Serratia marcescens is a common opportunistic pathogen in hospitals. Its carbapenem-resistant strains, especially those carrying the blaKPC-2 gene, pose a serious challenge to clinical infection treatment.

The bromodomain-containing protein 9 (BRD9) is a core subunit of mammalian SWI/SNF chromatin remodeling complex termed ncBAF. BRD9 has emerged as a potential target for anticancer drugs, particularly in the treatment of acute myeloid leukemia (AML). Herein, we reported 10m (Y22073) and 10t as new BRD9 selective bromodomain inhibitors. Crystallographic studies revealed that the key active imidazolyl group discovered from structure-activity relationship (SAR) can induce Phe163 flipping and significantly enhance the cellular potency of the compounds, making 10m the first BRD9 selective inhibitor with significant cellular activity against AML cells. We also validated the critical role of imidazolyl groups by modifying existing BRD9 inhibitors. The representative compounds 10m and 10t demonstrated potent binding affinity, outstanding selectivity toward BRD9 bromodomain, and significantly inhibited the proliferation of AML cell lines. 10m also showed good metabolic stability, solubility and pharmacokinetic properties. Additionally, oral administration of compounds 10m and 10t exhibited potent anti-tumor efficacy in the MV4-11 xenograft mouse model. The potent, selective, and orally available BRD9 bromodomain inhibitors may address the challenges of weak cellular activity and limited phenotypic efficacy faced by BRD9 inhibitors, and serve as new lead compounds for the development of anticancer agents for the treatment of AML.

Intra-articular glucocorticoid injections are widely used to alleviate knee osteoarthritis (OA) pain, but evidence suggests these injections may cause cartilage loss. The infrapatellar fat pad (IPFP) and synovium are important sources of inflammation in knee OA; injecting glucocorticoid into the IPFP may not only provide anti-inflammatory effects but also reduce cartilage deterioration in patients with inflammatory knee OA.

Understanding the dynamic interplay between gut microbiota development and bilirubin metabolism may provide new insights into the pathophysiology of neonatal jaundice. Identifying microbial taxa associated with bilirubin fluctuations could help inform early prediction and microbiota-targeted interventions for hyperbilirubinemia.

Chimeric antigen receptor T (CAR-T) cell therapy has shown promise in treating solid tumors, but the clinical success is often limited by insufficient tumor infiltration. In this study, we sought to engineered two MSLN-targeted CAR-T cell variants, Intra2 and Intra6, expressing CCR2 and CXCR6, respectively, to improve their migration toward the tumor microenvironment. Flow cytometry confirmed stable receptor expression. In vitro assays demonstrated that both Intra2 and Intra6 CAR-T cells exhibited significantly improved functional phenotype, migration and invasion, as well as persistence in killing target cells compared to conventional MSLN CAR-T cells. Notably, in vivo, Intra6 CAR-T cells displayed superior antitumor effects, showing enhanced tumor suppression and reduced exhaustion. RNA sequencing analysis revealed that CXCR6 expression upregulated genes related to immune activation, migration, adhesion, and cytoskeletal remodeling, such as LFA-1, PAK1, and FSCN1, suggesting improved migration and transendothelial infiltration. RT-qPCR and flow cytometry confirmed higher LFA-1 expression and enhanced migratory capacity in Intra6 CAR-T cells. Importantly, LFA-1 was crucial for CXCR6-driven migration. These results suggest that chemokine receptor modification of MSLN-targeted CAR-T cells can significantly improve their tumor infiltration and therapeutic efficacy, offering a potential strategy to optimize CAR-T cell therapy for mesothelin-expressing cancers.  METHODS: We engineered two CAR-T cell variants, Intra2 and Intra6, by introducing chemokine receptors CCR2 and CXCR6, respectively. The migration and tumor infiltration capabilities of these modified cells were evaluated in vitro through migration assays and in vivo using tumor-bearing mouse models. The phenotypic characteristics of the CAR-T cells, including memory T cell subsets (stem cell memory and central memory), were analyzed by flow cytometry. Tumor growth inhibition was assessed, and markers of immune exhaustion and evasion were quantified.

Avian Pathogenic Escherichia coli (APEC) is a major cause of economic loss in poultry, exacerbated by the rising prevalence of antibiotic resistance. While sulfur metabolism is essential for bacterial growth, its specific role and regulation in APEC virulence remain poorly understood. This study identifies the LsrR-cysN axis as a novel regulatory pathway that critically governs APEC virulence. We demonstrate that the quorum-sensing regulator LsrR directly binds to the cysN promoter, activating its transcription. Functional analysis revealed that cysN deletion drastically attenuated virulence, significantly reducing biofilm formation, serum resistance, adhesion, invasion, and motility. The APEC94∆cysN also exhibited altered antibiotic resistance profiles, which were linked to the upregulation of efflux pumps acrA and tolC. Crucially, in a murine model, the APEC94∆cysN showed a 75% reduction in mortality and severe impairment in colonization of blood, lungs, liver, spleen, and kidneys. This attenuation was associated with a skewed host immune response, characterized by reduced levels of IL-2 and IL-6 and elevated levels of IL-4 and TNF-α. Our findings establish the LsrR-cysN axis as a central regulator connecting quorum sensing to virulence in APEC, revealing a promising target for novel anti-virulence strategies.

Ubiquitin-like with PHD and ring finger domains 1 (UHRF1) promotes DNA methylation of tumor suppressor genes, contributing to cancer development. Given its observed upregulation in melanoma, this study aimed to its functional roles and elucidate the underlying molecular mechanisms.

Microsurgical 2-layer vasovasostomy is a commonly used technique to treat vasal obstruction in male infertility, and optimizing the surgical approach has important clinical implications.

Cancer treatment faces significant challenges due to drug resistance, non-specific toxicity, and limited penetration of therapeutic agents. Here, we discuss the latest advancements in the design and application of tumor-targeted nanoparticles, focusing on polymer-based, biomimetic, and inorganic nanocarriers, as well as innovative surface modification strategies, to enhance diagnostic and therapeutic approaches in cancer treatment, including the co-delivery of chemotherapeutic agents with biologicals or photo/sonosensitizers for synergistic therapeutic effects. This review not only highlights the current importance of nanoparticle design and application for tumor targeting but also provides insights into future directions for more effective cancer therapies. By integrating advanced material science with biology, these strategies hold the potential to transform the landscape of cancer treatment, offering hope for improved patient outcomes and personalized therapeutic approaches.

As a typical pathological feature of pancreatic ductal adenocarcinoma, reprogramming of glucose metabolism synergistically drives the tumorigenesis and development process through molecular mechanisms such as regulating the expression of driver genes, modifying key functional proteins, triggering mitochondrial metabolism abnormality, and remodeling the tumor microenvironment. It is worth noting that this metabolic remodeling phenomenon is significantly associated with the formation of chemoresistance. Based on the latest research progress, this paper systematically describes the molecular basis of glucose metabolic reprogramming in pancreatic cancer, drug resistance characteristics and its targeted intervention strategies, and provides a theoretical framework for the research and development of innovative drugs.

T-cell suppression in patients with Acute myeloid leukemia (AML) limits tumor cell clearance. This study aimed to explore the role of T-cell senescence-related genes in AML progression using single-cell RNA sequencing (scRNA-seq), bulk RNA sequencing (RNA-seq), and survival data of patients with AML in the TCGA database.

Substituting chemical fertilizers with organic alternatives has gained increasing attention for its potential to enhance crop yield, quality, and soil health. In the early stages of licorice cultivation, the short-term effects of organic fertilization on microbial community dynamics, soil properties, and bioactive compound accumulation remain insufficiently understood. A metagenomic approach was applied to analyze microbial compositions in both bulk and rhizosphere soils under different fertilization treatments. Results showed that organic fertilization significantly increased licorice yield and the accumulation of bioactive compounds compared to chemical fertilization. Full organic substitution improved soil nutrient content, organic matter, and carbon levels while reducing enzyme activities such as urease and protease. Additionally, organic fertilization promoted bacterial diversity, with notable increases in Actinobacteria and fungal taxa such as Ascomycota and Basidiomycota. Correlations between soil microbial communities, enzyme activity, and secondary metabolite synthesis-particularly glycyrrhizic acid-were observed. These findings suggest that organic fertilization fosters microbial diversity and soil health, ultimately benefiting licorice production and quality in the early stages of cultivation while contributing to sustainable agricultural practices.

Two new species of the primitively segmented spider genus Songthela Ono, 2000, which were collected from Hunan Province, China, are described based on specimens of both sexes: S.dongta sp. nov. (♂♀), and S.lixi sp. nov. (♂♀). Songtheladongta sp. nov. is assigned to the bispina-group, while S.lixi sp. nov. belongs to the unispina-group, based on the morphology of male palps and female genitalia. We also provide mitochondrial cytochrome c oxidase subunit I (COI) sequences for species identification and calculate the intra- and interspecific genetic distance among these two new species and 26 known Songthela species. These molecular data highlight distinct genetic divergence between the two new species and their congeners, facilitating future species delimitation. This study not only expands the known diversity of Songthela, but also contributes to a growing framework for understanding biogeographic patterns and evolutionary processes in ancient spider lineages.

Von Willebrand Factor (VWF) and Neutrophil Extracellular Traps (NETs) are involved in the inflammatory response during thrombi formation and are widely found in thrombi of Acute Ischemic Stroke (AIS) patients. Inflammation may mediate the relationship between cerebrovascular risk factors (such as blood glucose) and thrombi components. This study uses overall leukocyte levels to identify potential links between risk factors and VWF, NETs in thrombi.

Alkaline phosphatase (ALP) has played a pivotal role in vascular diseases in recent years. However, the association between ALP level and postoperative complications of moyamoya disease (MMD) has not been studied.

Recent progress in synthetic biology has empowered engineered probiotics to sense tumor-specific physicochemical signals, thereby facilitating targeted in situ drug delivery. Here, an engineered probiotic consortium capable of integrating multiple tumor microenvironment (TME) signals and orchestrating multi-therapeutic payloads release through an orthogonal quorum-sensing system is designed. The probiotic consortium can respond to three characteristic TME parameters, pH, hypoxia, and high-lactate levels, in order to achieve controlled release of lactate depletion enzyme (LdhA) for metabolic environment improvement and the programmed death ligand 1 (PD-L1) nanobody for immune checkpoint inhibition. Using the humanized PD-1 mouse model bearing hPD-L1 MC38 tumor and the humanized peripheral blood mononuclear cells (PBMC) mouse model bearing HT-29 tumor, it is demonstrated that this self-regulating microbial consortium achieves sustained oscillations and significantly suppresses tumor progression. Mechanistic studies reveal that the antitumor efficacy activates CD8+, CD4+, and IFN-γ+ T cells, coupled with diminished immunosuppressive Foxp3+ regulatory T cell infiltration. This work advances the development of engineered live biotherapeutic products for cancer therapy and provides a modular platform for microbial consortium-based precision medicine.

Macrophage plasticity, critical for immune response, is often dysregulated in various infectious and inflammatory diseases. While ion channels have been implicated in immune cell modulation, how they influence macrophage polarization remains poorly understood. Here, it is demonstrated that ectosomes carrying the ion channel Calhm6 effectively suppress severe inflammation triggered by LPS. These Calhm6-bearing ectosomes, secreted by macrophages, facilitate M2-like polarization, elicit an anti-inflammatory response, and foster immune tolerance. Conversely, Calhm6 deficiency leads to suppressed Creb1 activity, which in turn augments M1-like macrophage polarization, enhancing bactericidal activity and the secretion of pro-inflammatory cytokines. Mechanistically, Chp1 serves as a scaffold protein and undergoes phosphorylation by CaMK4. This phosphorylation enhances the localization of the Calhm6-Chp1-CaMK4 complex to the cell membrane, promoting Creb1 activation and M2-like macrophage polarization calcium-dependently. Moreover, the M1-like polarization inducers LPS and IFNγ enhance the binding of Irf1 to the Calhm6 promoter, upregulating its expression and stimulating ectosome formation. Conversely, Stat6, activated by IL-4, competes with Irf1 for binding to the Calhm6 promoter, thereby suppressing its expression. In summary, our findings unravel the intricate interplay between ion channels, ectosomes, and macrophage polarization, revealing that ectosomal-Calhm6 can serve as a novel therapeutic agent to modulate inflammatory responses and facilitate tissue repair.

Rumination is a maladaptive cognitive style and a risk factor for relapse of depression. However, the clinically relevant pattern of dynamic network reconfiguration during rumination in remitted depression and its implication in relapse remained unclear.

This study was performed to compare the operative clinical outcomes of helical plating, intramedullary nailing (IMN), and long straight lateral plating in the treatment of humeral shaft fractures extending into the proximal humerus, as well as to identify the optimal fixation strategy for managing such injuries.

Portulaca oleracea L. extract (POE) shows potential for enhancing poultry production, but its effects on Wenchang chickens are unclear. A total of 90 one-day-old female Wenchang chickens were randomly allocated into three treatment groups: a control group (CON) receiving a basal diet, and two experimental groups (POL and POH) receiving the basal diet supplemented with 0.2 % and 0.4 % POE, respectively. Compared to the CON group, the POL group exhibited significantly higher average daily gain (ADG) and lower feed conversion ratio (FCR) (P < 0.05). POL also significantly enhanced immune function: increased serum immunoglobulins (IgG, IgA, IgM), cytokines (IL-1, IL-4, IFN-γ), secretory IgA (sIgA), and spleen index (P < 0.05). Meat quality improved in POL, with reduced drip loss, cooking loss, and shear force, alongside increased flavor-enhancing amino acids and inosine monophosphate (IMP) (P < 0.05). Jejunal morphology (villus height, VH/CD ratio) and tight junction protein (Claudin-1, Occludin, ZO-1) expression were upregulated in POL (P < 0.05). Gut microbiota analysis revealed POL increased Bacteroides and Faecalibacterium abundance while lowering the Firmicutes / Bacteroidota ratio (P < 0.05). Metabolomics indicated enrichment in tryptophan, arginine, and proline metabolism pathways in POL. Dietary 0.2 % POE improved growth, immunity, and meat quality in Wenchang chickens, potentially mediated by enhanced intestinal health and modulation of tryptophan, arginine, and proline metabolism.