Ense-i6mA: Identification of DNA N6-methyl-adenine Sites Using XGB-RFE Feature Se-lection and Ensemble Machine Learning.

DNA N6-methyladenine (6mA) is an important epigenetic modification that plays a vital role in various cellular processes. Accurate identification of the 6mA sites is fundamental to elucidate the biological functions and mechanisms of modification. However, experimental methods for detecting 6mA sites are high-priced and time-consuming. In this study, we propose a novel computational method, called Ense-i6mA, to predict 6mA sites. Firstly, five encoding schemes, i.e., one-hot encoding, gcContent, Z-Curve, K-mer nucleotide frequency, and K-mer nucleotide frequency with gap, are employed to extract DNA sequence features. Secondly, to our knowledge, it is the first time that eXtreme gradient boosting coupled with recursive feature elimination is applied to 6mA sites prediction domain to remove noisy features for avoiding over-fitting, reducing computing time and complexity. Then, the best subset of features is fed into base-classifiers composed of Extra Trees, eXtreme Gradient Boosting, Light Gradient Boosting Machine, and Support Vector Machine. Finally, to minimize generalization errors, the prediction probabilities of the base-classifiers are aggregated by averaging for inferring the final 6mA sites results. We conduct experiments on two species, i.e., Arabidopsis thaliana and Drosophila melanogaster, to compare the performance of Ense-i6mA against the recent 6mA sites prediction methods. The experimental results demonstrate that the proposed Ense-i6mA achieves area under the receiver operating characteristic curve values of 0.967 and 0.968, accuracies of 91.4% and 92.0%, and Mathew's correlation coefficient values of 0.829 and 0.842 on two benchmark datasets, respectively, and outperforms several existing state-of-the-art methods.

Associations between adverse childhood experiences and pain in middle-aged and older adults: findings from the China Health and Retirement Longitudinal Study.

OBJECTIVE: Adverse childhood experiences (ACEs) have been associated with a range of adverse health outcomes, with pain being potentially one of them. This population-based cross-sectional study aimed to investigate the associations between Adverse Childhood Experiences (ACEs) and pain in Chinese adults and evaluate whether physical activity and demographic and socioeconomic characteristics modify this associations. METHODS: Cross-sectional data from the China Health and Retirement Longitudinal Study (CHARLS), were utilized in this study. A total of 9923 respondents with information on 12 ACE indicators and 15 self-reported body pains were included. Logistic regression models were used to assess associations of the ACEs and pain. Modification of the associations by physical activity, demographic and socioeconomic characteristics was assessed by stratified analyses and tests for interaction. RESULTS: Among the 9923 individuals included in the primary analyses, 5098 (51.4%) males and the mean (SD) age was 61.18 (10·.44) years. Compared with individuals with 0 ACEs, those who with ≥ 5 ACEs had increased risk of single pains and multiple pain. A dose-response association was found between the number of ACEs and the risk of pain (e.g. neck pain for ≥ 5 ACEs vs. none: OR, 1.107; 95% CI, 0.903-1.356; p < 0.001 for trend). In the associations of each body pain with each ACE indicator, most ACE indicators were associated with an increased risk of pain. In addition, physical activity, sociodemographic and socioeconomic characteristics, such as age, sex, educational level, area of residence, childhood economic hardship, did not demonstrate a significant modify on the associations between ACEs and pain. CONCLUSIONS: These findings indicate that cumulative ACE exposure is associated with increased odds of self-reported pain in Chinese adults, regardless of adult physical activity, sociodemographic and socioeconomic characteristics.

Intermittent and mild cold stimulation enhances immune function of broilers via co-regulation of CIRP and TRPM8 on NF-κB and MAPK signaling pathways.

Improving immune function is an important indicator for establishing cold adaptation in broilers. In the study, to explore the effects and molecular mechanisms of intermittent and mild cold stimulation (IMCS) on the immune function of broilers, CIRP and TRPM8, induced by cold stimulation, as well as the NF-κB and MAPK pathways which play an important role in immune response, were selected to investigate. A total of 192 one-day-old broilers (Ross 308) were selected and randomly divided into the control group (CC) and the cold stimulation group (CS). The broilers in CC were raised at normal feeding temperature from d 1 to 43, while the broilers in CS were subjected to cold stimulation from day 15 to 35, with a temperature 3 °C below that of the CC group for 5 h, at 1 d intervals. The results showed that IMCS had little effect on the broiler hearts, and the myocardial structure was not damaged. On d 22, IMCS significantly increased the mRNA levels of CIRP, TRPM8, P65, P38, COX-2, TNF-α, IFN- γ, IL-6, IL-10, and the protein levels of CIRP, P65, P38, IL-1ß and iNOS in the hearts, and the levels of CIRP and all cytokines in the serum (P ≤ 0.05). The mRNA and protein levels of IκB-α were significantly reduced (P ≤ 0.05). On d 36, the mRNA levels of TRPM8, P65, ERK, and IL-10 in the hearts and the content of COX-2 in the serum in CS were increased significantly (P ≤ 0.05), while the mRNA levels of IκB-α, P38, and IL-1ß were decreased significantly (P ≤ 0.05). On d 43, IMCS significantly upregulated the mRNA levels of TRPM8, IFN- γ, IL-4, IL-6, IL-10, and the protein levels of IκB-α, P38, and the levels of iNOS, TNF-α, IL6 and IL10 in the serum (P ≤ 0.05); whereas it significantly downregulated CIRP, JNK, P38, iNOS, TNF-α mRNA levels, and CIRP, P65, ERK, JNK, IL1ß and iNOS protein levels (P ≤ 0.05). Therefore, IMCS can enhance broiler immune function through co-regulation of CIRP and TRPM8 on the NF-κB and MAPK pathways, which facilitate the cold adaptation in broilers.

Silver-Promoted Three-Component Synthesis of Perfluoroalkenyl Pyrroles through Partial Defluorinative Functionalization of Perfluoroalkyl Halides.

A silver-promoted three-component heterocyclization of alkynes, perfluoroalkyl halides, and 1,3-dinucleophiles was developed for the efficient synthesis of privileged (E)-perfluoroalkenyl pyrroles. The reaction proceeded through a rationally designed sequence of radical perfluoroalkylation and intramolecular defluorinative [3 + 2]-heterocyclization. The utility of perfluoroalkyl halide as a perfluoroalkenyl reagent, by selective and controllable functionalization of two inert C(sp3)-F bonds at vicinal carbon centers on the perfluoroalkyl chain, provides a new reaction mode for the synthesis of value-added organofluorides starting from the easily available and low-cost fluorinated feedstock.

Efficacy and safety of atogepant, a small molecule CGRP receptor antagonist, for the preventive treatment of migraine: a systematic review and meta-analysis.

BACKGROUND: Migraine is one of the most common diseases worldwide while current treatment options are not ideal. New therapeutic classes of migraine, the calcitonin gene-related peptide (CGRP) antagonists, have been developed and shown considerable effectiveness and safety. The present study aimed to systematically evaluate the efficacy and safety of atogepant, a CGRP antagonist, for migraine prophylaxis from the results of randomized controlled trials (RCTs). METHODS: The Cochrane Library, Embase, PubMed and https://www. CLINICALTRIALS: gov/ were searched for RCTs that compared atogepant with placebo for migraine prophylaxis from inception of the databases to Feb 1, 2024. Outcome data involving efficacy and safety were combined and analyzed using Review Manager Software version 5.3 (RevMan 5.3). For each outcome, risk ratios (RRs) or standardized mean difference (SMD) were calculated. RESULTS: 4 RCTs with a total of 2813 subjects met our inclusion criteria. The overall effect estimate showed that atogepant was significantly superior to placebo in terms of the reduction of monthly migraine (SMD - 0.40, 95% CI -0.46 to -0.34) or headache (SMD - 0.39, 95% CI -0.46 to -0.33) days, the reduction of acute medication use days (SMD - 0.45, 95% CI -0.51 to -0.39) and 50% responder rate (RR 1.66, 95% CI 1.46 to 1.89), while no dose-related improvements were found between different dosage groups. For the safety, significant number of patients experienced treatment-emergent adverse events (TEAEs) with atogepant than with placebo (RR 1.10, 95% CI 1.02-1.21) while there was no obvious difference between the five dosage groups. Most TEAEs involved constipation (RR 2.55, 95% CI 1.91-3.41), nausea (RR 2.19, 95% CI 1.67-2.87) and urinary tract infection (RR 1.49, 95% CI 1.05-2.11). In addition, a high dosage of atogepant may also increase the risk of treatment-related TEAEs (RR 1.64, 95% CI 1.02-2.63) and fatigue (RR 3.07, 95% CI 1.13-8.35). CONCLUSIONS: This meta-analysis suggests that atogepant is effective and tolerable for migraine prophylaxis including episodic or chronic migraine compared with placebo. It is critical to weigh the benefits of different doses against the risk of adverse events in clinical application of atogepant. Longer and multi-dose trials with larger sample sizes are required to verify the current findings.

Transition-Metal-Free Hydrodefluoroamination of Trifluoromethyl Enones for the Synthesis of α-Fluoroenamides.

A three-component strategy was developed to enable hydrodefluoroamination of ß-trifluoromethyl enones by selectively activating two C(sp3)-F bonds in the trifluoromethyl group. The method involved a sequence of carbonyl reduction, hydrodefluorination, and defluoroamination under transition-metal-free conditions. Synthetically useful (E)-stereospecific α-fluoroenamides were obtained in good yields with diverse functional group tolerance, which could be easily transformed into valuable organofluorides and heterocycles. The carbonyl auxiliary exerts both electronic and steric impacts on the CF3-alkenes, allowing for controllable and selective defluorination.

Novel Diagnostic Biomarkers Related to Necroptosis and Immune Infiltration in Coronary Heart Disease.

Purpose: Necroptosis, a monitored form of inflammatory cell death, contributes to coronary heart disease (CHD) progression. This study examined the potential of using necroptosis genes as diagnostic markers for CHD and sought to elucidate the underlying roles. Methods: Through bioinformatic analysis of GSE20680 and GSE20681, we first identified the differentially expressed genes (DEGs) related to necroptosis in CHD. Hub genes were identified using least absolute shrinkage and selection operator (LASSO) regression and random forest analysis after studying immune infiltration and transcription factor-miRNA interaction networks according to the DEGs. Quantitative polymerase chain reaction and immunohistochemistry were used to further investigate hub gene expression in vivo, for which a diagnostic model was constructed and the predictive efficacy was validated. Finally, the CHD group was categorized into high- and low-score groups in accordance with the single-sample gene set enrichment analysis (ssGSEA) score of the necroptosis genes. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, GSEA, and further immune infiltration analyses were performed on the two groups to explore the possible roles of hub genes. Results: Based on the results of the LASSO regression and random forest analyses, four genes were used to construct a diagnostic model to establish a nomogram. Additionally, an extensive analysis of all seventeen necroptosis genes revealed notable distinctions in expression between high-risk and low-risk groups. Evaluation of immune infiltration revealed that neutrophils, monocytes, B cells, and activated dendritic cells were highly distributed in the peripheral blood of patients with CHD. Specifically, the high CHD score group exhibited greater neutrophil and monocyte infiltration. Conversely, the high-score group showed lower infiltration of M0 and M2 macrophages, CD8+ T, plasma, and resting mast cells. Conclusion: TLR3, MLKL, HMGB1, and NDRG2 may be prospective biomarkers for CHD diagnosis. These findings offer plausible explanations for the role of necroptosis in CHD progression through immune infiltration and inflammatory response.

Analysis of quadriceps strength and knee pain Among US Adults.

OBJECTIVE: To investigate the association of quadriceps strength with the presence of knee pain. DESIGN: This cross-sectional study was based on data from the 1999-2000 and 2001-2002 National Health and Nutrition Examination Survey. SETTING: This was a community-based study. PARTICIPANTS: This study included 2,619 adults with complete data for knee pain, quadriceps strength, and covariates. INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: Self-reported knee pain. RESULTS: This study included 2,619 individuals, 1,287 (52.66%) of whom were female and 1,543 (81.66%) identified as Mexican-American. The mean ± standard deviation age was 62.48 ± 9.71 years. After adjusting for covariates, the odds of knee pain decreased with every 20 N/m increase in quadriceps strength (odds ratio, 0.87; 95% CI, 0.81-0.94). Individuals in the upper quartile of quadriceps strength had lower odds of knee pain than those in the lower quartile (Q4 vs. Q1 [reference]: odds ratio, 0.28, 95% CI, 0.15-0.52; ptrend = 0.006). Non-linear analyses indicated L-shaped associations for knee pain. The subgroup analyses showed no significant interactions, except for sex (pinteraction = 0.046). The significance of the sex interaction indicated a correlation exclusively in females. CONCLUSIONS: The results demonstrated an inverse association between quadriceps strength and the presence of knee pain. The subgroup analysis by sex showed that this inverse relationship was statistically significant in the female but not in the male subgroup.

Explainable coronary artery disease prediction model based on AutoGluon from AutoML framework.

Objective: This study focuses on the innovative application of Automated Machine Learning (AutoML) technology in cardiovascular medicine to construct an explainable Coronary Artery Disease (CAD) prediction model to support the clinical diagnosis of CAD. Methods: This study utilizes a combined data set of five public data sets related to CAD. An ensemble model is constructed using the AutoML open-source framework AutoGluon to evaluate the feasibility of AutoML in constructing a disease prediction model in cardiovascular medicine. The performance of the ensemble model is compared against individual baseline models. Finally, the disease prediction ensemble model is explained using SHapley Additive exPlanations (SHAP). Results: The experimental results show that the AutoGluon-based ensemble model performs better than the individual baseline models in predicting CAD. It achieved an accuracy of 0.9167 and an AUC of 0.9562 in 4-fold cross-bagging. SHAP measures the importance of each feature to the prediction of the model and explains the prediction results of the model. Conclusion: This study demonstrates the feasibility and efficacy of AutoML technology in cardiovascular medicine and highlights its potential in disease prediction. AutoML reduces the barriers to model building and significantly improves prediction accuracy. Additionally, the integration of SHAP enhances model transparency and explainability, which is critical to ensuring model credibility and widespread adoption in cardiovascular medicine.

Overexpression of macrophage migration inhibitory factor protects against pressure overload-induced cardiac hypertrophy through regulating the miR-29b-3p/HBP1 axis.

Cardiac hypertrophy is an adaptive response to stressors such as high cardiac workload, which might lead to abnormal cardiac function and heart failure. Previous studies have indicated that macrophage migration inhibitory factor (MIF) might play a protective role in cardiac hypertrophy. Here, we aimed to illustrate the mechanism of MIF in protecting against pressure overload-induced cardiac hypertrophy. Transverse aortic constriction (TAC) mouse model was established and we found that overexpression of MIF protected against pressure overload-induced cardiac hypotrophy in TAC treated mice, as evidenced by significantly decreased the heart weight. In addition, transthoracic echocardiography showed that overexpression of MIF restored ejection fraction in TAC-treated mice. While TAC treatment resulted in a much larger cardiomyocyte size in mice, MIF overexpression notably decreased the cardiomyocyte size. Next, we demonstrated that MIF overexpression promoted the expression of miR-29b-3p which further downregulated the expression of its downstream target HMG box protein 1 (HBP1). Overexpression of HBP1 reversed the effect of MIF in alleviating Ang-II induced oxidative stress in cardiomyocytes. In conclusion, our findings suggest that MIF could attenuate pressure overload-induced cardiac hypertrophy through regulating the miR-29b-3p/HBP1 axis.

MgO-based supersulfated cement with different industrial by-product gypsum: Experiments and molecular dynamics simulation.

Super sulfate cement (SSC) emerges as a sustainable alternative to ordinary Portland cement, boasting minimal carbon emissions and exceptional performance. As the quest for eco-friendly alternatives intensifies, there's a growing focus on exploring alkaline and sulfate activators conducive to SSC's environmental goals. This study delves into the viability of utilizing MgO as an alkaline activator in producing MgO-based supersulfated cement, while also investigating the impact of various industrial by-product gypsums on its performance. Findings reveal that employing MgO as an alkaline activator yields favorable hydration properties and mechanical strength in SSC. The optimized formulation comprises 15 % industrial by-product gypsum, 83 % granulated blast furnace slag (GGBFS), and 2 % MgO. Incorporating building gypsum and flue gas desulfurization (FGD) gypsum demonstrates superior unconfined compressive strength (UCS) growth compared to citric gypsum and phosphogypsum. Notably, gel-pores below 20 nm dominate the matrix, with variations in their distribution linked to the gypsum type used. The pH level and crystal structure of the industrial by-product gypsum emerge as pivotal factors dictating the hydration process. The interaction energy between hydrated building gypsum crystal planes and water molecules proves lower, contributing to the root cause of its high sulfate activating capability. Compared to traditional SSC, MgO-based supersulfated cement requires less alkaline activator content and accommodates more industrial by-product gypsums, thus reducing costs, CO2 emissions, and promoting the efficient utilization of these solid wastes.

Regulating the Solvation Structure in Polymer Electrolytes for High-Voltage Lithium Metal Batteries.

Solid polymer electrolytes are promising electrolytes for safe and high-energy-density lithium metal batteries. However, traditional ether-based polymer electrolytes are limited by their low lithium-ion conductivity and narrow electrochemical window because of the well-defined and intimated Li+-oxygen binding topologies in the solvation structure. Herein, we proposed a new strategy to reduce the Li+-polymer interaction and strengthen the anion-polymer interaction by combining strong Li+-O (ether) interactions, weak Li+-O (ester) interactions with steric hindrance in polymer electrolytes. In this way, a polymer electrolyte with a high lithium ion transference number (0.80) and anion-rich solvation structure is obtained. This polymer electrolyte possesses a wide electrochemical window (5.5 V versus Li/Li+) and compatibility with both Li metal anode and high-voltage NCM cathode. Li||LiNi0.5Co0.2Mn0.3O2 full cells with middle-high active material areal loading (~7.5 mg cm-2) can stably cycle at 4.5 V. This work provides new insight into the design of polymer electrolytes for high-energy-density lithium metal batteries through the regulation of ion-dipole interactions.

Establishment of a scoring model for predicting clinical outcomes in patients with unilateral primary aldosteronism after superselective adrenal artery embolization.

OBJECTIVE: Superselective adrenal arterial embolization (SAAE) is a potential alternative treatment for patients with unilateral primary aldosteronism (PA) who refuse unilateral adrenalectomy. Therefore, we aimed to establish a scoring model to differentiate between hypertensive remission after SAAE. METHODS: This prospective cohort study involved 240 patients who underwent SAAE for unilateral PA. Patients were randomly divided into a model training set and a validation set at a ratio of 7:3. The clinical outcome was a response to hypertension remission, defined as complete, partial, or absent success at 6 months after SAAE. Multivariate logistic regression was performed to identify independent parameters and develop a nomogram to predict clinical outcomes after SAAE. The discrimination, calibration efficacy, and clinical utility of the predictive model were assessed. RESULTS: Five independent predictors were identified: female sex, duration of hypertension, defined daily dose of antihypertensive medication, diabetes, and target organ damage. The above five independent predictors were put into a predictive model that was presented as a nomogram. Using bootstrapping for internal validation, the C-statistic for the predictive model was 0.866 (95% confidence interval [CI]: 0.834 to 0.898). In the validation cohort, the area under the curve (AUC) of the nomogram for predicting hypertension remission after SAAE was 0.809. CONCLUSION: The present model is the first nomogram-based score that specifically predicts hypertension remission after SAAE in patients with unilateral PA using conventional parameters. This is an effective risk stratification tool that can be used by clinicians for timely and tailored preoperative risk discussions.

Occurrence and Reduction of Hepatitis B Vaccine Hesitancy Among Medical University Students - Shanxi Province, China, 2020.

What is already known about this topic?: Previous research has primarily examined the issue of hepatitis B vaccine hesitancy in migrant workers and other adult populations. However, there is a lack of studies that have specifically investigated the prevalence of hepatitis B vaccine hesitancy among university students. What is added by this report?: In this study, 19.84% of students expressed hesitancy towards receiving the hepatitis B immunization. A negative correlation was observed between hepatitis B vaccine hesitancy and knowledge, attitudes, and practices related to hepatitis B. Conversely, a positive relationship was identified between hepatitis B-related knowledge and attitudes and practices. What are the implications for public health practice?: This study examines the factors contributing to vaccine hesitancy towards hepatitis B at a medical university in China. The results have significant implications for developing strategies to improve hepatitis B vaccination rates.

Doping and strain modulation of the electronic, optical and photocatalytic properties of the GaN/C2N heterostructure.

The electronic, optical and photocatalytic properties of GaN/C2N van der Waals heterostructures are investigated using the first-principles theory, and effective regulation through element doping or strain is achieved further. The results show that the GaN/C2N heterostructure exhibits a type-II band alignment with an indirect band gap of 2.25 eV, which benefits photocatalytic water splitting. In this study, both type-I and type-II band alignments can be obtained through doping or strain modulation. Doping with P or As atoms reduces the band gap of the GaN/C2N heterostructure and transforms it to a type-I direct bandgap semiconductor, which makes the doped GaN/C2N heterostructure more suitable for optoelectronic devices. In addition, the GaN/C2N heterostructure retains type-II band alignment and has a decreased band gap under tensile strain (0 to +4%), which is more favorable for photocatalytic water splitting. Compressive strain (0 to -4%) converts the type-II band alignment to type-I, resulting in a wider light absorption range, making the GaN/C2N heterostructure more suitable for optoelectronic devices. These theoretical results are helpful for the design of GaN/C2N vdW heterostructures in the fields of optoelectronic devices and photocatalysts.

A mitochondrion-targeted cyanine agent for NIR-II fluorescence-guided surgery combined with intraoperative photothermal therapy to reduce prostate cancer recurrence.

Poorly identified tumor boundaries and nontargeted therapies lead to the high recurrence rates and poor quality of life of prostate cancer patients. Near-infrared-II (NIR-II) fluorescence imaging provides certain advantages, including high resolution and the sensitive detection of tumor boundaries. Herein, a cyanine agent (CY7-4) with significantly greater tumor affinity and blood circulation time than indocyanine green was screened. By binding albumin, the absorbance of CY7-4 in an aqueous solution showed no effects from aggregation, with a peak absorbance at 830 nm and a strong fluorescence emission tail beyond 1000 nm. Due to its extended circulation time (half-life of 2.5 h) and high affinity for tumor cells, this fluorophore was used for primary and metastatic tumor diagnosis and continuous monitoring. Moreover, a high tumor signal-to-noise ratio (up to ~ 10) and excellent preferential mitochondrial accumulation ensured the efficacy of this molecule for photothermal therapy. Therefore, we integrated NIR-II fluorescence-guided surgery and intraoperative photothermal therapy to overcome the shortcomings of a single treatment modality. A significant reduction in recurrence and an improved survival rate were observed, indicating that the concept of intraoperative combination therapy has potential for the precise clinical treatment of prostate cancer.

Associations between Physical Activity and the Incidence of Cerebrovascular Disease or All-Cause Mortality among 146,742 Older Adults: A 13-Year Prospective Cohort Study.

OBJECTIVES: Although studies have indicated that physical activity (PA) is related to cardiovascular disease, the specific association between PA and incident cerebrovascular disease (CBVD) remains uncertain. The current study aimed to investigate the associations between PA levels and the CBVD incidence or all-cause mortality. DESIGN: Prospective cohort study. SETTINGS AND PARTICIPANTS: Older participants (aged >60 years) from the UK Biobank. METHODS: The baseline PA was classified as total, light, moderate, and vigorous PA based on the metabolic equivalent-minutes per week (MET-min/wk) and considered as exposures, whereas CBVD incidence and all-cause mortality were considered as the outcomes. Cox proportional hazards were used to calculate the hazard ratios (HRs) and 95% CIs for the influence of the association between PA and CBVD incidence and all-cause mortality. RESULTS: A total of 146,742 participants aged 60 years and older were included. During a median follow-up period of 13.5 years (interquartile range of 12.8-14.2), 9338 older individuals developed CBVD and 3033 death were recorded (including 767 CBVD-related deaths). High volumes of PA were consistently associated with lower risks of CBVD and all-cause mortality. The lowest risk of CBVD incidence was observed at 2001-2500 MET-min/wk of total PA (HR 0.61, 95% CI 0.53-0.70), and the lowest risk of all-cause mortality was observed at 2501-5000 MET-min/wk (HR 0.52, 95% CI 0.43-0.63) in older adults. Total PA at 2001-2500 MET-min/wk significantly reduced the CBVD incidence in older women (HR 0.57, 95% CI 0.46-0.71), which was more pronounced than that in older men (HR for 2001-2500 MET-min/wk: 0.64, 95% CI 0.50-0.77). CONCLUSIONS AND IMPLICATIONS: Total PA at 2001-2500 MET-min/wk significantly reduced the risk of incident CBVD and all-cause mortality in adults aged >60 years, although the extents of risk reduction vary in men and women.

Ganoderic acid A mitigates dopaminergic neuron ferroptosis via inhibiting NCOA4-mediated ferritinophagy in Parkinson's disease mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Ganoderma lucidum, a renowned tonic traditional Chinese medicine, is widely recognized for the exceptional activity in soothing nerves and nourishing the brain. It has been extensively employed to alleviate various neurological disorders, notably Parkinson's disease (PD). AIM OF THE STUDY: To appraise the antiparkinsonian effect of GAA, the main bioactive constituent of G. lucidum, and clarify the molecular mechanism through the perspective of ferritinophagy-mediated dopaminergic neuron ferroptosis. MATERIALS AND METHODS: PD mouse and cell models were established using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 1-methyl-4-phenylpyridinium (MPP+), respectively. Cell viability, behavioral tests and immunofluorescence analysis were performed to evaluate the neurotoxicity, motor dysfunction and dopaminergic loss, respectively. Biochemical assay kits were used to determine the levels of iron, lipid reactive oxygen species (ROS), malondialdehyde (MDA), total ROS and glutathione (GSH). Western blot and immunofluorescence were applied to detect the expressions of nuclear receptor co-activator 4 (NCOA4), ferritin heavy chain 1 (FTH1), p62 and LC3B. Additionally, NCOA4-overexpressing plasmid vector was constructed to verify the inhibitory effect of GAA on the neurotoxicity and ferroptosis-related parameters in PD models. RESULTS: GAA significantly mitigated MPP+/MPTP-induced neurotoxicity, motor dysfunction and dopaminergic neuron loss (p＜0.01 or p＜0.05). In contrast to MPP+/MPTP treatment, GAA treatment decreased the levels of iron, MDA, lipid and total ROS, while increasing the GSH level. GAA also reduced the levels of NCOA4 and LC3B, and enhanced the expressions of FTH1 and p62 in PD models (p＜0.01 or p＜0.05). However, the protective effect of GAA against the neurotoxicity, NCOA4-mediated ferritinophagy and ferroptosis in PD model was abolished by the overexpression of NCOA4 (p＜0.01). CONCLUSION: GAA exerted a protective effect on PD, and this effect was achieved by suppressing dopaminergic neuron ferroptosis through the inhibition of NCOA4-mediated ferritinophagy.

Polyfluoroalkyl Tag Decoration Enables Significantly Enhanced Tumor Penetration Ability of a PTK7 Targeting Aptamer.

Aptamers are widely used molecular recognition tools in targeted therapy, but their ability to effectively penetrate deep into solid tumors remains a significant challenge, leading to suboptimal treatment efficacy. Here, we developed a polyfluoroalkyl (PFA) decoration strategy to enhance aptamer recognition, cell internalization, and solid tumor penetration. Our results indicate that PFA with around 11 fluorine atoms significantly improves aptamer internalization both in vitro and in vivo settings. However, we also observed that the use of PFA tags containing 19 and 23 fluorine atoms on aptamers resulted in nonspecific cell anchoring in control cell lines, affecting the specificity of aptamers. Overall, we found that using a chemical modification strategy could enhance the deep tumor penetration ability of aptamers and validate their effectiveness in vivo. This approach has significant practical applications in targeted drug delivery for cancer treatment.

Kinetic Evaluation on Lithium Polysulfide in Weakly Solvating Electrolyte toward Practical Lithium-Sulfur Batteries.

Lithium-sulfur (Li-S) batteries are highly considered as next-generation energy storage techniques. Weakly solvating electrolyte with low lithium polysulfide (LiPS) solvating power promises Li anode protection and improved cycling stability. However, the cathodic LiPS kinetics is inevitably deteriorated, resulting in severe cathodic polarization and limited energy density. Herein, the LiPS kinetic degradation mechanism in weakly solvating electrolytes is disclosed to construct high-energy-density Li-S batteries. Activation polarization instead of concentration or ohmic polarization is identified as the dominant kinetic limitation, which originates from higher charge-transfer activation energy and a changed rate-determining step. To solve the kinetic issue, a titanium nitride (TiN) electrocatalyst is introduced and corresponding Li-S batteries exhibit reduced polarization, prolonged cycling lifespan, and high actual energy density of 381 Wh kg-1 in 2.5 Ah-level pouch cells. This work clarifies the LiPS reaction mechanism in protective weakly solvating electrolytes and highlights the electrocatalytic regulation strategy toward high-energy-density and long-cycling Li-S batteries.