Otilonium Bromide Exhibits Potent Antifungal Effects by Blocking Ergosterol Plasma Membrane Localization and Triggering Cytotoxic Autophagy in Candida Albicans.

Candidiasis, which presents a substantial risk to human well-being, is frequently treated with azoles. However, drug-drug interactions caused by azoles inhibiting the human CYP3A4 enzyme, together with increasing resistance of Candida species to azoles, represent serious issues with this class of drug, making it imperative to develop innovative antifungal drugs to tackle this growing clinical challenge. A drug repurposing approach is used to examine a library of Food and Drug Administration (FDA)-approved drugs, ultimately identifying otilonium bromide (OTB) as an exceptionally encouraging antifungal agent. Mechanistically, OTB impairs vesicle-mediated trafficking by targeting Sec31, thereby impeding the plasma membrane (PM) localization of the ergosterol transporters, such as Sip3. Consequently, OTB obstructs the movement of ergosterol across membranes and triggers cytotoxic autophagy. It is noteworthy that C. albicans encounters challenges in developing resistance to OTB because it is not a substrate for drug transporters. This study opens a new door for antifungal therapy, wherein OTB disrupts ergosterol subcellular distribution and induces cytotoxic autophagy. Additionally, it circumvents the hepatotoxicity associated with azole-mediated liver enzyme inhibition and avoids export-mediated drug resistance in C. albicans.

Association between primary biliary cholangitis with diabetes and cardiovascular diseases: a bidirectional multivariable Mendelian randomization study.

BACKGROUND AND AIMS: Primary biliary cholangitis (PBC) is an autoimmune disease often accompanied by multisystem damage. This study aimed to explore the causal association between genetically predicted PBC and diabetes, as well as multiple cardiovascular diseases (CVDs). METHODS: Genome-wide association studies (GWAS) summary data of PBC in 24,510 individuals of European ancestry from the European Association for the Study of the Liver was used to identify genetically predicted PBC. We conducted 2-sample single-variable Mendelian randomization (SVMR) and multivariable Mendelian randomization (MVMR) to estimate the impacts of PBC on diabetes (N = 17,685 to 318,014) and 20 CVDs from the genetic consortium (N = 171,875 to 1,030,836). RESULTS: SVMR provided evidence that genetically predicted PBC is associated with an increased risk of type 1 diabetes (T1D), type 2 diabetes (T2D), myocardial infarction (MI), heart failure (HF), hypertension, atrial fibrillation (AF), stroke, ischemic stroke, and small-vessel ischemic stroke. Additionally, there was no evidence of a causal association between PBC and coronary atherosclerosis. In the MVMR analysis, PBC maintained independent effects on T1D, HF, MI, and small-vessel ischemic stroke in most models. CONCLUSION: Our findings revealed the causal effects of PBC on diabetes and 7 CVDs, and no causal relationship was detected between PBC and coronary atherosclerosis.

Oxygen Functional Groups Regulate Cobalt-Porphyrin Molecular Electrocatalyst for Acidic H2O2 Electrosynthesis at Industrial-Level Current.

Electrosynthesis of hydrogen peroxide (H2O2) based on proton exchange membrane (PEM) reactor represents a promising approach to industrial-level H2O2 production, while it is hampered by the lack of high-efficiency electrocatalysts in acidic medium. Herein, we present a strategy for the specific oxygen functional group (OFG) regulation to promote the H2O2 selectivity up to 92% in acid on cobalt-porphyrin molecular assembled with reduced graphene oxide. In-situ X-ray adsorption spectroscopy, in-situ Raman spectroscopy and Kelvin probe force microscopy combined with theoretical calculation unravel that different OFGs exert distinctive regulation effects on the electronic structure of Co center through either remote (carboxyl and epoxy) or vicinal (hydroxyl) interaction manners, thus leading to the opposite influences on the promotion in 2e- ORR selectivity. As a consequence, the PEM electrolyzer integrated with the optimized catalyst can continuously and stably produce the high-concentration of ca. 7 wt% pure H2O2 aqueous solution at 400 mA cm-2 over 200 h with a cell voltage as low as ca. 2.1 V, suggesting the application potential in industrial-scale H2O2 electrosynthesis.

HLA-mismatched allogeneic adoptive immune therapy in patients with severely immunosuppressed AIDS: a multicenter, open-label, controlled, phase 2a study.

Recurrent opportunistic infections (OIs) in patients with severely immunosuppressed AIDS remain an unresolved medical challenge despite advancements in antiretroviral therapy (ART). To address this gap, we developed an HLA-mismatched allogeneic adoptive immune therapy (AAIT) specifically targeting this patient population. The safety and efficacy of this novel therapeutic approach were preliminarily confirmed in our phase 1 trial. Subsequently, a multicenter, open-label, controlled, phase 2a trial was conducted to evaluate the efficacy of AAIT in combination with ART compared with the conventional ART-only regimen. No difference in the incidence of adverse events (AEs) was observed between the two groups at the 96-week follow-up. AAIT treatment improved CD4+ T cell recovery at weeks 72 (P = 0.048) and 96 (P = 0.024) compared to the Control Group. Additionally, stratified analysis of patients in the AAIT Group showed that donor/recipient sex mismatch was significantly associated with the likelihood of patients achieving an immunological response (OR = 8.667; 95% CI, 2.010-37.377; P = 0.004). These findings suggest that AAIT serves as a promising adjunct therapy for improving the outcomes of patients with severely immunosuppressed AIDS. Further studies are needed to elucidate the immunological mechanisms underlying AAIT and identify the subpopulations that respond optimally to this therapeutic approach. This trial is registered at www.clinicaltrials.gov (NCT04098770).Trial registration: ClinicalTrials.gov identifier: NCT04098770.Trial registration: ClinicalTrials.gov identifier: NCT02651376.

The Dilemma of Balancing Anti-Tumor Necrosis Factor-Alpha (Anti-TNF-α) Biologics for Psoriatic Arthritis Control With the Risk of Severe Systemic Infection.

The treatment landscape for psoriatic arthritis (PsA) has evolved significantly with the introduction of biologic therapies, such as adalimumab, which effectively inhibits tumor necrosis factor-alpha (TNF-α) activity. However, despite their efficacy in controlling inflammation, biologic therapies are associated with heightened risks of infectious complications and malignancies. We present a case of a 66-year-old female with PsA treated with adalimumab who presented with recurrent systemic bacterial infections. Despite attempts to adjust dosing intervals to minimize infection risks, the patient experienced severe complications, including urosepsis, endocarditis, and liver abscesses. The dilemma arises in balancing PsA control with anti-TNFα therapy while minimizing infection risks. Current evidence supporting prophylactic antibiotics in such cases is limited, and determining the next steps for treatment involves challenging decisions such as withholding TNF inhibitors or switching to alternative immunomodulators. This case underscores the need for further research into prophylactic treatment and monitoring protocols to manage recurrent infections during anti-TNF-α therapy effectively.

Universal Formation of Single Atoms from Molten Salt for Facilitating Selective CO2 Reduction.

Clarifying the formation mechanism of single-atom sites guides the design of emerging single-atom catalysts (SACs) and facilitates the identification of the active sites at atomic scale. Herein, a molten-salt atomization strategy is developed for synthesizing zinc (Zn) SACs with temperature universality from 400 to 1000/1100 °C and an evolved coordination from Zn-N2Cl2 to Zn-N4. The electrochemical tests and in situ attenuated total reflectance-surface-enhanced infrared absorption spectroscopy confirm that the Zn-N4 atomic sites are active for electrochemical carbon dioxide (CO2) conversion to carbon monoxide (CO). In a strongly acidic medium (0.2 m K2SO4, pH = 1), the Zn SAC formed at 1000 °C (Zn1NC) containing Zn-N4 sites enables highly selective CO2 electroreduction to CO, with nearly 100% selectivity toward CO product in a wide current density range of 100-600 mA cm-2. During a 50 h continuous electrolysis at the industrial current density of 200 mA cm-2, Zn1NC achieves Faradaic efficiencies greater than 95% for CO product. The work presents a temperature-universal formation of single-atom sites, which provides a novel platform for unraveling the active sites in Zn SACs for CO2 electroreduction and extends the synthesis of SACs with controllable coordination sites.

How breaking a sweat affects mood: The mediating role of self-efficacy between physical exercise and emotion regulation ability.

OBJECTIVE: This study investigates the association between physical exercise and emotion regulation abilities among college students, introducing self-efficacy as a mediating variable to analyze the pathway mechanism through which physical exercise affects emotion regulation abilities. METHODS: A cross-sectional study design was employed, utilizing a stratified random sampling method to survey three colleges in Jiangsu Province, China. Physical Activity Rating Scale, Physical Activity Self-efficacy Scale, and Emotional Intelligence Scale were used to measure the college student population. Regression analysis and mediation tests assessed whether self-efficacy mediates the relationship between physical exercise and college students' emotion regulation abilities. A total of 5,430 valid questionnaires were collected. RESULTS: The distribution of college students' physical activities was 77.0% for low, 13.1% for medium, and 9.3% for high levels. Physical activities were significantly and positively correlated with self-efficacy and emotional management abilities (r = 0.298,0.105;P<0.01), and self-efficacy was significantly and positively correlated with emotional management abilities (r = 0.322, P<0.01). Situational motivation and subjective support under self-efficacy were 0.08 and 0.255, respectively, and the adjusted R2 was 0.107. Self-efficacy played a fully mediating role between physical activities and emotional management abilities, with a total effect value of 0.032. The values of the direct and indirect effects were 0.003 and 0.029, accounting for 8.95% and 90.74% of the total effect, respectively. CONCLUSION: The physical exercise behavior of college students is primarily characterized by low intensity. Physical exercise among college students can positively predict their ability to regulate emotions. Self-efficacy fully mediates the relationship between physical exercise and emotion regulation ability among college students. College students can indirectly influence their ability to regulate emotions through physical exercise and self-efficacy.

Identifying therapeutic targets for breast cancer: insights from systematic Mendelian randomization analysis.

Background: Breast cancer (BC) exhibits a high incidence rate, imposing a substantial burden on healthcare systems. Novel drug targets are urgently needed for BC. Mendelian randomization (MR) has gained widespread application for identifying fresh therapeutic targets. Our endeavor was to pinpoint circulatory proteins causally linked to BC risk and proffer potential treatment targets for BC. Methods: Through amalgamating protein quantitative trait loci from 2,004 circulating proteins and comprehensive genome-wide association study data from the Breast Cancer Association Consortium, we conducted MR analyses. Employing Steiger filtering, bidirectional MR, Bayesian colocalization, phenotype scanning, and replication analyses, we further solidified MR study outcomes. Additionally, protein-protein interaction (PPI) network was harnessed to unveil latent associations between proteins and prevailing breast cancer medications. The phenome-wide MR (Phe-MR) was employed to assess potential side effects and indications for the druggable proteins of BC. Finally, we further affirmed the drugability of potential drug targets through mRNA expression analysis and molecular docking. Results: Through comprehensive analysis, we identified five potential drug targets, comprising four (TLR1, A4GALT, SNUPN, and CTSF) for BC and one (TLR1) for BC_estrogen receptor positive. None of these five potential drug targets displayed reverse causation. Bayesian colocalization suggested that these five latent drug targets shared variability with breast cancer. All drug targets were replicated within the deCODE cohort. TLR1 exhibited PPI with current breast cancer therapeutic targets. Furthermore, Phe-MR unveiled certain adverse effects solely for TLR1 and SNUPN. Conclusion: Our study uncovers five prospective drug targets for BC and its subtypes, warranting further clinical exploration.

Influence of physical exercise on negative emotions in college students: chain mediating role of sleep quality and self-rated health.

Background: Negative emotions in college students are a significant factor affecting mental health, with suicide behaviors caused by negative emotions showing an annual increasing trend. Existing studies suggest that physical exercise is essential to alleviate negative feelings, yet the intrinsic mechanisms by which it affects negative emotions have not been fully revealed. Objective: Negative emotions in college students represent a significant issue affecting mental health. This study investigates the relationship between physical exercise and negative emotions among college students, incorporating sleep quality and self-rated health (SRH) as mediators to analyze the pathway mechanism of how physical exercise affects students' negative emotions. Methods: A cross-sectional study design was utilized, employing online questionnaires for investigation. The scales included the Physical Activity Rating Scale-3 (PARS-3), the Depression Anxiety Stress Scales-21 (DASS-21), the Pittsburgh Sleep Quality Index (PSQI), and the 12-Item Short Form Health Survey (SF-12), resulting in the collection of 30,475 valid questionnaires, with a validity rate of 91%. Chain mediation tests and Bootstrap methods were applied for effect analysis. Results: The proportions of university students engaged in low, medium, and high levels of physical exercise were 77.6, 13.1, and 9.3%, respectively. The proportions of students experiencing "very severe" levels of stress, anxiety, and depression were 4.5, 10.9, and 3.6%, respectively. Physical exercise was significantly positively correlated with self-rated health (r = 0.194, p < 0.01), significantly negatively correlated with sleep quality (r = -0.035, p < 0.01), and significantly negatively correlated with stress, anxiety, and depression (r = -0.03, p < 0.01; r = -0.058, p < 0.01; r = -0.055, p < 0.01). Sleep quality was significantly negatively correlated with self-rated health (r = -0.242, p < 0.01). Mediation effect testing indicated that sleep quality and self-rated health partially mediated the relationship between physical exercise and negative emotions, with total effect, total direct effect, and total indirect effect values of -1.702, -0.426, and - 1.277, respectively. Conclusion: College students primarily engage in low-intensity physical activity. Sleep quality and self-rated health mediate the impact of physical exercise on students' negative emotions. A certain level of physical activity can directly affect students' emotional states and indirectly influence their negative emotions via sleep and self-rated health. Regular engagement in physical activities primarily positively impacts emotional states by enhancing mood stability and overall emotional resilience.

Geldanamycin confers fungicidal properties to azole by triggering the activation of succinate dehydrogenase.

AIMS: Azoles have been widely employed for the treatment of invasive fungal diseases; however, their efficacy is diminished as pathogenic fungi tolerate them due to their fungistatic properties. Geldanamycin (GdA) can render azoles fungicidal by inhibiting the ATPase and molecular chaperone activities of heat shock protein 90 (Hsp90). Nonetheless, the clinical applicability of GdA is restricted due to its cytotoxic ansamycin scaffold structure, its induction of cytoprotective heat shock responses, and the conservative nature of Hsp90. Hence, it is imperative to elucidate the mechanism of action of GdA to confer fungicidal properties to azoles and mitigate the toxic adverse effects associated with GdA. MATERIALS AND METHODS: Through various experimental methods, including the construction of gene-deleted Candida albicans mutants, in vitro drug sensitivity experiments, Western blot analysis, reactive oxygen species (ROS) assays, and succinate dehydrogenase activity assays, we identified Hsp90 client proteins associated with the tolerance of C. albicans to azoles. KEY FINDINGS: It was observed that GdA effectively hindered the entry of Hsp90 into mitochondria, resulting in the alleviation of inhibitory effect of Hsp90 on succinate dehydrogenase. Consequently, the activation of succinate dehydrogenase led to an increased production of ROS. within the mitochondria, thereby facilitating the antifungal effects of azoles against C. albicans. SIGNIFICANCE: This research presents a novel approach for conferring fungicidal properties to azoles, which involves specifically disrupting the interaction of between Hsp90 and succinate dehydrogenase rather than employing a non-specific inhibition of ATPase activity of Hsp90.

Revealing Lithium Nitrate-Mediated Solid-Electrolyte Interphase of Lithium Metal Anode via Cryogenic Transmission Electron Microscopy.

The cycle stability of lithium metal anode (LMA) largely depends on solid-electrolyte interphase (SEI). Electrolyte engineering is a common strategy to adjust SEI properties, yet understanding its impact is challenging due to limited knowledge on ultrafine SEI structures. Herein, using cryogenic transmission electron microscopy, we reveal the atomic-level SEI structure of LMA in ether-based electrolytes, focusing on the role of LiNO3 additives in SEI modulation at different temperature (25 and 50 °C). Poor cycle stability of LMA in the baseline electrolyte without LiNO3 additives stems from the Li2CO3-rich mosaic-type SEI. Increased LiNO3 content and elevated operating temperature enhance cyclic performance by forming bilayer or multilayer SEI structures via preferential LiNO3 decomposition, but may thicken the SEI, leading to reduced initial Coulombic efficiency and increased overpotential. The optimal SEI features a multilayer structure with Li2O-rich inner layer and closely packed grains in the outer layer, minimizing electrolyte decomposition or corrosion.

Landscape of gut mucosal immune cells showed gap of follicular or memory B cells into plasma cells in immunological non-responders.

BACKGROUND: The gut is an important site for human immunodeficiency virus (HIV) infection and immune responses. The role of gut mucosal immune cells in immune restoration in patients infected with HIV undergoing antiretroviral therapy remains unclear. METHODS: Ileocytes, including 54 475 immune cells, were obtained from colonoscopic biopsies of five HIV-negative controls, nine immunological responders (IRs), and three immunological non-responders (INRs) and were analyzed using single-cell RNA sequencing. Immunohistochemical assays were performed for validation. The 16S rRNA gene was amplified using PCR in faecal samples to analyze faecal microbiota. Flow cytometry was used to analyze CD4+ T-cell counts and the activation of T cells. RESULTS: This study presents a global transcriptomic profile of the gut mucosal immune cells in patients infected with HIV. Compared with the IRs, the INRs exhibited a lower proportion of gut plasma cells, especially the IGKC+IgA+ plasma cell subpopulation. IGKC+IgA+ plasma cells were negatively associated with enriched f. Prevotellaceae the INRs and negatively correlated with the overactivation of T cells, but they were positively correlated with CD4+ T-cell counts. The INRs exhibited a higher proportion of B cells than the IRs. Follicular and memory B cells were significantly higher in the INRs. Reduced potential was observed in the differentiation of follicular or memory B cells into gut plasma cells in INRs. In addition, the receptor-ligand pairs CD74_MIF and CD74_COPA of memory B/ follicular helper T cells were significantly reduced in the INRs, which may hinder the differentiation of memory and follicular B cells into plasma cells. CONCLUSIONS: Our study shows that plasma cells are dysregulated in INRs and provides an extensive resource for deciphering the immune pathogenesis of HIV in INRs. KEY POINTS: An investigation was carried out at the single-cell-level to analyze gut mucosal immune cells alterations in PLWH after ART. B cells were significantly increased and plasma cells were significantly decreased in the INRs compared to the IRs and NCs. There are gaps in the transition from gut follicular or memory B cellsinto plasma cells in INRs.

Universal Synthesis of Single-Atom Catalysts by Direct Thermal Decomposition of Molten Salts for Boosting Acidic Water Splitting.

Single-atom catalysts (SACs) are considered prominent materials in the field of catalysis due to their high metal atom utilization and selectivity. However, the wide-ranging applications of SACs remain a significant challenge due to their complex preparation processes. Here, a universal strategy is reported to prepare a series of noble metal single atoms on different non-noble metal oxides through a facile one-step thermal decomposition of molten salts. By using a mixture of non-noble metal nitrate and a small-amount noble metal chloride as the precursor, noble metal single atoms can be easily introduced into the non-noble metal oxide lattice owing to the cation exchange in the in situ formed molten salt, followed by the thermal decomposition of nitrate anions during the heating process. Analyses using aberration-corrected high-angle annular dark-field scanning transmission electron microscopy and extended X-ray absorption fine structure spectroscopy confirm the formation of the finely dispersed single atoms. Specially, the as-synthesized Ir single atoms (10.97 wt%) and Pt single atoms (4.60 wt%) on the Co3O4 support demonstrate outstanding electrocatalytic activities for oxygen evolution reaction and hydrogen evolution reaction, respectively.

The mediating effect of psychological resilience between social support and anxiety/depression in people living with HIV/AIDS-a study from China.

Objective To understand the relationship between psychological resilience in social support and anxiety/depression in people living with HIV/AIDS and to verify whether there is a mediating effect. Methods The questionnaire was administered to 161 people living with HIV/AIDS in a hospital. The questionnaire contained a general questionnaire, the Hospital Anxiety and Depression Scale (HADS), the Psychological Resilience Inventory (CD-RICS), and the Social Collaborative Support Scale (PSSS), and Pearson correlation analyses were used to explore the correlation between the factors and anxiety/depression, stratified linear regression analyses were used to validate the mediation model, and the bootstrap method was used to test for mediating effects. Results Anxiety was negatively correlated with psychological resilience and social support (r=-0.232, P < 0.01; r=-0.293, P < 0.01); depression was negatively correlated with psychological resilience and social support (r=-0.382, P < 0.01; r=-0.482, P < 0.01); there was a mediation effect model of social support between psychological resilience and anxiety/depression; psychological resilience played a fully mediating role in social support and anxiety/depression, with an effect contribution of 68.42%/59.34% and a 95% CI(-0.256~-0.036)/(-0.341 to~-0.106). Conclusion Psychological resilience plays a complete mediating effect between social support and anxiety/depression. It is recommended that more channels of social support be provided to patients with HIV/AIDS, thereby enhancing their psychological resilience and reducing anxiety/depression levels.

Childhood abuse as a mediator of the relationship between early family socio-economic status and geriatric depression: A population-based study in China.

Previous studies have suggested that childhood socioeconomic status (SES) is linked to geriatric depressive symptoms in many developed countries. However, the potential pathways of the relationship between childhood SES and geriatric depressive symptoms need to be further explored. This study aimed to assess the mediating effect of being abused during childhood on the association between childhood SES and geriatric depressive symptoms, using evidence from a longitudinal study in China. The study cohort included 8137 individuals. Childhood abuse was defined as experiences related to parental violence, sibling abuse, school violence, community violence, and parental quarrel. Results indicated poor childhood SES was associated significantly with geriatric depressive symptoms. The indirect effect of poor childhood SES to high geriatric depressive risk through community violence, sibling abuse, school violence, and parental quarrel were 0.02, 0.01, 0.02, and 0.01, respectively. Our findings shed new light on the literature regarding the impact of childhood SES on elderly depressive symptoms. Furthermore, childhood SES demonstrated a significant correlation with geriatric depressive symptoms through bullying behaviors. The findings highlight the need to promote both childhood social welfare and psychological well-being within the elderly population.

Differing Electrolyte Implication on Anion and Cation Intercalation into Graphite.

Emerging dual-graphite batteries (DGBs) capture extensive interest for their high output voltage and exceptional cost-effectiveness. Yet, developing electrolytes compatible with both the cathode and anode stands to be a tremendous challenge, and how electrolyte impacts anion and cation intercalation into graphite remains inexplicit or controversial. Herein, we have evaluated the performance of graphite anode and cathode in typical ethyl methyl carbonate (EMC) based electrolytes and unveiled their electrode-electrolyte interphase using Cryogenic transmission electron microscopy (Cryo-TEM). The addition of fluoroethylene carbonate (FEC) brings substantial improvement in cycle stability and Coulombic efficiency for both the graphite cathode and anode, but its implication on cation and anion intercalation differs. FEC is involved in anodic side reactions to produce a LiF-embedded solid-electrolyte interphase layer. It is much thinner and more uniform than that formed in the electrolyte without FEC, which is correlated with less graphite exfoliation and enhanced stability. As for the graphite cathode, both basal and edge planes are largely bare, and only few scattered byproducts are found. In addition, we also reveal layer bending and local lattice disordering of the graphite cathode based on multiple Cryo-TEM images, which are speculated to be caused by high lattice strain induced by anion intercalation and local oxidation under high voltage. The absence of cathode-electrolyte interphase (CEI) layers overturns the paradigm of attributing cathodic performance to CEI features and is regarded as a fundamental reason for severe self-discharge of graphite cathode. FEC helps to alleviate graphite exfoliation issues and enhance cycle stability, and we ascribe it to weakened solvation, which means reduced probability of solvent co-intercalation during charging, rather than compositional changes of cathodic byproducts.

Clinical features, microbial spectrum, and antibiotic susceptibility patterns of spontaneous bacterial peritonitis in cirrhotic patients.

BACKGROUND AND AIMS: The microbial spectrum and antimicrobial resistance patterns change over time and vary across regions in patients with spontaneous bacterial peritonitis (SBP). There is an urgent need to clarify the factors associated with in-hospital mortality in these patients. METHODS: In this study, 377 patients with SBP and 794 patients with bacterascites were analyzed for the microbial spectrum, antimicrobial resistance profiles, and laboratory findings. RESULTS: The most common pathogens were Escherichia coli (96, 25.5%), Staphylococcus epidermidis (55, 14.6%), and Enterococcus faecium (42, 11.1%). Multidrug-resistant (MDR) bacteria comprised 49.7% of gram-positive bacteria (GPB) and 48.8% of gram-negative bacteria (GNB). The most sensitive antibiotics were amikacin (91.5%), meropenem (89.8%) and piperacillin/tazobactam (87.6%). Extensively drug-resistant (XDR) (OR=51.457, p < 0.001), neutrophil count (OR=1.088, p < 0.001), and the model for end-stage liver disease (MELD) score (OR=1.124, p < 0.001) were independent predictive factors of in-hospital mortality in patients with SBP. CONCLUSION: MDR represented nearly half of the bacteria isolated from patients with SBP, of which the high prevalence of extended-spectrum ß-lactamase-producing and Carbapenem-resistant bacteria is concerning. The presence of XDR, higher MELD score, and neutrophil count were independent predictive factors associated with higher in-hospital mortality in patients with SBP, indicating that intensive care should be provided to these patients.

The interaction effects of social support and four types of bullying on sleep quality in Chinese adolescents.

OBJECTIVES: The aims of this study were to examine the association of verbal, social, physical, and cyber bullying victimizations with sleep quality while taking social support as a moderator and to further examine gender and grade differences in the moderating effects of social support on bullying-associated sleep quality among Chinese adolescents. METHODS: An online cross-sectional survey was conducted in a province of northwestern China. A total of 20,320 students were included in our analyses. Multivariable linear regression analyses were conducted to examine the association between bullying victimization and sleep quality as well as the moderating effects of social support on these relationships. RESULTS: After adjusting for confounding variables, four types of bullying victimization were significantly associated with sleep quality. Social support only moderated the relationship of verbal, physical, and social bullying with sleep quality. Moreover, these positive moderating effects were found only for girls and, in terms of grade difference, only for primary students. Some reversed moderating effects of social support were also observed in the relationship of cyber, physical bullying with sleep quality. LIMITATIONS: This was a cross-sectional study, limiting the causal inference. CONCLUSIONS: This study revealed that bullying is a risk factor for poor sleep quality among adolescents in northwestern China. Furthermore, social support moderated the relationship between bullying and sleep quality in different ways depending on grade, gender, and type of bullying. More efforts are needed to prevent bullying and improve both school climate and students' sleep quality.

Lupenone improves type 2 diabetic nephropathy by regulating NF-κB pathway-mediated inflammation and TGF-ß1/Smad/CTGF-associated fibrosis.

BACKGROUND: Type 2 diabetic nephropathy is a common diabetic complication and the main cause of death in patients with diabetes. Research has aimed to find an ideal drug with minimal side effects for treating this disease. Banana peel has been shown to be anti-diabetic, with lupenone isolated from banana peel exhibiting antidiabetic and anti-inflammatory activities; However, the effects of lupenone on type 2 diabetic nephropathy are largely unknown. PURPOSE: This study aimed to investigate the ameliorative effect of lupenone on type 2 diabetic nephropathy, and its mechanism from both anti-inflammatory and anti-fibrotic perspectives. METHODS: Spontaneous type 2 diabetic nephropathy db/db mouse models were given three levels of lupenone (24 or 12 or 6 mg/kg/d) via intragastric administration for six weeks, and irbesartan treatment was used for the positive control group. We explored the effects and mechanism of lupenone action using enzyme-linked immunosorbent assay, automatic biochemical analyzer, hematoxylin-eosin and Masson staining, real time-PCR, and western blotting. Concurrently, a high-sugar and high-fat diet combined with a low-dose streptozotocin-induced type 2 diabetic nephropathy rat model was used for confirmatory research. RESULTS: Lupenone administration maintained the fasting blood glucose; reduced glycosylated hemoglobin, insulin, and 24 h proteinuria levels; and markedly regulated changes in biochemical indicators associated with kidney injury in serum and urine (including 24 h proteinuria, micro-albumin, N-acetyl-ß-d-glucosaminidase, α1-micro-globulin, creatinine, urea nitrogen, uric acid, total protein, and albumin) of type 2 diabetic nephropathy mice and rats. Hematoxylin-eosin and Masson staining as well as molecular biology tests revealed that inflammation and fibrosis are the two key processes affected by lupenone treatment. Lupenone protected type 2 diabetic nephropathy kidneys by regulating the NF-κB-mediated inflammatory response and TGF-ß1/Smad/CTGF pathway-associated fibrosis. CONCLUSION: Lupenone has potential as an innovative drug for preventing and treating diabetic nephropathy. Additionally, it has great value for the utilization of banana peel resources.

Elevated glutamate impedes anti-HIV-1 CD8 + T cell responses in HIV-1-infected individuals on antiretroviral therapy.

CD8 + T cells are essential for long-lasting HIV-1 control and have been harnessed to develop therapeutic and preventive approaches for people living with HIV-1 (PLWH). HIV-1 infection induces marked metabolic alterations. However, it is unclear whether these changes affect the anti-HIV function of CD8 + T cells. Here, we show that PLWH exhibit higher levels of plasma glutamate than healthy controls. In PLWH, glutamate levels positively correlate with HIV-1 reservoir and negatively correlate with the anti-HIV function of CD8 + T cells. Single-cell metabolic modeling reveals glutamate metabolism is surprisingly robust in virtual memory CD8 + T cells (TVM). We further confirmed that glutamate inhibits TVM cells function via the mTORC1 pathway in vitro. Our findings reveal an association between metabolic plasticity and CD8 + T cell-mediated HIV control, suggesting that glutamate metabolism can be exploited as a therapeutic target for the reversion of anti-HIV CD8 + T cell function in PLWH.