The anti-hyperlipidemia effect of Atractylodes macrocephala Rhizome increased HDL via reverse cholesterol transfer.

Aim: Atractylodes macrocephala Rhizome (AM) has been used to treat hyperlipidemia for centuries, but its functional components and mechanisms are not clear. This research aimed to investigate the active components in AM and the mechanisms that underlie its anti-hyperlipidemia effect. Methods: SD rats were fed a high-sucrose high-fat diet in conjunction with alcohol (HSHFDAC) along with different AM extracts (AMW, AMO, AME, and AMP) for 4 weeks. AM's active components were analyzed using multiple databases, and their mechanisms were explored through network pharmacology. The relationship between AM's effect of enhancing serum HDL-c and regulating the expression of reverse cholesterol transport (RCT)-related proteins (Apo-A1, LCAT, and SR-BI) was further validated in the HSHFDAC-induced hyperlipidemic rats. The kidney and liver functions of the rats were measured to evaluate the safety of AM. Results: AMO, mainly comprised of volatile and liposoluble components, contributed the most significant anti-hyperlipidemia effect among the four extracts obtained from AM, significantly improving the blood lipid profile. Network pharmacology analysis also suggested that volatile and liposoluble components, comprise AM's main active components and they might act on signaling pathways associated with elevated HDL-c. Validation experiments found that AMO substantially and dose-dependently increased HDL-c levels, upregulated the expression of Apo-A1, SR-BI, and LCAT, improved the pathological changes in the kidney and liver, and significantly reduced the serum creatinine levels in rats with hyperlipidemia. Conclusion: The main anti-hyperlipidemia active components of AM are its volatile and liposoluble components, which may enhance serum HDL-c by increasing the expression of the RCT-related proteins Apo-A1, LCAT, and SR-BI.

Alteration of the intestinal microbiota and serum metabolites in a mouse model of Pon1 gene ablation.

Mutations in the Paraoxonase 1 (Pon1) gene underlie aging, cardiovascular disease, and impairments of the nervous and gastrointestinal systems and are linked to the intestinal microbiome. The potential role of Pon1 in modulating the intestinal microbiota and serum metabolites is poorly understood. The present study demonstrated that mice with genomic excision of Pon1 by a multiplexed guide RNA CRISPR/Cas9 approach exhibited disrupted gut microbiota, such as significantly depressed alpha-diversity and distinctly separated beta diversity, accompanied by varied profiles of circulating metabolites. Furthermore, genomic knock in of Pon1 exerted a distinct effect on the intestinal microbiome and serum metabolome, including dramatically enriched Aerococcus, linoleic acid and depleted Bacillus, indolelactic acid. Specifically, a strong correlation was established between bacterial alterations and metabolites in Pon1 knockout mice. In addition, we identified metabolites related to gut bacteria in response to Pon1 knock in. Thus, the deletion of Pon1 affects the gut microbiome and functionally modifies serum metabolism, which can lead to dysbiosis, metabolic dysfunction, and infection risk. Together, these findings put forth a role for Pon1 in microbial alterations that contribute to metabolism variations. The function of Pon1 in diseases might at least partially depend on the microbiome.

Associations of Dietary Cholesterol Consumption With Incident Diabetes and Cardiovascular Disease: The Role of Genetic Variability in Cholesterol Absorption and Disease Predisposition.

OBJECTIVE: Whether genetic susceptibility to disease and dietary cholesterol (DC) absorption contribute to inconsistent associations of DC consumption with diabetes and cardiovascular disease (CVD) remains unclear. RESEARCH DESIGN AND METHODS: DC consumption was assessed by repeated 24-h dietary recalls in the UK Biobank. A polygenetic risk score (PRS) for DC absorption was constructed using genetic variants in the Niemann-Pick C1-Like 1 and ATP Binding Cassettes G5 and G8 genes. PRSs for diabetes, coronary artery disease, and stroke were also created. The associations of DC consumption with incident diabetes (n = 96,826) and CVD (n = 94,536) in the overall sample and by PRS subgroups were evaluated using adjusted Cox models. RESULTS: Each additional 300 mg/day of DC consumption was associated with incident diabetes (hazard ratio [HR], 1.17 [95% CI, 1.07-1.27]) and CVD (HR, 1.09 [95% CI, 1.03-1.17]), but further adjusting for BMI nullified these associations (HR for diabetes, 0.99 [95% CI, 0.90-1.09]; HR for CVD, 1.04 [95% CI, 0.98-1.12]). Genetic susceptibility to the diseases did not modify these associations (P for interaction ≥0.06). The DC-CVD association appeared to be stronger in people with greater genetic susceptibility to cholesterol absorption assessed by the non-high-density lipoprotein cholesterol-related PRS (P for interaction = 0.04), but the stratum-level association estimates were not statistically significant. CONCLUSIONS: DC consumption was not associated with incident diabetes and CVD, after adjusting for BMI, in the overall sample and in subgroups stratified by genetic predisposition to cholesterol absorption and the diseases. Nevertheless, whether genetic predisposition to cholesterol absorption modifies the DC-CVD association requires further investigation.

ROS-dependent S-palmitoylation activates cleaved and intact gasdermin D.

Gasdermin D (GSDMD) is the common effector for cytokine secretion and pyroptosis downstream of inflammasome activation and was previously shown to form large transmembrane pores upon cleavage by inflammatory caspases to generate the GSDMD N-terminal domain (GSDMD-NT)1-10. Here we report that GSDMD Cys191 is S-palmitoylated and palmitoylation is required for pore formation. S-palmitoylation, which does not affect GSDMD cleavage, is augmented by mitochondria-generated reactive oxygen species (ROS). Surprisingly, cleavage-deficient D275A GSDMD is also palmitoylated after inflammasome stimulation or treatment with ROS activators, and causes pyroptosis, although less efficiently than palmitoylated GSDMD-NT. Palmitoylated, but not unpalmitoylated, full-length GSDMD induces liposome leakage, and forms a pore similar in structure to GSDMD-NT pores shown by cryogenic electron microscopy. zDHHC5 and zDHHC9 are the major palmitoyltransferases that mediate GSDMD palmitoylation, and their expression is upregulated by inflammasome activation and ROS. The other human gasdermins are also palmitoylated in their N-termini. These data challenge the concept that cleavage is the only trigger for GSDMD activation. They suggest that reversible palmitoylation is a checkpoint for pore formation by both GSDMD-NT and intact GSDMD that serves as a general switch for the activation of this pore-forming family.

Sustainable treatment of aquaculture water employing fungi-microalgae consortium: Nutrients removal enhancement, bacterial communities optimization, emerging contaminants elimination, and mechanism analysis.

Fungi-microalgae consortium (FMC) has emerged as a promising system for advanced wastewater treatment due to its high biomass yield and environmental sustainability. This study aimed to investigate the nutrients removal, bacterial community shift, emerging contaminants elimination, and treatment mechanism of a FMC composed of Cordyceps militaris and Navicula seminulum for aquaculture pond water treatment. The fungi and microalgae were cultured and employed either alone or in combination to evaluate the treatment performance. The results demonstrated that the FMC could improve water quality more significantly by reducing nutrient pollutants and optimizing the bacterial community structures. Furthermore, it exhibited stronger positive correlation between the enrichment of functional bacteria for water quality improvement and pollutants removal performance than the single-species treatments. Moreover, the FMC outperformed other groups in eliminating emerging contaminants such as heavy metals, antibiotics, and pathogenic Vibrios. Superiorly, the FMC also showed excellent symbiotic interactions and cooperative mechanisms for pollutants removal. The results collectively corroborated the feasibility and sustainability of using C. militaris and N. seminulum for treating aquaculture water, and the FMC would produce more mutualistic benefits and synergistic effects than single-species treatments.

Antifouling binary liquid-infused membranes for biological sample pretreatment.

Hydrophobic membranes infused with mixed solvents including a low polar solvent and a specific solvent can efficiently separate analytes from blood upon applying a voltage. In contrast, membranes infused with a specific solvent alone show significantly reduced separation efficiencies for blood samples. Infusion of a low polar solvent is of importance for achieving antifouling ability of membranes for biological sample pretreatment.

Mortality and disability risk among older adults unable to complete grip strength and physical performance tests: a population-based cohort study from China.

BACKGROUND: The link between low grip strength, diminished physical performance, and adverse health outcomes in older adults has been well-established. However, the impact of older adults who cannot complete these tests on disability and mortality rates remains unexplored without longitudinal study. METHODS: We collected data from the China Health and Retirement Longitudinal Study (CHARLS). Participants aged 60-101 were enrolled at baseline. We analyzed the prevalence of populations unable to complete handgrip strength (HGS), gait speed (GS), and five times chair stand test (FTCST). Completing risk models were used to estimate the risk of mortality and disability over seven years. RESULTS: A total of 3,768 participants were included in the analysis. The percentage of older adults unable to complete the GS and FTCST tests increased notably with age, from 2.68 to 8.90% and 2.60-20.42%, respectively. The proportion of older people unable to perform the HGS was relatively stable, ranging from 1.40 to 3.66%. Compared to older adults who can complete these tests, those who cannot perform FTCST face a significantly higher risk of mortality, with 49.1% higher risk [hazard ratio (HR) = 1.491, 95% CI = 1.156, 1.922; subdistribution hazard ratio (SHR) = 1.491, 95%CI = 1.135,1.958)]. Participants who were unable to complete the GS test had a higher risk of developing ADL disability, regardless of whether they were compared to the lowest-performing group (HR = 1.411, 95%CI = 1.037,1.920; SHR = 1.356, 95%CI = 1.030,1.785) or those who can complete the GS (HR = 1.727, 95%CI = 1.302,2.292; SHR = 1.541, 95%CI = 1.196,1.986). No statistically significant difference in the risk of developing ADL disability among older adults who were unable to complete the HGS test compared with either the poorest performing group (HR = 0.982, 95% CI = 0.578, 1.666; SHR = 1.025, 95% CI = 0.639, 1.642) or those who were able to complete the HGS test (HR = 1.008, 95% CI = 0.601, 1.688; SHR = 0.981, 95% CI = 0.619, 1.553). The risk of all-cause mortality was not significantly different for older adults who were unable to complete the HGS test compared to those with the worst performance (HR = 1.196, 95%CI = 0.709-2.020; SHR = 1.196, 95%CI = 0.674, 2.124) or those who were able to complete the test (HR = 1.462, 95%CI = 0.872-2.450; SHR = 1.462, 95%CI = 0.821,2.605). CONCLUSION: The risks of adverse events faced by older adults unable to complete the tests vary, indicating the necessity for future research to conduct separate analyses on this high-risk population.

Heterometallic MIL-125(Ti-Al) frameworks for electrochemical determination of ascorbic acid, dopamine and uric acid.

The detection of ascorbic acid (AA), dopamine (DA), and uric acid (UA) is not only of great significance in the areas of biomedicine and neurochemistry but also helpful in disease diagnosis and pathology research. Due to their diverse structures, designability, and large specific surface areas, metal-organic frameworks (MOFs) have recently caught considerable attention in the electrochemical field. Herein, a family of heterometallic MOFs with amino modification, MIL-125(Ti-Al)-xNH2 (x = 0%, 25%, 50%, 75%, and 100%), were synthesized and employed as electrochemical sensors for the detection of AA, DA, and UA. Among them, MIL-125(Ti-Al)-75%NH2 exhibited the most promising electrochemical behavior with 40% doping of carbon black in 0.1 M PBS (pH = 7.10), which displayed individual detection performance with wide linear detection ranges (1.0-6.5 mM for AA, 5-100 µM for DA and 5-120 µM for UA) and low limits of detection (0.215 mM for AA, 0.086 µM for DA, and 0.876 µM for UA, S/N = 3). Furthermore, the as-prepared MIL-125(Ti-Al)-75%NH2/GCE provided a promising platform for future application in real sample analysis, owing to its excellent anti-interference performance and good stability.

Unconventional Superconducting Diode Effects via Antisymmetry and Antisymmetry Breaking.

Symmetry breaking plays a pivotal role in unlocking intriguing properties and functionalities in material systems. For example, the breaking of spatial and temporal symmetries leads to a fascinating phenomenon: the superconducting diode effect. However, generating and precisely controlling the superconducting diode effect pose significant challenges. Here, we take a novel route with the deliberate manipulation of magnetic charge potentials to realize unconventional superconducting flux-quantum diode effects. We achieve this through suitably tailored nanoengineered arrays of nanobar magnets on top of a superconducting thin film. We demonstrate the vital roles of inversion antisymmetry and its breaking in evoking unconventional superconducting effects, namely a magnetically symmetric diode effect and an odd-parity magnetotransport effect. These effects are nonvolatilely controllable through in situ magnetization switching of the nanobar magnets. Our findings promote the use of antisymmetry (breaking) for initiating unconventional superconducting properties, paving the way for exciting prospects and innovative functionalities in superconducting electronics.

Bioinformatics and LC-QTOF-MS based discovery of pharmacodynamic and Q-markers of Pitongshu against functional dyspepsia.

ETHNOPHARMACOLOGICAL RELEVANCE: Pitongshu (PTS) is a clinically effective empirical formula for the treatment of FD. The efficacy and safety of PTS have been demonstrated in randomized, controlled, double-blind trials, but there is a lack of understanding of the systematic evaluation of the efficacy of PTS and its material basis. OBJECTIVE: To investigate the efficacy of PTS in Functional dyspepsia (FD) mice and possible Q-markers. METHOD: In this study, we used "irregular feeding + chronic unpredictable chronic stimulation" to establish a mice model of FD with hepatogastric disharmony. The efficacy of PTS was assessed from hair condition, behavioral, pain, gastrointestinal function, and serum 5-HT, GAS, MTL levels in mice by instillation of different doses of PTS. In addition, the composition of drugs in blood was analyzed by LC-QTOF-MS and potential Q-markers were selected by combining network pharmacology, molecular docking and actual content. RESULT: Our study showed that different doses of PTS increased pain threshold and writhing latency, decreased the number of writhings, increased gastric emptying rate and small intestinal propulsion rate, decreased total acidity of gastric contents and gastric acid secretion, and increased serum levels of 5-HT, GAS, and MTL in mice to different degrees. Enrichment analysis showed that PTS may be anti-FD through multiple pathways such as Serotonergic synapse, thyroid hormone signaling pathway, cholinergic synapse, and dopaminergic synapse. In addition, potential active ingredient substances were explored by LC-QTOF-MS combined with bioinformatics. Combined with the actual contentselected six constituents, hesperidin, neohesperidin, naringin, paeoniflorin, magnolol and honokiol, possible as Q-markers. CONCLUSION: PTS may exert its anti-FD effects through multi-component, multi-target and multi-pathway". Constituents, hesperidin, neohesperidin, naringin, paeoniflorin, magnolol and honokiol may be the Q-markers of its anti-FD effects.

First-Line Anlotinib Treatment for Soft Tissue Sarcoma in Chemotherapy-Ineligible Patients: An Open-label, Single-arm, Phase 2 Clinical Trial.

PURPOSE: Standard treatment for patients with unresectable locally advanced or metastatic soft-tissue sarcoma (LA/M STS) is chemotherapy based on anthracyclines, but patient tolerance of chemotherapy is limited. The present trial (NCT03792542) investigated the use of anlotinib as first-line treatment for patients with advanced STS, in particular liposarcoma (LPS). PATIENTS AND METHODS: Eligible patients were previously untreated, pathologically confirmed, unresectable LA/M STS cases. Anlotinib was given orally at a dose of 12 mg once daily from day 1 to day 14 every 3 weeks until disease progression or intolerable adverse events (AEs) occurred. The primary endpoint was progression-free survival (PFS) and the secondary endpoints overall survival (OS), the objective response rate and the disease control rate (DCR). The safety profile was also evaluated. RESULTS: Forty patients were enrolled from April 2019 to Jun 2022 and are included in the intention-to-treat analysis. The median PFS was 6.83 months [95% confidence interval (CI): 4.17-8.71] and the median OS 27.40 months (95% CI: 16.43-not evaluable); 1 patient reached partial response and 26 attained stable disease, with a DCR of 67.5% (27/40). Median PFS and OS times for LPS patients were 8.71 and 16.23 months, respectively. Ten (25.0%) patients had treatment-related AEs ≥ grade 3, with in particular a higher incidence of hypertension (15.0%) and proteinuria (7.5%). CONCLUSIONS: The findings suggest a potential benefit in employing front-line anlotinib to treat patients with STS, who are not eligible for cytotoxic chemotherapy. Of note, the clinical outcomes for the LPS subgroup of patients were encouraging.

Effectiveness of a narrative nursing intervention on reproductive concerns in women of childbearing age undergoing cervical cancer surgery: A randomized controlled trial.

OBJECTIVE: This study aims to explore the intervention effects of narrative nursing on the reproductive concerns of cervical cancer patients of childbearing age undergoing surgical treatment. METHODS: Patients undergoing cervical cancer surgery with moderate to severe levels of reproductive concerns, treated between January and December 2023 at a tertiary Grade-A oncology hospital in China, were selected as the research subjects. Patients were randomized into an intervention group and a control group, each consisting of 33 patients. The control group received standard nursing care, while the intervention group received a narrative nursing intervention in addition to standard care. The changes in the levels of reproductive concerns, post-traumatic growth, and quality of life scores before and after the intervention were compared between the two groups. RESULTS: After the intervention, the reproductive concerns scores of the cervical cancer patients in the intervention group (32.53 ± 4.77) were significantly lower than those in the control group (59.29 ± 3.24), with a statistically significant difference (t = 26.143, p < 0.001). The post-traumatic growth scores in the intervention group (86.78 ± 3.52) were significantly higher than those in the control group (68.06 ± 6.24), with a statistically significant difference (t = -14.595, p < 0.001). The quality of life scores in the intervention group (149.00 [IQR = 8.75]) were significantly higher than those in the control group (129.00 [IQR = 13.00]), with a statistically significant difference (z = -5.799, p < 0.001). CONCLUSION: Narrative nursing can effectively alleviate reproductive concerns in cervical cancer patients undergoing surgical treatment, promote positive psychological changes post-trauma, and improve patients' quality of life.

Venetoclax plus a hypomethylating agent versus cytarabine, aclarubicin, and granulocyte colony-stimulating factor chemotherapy as a first-line therapy for newly diagnosed acute myeloid leukemia: A propensity score-matched analysis.

BACKGROUND: Both venetoclax plus a hypomethylating agent (VEN/HMA) and cytarabine, aclarubicin, and granulocyte colony-stimulating factor (CAG) are low-intensity regimens for older patients with acute myeloid leukemia (AML) that show good efficacy and safety. It is unknown how VEN/HMA compares with the CAG regimen for the treatment of newly diagnosed AML. METHODS: The outcomes of patients with newly diagnosed AML treated with VEN/HMA were compared with those of patients treated with a CAG-based regimen. Propensity score matching between these two cohorts at a 1:1 ratio was performed according to age at diagnosis, sex, Eastern Cooperative Oncology Group performance status, state of fitness, and European LeukemiaNet (ELN) 2022 risk stratification to minimize bias. RESULTS: A total of 84 of 96 patients in the VEN/HMA cohort were matched with 84 of 147 patients in the CAG cohort. VEN/HMA resulted in a better response than the CAG-based regimens, as indicated by a higher composite complete remission (CRc) rate (82.1% vs. 60.7%; p = .002) and minimal residual disease negativity rate (88.2% vs. 68.2%; p = .009). In patients with an ELN adverse risk, VEN/HMA was associated with a higher CRc rate compared to CAG (80.5% vs. 58.3%; p = .006). VEN/HMA was associated with longer event-free survival (EFS) (median EFS, not reached vs. 4.5 months; p = .0004), whereas overall survival (OS) was comparable between the two cohorts (median OS, not reached vs. 18 months; p = .078). CONCLUSIONS: The VEN/HMA regimen may result in a better response than CAG-based treatment in older patients with newly diagnosed AML.

Dendrobium officinale flowers' topical extracts improve skin oxidative stress and aging.

BACKGROUND: Dendrobium officinale flowers (DOF) have the effects of antiaging and nourishing yin, but it lacks pharmacological research on skin aging. OBJECTIVE: Confirming the role of DOF in delaying skin aging based on the "in vitro animal-human" model. METHODS: In this experiment, three kinds of free radical scavenging experiments in vitro, D-galactose-induced aging mouse model, and human antiaging efficacy test were used to test whether DOF can improve skin aging through anti-oxidation. RESULTS: In vitro experiment shows that DOF has certain scavenging effect on 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical, hydroxyl free radical, and superoxide free radical, and its IC50 is 0.2090 µg/mL, 15.020, and 1.217 mg/mL respectively. DOF can enhance the activities of T-AOC, SOD, CAT, and GSH Px in the serum of aging mice, increase the content of GSH, and reduce the content of MDA when administered with DOF of 1.0, 2.0, and 4.0 g/kg for 6 weeks. In addition, it can enhance the activity of SOD in the skin of aging mice, increase the content of Hyp, and decrease the content of MDA, activated Keap1/Nrf2 pathway in the skin of aging mice. Applying DOF with a concentration of 0.2 g/mL on the face for 8 weeks can significantly improve the skin water score and elasticity value, reduce facial wrinkles, pores, acne, and UV spots, and improve the facial brown spots and roughness. CONCLUSION: DOF can significantly improve skin aging caused by oxidative stress, and its mechanism may be related to scavenging free radicals in the body and improving skin quality.

Postpartum quality of life and mental health in women with heart disease: Integrated clinical communication and treatment.

BACKGROUND: Postpartum quality of life (QoL) in women with heart disease has been neglected. AIM: To improve clinical communication and treatment, we integrated medical data and subjective characteristics to study postpartum QoL concerns. METHODS: The study assessed QoL 6 wk after birth using the 12-Item Short-Form Health Survey. The Edinburgh Postnatal Depression Scale, Cardiac Anxiety Questionnaire, European Heart Failure Self-Care Behavior Scale, and a self-designed questionnaire based on earlier research were also used to assess patient characteristics. Patient data were collected. Prediction models were created using multiple linear regression. RESULTS: This retrospective study examined postpartum QoL in 105 cardiac patients. Postpartum QoL scores were lower (90.69 ± 13.82) than those of women without heart disease, with physical component scores (41.09 ± 9.91) lower than mental component scores (49.60 ± 14.87). Postpartum depression (33.3%), moderate anxiety (37.14%), pregnancy concerns (57.14%), offspring heart problems (57.14%), and life expectancy worries (48.6%) were all prevalent. No previous cardiac surgery, multiparity, higher sadness and cardiac anxiety, and fear of unfavorable pregnancy outcomes were strongly related to lower QoL (R2 = 0.525). CONCLUSION: Postpartum QoL is linked to physical and mental health in women with heart disease. Our study emphasizes the need for healthcare workers to recognize the unique characteristics of these women while developing and implementing comprehensive management approaches during their maternity care.

High Thermal Performance Ultraviolet (368 nm) AlGaN-Based Flip-Chip LEDs with an Optimized Structure.

In this study, we have fabricated a 368 nm LED with an epitaxial Indium Tin Oxide (ITO) contact layer. We analyze the thermal performance of the flip-chip LED with a symmetric electrode and metal reflective layer, applying ANSYS to build a coupled electro-thermal finite element model (FEM) of the temperature distribution in the multiple quantum wells (MQWs). We compare our system with the traditional Au-bump flip-chip LED and a flip-chip LED with a Distributed Bragg Reflector (DBR) layer. The simulation results have shown that the flip-chip LED with a metal reflective layer and symmetric electrode exhibits better heat dissipation performance, particularly at high input power. The influence of the insulating layer on the LED chip junction temperature is also examined. The simulation data establish an effect due to the thermal conductivity of the insulating layer in terms of heat dissipation, but this effect is negligible at an insulation layer thickness ≤1 µm.

Prognostic model development and molecular subtypes identification in bladder urothelial cancer by oxidative stress signatures.

BACKGROUND: Mounting studies indicate that oxidative stress (OS) significantly contributes to tumor progression. Our study focused on bladder urothelial cancer (BLCA), an escalating malignancy worldwide that is growing rapidly. Our objective was to verify the predictive precision of genes associated with overall survival (OS) by constructing a model that forecasts outcomes for bladder cancer and evaluates the prognostic importance of these genetic markers. METHODS: Transcriptomic data were obtained from TCGA-BLCA and GSE31684, which are components of the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), respectively. To delineate distinct molecular subtypes, we employed the non-negative matrix factorization (NMF)method. The significance of OS-associated genes in predicting outcomes was assessed using lasso regression, multivariate Cox analysis, and univariate Cox regression analysis. For external validation, we employed the GSE31684 dataset. CIBERSORT was utilized to examine the tumor immune microenvironment (TIME). A nomogram was created and verified using calibration and receiver operating characteristic (ROC) curves, which are based on risk signatures. We examined variations in clinical characteristics and tumor mutational burden (TMB) among groups classified as high-risk and low-risk. To evaluate the potential of immunotherapy, the immune phenomenon score (IPS) was computed based on the risk score. In the end, the pRRophetic algorithm was employed to forecast the IC50 values of chemotherapy medications. RESULTS: In our research, we examined the expression of 275 genes associated with OS in 19 healthy and 414 cancerous tissues of the bladder obtained from the TCGA database. As a result, a new risk signature was created that includes 4 genes associated with OS (RBPMS, CRYAB, P4HB, and PDGFRA). We found two separate groups, C1 and C2, that showed notable variations in immune cells and stromal score. According to the Kaplan-Meier analysis, patients classified as high-risk experienced a considerably reduced overall survival in comparison to those categorized as low-risk (P<0.001). The predictive capability of the model was indicated by the area under the curve (AUC) of the receiver operating characteristic (ROC) curve surpassing 0.6. Our model showed consistent distribution of samples from both the GEO database and TCGA data. Both the univariate and multivariate Cox regression analyses validated the importance of the risk score in relation to overall survival (P < 0.001). According to our research, patients with a lower risk profile may experience greater advantages from using a CTLA4 inhibitor, whereas patients with a higher risk profile demonstrated a higher level of responsiveness to Paclitaxel and Cisplatin. In addition, methotrexate exhibited a more positive outcome in patients with low risk compared to those with high risk. CONCLUSIONS: Our research introduces a novel model associated with OS gene signature in bladder cancer, which uncovers unique survival results. This model can assist in tailoring personalized treatment approaches and enhancing patient therapeutic effect in the management of bladder cancer.

Relationship between circulating metabolites and diabetic retinopathy: a two-sample Mendelian randomization analysis.

Diabetic retinopathy (DR) is the most frequent microvascular complication of diabetes mellitus, however, its underlying biological mechanisms remain poorly understood. We examined single nucleotide polymorphisms linked to 486 blood metabolites through extensive genome-wide association studies conducted on individuals of European ancestry. The FinnGen Biobank database served as a reference to define DR. Two-sample MR analysis was conducted to reveal the association between the levels of genetically predicted circulating metabolites and the susceptibility to DR. To validate the robustness of the obtained findings, sensitivity analyses with weighted median, weighted mode, and MR-Egger were conducted. 1-oleoylglycerophosphoethanolamine (odds ratio [OR] (OR per one standard deviation [SD] increase) = 0.414; 95% confidence interval [CI] 0.292-0.587; P = 7.613E-07, PFDR = 6.849E-06), pyroglutamine (OR per one SD increase = 0.414; 95% confidence interval [CI] 0.292-0.587; P = 8.31E-04, PFDR = 0.007), phenyllactate (PLA) (OR per one SD increase = 0.591; 95% confidence interval [CI] 0.418-0.836; P = 0.003, PFDR = 0.026), metoprolol acid metabolite (OR per one SD increase = 0.978; 95% confidence interval [CI] 0.962-0.993; P = 0.005, PFDR = 0.042), 10-undecenoate (OR per one SD increase = 0.788; 95% confidence interval [CI] 0.667-0.932; P = 0.005, PFDR = 0.049), erythritol (OR per one SD increase = 0.691; 95% confidence interval [CI] 0.513-0.932; P = 0.015, PFDR = 0.034), 1-stearoylglycerophosphoethanolamine (OR per one SD increase = 0.636; 95% confidence interval [CI] 0.431-0.937; P = 0.022, PFDR = 0.099), 1-arachidonoylglycerophosphoethanolamine (OR per one SD increase = 0.636; 95% confidence interval [CI] 0.431-0.937; P = 0.030, PFDR = 0.099) showed a significant causal relationship with DR and could have protective effects. stachydrine (OR per one SD increase = 1.146; 95% confidence interval [CI] 1.066-1.233; P = 2.270E-04, PFDR = 0.002), butyrylcarnitine (OR per one SD increase = 1.117; 95% confidence interval [CI] 1.023-1.219; P = 0.014, PFDR = 0.062), 5-oxoproline (OR per one SD increase = 1.569; 95% confidence interval [CI] 1.056-2.335; P = 0.026, PFDR = 0.082), and kynurenine (OR = 1.623; 95% CI 1.042-2.526; P = 0.041, PFDR = 0.097) were significantly associated with an increased risk of DR. This study identified metabolites have the potential to be considered prospective compounds for investigating the underlying mechanisms of DR and for selecting appropriate drug targets.

The Interaction Mechanism of Picolinamide Fungicide Targeting on the Cytochrome bc1 Complex and Its Structural Modification.

Picolinamide fungicides, structurally related to UK-2A and antimycin-A, bind into the Qi-site in the bc1 complex. However, the detailed binding mode of picolinamide fungicides remains unknown. In the present study, antimycin-A and UK-2A were selected to study the binding mode of picolinamide inhibitors with four protonation states in the Qi-site by integrating molecular dynamics simulation, molecular docking, and molecular mechanics Generalized Born surface area (MM/GBSA) calculations. Subsequently, a series of new picolinamide derivatives were designed and synthesized to further understand the effects of substituents on the tail phenyl ring. The computational results indicated that the substituted aromatic rings in antimycin-A and UK-2A were the pharmacophore fragments and made the primary contribution when bound to a protein. Compound 9g-hydrolysis formed H-bonds with Hie201 and Ash228 and showed an IC50 value of 6.05 ± 0.24 µM against the porcine bc1 complex. Compound 9c, with a simpler chemical structure, showed higher control effects than florylpicoxamid against cucumber downy mildew and expanded the fungicidal spectrum of picolinamide fungicides. The structural and mechanistic insights obtained from the present study will provide a valuable clue for the future designing of new promising Qi-site inhibitors.

Resource-Efficient Direct Characterization of General Density Matrix.

Sequential weak measurements allow for the direct extraction of individual density-matrix elements, rather than relying on global reconstruction of the entire density matrix, which opens a new avenue for the characterization of quantum systems. Nevertheless, extending the sequential scheme to multiqudit quantum systems is challenging due to the requirement of multiple coupling processes for each qudit and the lack of appropriate precision evaluation. To address these issues, we propose a resource-efficient scheme (RES) that directly characterizes the density matrix of general multiqudit systems while optimizing measurements and establishing a feasible estimation analysis. In the RES, an efficient observable of the quantum system is constructed such that a single meter state coupled to each qudit is sufficient to extract the corresponding density-matrix element. An appropriate model based on the statistical distribution of errors is utilized to evaluate the precision and feasibility of the scheme. We have experimentally applied the RES to the direct characterization of general single-photon qutrit states and two-photon entangled states. The results show that the RES outperforms sequential schemes in terms of efficiency and precision in both weak- and strong-coupling scenarios. This Letter sheds new light on the practical characterization of large-scale quantum systems and the investigation of their nonclassical properties.