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T cells rewire their metabolic activities to meet the demand of immune responses, but how to coordinate the immune response by metabolic regulators in activated T cells is unknown. Here, we identified autocrine VEGF-B as a metabolic regulator to control lipid synthesis and maintain the integrity of the mitochondrial inner membrane for the survival of activated T cells. Disruption of autocrine VEGF-B signaling in T cells reduced cardiolipin mass, resulting in mitochondrial damage, with increased apoptosis and reduced memory development. The addition of cardiolipin or modulating VEGF-B signaling improved T cell mitochondrial fitness and survival. Autocrine VEGF-B signaling through GA-binding protein α (GABPα) induced sentrin/SUMO-specific protease 2 (SENP2) expression, which further de-SUMOylated PPARγ and enhanced phospholipid synthesis, leading to a cardiolipin increase in activated T cells. These data suggest that autocrine VEGF-B mediates a signal to coordinate lipid synthesis and mitochondrial fitness with T cell activation for survival and immune response. Moreover, autocrine VEGF-B signaling in T cells provides a therapeutic target against infection and tumors as well as an avenue for the treatment of autoimmune diseases.

Candidalysin, a cytolytic peptide toxin secreted by the human fungal pathogen Candida albicans , is critical for fungal pathogenesis. Yet, its intracellular targets have not been extensively mapped. Here, we performed a high-throughput enhanced yeast two-hybrid (HT-eY2H) screen to map the interactome of all eight Ece1 peptides with their direct human protein targets and identified a list of potential interacting proteins, some of which were shared between the peptides. CCNH, a regulatory subunit of the CDK-activating kinase (CAK) complex involved in DNA damage repair, was identified as one of the host targets of candidalysin. Mechanistic studies revealed that candidalysin triggers a significantly increased double-strand DNA breaks (DSBs), as evidenced by the formation of γ-H2AX foci and colocalization of CCNH and γ-H2AX. Importantly, candidalysin binds directly to CCNH to activate CAK to inhibit DNA damage repair pathway. Loss of CCNH alleviates DSBs formation under candidalysin treatment. Depletion of candidalysin-encoding gene fails to induce DSBs and stimulates CCNH upregulation in a murine model of oropharyngeal candidiasis. Collectively, our study reveals that a secreted fungal toxin acts to hijack the canonical DNA damage repair pathway by targeting CCNH and to promote fungal infection. Candidalysin is a toxin secreted by Candida albicans . Although critical for pathogenesis, its intracellular targets are not well mapped. Here, Zhang et al screen for interacting proteins and identify that candidalysin can modulate the DNA damage repair pathway to promote fungal infection.

The intratumoral microbiome is an emerging hallmark of cancer, yet its multi‐kingdom host–microbiome ecosystem in colorectal cancer (CRC) remains poorly characterized. Here, we conducted an integrated analysis using deep shotgun metagenomics and proteomics on 185 tissue samples, including adenoma (A), paired tumor (T), and para‐tumor (P). We identified 4057 bacterial, 61 fungal, 108 archaeal, and 374 viral species in tissues and revealed distinct intratumor microbiota dysbiosis, indicating a CRC‐specific multi‐kingdom microbial ecosystem. Proteomic profiling uncovered four CRC subtypes (C1–C4), each with unique clinical prognoses and molecular signatures. We further discovered that host‐microbiome interactions are dynamically reorganized during carcinogenesis, where different microbial taxa converge on common host pathways through distinct proteins. Leveraging this interplay, we identified 14 multi‐kingdom microbial and 8 protein markers that strongly distinguished A from T samples (area under the receiver operating characteristic curve (AUROC) = 0.962), with external validation in two independent datasets (AUROC = 0.920 and 0.735). Moreover, we constructed an early‐ versus advanced‐stage classifier using 8 microbial and 4 protein markers, which demonstrated high diagnostic accuracy (AUROC = 0.926) and was validated externally (AUROC = 0.659–0.744). Functional validation in patient‐derived organoids and murine allograft models confirmed that enterotoxigenic Bacteroides fragilis and Fusobacterium nucleatum promoted tumor growth by activating Wnt/β‐catenin and NF‐κB signaling pathways, corroborating the functional potential of these biomarkers. Together, these findings reveal dynamic host–microbiome interactions at the protein level, tracing the transition from adenoma to carcinoma and offering potential diagnostic and therapeutic targets for CRC. This study integrated metagenomic and proteomic profiling of 185 colorectal tissue samples—spanning adenoma (A), tumor (T), and para‐tumor (P)—to characterize multi‐kingdom microbiome and host protein dynamics in colorectal cancer (CRC). In total, 4057 bacterial, 61 fungal, 108 archaeal, and 374 viral species were identified, revealing CRC‐specific microbial dysbiosis. Proteomic analysis defined four molecular subtypes (C1–C4) with distinct clinical outcomes. This study further developed a diagnostic model based on 14 microbial and 8 protein markers, which robustly distinguished adenoma from tumor (achieved an area under the receiver operating characteristic curve (AUROC) = 0.962) and early from advanced stages (AUROC = 0.926), with validation across multiple independent cohorts. Functional assays in patient‐derived organoids and murine allografts confirmed that enterotoxigenic Bacteroides fragilis and Fusobacterium nucleatum promote tumor growth through Wnt/β‐catenin and NF‐κB pathway activation. These findings highlight dynamic host–microbiome interactions in CRC progression and provide novel biomarkers and therapeutic targets. Highlights Integrated metagenomic and proteomic profiling of 185 colorectal tissue samples. and identification of colorectal cancer (CRC)‐specific multi‐kingdom microbial ecosystems and four molecular subtypes with distinct clinical features. Discovery of 14 microbial and 8 protein markers with high diagnostic accuracy for adenoma versus tumor and early versus advanced stage classification. Functional validation of Bacteroides fragilis and Fusobacterium nucleatum as key microbial drivers promoting tumor growth via Wnt/β‐catenin and NF‐κB signaling. Insights into dynamic host–microbiome interactions with potential diagnostic and therapeutic relevance.

The authors previously demonstrated that unconjugated bilirubin (UCB) may inhibit the activities of various digestive proteases, including trypsin and chymotrypsin. The digestive proteases in the lower gut are important in the pathogenesis of inflammatory bowel diseases. The effects of UCB on the inflammation and levels of digestive proteases in feces of rats with colitis have not yet been revealed. The present study investigated the effect of UCB on the inflammatory status and levels of trypsin and chymotrypsin in the feces of rats with trinitrobenzenesulfonic acid (TNBS)-induced colitis. The data indicated that treatment with TNBS resulted in a marked reduction in weight gain, which was significantly alleviated in UCB-treated rats. Furthermore, UCB treatment alleviated the inflammation induced by TNBS, detected via macroscopic damage and microscopic inflammation scores, and pro-inflammatory markers including myeloperoxidase (MPO), tumor necrosis factor (TNF)-α and interleukin (IL)-1β. Furthermore, rats with colitis demonstrated significant increases in fecal trypsin and chymotrypsin levels, whereas UCB treatment significantly alleviated these increases. A significant positive correlation was additionally revealed among the pro-inflammatory markers (MPO, TNF-α and IL-1β) and fecal digestive proteases (trypsin and chymotrypsin) in colitis. The results of the present study demonstrated that UCB ameliorated the inflammation and digestive protease increase in TNBS-induced colitis.

Background Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies worldwide because of rapid progression and high incidence of metastasis or recurrence. Accumulating evidence shows that CD73-expressing tumor cell is implicated in development of several types of cancer. However, the role of CD73 in HCC cell has not been systematically investigated and its underlying mechanism remains elusive. Methods CD73 expression in HCC cell was determined by RT-PCR, Western blot, and immunohistochemistry staining. Clinical significance of CD73 was evaluated by Cox regression analysis. Cell counting kit-8 and colony formation assays were used for proliferation evaluation. Transwell assays were used for motility evaluations. Co-immunoprecipitation, cytosolic and plasma membrane fractionation separation, and ELISA were applied for evaluating membrane localization of P110β and its catalytic activity. NOD/SCID/γc(null) (NOG) mice model was used to investigate the in vivo functions of CD73. Results In the present study, we demonstrate that CD73 was crucial for epithelial-mesenchymal transition (EMT), progression and metastasis in HCC. CD73 expression is increased in HCC cells and correlated with aggressive clinicopathological characteristics. Clinically, CD73 is identified as an independent poor prognostic indicator for both time to recurrence and overall survival. CD73 knockdown dramatically inhibits HCC cells proliferation, migration, invasion, and EMT in vitro and hinders tumor growth and metastasis in vivo. Opposite results could be observed when CD73 is overexpressed. Mechanistically, adenosine produced by CD73 binds to adenosine A2A receptor (A2AR) and activates Rap1, which recruits P110β to the plasma membrane and triggers PIP3 production, thereby promoting AKT phosphorylation in HCC cells. Notably, a combination of anti-CD73 and anti-A2AR achieves synergistic depression effects on HCC growth and metastasis than single agent alone. Conclusions CD73 promotes progression and metastasis through activating PI3K/AKT signaling, indicating a novel prognostic biomarker for HCC. Our data demonstrate the importance of CD73 in HCC in addition to its immunosuppressive functions and revealed that co-targeting CD73 and A2AR strategy may be a promising novel therapeutic strategy for future HCC management.

Emerging for future spintronic/electronic applications, magnetic semiconductors have stimulated intense interest due to their promises for new functionalities and device concepts. So far, the so-called diluted magnetic semiconductors attract many attentions, yet it remains challenging to increase their Curie temperatures above room temperature, particularly those based on III–V semiconductors. In contrast to the concept of doping magnetic elements into conventional semiconductors to make diluted magnetic semiconductors, here we propose to oxidize originally ferromagnetic metals/alloys to form new species of magnetic semiconductors. We introduce oxygen into a ferromagnetic metallic glass to form a Co 28.6 Fe 12.4 Ta 4.3 B 8.7 O 46 magnetic semiconductor with a Curie temperature above 600 K. The demonstration of p – n heterojunctions and electric field control of the room-temperature ferromagnetism in this material reflects its p -type semiconducting character, with a mobility of 0.1 cm 2  V −1  s −1 . Our findings may pave a new way to realize high Curie temperature magnetic semiconductors with unusual multifunctionalities. Magnetic semiconductors provide control of spin states in addition to charge states realized in conventional semiconductors, yet currently limited to weak magnetism at low temperature. Liu et al . introduce oxygen into a ferromagnetic metallic glass, resulting in a Curie temperature above 600 K.

HR18034, composed of the ropivacaine encapsulated in multi-lamellar, concentric circular structure liposomes as the major component and a small amount of free ropivacaine, has performed well in animal experiments and phase I clinical trials. This trial was to investigate the efficacy, safety, pharmacokinetic profile and the minimum effective dose of HR18034 for postoperative analgesia after hemorrhoidectomy compared with ropivacaine. A multicenter, randomized, double-blind trial. 19 medical centers in China. 85 patients undergoing hemorrhoidectomy between October 2022 to November 2022. Patients were randomly divided into HR 18034 190 mg group, 285 mg group, 380 mg group and ropivacaine 75 mg group, receiving single local anesthetic perianal injection for postoperative analgesia. The primary outcome was the area under the resting state NRS score -time curve within 72 h after injection. The second outcomes included the proportion of patients without pain, the proportion of patients not requiring rescue analgesia, cumulative morphine consumption for rescue analgesia, etc. Safety was evaluated by adverse events incidence and plasma ropivacaine concentrations were measured to explore the pharmacokinetic characteristics of HR18034. The areas under the NRS score (at rest and moving states)-time curve were significantly lower in HR 18034 380 mg group than ropivacaine 75 mg at 24 h, 48 h, and 72 h after administration. However, this superiority was not observed in HR18034 190 mg group and 285 mg group. There was no difference in cumulative morphine consumption for rescue analgesia between HR 18034 groups and ropivacaine group. HR 18034 380 mg showed superior analgesic efficacy and equivalent safety compared to ropivacaine 75 mg after hemorrhoidectomy, thus preliminarily determined as minimum effective dose. HR 18034 380 mg showed superior analgesic efficacy (lower area under the resting and moving states NRS score-time curve, The higher proportion of patients free of pain) and equivalent safety compared to ropivacaine 75 mg after hemorrhoidectomy, thus preliminarily determined as minimum effective dose. [Display omitted] •Few clinical studies have been conducted on liposomal ropivacaine. No randomized controlled trial of perianal injection, local infiltration anesthesia for post-hemorrhoidectomy analgesia has been reported.•Consisted of a small fraction of free ropivacaine and a predominant portion of ropivacaine encapsulated by multi-layered concentric circular liposome, HR 18034 has an innovative structure, providing rapid pain relief of operative incision through free ropivacaine and sustained analgesia via slow release of the encapsulated ropivacaine from the liposome.•In addition to evaluating the safety and efficacy of the drug, the pharmacokinetic characteristics of the HR 18034 were reported in this study to further guide the clinical applications.

A series of modified HUSY zeolites were prepared by immersing with different concentration of NH 4 F solution at low temperature, and their catalytic performance for isobutane/1-butene alkylation reaction was investigated. The physicochemical properties of modified catalysts were characterized by XRD, N 2 adsorption–desorption isotherms, ICP, pyridine-IR and SEM. The results indicated that HUSY zeolite with higher Si/Al ratio is more sensitive to NH 4 F leaching, resulting in more severe structural amorphization. NH 4 F modification affects not only the pore structure but also the acid properties. The amount of Lewis acid sites on the modified zeolites was reduced and the ratio of Brønsted/Lewis acid sites was significantly enhanced in comparison with that of parent zeolite. Such properties of modified zeolites account for the superior performance for isobutane/1-butene alkylation. The initial C8 selectivity was increased to 74 wt% over the modified HUSY (Si/Al = 2.7) zeolite using 5 wt% NH 4 F solution, which was about 15 wt% higher than that achieved on the HUSY parent. TG and in situ IR analyses of the deactivated catalyst indicated that some deposits were formed on the catalyst and the alkylation activity could be restored by regeneration at suitable conditions (520 °C under air atmosphere). Graphic Abstract

Background Gap junctions are involved in the development of cerebral vasospasm (CVS) after subarachnoid hemorrhage (SAH). However, the specific roles and regulatory functions of related connexin isoforms remain unknown. The aim of this study was to investigate the importance of connexin 43 (Cx43) in CVS and determine whether Cx43 alterations are modulated via the protein kinase C (PKC) signaling transduction pathway. Methods Oxyhemoglobin (OxyHb)-induced smooth muscle cells of basilar arterial and second-injection model in rat were used as CVS models in vitro and in vivo. In addition, dye transfer assays were used for gap junction-mediated intercellular communication (GJIC) observation in vitro and delayed cerebral ischemia (DCI) was observed in vivo by perfusion-weighted imaging (PWI) and intravital fluorescence microscopy. Results Increase in Cx43 mediated the development of SAH-induced CVS was found in both in vitro and in vivo CVS models. Enhanced GJIC was observed in vitro CVS model, this effect and increased Cx43 were reversed by preincubation with specific PKC inhibitors (chelerythrine or GF 109203X). DCI was observed in vivo on day 7 after SAH. However, DCI was attenuated by pretreatment with Cx43 siRNA or PKC inhibitors, and the increased Cx43 expression in vivo was also reversed by Cx43 siRNA or PKC inhibitors. Conclusions These data provide strong evidence that Cx43 plays an important role in CVS and indicate that changes in Cx43 expression may be mediated by the PKC pathway. The current findings suggest that Cx43 and the PKC pathway are novel targets for developing treatments for SAH-induced CVS.

Background Human epidermal growth factor receptor2+ subtype breast cancer has a high degree of malignancy and a poor prognosis. The aim of this study is to develop a prediction model for the human epidermal growth factor receptor2+ subtype (non-luminal) of breast cancer based on the clinical and ultrasound features related with estrogen receptor, progesterone receptor, and human epidermal growth factor receptor2. Methods We collected clinical data and reviewed preoperative ultrasound images of enrolled breast cancers from September 2017 to August 2020. We divided the data into in three groups as follows. Group I: estrogen receptor ± , Group II: progesterone receptor ± and Group III: human epidermal growth factor receptor2 ± . Univariate and multivariate logistic regression analyses were used to analyze the clinical and ultrasound features related with biomarkers among these groups. A model to predict human epidermal growth factor receptor2+ subtype was then developed based on the results of multivariate regression analyses, and the efficacy was evaluated using the area under receiver operating characteristic curve, accuracy, sensitivity, specificity. Results The human epidermal growth factor receptor2+ subtype accounted for 138 cases (11.8%) in the training set and 51 cases (10.1%) in the test set. In the multivariate regression analysis, age ≤ 50 years was an independent predictor of progesterone receptor + (p = 0.007), and posterior enhancement was a negative predictor of progesterone receptor + (p = 0.013) in Group II; palpable axillary lymph node, round, irregular shape and calcifications were independent predictors of the positivity for human epidermal growth factor receptor-2 in Group III (p = 0.001, p = 0.007, p = 0.010, p < 0.001, respectively). In Group I, shape was the only factor related to estrogen receptor status in the univariate analysis (p < 0.05). The area under receiver operating characteristic curve, accuracy, sensitivity, specificity of the model to predict human epidermal growth factor receptor2+ subtype breast cancer was 0.697, 60.14%, 72.46%, 58.49% and 0.725, 72.06%, 64.71%, 72.89% in the training and test sets, respectively. Conclusions Our study established a model to predict the human epidermal growth factor receptor2-positive subtype with moderate performance. And the results demonstrated that clinical and ultrasound features were significantly associated with biomarkers.