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Available evidence suggests that air pollutants can cause stroke, but little research has investigated the confounding effects of urban-rural differences. Here, we investigated the urban-rural difference in the correlation between particulate matter (PM 2.5 and PM 10 ) exposure and stroke. This cohort study was based on a prospective multi-city community-based cohort (Guizhou Population Health Cohort Study (GPHCS)) in Guizhou Province, China. A total of 7988 eligible individuals (≥18 years) were enrolled with baseline assessments from November 2010 to December 2012, and follow-up was completed by June 2020. Two major particulate matters (PMs, including PM 2.5 and PM 10 ) were assessed monthly from 2000 by using satellite-based spatiotemporal models. The risk of stroke was estimated using a Cox proportional hazard regression model. The association between particulate matters' exposure and stroke in different areas (total, urban, and rural) and the potential modification effect of comorbidities (hypertension, diabetes, and dyslipidemia) and age (≤65/>65 years) were examined using stratified analyses. The risk of stroke increased for every 10 μg/m 3 increase in mean PMs' concentrations during the previous 1 year at the residential address (HR: 1.26, 95%CI: 1.24, 1.29 (PM 2.5 ); HR: 1.13, 95%CI: 1.11, 1.15 (PM 10 )). The presence of diabetes and dyslipidemia increased the risk of PM 10 -induced stroke in whole, urban, and rural areas. Specifically, people living in rural areas were more likely to experience the effects of PMs in causing a stroke. The risk of stroke due to PMs was statistically increased in the young and older populations living in rural areas. In conclusion, long-term exposure to PMs increased the risk of stroke and such association was more pronounced in people living in rural areas with lower income levels. Diabetes and dyslipidemia seemed to strengthen the association between PMs and stroke., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: Hormone replacement therapy (HRT) is a commonly used strategy for treating menopausal symptoms, while its relation with periodontitis remains unclear. This study aimed to explore the potential effects of HRT on periodontitis, mainly in aspects of bone loss and inflammation., Methods: The alveolar bone height (ABH), alveolar bone thickness (ABT), and bone mineral density (BMD) were measured in menopausal women with periodontitis who had received HRT or had not received HRT by cone beam computed tomography. Based on a rat model of periodontitis, the alveolar bone loss was evaluated by micro-computed tomography and bone-related biochemical markers. The expression/levels of inflammatory markers were measured to reflect periodontal inflammation., Results: Although the differences were not all significant in each premolars/molars, the mesial/distal ABH and buccal/lingual ABT were lower, and the mesial/distal BMD was higher in patients in the HRT group than those in the control group. In a rat model of periodontitis, the alveolar bone loss was relieved by HRT. Additionally, HRT significantly weakened the elevation of inflammatory markers, including TNF-α, IL-1β, and IL-6 in periodontitis rats., Conclusions: HRT contributes to the remission of periodontitis by inhibiting alveolar bone loss and inflammation., (© 2024 John Wiley & Sons Ltd.)

As one molecule related to cytotoxicity, surface expression of C-X3-C motif receptor 1 (CX3CR1) was highly correlated with intracellular granzyme B (GZMB) in natural killer and cytolytic T cells. However, the expression of CX3CR1 and GZMB in B cells has not been clarified, and their clinical significance in systemic lupus erythematosus (SLE) remains unclear. This study aimed to clarify the changes and clinical significance of peripheral blood B cells expressing GZMB and/or CX3CR1 in SLE. Peripheral blood was collected from 39 patients with SLE and 48 healthy controls. We found that GZMB and CX3CR1 expression varied in different B-cell subsets, with plasmablasts possessing the highest positive percentages, consistent with bioinformatics prediction. GZMB+ and CX3CR1+ percentages in circulating B cells and plasmablasts were increased in patients with SLE. CX3CR1 was upregulated on B cells after in vitro stimulation. Notch intracellular domain expression was significantly decreased in plasmablasts of patients with SLE, and CX3CR1 in plasmablasts was downregulated with the addition of JAG1. In conclusion, GZMB and CX3CR1 were increased in B cells and in plasmablasts of patients with SLE and CX3CR1 was negatively regulated by Notch signal in plasmablasts, which may be involved in SLE pathogenesis., Competing Interests: Conflict of interest statement. None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for Leukocyte Biology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

The instability to moisture, heat, and ultraviolet (UV) light is the main problem in the application of quantum dot solar cells (QDSCs). Thin film encapsulation can effectively improve their operational stability. However, it is difficult to achieve multiple barrier effects with single layer of encapsulated film. Here, a hybrid thin-film encapsulation strategy is reported to encapsulate lead sulfide QDSCs, which can isolate moisture and partial thermal, and prevent the penetration of UV light, thus retarding the surface oxidation process of the quantum dots. After 60 h, the encapsulated device retains a normalized power conversion efficiency of 83.8% and 80.6% at 85% humidity and 75 °C, respectively, which is three and six times of the value obtained in unencapsulated devices. At continuous UV illumination, encapsulated device exhibits five times higher stability than the reference. This strategy provides the way for the overall improvement of the operating stability of lead sulfide QDSCs in harsh environments of high humidity, high temperature, and UV light., (© 2024 Wiley‐VCH GmbH.)

Background: Acne is a chronic inflammatory and immune-mediated disease of the pilosebaceous unit (the skin structure consisting of a hair follicle and its associated sebaceous gland). It is characterised by non-inflammatory lesions (open and closed comedones) and inflammatory lesions (papules, pustules, nodules, and cysts). Lesions may be present on the face, thorax, and back, with variable severity. Acne exhibits a global distribution and has a growing prevalence. Acne vulgaris is the most common form. Acne gives rise to complications such as scars and can seriously affect people's mental health, especially those with severe acne. Acne has a huge impact on the quality of life and self-esteem of those affected., Objectives: To synthesise the existing evidence on the efficacy and safety of non-systemic pharmacological interventions and non-pharmacological interventions (physical therapy and complementary therapies) in the treatment of acne vulgaris and related skin complications., Methods: We searched the Cochrane Database of Systematic Reviews, Epistemonikos, MEDLINE, and Embase to 2 December 2021, and checked the reference lists of included reviews. At least two authors were responsible for screening, data extraction, and critical appraisal. We excluded reviews with high risk of bias as assessed with the ROBIS tool. We evaluated the overall certainty of the evidence according to GRADE (as carried out by the authors of the included reviews or ourselves). We provide comprehensive evidence from the review data, including summary of findings tables, summary of results tables, and evidence maps., Main Results: We retrieved and assessed a total of 733 records; however, only six reviews (five Cochrane reviews and one non-Cochrane review) with low risk of bias met the overview inclusion criteria. The six reviews involved 40,910 people with acne from 275 trials and 1316 people with acne scars from 37 trials. The age of the participants ranged from 10 to 59 years, with an average age range from 9.8 to 30 years. Four reviews included original trials involving only female participants and three reviews included original trials with only male participants. Main results for clinically important comparisons: Benzoyl peroxide versus placebo or no treatment: In two trials involving 1012 participants over 12 weeks, benzoyl peroxide may reduce the total (mean difference (MD) -16.14, 95% confidence interval (CI) -26.51 to -5.78), inflammatory (MD -6.12, 95% CI -11.02 to -1.22), and non-inflammatory lesion counts (MD -9.69, 95% CI -15.08 to -4.29) when compared to placebo (long-term treatment), but the evidence is very uncertain (very low-certainty evidence). Two trials including 1073 participants (time point: 10 and 12 weeks) suggested benzoyl peroxide may have little to no effect in improving participants' global self-assessment compared to placebo (long-term treatment), but the evidence is very uncertain (risk ratio (RR) 1.44, 95% CI 0.94 to 2.22; very low-certainty evidence). Very low-certainty evidence suggested that benzoyl peroxide may improve investigators' global assessment (RR 1.77, 95% CI 1.37 to 2.28; 6 trials, 4110 participants, long-term treatment (12 weeks)) compared to placebo. Thirteen trials including 4287 participants over 10 to 12 weeks suggested benzoyl peroxide may increase the risk of a less serious adverse event compared to placebo (long-term treatment), but the evidence is very uncertain (RR 1.46, 95% CI 1.01 to 2.11; very low-certainty evidence). Benzoyl peroxide versus topical retinoids: Benzoyl peroxide may increase the percentage change in total lesion count compared to adapalene (long-term treatment), but the evidence is very uncertain (MD 10.8, 95% CI 3.38 to 18.22; 1 trial, 205 participants, 12 weeks; very low-certainty evidence). When compared to adapalene, benzoyl peroxide may have little to no effect on the following outcomes (long-term treatment): percentage change in inflammatory lesion counts (MD -7.7, 95% CI -16.46 to 1.06; 1 trial, 142 participants, 11 weeks; very low-certainty evidence), percentage change in non-inflammatory lesion counts (MD -3.9, 95% CI -13.31 to 5.51; 1 trial, 142 participants, 11 weeks; very low-certainty evidence), participant's global self-assessment (RR 0.96, 95% CI 0.86 to 1.06; 4 trials, 1123 participants, 11 to 12 weeks; low-certainty evidence), investigators' global assessment (RR 1.16, 95% CI 0.98 to 1.37; 3 trials, 1965 participants, 12 weeks; low-certainty evidence), and incidence of a less serious adverse event (RR 0.77, 95% CI 0.48 to 1.25, 1573 participants, 5 trials, 11 to 12 weeks; very low-certainty evidence). Benzoyl peroxide versus topical antibiotics: When compared to clindamycin, benzoyl peroxide may have little to no effect on the following outcomes (long-term treatment): total lesion counts (MD -3.50, 95% CI -7.54 to 0.54; 1 trial, 641 participants, 12 weeks; very low-certainty evidence), inflammatory lesion counts (MD -1.20, 95% CI -2.99 to 0.59; 1 trial, 641 participants, 12 weeks; very low-certainty evidence), non-inflammatory lesion counts (MD -2.4, 95% CI -5.3 to 0.5; 1 trial, 641 participants, 12 weeks; very low-certainty evidence), participant's global self-assessment (RR 0.95, 95% CI 0.68 to 1.34; 1 trial, 240 participants, 10 weeks; low-certainty evidence), investigator's global assessment (RR 1.10, 95% CI 0.83 to 1.45; 2 trials, 2277 participants, 12 weeks; very low-certainty evidence), and incidence of a less serious adverse event (RR 1.27, 95% CI 0.98 to 1.64; 5 trials, 2842 participants, 10 to 12 weeks; low-certainty evidence). For these clinically important comparisons, no review collected data for the following outcomes: frequency of participants experiencing at least one serious adverse event or quality of life. No review collected data for the following comparisons: topical antibiotics versus placebo or no treatment, topical retinoids versus placebo or no treatment, or topical retinoids versus topical antibiotics., Authors' Conclusions: This overview summarises the evidence for topical therapy, phototherapy, and complementary therapy for acne and acne scars. We found no high-certainty evidence for the effects of any therapy included. Randomised controlled trials and systematic reviews related to acne and acne scars had limitations (low methodological quality). We could not summarise the evidence for topical retinoids and topical antibiotics due to insufficient high-quality systematic reviews. Future research should consider pooled analysis of data on new emerging drugs for acne treatment (e.g. clascoterone) and focus more on acne complications., (Copyright © 2024 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background: To estimate and compare the association between metabolically healthy overweight/obesity (MHO) and the risk of type 2 diabetes (T2DM) among different ethnic groups in southwest China, while also exploring possible ethnic differences., Methods: This is a prospective cohort study of 6,820 participants in Southwest China. MHO was defined as body mass index (BMI) ≥ 24 kg/m 2 and the presence of ≤ 1 component of metabolic syndrome. Cox proportional risk models were utilized to analyze the association between MHO and the risk of T2DM., Results: The median follow-up time was 6.58 years, during which 708 new cases of T2DM were diagnosed. In the total population, after adjusting for confounding factors, MHO was found to increase the risk of T2DM compared to metabolically healthy normal weight (MHNW) individuals (HR = 1.49, 95% CI: 1.15-1.93). Subgroup analysis by ethnicity revealed that, MHO increased the risk of T2DM in the Han population (HR = 1.64, 95% CI: 1.21-2.23), however, the difference was not statistically significant in the ethnic minority population.The results of sensitivity analysis further supported the robustness of these findings. Meanwhile, stratified by sex, age, and urban/rural, it was found that ethnic differences in the association between MHO and T2DM still existed, however, it is important to note that the association between MHO and T2DM was not statistically significant in the Han population subgroup aged ≥ 45 years (p > 0.05)., Conclusion: MHO was associated with an increased risk of T2DM compared to MHNW, and there are ethnic differences. Future interventions need to be strengthened for Han Chinese key populations to reduce the risk of T2DM., (© 2024. The Author(s).)

Landfills are struggling to accommodate the increasing amounts of carbon soot ash waste from oil refineries. Due to extensive industrial productions, large quantities of lead ions are released into the environment, which not only pollutes the environment but also affects flora and fauna. In this work, these urgent environmental issues will be tackled by studying the use of modified carbon soot ash for specific heavy metal adsorption. Carbon soot ash modified with chemical leaching and physical ball-milling was loaded onto the surface of graphene oxide. This adsorbent was found to selectively adsorb and remove toxic lead ions (>99%) from a mixed heavy metal solution. The adsorption efficiency was found to increase with temperature (20-60 °C) and pH (2-8). Langmuir isotherm and pseudo-second order kinetics were found to fit the adsorption process through curve fitting, where the adsorbent reached a maximum capacity of 194.55 mg/g. Potential mechanisms for lead adsorption and metal specificity are also discussed here. This work aligns with the waste-to-resource pathway, where waste carbon soot ash is diverted from landfilling and is formulated as a specific heavy metal adsorbent, that shows promise for environmental remediation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objective: To investigate the causal effect of protein intake on hypertension and the related mediating pathways., Patients and Methods: Using genome-wide association study summary statistics of European ancestry, we applied univariable and multivariable Mendelian randomization to estimate the bidirectional associations of relative protein intake and related metabolomic signatures with hypertension (FinnGen: Ncase=42,857/Ncontrol=162,837; UK Biobank: Ncase=77,723/Ncontrol=330,366) and blood pressure (International Consortium of Blood Pressure: N=757,601) and two-step Mendelian randomization to assess the mediating roles of 40 cardiometabolic factors therein. Mendelian randomization estimates of hypertension from FinnGen and UK Biobank were meta-analyzed without heterogeneity. We performed the study from May 15, 2023, to September 15, 2023., Results: Each 1-SD higher relative protein intake was causally associated with 69% (odds ratio, 0.31; 95% CI, 0.11 to 0.89) lower hypertension risk independent of the effects of other macronutrients, and was the only macronutrient associated with 2.21 (95% CI, 0.52 to 3.91) mm Hg lower pulse pressure, in a unidirectional manner. Higher plant protein-related metabolomic signature (glycine) was associated with lower hypertension risk and pulse pressure, whereas higher animal protein-related metabolomic signatures (leucine, isoleucine, valine, and isovalerylcarnitine [only systolic blood pressure]) were associated with higher hypertension risk, pulse pressure, and systolic blood pressure. The effect of relative protein intake on hypertension was causally mediated by frailty index (mediation proportion, 40.28%), monounsaturated fatty acids (13.81%), saturated fatty acids (11.39%), grip strength (5.34%), standing height (3.99%), and sitting height (3.61%)., Conclusion: Higher relative protein intake causally reduces the risk of hypertension, partly mediated by physical fitness and circulating fatty acids., (Copyright © 2024 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Aims and Objectives: This study explores the situation of workload, work-family conflict and job burnout among primary health workers in China in the context of COVID-19 and identifies the mediating effect of work-family conflict between workload and job burnout., Background: Since the breakout of the COVID-19 pandemic, primary health workers have been working on the frontline of the epidemic and may experience increasing workload, work-family conflict and job burnout. It is important to focus on the issue of how to alleviate job burnout of primary health workers., Design: A cross-sectional study (STROBE) was used., Methods: Data were collected from 785 primary health workers in China. Multiple regression analysis was used to examine the mediating effect of work-family conflict between workload and job burnout., Results: 18.7%, 10.4% and 39.5% of respondents had high job burnout in the dimensions of emotional exhaustion, depersonalization and personal accomplishment, respectively. 34.6% of the respondents had high or very high workload, and 12.8% of the respondents had high or very high work-family conflict. Results of multiple regression analysis indicated that work-family conflict mediated the relationship between workload and job burnout. Workload (β = .163, CI = .207-.549) and work-family conflict (β = .211, CI = .311-.640) positively influenced job burnout, and workload (β = .428, CI = .375-.508) positively influenced work-family conflict., Conclusion: The study indicated that primary health workers experienced a high level of job burnout, especially in the personal accomplishment dimension. Furthermore, this study verified the mediating effect of work-family conflict between workload and job burnout., Relevance to Clinical Practice: Some interventions for alleviating workload, work-family conflict and job burnout should be taken, including workplace assistance programmes, family-friendly policies and a well-integrated healthcare system., No Patient or Public Contribution: This study does not involve patient or public contribution in any part., Impact Statement: Nurses and other primary health workers are health gatekeepers of residents and play a vital role in the healthcare system. Due to the breakout of COVID-19, they have taken more work and are more vulnerable to work overload, work-family conflict and the consequent job burnout. Some interventions should be taken to effectively alleviate their job burnout and improve their health and performance., (© 2024 John Wiley & Sons Ltd.)

Background: Body roundness index (BRI) is an anthropometric measure related to obesity, combining waist circumference (WC) and height to more accurately reflect body fat. This study aims to investigate the relationship between BRI and the risk of hypertension using data from a prospective cohort study in Southwest China., Methods: Data for the study were derived from Guizhou Population Health Cohort Study (GPHCS), established in 2010. A total of 9,280 participants (aged 18 to 95 years, mean 41.53 ± 14.15 years) from 48 townships across 12 districts/counties were surveyed at baseline through multistage stratified random cluster sampling. Cox proportional risk models were employed to analyze the association between BRI and the risk of hypertension, estimating hazard ratios (HRs) and 95% confidence intervals (CIs) after adjusting for confounding factors. The relationship between BRI and the onset time of hypertension was analyzed using the time failure acceleration model., Results: Over a median follow-up period of 6.64 years, 1,157 participants were diagnosed with hypertension. After adjusting for confounding variables, each unit increase in BRI was associated with a 17% increase in hypertension risk (HR = 1.17, 95% CI: 1.11, 1.24, P for trend < 0.001). Compared to participants in the first quartile (Q1) of BRI, the risk of hypertension for those in the third quartile (Q3) and fourth quartile (Q4) was 1.31 (95% CI: 1.10, 1.56) and 1.53 (95% CI: 1.28, 1.84), respectively. Each unit increase in BRI advanced the onset of hypertension by 0.26 years (95% CI: 0.16, 0.35)., Conclusion: This study indicates that BRI has a positive association with hypertension and can accelerate the onset of hypertension in the Chinese population. It is suggested that reducing BRI by controlling abdominal fat may be one of the effective measure to prevent hypertension., (© 2024. The Author(s).)

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder marked by the degeneration of motor neurons and progressive muscle weakness. Heredity plays an important part in the pathogenesis of ALS. Recently, with the emergence of the oligogenic pathogenic mechanism in ALS and the ongoing discovery of new mutated genes and genomic variants, there is an emerging need for larger-scale and more comprehensive genetic screenings in higher resolution. In this study, we performed whole-genome sequencing (WGS) on 34 familial ALS probands lacking the most common disease-causing mutations to explore the genetic landscape of Chinese ALS patients further. Among them, we identified a novel ARPP21 c.1231G > A (p.Glu411Lys) variant and two copy number variations (CNVs) affecting the PFN1 and RBCK1 genes in a patient with ALS-frontotemporal dementia (FTD). This marks the first report of an ARPP21 variant in Chinese ALS-FTD patients, providing fresh evidence for the association between ARPP21 and ALS. Our findings also underscore the potential role of CNVs in ALS-FTD, suggesting that the cumulative effect of multiple rare variants may contribute to disease onset. Furthermore, compared to the averages in our cohort and the reported Chinese ALS population, this patient displayed a shorter survival time and more rapid disease progression, suggesting the possibility of an oligogenic mechanism in disease pathogenesis. Further research will contribute to a deeper understanding of the rare mutations and their interactions, thus advancing our understanding of the genetic mechanisms underlying ALS and ALS-FTD., (© 2024. Fondazione Società Italiana di Neurologia.)

Objectives: The characterization of DNA polymerase epsilon (POLE) mutations has transformed the classification of endometrial endometrioid carcinomas (EECs), highlighting the need for efficient identification methods. This study aims to examine the relationship between distinct morphologic features-namely, squamous morules and squamous differentiation (SD), as well as β-catenin expression-and the POLE mutation status in endometrial cancer (EC)., Methods: Our study included 35 POLE-mutated (POLEmut) EC cases and 395 non-POLEmut EEC cases., Results: Notably, we observed no presence of morules in POLEmut cases, while SD was identified in 20% of instances. Conversely, morules and SD were identified in 12.7% and 26.1% of non-POLEmut EC cases, respectively, with morules consistently linked to a POLE wild-type status. The nuclear β-catenin expression is typically absent in tumors with wild-type POLE (wt-POLE) status., Conclusions: Our findings suggest that the presence of either morules or nuclear β-catenin expression in EEC could practically rule out the presence of POLE mutations. These morphologic and immunohistochemical features can be used as preliminary screening tools for POLE mutations, offering significant savings in time and resources and potentially enhancing clinical decision-making and patient management strategies. However, further validation in larger, multi-institutional studies is required to fully understand the implications of these findings on clinical practice., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Society for Clinical Pathology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

High-quality transparent electrodes are indispensable components of flexible optoelectronic devices as they guarantee sufficient light transparency and electrical conductivity. Compared to commercial indium tin oxide, metal nanowires are considered ideal candidates as flexible transparent electrodes (FTEs) owing to their superior optoelectronic properties, excellent mechanical flexibility, solution treatability, and higher compatibility with semiconductors. However, certain key challenges associated with material preparation and device fabrication remain for the practical application of metal nanowire-based electrodes. In this review, we discuss state-of-the-art solution-processed metal nanowire-based FTEs and their applications in flexible and stretchable optoelectronic devices. Specifically, the important properties of FTEs and a cost-benefit analysis of existing technologies are introduced, followed by a summary of the synthesis strategy, key properties, and fabrication technologies of the nanowires. Subsequently, we explore the applications of metal-nanowire-based FTEs in different optoelectronic devices including solar cells, photodetectors, and light-emitting diodes. Finally, the current status, future challenges, and emerging strategies in this field are presented.

Benign prostatic hyperplasia (BPH) is a prevalent urological condition that predominantly affects the geriatric male population, resulting in lower urinary tract symptoms. Saw palmetto is a traditional Chinese medicine for treating BPH. This study aimed to investigate the potential therapeutic mechanisms of saw palmetto in BPH treatment. The active ingredients and potential targets of saw palmetto were obtained through the TCMSP database. BPH-related targets were retrieved from the GeneCards database. PPI, GO, and KEEG analyses were performed to predict the potential therapeutic mechanism. The active ingredient-common target and common target-pathway networks were constructed by Cytoscape software. Molecular docking and cellular experiments were carried out to further validate the potential mechanism. We obtained 13 active components in saw palmetto and 56 common targets in BPH treatment. KEEG analysis showed that the estrogen signaling pathway was the most enriched and exhibited a close association with BPH. PPI analysis, along with ingredient-target and target-pathway network analyses, indicated that stigmasterol was the core ingredient and PGR, NCOA1, and NCOA2 were identified as the hub genes mediating the effects of saw palmetto against BPH. In addition, molecular docking showed that stigmasterol had strong binding to PGR, NCOA1, and NCOA2. Cellular experiments revealed that stigmasterol significantly increased the percentage of BPH-1 cells in the G0/G1 phase and inhibited cell viability and division. Furthermore, it notably reduced the expression of PGR, NCOA1, and NCOA2. Saw palmetto might inhibit cell viability and division by suppressing the expression of PGR, NCOA1, and NCOA2, thereby playing a therapeutic role in treating BPH., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Metabolic syndrome(MetS) and depression are independently associated with type 2 diabetes (T2DM) risk. However, little is known about the combined effect of MetS and depression on the risk of T2DM. The present study aims to prospectively explore the impact of MetS and depression on T2DM susceptibility among the Chinese general population., Methods: 6489 general population without T2DM adults in Southwest China were recruited from 2010 to 2012. Depression and MetS were prospectively assessed using a 9-item Patient Health Questionnaire(PHQ-9) and Guideline for the prevention and treatment of type 2 diabetes mellitus in China (2020 edition) (CDS2020) during 2016-2020, respectively. Modified Poisson regression models were conducted to estimate relative risk(RR) and 95% confidence intervals (95%CI) for independent and combined associations of MetS and depression with an incidence of T2DM., Results: During a median follow-up of 6.6 years, 678 cases of T2DM were documented. Individuals with MetS were 1.33 times more likely to develop T2DM than those without MetS. The corresponding RR(95%CI) for depression with no depression was 1.45(1.22-1.72). Notably, compared with no MetS or depression, the multivariate-adjusted RR for a combined effect of MetS and depression on the risk of T2DM was 2.11(1.39-3.22). Moreover, an increased risk of T2DM was more apparent in those ≥ 60 years, males, and overweight., Conclusions: Individuals with multimorbidity of MetS and depression are at a higher risk of T2DM compared with those with no MetS or depression., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Cai, Zhou, Fan, Yang, Tian, Luo, Deng, Dai, Wang, Zhu and Liu.)

The human in vitro organotypic air-liquid-interface (ALI) airway tissue model is structurally and functionally similar to the human large airway epithelium and, as a result, is being used increasingly for studying the toxicity of inhaled substances. Our previous research demonstrated that DNA damage and mutagenesis can be detected in human airway tissue models under conditions used to assess general and respiratory toxicity endpoints. Expanding upon our previous proof-of-principle study, human airway epithelial tissue models were treated with 6.25-100 µg/mL ethyl methanesulfonate (EMS) for 28 days, followed by a 28-day recovery period. Mutagenesis was evaluated by Duplex Sequencing (DS), and clonal expansion of bronchial-cancer-specific cancer-driver mutations (CDMs) was investigated by CarcSeq to determine if both mutation-based endpoints can be assessed in the same system. Additionally, DNA damage and tissue-specific responses were analyzed during the treatment and following the recovery period. EMS exposure led to time-dependent increases in mutagenesis over the 28-day treatment period, without expansion of clones containing CDMs; the mutation frequencies remained elevated following the recovery. EMS also produced an increase in DNA damage measured by the CometChip and MultiFlow assays and the elevated levels of DNA damage were reduced (but not eliminated) following the recovery period. Cytotoxicity and most tissue-function changes induced by EMS treatment recovered to control levels, the exception being reduced proliferating cell frequency. Our results indicate that general, respiratory-tissue-specific and genotoxicity endpoints increased with repeat EMS dosing; expansion of CDM clones, however, was not detected using this repeat treatment protocol. DISCLAIMER: This article reflects the views of its authors and does not necessarily reflect those of the U.S. Food and Drug Administration. Any mention of commercial products is for clarification only and is not intended as approval, endorsement, or recommendation., Competing Interests: Declaration of Competing Interest Authors have no conflict of interest, financial or otherwise., (Copyright © 2024. Published by Elsevier B.V.)

Objective: The present study aimed to investigate the specific alterations of brain networks in patients with post-stroke depression (PSD), and further assist in elucidating the brain mechanisms underlying the PSD which would provide supporting evidence for early diagnosis and interventions for the disease., Methods: Resting-state functional magnetic resonace imaging data were acquired from 82 nondepressed stroke patients (Stroke), 39 PSD patients, and 74 healthy controls (HC). Voxel-wise degree centrality (DC) conjoined with seed-based functional connectivity (FC) analyses were performed to investigate the PSD-related connectivity alterations. The relationship between these alterations and depression severity was further examined in PSD patients., Results: Relative to both Stroke and HC groups, (1) PSD showed increased centrality in regions within the default mode network (DMN), including contralesional angular gyrus (ANG), posterior cingulate cortex (PCC), and hippocampus (HIP). DC values in contralesional ANG positively correlated with the Patient Health Questionnaire-9 (PHQ-9) scores in PSD group. (2) PSD exhibited increased connectivity between these three seeds showing altered DC and regions within the DMN: bilateral medial prefrontal cortex and middle temporal gyrus and ipsilesional superior parietal gyrus, and regions outside the DMN: bilateral calcarine, ipsilesional inferior occipital gyrus and contralesional lingual gyrus, while decreased connectivity between contralesional ANG and contralesional supramarginal gyrus. Moreover, these FC alterations could predict PHQ-9 scores in PSD group., Interpretation: These findings highlight that PSD was related with increased functional connectivity strength in some areas within the DMN, which might be attribute to the specific alterations of connectivity between within DMN and outside DMN regions in PSD., (© 2024 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Running exercise has been shown to alleviate depressive symptoms. However, the mechanism underlying the antidepressant effects of running exercise is not fully understood. The imbalance of M1/M2 microglia phenotype/polarization and concomitant dysregulation of neuroinflammation play crucial roles in the pathogenesis of depression. Running exercise increases circulating levels of adiponectin which is known to cross the blood‒brain barrier and suppress inflammatory responses. AdipoR1 is an adiponectin receptor that is involved in regulating microglial phenotypes and activation states. However, whether running exercise regulates hippocampal microglial phenotypes and neuroinflammation through adiponectin/AdipoR1 to exert its antidepressant effects remains unclear. In the current study, 4 weeks of running exercise significantly alleviated the depressive-like behaviors of chronic unpredictable stress (CUS)-exposed mice. Moreover, running exercise decreased the microglial numbers and altered microglial morphology in three subregions of the hippocampus to restore the M1/M2 balance; these effects were accompanied by regulation of pro-/anti-inflammatory cytokine production and secretion in CUS-exposed mice. These effects may involve elevation of peripheral tissue (adipose tissue and muscle) and plasma adiponectin levels, and hippocampal AdipoR1 levels as well as activation of the AMPK-NF-κB/STAT3 signaling pathway by running exercise. When an adeno-associated virus was used to knock down hippocampal AdipoR1, mice showed depressive-like behaviors and alterations in microglia and inflammatory factor expression in the hippocampus that were similar to those observed in CUS-exposed mice. Together, these results suggest that running exercise maintains the M1/M2 balance and inhibits neuroinflammation in the hippocampus of CUS-exposed mice. These effects might occur via adiponectin/AdipoR1-mediated activation of the AMPK-NF-κB/STAT3 signaling pathway., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Whole-body vibration (WBV) is a commonly used physical exercise for disease prevention and rehabilitation. Recent studies indicated the beneficial mechanism of WBV may be associated with its anti-inflammatory potential, however, its regulatory roles on different inflammatory mediators remained controversial. The aim of this study was to perform a meta-analysis to re-confirm the effects of WBV exercise on various inflammatory factors., Methods: The PubMed, EMBASE and Cochrane Library databases were searched up to September 2023 to collect all articles comparing WBV with control (or post-pre trials). The effect size was expressed as the standardized mean difference (SMD) and 95% confidence intervals (CI)., Results: A total of 31 eligible studies were included, including 14 pre-clinical and 17 clinical studies. The meta-analysis of pre-clinical studies showed that compared with the control group, WBV exercise could significantly reduce the level of IL-6 (SMD: -1.03, 95% CI: -1.93, -0.13), TNF-α (SMD: -1.36, 95% CI: -2.54, -0.17) (for disease subgroup), IL-1β (SMD: -2.20, 95% CI: -3.24, -1.15), IFN-γ (SMD: -1.91, 95% CI: -2.71, -1.12), IL-4 (SMD: -0.71, 95% CI: -1.39, -0.03) and IL-17 (SMD: -1.32, 95% CI: -2.05, -0.59) overall. Pooling of clinical studies revealed WBV exercise significantly reduced the level of TNF-α (WBV vs control: SMD: -1.11, 95% CI: -2.16, -0.06; post vs pre: SMD: -1.29, 95% CI: -1.91, -0.67), CRP (SMD: -3.59, 95% CI: -6.36, -0.82, P = 0.011) and enhanced the level of IL-10 (WBV vs control: SMD: 2.90, 95% CI: 1.10, 4.71; post vs pre: SMD: 1.75, 95% CI: 0.64, 2.87) and IL-6 (SMD: 0.91, 95% CI: 0.31, 1.52) (healthy subgroup)., Conclusion: WBV may be an effective prevention and rehabilitation tool for inflammatory diseases., Competing Interests: None., (AJCEI Copyright © 2024.)

Recent studies have hinted at a potential link between Alzheimer's Disease (AD) and cancer. Thus, our study focused on finding genes common to AD and Liver Hepatocellular Carcinoma (LIHC), assessing their promise as diagnostic indicators and guiding future treatment approaches for both conditions. Our research utilized a broad methodology, including differential gene expression analysis, Weighted Gene Co-expression Network Analysis (WGCNA), gene enrichment analysis, Receiver Operating Characteristic (ROC) curves, and Kaplan-Meier plots, supplemented with immunohistochemistry data from the Human Protein Atlas (HPA) and machine learning techniques, to identify critical genes and significant pathways shared between AD and LIHC. Through differential gene expression analysis, WGCNA, and machine learning methods, we identified nine key genes associated with AD, which served as entry points for LIHC analysis. Subsequent analyses revealed IKBKE and HSPA1A as shared pivotal genes in patients with AD and LIHC, suggesting these genes as potential targets for intervention in both conditions. Our study indicates that IKBKE and HSPA1A could influence the onset and progression of AD and LIHC by modulating the infiltration levels of immune cells. This lays a foundation for future research into targeted therapies based on their shared mechanisms.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by progressive damage to both upper and lower motor neurons. Genetic factors are known to play a crucial role in ALS, as genetic studies not only advance our comprehension of disease mechanisms but also help unravel the complex phenotypes exhibited by patients. To gain further insights into the genetic landscape of ALS in the Chinese population and explore genotype-phenotype correlations among individuals, we conducted whole-genome sequencing to screen genes in 34 Chinese familial ALS (FALS) probands lacking the most common ALS-associated genes. Within this cohort, we identified a rare heterozygous missense mutation in the N-terminal domain of KIF5A (c.86A>G) in one of the probands. This finding is significant as mutations in the KIF5A gene have been implicated in ALS in European cohorts since 2018, predominantly characterized by C-terminal mutations. Analysis of the clinical phenotype within this familial lineage revealed a delayed onset of symptoms, an extended survival duration, and initial manifestations in both upper limbs. These observations underscore the clinical heterogeneity observed in ALS patients harboring KIF5A mutations. In conclusion, our study contributes to the growing body of evidence linking KIF5A to ALS and enhances our understanding of the intricate genetic landscape of this disease.

Purpose: To investigate the correlation between socioeconomic status (SES) and the incidence of hypertension among adults aged 18 or above in southwest China., Methods: A multistage proportional stratified cluster sampling method was employed to recruited 9280 adult residents from 12 counties in southwest China, with all participants in the cohort tracked from 2016 to 2020. The questionnaire survey gathered information on demographics, lifestyle habits, and household income. The physical exam recorded height, weight, and blood pressure. Biochemical tests measured cholesterol levels. The chi-square test was employed to assess the statistical differences among categorical variables, while the Cox proportional hazards regression model was applied to evaluate the association between socioeconomic status (SES) and the incidence of hypertension., Results: The finally effective sample size for the cohort study was 3546 participants, after excluding 5734 people who met the exclusion criteria. Adults in the highest household income group had a significantly lower risk of hypertension compared to those in the lowest income group (HR = 0.636, 95% CI: 0.478-0.845). Besides, when compared to individuals in the illiterate population, the risk of hypertension among adults with elementary school, junior high school, senior high school and associate degree educational level decreased respectively by 34.4% (HR = 0.656, 95%CI: 0.533-0.807), 44.9% (HR = 0.551, 95%CI: 0.436-0.697), 44.9% (HR = 0.551, 95%CI: 0.405-0.750), 46.1% (HR = 0.539, 95%CI: 0. 340-0.854). After conducting a thorough analysis of socioeconomic status, compared with individuals with a score of 6 or less, the risk of hypertension in participants with scores of 8, 10, 11, 12, and greater than 12 decreased respectively by 23.9% (HR = 0.761, 95%CI: 0.598-0.969), 29.7% (HR = 0.703, 95%CI: 0.538-0.919), 34.0% (HR = 0.660, 95%CI: 0.492-0.885), 34.3% (HR = 0.657, 95%CI: 0.447-0.967), 43.9% (HR = 0.561, 95%CI: 0.409-0.769)., Conclusion: The findings indicate a negative correlation between socioeconomic status and hypertension incidence among adults in southwest China, suggesting that individuals with higher socioeconomic status are less likely to develop hypertension., (© 2024. The Author(s).)

Photosensitizer-mediated abiotic oxidation of Mn(II) can yield soluble reactive Mn(III) and solid Mn oxides. In eutrophic water systems, the ubiquitous algal extracellular organic matter (EOM) is a potential photosensitizer and may have a substantial impact on the oxidation of Mn(II). Herein, we focused on investigating the photochemical oxidation process from Mn(II) to solid Mn oxide driven by EOM. The results of irradiation experiments demonstrated that the generation of Mn(III) intermediate was crucial for the successful photo oxidization of Mn(II) to solid Mn oxide mediated by EOM. EOM can serve as both a photosensitizer and a ligand, facilitating the formation of the Mn(III)-EOM complex. The complex exhibited excellent efficiency in removing 17α-ethinylestradiol. Furthermore, the complex underwent decomposition as a result of reactions with reactive intermediates, forming a solid Mn oxide. The presence of nitrate can enhance the photochemical oxidation process, facilitating the conversion of Mn(II) to Mn(III) and then to solid Mn oxide. This study deepens our grasp of Mn(II) geochemical processes in eutrophic water and its impact on organic micropollutant fate.

Objective: Visceral adipose tissue assessment holds significant importance in hypertension prevention. This study aimed to explore the association between the Metabolic Score for Visceral Fat (METS-VF), a new indicator based on laboratory and anthropometry measures, and hypertension risk and to further investigate the association between the METS-VF and the risk of hypertension in different ethnic groups., Methods: In this study, a total of 9,280 people from 48 townships in 12 districts (counties) of Guizhou Province were selected for the survey using a multistage cluster random sampling method, and 5,127 cases were finally included in the analysis after excluding those with missing relevant data, losing visits, dying at follow-up, those who suffered from hypertension at baseline, and those whose information on the outcome of hypertension was not clear. Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (95% CIs) between METS-VF and incident hypertension, and an accelerated failure time (AFT) model was applied to analyze the association between METS-VF and the onset time of hypertension., Results: The total person-years (PYs) of the 5,127 subjects were 36,188.52 years, and the median follow-up time was 6.64 years. During follow-up, 1,127 patients were newly diagnosed with hypertension, and the incidence density was 31.14/1,000 PYs. After adjusting for multivariables, compared with the METS-VF first (Q1), the third (Q3) and fourth (Q4) groups of the METS-VF increased by 29.9% and 61.5%, respectively (HR = 1.299 [1.061, 1.590] and 1.615 [1.280, 2.036]). The risk of hypertension increased with higher METS-VF values (HR = 1.323 [1.167, 1.500], p trend < 0.001). In the Han Chinese population, Q2 and Q3 increased the risk of hypertension (HR = 1.459 [1.111, 1.917], 1.999 [1.417, 2.718]), and the onset of hypertension was advanced by 0.653 (β = -0.653 (-0.930, -0.375]) years for per 1 unit increase in METS-VF. However, these associations were not found in ethnic minorities., Conclusion: METS-VF was significantly positively associated with the risk of hypertension, and the association was different among ethnic groups., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhang, Wang, Zhou, Yu, Wang, Liu and Yu.)

As one of the most significant pathological changes of diabetic nephropathy (DN), tubulointerstitial fibrosis (TIF) had a close relationship with tubulointerstitial inflammation (TI), and the occurrence of TI could have resulted from the disrupted tight junctions (TJs) of renal tubular epithelial cells (RTECs). Studies have demonstrated that sodium butyrate (NaB), a typical short chain fatty acid (SCFA), played an important regulatory role in intestinal TJs and inflammation. In this study, our in vivo and in vitro results showed that accompanied by TI, renal tubular TJs were gradually disrupted in the process of DN-related TIF. In HG and LPS co-cultured HK-2 cells and db / db mice, NaB treatment regained the TJs of RTECs via the sphingosine 1-phosphate receptor-1 (S1PR1)/AMPK signaling pathway, relieving inflammation. Small interfering RNA of S1PR1, S1PR1 antagonist W146 and agonist SEW2871, and AMPK agonist AICAR were all used to further confirm the essential role of the S1PR1/AMPK signaling pathway in NaB's TJ protection in RTECs in vitro . Finally, NaB administration not only improved the renal function and TIF, but also relieved the TI of db / db mice. These findings suggested that the use of NaB might be a potential adjuvant treatment strategy for DN-associated TIF, and this protective effect was linked to the TJ modulation of RTECs via the S1PR1/AMPK signaling pathway, leading to the improvement of TI.

This article addresses the issues of unreasonable water scheduling and high costs in coal mine shafts, proposing a hierarchical optimization scheduling strategy. Taking the water quality and quantity of a certain mining area in Inner Mongolia as the research object, it designs the objective function with the highest reuse efficiency and the lowest reuse cost of mine water resources, and establishes the constraint conditions of water quality and quantity for each water-using unit. In response to the problem that traditional genetic algorithms are prone to local optima, an adaptive autobiographical operator is proposed and improved based on Metropolis principle of simulated annealing algorithm. The improved algorithm is applied to the calculation of the scheduling model, and the results show that the recovery cost in the heating season is reduced by 66779.36 CNY/month, a decrease of 10.34%; the recovery cost in the non-heating season is reduced by 61469.28 CNY/month, a decrease of 9.91%. At the same time, the heating season and the non-heating season have reduced by 136.99 h/month and 154.52 h/month respectively, significantly reducing the recovery cost and time., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

Objective: Investigation of the effects of 5-5- (4-N, N-diacetoxylphenyl)-10,15,20- tetraphenylporphyrin (DTPP)-mediated photodynamic therapy (PDT) on oxidative stress and mitochondrial apoptosis in LA795 lung cancer cells., Methods: Proteomics was used to identify differentially expressed proteins after PDT treatment. The apoptosis rate was determined by flow cytometry. Morphologic observation of apoptosis, reactive oxygen species (ROS) levels, antioxidant indices, nitric oxide (NO) content, mitochondrial membrane potential (MMP), and Caspase- 9 and Caspase-3 were determined by assays; apoptosis-related protein levels of Cytochrome (Cyto) c, Bcl- 2, Bax were determined by Western blot., Results: Typical apoptosis morphology of LA795 cells was observed after PDT. The cells were mainly in the apoptosis death pathway with high cell apoptosis rates. The proteomics study observed the apoptosis-associated proteins, oxidative stress proteins, antioxidant proteins, the cytoskeletal protein and mitochondrial dysfunction in LA 795 cells. Additional results indicated that PDT could increase levels of ROS, NO; decrease glutathione (GSH) content and MMP; upregulated Bax, Cyto c, and Caspase-3 protein expression, inhibited Bcl-2 protein expression, and further induced cell apoptosis. The effect of DTPP-PDT on lung cancer was: first, mitochondrial Cyto c is released into the cytoplasm, then Caspase- 9 / Caspase-3 was activated, Bcl-2 decreased/Bax increased, initiating cell apoptosis., Conclusion: DTPP-PDT could induce oxidative stress and apoptosis via mitochondrial pathways in LA795 cells., (Copyright © 2023. Published by Elsevier B.V.)

Di-n-butyl phthalate (DBP) is widely used as plasticizer that has potential carcinogenic, teratogenic, and endocrine effects. In the present study, an efficient DBP-degrading bacterial strain 0426 was isolated and identified as a Glutamicibacter sp. strain 0426. It can utilize DBP as the sole source of carbon and energy and completely degraded 300 mg/L of DBP within 12 h. The optimal conditions (pH 6.9 and 31.7 °C) for DBP degradation were determined by response surface methodology and DBP degradation well fitted with the first-order kinetics. Bioaugmentation of contaminated soil with strain 0426 enhanced DBP (1 mg/g soil) degradation, indicating the application potential of strain 0426 for environment DBP removal. Strain 0426 harbors a distinctive DBP hydrolysis mechanism with two parallel benzoate metabolic pathways, which may account for the remarkable performance of DBP degradation. Sequences alignment has shown that an alpha/beta fold hydrolase (WP&#95;083586847.1) contained a conserved catalytic triad and pentapeptide motif (GX1SX2G), of which function is similar to phthalic acid ester (PAEs) hydrolases and lipases that can efficiently catalyze hydrolysis of water-insoluble substrates. Furthermore, phthalic acid was converted to benzoate by decarboxylation, which entered into two different pathways: one is the protocatechuic acid pathway under the role of pca cluster, and the other is the catechol pathway. This study demonstrates a novel DBP degradation pathway, which broadens our understanding of the mechanisms of PAE biodegradation., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Kidney beans ( Phaseolus vulgaris L.) are an important legume source of carbohydrates, proteins, and bioactive molecules and thus have attracted increasing attention for their high nutritional value and sustainability. Non-starch polysaccharides (NSPs) in kidney beans account for a high proportion and have a significant impact on their biological functions. Herein, we critically update the information on kidney bean varieties and factors that influence the physicochemical properties of carbohydrates, proteins, and phenolic compounds. Furthermore, their extraction methods, structural characteristics, and health regulatory effects, such as the regulation of intestinal health and anti-obesity and anti-diabetic effects, are also summarized. This review will provide suggestions for further investigation of the structure of kidney bean NSPs, their relationships with biological functions, and the development of NSPs as novel plant carbohydrate resources.

Background: Diabesity is a term used to emphasize the dual epidemic and the combined detrimental effects of diabetes and obesity. We aimed to investigate the associations of diabesity with the incidence and resolution of nonalcoholic fatty liver disease (NAFLD)., Methods: This prospective cohort study included 5549 participants with a median follow-up of 4.3 years (2010-2015). Diabesity was defined as six categories by the combinations of glucose tolerance status (normal glucose tolerance [NGT], prediabetes, and diabetes) diagnosed by fasting and oral glucose tolerance test 2-h glucose and hemoglobin A1c and general or abdominal obesity status. We examined the odds ratios (ORs) for the incidence and resolution of NAFLD associated with diabesity categories, respectively., Results: For NAFLD incidence, compared with the diabesity category of NGT with nonobesity, the categories of either glucose intolerance or general obesity were associated with higher risks of NAFLD, of which the categories with obesity, regardless of glucose intolerance status, exhibited greater risks (ORs ranged from 3.19 to 4.49) than the categories of nonobesity. For NAFLD resolution, the categories of prediabetes or diabetes with obesity were associated with decreased likelihoods of a resolution of NAFLD (ORs ranged from 0.40 to 0.58). These association patterns were consistent across various definitions of diabesity by glucose tolerance status diagnosed by different combinations of glycemic parameters and general or abdominal obesity., Conclusions: The diabesity association pattern with NAFLD incidence was mainly determined by obesity, while that with NAFLD resolution was driven by the combined phenotype of glucose intolerance and obesity., (© 2023 The Authors. Journal of Diabetes published by Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

Purpose: To evaluate the effectiveness of fecal immunochemical testing (FIT) in colorectal cancer screening., Methods: We conducted a prospective cohort study among 5,598 participants age 40-74 years between 2012 and 2020 in Tianjin, China. Inverse probability weighting was adopted to adjust for potential imbalanced factors between groups. A Cox proportional hazards model was used to estimate the weighted associations between FIT screening and advanced colorectal neoplasia. A difference-in-difference (DID) model was adopted to compare the incidence rates of advanced colorectal neoplasia between groups., Results: In DID analysis, the rate of incidence was reduced by 0.34 cases per person-years in the screening group as compared with the historical FIT screening group (rate ratio [RR], 0.08 [95% CI, 0.07 to 0.10]) and by 0.06 cases per person-years in the non-FIT screening group as compared with the historical non-FIT screening group (RR, 0.37 [95% CI, 0.29 to 0.48]; P < .001 for both comparisons), with a relative reduction of 0.28. Similar benefit effect from FIT screening was observed in sex and age subgroups., Conclusion: FIT screening was associated with a reduction in incidence density from advanced colorectal neoplasia.

Feedstock properties play a crucial role in thermal conversion processes, where understanding the influence of these properties on treatment performance is essential for optimizing both feedstock selection and the overall process. In this study, a series of van Krevelen diagrams were generated to illustrate the impact of H/C and O/C ratios of feedstock on the products obtained from six commonly used thermal conversion techniques: torrefaction, hydrothermal carbonization, hydrothermal liquefaction, hydrothermal gasification, pyrolysis, and gasification. Machine learning methods were employed, utilizing data, methods, and results from corresponding studies in this field. Furthermore, the reliability of the constructed van Krevelen diagrams was analyzed to assess their dependability. The van Krevelen diagrams developed in this work systematically provide visual representations of the relationships between feedstock and products in thermal conversion processes, thereby aiding in optimizing the selection of feedstock and the choice of thermal conversion technique., (© 2023. The Author(s).)

Background: Previous observational studies have documented an inverse association of birthweight with myocardial infarction (MI) but a positive association with atrial fibrillation (AF). However, the causality of these associations and the underlying mediating pathways remain unclear. We aimed to investigate the causal effects of birthweight, incorporating both fetal and maternal genetic effects, on MI and AF, and identify potential mediators in their respective pathways., Methods: We performed Mendelian randomization (MR) analyses using genome-wide association study summary statistics for birthweight (N = 297,356 for own birthweight and 210,248 for offspring birthweight), MI (N case =61,000, N control =577,000), AF (N case =60,620, N control =970,216), and 52 candidate mediators (N = 13,848-1,295,946). Two-step MR was employed to identify and assess the mediation proportion of potential mediators in the associations of birthweight with MI and AF, respectively. As a complement, we replicated analyses for fetal-specific birthweight and maternal-specific birthweight., Results: Genetically determined each 1-SD lower birthweight was associated with a 40% (95% CI: 1.22-1.60) higher risk of MI, whereas each 1-SD higher birthweight was causally associated with a 29% (95% CI: 1.16-1.44) higher risk of AF. Cardiometabolic factors, including lipids and lipoproteins, glucose and insulin, blood pressure, and fatty acids, each mediated 4.09-23.71% of the total effect of birthweight on MI, followed by body composition and strength traits (i.e., appendicular lean mass, height, and grip strength) and socioeconomic indicators (i.e., education and household income), with the mediation proportion for each factor ranging from 8.08 to 16.80%. By contrast, appendicular lean mass, height, waist circumference, childhood obesity, and body mass index each mediated 15.03-45.12% of the total effect of birthweight on AF. Both fetal-specific birthweight and maternal-specific birthweight were inversely associated with MI, while only fetal-specific birthweight was positively associated with AF. Psychological well-being and lifestyle factors conferred no mediating effect in either association., Conclusions: Cardiometabolic factors mainly mediated the association between lower birthweight and MI, while body composition and strength traits mediated the association between higher birthweight and AF. These findings provide novel evidence for the distinct pathogenesis of MI and AF and advocate adopting a life-course approach to improving fetal development and subsequent causal mediators to mitigate the prevalence and burden of cardiovascular diseases., (© 2023. The Author(s).)

Background: Patinopecten yessoensis, a large and old molluscan group, has been one of the most important aquaculture shellfish in Asian countries because of its high economic value. However, the aquaculture of the species has recently been seriously affected by the frequent outbreaks of Polydora disease, causing great economic losses. Long non-coding RNAs (lncRNAs) exhibit exhibit crucial effects on diverse biological processes, but still remain poorly studied in scallops, limiting our understanding of the molecular regulatory mechanism of P. yessoensis in response to Polydora infestation., Results: In this study, a high-throughput transcriptome analysis was conducted in the mantles of healthy and Polydora-infected P. yessoensis by RNA sequencing. A total of 19,133 lncRNAs with 2,203 known and 16,930 novel were identified. The genomic characterizations of lncRNAs showed shorter sequence and open reading frame (ORF) length, fewer number of exons and lower expression levels in comparison with mRNAs. There were separately 2280 and 1636 differentially expressed mRNAs and lncRNAs (DEGs and DELs) detected in diseased individuals. The target genes of DELs were determined by both co-location and co-expression analyses. Functional enrichment analysis revealed that DEGs involved in melanization and biomineralization were significantly upregulated; further, obviously increased melanin granules were observed in epithelial cells of the edge mantle in diseased scallops by histological and TEM study, indicating the crucial role of melanizaiton and biomineralization in P. yessoensis to resist against Polydora infestation. Moreover, many key genes, such as Tyrs, Frizzled, Wnts, calmodulins, Pifs, perlucin, laccase, shell matrix protein, mucins and chitins, were targeted by DELs. Finally, a core lncRNA-mRNA interactive network involved in melanization and biomineralization was constructed and validated by qRT-PCR., Conclusions: This work provides valuable resources for studies of lncRNAs in scallops, and adds a new insight into the molecular regulatory mechanisms of P. yessoensis defending against Polydora infestation, which will contribute to Polydora disease control and breeding of disease-resistant varieties in molluscs., (© 2023. The Author(s).)

Background: Emerging evidence has indicated that remnant cholesterol (RC) could predict cardiovascular disease (CVD) incidence. Nevertheless, the relationship between RC and CVD risk, especially within the general Chinese population, remains scarce., Objective: The present research aimed to assess whether RC concentrations and CVD outcomes in general Chinese adults are related., Methods: The Cox proportional hazard model was established to explore the relationship between RC and the outcomes of CVD and CVD subgroups. A restricted cubic spline (RCS) was utilized to investigate the dose-response connection between RC and the risk of CVD outcomes, and the ROC curve was used to calculate the corresponding cutoff values. Moreover, stratified analysis was conducted to investigate the potential effect modification in the association between RC and CVD outcomes., Results: Significant positive associations were found between elevated categorical RC and increased risk of CVD (HR Q4, 1.80; 95% CI 1.15-2.79; P -value = 0.008), atherosclerotic cardiovascular disease (HR Q4, 2.00; 95% CI 1.22-3.27; P -value = 0.007), stroke (HR Q4, 1.66; 95% CI 1.02-2.69; P -value = 0.040), and ischemic stroke (HR Q4, 1.87, 95% CI 1.08-3.25; P -value = 0.034), respectively. Our study suggested that the incidence of CVD outcomes increased when RC levels were above 0.75 mmol/L. Importantly, the CVD risks related to RC were more likely to be those found in subjects aged above 60 years, women, subjects with BMI <24 kg/m 2 , and subjects with hypertension and unhealthy diet patterns., Conclusions: Aberrant high level of RC is associated with elevated CVD risk, independent of low-density lipoprotein cholesterol (LDL-C). Our data reveal urgent primary prevention for subjects with high RC levels to a low incidence of CVD, especially for the elderly, women, and those with hypertension and unhealthy diet patterns., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Liu, Dai, Tian, Zhou, Luo, Zeng, Yan, Xiao, Wang, Deng, Lei and Liu.)

Observations of the association between carbohydrate intake and hypertension are inconsistent, with mediating pathways unclear. We aimed to investigate the causal effect of relative carbohydrate intake on hypertension and the mediating roles of psychological well-being and adiposity. Using summary-level statistics of genome-wide association studies of European ancestry, we conducted univariable and multivariable Mendelian randomization (MR) to estimate the bidirectional causal association between relative carbohydrate intake (total energy-adjusted, mean: 42-51%) and hypertension (FinnGen: 42,857 cases/162,837 controls; UK Biobank: 77,723 cases/330,366 controls) and two-step MR to assess the mediating effects of psychological well-being indicators and adiposity traits on the association. MR estimates of hypertension from FinnGen and UK Biobank were meta-analyzed using the fixed-effect model given no heterogeneity. Meta-analyses of multivariable MR estimates from FinnGen and UK Biobank indicated that each one-SD higher relative carbohydrate intake was associated with 71% (odds ratio: 0.29; 95% confidence interval: 0.11-0.79) lower risk of hypertension, independently of other dietary macronutrients. Hypertension showed no reverse effect on carbohydrate intake. Five psychological well-being indicators and four adiposity traits causally mediated the association between relative carbohydrate intake and hypertension, including body mass index (mediation proportion: 51.37%), waist circumference (40.54%), waist-to-hip ratio (35.00%), hip circumference (24.77%), major depressive disorder (23.37%), positive affect (17.08%), depressive symptoms (16.52%), life satisfaction (16.05%), and neuroticism (11.22%). Higher relative carbohydrate intake was causally associated with lower hypertension risk, substantially mediated by better psychological well-being and less adiposity. Our findings inform causal targets and pathways for the prevention and intervention of hypertension.

Background: Depression may be associated with the risk of developing type 2 diabetes. The goal of this study was to explore the association of severe of depression with the risk of type 2 diabetes in adults in Guizhou, China., Methods: A 10-year prospective cohort study of 7158 nondiabetes adults aged 18 years or older was conducted in Guizhou, southwest China from 2010 to 2020. The Patient Health Questionnaire-9 (PHQ-9) was used to measure the prevalence of depression. Cox proportional hazard models were used to estimated hazard ratios (HRs) and 95% confidence intervals (95% CIs) of depression and incident type 2 diabetes. A quantile regression (QR) analytical approach were applied to evaluate the associations of PHQ-9 score with plasma glucose values., Results: A total of 739 type 2 diabetes cases were identified during a median follow-up of 6.59 years. The HR (95% CI) per 1-SD increase for baseline PHQ-9 score was 1.051 (1.021, 1.082) after multivariable adjustment. Compared with participants without depression, those with mild or more advanced depression had a higher risk of incident type 2 diabetes (HR:1.440 [95% CI, 1.095, 1.894]). Associations between depression with type 2 diabetes were suggested to be even stronger among women or participants aged ≥45 years (p < .05). There are significant positive associations of PHQ-9 score with 2-h oral glucose tolerance test blood glucose levels., Conclusion: Depression significantly increased the risk of incident type 2 diabetes, especially in women, participants aged ≥45 years, Han ethnicity, and urban residents. These findings highlighted the importance and urgency of depression health care., (© 2023 The Authors. Journal of Diabetes published by Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

Background and Aims: Educational attainment is an essential socio-economic indicator with broad implications for lifestyle behaviour and metabolic health. We aimed to investigate the causal effect of education on chronic liver diseases and the potential mediating pathways., Methods: We applied univariable Mendelian randomization (MR) to assess the causal associations between educational attainment and non-alcoholic fatty liver disease (NAFLD) (cases/controls: 1578/307 576 in FinnGen; 1664/400 055 in UK Biobank), viral hepatitis (1772/307 382; 1215/403 316), hepatomegaly (199/222 728; 297/400 055), chronic hepatitis (699/301 014; 277/403 316), cirrhosis (1362/301 014; 114/400 055) and liver cancer (518/308 636; 344/393 372) using summary statistics of genome-wide association studies from the FinnGen Study and the UK Biobank, respectively. We used two-step MR to evaluate potential mediators and their mediation proportions in the association., Results: Meta-analysis of inverse variance weighted MR estimates from FinnGen and UK Biobank showed that genetically predicted 1-SD (4.2 years) higher education was causally associated with decreased risks of NAFLD (OR: 0.48; 95%CI: 0.37-0.62), viral hepatitis (0.54; 0.42-0.69) and chronic hepatitis (0.50; 0.32-0.79), but not hepatomegaly, cirrhosis and liver cancer. Nine, two and three out of 34 modifiable factors were identified as causal mediators in the associations of education with NAFLD, viral hepatitis and chronic hepatitis, respectively, including six adiposity traits (mediation proportion: 16.5%-32.0%), major depression (16.9%), two glucose metabolism-related traits (2.2%-15.8%) and two lipids (9.9%-12.1%)., Conclusions: Our findings supported the causal protective effects of education on chronic liver diseases and outlined mediating pathways to inform prevention and intervention strategies to reduce the burden of liver diseases, especially for individuals with lower education., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: To investigate the expression of layilin (LAYN) in human circulating monocytes and lymphocytes and its clinical significance in systemic lupus erythematosus (SLE)., Methods: Blood samples were collected from 51 SLE patients and 50 healthy controls. Flow cytometry was used to analyze LAYN in lymphocytes and monocyte subsets. Functionally characterized molecules including human HLA, CD74 and CD62L were studied in LAYN+ monocytes. A correlation analysis was conducted between LAYN-related subsets and clinical indicators of SLE such as anti-double-stranded DNA and complements levels. ROC curves were used to explore the potential clinical diagnostic value of LAYN in SLE., Results: LAYN was significantly higher in monocytes than in lymphocytes and higher in CD14+CD16+ monocytes than in CD14-CD16+ and CD14+CD16- monocytes. CD74 was upregulated and CD62L was downregulated in LAYN+ monocytes compared with LAYN- monocytes. The absolute number of LAYN+ monocytes was increased in SLE patients, and the median fluorescence intensity of HLA was decreased. LAYN+ monocytes were positively correlated with complement C4, while decreased CD62L+ percentages in LAYN+ monocytes were negatively correlated with C4. The ROC analysis revealed that the area under the curve (AUCs) for CD62L+ percentages in LAYN+ monocytes, LAYN+ lymphocyte numbers, and LAYN+ monocyte numbers to distinguish SLE from healthy individuals were 0.6245, 0.6196 and 0.6173, respectively., Conclusion: LAYN is differentially expressed in monocytes and their subpopulations and has corresponding functional differences. Changes in LAYN expression on monocytes are associated with complement C4 levels in SLE patients. These suggest that LAYN may be involved in the pathogenesis of SLE., Abbreviation: ANOVA: analysis of variance; anti-dsDNA: anti-double-stranded DNA; anti-ENA: anti-extractable nuclear antigen; anti-SSA: anti-Sjogren syndrome A; anti-SSB: anti-Sjogren syndrome B; anti-U1RNP: anti-U1 ribonucleoprotein; AUC: area under the ROC curve; CBC: complete blood count; CD62L: L-selectin; CD74/Ii: MHC class II invariant chain; CD44/HCAM: homing cell adhesion molecule; cMos: classical monocytes; CRP: C-reactive protein; CXCR2: C-X-C motif chemokine receptor 2; CXCR4: C-X-C motif chemokine receptor 4; ESR: erythrocyte sedimentation rate; HCs: healthy controls; HA: hyaluronan; HLA: human leukocyte antigen; Ig: immunoglobulin; iMos: intermediate monocytes; LAYN: layilin; MFI: median fluorescence intensity; MIF: migration inhibitory factor; ncMos: nonclassical monocytes; PBMCs: peripheral blood mononuclear cells; ROC: receiver operating characteristic curve; SLE: systemic lupus erythematosus; SLEDAI, SLE disease activity index; Treg: regulatory T cells; WBCs: white blood cells.

High-grade serous ovarian cancer (HGSC), with a modest response to immune checkpoint blockade (ICB) targeting PD-1/PD-L1 monotherapy, is densely infiltrated by M2-polarized tumor-associated macrophages (TAMs) and regulatory T (Treg) cells. The complement C5a/C5aR1 axis contributes to the programming of the immunosuppressive phenotype of TAMs in solid tumors and represents a promising immunomodulatory target for treating HGSCs. Here, we aimed to identify the relevance of C5aR1 in prognosis, immune microenvironment, and immunotherapy response in HGSCs. The expression and relationship of C5aR1 with tumor-infiltrating immune cells were assessed by immunohistochemistry and flow cytometry in the training cohort ( n  = 120) and fresh HGSC tissues ( n  = 36). Transcriptomic analyses of the xenografts delineated the mechanisms driving the immunomodulatory activity of PMX53, an orally bioavailable C5aR1 inhibitor. Therapeutic relevance was confirmed in ex vivo tumor cultures and The Cancer Genome Atlas (TCGA) datasets. C5aR1 expression independently predicted dismal prognosis and was linked to the immunoevasive subtype of HGSC, characterized by increased infiltration of pro-tumor cells (Treg cells, M2-polarized macrophages, and neutrophils) and impaired CD8 + T functions. PMX53 antagonized subcutaneous tumor growth, modulated immunosuppressive mechanisms and synergized with aPD-1 in several tumor types. Single-cell RNA-seq analysis revealed predominant C5aR1 expression in TAMs, with an immunosuppressive-related expression signature in C5aR1 + TAMs. Furthermore, the combination of C5aR1 and PD-L1 was associated with specific molecular characteristics and matched clinical response annotations. Therefore, the abundance of C5aR1 could predict an inferior prognosis in HGSCs, and incorporating PD-L1 may serve as a novel predictive biomarker to guide therapeutic options., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2023 The Author(s). Published with license by Taylor & Francis Group, LLC.)

The protein force field based on the restrained electrostatic potential (RESP) charges has limitations in accurately describing hydrogen bonding interactions in proteins. To address this issue, we propose an alternative approach called the electrostatic energy-based charges (EEC) model, which shows improved performance in describing electrostatic interactions (EIs) of hydrogen bonds in proteins. In this study, we further investigate the performance of the EEC model in modeling EIs in water solvent. Our findings demonstrate that the fixed EEC model can effectively reproduce the quantum mechanics/molecular mechanics (QM/MM)-calculated EIs between a water molecule and various water solvent environments. However, to achieve the same level of computational accuracy, the electrostatic potential (ESP) charge model needs to fluctuate according to the electrostatic environment. Our analysis indicates that the requirement for charge adjustments depends on the specific mathematical and physical representation of EIs as a function of the environment for deriving charges. By comparing with widely used empirical water models calibrated to reproduce experimental properties, we confirm that the performance of the EEC model in reproducing QM/MM EIs is similar to that of general purpose TIP4P-like water models such as TIP4P-Ew and TIP4P/2005. When comparing the computed 10,000 distinct EI values within the range of -40 to 0 kcal/mol with the QM/MM results calculated at the MP2/aug-cc-pVQZ/TIP3P level, we noticed that the mean unsigned error (MUE) for the EEC model is merely 0.487 kcal/mol, which is remarkably similar to the MUE values of the TIP4P-Ew (0.63 kcal/mol) and TIP4P/2005 (0.579 kcal/mol) models. However, both the RESP method and the TIP3P model exhibit a tendency to overestimate the EIs, as evidenced by their higher MUE values of 1.761 and 1.293 kcal/mol, respectively. EEC-based molecular dynamics simulations have demonstrated that, when combined with appropriate van der Waals parameters, the EEC model can closely reproduce oxygen-oxygen radial distribution function and density of water, showing a remarkable similarity to the well-established TIP4P-like empirical water models. Our results demonstrate that the EEC model has the potential to build force fields with comparable accuracy to more sophisticated empirical TIP4P-like water models.

Background: Lesion locations of post-stroke depression (PSD) mapped to a depression circuit which centered by the left dorsolateral prefrontal cortex (DLPFC). However, it remains unknown whether the compensatory adaptations that may occur in this depression circuit due to the lesions in PSD., Methods: Rs-fMRI data were collected from 82 non-depressed stroke patients (Stroke), 39 PSD patients and 74 healthy controls (HC). We tested the existence of depression circuit, examined PSD-related alterations of DLPFC-seeded connectivity and their associations with depression severity, and analyzed the connectivity between each repetitive transcranial magnetic stimulation (rTMS) target and DLPFC to find the best treatment target for PSD., Results: We found that: 1) the left DLPFC showed significantly stronger connectivity to lesions of PSD than Stroke group; 2) in comparison to both Stroke and HC groups, PSD exhibited increased connectivity with DLPFC in bilateral lingual gyrus, contralesional superior frontal gyrus, precuneus, and middle frontal gyrus (MFG); 3) the connectivity between DLPFC and the contralesional lingual gyrus positively correlated with depression severity; 4) the rTMS target in center of MFG showed largest between-group difference in connectivity with DLPFC, and also reported the highest predicted clinical efficacy., Limitations: Longitudinal studies are required to explore the alterations of depression circuit in PSD as the disease progress., Conclusion: PSD underwent specific alterations in depression circuit, which may help to establish objective imaging markers for early diagnosis and interventions of the disease., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2023. Published by Elsevier B.V.)

The causal influence of sarcopenia on cardiometabolic disease and Alzheimer's disease and whether and to what extent insulin resistance plays a mediating role therein were unclear. We performed two-step, two-sample Mendelian randomization applying genetic instruments of sarcopenia-related traits based on GWASs from the UK Biobank (up to 461,026 European participants) to examine their causal associations with six cardiometabolic diseases and Alzheimer's disease extracted from large-scale European descent GWASs with adjustment for body fat percentage and physical activity, and to assess proportions of the causal effects mediated by insulin resistance. Genetic instruments of insulin resistance were derived from the GWASs by Meta-Analyses of Glucose and Insulin-related traits Consortium and Global Lipids Genetics Consortium. Each 1-SD lower grip strength, appendicular lean mass (ALM) and whole-body lean mass (WBLM), as well as lower walking pace, were causally associated with higher risks of diabetes (odds ratio [OR] range: 1.20 [95% confidence interval: 1.10-1.32] for ALM to 2.30 [1.14-4.68] for walking pace), nonalcoholic fatty liver disease ([NAFLD], 1.33 [1.08-1.64] for ALM to 2.30 [1.02-5.18] for grip strength), hypertension (1.12 [1.05-1.20] for ALM to 4.43 [2.68-7.33] for walking pace), coronary heart disease ([CHD], 1.20 [1.13-1.27] for ALM to 2.73 [1.84-4.05] for walking pace), myocardial infarction ([MI], 1.18 [1.11-1.25] for ALM to 2.47 [1.63-3.73] for walking pace), small vessel stroke (1.25 [1.15-1.37] for ALM to 1.29 [1.10-1.52] for WBLM), and Alzheimer's disease (1.10 [1.05-1.15] for ALM to 1.28 [1.19-1.38] for WBLM). These causal associations were largely independent of body fat percentage and physical activity. Insulin resistance mediated 16%-34% of the effect of grip strength and 7%-28% of the effect of ALM on diabetes, NAFLD, hypertension, CHD, and MI. The direct effect of WBLM on diabetes diminished toward null with adjustment for insulin resistance. We found no evidence that insulin resistance was on the causal pathways from walking pace to the studied disease outcomes. Causal findings from the inverse-variance weighted method were validated by sensitivity analyses. These findings support improving sarcopenia-related traits as precautions against major cardiometabolic diseases and Alzheimer's disease, with particular emphasis on insulin resistance as a target in the intervention of sarcopenia-related cardiometabolic risk., (© 2023 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

Background: The potent immunosuppressive properties of sialic acid-binding immunoglobulin-like lectin-9 (Siglec-9) on myeloid cells and lymphocytes provide a strong rationale for serving as a therapeutic target. However, the expression profile and critical role of Siglec-9 in high-grade serous ovarian cancer (HGSC) remain obscure. This study aimed to elucidate the prognostic significance of Siglec-9 expression and its predictive value for immunotherapy in HGSC., Methods: Study enrolled two cohorts, consisting of 120 tumor microarray specimens of HGSC for immunohistochemistry (IHC) and 40 fresh tumor specimens for flow cytometry (FCM). Expression profile of Siglec-9 in immune cells was analyzed by both bioinformatics analysis and FCM. Role of Siglec-9 was studied to identify that Siglec-9 + TAMs linked with an immunosuppressive phenotype by IHC and FCM, and block Siglec-9 was sensitive to immunotherapy by ex vivo and in vitro assays., Results: Siglec-9 is predominantly expressed on tumor-associated macrophages (TAMs). High Siglec-9 + TAMs were associated with inferior overall survival (OS). Both tumor-conditioned medium (TCM) and tumor ascites induced enrichment of Siglec-9 + TAMs with protumorigenic phenotypes. Siglec-9 + TAMs were associated with immunosuppressive tumor microenvironment (TME) characterized by exhausted CD8 + T cells and increased immune checkpoint expression. Blockade of Siglec-9 suppressed phosphorylation of the inhibitory phosphatase SHP-1 and repolarized TAMs to antitumorigenic phenotype and retrieved cytotoxic activity of CD8 + T cells in vitro and ex vivo. Responders toward antiprogrammed death receptor-1 (anti-PD-1) therapy present more Siglec-9 + TAMs than non-responders. Furthermore, blockade Siglec-9 synergized with anti-PD-1 antibody to enhance the cytotoxic activity of CD8 + T cells in tissues with higher Siglec-9 + TAMs., Conclusions: Siglec-9 + TAMs may serve as an independent prognostic of poor survival but a predictive biomarker for anti-PD-1/antiprogrammed death ligand-1 immunotherapy in HGSC. In addition, the potential of immunosuppressive Siglec-9 + TAMs as a therapeutic target is worth further exploration., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Hypertriglyceridemic hyperapoB is an adverse lipoprotein phenotype characterized by low high density lipoprotein (HDL) cholesterol, high triglycerides, high apolipoprotein B (ApoB), and low low density lipoprotein (LDL) cholesterol to ApoB ratio. We investigated whether and to what extent hypertriglyceridemic hyperapoB associates with the incidence and resolution of nonalcoholic fatty liver disease (NAFLD). This prospective cohort study included 9,019 Chinese participants 40 years or older, from 2010 to 2015. Logistic regression models were used to examine the odds ratios (ORs) for the incidence and resolution of NAFLD associated with the hypertriglyceridemic hyperapoB lipoprotein phenotype and individual lipid and lipoprotein parameters. During a median 4.3 years of follow-up, compared with participants with optimal phenotype, the fully adjusted ORs (95% CIs) for participants with hypertriglyceridemic hyperapoB were 2.75 (1.91, 3.95) and 0.57 (0.33, 1.00) for incidence and resolution of NAFLD, respectively. These associations were consistent across subgroup participants with varied demographic, lifestyle, and metabolic status. Individually, each unit increase in HDL cholesterol (OR: 0.98; 95% CI: 0.97, 0.99), natural logarithm-transformed triglycerides (1.89; 1.52, 2.36), and ApoB (1.006; 1.002, 1.011) was independently associated with NAFLD incidence, and only triglycerides (0.77; 0.60, 0.99) was independently associated with NAFLD resolution. Our findings suggest that Chinese adults with hypertriglyceridemic hyperapoB have a higher risk of NAFLD incidence and a lower likelihood of NAFLD resolution. These associations were stable among adults with different demographic, lifestyle, and metabolic status, supporting hypertriglyceridemic hyperapoB as a valuable clinical marker for the prevention and control of NAFLD., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

GrimAge acceleration (GrimAgeAccel) and PhenoAge acceleration (PhenoAgeAccel) are DNA methylation-based markers of accelerated biological aging, standing out in predicting mortality and age-related cardiometabolic morbidities. Causal risk factors for GrimAgeAccel and PhenoAgeAccel are unclear. In this study, we performed 2-sample univariable and multivariable Mendelian randomization (MR) to investigate causal associations of 19 modifiable socioeconomic, lifestyle, and cardiometabolic factors with GrimAgeAccel and PhenoAgeAccel. Instrument variants representing 19 modifiable factors were extracted from genome-wide association studies (GWASs) with up to 1 million Europeans. Summary statistics for GrimAgeAccel and PhenoAgeAccel were derived from a GWAS of 34 710 Europeans. We identified 12 and 8 factors causally associated with GrimAgeAccel and PhenoAgeAccel, respectively. Smoking was the strongest risk factor (β [standard error {SE}]: 1.299 [0.107] year) for GrimAgeAccel, followed by higher alcohol intake, higher waist circumference, daytime napping, higher body fat percentage, higher body mass index, higher C-reactive protein, higher triglycerides, childhood obesity, and type 2 diabetes; whereas education was the strongest protective factor (β [SE]: -1.143 [0.121] year), followed by household income. Furthermore, higher waist circumference (β [SE]: 0.850 [0.269] year) and education (β [SE]: -0.718 [0.151] year) were the leading causal risk and protective factors for PhenoAgeAccel, respectively. Sensitivity analyses strengthened the robustness of these causal associations. Multivariable MR analyses further demonstrated independent effects of the strongest risk and protective factors on GrimAgeAccel and PhenoAgeAccel, respectively. In conclusion, our findings provide novel quantitative evidence on modifiable causal risk factors for accelerated epigenetic aging, suggesting promising intervention targets against age-related morbidity and improving healthy longevity., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Aberrant sialylation functions as an important modulator of all steps of malignant transformation. Therefore, targeting sialylation regulators, such as sialyltransferases and neuraminidases, is a potential strategy for treating cancer. Here, we found that elevated α2,3-sialyltransferase III (St3gal3) was associated with dismal prognosis in high-grade serous ovarian carcinoma (HGSC). St3gal3 knockdown antagonized subcutaneous tumor growth in immunocompetent, but not immunodeficient mice, with enhanced accumulation of functional CD8+ T cells and antitumor immune gene signatures. St3gal3 knockdown inhibited intraperitoneal tumor growth and repolarized tumor-associated macrophages from a protumorigenic M2-like to a tumor-suppressive M1-like phenotype. In vitro, St3gal3 knockdown tumor cells guided bone marrow-derived macrophages (BMDM) toward the M1-like phenotype under both direct contact and distant Transwell coculture conditions. Depletion of macrophages rescued the suppressed tumor growth induced by St3gal3 knockdown and completely suppressed infiltration of functional CD8+ T cells that rely on macrophage-derived CXCL10. St3gal3 engendered an immunosuppressive HGSC microenvironment characterized by an abundance of pro-tumorigenic macrophages and reduced cytotoxic T-cell infiltration. In vivo, St3gal3 knockdown improved effectiveness of dual immune checkpoint blockade (ICB) with αPD-1 and αCTLA4 antibodies. Preclinical inhibition of sialylation with ambroxol resulted in decreased tumor growth and prolonged the survival of tumor-bearing mice, which was enhanced by the addition of dual ICB. These findings indicate that altered sialylation induced by St3gal3 upregulation promotes a tumor-suppressive microenvironment in HGSC and targeting α2,3-sialylation may reprogram the immunosuppressive tumor microenvironment and improve the efficacy of immunotherapy., Significance: Blocking sialylation augments antitumor immunity and enhances response to immune checkpoint blockade therapy, highlighting a potential therapeutic approach for treating patients with high-grade serous ovarian cancer., (©2023 American Association for Cancer Research.)

Gastric cancer (GC) is one of the most common malignancies, and it has become the third most common malignant tumour in the world. Targeting metastasis has also become a key and difficult point in the treatment of GC. Solasodine is an active ingredient isolated from Solanum nigrum L. for the treatment of various cancers, such as breast cancer, pancreatic cancer and lung cancer. In the present study, we investigated the role and mechanism of solasodine in inhibiting GC. In vitro, we found that solasodine not only promoted cell death but also inhibited the migration and invasion of HGC27 and AGS cells. Solasodine regulated epithelial-mesenchymal transition (EMT) and reduced the expression of claudin-2 (CLDN2). Moreover, overexpression of CLDN2 inhibited the prometastatic phenotype and EMT of GC, and solasodine recovered this phenotype. Furthermore, the knockdown of CLDN2 had the opposite effect. We also found that the AMPK activators metformin and AICAR activated phosphorylation of AMPK and downregulated the expression of RhoA and CLDN2, indicating that AMPK was the upstream regulator of CLDN2. Solasodine could also activate AMP-activated protein kinase (AMPK) and inhibit the phosphorylation of STAT3 and the nuclear translocation of NF-κB. Therefore, solasodine may have prevented EMT by modulating the AMPK/STAT3/NF-κB/CLDN2 signalling pathway. In vivo, we established a xenograft model to investigate the phosphorylation of AMPK and the expression of CLDN2 from tumour tissues, and we found that solasodine inhibited tumour growth through AMPK-CLDN2 pathway. To sum up, solasodine prevented EMT by modulating the AMPK/STAT3/NF-κB/CLDN2 signalling pathway, becoming a new solution for inhibiting GC metastasis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)