The mammalian life cycle initiates with the transition of genetic control from the maternal to the embryonic genome during zygotic genome activation (ZGA), which becomes pivotal for development. Nevertheless, understanding the conservation of genes and transcription factors (TFs) that underlie mammalian ZGA remains limited. Here, we compiled a comprehensive set of ZGA genes from mice, humans, pigs, bovines and goats, including Nr5a2 and TPRX1/2. The identification of 111 homologous genes through comparative analyses was followed by the discovery of a conserved genetic coding region, suggesting potential sequence preferences for ZGA genes. Notably, an interpretable machine learning model based on k-mer core features showed excellent performance in predicting ZGA genes (area under the ROC curve [AUC] > 0.81), revealing abundant and intricate 6-base sequence specific patterns and potential binding TFs, including motifs from NR5A2 and TPRX1/2. Further analysis demonstrated that gene sequence features and epigenetic modification features play equally important roles in regulating ZGA genes. Ultimately, we developed the ZGAExplorer platform to provide an invaluable resource for screening ZGA genes. Our study unravels the sequence determinants of ZGA genes across species through multi-omics data integration and machine learning, yielding insights into ZGA regulatory mechanisms and embryonic developmental arrest.

Continual evolution of SARS-CoV-2 spike drives the emergence of Omicron variants that show increased spreading and immune evasion. Understanding how the variants orientate themselves towards host immune defence is crucial for controlling future pandemics. Herein, we demonstrate that human cathelicidin LL-37, a crucial component of innate immunity, predominantly binds to the S2 subunit of SARS-CoV-2 spike protein, occupying sites where TMPRSS2 typically binds. This binding impedes TMPRSS2-mediated priming at site S2' and subsequent membrane fusion processes. The mutation N764K within S2 subunit of Omicron variants reduces affinity for LL-37 significantly, thereby diminishing binding capacity and inhibitory effects on membrane fusion. Moreover, the early humoral immune response enhanced by LL-37 is observed in mice against SARS-CoV-2 spike but not Omicron BA.4/5 spike. These findings reveal the mechanism underlying interactions amongst LL-37, TMPRSS2 and SARS-CoV-2 and VOCs, and highlight the distinct mutation for Omicron variants to evade the fusion activity inhibition by host innate immunity.

This study aimed to investigate the impact of repetitive transcranial magnetic stimulation (rTMS) on cognitive recovery in Alzheimer's disease (AD) by exploring the role of GABAergic neuron activation and modulation of the Cx3cl1-Cx3cr1 signalling axis. The 5xFAD mouse model was utilised for scRNA-seq analysis to examine changes in gene expression post-rTMS. Microglial phagocytic activity, amyloid plaque burden, cell–cell communication, microglial morphology and neuroinflammation markers were assessed. Following rTMS, upregulation of Cx3cl1 in GABAergic neurons was observed, leading to enhanced microglial phagocytosis, reduced amyloid plaque burden, improved cell–cell communication, altered microglial morphology and decreased neuroinflammation markers. This study demonstrates that rTMS promotes Aβ clearance and cognitive recovery in AD by activating GABAergic neurons and enhancing Cx3cl1-Cx3cr1 signalling, providing a novel molecular target for non-invasive AD therapy. These findings support the transition from invasive to non-invasive AD treatments, improving patient adherence and therapeutic outcomes. Furthermore, the elucidation of cellular and molecular mechanisms facilitates drug development targeting the Cx3cl1-Cx3cr1 axis, offering new opportunities for AD intervention.

The heterogeneity of cancer-associated fibroblasts (CAFs) could affect the response to immune checkpoint inhibitor (ICI) therapy. However, limited studies have investigated the role of inflammatory CAFs (iCAFs) in ICI therapy using pan-cancer single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics sequencing (ST-seq) analysis. We performed pan-cancer scRNA-seq and ST-seq analyses to identify the subtype of GSN⁺ iCAFs, exploring its spatial distribution characteristics in the context of ICI therapy. The pan-cancer scRNA-seq and bulk RNA-seq data are incorporated to develop the Caf.Sig model, which predicts ICI response based on CAF gene signatures and machine learning approaches. Comprehensive scRNA-seq analysis, along with in vivo and in vitro experiments, investigates the mechanisms by which GSN⁺ iCAFs influence ICI efficacy. The Caf.Sig model demonstrates well performances in predicting ICI therapy response in pan-cancer patients. A higher proportion of GSN⁺ iCAFs is observed in ICI non-responders compared to responders in the pan-cancer landscape and clear cell renal cell carcinoma (ccRCC). Using real-world immunotherapy data, the Caf.Sig model accurately predicts ICI response in pan-cancer, potentially linked to interactions between GSN⁺ iCAFs and CD8⁺ Tex cells. ST-seq analysis confirms that interactions and cellular distances between GSN⁺ iCAFs and CD8⁺ exhausted T (Tex) cells impact ICI efficacy. In a co-culture system of primary CAFs, primary tumour cells and CD8⁺ T cells, downregulation of GSN on CAFs drives CD8⁺ T cells towards a dysfunctional state in ccRCC. In a subcutaneously tumour-grafted mouse model, combining GSN overexpression with ICI treatment achieves optimal efficacy in ccRCC. Our study provides the Caf.Sig model as an outperforming approach for patient selection of ICI therapy, and advances our understanding of CAF biology and suggests potential therapeutic strategies for upregulating GSN in CAFs in cancer immunotherapy.

Identification of the epidermal growth factor receptor (EGFR) in biological specimens is essential for cancer diagnostics, drug development and therapeutic monitoring. However, real-time techniques for accurate EGFR expression monitoring are currently limited. In this study, we report the development of a novel nano detector (Cy3-Apt_EGFR@BPNSs) with the capabilities of quenching and recovery to enable visual EGFR expression analysis. Cy3-Apt_EGFR is a Cy3-labelled single-stranded RNA (ssRNA) that exhibits specific binding to EGFR. Black phosphorus nanosheets (BPNSs) possess the ability to adsorb Cy3-Apt_EGFR via van der Waals forces, quenching its fluorescence when combined. The detection of EGFR receptors on cancer cell surfaces prompts the release of Cy3-Apt_EGFR from BPNSs, a consequence of the robust binding interaction between the receptor and aptamer, thereby leading to fluorescence reinstatement. The recovered fluorescence intensity of this detector is found to be directly correlated with EGFR expression levels in cancer cells, indicating its potential for guiding tumour diagnosis and treatment. The specificity of Cy3-Apt_EGFR@BPNSs further enhances its utility in detecting EGFR. More importantly, our research demonstrates that the reduction in EGFR expression levels within cancer cells corresponds to a proportional decline in fluorescence intensity, thereby facilitating precise tracking of EGFR dynamics.

With the continuous increase of the elderly population and the deepening of population ageing in China, osteoporosis has gradually become one of the significant public health problems. Elucidating the pathophysiological mechanisms that induce osteoporosis and identifying more effective therapeutic targets is of great clinical significance. In this study, in vitro experiments demonstrated that endothelial cell exosomes (EC-EXOs) promoted osteogenic and inhibited adipogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). Aged and ovariectomy (OVX)-induced osteoporosis mice models injected with EC-EXOs confirmed that EC-EXOs delayed bone loss. Proteomic analysis revealed a key protein regulating the differentiation of BMSCs. Expression of THBS3 was significantly higher in EC-EXOs than in Human microvascular endothelial cells (HMEC-1). In vitro and in vivo experiments further validated that THBS3 promoted BMSCs' osteogenic differentiation, inhibited their adipogenic differentiation, and retarded bone loss. Computational biology analysis found that CD47 is a downstream target and potentially functional receptor in BMSCs that bind to THBS3. THBS3 treatment of BMSCs down-regulated the expression of CD47 in in vitro experiments. The aged/OVX models further confirmed that EC-EXOs can regulate the differentiation of BMSCs and delay the process of bone loss via the THBS3–CD47 axis. CD47 antibody may be a potential therapeutic agent for treating ageing-associated bone loss.

Despite the regenerative and self-repair capabilities of bone tissues, significant bone loss can result in substantial bone defects. This study was aimed at investigating the role and underlying mechanisms of the mechanosensitive protein PDZ and LIM Domain 5 (PDLIM5) in the osteogenic differentiation of human adipose-derived stem cells (hASCs) under cyclic tensile stress conditions relevant to bone tissue repair. Utilising proteomics and single-cell RNA sequencing, we identified PDLIM5 and serpin E2 as key genes associated with the osteogenic differentiation of stem cells. To evaluate the expression levels of these genes and related proteins, we utilised western blotting, immunofluorescence and alkaline phosphatase (ALP) staining. Furthermore, lentiviral transfection, Cell Counting Kit-8 (CCK-8) assays, transwell migration assays, wound healing assays and protein–protein interaction analyses were conducted to evaluate changes in osteogenic differentiation under both chemical and physical stimuli, as well as to explore the relationship between serine protease inhibitor E2 (serpin E2) and its downstream effector, PDLIM5. The interactions among serpin E2, integrin β3 and PDLIM5 were confirmed through Haematoxylin and Eosin (H&E) staining, immunohistochemistry and immunofluorescence staining of bone tissues and primary adipose-derived stem cells isolated from integrin β3 knockout mice. Our findings indicate that PDLIM5 modulates the osteogenic differentiation of hASCs via a signalling pathway involving serpin E2, integrin β3 and lamin A.

The appropriate allocation of nutrients between the mother and the fetus during mammalian pregnancy primarily depends on a healthy placenta. Fetal growth restriction (FGR) is frequently associated with inadequate maternal nutrition supply and impaired placental function. The precise mechanisms linking maternal nutrient deficiency to compromised fetal and placental development remain largely elusive. In this study, we conducted an in-depth analysis by integrating single-cell/single-nucleus RNA sequencing data from human and mouse placentas along with transcriptomic data from FGR placenta, identifying the GAB1 (GRB2-associated binding protein 1) gene as a potential mediator of dysregulated maternal–fetal exchange, thereby affecting fetal growth. Using a mouse model, we demonstrated that food restriction significantly impeded fetal growth and disrupted placental labyrinth development. Through an in vitro trophoblast differentiation model, we revealed that nutritional restriction impaired GAB1 stability via LC3-interacting region (LIR) motif-mediated selective autophagic degradation, thereby hindering GAB1-MAPK signalling-enhanced trophoblast syncytialisation. These findings elucidate the mechanisms by which placental GAB1 links maternal nutrition status with fetal growth and suggest potential therapeutic strategies for managing pregnancy complications such as FGR.

Histone deacetylase(HDAC) is Zn²⁺-dependent histone deacetylases that regulate the key signalling pathways involved in gene transcription. 11 isoforms have been identified. Recent in vitro and in vivo studies have shown that HDACs are involved in the pathophysiology of cardiovascular diseases (CVDs) and play important roles in cell proliferation, differentiation and mitochondrial metabolism. In terms of physiological mechanisms, HDAC1–6 may play important roles in normal cardiac development and physiological function, while HDAC7 regulates angiogenesis. In pathological processes, class I HDACs function as pro-hypertrophic mediators, whereas class II HDACs act as anti-hypertrophic mediators. HDAC1–3, 6, 9, and 11 participate in lipid cell formation, oxidative stress and endothelial cell injury through multiple signalling pathways, contributing to the pathogenesis of atherosclerosis. In addition, HDACs also play a role in CVDs such as heart failure, myocardial fibrosis, pulmonary hypertension and diabetic cardiomyopathy. In view of this, we reviewed the regulatory pathways and molecular targets of HDACs in the pathogenesis of CVD. In addition, we summarise the current discovery of inhibitors targeting HDACs. HDAC inhibitors have shown promising therapeutic progress in animal experiments, but clinical trials to demonstrate their efficacy in humans are still lacking. A better understanding of the role of HDACs in CVD provides a new direction for the development of therapeutic interventions and holds significant research value.

Cell size is an important component of cell morphological characteristics. It reflects the characteristics of the cell type, nutritional status, growth stage and physiological function. The cell size of cells of the same type tends to be homogeneous and stable. However, in tumour cells, mutations in cell cycle genes and cytoskeletal genes and overexpression of the corresponding signalling pathways often lead to large variations in tumour cell size. Tumour cells regulate cell size and growth and proliferation through multiple signalling pathways, such as PI3K/Akt/mTOR, Myc and Hippo pathways, which work together to regulate cell size and proliferation. This allows tumour cells to adapt to different survival environments. Alterations in cell size also cause tumours to perform different functions, leading to alterations in tumour stemness, invasive migration and anti-tumour immunity by affecting immune cells in the tumour immune microenvironment. In this review, we describe the endogenous and exogenous factors affecting tumour cell size, analyse the mechanisms by which tumour cells regulate cell size and the effects of cell size on tumour malignancy and tumour immunity, summarise the potential therapeutic targets for cell size, and look forward to possible future research directions and clinical applications.

PE is a life-threatening pregnancy disorder that can lead to adverse events for both the fetus and the mother. Autophagy is a cellular process involved in cellular renovation and maintaining homeostasis. There is a growing body of evidence suggesting that autophagy in trophoblasts plays a significant role in the development and pathogenesis of PE. However, the exact mechanisms are not yet fully understood. This article provides an overview of recent evidence regarding the role of autophagy in trophoblast invasion, vascular remodelling, inflammation, immune response, and maternal factors in the context of PE. It is believed that impaired or excessive autophagy can contribute to placental ischaemia and hypoxia, thereby exacerbating PE progression. Therefore, understanding the molecular mechanisms that regulate autophagy in PE is crucial for the development of targeted therapeutic interventions in the future.