Lung cancer is the leading cause of cancer-related deaths worldwide. Existing therapeutic options have limited efficacy, particularly for lung squamous cell carcinoma (LUSC), underscoring the critical need for the identification of new therapeutic targets. We previously demonstrated that the Transmembrane Serine Protease TMPRSS11B promotes the transformation of human bronchial epithelial cells and enhances lactate export from LUSC cells. Here, we evaluate the impact of TMPRSS11B activity on the host immune system and the tumor microenvironment (TME). Tmprss11b depletion significantly reduces tumor burden in immunocompetent mice and triggers an infiltration of immune cells. RNA FISH analysis and spatial transcriptomics in the autochthonous Rosa26-Sox2-Ires-GfpLSL/LSL; Nkx2-1fl/fl; Lkb1fl/fl (SNL) model reveal an enrichment of Tmprss11b expression in LUSC tumors, specifically in Krt13+ hillock-like cells. Furthermore, utilizing ultra-pH-sensitive nanoparticle imaging and metabolite analysis, we identify regions of acidification, elevated lactate, and enrichment of immunosuppressive (M2-like) macrophages in LUSC tumors. These results demonstrate that TMPRSS11B promotes an acidified and immunosuppressive TME and nominate this enzyme as a therapeutic target in LUSC.

Polycystic ovary syndrome (PCOS) is a prevalent endocrine-metabolic disorder characterized by hyperandrogenism, ovulatory dysfunction, and metabolic abnormalities. Despite increasing recognition of immune and metabolic dysregulation in its pathogenesis, the cell-specific molecular mechanisms, particularly within granulosa cells, remain poorly understood. This study aimed to elucidate the transcriptomic landscape and regulatory pathways of granulosa cells in PCOS using integrative bioinformatics and experimental validation.

Colorectal cancer (CRC) is an aggressive malignancy with high mortality, and the identification of upstream regulators of stemness represents a critical step toward developing more effective targeted therapies. This study aimed to define the role of NR5A2 in CRC, particularly in the context of cancer stem cells (CSCs).

Diabetic Kidney Disease (DKD) is one of the most serious complications of diabetes mellitus, and a main cause of end-stage kidney disease (ESKD). The identification of clinically applicable molecular biomarkers for monitoring DKD progression has become increasingly essential. In this study, we aim to investigate the relationship between the expression of fructose-1,6-bisphosphatase 1 (FBP1), a rate-limiting enzyme in gluconeogenesis, and DKD.

Nowadays, cancer researches widely employed organoids as research model. Organoids provide a realistic applicate scene but how to real-time detect and quantified the organoid status is still a bottleneck. To bridge this knowledge gap, we developed an all-in-one microfluidic platform that, for the first time, seamlessly integrates a vascularized tumor organoids-on-a-chip model (VOoC) with a real-time ELISA detection module for advanced tumor research and point of care testing (POCT). The platform features a unique integration of two cutting-edge technologies: (1) VOoC consists of a perfusable self-forming vessel network throughout the tumor organoid, emulates in vivo tumor angiogenesis, and (2) a real-time microfluidic diagnostic chip equipped with ELISA for simultaneously monitoring of tumor biomarker expression levels. We demonstrated the platform's capabilities using cervical cancer organoids and evaluated the drug efficacy of cisplatin and bevacizumab. This coupled system enables simultaneous tumor microenvironment modeling and continuous, real-time monitoring of secreted biomarkers, a capability not achievable with conventional disconnected systems. By combining these two systems, our dual-effect bimodal chip platform holds great promise for advancing personalized medicine and cancer research, offering a powerful tool for both drug screening and quick diagnosis.

Psoriasis is linked to gut dysbiosis and disturbed sphingolipid metabolism. PSORI-CM02 improves epidermal differentiation, yet its impact on the microbiota-sphingolipid axis remains unknown.

The prevalence of autoimmune diseases such as inflammatory bowel disease (IBD) and rheumatoid arthritis (RA) is increasing. Glucocorticoid-induced TNFR-related protein (GITR), a TNF receptor superfamily (TNFRSF) member, is activated by GITR-ligand (GITRL). GITR signaling is pathogenic in models of RA and IBD, leading to lymphocyte proliferation and secretion of pro-inflammatory cytokines. Despite promising preclinical data, GITR neutralization in autoimmune diseases remains under-explored, due to challenges in avoiding antibody-mediated GITR activation. Therefore, we developed a human GITR-specific antibody that inhibits GITRL-mediated GITR-signaling, while preserving the GITRL epitope on GITR. The antibody strongly inhibited GITR signaling in the in vitro assays via a novel mechanism of disrupting downstream higher-order structures rather than direct blocking of GITR binding. Even though the antibody did not demonstrate efficacy in an NSG human skin graft transplant model, this general mechanism might be a viable therapeutic intervention for other TNFRSF members relying more significantly on soluble ligands.

This study aimed to investigate the role of a novel duck miR-290, which targets Phosphatidyqinositol-3 kinase (PI3K), in regulating melanogenesis in Liancheng white ducks. Differentially expressed miRNAs (DEmiRNA) associated with melanogenesis were first screened by transcriptome sequencing of mouth skin and skin from 130-day-old Liancheng white ducks. The interaction between novel miR-290 and the PI3K 3'UTR was verified by a dual-luciferase reporter assay. Primary duck melanocytes were then isolated from the mouth skin tissue, and the function of miR-290 was examined at the cellular level. The results revealed that novel miR-290 directly targeted PI3K, and the levels of p-PI3K and p-AKT were significantly decreased in the mouth skin compared with skin (P < 0.05), whereas p-GSK3β, Integrin-linked kinase (ILK), Microphthalmia-associated transcription factor (MITF), tyrosinase (TYR), and Melanocortin 1 Receptor (MC1R) were significantly increased in the mouth skin(P < 0.05). The isolated melanocytes were spindle-shaped and positive for DOPA and melanocytic markers.Overexpression of miR-290 significantly promoted melanocyte proliferation and melanin production (P < 0.01);(RT-qPCR) and Western blot analysis revealed that miR-290 inhibited the expression of PI3K and protein kinase B (AKT) (P < 0.05) and increased the expression of ILK, Glycogen Synthase Kinase 3β (GSK3β), MC1R, MITF, TYR, tyrosinase-related protein 1 (TYRP1), and tyrosinase-related protein 2 (TYRP2) (P < 0.05). In conclusion, this study identifies a novel duck miR-290 as a positive regulator of melanogenesis, which promotes melanocyte proliferation and melanin synthesis in Liancheng white ducks by suppressing PI3K/AKT signaling and activating downstream melanogenic genes.

Compared with other forms of online mental health interventions, programs delivered through social media apps may require less training and be more acceptable and accessible to various populations. During and after the pandemic, both the number of social media users and the prevalence of social-media-based mental health interventions increased significantly. However, to the best of the authors' knowledge, no meta-analysis so far has focused on rigorous social-media-based mental health interventions for general populations.

Sepsis-induced liver injury (SILI) indicates liver functional or structural impairment occurring during sepsis and is one of the common complications of sepsis. N6-methyladenosine (m6A) modification plays a significant role in the pathological processes of SILI, but its specific mechanisms remain unclear and require further elucidation. In this study, an experimental sepsis model exhibiting characteristic symptoms and hepatic damage was established through cecal ligation and puncture (CLP) surgery. Comprehensive analyses of hepatic tissues from CLP-treated and Sham operation mice through RNA Sequencing (RNA-Seq) and Methylated RNA Immunoprecipitation Sequencing (MeRIP-Seq) methodologies revealed distinct m6A peaks and differentially expressed genes (DEGs). A total of 2002 m6A peaks were detected (|log2FC|≥ 1, p < 0.05). Our analyses demonstrated that 71% of m6A peaks clustered within the coding sequences (CDS) and 3' untranslated region starts (3' UTR) of transcripts. When compared with the Sham group, the CLP group showed an increase of 1741 DEGs and a decrease of 1815 DEGs. And 458 genes exhibited both m6A modifications and changes in mRNA levels. Functional enrichment assessments through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses revealed that m6A-modified hepatic genes in septic mice were significantly enriched in the cytoplasm, nucleus and protein binding, which mainly involved in regulating cell survival, immune responses, inflammatory responses and other related pathways. The results of Cell Counting Kit-8 (CCK8) assay and 5-ethynyl-2'-deoxyuridine (EdU) assay showed that the proliferation ability of liver cell lines was enhanced after knocking down m6A regulatory factor METTL3, which indicates the m6A modifications play an important role in the proliferation ability of normal liver cells. This study validated the presence of m6A-epitranscriptomic modifications and their regulatory roles in sepsis-affected hepatic systems, establishing comprehensive m6A landscapes in septic liver tissues.

Diabetic wounds remain a major clinical challenge due to bacterial infection, persistent inflammation, and excessive accumulation of reactive oxygen species (ROS). This highlights the urgent need for wound dressings that provide sustained antibacterial effects, stable ROS scavenging, and effective immune modulation. To this end, we developed a multifunctional electrospun polyvinyl alcohol-chitosan (PVA-CS) nanofibrous dressing by integrating black phosphorus nanosheets (BPNSs) with polydopamine-coated zinc oxide nanoparticles (PDA@ZnO NPs). This dressing achieved synergistic photothermal-Zn2+ ion antibacterial activity, rapidly reducing the viability of MRSA, MSSA, and E. coli, along with their biofilms, to 0-2% in 3 min while enabling Zn2+ release to support a sustained antibacterial microenvironment. The dresssing also provided sustained ROS scavenging due to stabilized BPNSs, with intracellular ROS levels reduced to 13-20%, accompanied by an overall 50-70% improvement in antioxidant capacity, thereby alleviating oxidative stress and suppressing inflammation. In addition, ZnO NPs also promoted anti-inflammatory macrophage polarization, accelerated tissue healing, and supported natural repair processes. This work introduces a multifunctional wound dressing with rapid and sustained antibacterial, antioxidative, and anti-inflammatory properties, offering a promising solution for chronic diabetic wounds.

Postnatal mammary gland development involves the formation of a highly branched epithelial ductal tree, primarily through the elongation and branching morphogenesis of mammary epithelial ducts. Multiple factors are involved in this process, in which both estrogen and progesterone receptors (ER/PR) play a crucial role. In this study, we identified a role of DCAF8 in promoting mammary ductal elongation and branching through its impacts on ER/PR signaling. Homozygous Dcaf8 knockout mice exhibited significant delay in mammary ductal elongation during puberty, which was characterized by a reduction in mammary ductal elongation area and distance, and terminal end buds (TEBs); abnormal branching morphogenesis of mammary ducts was also observed in adult Dcaf8 null mice, which was characterized by a reduction of lateral branches and an increase of ductal bifurcation. To further elucidate the mechanism underlying DCAF8’s role in mouse mammary development, we performed transcriptomic sequencing and biochemical experiments. The results revealed that downstream key effectors of the PR signaling pathway were significantly downregulated, while the expression of ERβ, a potential inhibitor of ERα/PR signaling, was significantly elevated in the mammary gland of Dcaf8 null mice. Collectively, this study suggests that DCAF8 may play an important role in mammary development by promoting ductal elongation and branching morphogenesis, through ERβ-mediated inhibition of ERα/PR signaling pathway.

The vast majority of Alzheimer's disease (AD) cases are sporadic, without a clear etiology. We have previously found increased expression of Serum and Glucocorticoid-regulated Kinase 1 (SGK1) in mouse models of dementia, postmortem cortical tissues and induced pluripotent stem cells (iPSCs)-derived cortical neurons from patients with sporadic AD (sAD). SGK1 is induced by a variety of cellular stress. The physiological consequences of elevated SGK1 in sAD is unclear. Here, we differentiated iPSCs from four sAD patients and four age- and sex-matched healthy controls into electrophysiologically mature cortical neurons with prolonged culture for more than 100 days. The sAD cortical neurons exhibited significant reductions in voltage-gated Na+ currents, amplitudes of evoked action potentials, and frequencies of spontaneous excitatory postsynaptic currents and spontaneous action potentials. Application of a selective inhibitor of SGK1 reversed all these phenotypes in sAD neurons without affecting control neurons. The SGK1-dependent hypoexcitability suggests that a convergent and inborn mechanism attenuates neuronal communications despite different genetic background of the sAD patients. Their iPSC-derived cortical neurons have captured the defective neurotransmission, which underlies cognitive and memory symptoms of AD, many decades before clinical manifestations. The study offers a new pathway to restore synaptic transmission in AD.

Effective diagnosis and treatment of lung adenocarcinoma depends on accurate typing, subtyping, and grading. Herein, we present the CLWD dataset, a valuable resource for the lung cancer pathology community, comprising 408 whole-slide images (WSIs) from 210 patients specifically curated for the study of lung adenocarcinoma subtypes. Scanned at 80 × magnification, it is one of the largest datasets in Asia, with a particular emphasis on Chinese patient demographics. Notably, the dataset includes comprehensive clinical information, such as age, sex, and diagnosis, providing a robust foundation for diverse research needs. Publicly accessible, it supports a range of applications, including machine learning model development and validation. An initial evaluation of lung adenocarcinoma subtype classification using a multi-instance learning framework demonstrated that this dataset can substantially advance global research and improve the accuracy of subtype diagnosis.

A single exposure to general anesthetic can induce acute increase in neuronal apoptosis of the neonatal brain; however, how the brain counteracts the anesthetic-induced neurotoxicity remains unknown. The aim of this study is to explore how the neonatal cerebral cortex responds to anesthetic-induced neuronal apoptosis and the underlying mechanisms involved.

Arenaviruses encompass a diverse group of infectious agents, some of which, like Lassa virus (LASV), pose significant threats to global public health due to their acute virulence, while others, such as lymphocytic choriomeningitis virus (LCMV), are less pathogenic but still clinically relevant. Both Old World arenaviruses LASV and LCMV exploit host tyrosine kinase signaling to establish infection, though the molecular mechanisms remain incompletely understood. In this study, phosphorylated receptor tyrosine kinase antibody array screening revealed that recombinant LASV (rLCMV-LASV GP) infection specifically activates Src family kinases (SFKs), Fyn and Lyn, with their phosphorylation levels markedly elevated during early infection. Subsequent co-immunoprecipitation assays confirmed rLCMV-LASV GP-induced tyrosine phosphorylation of Fyn and Lyn activation. RNAi experiments demonstrated that knockdown of Fyn/Lyn significantly suppressed rLCMV-LASV GP and LCMV nucleocapsid protein expression, viral RNA synthesis, and viral production, highlighting the critical role of SFKs in viral infection. Further investigations showed that saracatinib, an Src inhibitor, exhibited broad-spectrum antiviral activity against LCMV strains, as well as the authentic LASV strain Lassa_HX strain. In vivo studies revealed that saracatinib substantially reduced viral loads in splenic and hepatic tissues and alleviated infection-associated histopathological damage. These findings identify Src family kinase Fyn/Lyn as novel host targets for arenavirus and provide new targets of prevention and treatment for arenaviral infection.IMPORTANCEArenaviruses, including the highly pathogenic Lassa virus (LASV) and clinically relevant lymphocytic choriomeningitis virus (LCMV), pose severe global health threats due to limited therapeutic options. This study unveils a critical host-pathogen interaction mechanism by which Src family kinases (SFKs) Fyn and Lyn facilitate LASV and LCMV infection. Through phosphorylation profiling and functional validation, we establish that viral activation of these kinases drives arenavirus infection. Moreover, the FDA-approved Src inhibitor saracatinib exhibits broad-spectrum efficacy, suppressing LCMV strains as well as the authentic LASV in vitro, while reducing LCMV viral loads and histopathology in vivo. These findings redefine tyrosine kinases as host targets, offering a novel host-directed antiviral strategy by repurposing existing clinical compounds.

Peach (Prunus persica L. Batsch) is among the most economically important fruit tree crops. Carotenoids in peach fruit have been intensively studied because of their relationship with fruit color and nutritional value. High carotenoid accumulation is generally a desirable trait in fruits and is associated with their aggregation in plastids. However, the understanding of the functions of carotenoid aggregates is still limited, especially with respect to their effects on chromoplast differentiation. The present study revealed that carotenoid aggregates have significant biological effects on peach. Lycopene and β-carotene aggregates promoted chlorophyll degradation and thylakoid membrane remodeling, leading to the differentiation of chloroplasts into chromoplasts in peach fruit and callus. However, the phytoene and phytofluene did not produce this effect in peach fruit. Interestingly, during lycopene and β-carotene aggregation, the stay-green-like (SGRL) gene was significantly activated, and further confirmed that it was an important factor affecting peach chlorophyll degradation and carotenoid accumulation. Furthermore, molecular dynamics analysis confirmed that lycopene and β-carotene had a greater effect on membrane thickness and rigidity than phytoene. This study contributes to a deeper understanding of peach carotenoid aggregates and their biological effects, confirming the effectiveness of the transgenic peach callus system.

Accurate prognostic prediction remains a significant challenge in the management of low-grade serous ovarian cancer (LGSOC), a rare and molecularly distinct histologic subtype. This study aimed to develop a prediction model visualized by nomogram to predict recurrence and survival outcomes in LGSOC patients.

Transcription factors establish cell identity during development by binding regulatory DNA in a sequence-specific manner, often promoting local chromatin accessibility and regulating gene expression1. Mapping accessible chromatin offers critical insights into transcriptional control, but available datasets for human development are restricted to bulk tissue, single organs or single modalities2. Here we present the Human Development Multiomic Atlas, a single-cell atlas of chromatin accessibility and gene expression from 817,740 fetal cells across 12 organs, spanning 203 cell types and more than 1 million candidate cis-regulatory elements, many of which exhibit organ-specific in vivo enhancer activity. Deep learning models trained to predict accessibility from local DNA sequence unravel a comprehensive lexicon of motifs that influence accessibility, including composite motifs exhibiting distinct syntactic constraints that are predicted to mediate transcription factor cooperativity. We identify 'hard' syntactic rules requiring precise motif spacing and orientation, 'soft' rules allowing flexible motif arrangements, and ubiquitous motifs inhibiting accessibility. Model-based interpretation of genetic variants reveals that disruption of motifs with positive and negative effects is associated with concordant effects on gene expression. Our work delineates how motif syntax governs cell-type-specific chromatin accessibility and provides a foundational resource for decoding cis-regulatory logic and interpreting genetic variation during human development.

Kinase-mediated phosphorylation is crucial for thermal adaptation. While extracellular signal-regulated kinase 1/2 (ERK1/2) signaling is well characterized in model organisms, its functional divergence and genetic regulation in marine species with distinct thermal adaptations remain poorly understood. In this study, we investigated the genetic basis of differential ERK activation under heat stress using two oyster subspecies from distinct thermal niches: Crassostrea gigas and Crassostrea angulata. Combining ERK inhibition assays with heat stress treatments, followed by proteomic and phosphoproteomic profiling, we constructed a heat-responsive ERK network and identified that ERK phosphorylates ATP-dependent 6-phosphofructokinase (PFK) at Thr775, enhancing its enzymatic activity and glycolytic capacity. Genome-wide association analysis further revealed that a synonymous mutation in the leucine-rich repeat protein SHOC2 drives divergent ERK phosphorylation patterns between the two subspecies by altering RNA structure and expression. Our findings demonstrated that the heat-responsive SHOC2-BRAF-ERK-PFK cascade exhibits stronger activation in thermotolerant species, enabling marine ectotherms to fine-tune metabolic responses to temperature variation. This study serves as an experimental case elucidating how genetic variations shape thermal adaptation divergence through phosphorylation-mediated regulation, thereby providing a molecular framework for adaptive mechanisms of climate variability.