as a bridge between these processes. In this study, we demonstrate that H3K36me3 caused by SETD2 is critical for ISC stemness. H3K36me3 deficiency results in reduced ISC proliferation and differentiation, disrupts fatty acid oxidation (FAO), and promotes ISC senescence. Mechanistically, the loss of H3K36me3 triggers the activity of the SWI/SNF chromatin remodeling complex and leads to increased chromatin accessibility and enhancer activation, which alters FAO- and senescence-related gene expression. Importantly, our data demonstrate that metabolic intervention can prevent the senescence of ISC due to H3K36me3 deficiency. Our findings reveal a crucial role for H3K36me3 in maintaining the epigenetic landscape that orchestrates FAO and determines intestinal stem cell functions, emphasizing the role of FAO as a key modulator between H3K36me3 and ISC aging, suggesting that metabolic intervention may help mitigate age-related ISC dysfunction.

Microvascular rarefaction is a predominant pathological hallmark of chronic kidney disease (CKD), functioning simultaneously as a catalyst and consequence of progressive renal compromise. Although endothelial senescence constitutes a cardinal mediator of microvascular attrition in CKD, its upstream regulatory mechanism remains elusive. Here, using integrated single-cell/spatial transcriptomics, decellularized scaffold modeling, diverse murine CKD models, vascular ultrasonography, and tissue-clearing-enabled 3D imaging, we identify fibrillin-1 (FBN1), a core constituent of the fibrogenic niche, as an architect of a pro-senescent microenvironment that directly triggers endothelial senescence. Mechanistically, FBN1 upregulates the transcription factor ZEB1, which binds to the EDN1 promoter to enhance endothelin-1 (ET-1) transcription, thereby activating the ET-1/β-catenin signaling axis to execute cellular senescence. This cascade is abolished by ZEB1 knockdown, ET-1 receptor antagonism, or β-catenin inhibition. Importantly, tubule-specific Fbn1 deletion suppresses endothelial senescence, attenuates capillary rarefaction, and ameliorates renal function across CKD models. Our study unveils the FBN1/ZEB1/ET-1/β-catenin axis as a spatially organized signaling pathway linking to endothelial senescence, demonstrating how matrix-embedded components actively perpetuate pathogenesis by orchestrating stable pathological microenvironments. These findings provide a conceptual framework for CKD-associated vascular deterioration and highlight microenvironmental reprogramming as a therapeutic paradigm.

Previous studies have established a strong link between central nervous system inflammation and depression development. However, the role and function of circulating cytokines in depression remain a topic of debate.

Current antiplatelet therapies effectively prevent thrombosis but are associated with an increased risk of bleeding, highlighting the need for safer alternatives. Ursodeoxycholic acid (UDCA) is a bile acid derivative with an established clinical safety profile, but its effects on platelet function and thrombosis remain poorly defined.

Mobile phone addiction not only poses potential adverse effects on the effective implementation of educational and teaching activities, but also exerts a detrimental influence on students' mental health. Negative life events have been identified as a significant contributing factor to mobile phone addiction among vocational college students. Although prior research has investigated the relationship between life events and problematic mobile phone use, this study represents the first comprehensive examination of the sequential mediating roles of perceived stress and psychological resilience in the association between negative life events and mobile phone addiction. This investigation not only extends the application of stress-coping theory within the domain of digital behavior addiction, but also offers novel empirical insights and potential intervention strategies for understanding the psychological vulnerability and adaptive mechanisms involved in the development of mobile phone addiction among vocational college students.

The objective of this study is to mitigate the bottom-out failure and improve the energy absorption of conventional helmet liners during high-energy impacts, thereby reducing the risk of head injuries. To this end, a locally reinforced Primitive-type triply periodic minimal surface (P-TPMS) energy-absorbing liner is proposed for the helmet forehead region, which facilitates progressive energy dissipation through layer-by-layer buckling deformation. A finite element model of a helmet-head coupling was created based on a previously verified high-fidelity head model and subsequently validated against the ECE 22.06 standard drop-test methodology. Three critical design parameters-outer protective layer thickness, triply periodic minimal surface (TPMS) unit cell size, and wall thickness-were optimized employing the Box-Behnken Design (BBD) response surface methodology, resulting in quadratic regression models for the head injury criteria (HIC) and peak linear acceleration (PLA) with good fit (R2 > 0.97). Optimal parameter combinations were established using multi-objective optimization, with protective efficacy carefully assessed from both head dynamic response and biomechanical response perspectives. The ideal P-TPMS liner possesses an outer protective layer thickness of 14.95 mm, a TPMS unit cell size of 12.23 mm, and a wall thickness of 3.93 mm. Compared to the traditional expanded polystyrene (EPS) liner, the optimized P-TPMS liner significantly reduces HIC (by ∼16%) and PLA (by ∼14%) while extending the impact duration. More critically, it transitions both intracranial pressure and brain tissue strain below their respective clinical injury thresholds, substantially lowering the risks of skull fracture and mild traumatic brain injury (mTBI). The P-TPMS construction facilitates continuous energy dissipation during impacts via incremental layer-by-layer buckling deformation, hence extending impact duration and markedly improving helmet protective efficacy. These findings offer theoretical foundations and technical direction for the creation of localized heterogeneous liner designs in advanced high-performance helmets, although the results are limited to frontal flat-anvil impact conditions.

Nasopharyngeal carcinoma (NPC) is a malignant epithelial tumor strongly associated with Epstein-Barr virus (EBV) infection. EBV-mediated dysregulation of host microRNAs (miRNAs) contributes to NPC pathogenesis, but the functions of many EBV-regulated host miRNAs remain incompletely defined. miR-10b-3p is markedly downregulated in EBV-positive NPC, yet its biological significance and downstream mechanism remain unclear. Here, we found that miR-10b-3p was reduced in EBV-positive NPC tissues and was further suppressed following EBV infection of non-malignant nasopharyngeal epithelial cells and EBV-negative NPC cell lines. Restoration of miR-10b-3p expression markedly inhibited cell proliferation, colony formation, migration, invasion, and epithelial-mesenchymal transition (EMT) in EBV-positive NPC cells, whereas inhibition of miR-10b-3p in EBV-negative NPC cells produced the opposite effects. In nude mouse xenograft and lung metastasis models, overexpression of miR-10b-3p significantly reduced tumor growth and pulmonary metastasis. Mechanistically, miR-10b-3p directly targeted the 3'-UTR of integrin subunit alpha V (ITGAV), leading to decreased ITGAV expression and subsequent attenuation of STAT5 and ERK1/2 signaling. Forced ITGAV expression partially reversed the suppressive effects of miR-10b-3p on tumor cell proliferation, migration, invasion, and EMT. Moreover, miR-10b-3p levels were inversely correlated with ITGAV expression in NPC tissues. Collectively, these findings identify an EBV-regulated miR-10b-3p/ITGAV/STAT5-ERK1/2 axis in NPC and show that loss of miR-10b-3p promotes tumor growth and metastasis by relieving ITGAV repression, suggesting potential therapeutic targets for EBV-associated NPC.

Autosomal recessive polycystic kidney disease (ARPKD) is a pediatric genetic nephropathy caused by mutations in PKHD1, which encodes fibrocystin. The cellular basis and epithelial dynamics of cyst formation remain incompletely understood. We used lineage-tracing systems in rat and mouse to define epithelial behavior during cystogenesis. Clonal labeling revealed that renal and biliary epithelial cells undergo marked expansion as cysts form. Genetic mosaic analysis showed that individual Pkhd1-deficient cholangiocytes can generate millimeter-scale cysts within one year. Mathematical modeling demonstrated that biliary epithelial proliferation alone can account for cyst growth to millimeter size within weeks to months, depending on initial cell number and doubling time. Transcriptomic profiling of early cystic liver identified upregulated cell-cycle regulators, including CDK1. Pharmacological CDK1 inhibition attenuated fibrocystic liver disease in vivo. These findings show that epithelial cell expansion is the primary driver of cystogenesis and loss of fibrocystin activates a pro-proliferative program that can be therapeutically targeted.

Transthyretin amyloid cardiomyopathy is a progressive infiltrative cardiomyopathy driven by the deposition of amyloid fibrils derived from destabilized transthyretin (TTR). Although several pathogenic TTR variants have been characterized, the clinical significance and molecular behavior of rare mutations remain poorly understood.

Colorectal cancer (CRC) is one of the most common malignancies of the digestive tract, with conventional clinical diagnoses often made at advanced stages. There is an urgent need for a genetic diagnostic model to predict the onset of CRC at early stages, thereby reducing the disease burden associated with it. This study aimed to construct and validate a CRC diagnostic model based on exosome-related genes and to explore potential target drugs.

Stem cells and their paracrine factors hold promise for alopecia treatment, yet research on human skin-derived precursors (hSKPs), which are closely related to hair follicles in biological positioning and function, remains limited. We demonstrated that extracellular vesicles of human transformed skin-derived precursors (htSKP-EVs), harvested utilizing our directed induction, culture transition and gradient ultracentrifugation technology, exhibited superior efficiency and quality determined by transmission electron microscopy, nanoparticle tracking analysis, and detection of specific markers. Using CCK8, scratch assay, immunofluorescence, H&E staining, immunohistochemistry staining, dermoscope, qRT-PCR and Western blotting, it was found that htSKP-EVs significantly promoted the proliferation of hair follicle stem cells (hHFSCs) by effectively modulating the Wnt signaling pathway, thereby enhancing overall hair follicle growth. Notably, miR-221-3p, highly expressed in htSKP-EVs, suppressed DKK2 expression, activated the Wnt pathway in human dermal papilla cells (hDPCs), and induced hair follicles to enter and sustain the anagen phase, based on the aforementioned similar in vivo and in vitro experiments. These findings, validated in hHFSCs, hDPCs and human hair follicles in vitro and in a murine alopecia model in vivo, revealed the potential mechanism of htSKP-EVs in hair growth and identified a new therapeutic target for alopecia in regenerative medicine.

Although immunotherapy-based regimens have improved overall survival for some patients with advanced hepatocellular carcinoma (HCC), many patients ultimately experience disease progression. Macrophages are abundant in the HCC microenvironment and represent promising therapeutic effectors, yet the potential of combining chimeric antigen receptor macrophages (CAR-M) with macrophage checkpoint targeting remains underexplored. Given that glypican-3 (GPC3), a cell-surface heparan sulfate proteoglycan, is highly expressed in HCC, we developed a GPC3-targeted CAR-M system and evaluated its efficacy alone and in combination with USP22 inhibition. USP22, a deubiquitinating enzyme previously linked to tumor CD24 expression, was selected as a combinatorial target to potentially relieve CD24-associated phagocytic suppression. In vitro assays demonstrated that GPC3 CAR-M cells exhibited specific binding, phagocytosis, and potent cytotoxicity against multiple GPC3-positive HCC cell lines. RNA sequencing and flow cytometry revealed a statistically significant positive correlation between USP22 and the macrophage checkpoint CD24. The addition of the USP22 inhibitor significantly enhanced the tumor-killing capacity of CAR-M in a dose-dependent manner and was associated with reduced CD24 expression on tumor cells. This combinatory strategy robustly suppressed tumor growth in both a murine peritoneal dissemination model and a patient-derived xenograft (PDX) model of HCC. Importantly, the enhanced efficacy was consistently observed across CAR-M cells derived from THP-1, human monocyte-derived macrophages (hMDMs), and human pluripotent stem cells (hPSCs), underscoring its broad applicability. Our findings provide proof-of-concept preclinical evidence supporting further evaluation of combining GPC3 CAR-M therapy with USP22 inhibition as a potential immunotherapeutic strategy for HCC.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality worldwide. ICU patients with COPD are facing particularly poor outcomes. Existing biomarkers like blood urea nitrogen (BUN) have shown inconsistent prognostic value. Recent evidence suggests the urea-to-creatinine ratio (UCR) may better reflect muscle catabolism and systemic dysfunction in critical illness. However, its clinical role in predicting prognosis for COPD patients needs to be confirmed. This study aimed to investigate the correlation between UCR levels and poor prognosis in ICU patients with COPD. METHODS: The clinical data of 2,305 COPD patients were retrieved from the database of Medical Information Mart for Intensive Care IV (MIMIC-IV), including demographic information, vital signs upon ICU admission, comorbidities, laboratory test indicators, arterial blood gas analysis results, and disease severity scores. Patients were grouped into U1 group (UCR < 15.71, n = 558), U2 group (15.71 ≤ UCR < 20.57, n = 593), U3 group (20.57 ≤ UCR < 27.575, n = 578), and U4 group (UCR ≥ 27.575, n = 576) based on the quartile levels of UCR measured at ICU admission. The primary endpoint was 90-day mortality. Clinical baseline characteristics and prognostic endpoints were compared across groups. Logistic regression analysis and restricted cubic spline (RCS) analysis were employed to evaluate the correlation between different UCR levels and the poor prognosis of COPD patients. RESULTS: Patients in the higher UCR groups showed an increased rate of mechanical ventilation and significantly higher mortality rates within the ICU, at 28 days, 30 days, and 90 days (all p < 0.001). A logistic regression model, constructed using important feature variables selected by random forest, revealed that patients in the highest UCR quartile (U4 group) had a significantly elevated mortality risk (OR = 1.835, 95% CI: 1.37 ~ 2.458, p < 0.01). RCS analysis demonstrated a linear correlation between UCR levels and both patient mortality risk and the rate of mechanical ventilation. CONCLUSION: High UCR is correlated with poor prognosis of patients with COPD.

Immunotherapy has attracted increasing attention in cancer treatment, but its efficacy is greatly limited due to the low immunogenicity of tumors and immunosuppressive tumor microenvironment (TME). To address this, we constructed a biomimetic M1 macrophage membrane-Camouflaged nanoplatform (M1@CTP) for the co-delivery of the natural antitumor compound Tanshinone IIA (Tan IIA) and the immunogenic cell death (ICD) inducer Copper-diethyldithiocarbamate (CuET) to enhance antitumor immunity.

Ischemic stroke (IS) imposes a major global health burden. To uncover new diagnostic and therapeutic targets, we profiled neuronal heterogeneity during IS using single-cell RNA sequencing. Our analysis decoded neuronal lineage trajectories, identified a critical cell-cell communication network, and pinpointed key gene modules. By integrating multiple machine learning algorithms, we constructed a highly accurate diagnostic model based on the hub genes Il18 and Cherp. This model was rigorously validated across multi-omics datasets and species. We further confirmed that Cherp promotes neuronal repair by regulating calcium homeostasis, while Il18 serves as a potential early blood biomarker. This work provides effective targets and translatable tools for advancing IS precision medicine.