摘要：Introduction Gender and sex are related to important quality and safety issues in scientific,health,and clinical research.Sex refers to biological characteristics,while gender encompasses the sociocultural norms,identities,and relationships that shape communities and organiza-tions,as well as influence actions,behaviors,contexts,and knowledge. Both gender and sex intersect with other social categories. In this context,in addition to sex or gender,the intersectionality refers to overlapping or interdependent systems of discrimi-nation by more than one factor,such as age,disability,ethnicity,geographic location,socioeconomic status,and sexuality,among others.

摘要：V-raf-leukemia viral oncogene 1(RAF1),a serine/threonine protein kinase,is well established to play a crucial role in tumorigenesis and cell development.However,the specific role of hypothalamic RAF1 in regulating energy metabolism remains unknown.In this study,we found that the expression of RAF1 was significantly increased in hypothalamic AgRP neurons of diet-induced obesity(DIO)mice.Under normal chow diet feeding,overexpression of Raf1 in AgRP neurons led to obesity in mice characterized by increased body weight,fat mass,and impaired glucose tolerance.Conversely,Raf1 knockout in AgRP neurons protected against diet-induced obesity,reducing fat mass and improving glucose tolerance.Mechanistically,Raf1 activated the MAPK signaling pathway,culminating in the phosphorylation of cAMP response element-binding protein(CREB),which enhanced transcription of Agrp and Npy.Insulin stimulation further potentiated the RAF1-MEK1/2-ERK1/2-CREB axis,highlighting RAF1's role in integrating hormonal and nutritional signals to regulate energy balance.Collectively,these findings underscore the important role of RAF1 in AgRP neurons in maintaining energy homeostasis and obesity pathogenesis,positioning it and its downstream pathways as potential therapeutic targets for innovative strategies to combat obesity and related metabolic diseases.

摘要：As the prevalence of obesity increases dramatically,obesity-associated cardiac dysfunction constitutes a considerable challenge to human health.This study aimed to identify more useful lipid/inflammatory markers to predict the risk of obesity-associated cardiac dysfunction.By retrospectively analyzing the clinical characteristics of 5 648 cardiac disease patients,we found that both the plasma level of high-density lipoprotein cholesterol(HDL-C)and the blood monocyte count were significantly associated with impairment of the left ventricular ejection fraction(LVEF).Univariate and multivariate regression analyses revealed that the monocyte to HDL-C ratio(MHR)was a more powerful predictor of the risk of LVEF decline than either HDL-C or monocyte alone.Mediation analysis further revealed a mediating effect of a high MHR on the decline in obesity-associated cardiac systolic function.Collectively,our results demonstrate a superior role of MHR in predicting the risk of an obesity-associated decline in cardiac systolic function among routine metabolic/inflammatory markers.

摘要：Diabetic retinopathy(DR),a common complication of diabetes,is characterized by retinal angiogenesis and inflammation.The role of hepatoma-derived growth factor(HDGF)in mediating inflammation during DR remains unclear.We measured HDGF levels in the aqueous humor and found that HDGF was increased in DR but decreased after anti-angiogenesis treatment.Using public single-cell RNA sequencing datasets,we found that elevated HDGF in DR was mainly produced by Müller cells and targeted microglia.Additionally,integrin beta 2(Itgb2),a target gene of HDGF that induces microglial activation,was significantly upregulated in DR.To verify these results,we performed enzyme-linked immunosorbent assays,quantitative reverse transcription-PCR,Western blotting,and fluorescence immunostaining in cultured Müller and microglial cells treated with HDGF or anti-HDGF,as well as in DR mice receiving intravitreal injections of HDGF or its antibody.Exogenous HDGF further promoted microglial activation,migration,and secretion of pro-inflammatory cytokines,while neutralization of HDGF suppressed these effects caused by high glucose.Furthermore,the HDGF receptor nucleolin was overexpressed in microglia under high glucose stimulation.Therefore,blocking HDGF from Müller cells in DR reduced the excessive inflammatory response in microglia,highlighting HDGF as a potential therapeutic target.

摘要：Dear Editor, Psoriasis is increasingly recognized as a systemic inflammatory disease associated with several comorbidities,including metabolic syndrome,depression,and malignancies[1]. Colorectal cancer(CRC) is the third most common cancer worldwide and ranks second in mortality among all malignancies.Currently,it has become one of the most severe challenges faced by healthcare systems in many countries[2]. A previous study has found that patients with psoriasis have a significantly increased risk of developing CRC[3];however,the stratified characteristics between them are unclear. We performed a meta-analysis of observational studies examining the relationship between psoriasis and CRC. An Embase and Medline search was conducted on January 19,2025,which identified 377 relevant studies. The search strategy and PRISMA study flow chart are presented in Supplementary Table 1 and Supplementary Fig. 1. Following screening,a total of 10 relevant articles were selected for inclusion. We extracted study design,first author's last name,publication year,population information,and risk estimates (i.e.,hazard ratio[HR],incidence rate ratio[IRR],risk ratio[RR],and odds ratio[OR]) with 95％confidence intervals (CIs) for the association between psoriasis and CRC (Supplementary Table 2). The Newcastle-Ottawa Scale was used to assess the risk of bias in the included studies (Supplementary Fig. 2).Data analysis was conducted using RevMan 5.4. The inverse-variance weighting method,random-effects model,and I2 statistics for heterogeneity were used for analysis (Supplementary Fig. 3).

摘要：Clostridioides difficile(C.difficile)is one of the major causes of nosocomial infections.Pregnant women,who are generally considered at low risk for C.difficile infection(CDI),have attracted attention because of an increasing number of reports.Oral vancomycin,the only first-line treatment for pregnant women infected with C.difficile,has been associated with increasing strain resistance,leading to decreased efficacy.Fecal microbiota transplantation(FMT)is recommended for severe,fulminant,and recurrent CDI;however,it is generally avoided in pregnant women because of safety concerns.We report a case of a pregnant woman with a primary ribotype 027 CDI who experienced a successful outcome with washed microbiota transplantation(WMT),an improved form of FMT,via enema.The specific strain of ribotype 027 is related to severe outcomes but has not previously been reported in pregnant women.The follow-up lasted for two years,during which the patient's diarrhea was fully alleviated without recurrence.The baby showed normal growth and development,and no adverse events were recorded for either.This case provides evidence for the efficacy and safety of WMT in pregnant women infected with C.difficile,indicating that WMT via enema may be a viable therapeutic strategy for this population for treating CDI.

摘要：Prenatal maternal psychological distress,particularly depression,has been increasingly recognized as a factor that influences fetal growth;however,its impact on early childhood development remains less well understood.The present study investigated the association between prenatal depression and children's growth trajectories,as well as the odds of overweight and obesity from 1 to 36 months,while also accounting for maternal anxiety and stress.We analyzed data from 4 710 mother-child dyads in the Jiangsu Birth Cohort,assessing maternal psychological distress across trimesters and categorizing participants into groups with mild,moderate,and severe depressive symptomatology.Children's weight-for-length z-scores(WLZ)were used to assess overweight/obesity prevalence,and growth patterns were identified through trajectory models.The results from the generalized estimating equations analysis showed that greater depressive symptomatology during pregnancy was associated with a 28%to 41%increase in the odds of childhood overweight/obesity across all three trimesters,compared with mild depressive symptomatology.We identified five distinct WLZ growth trajectory patterns,and found that mothers with greater depressive symptomatology were 39%-47%more likely to have children who followed a very-high-stable growth trajectory,compared with mothers with mild depressive symptomatology.These findings highlight the significant impact of prenatal depression on adverse growth patterns and childhood overweight/obesity,underscoring the need for early intervention.

摘要：Dear Editor, Lymphocyte activation gene 3 (LAG3),the third established target for immune checkpoint blockade therapy,suppresses T cell function by binding to major histocompatibility complex class Ⅱ (MHC Ⅱ).Despite its significant therapeutic potential in cancer immunotherapy and the substantial attention it has received from academia and industry,the molecular mechanisms of LAG3-mediated immunosuppression remain poorly understood,primarily because of its unique ligand-binding characteristics and intracellular domains[1]. Recent studies have advanced our understanding of LAG3 function. Maruhashi et al[2]have demonstrated that stable peptide-MHC Ⅱ,rather than fibrinogen-like protein (FGL1),serves as the functional ligand for LAG3-mediated T cell suppression in both autoimmunity and anti-cancer immunity. Jiang et al[3]have revealed the molecular mechanism by which LAG3 is activated by MHC Ⅱ-mediated ligand engagement,with ubiquitination activating LAG3 by releasing its cytoplasmic tail (CT)from the membrane. Notably,LAG3 associates with the T cell receptor (TCR)-CD3 complex and traffics to the immunological synapse (IS),where clustering of its CT through a phase separation mechanism disrupts interactions between coreceptors CD4/CD8 and the kinase Lck,thereby impairing TCR signaling and reducing T cell activation[4]. These studies have deepened our understanding of LAG3's immuno-modulatory mechanisms and highlighted the need to elucidate the molecular mechanisms underlying the biological function of the LAG3-MHC Ⅱ interaction in a true cell-cell contact system.

摘要：Acute kidney injury(AKI)is a critical condition with limited effective therapies.Akkermansia muciniphila(A.muciniphila)is a probiotic with multiple beneficial effects,including the regulation of epithelial cell tight junctions.Since renal pathophysiology is associated with gut barrier integrity,we hypothesized that A.muciniphila may have preventive effects on AKI.We established a lipopolysaccharide(LPS)-induced AKI mouse model to evaluate the effects of A.muciniphila.Our findings showed that pretreatment with A.muciniphila significantly attenuated kidney injury,as evidenced by reduced serum creatinine and urea nitrogen levels,alongside decreased tubular necrosis and apoptosis.A.muciniphila preserved intestinal barrier integrity and induced marked shifts in gut microbial ecology and the metabolome.A.muciniphila notably induced an increase in the relative abundance of the phylum Proteobacteria while decreasing in that of the phylum Bacteroidetes.At the genus level,Prevotella,Faecalibaculum,Moraxella,and Lactobacillus were more abundant in A.muciniphila-pretreated mice.Metabolomic analysis revealed that A.muciniphila altered the gut metabolome,with changes involving pathways such as tyrosine metabolism,alanine/aspartate/glutamate homeostasis,cancer-related carbon flux,and GABAergic synaptic signaling.In conclusion,our findings indicate that A.muciniphila exerts renoprotective effects by modulating the gut-kidney axis,thereby establishing a foundation for future studies to explore the connection between gut microbiota and AKI.

摘要：While a healthy lifestyle is known to reduce the risk of stroke,the extent to which blood pressure(BP)mediates this association remains unclear.The present study aimed to quantify the mediating role of BP in the association between combined lifestyle factors and stroke incidence.Using data from 51 929 participants free of major cardiovascular diseases or cancer at baseline,we employed structural equation modeling to assess the mediating effects of systolic(SBP)and diastolic(DBP)blood pressure.During the follow-up,2 811 incident stroke cases were identified.A healthy lifestyle was significantly associated with a reduced risk of stroke,with SBP mediating 44.70%(β=-0.001 4,95%confidence interval[CI]:-0.001 6 to-0.001 2)and DBP mediating 37.81%(β=-0.001 2,95%CI:-0.001 5 to-0.000 9)of this association.The mediating effects were attenuated but remained significant for ischemic stroke(SBP:33.21%;DBP:27.24%).In conclusion,approximately two-fifths of the protective association between a healthy lifestyle and stroke may be mediated by BP.These findings suggest that BP control may serve as an important early indicator for evaluating the effectiveness of lifestyle interventions in reducing stroke risk.

摘要：Dear Editor, Linear and whorled nevoid hypermelanosis (LWNH)is a rare,sporadic pigmentary disorder characterized by hyperpigmented macules arranged in linear streaks and whorls along Blaschko's lines,typically appearing within the first few weeks of life[1],and remains a challenge to treat. Here,we report a case of LWNH and review the relevant literature to help clinicians better understand this disease.

摘要：Interferon-related genes are involved in antiviral responses,inflammation,and immunity,which are closely related to sepsis-associated acute respiratory distress syndrome(ARDS).We analyzed 1 972 participants with genotype data and 681 participants with gene expression data from the Molecular Epidemiology of ARDS(MEARDS),the Molecular Epidemiology of Sepsis in the ICU(MESSI),and the Molecular Diagnosis and Risk Stratification of Sepsis(MARS)cohorts in a three-step study focusing on sepsis-associated ARDS and sepsis-only controls.First,we identified and validated interferon-related genes associated with sepsis-associated ARDS risk using genetically regulated gene expression(GReX).Second,we examined the association of the confirmed gene(interferon regulatory factor 1,IRF1)with ARDS risk and survival and conducted a mediation analysis.Through discovery and validation,we found that the GReX of IRF1 was associated with ARDS risk(odds ratio[ORMEARDS]=0.84,P=0.008;ORMESSI=0.83,P=0.034).Furthermore,individual-level measured IRF1 expression was associated with reduced ARDS risk(OR=0.58,P=8.67×10-4),and improved overall survival in ARDS patients(hazard ratio[HR28-day]=0.49,P=0.009)and sepsis patients(HR28-day=0.76,P=0.008).Mediation analysis revealed that IRF1 may enhance immune function by regulating the major histocompatibility complex,including HLA-F,which mediated more than 70%of protective effects of IRF1 on ARDS.The findings were validated by in vitro biological experiments including time-series infection dynamics,overexpression,knockout,and chromatin immunoprecipitation sequencing.Early prophylactic interventions to activate IRF1 in sepsis patients,thereby regulating HLA-F,may reduce the risk of ARDS and mortality,especially in severely ill patients.

摘要：It is often challenging to diagnose acute myocardial infarction(AMI)in patients with elevated high-sensitivity cardiac troponin T(hs-cTnT)before observing a significant rise and/or fall in hs-cTnT.The current study aimed to identify an optimal cut-off to rule in AMI.A total of 76 411 patients with elevated hs-cTnT were included.The predictive cut-off values for diagnosing ST-segment elevation myocardial infarction(STEMI)and non-ST-segment elevation myocardial infarction(NSTEMI)were assessed using the area under the receiver operating characteristic curve(AUC).Among the patients,50 466(66.0%)had non-cardiac diseases,25 945(34.0%)had cardiac diseases,and 15 502(20.3%)had AMI,including 816(1.1%)with STEMI and 14 686(19.2%)with NSTEMI.The median hs-cTnT level was 3 788.0 ng/L in STEMI patients and 67.2 ng/L in NSTEMI patients.The optimal cut-off for diagnosing STEMI was 251.9 ng/L,with a sensitivity of 90.7%,specificity of 86.5%,and an AUC of 0.942;the optimal cut-off for diagnosing NSTEMI was 130.5 ng/L,with a sensitivity of 40.9%,specificity of 83.8%,and an AUC of 0.638.Collectively,optimizing the cut-off values for diagnosing STEMI and NSTEMI to 251.9 ng/L and 130.5 ng/L,respectively,demonstrated high accuracy in a large cohort of Chinese patients with elevated hs-cTnT.

摘要：A mutation in oxysterol-binding protein-like 2(OSBPL2)has been identified as the genetic cause of autosomal dominant nonsyndromic hearing loss(DFNA67,Online Mendelian Inheritance in Man No.616340).However,the pathogenesis of the OSBPL2 mutation in DFNA remains unclear.Our previous work showed that Osbpl2 deficiency impaired cell adhesion in auditory HEI-OC1 cells.In addition,loss of hair cells(HCs)and morphological abnormalities of HC stereocilia were detected in OSBPL2-knockout pigs,suggesting that OSBPL2 plays an important role in regulating the actin cytoskeleton in auditory cells.In the present study,we found that Osbpl2 deficiency inhibited the Rho/ROCK2 signaling pathway and downregulated phosphorylated ezrin-radixin-moesin(p-ERM),resulting in abnormal F-actin morphology in HEI-OC1 cells and stereociliary defects in mouse HCs.The present study demonstrates the underlying mechanism of OSBPL2 in regulating the actin cytoskeleton in HCs,contributing to a deeper understanding of the pathogenesis of OSBPL2 mutations in DFNA.

摘要：Dear Editor, Bronchial asthma (BA) is a common chronic inflammatory disease of the airways,characterized by variable obstruction and airway hyperreactivity.

摘要：Primordial germ cells(PGCs),the precursors of oocytes and spermatozoa,are highly pluripotent.In recent years,the in vitro induction of human primordial germ cell-like cells(hPGCLCs)has advanced significantly.However,the stability and efficacy of obtaining hPGCLCs in vitro still require improvement.In the current study,we identified a novel induction system using Dulbecco's Modified Eagle Medium/Nutrient Mixture F-12(DMEM/F-12)as the basal medium,supplemented with B27 and N2(referred to as N2B27)in combination with four cytokines:bone morphogenetic protein 4,stem cell factor,epidermal growth factor,and leukemia inhibitory factor.The hPGCLCs induced under these conditions closely resembled PGCs from 4-to 5-week-old embryos at the transcriptomic level.Compared with traditional GK15(GMEM supplemented with 15％KnockoutTM Serum Replacement)-based induction conditions,the N2B27 system significantly increased the speed and efficacy of hPGCLC induction.RNA sequencing analysis revealed that this improvement was due to an increased cellular capacity to cope with hypoxic stress and avoid apoptosis.The N2B27 medium promoted enhanced mitochondrial activity,enabling cells to better manage hypoxic stress while reducing the production of reactive oxygen species.Moreover,through gradient concentration experiments,we demonstrated that the addition of the common antioxidant N-acetyl-L-cysteine at an optimized concentration further enhanced the efficiency of PGCLC induction under GK15 conditions.In summary,we have established an optimized induction system that enhances the efficiency of hPGCLC differentiation by improving cellular resilience to hypoxic stress and apoptosis.

摘要：The Optimal Management of Antithrombotic and Thrombolytic Agents-5(OPTIMA-5)study demonstrated that a single bolus of half the standard dose of recombinant staphylokinase(r-SAK)before primary percutaneous coronary intervention(PCI)significantly improved the patency of the infarct-related artery in patients with ST-segment elevation myocardial infarction(STEMI),who were expected to undergo PCI within 120 min.The present study aimed to investigate the one-year clinical outcomes and the effect of the anti-r-SAK antibodies on a second r-SAK thrombolysis in OPTIMA-5 patients.The clinical outcome measured was major adverse cardiovascular events(MACE)within 360 days.Patients'anti-r-SAK antibody levels were determined on day 90(±7 days),day 180(±7 days),and day 360(±14 days)after thrombolysis,and in vitro r-SAK antibody neutralization experiments were performed to explore an optimal interval for a second r-SAK thrombolysis.Results showed that the MACE incidence was numerically lower in the r-SAK group compared with the normal saline(NS)group(14.0%vs.20.0%,hazard ratio[HR]=0.67,95%confidence interval[CI]:0.34-1.32;log-rank P=0.245).The anti-r-SAK antibody levels in the r-SAK group decreased with time,but remained significantly higher than those in the NS group on day 90(±7 days)(2.96±0.68 vs.0.22±0.53,P<0.001),day 180(±7 days)(2.19±0.74 vs.0.44±0.65,P<0.001),and day 360(±14 days)(1.73±0.97 vs.0.37±0.71,P<0.001).The in vitro anti-r-SAK antibody neutralization experiments demonstrated that the thrombolysis rate decreased exponentially as the antibody titer increased from 1.90 to 2.20(67.80%±14.19%vs.44.32%±21.54%,P<0.000 1).Therefore,for STEMI patients who are expected to undergo PCI within 120 min,a single bolus of half-dose r-SAK before primary PCI may reduce the one-year MACE risk.The anti-r-SAK antibody persists over one year,and a second r-SAK thrombolysis may not be indicated until at least one year after the first administration,if necessary.

摘要：This study aimed to evaluate the association of a healthy lifestyle pattern with mortality risk among patients with type 2 diabetes mellitus(T2DM).Data were derived from a prospective cohort study enrolling 13 776 Chinese patients with T2DM.A healthy lifestyle pattern was constructed based on six lifestyle factors,including smoking status,alcohol consumption,dietary habits,physical activity,sedentary time,and sleep duration.Multivariate Cox proportional hazards models were used to estimate hazard ratios(HRs)and 95%confidence intervals(CIs)for all-cause and cause-specific mortality.During a median follow-up of 9.78 years,2 497 deaths were recorded.Compared with T2DM patients with a lifestyle pattern scoring 0-2,those scoring 5-6 had a 40%lower risk for all-cause mortality(HR=0.60,95%CI:0.52-0.69),a 33%lower risk for cardiovascular disease mortality(HR=0.67,95%CI:0.52-0.86),and a 25%lower risk for cancer mortality(HR=0.75,95%CI:0.58-0.97).Additionally,we found that the association between the lifestyle pattern and all-cause mortality risk was stronger in females than in males(P for interaction<0.05).In conclusion,adherence to a healthy lifestyle pattern is associated with a decreased risk of all-cause,cardiovascular disease,and cancer mortality.These findings have important implications for reducing premature mortality among patients with T2DM.

摘要：Dear Editor, Early pregnancy loss is a condition whose relevance is determined not only by high incidence but also by the frequency of this pathology progressing into habitual miscarriage.

摘要：The circadian clock is crucial for the progression of cardiovascular diseases.Our previous studies showed that acrolein,an environmental pollutant,exacerbated atherosclerosis by reducing CLOCK/BMAL1 levels and disrupting circadian rhythm;in contrast,intermittent fasting(IF),a dietary regimen,ameliorated acrolein-induced atherosclerosis.In the current study,mice were administered acrolein at a dose of 3 mg/(kg·day)via drinking water and subjected to IF for 18 h(from 0:00 to 18:00).We observed that IF reduced the formation of aortic lesions accelerated by acrolein in ApoE-/-mice.Upon exposure to acrolein,the expression of RelA,Il1b,and Tnf increased in the liver and heart tissues,but these changes were reversed by IF treatment.Notably,IF treatment upregulated the expression of adenosine monophosphate(AMP)-activated protein kinase catalytic subunit alpha-1(AMPKα1),p-AMPKα1,and sirtuin 1(SIRT1),while inhibiting acrolein-induced mitogen-activated protein kinase(MAPK)activation.Additionally,the expression of circadian genes Clock/Bmal1 was suppressed and disrupted by acrolein,whereas IF restored their expression.Moreover,consistent with the in vivo findings,short-term starvation in vitro,as a fasting cell model,alleviated the dysregulation of CLOCK/BMAL1 and upregulated SIRT1 expression by modulating the AMPK and reactive oxygen species(ROS)-MAPK pathways activated by acrolein.In summary,we demonstrated that IF suppressed the ROS-MAPK pathway but activated the AMPK pathway to enhance the expression of circadian clock genes,thereby ameliorating acrolein-induced atherogenesis,which may shed light on strategies for preventing cardiovascular diseases.