Logistic regression model for predicting risk factors and contribution of cerebral microbleeds using renal function indicators.

Background: The brain and kidneys share similar low-resistance microvascular structures, receiving blood at consistently high flow rates and thus, are vulnerable to blood pressure fluctuations. This study investigates the causative factors of cerebral microbleeds (CMBs), aiming to quantify the contribution of each risk factor by constructing a multivariate model via stepwise regression. Methods: A total of 164 hospitalized patients were enrolled from January 2022 to March 2023 in this study, employing magnetic susceptibility-weighted imaging (SWI) to assess the presence of CMBs. The presence of CMBs in patients was determined by SWI, and history, renal function related to CMBs were analyzed. Results: Out of 164 participants in the safety analysis, 36 (21.96%) exhibited CMBs and 128 (78.04%) did not exhibit CMBs, and the median age of the patients was 66 years (range: 49-86 years). Multivariate logistic regression identified hypertension (OR = 13.95%, 95% CI: 4.52, 50.07%), blood urea nitrogen (BUN) (OR = 1.57, 95% CI: 1.06-2.40), cystatin C (CyC) (OR = 4.90, 95% CI: 1.20-22.16), and urinary ß-2 microglobulin, (OR = 2.11, 95% CI: 1.45-3.49) as significant risk factors for CMBs. The marginal R-square ( R M 2 ) was 0.25. Among all determinants, hypertension (47.81%) had the highest weight, followed by UN (11.42%). Quasi-curves plotted using the bootstrap method (999 times) showed good agreement between the predictive model and actual observations. Conclusion: Hypertension, BUN, urinary ß-2 microglobulin, CyC were risk factors for CMBs morbidity, and controlling the above indicators within a reasonable range will help to reduce the incidence of CMBs.

Progress of rituximab in the treatment of systemic lupus erythematosus and lupus nephritis.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with heterogeneous clinical manifestations, often leading to significant morbidity and mortality, particularly due to lupus nephritis (LN). The standard therapeutic approach involving mycophenolate mofetil, cyclophosphamide, and glucocorticoids has shown limitations due to cumulative toxicity and side effects. The introduction of biologic agents, especially rituximab (RTX), a chimeric monoclonal antibody targeting CD20+ B cells, has revolutionized the treatment landscape. This review synthesized the current understanding of B cells' role in SLE and LN and evaluates RTX's therapeutic impact. B cells contribute to disease pathogenesis through autoantibody production and immune complex formation, leading to tissue damage. RTX's mechanisms of action, including Complement-Dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), and induction of apoptosis, have demonstrated efficacy in both SLE and LN treatment. Clinical studies have reported remission rates and improved renal outcomes with RTX use, although challenges such as human anti-chimeric antibody development and optimal dosing persist. The review emphasized the need for continued research to elucidate RTX's long-term benefits and risks, and to explore personalized treatment strategies that incorporate B cell biology for better disease management in SLE and LN.

PEGylation Can Effectively Strike a Balance in siRNA Delivery Performances of Guanidinylated Linear Synthetic Polypeptides with Potential Use for Transcriptional Gene Silencing.

The prevailing design philosophy for polymeric vectors delivering siRNA is rooted in the post-transcriptional gene silencing (PTGS) mechanism. Yet, the transcriptional gene silencing (TGS) mechanism offers a potentially more durable silencing effect, which necessitates efficient siRNA delivery into the nucleus. However, it remains a challenge for the polymeric vectors to efficiently deliver siRNA into the nucleus. We have explored guanidinylated cyclic synthetic polypeptides (GCSPs) to enhance the nuclear delivery of siRNA, but an increased cytotoxicity and difficulty in producing the GCSPs on a large scale limit their utility. Herein, we simply prepare PEGylated guanidinylated linear synthetic polypeptides (PGLSPs) exhibiting improved membrane penetration, direct siRNA transport to the nucleus, reduced toxicity, high cellular uptake, and mitigation of protein corona formation. The PEGylation can effectively balance the vector's nuclear delivery capacity with other critical aspects of performances for siRNA delivery. Therefore, the PGLSPs hold promise as TGS-based delivery vectors, offering potential for future therapeutic applications.

Differential Cytoophidium Assembly between Saccharomyces cerevisiae and Schizosaccharomyces pombe.

The de novo synthesis of cytidine 5'-triphosphate (CTP) is catalyzed by the enzyme CTP synthase (CTPS), which is known to form cytoophidia across all three domains of life. In this study, we use the budding yeast Saccharomyces cerevisiae and the fission yeast Schizosaccharomyces pombe as model organisms to compare cytoophidium assembly under external environmental and intracellular CTPS alterations. We observe that under low and high temperature conditions, cytoophidia in fission yeast gradually disassemble, while cytoophidia in budding yeast remain unaffected. The effect of pH changes on cytoophidia maintenance in the two yeast species is different. When cultured in the yeast-saturated cultured medium, cytoophidia in fission yeast disassemble, while cytoophidia in budding yeast gradually form. Overexpression of CTPS results in the presence and maintenance of cytoophidia in both yeast species from the log phase to the stationary phase. In summary, our results demonstrate differential cytoophidium assembly between Saccharomyces cerevisiae and Schizosaccharomyces pombe, the two most studied yeast species.

Electric Field Assisted Tangential Flow Filtration Device for Highly Effective Isolation of Bioactive Small Extracellular Vesicles from Cell Culture Medium.

Small extracellular vesicles (sEVs) are proven to hold great promise for diverse therapeutic and diagnostic applications. However, batch preparation of sEVs with high purity and bioactivity is a prerequisite for their clinical translations. Herein, we present an electric field assisted tangential flow filtration system (E-TFF), which integrates size-based filtration with electrophoretic migration-based separation to synergistically achieve the isolation of high-quality sEVs from cell culture medium. Compared with the gold-standard ultracentrifugation (UC) method, E-TFF not only improved the purity of sEVs by 1.4 times but also increased the yield of sEVs by 15.8 times. Additionally, the entire isolation process of E-TFF was completed within 1 h, about one-fourth of the time taken by UC. Furthermore, the biological activity of sEVs isolated by E-TFF was verified by co-incubation of sEVs derived from human umbilical cord mesenchymal stem cells (hUCMSCs) with HT22 mouse hippocampal neuronal cells exposed to amyloid-ß (Aß). The results demonstrated that the sEVs isolated by E-TFF exhibited a significant neuroprotective effect. Overall, the E-TFF platform provides a promising and robust strategy for batch preparation of high-quality sEVs, opening up a broad range of opportunities for cell-free therapy and precision medicine.

The rehabilitation efficacy of diaphragmatic breathing combined with limb coordination training for lower limb lymphedema following gynecologic cancer surgery.

Objective: To investigate the impact of diaphragmatic breathing combined with limb training on lower limb lymphedema following surgery for gynecological cancer. Methods: From January 2022 to May 2022, 60 patients with lower limb lymphedema post-gynecologic cancer surgery were chosen. They were split into a control group (n = 30) and a treatment group (n = 30). The control group underwent complex decongestive therapy (CDT) for managing lower limb lymphedema after gynecologic cancer surgery, while the treatment group received diaphragmatic breathing combined with limb coordination training alongside CDT. Both groups completed a 4-week treatment regimen. The lower limb lymphedema symptoms were evaluated using the genital, lower limb, buttock, and abdomen (GCLQ) scores; bilateral lower limb circumference measurements; and anxiety and depression scores. Results: Compared to sole CDT administration, individuals undergoing diaphragmatic breathing coupled with limb coordination training experienced notable reductions in scores for the self-perceived symptom assessment questionnaire (GCLQ), bilateral lower limb circumference, as well as anxiety and depression scores. Conclusion: The incorporation of diaphragmatic breathing combined withalongside limb coordination training can accelerate and augment the efficacy of treating lower limb lymphedema post-gynecologic cancer surgery.

PLAG1 interacts with GPX4 to conquer vulnerability to sorafenib induced ferroptosis through a PVT1/miR-195-5p axis-dependent manner in hepatocellular carcinoma.

BACKGROUND: Sorafenib is a standard first-line treatment for advanced hepatocellular carcinoma (HCC), yet its effectiveness is often constrained. Emerging studies reveal that sorafenib triggers ferroptosis, an iron-dependent regulated cell death (RCD) mechanism characterized by lipid peroxidation. Our findings isolate the principal target responsible for ferroptosis in HCC cells and outline an approach to potentially augment sorafenib's therapeutic impact on HCC. METHODS: We investigated the gene expression alterations following sgRNA-mediated knockdown induced by erastin and sorafenib in HCC cells using CRISPR screening-based bioinformatics analysis. Gene set enrichment analysis (GSEA) and the "GDCRNATools" package facilitated the correlation studies. We employed tissue microarrays and cDNA microarrays for validation. Ubiquitination assay, Chromatin immunoprecipitation (ChIP) assay, RNA immunoprecipitation (RIP) assay, and dual-luciferase reporter assay were utilized to delineate the specific mechanisms underlying ferroptosis in HCC cells. RESULTS: Our study has revealed that pleiomorphic adenoma gene 1 (PLAG1), a gene implicated in pleomorphic adenoma, confers resistance to ferroptosis in HCC cells treated with sorafenib. Sorafenib leads to the opposite trend of protein and mRNA levels of PLAG1, which is not caused by affecting the stability or ubiquitination of PLAG1 protein, but by the regulation of PLAG1 at the transcriptional level by its upstream competitive endogenous long non-coding RNA (lncRNA) plasmacytoma variant translocation 1 (PVT1). Data from 139 HCC patients showed a significant positive correlation between PLAG1 and GPX4 levels in tumor samples, and PLAG1 is instrumental in redox homeostasis by driving the expression of glutathione peroxidase 4 (GPX4), the enzyme that reduces lipid peroxides (LPOs), which further leads to ferroptosis inhibition. CONCLUSIONS: Ferroptosis is a promising target for cancer therapy, especially for patients resistant to standard chemotherapy or immunotherapy. Our findings indicate that PLAG1 holds therapeutic promise and may enhance the efficacy of sorafenib in treating HCC.

Enhancing physically-based hydrological modeling with an ensemble of machine-learning reservoir operation modules under heavy human regulation using easily accessible data.

Dams and reservoirs have significantly altered river flow dynamics worldwide. Accurately representing reservoir operations in hydrological models is crucial yet challenging. Detailed reservoir operation data is often inaccessible, leading to relying on simplified reservoir operation modules in most hydrological models. To improve the capability of hydrological models to capture flow variability influenced by reservoirs, this study proposes a hybrid hydrological modeling framework, which combines a process-based hydrological model with a machine-learning-based reservoir operation module designed to simulate runoff under reservoir operations. The reservoir operation module employs an ensemble of three machine learning models: random forest, support vector machine, and AutoGluon. These models predict reservoir outflows using precipitation and temperature data as inputs. The Soil and Water Assessment Tool (SWAT) then integrates these outflow predictions to simulate runoff. To evaluate the performance of this hybrid approach, the Xijiang Basin within the Pearl River Basin, China, is used as a case study. The results highlight the superiority of the SWAT model coupled with machine learning-based reservoir operation models compared to alternative modeling approaches. This hybrid model effectively captures peak flows and dry period runoff. The Nash-Sutcliffe Efficiency (NSE) in daily runoff simulations shows substantial improvement, ranging from 0.141 to 0.780, with corresponding enhancements in the coefficient of determination (R2) by 0.098-0.397 when compared to the original reservoir operation modules in SWAT. In comparison to parameterization techniques lacking a dedicated reservoir module, NSE enhancements range from 0.068 to 0.537, and R2 improvements range from 0.027 to 0.139. The proposed hybrid modeling approach effectively characterizes the impact of reservoir operations on river flow dynamics, leading to enhanced accuracy in runoff simulation. These findings offer valuable insights for hydrological forecasting and water resources management in regions influenced by reservoir operations.

Correlation of Blood and Intestinal Mucosa miR-34a Expressions with Disease Severity in Ulcerative Colitis Patients.

BACKGROUND: miR-34a has been implicated in many autoimmune diseases and gastrointestinal diseases. However, the expression of miR-34 in ulcerative colitis (UC) patients were not fully studied. This study was performed to in-vestigate the association of blood and intestinal tissue miR-34a expression of patients with disease severity in UC patients. METHODS: Our study enrolled 82 patients with UC and 80 age- and gender- matched healthy individuals. Blood miR-34a expressions were detected using reverse transcription-polymerase chain reaction (RT-PCR). Local intestinal miR-34a, STAT3 mRNA and IL-23 mRNA expressions were also detected in the lesioned area and adjacent non-affected intestinal tissue in patients. Disease severity of UC was assessed by Mayo score. The diagnostic value of both blood and local miR-34a expression for UC patients was assessed by receiver operating characteristic (ROC) curve. RESULTS: Blood miR-34a was increased in UC patients in contrast with healthy individuals with statistical significance. In UC patients, local intestinal miR-34a expressions were markedly upregulated compared to adjacent non-affected intestinal tissue. Local intestinal miR-34a expressions were positively correlated with STAT3 mRNA and IL-23 mNRA. Both blood and local miR-34a expressions were significantly and positively related to Mayo scores. ROC curve analysis indicated that both blood and local miR-34a expressions may act as decent marker for Mayo grade. CONCLUSIONS: Blood and intestinal tissue miR-34a expressions are correlated with disease severity in UC patients. Both blood and intestinal tissue miR-34a expressions may serve as potential diagnostic and prognostic makers for UC. Therapeutic methods targeting miR-34a may act as potential ways for UC treatment.

Ferroptosis inhibitor alleviates sorafenib-induced cardiotoxicity by attenuating KLF11-mediated FSP1-dependent ferroptosis.

Sorafenib is a standard first-line drug for advanced hepatocellular carcinoma, but the serious cardiotoxic effects restrict its therapeutic applicability. Here, we show that iron-dependent ferroptosis plays a vital role in sorafenib-induced cardiotoxicity. Remarkably, our in vivo and in vitro experiments demonstrated that ferroptosis inhibitor application neutralized sorafenib-induced heart injury. By analyzing transcriptome profiles of adult human sorafenib-treated cardiomyocytes, we found that Krüppel-like transcription factor 11 (KLF11) expression significantly increased after sorafenib stimulation. Mechanistically, KLF11 promoted ferroptosis by suppressing transcription of ferroptosis suppressor protein 1 (FSP1), a seminal breakthrough due to its ferroptosis-repressing properties. Moreover, FSP1 knockdown showed equivalent results to glutathione peroxidase 4 (GPX4) knockdown, and FSP1 overexpression counteracted GPX4 inhibition-induced ferroptosis to a substantial extent. Cardiac-specific overexpression of FSP1 and silencing KLF11 by an adeno-associated virus serotype 9 markedly improved cardiac dysfunction in sorafenib-treated mice. In summary, FSP1-mediated ferroptosis is a crucial mechanism for sorafenib-provoked cardiotoxicity, and targeting ferroptosis may be a promising therapeutic strategy for alleviating sorafenib-induced cardiac damage.

An Outbreak of Serogroup Y Meningococcal Meningitis in a Private Secondary Vocational School - Guangzhou City, Guangdong Province, China, 2023.

What is already known about this topic?: The inclusion of meningococcal vaccines in the National Immunization Program (NIP) over several years has significantly reduced the incidence of meningococcal meningitis in China to historic lows. Worldwide, there has been a diversification of meningococcal serogroups, leading to a shift in dominant serogroups in China from serogroup A to serogroups C and B, accompanied by a rise in reports of serogroups Y and W. What is added by this report?: An outbreak of serogroup Y Neisseria meningitidis (Nm) in a secondary vocational school involved a single confirmed severe case and 24 individuals with laboratory-confirmed Nm carriage. Epidemiological investigation revealed that the outbreak was localized to the classroom of the confirmed case. Prolonged close contact within a confined space was identified as a significant risk factor for Nm transmission. The genotype sequence identified was type 1655 (ST-1655), which is categorized under clonal complex 23 (CC-23) and bears resemblance to 8 previously confirmed cases of serogroup Y meningococcal meningitis within Guangdong Province. This suggests that serogroup Y infections continue to sporadically emerge and have become prevalent strains. What are the implications for public health practice?: This outbreak underscores the critical need to enhance surveillance of meningococcal serogroups and population carrier, and advocate for vaccination with MenY-containing vaccines.

Sediment record of heavy metals in Xincun Lagoon indicating anthropogenic impact over the last 200 years.

Anthropogenic metal pollution is a leading environmental problem in southern China, especially in remote regions where its impact remains poorly understood. This study investigates the historical variation of heavy metal pollution over the last 200 years using a sediment core from Xincun Lagoon, Hainan Island, South China. The temporal evolution of heavy metal pollution aligns with China's socioeconomic development. Prior to the 1950s, heavy metal concentrations were at geochemical background levels, reflecting China's agrarian status. Since the 1950s, the increased heavy metal accumulation may be attributed to intensified human activities linked to rapid urbanization and industrialization. Despite the increase in heavy metal enrichments since the 1950s, Xincun Lagoon currently faces a low ecological risk.

Correlation between systolic blood pressure and mortality in heart failure patients with hypertension.

BACKGROUND: The correlation between systolic blood pressure (SBP) and mortality in hypertensive patients with different phenotypes of heart failure (HF) has not been adequately studied, and optimal blood pressure control targets remain controversial. To explore the link between SBP and prognosis in all or three ejection fraction (EF) phenotypes of HF patients with hypertension. METHODS: We analyzed 1279 HF patients complicated by hypertension in a retrospective cohort. The SBP <130 mmHg group included 383 patients, and the SBP ≥130 mmHg group included 896 patients. The major end point was all-cause mortality. RESULTS: Of the 1279 study patients, with a median age of 66.0 ±â€Š12.0 years, 45.3% were female. The proportions of the three subtypes of heart failure complicated with hypertension (HFrEF, HEmrEF, and HFpEF) were 26.8%, 29.3%, and 43.9%, respectively. During the 1-year follow-up, 223 patients experienced all-cause death, and 133 experienced cardiovascular death. Restricted cubic splines showed that the risk of all-cause and cardiovascular death increased gradually as the SBP level decreased in patients with HFrEF and HFmrEF. Furthermore, the multivariate Cox proportional hazards model revealed that SBP <130 mmHg was also associated with an increased risk of all-cause death [hazard ratio (HR) 2.53, 95% confidence interval (CI) 1.23-5.20, P  = 0.011] and cardiovascular death (HR 1.91, 95% CI 1.01-3.63, P  = 0.047) in HFrEF patients. A trend toward increased risk was observed among HFmrEF patients, but it was not statistically significant. This trend was not observed in HFpEF patients. CONCLUSION: In HFrEF patients, SBP <130 mmHg was associated with an increased risk of all-cause and cardiovascular mortality. A trend toward increased risk was observed among HFmrEF patients, but not among HFpEF patients.

Cytoophidia Influence Cell Cycle and Size in Schizosaccharomyces pombe.

Cytidine triphosphate synthase (CTPS) forms cytoophidia in all three domains of life. Here we focus on the function of cytoophidia in cell proliferation using Schizosaccharomyces pombe as a model system. We find that converting His359 of CTPS into Ala359 leads to cytoophidium disassembly. By reducing the level of CTPS protein or specific mutation, the loss of cytoophidia prolongs the G2 phase and expands cell size. In addition, the loss-filament mutant of CTPS leads to a decrease in the expression of genes related to G2/M transition and cell growth, including histone chaperone slm9. The overexpression of slm9 alleviates the G2 phase elongation and cell size enlargement induced by CTPS loss-filament mutants. Overall, our results connect cytoophidia with cell cycle and cell size control in Schizosaccharomyces pombe.

Sepsis induced cardiotoxicity by promoting cardiomyocyte cuproptosis.

BACKGROUND: Currently, sepsis induced cardiotoxicity is among the major causes of sepsis-related death. The specific molecular mechanisms of sepsis induced cardiotoxicity are currently unknown. Therefore, the purpose of this paper is to identify the key molecule mechanisms for sepsis induced cardiotoxicity. METHODS: Original data of sepsis induced cardiotoxicity was derived from Gene Expression Omnibus (GEO; GSE63920; GSE44363; GSE159309) dataset. Functional enrichment analysis was used to analysis sepsis induced cardiotoxicity related signaling pathways. Our findings also have explored the relationship of cuproptosis and N6-Methyladenosine (m6A) in sepsis induced cardiotoxicity. Mice are randomly assigned to 3 groups: saline treatment control group, LPS group administered a single 5 mg/kg dose of LPS for 24 h, LPS + CD274 inhibitor group administered 10 mg/kg CD274 inhibitor for 24 h. RESULTS: Overall, expression of cuproptosis-related genes (CRGs) CD274, Ceruloplasmin (CP), Vascular endothelial growth factor A (VEGFA), Copper chaperone for cytochrome c oxidase 11 (COX11), chemokine C-C motif ligand 8 (CCL8), Mitogen-activated protein kinase kinase 1(MAP2K1), Amine oxidase 3 (AOC3) were significantly altered in sepsis induced cardiotoxicity. The results of spearman correlation analysis was significant relationship between differentially regulated genes (DEGs) of CRGs and the expression level of m6A methylation genes. GO and KEGG showed that these genes were enriched in response to interferon-beta, MHC class I peptide loading complex, proteasome core complex, chemokine receptor binding, TAP binding, chemokine activity, cytokine activity and many more. These findings suggest that cuproptosis is strongly associated with sepsis induced cardiotoxicity. CONCLUSION: In the present study, we found that cuproptosis were associated with sepsis induced cardiotoxicity. The CD274, CP, VEGFA, COX11, CCL8, MAP2K1, AOC3 genes are showing a significant difference expression in sepsis induced cardiotoxicity. Our studies have found significant correlations between CRGs and m6A methylation related genes in sepsis induced cardiotoxicity. These results provide insight into mechanism for sepsis induced cardiotoxicity.

Isotopic Constraints on Sources and Transformations of Nitrate in the Mount Everest Proglacial Water.

Glacier melting exports a large amount of nitrate to downstream aquatic ecosystems. Glacial lakes and glacier-fed rivers in proglacial environments serve as primary recipients and distributors of glacier-derived nitrate (NO3-), yet little is known regarding the sources and cycling of nitrate in these water bodies. To address this knowledge gap, we conducted a comprehensive analysis of nitrate isotopes (δ15NNO3, δ18ONO3, and Δ17ONO3) in waters from the glacial lake and river of the Rongbuk Glacier-fed Basin (RGB) in the mountain Everest region. The concentrations of NO3- were low (0.43 ± 0.10 mg/L), similar to or even lower than those observed in glacial lakes and glacier-fed rivers in other high mountain regions, suggesting minimal anthropogenic influence. The NO3- concentration decreases upon entering the glacial lake due to sedimentation, and it increases gradually from upstream to downstream in the river as a soil source is introduced. The analysis of Δ17ONO3 revealed a substantial contribution of unprocessed atmospheric nitrate, ranging from 34.29 to 56.43%. Denitrification and nitrification processes were found to be insignificant in the proglacial water of RGB. Our study highlights the critical role of glacial lakes in capturing and redistributing glacier-derived NO3- and emphasizes the need for further investigations on NO3- transformation in the fast-changing proglacial environment over the Tibetan Plateau and other high mountain regions.

SIRT1 mediates the inhibitory effect of Dapagliflozin on EndMT by inhibiting the acetylation of endothelium Notch1.

BACKGROUND: Endothelial-mesenchymal transition (EndMT) plays a crucial role in promoting myocardial fibrosis and exacerbating cardiac dysfunction. Dapagliflozin (DAPA) is a sodium-glucose-linked transporter 2 (SGLT-2) inhibitor that has been shown to improve cardiac function in non-diabetic patients with heart failure (HF). However, the precise mechanisms by which DAPA exerts its beneficial effects are yet to be fully elucidated. METHODS: Isoproterenol (ISO) was used to generate a HF model in mice. For in vitro experiments, we used TGF-ß1-stimulated human umbilical vein endothelial cells (HUVECs) and mouse aortic endothelial cells (MAECs). RESULTS: Both our in vivo and in vitro results showed that EndMT occurred with decreased SIRT1 (NAD+-dependent deacetylase) protein expression, which could be reversed by DAPA therapy. We found that the protective effect of DAPA was significantly impaired upon SIRT1 inhibition. Mechanistically, we observed that SIRT1 phosphorylation, a required modification for its ubiquitination and degradation, was reduced by DAPA treatment, which induces the nucleus translocation of SIRT1 and promotes its binding to the active intracellular domain of Notch1 (NICD). This interaction led to the deacetylation and degradation of NICD, and the subsequent inactivation of the Notch1 signaling pathway which contributes to ameliorating EndMT. CONCLUSIONS: Our study revealed that DAPA can attenuate EndMT induced by ISO in non-diabetic HF mice. This beneficial effect is achieved through SIRT1-mediated deacetylation and degradation of NICD. Our findings provide greater insight into the underlying mechanisms of the therapeutic effects of DAPA in non-diabetic HF.

Predicting life span of type 2 diabetes patients through alkaline phosphatase and vitamin D: Results from NHANES 1999-2018.

BACKGROUND AND AIMS: Disparities in serum biomarker levels related to mortality persist within the US diabetic population. We conducted a study to explore the impact of alkaline phosphatase (ALP) on all-cause mortality and cardiovascular disease (CVD) mortality in type 2 diabetes patients. METHODS: We analyzed a nationally representative sample of individuals aged 20 years and above from the National Health and Nutrition Examination Survey (NHANES) conducted in the United States between 1999 and 2018. Baseline demographic information and biochemical markers, including blood glucose, γ-glutamyltranspeptidase, vitamin D and albumin, were collected. Participants were divided into four groups based on ALP levels and linked to the National Death Index to assess mortality. Follow-up continued until December 2019, and multiple mediation analyses were performed to assess the combined impact of different indicators on ALP differences in all-cause mortality and cardiovascular mortality risk. RESULTS: Our analysis included 6481 NHANES participants, categorized as follows: 1626 (21.9%) had ALP levels below 58 U/L, 1674 in the second quartile (58-72 U/L), 1569 in the third quartile (72-88.3 U/L), and 1612 in the fourth quartile (above 88.3U/L). Significantly higher all-cause mortality and cardiovascular mortality rates were observed among participants in the 4th ALP quartile compared to other levels. The all-cause mortality rate was 38.06 per 1000 person-years (95% CI 34.89-41.51), and the cardiovascular mortality rate was 10.67 (9.06-12.57). Mediation analysis indicated that Vitamin D and albumin played a mediating role in the association between all-cause mortality, cardiovascular mortality, and ALP levels, with mediation proportions ranging from 10.33% to 27.64%. CONCLUSIONS: Our study suggests that ALP levels have clinical value in predicting all-cause and CVD mortality risk in T2DM patients. The upregulation of Vitamin D and albumin might play a significant role in improving risk prediction and enable targeted interventions for reducing mortality risk in this population.

Anthropogenic influences on the sources and distribution of organic carbon, black carbon, and heavy metals in Daya Bay's surface sediments.

The total organic carbon (TOC), total nitrogen (TN), black carbon (BC), δ13CTOC, δ15N, δ13CBC, grain size, and heavy metals of surface sediments collected from Daya Bay were determined to investigate the spatial distributions of these parameters and to evaluate the influences of human activities. Marine organic matter was found to constitute approximately 84.41 ± 7.70 % of these sediments on average. The western and northern regions of Daya Bay exhibited relatively fine grain sizes, weak hydrodynamic conditions, and high sedimentation rates, which favored the burial and preservation of organic matter. The high concentration of organic matter could be attributed to the influence of petroleum and aquaculture industries. Fossil fuels were the main source of BC. The enrichment factor (EF) and geo-accumulation index (Igeo) were used to evaluate the sources and pollution levels of heavy metals. The results revealed that the source and distribution of heavy metals were strongly influenced by human activities, resulting in moderate pollution levels across most regions of Daya Bay. A strong correlation was observed between the Igeo values of heavy metals and BC, TOC, TN, and mean particle grain size (Mz). This suggests that the ability of sediments in Daya Bay to enrich and adsorb heavy metals depends on the sediment grain size, the content and type of organic matter. Importantly, sediments in the inner bay of Daya Bay exhibited a greater capacity to impede the migration of heavy metals compared to those in the outer bay.

The level of macrophage migration inhibitory factor is negatively correlated with the efficacy of PD-1 blockade immunotherapy combined with chemotherapy as a neoadjuvant therapy for esophageal squamous cell carcinoma.

PURPOSE: This study aimed to screen biomarkers to predict the efficacy of programmed cell death 1 (PD-1) blockade immunotherapy combined with chemotherapy as neoadjuvant therapy for esophageal squamous cell carcinoma (ESCC). METHODS: In the first stage of the study, the baseline concentrations of 40 tumor-related chemokines in the serum samples of 50 patients were measured to screen for possible biomarkers. We investigated whether the baseline concentration of the selected chemokine was related to the therapeutic outcomes and tumor microenvironment states of patients treated with the therapy. In the second stage, the reliability of the selected biomarkers was retested in 34 patients. RESULTS: The baseline concentration of macrophage migration inhibitory factor (MIF) was negatively correlated with disease-free survival (DFS) and overall survival (OS) in patients treated with the therapy. In addition, a low baseline expression level of MIF is related to a better tumor microenvironment for the treatment of ESCC. A secondary finding was that effective treatment decreased the serum concentration of MIF. CONCLUSION: Baseline MIF levels were negatively correlated with neoadjuvant therapy efficacy. Thus, MIF may serve as a predictive biomarker for this therapy. The accuracy of the prediction could be improved if the serum concentration of MIF is measured again after the patient received several weeks of treatment.