Association between frailty and acute kidney injury after cardiac surgery: unraveling the moderation effect of body fat through an international, retrospective, multi-cohort study.

BACKGROUND: Acute kidney injury (AKI) is a common and serious complication after cardiac surgery that significantly affects patient outcomes. Given the limited treatment options available, identifying modifiable risk factors is critical. Frailty and obesity, two heterogeneous physiological states, have significant implications for identifying and preventing AKI. Our study investigated the interplay among frailty, body composition, and AKI risk after cardiac surgery to inform patient management strategies. MATERIAL AND METHODS: This retrospective cohort study included three international cohorts. Primary analysis was conducted in adult patients who underwent cardiac surgery between 2014 and 2019 at Wuhan XX Hospital, China. We tested the generalizability of our findings with data from two independent international cohorts, the Medical Information Mart for Intensive Care IV (MIMIC-IV) and the eICU Collaborative Research Database. Frailty was assessed using a clinical lab-based frailty index (FI-LAB), while total body fat percentage (BF%) was calculated based on a formula accounting for BMI, sex, and age. Logistic regression models were used to analyze the associations between frailty, body fat, and AKI, adjusting for pertinent covariates. RESULTS: A total of 8785 patients across three international cohorts were included in the study. In the primary analysis of 3,569 patients from Wuhan XX Hospital, moderate and severe frailty were associated with an increased AKI risk after cardiac surgery. Moreover, a nonlinear relationship was observed between body fat percentage and AKI risk. When stratified by the degree of frailty, lower body fat correlated with a decreased incidence of AKI. Extended analyses using the MIMIC-IV and eICU cohorts (n=3,951 and n=1,265, respectively) validated these findings and demonstrated that a lower total BF% was associated with decreased AKI incidence. Moderation analysis revealed that the effect of frailty on AKI risk was moderated by the body fat percentage. Sensitivity analyses demonstrated results consistent with the main analyses. CONCLUSION: Higher degrees of frailty were associated with an elevated risk of AKI following cardiac surgery, and total BF% moderated this relationship. This research underscores the significance of integrating frailty and body fat assessments into routine cardiovascular care to identify high-risk patients for AKI and implement personalized interventions to improve patient outcomes.

Balance Control Deficits are Associated with Diminished Ankle Force Sense, Not Position Sense, in Athletes with Chronic Ankle Instability.

OBJECTIVES: To compare balance control and ankle proprioception between athletes with and without chronic ankle instability (CAI). A further objective was to explore the relationship between balance control performance and ankle proprioception in athletes with CAI. DESIGN: Cross-sectional study. SETTINGS: Sports Rehabilitation Laboratory. PARTICIPANTS: Eighty-eight recreational athletes (47 CAI and 41 healthy control) were recruited. INTERVENTIONS: No applicable. MAIN OUTCOME MEASURES: Balance control performance was assessed using the sway velocity of the centre of the pressure during the one-leg standing tasks. Ankle proprioception, including joint position sense and force sense, were tested using absolute error (AE) associated with joint position reproduction and force reproduction tasks in four directions, i.e., plantarflexion, dorsiflexion, inversion, and eversion. RESULTS: Athletes with CAI performed significantly worse than those without CAI in balance control tasks. In addition, CAI athletes showed significantly worse joint position sense and force sense in all three movement directions tested (plantarflexion, inversion, and eversion). Correlation analysis showed that the AE of the plantarflexion force sense was significantly moderately correlated with medial-lateral sway velocity in the one-leg standing with eyes open and closed conditions (r = 0.372-0.403, p = 0.006-0.012), and the AE of inversion force sense was significantly moderately correlated with medial-lateral sway velocity in the one-leg standing with eyes open (r = 0.345, p = 0.018) in athletes with CAI, but the joint position sense measures were not (all p > 0.05). CONCLUSIONS: Athletes with CAI showed significantly impaired balance control performance and diminished ankle proprioception. Deficit in force sense was deemed as a moderate predictor of one-leg standing balance control deficits in athletes with dominant-side injury CAI, while ankle position sense may be a small predictor.

Gegen Qinlian decoction inhibited M1 macrophage polarization and ulcerative colitis progression through regulating histone lactylation.

Ulcerative colitis (UC) is a persistent inflammatory condition affecting the bowels. Gegen Qinlian decoction (GQD) has been widely used in the therapy of gastrointestinal diseases. We investigated the protective impacts and mechanism of GQD against UC. To establish the UC model, dextran sulfate sodium (DSS) was utilized. The disease activity index (DAI), colon length and colonic pathology were assessed to examine the impacts of GQD on UC. The level of pan-lysine lactylation (Pan kla) and specific sites were detected using western blot. Then, the inflammatory factors and the oxidative stress parameters were measured via the corresponding kits, respectively. Our findings demonstrated that GQD suppressed the lactate generation and LDH activity. The western blot revealed that GQD inhibited the expression of Pan kla and specific sites of H3K18la, H3K23la, H4K8la, and H4K12la. Furthermore, the suppressive effects on inflammation and oxidative stress caused by GQD were counteracted upon the exogenous lactate. GQD suppressed the phenotypic differentiation of M1 macrophages by reducing the expression of M1 markers, which was also reversed by exogenous lactate. In conclusion, GQD effectively suppressed UC progression through histone lactylation. Our results broadened the theoretical basis for the clinical use of GQD.

T2DM may exert a protective effect against digestive system tumors in East Asian populations: a Mendelian randomization analysis.

Introduction: Type 2 diabetes mellitus (T2DM) was associated with digestive system tumors. We analyzed publicly available data from GWAS studies using Mendelian randomization methods to clarify its causal relationship and mechanisms. Five common digestive system tumors and four diabetes-related phenotypes were included. Methods: Inverse variance weighted method was the main analytical method. Meta-analysis was used to summarize results of multiple data sources. Horizontal pleiotropy was tested using Egger-intercept method and validated by MRPRESSO method. Heterogeneity and sensitivity analysis were conducted by Cochran's Q test and leave-one-out method, respectively. Results: T2DM is associated with a reduced risk of esophageal (OR: 0.77, 95% CI: 0.71 to 0.83, P< 0.001), gastric (OR: 0.87, 95% CI: 0.84 to 0.90, P< 0.001) and colorectal cancer (OR: 0.88, 95% CI: 0.85 to 0.91, P< 0.001) and hepatocellular carcinoma (OR: 0.92, 95% CI: 0.86 to 0.97, P = 0.005) and an increased risk of pancreatic cancer (OR: 1.92, 95% CI: 1.47 to 2.50, P< 0.001) in East Asian population. T2DM causes decreased fasting insulin levels (OR = 0.966, 95% CI: 0.95 to 0.98, P< 0.001) and increased glycated hemoglobin levels (OR=1.41, 95% CI: 1.39 to 1.44, P<0.001). Elevated fasting insulin levels increase the risk of esophageal cancer (OR = 10.35, 95% CI: 1.10 to 97.25, P = 0.041), while increased glycated hemoglobin levels increase pancreatic cancer risk (OR=2.33, 95% CI: 1.37 to 3.97, P=0.002) but decrease gastric cancer risk (OR=0.801, 95% CI: 0.65 to 0.99, P=0.044). Conclusion: T2DM is associated with a reduced risk of esophageal, gastric and colorectal cancer and hepatocellular carcinoma in East Asian populations. The causal relationships between T2DM with esophageal and gastric cancer are partially mediated by decreased fasting insulin and increased glycated hemoglobin levels, respectively. T2DM indirectly increases the risk of pancreatic cancer by increasing glycated hemoglobin levels.

Novel mRNA adjuvant ImmunER enhances prostate cancer tumor-associated antigen mRNA therapy via augmenting T cell activity.

Prostate cancer (PCa) is characterized as a "cold tumor" with limited immune responses, rendering the tumor resistant to immune checkpoint inhibitors (ICI). Therapeutic messenger RNA (mRNA) vaccines have emerged as a promising strategy to overcome this challenge by enhancing immune reactivity and significantly boosting anti-tumor efficacy. In our study, we synthesized Tetra, an mRNA vaccine mixed with multiple tumor-associated antigens, and ImmunER, an immune-enhancing adjuvant, aiming to induce potent anti-tumor immunity. ImmunER exhibited the capacity to promote dendritic cells (DCs) maturation, enhance DCs migration, and improve antigen presentation at both cellular and animal levels. Moreover, Tetra, in combination with ImmunER, induced a transformation of bone marrow-derived dendritic cells (BMDCs) to cDC1-CCL22 and up-regulated the JAK-STAT1 pathway, promoting the release of IL-12, TNF-α, and other cytokines. This cascade led to enhanced proliferation and activation of T cells, resulting in effective killing of tumor cells. In vivo experiments further revealed that Tetra + ImmunER increased CD8+T cell infiltration and activation in RM-1-PSMA tumor tissues. In summary, our findings underscore the promising potential of the integrated Tetra and ImmunER mRNA-LNP therapy for robust anti-tumor immunity in PCa.

Chromosome-level Genome Assembly of Theretra japonica (Lepidoptera: Sphingidae).

Theretra japonica is an important pollinator and agricultural pest in the family Sphingidae with a wide range of host plants. High-quality genomic resources facilitate investigations into behavioral ecology, morphological and physiological adaptations, and the evolution of genomic architecture. However, chromosome-level genome of T. japonica is still lacking. Here we sequenced and assembled the high-quality genome of T. japonica by combining PacBio long reads, Illumina short reads, and Hi-C data. The genome was contained in 95 scaffolds with an accumulated length of 409.55 Mb (BUSCO calculated a genome completeness of 99.2%). The 29 pseudochromosomes had a combined length of 403.77 Mb, with a mapping rate of 98.59%. The genomic characterisation of T. japonica will contribute to further studies for Sphingidae and Lepidoptera.

Three new compounds from the fruits of Solanum virginianum L. and their anti-inflammatory activities.

Three new compounds 1-glyceryl 9(ß), 10(α), 11(ß)-trihydroxy-12(Z)-octadecenoate, 2'S-20-O-p-hydroxyphenylpropionyloxy-20-hyd-roxyarachidic acid glycerol ester (2), 3-O-α-l-arabinopyranosyl-(1→6)-ß-d-glucopyranoside of ethyl (3S)-hydroxybutanoate (3), as well as a new natural product (4) were isolated from the fruits of Solanum virginianum L. The structures of 26 compounds were determined by comprehensive spectroscopic analyses, NMR calculation, chemical methods, and comparisons of spectroscopic data. Compounds 2 and 16 exhibited good anti-inflammatory activity in the LPS-induced RAW 264.7 inflammatory model with IC50 values of 16.75 ± 1.54 and 22.43 ± 2.01 µM, respectively.

Mechanism of Lian Hua Qing Wen capsules regulates the inflammatory response caused by M1 macrophage based on cellular experiments and computer simulations.

PURPOSE: The polarization of macrophages with the resulting inflammatory response play a crucial part in tissue and organ damage due to inflammatory. Study has proved Lian Hua Qing Wen capsules (LHQW) can reduce activation of inflammatory response and damage of tissue derived from the inflammatory reactions. However, the mechanism of LHQW regulates the macrophage-induced inflammatory response is unclear. Therefore, we investigated the mechanism of LHQW regulated the inflammatory response of M1 macrophages by cellular experiments and computer simulations. METHODS: This study has analysed the targets and mechanisms of macrophage regulating inflammatory response at gene and protein levels through bioinformatics. The monomeric components of LHQW were analyzed by High Performance Liquid Chromatography (HPLC). We established the in vitro cell model by M1 macrophages (Induction of THP-1 cells into M1 macrophages). RT-qPCR and immunofluorescence were used to detect changes in gene and protein levels of key targets after LHQW treatment. Computer simulations were utilized to verify the binding stability of monomeric components and protein targets. RESULTS: Macrophages had 140,690 gene targets, inflammatory response had 12,192 gene targets, intersection gene targets were 11,772. Key monomeric components (including: Pinocembrin, Fargesone-A, Nodakenin and Bowdichione) of LHQW were screened by HPLC. The results of cellular experiments indicated that LHQW could significantly reduce the mRNA expression of CCR5, CSF2, IFNG and TNF, thereby alleviating the inflammatory response caused by M1 macrophage. The computer simulations further validated the binding stability and conformation of key monomeric components and key protein targets, and IFNG/Nodakenin was able to form the most stable binding conformation for its action. CONCLUSION: In this study, the mechanism of LHQW inhibits the polarization of macrophages and the resulting inflammatory response was investigated by computer simulations and cellular experiments. We found that LHQW may not only reduce cell damage and death by acting on TNF and CCR5, but also inhibit the immune recognition process and inflammatory response by regulating CSF2 and IFNG to prevent polarization of macrophages. Therefore, these results suggested that LHQW may act through multiple targets to inhibit the polarization of macrophages and the resulting inflammatory response.

Mitoregulin self-associates to form likely homo-oligomeric pore-like structures.

We and others previously found that a misannotated long noncoding RNA encodes for a conserved mitochondrial transmembrane microprotein named Mitoregulin (Mtln). Beyond an established role for Mtln in lipid metabolism, Mtln has also been shown to more broadly influence mitochondria, boosting respiratory efficiency and Ca 2+ retention capacity, while lowering ROS, yet the underlying mechanisms remain unresolved. Prior studies have identified possible Mtln protein interaction partners; however, a lack of consensus persists, and no claims have been made about Mtln's structure. We previously noted two key published observations that seemingly remained overlooked: 1) endogenous Mtln co-immunoprecipitates with epitope-tagged Mtln at high efficiency, and 2) Mtln primarily exists in a ∼66 kDa complex. To investigate if Mtln may self-oligomerize into higher-order complexes, we performed co-immunoprecipitation, protein modeling simulations, and native gel assessments of Mtln-containing complexes in cells and tissues, as well as tested whether synthetic Mtln protein itself forms oligomeric complexes. Our combined results provide strong support that Mtln self-associates and likely forms a hexameric pore-like structure.

Scalable Compliant Graphene Fiber-Based Thermal Interface Material with Metal-Level Thermal Conductivity via Dual-Field Synergistic Alignment Engineering.

High-performance thermal interface materials (TIMs) are highly desired for high-power electronic devices to accelerate heat dissipation. However, the inherent trade-off conflict between achieving high thermal conductivity and excellent compliance of filler-enhanced TIMs results in the unsatisfactory interfacial heat transfer efficiency of existing TIM solutions. Here, we report the graphene fiber (GF)-based elastic TIM with metal-level thermal conductivity via mechanical-electric dual-field synergistic alignment engineering. Compared with state-of-the-art carbon fiber (CF), GF features both superb high thermal conductivity of ∼1200 W m-1 K-1 and outstanding flexibility. Under dual-field synergistic alignment regulation, GFs are vertically aligned with excellent orientation (0.88) and high array density (33.5 mg cm-2), forming continuous thermally conductive pathways. Even at a low filler content of ∼17 wt %, GF-based TIM demonstrates extraordinarily high through-plane thermal conductivity of up to 82.4 W m-1 K-1, exceeding most CF-based TIMs and even comparable to commonly used soft indium foil. Benefiting from the low stiffness of GF, GF-based TIM shows a lower compressive modulus down to 0.57 MPa, an excellent resilience rate of 95% after compressive cycles, and diminished contact thermal resistance as low as 7.4 K mm2 W-1. Our results provide a superb paradigm for the directed assembly of thermally conductive and flexible GFs to achieve scalable and high-performance TIMs, overcoming the long-standing bottleneck of mechanical-thermal mismatch in TIM design.

Blocking Sigmar1 exacerbates methamphetamine-induced hypertension.

AIM: Methamphetamine (METH) chronic exposure is an important risk factor for hypertension development. However, the mechanisms behind METH-induced hypertension remain unclear. Therefore, we aimed to reveal the potential mechanisms underlying METH-induced hypertension. METHODS AND RESULTS: We structured the mouse hypertension model by METH, and observed that METH-treated mice have presented vascular remodeling (large-and small-size arteries) with collagen deposit around the vessel and increasing blood pressure (BP) and Sigma1 receptor (Sigmar1) in vascular tissue. We hypothesized that Sigmar1 is crucial in METH-induced hypertension and vascular remodeling. Sigmar1 knockout (KO) mice and antagonist (BD1047) pretreated mice exposed to METH for six-week showed higher BP and more collagen deposited around vessels than wild-type (WT) mice exposed to METH for six-week, in contrast, mice pretreated with Sigmar1 agonist (PRE-084) had unchanged BP and perivascular collagen despite the six-week METH exposure. Furthermore, we found that METH exposure induced vascular smooth muscle cells (VSMCs) and mesenchymal stem cells to differentiate into the myofibroblast-like cell and secrete collagen into surrounding vessels. Mechanically, Sigmar1 can suppress the COL1A1 expression by blocking the classical fibrotic TGF-ß/Smad2/3 signaling pathway in METH-exposed VSMCs and mesenchymal stem cells. CONCLUSION: Our results suggest that Sigmar1 is involved in METH-induced hypertension and vascular fibrosis by blocking the activation of the TGF-ß/Smad2/3 signaling pathway. Accordingly, Sigmar1 may be a novel therapeutic target for METH-induced hypertension and vascular fibrosis.

Progress of research and application of Heyndrickxia coagulans (Bacillus coagulans) as probiotic bacteria.

Probiotics are defined as living or dead bacteria and their byproducts that maintain the balance of the intestinal microbiome. They are non-toxic, non-pathogenic, and do not release any toxins either within or outside the body. Adequate consumption of probiotics can enhance metabolite production, increase immunity, maintain a balanced intestinal flora, and stimulate growth. Probiotics do not have negative antibiotic effects and help maintain the natural flora in animals in a balanced state or prevent dysbacteriosis. Heyndrickxia coagulans (H. coagulans) is a novel probiotic species that is gradually being used for the improvement of human health. Compared to commonly used probiotic lactic acid bacteria, H. coagulans can produce spores, which provide the species with high resistance to adverse conditions. Even though they are transient residents of the gut, beneficial bacteria can have a significant impact on the microbiota because they can outnumber harmful germs, and vice versa. This article discusses the probiotic mechanisms of H. coagulans and outlines the requirements for a substance to be classified as a probiotic. It also addresses how to assess strains that have recently been discovered to possess probiotic properties.

Ceramic Meta-Aerogel with Thermal Superinsulation up to 1700 °C Constructed by Self-Crosslinked Nanofibrous Network via Reaction Electrospinning.

Thermal insulation under extreme conditions requires the materials to be capable of withstanding complex thermo-mechanical stress, significant gradient temperature transition, and high-frequency thermal shock. The excellent structural and functional properties of ceramic aerogels make them attractive for thermal insulation. However, in extremely high-temperature environments (above 1500 °C), they typically exhibit limited insulation capacity and thermo-mechanical stability, which may lead to catastrophic accidents, and this problem is never effectively addressed. Here, a novel ceramic meta-aerogel constructed from a crosslinked nanofiber network using a reaction electrospinning strategy, which ensures excellent thermo-mechanical stability and superinsulation under extreme conditions, is designed. The ceramic meta-aerogel has an ultralow thermal conductivity of 0.027 W m-1 k-1, and the cold surface temperature is only 303 °C in a 1700 °C high-temperature environment. After undergoing a significant gradient temperature transition from liquid nitrogen to 1700 °C flame burning, the ceramic meta-aerogel can still withstand thousands of shears, flexures, compressions, and other complex forms of mechanical action without structural collapse. This work provides a new insight for developing ceramic aerogels that can be used for a long period in extremely high-temperature environments.

Quantum-Enhanced Metrology with Network States.

Armed with quantum correlations, quantum sensors in a network have shown the potential to outclass their classical counterparts in distributed sensing tasks such as clock synchronization and reference frame alignment. On the other hand, this analysis was done for simple and idealized networks, whereas the correlation shared within a practical quantum network, captured by the notion of network states, is much more complex. Here, we prove a general bound that limits the performance of using quantum network states to estimate a global parameter, establishing the necessity of genuine multipartite entanglement for achieving a quantum advantage. The bound can also serve as an entanglement witness in networks and can be generalized to states generated by shallow circuits. Moreover, while our bound prohibits local network states from achieving the Heisenberg limit, we design a probabilistic protocol that, once successful, attains this ultimate limit of quantum metrology and preserves the privacy of involved parties. Our work establishes both the limitation and the possibility of quantum metrology within quantum networks.

Exploring the Effects of Different Drying Methods on Related Differential Metabolites of Pleurotus citrinopileatus Singer Based on Untargeted Metabolomics.

Pleurotus citrinopileatus Singer (PCS) has attracted increasing attention as a raw material for medicine and food. Its quality is greatly affected by the accumulation of metabolites, which varies with the applied drying methods. In this study, we utilize an approach based on ultra-high-performance liquid chromatography/Q Exactive mass spectrometry (UHPLC-QE-MS) to reveal the metabolic profiles of PCS from three different drying methods (natural air-drying, NAD; hot-air-drying, HAD; vacuum freeze-drying, VFD). The results showed that lipids, amino acids and their derivatives were all important secondary metabolites produced during NAD, HAD and VFD treatments, with the key differential metabolites of PCS during drying including fifteen lipids and seven amino acids. Meanwhile, VFD was the best way for long-term preservation of dried PCS. Hot-drying methods, especially HAD, can improve the medicinal component of PCS. Furthermore, KEGG enrichment analysis highlighted 16 pathways and indicated that amino acid metabolism might be the key metabolite pathway for the PCS drying process. Our study elucidates the relationship between drying methods and metabolites or metabolic pathways of PCS to determine the mechanisms affecting the quality of PCS, and finally provides reference values for further development and application in functional food and medications.

In Vivo Cavitation-based Aberration Correction of Histotripsy in Porcine Liver.

Histotripsy is a non-invasive ablation technique that focuses ultrasound pulses into the body to destroy tissues via cavitation. Heterogeneous acoustic paths through tissue introduce phase errors that distort and weaken the focus, requiring additional power output from the histotripsy transducer to perform therapy. This effect, termed phase aberration, limits the safety and efficacy of histotripsy ablation. It has been shown in vitro that the phase errors from aberration can be corrected by receiving the acoustic signals emitted by cavitation. For transabdominal histotripsy in vivo, however, cavitation-based aberration correction is complicated by acoustic signal clutter and respiratory motion. This study develops a method that enables robust, effective cavitation-based aberration correction in vivo and evaluates its efficacy in the swine liver. The method begins with a high-speed pulsing procedure to minimize the effects of respiratory motion. Then, an optimal phase correction is obtained in the presence of acoustic clutter by filtering with the singular value decomposition. This aberration correction method reduced the power required to generate cavitation in the liver by 26% on average (range: 0% to 52%) and required ~2 s for signal acquisition and processing per focus location. These results suggest that the cavitation-based method could enable fast and effective aberration correction for transabdominal histotripsy.

Berberine hydrochloride reduces staphyloxanthin synthesis by inhibiting fni genes in methicillin-resistant Staphylococcus aureus.

BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) poses a great health threat to humans. Looking for compounds that could reduce the resistance of S. aureus towards methicillin is an effective way to alleviate the antimicrobial resistance crisis. METHODS AND RESULTS: Minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), Time-killing growth curve, staphyloxanthin and penicillin-binding protein 2a (PBP2a) were detected. A quantitative polymerase chain reaction was used to measure the effect of BBH on the gene transcription profiles of MRSA. The MIC of MRSA-ST59-t437 towards oxacillin was 8 µg/ml, and MBC was 128 µg/ml. After adding a sub-inhibitory concentration of BBH, the MIC and MBC of MRSA-ST59-t478 towards oxacillin went down to 0.125 and 32 µg/ml respectively. The amount of PBP2a and staphyloxanthin were reduced after treatment with BBH. Moreover, the transcription levels of sarA, mecA and fni genes were downregulated. CONCLUSIONS: It is for the first time reported that BBH could inhibit staphyloxanthin synthesis by inhibiting fni gene. Moreover, fni might be the target gene of sarA, and there might be another regulatory pathway to inhibit staphyloxanthin biosynthesis. BBH could effectively reduce the methicillin resistance of MRSA-ST59-t437 by downregulating fni, sarA and mecA genes.

Src inhibition modulates AMBRA1-mediated mitophagy to counteract endothelial-to-mesenchymal transition in renal allograft fibrosis.

Chronic allograft dysfunction (CAD) poses a significant challenge in kidney transplantation, with renal vascular endothelial-to-mesenchymal transition (EndMT) playing a vital role. While renal vascular EndMT has been verified as an important contributing factor to renal allograft interstitial fibrosis/tubular atrophy in CAD patients, its underlying mechanisms remain obscure. Currently, Src activation is closely linked to organ fibrosis development. Single-cell transcriptomic analysis in clinical patients revealed that Src is a potential pivotal mediator in CAD progression. Our findings revealed a significant upregulation of Src which closely associated with EndMT in CAD patients, allogeneic kidney transplanted rats and endothelial cells lines. In vivo, Src inhibition remarkably alleviate EndMT and renal allograft interstitial fibrosis in allogeneic kidney transplanted rats. It also had a similar antifibrotic effect in two endothelial cell lines. Mechanistically, the knockout of Src resulted in an augmented AMBRA1-mediated mitophagy in endothelial cells. We demonstrate that Src knockdown upregulates AMBRA1 level and activates mitophagy by stabilizing Parkin's ubiquitination levels and mitochondrial translocation. Subsequent experiments demonstrated that the knockdown of the Parkin gene inhibited mitophagy in endothelial cells, leading to increased production of Interleukin-6, thereby inducing EndMT. Consequently, our study underscores Src as a critical mediator of renal vascular EndMT and allograft interstitial fibrosis, exerting its impact through the regulation of AMBRA1/Parkin-mediated mitophagy.

REEP3 is a potential diagnostic and prognostic biomarker correlated with immune infiltration in pancreatic cancer.

Receptor Expression-Enhancing Protein 3 (REEP3) serves as a pivotal enzyme crucial for endoplasmic reticulum (ER) clearance during mitosis and is implicated in the advancement of diverse malignancies. Nonetheless, the biological role and mechanisms of REEP3 in pancreatic cancer patients, along with its interplay with immune infiltration, remain inadequately elucidated. In this study, we initially analyzed the differential expression of REEP3 between pancreatic cancer tissues and normal pancreas tissues using the Cancer Genome Atlas (TCGA), GTEx and Gene Expression Omnibus (GEO) databases. Subsequently, we utilized Kaplan-Meier analysis, Cox regression and ROC curve to determine the predictive value of REEP3 for the clinical outcomes of pancreatic cancer patients. Functional enrichment analyses, including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Set Enrichment Analysis (GSEA), were conducted to explore the potential signaling pathways and biological functions associated with pancreatic cancer. Furthermore, we investigated the PPI network, miRNA, RBP and transcription factor interactions of REEP3 using databases such as GeneMania, STRING, StarBase, KnockTK, ENCODE, Jaspar and hTFtarget. Lastly, the "ssGSEA" algorithm and TIMER database were employed to investigate the correlation between REEP3 expression and immune infiltration as well as immune checkpoints. The expression of REEP3 in pancreatic cancer showed a significantly higher level compared to that in normal tissues. ROC curve analysis indicated that REEP3 holds substantial diagnostic potential for pancreatic cancer patients. Elevated REEP3 expression correlated with unfavorable outcomes in terms of both overall survival and relapse-free survival, establishing it as a notable adverse prognostic marker in pancreatic cancer. Moreover, both univariate and multivariate Cox regression analyses demonstrated that REEP3 maintained an independent association with overall survival. Functional enrichment analyses revealed pathways significantly linked to REEP3, including cytoplasmic translation, wound healing, viral processes, regulation of cellular component size and actin filament organization. Additionally, REEP3 expression displayed a significant positive correlation with CD8+ T cells, B cells, natural killer cells, dendritic cells and macrophages. REEP3 is a potential diagnostic, prognostic marker and immunotherapeutic target for pancreatic cancer.

An evolutionary game-theoretic analysis of the "multi-agent co-governance" system of unfair competition on internet platforms.

The increasingly prominent issue of unfair competition on Internet platforms (IPUC) severely restricts the healthy and sustainable development of the platform economy. Based on the IPUC "multi-agent co-governance" scenario, this paper introduces stochastic disturbances and continuous strategy set to improve the classical binary deterministic evolutionary game system. The results show that after considering stochastic disturbances, the positive state corresponding to the equilibrium point (1,1) is no longer stable, and the required parameter conditions are more stringent. The IPUC "multi-agent co-governance" system under stochastic disturbances exhibits specific vulnerability. In the continuous strategy set evolutionary game system, government departments and Internet platforms can flexibly make optimal decisions based on maximizing expected returns, and strategy selection has better elasticity. Regardless of the evolutionary game scenario, maintaining the participation level of NGOs and the public above a certain threshold while increasing the penalty intensity is conducive to the evolution of the game system toward the positive state. The analysis process and conclusions provide insights and guidance for the governments to design the IPUC regulatory system and frameworks.