摘要：Myocardial fibrosis is a major pathogenic factor contributing to cardiac remodeling and heart failure.Recent research has indicated that microRNAs play a crucial role in the progression of cardiac fibrosis.Bone morphogenetic protein and activin membrane-bound inhibitor(BAMBI)have been shown to alleviate myocardial fibrosis by inhibiting the transforming growth factor β1(TGF-β1)signaling pathway.Therefore,the current study aimed to elucidate the post-transcriptional regulation of BAMBI by miR-19a-3p and its role in TGF-β1-induced cardiac fibroblast activation.We found that transverse aortic constriction induced both myocardial interstitial and perivascular collagen deposition.Quantitative reverse transcription-PCR(qRT-PCR)analysis showed that the expression level of miR-19a-3p was increased in the myocardial tissues of cardiac fibrosis,and TGF-β1 induced an upregulation in miR-19a-3p expression in cardiac fibroblasts.The dual-luciferase reporter assay and qRT-PCR verified that miR-19a-3p directly bound to the 3′ untranslated regions of BAMBI mRNA,thereby reducing BAMBI expression and diminishing its ability to inhibit the TGF-β1 signaling pathway.Furthermore,overexpression of miR-19a-3p mimic increased the activation of TGF-β1/SMAD2/3 pathway signaling,promoting cardiac fibroblast activation.However,this activation was blocked by BAMBI overexpression.These findings imply that miR-19a-3p enhances the activation of TGF-β1/SMAD2/3 by inhibiting BAMBI,further boosting the activation of cardiac fibroblasts and contributing to myocardial fibrosis.

摘要：Renal transplant patients receive several immunosuppressive drug regimens that are potentially nephrotoxic for treatment.Serum creatinine is the standard for monitoring kidney function;however,cystatin C(Cys C)and kidney injury molecule-1(KIM-1)have been found to indicate kidney injury earlier than serum creatinine and provide a better reflection of kidney function.Here,we assessed Cys C and KIM-1 serum levels in renal transplant patients receiving mycophenolate mofetil,tacrolimus,sirolimus,everolimus,or cyclosporine to evaluate kidney function.We used both the Chronic Kidney Disease Epidemiology Collaboration(CKD-EPI)2021 equation,which is based on creatinine and combined creatinine with Cys C,and the CKD-EPI 2012 equation,which is based on Cys C alone,to estimate glomerular filtration rate(GFR).Then,we assessed the association between serum KIM-1 and GFR<90 mL per minute per 1.73 m2.We observed significantly higher serum Cys C levels in patients with the elevated serum creatinine,compared with those with normal serum creatinine.The estimated GFRs based on creatinine were significantly higher than those based on the other equations,while a significant positive correlation was observed among all equations.Serum KIM-1 levels were negatively correlated with the estimated GFRs by the CKD-EPI Cys C and the combined creatinine with Cys C equations.A serum KIM-1 level above 0.71 ng/mL is likely to indicate GFR<90 mL per minute per 1.73 m2).We observed a significant correlation between serum creatinine and Cys C in our renal transplant patients.Therefore,serum KIM-1 may be used to monitor renal function when using potentially nephrotoxic drugs in renal transplants.

摘要：Cancer research is at the forefront of medical science, aimed at clarifying the pathogenesis of carcinogenesis as well as prevention, diagnosis, and treatment of cancers.

摘要：Achondroplasia is a genetic condition characterized by skeletal dysplasia that results in characteristic craniofacial and spinal abnormalities.It is the most common form of short-limbed skeletal dysplasia.A morbidly obese pregnant patient warrants specific anatomical and physiological considerations,such as a difficult airway with potential hypoxia,full stomach precautions,and a reduced functional residual capacity.Achondroplasia increases the risks of maternal and fetal complications.Although neuraxial techniques are generally preferred for cesarean sections,there is no consensus among patients with achondroplasia.We aimed to discuss the anesthetic challenges in an achondroplastic patient and report our regional anesthesia approach for an elective cesarean section.

摘要：The current study aimed to compare the effects between remimazolam and propofol on hemodynamic stability during the induction of general anesthesia in elderly patients.We used propofol at a rate of 60 mg/(kg·h)in the propofol group(group P)or remimazolam at a rate of 6 mg/(kg·h)in the remimazolam group(group R)for the induction.A processed electroencephalogram was used to determine whether the induction was successful and when to stop the infusion of the study drug.We measured when patients entered the operating room(T0),when the induction was successful(T1),and when before(T2)and 5 min after successful endotracheal intubation(T3).We found that mean arterial pressure(MAP)was lower at T1-3,compared with T0 in both groups,but higher at T2 in the group R,while ΔMAPT0-T2 and ΔMAPmax were smaller in the group R(ΔMAPT0-T2:the difference between MAP at time point T0 and T2,ΔMAPmax:the difference between MAP at time point T0 and the lowest value from T0 to T3).Cardiac index and stroke volume index did not differ between groups,whereas systemic vascular resistance index was higher at T1-3 in the group R.These findings show that remimazolam,compared with propofol,better maintains hemodynamic stability during the induction,which may be attributed to its ability to better maintain systemic vascular resistance levels.

摘要：Deterministic compartment models(CMs)and stochastic models,including stochastic CMs and agent-based models,are widely utilized in epidemic modeling.However,the relationship between CMs and their corresponding stochastic models is not well understood.The present study aimed to address this gap by conducting a comparative study using the susceptible,exposed,infectious,and recovered(SEIR)model and its extended CMs from the coronavirus disease 2019 modeling literature.We demonstrated the equivalence of the numerical solution of CMs using the Euler scheme and their stochastic counterparts through theoretical analysis and simulations.Based on this equivalence,we proposed an efficient model calibration method that could replicate the exact solution of CMs in the corresponding stochastic models through parameter adjustment.The advancement in calibration techniques enhanced the accuracy of stochastic modeling in capturing the dynamics of epidemics.However,it should be noted that discrete-time stochastic models cannot perfectly reproduce the exact solution of continuous-time CMs.Additionally,we proposed a new stochastic compartment and agent mixed model as an alternative to agent-based models for large-scale population simulations with a limited number of agents.This model offered a balance between computational efficiency and accuracy.The results of this research contributed to the comparison and unification of deterministic CMs and stochastic models in epidemic modeling.Furthermore,the results had implications for the development of hybrid models that integrated the strengths of both frameworks.Overall,the present study has provided valuable epidemic modeling techniques and their practical applications for understanding and controlling the spread of infectious diseases.

摘要：Dear Editor, Neurodegenerative disorders (NDDs) are age-related disorders characterized by the deposition of abnormal forms of proteins or the progressive loss of neurons in the brain. NDDs are classified according to their pathophysiological properties,including cognitive dysfunction,Alzheimer's disease (AD) and other dementias,Parkinson's disease,and motor neuron disease. The increased oxidative stress and neuro-inflammatory events contribute to neuronal atrophy and death in NDDs[1]. Nitric oxide in the central nervous system has several functions,including the regulation of synaptic plasticity and neurosecretion. The physiological amount of nitric oxide is neuroprotective,whereas higher doses are noticeably neurotoxic[2].

摘要：Microtubule-severing enzymes(MTSEs)play important roles in mitosis and meiosis of the primitive organisms.However,their roles in mammalian female meiosis,which accounts for over 80%of gamete-originated human reproductive diseases,remain unexplored.In the current study,we reported that katanin-like 2(KL2)was the only MTSE concentrating at chromosomes.Furthermore,the knockdown of KL2 significantly reduced the chromosome-based increase in the microtubule(MT)polymer,increased aberrant kinetochore-MT(K-MT)attachment,delayed meiosis,and severely affected normal fertility.We demonstrated that the inhibition of aurora B,a key kinase for correcting aberrant K-MT attachment,significantly eliminated KL2 expression from chromosomes.Additionally,KL2 interacted with phosphorylated eukaryotic elongation factor-2 kinase,and they competed for chromosome binding.Phosphorylated KL2 was also localized at spindle poles,with its phosphorylation regulated by extracellular signal-regulated kinase 1/2.In summary,the current study reveals a novel function of MTSEs in mammalian female meiosis and demonstrates that multiple kinases coordinate to regulate the levels of KL2 at chromosomes.

摘要：As a potential endocrine-disrupting chemical,bisphenol F(BPF)may cause nonalcoholic fatty liver disease(NAFLD)-like changes,but the mechanisms under its pathogenesis as well as the intervention strategies remain unclear.Using the electron microscopy technology,along with LipidTOX Deep Red neutral and Bodipy 493/503 staining assays,we observed that BPF treatment elicited a striking accumulation of lipid droplets in HepG2 cells,accompanied by an increased total level of triglycerides.At the molecular level,the lipogenesis-associated mRNAs and proteins,including acetyl-CoA carboxylase,fatty acid synthase,stearoyl-CoA desaturase-1,peroxisome proliferator-activated receptor gamma,and CCAAT-enhancer-binding proteins,increased significantly via the AMP-activated protein kinase(AMPK)-mammalian target of rapamycin(mTOR)signaling regulation in both in vitro and in vivo studies.Furthermore,the immunofluorescence results also showed the robust lipogenesis induced by BPF,evident in its ability to promote the translocation of sterol regulatory element-binding protein-1c from the cytoplasm to the nuclei.To investigate the intervention strategies for BPF-induced NAFLD-like changes,we demonstrated that bellidifolin,isolated and purified from Swertia chirayita,significantly attenuated BPF-induced lipid droplet deposition in HepG2 cells and NAFLD-like changes in mice by blocking the expression of lipogenesis-associated proteins.Therefore,the present study elucidates the mechanisms underlying the BPF-induced lipid accumulation in HepG2 cells,while also highlighting the potential of bellidifolin to mitigate BPF-induced NAFLD-like changes.

摘要：Atherosclerosis is extremely widespread.Traditionally,it is considered a disease of older people,who most often experience problems with the heart and blood vessels.While much attention from the scientific community has been paid to studying the association between aging and atherosclerosis,as well as its consequences,there is evidence that atherosclerosis occurs at an early age.Atherosclerosis may form both during intrauterine development and in childhood.Nutrition plays an important role in childhood atherosclerosis,along with previous infectious diseases and excess weight of both the child and the mother.In the present review,we examined the development of atherosclerosis and the prerequisites in childhood.

摘要：Systemic lupus erythematosus(SLE)is characterized by a systemic dysfunction of both the innate and adaptive immune systems,leading to an attack on healthy tissues of the body.During the development of SLE,pathogenic features,such as the formation of autoantibodies against self-nuclear antigens,cause tissue damage including necrosis and fibrosis,with increased expression levels of the type Ⅰ interferon-regulated genes.Standard treatments for lupus with immunosuppressants and glucocorticoids are not effective enough but cause side effects.As an alternative,more effective immunotherapies have been developed,including monoclonal and bispecific antibodies that target B cells,T cells,co-stimulatory molecules,cytokines or their receptors,and signaling molecules.Encouraging results have been observed in clinical trials with some of these therapies.Furthermore,a chimeric antigen receptor T cell therapy has emerged as the most effective,safe,and promising treatment option for SLE,as demonstrated by successful pilot studies.Additionally,some emerging evidence suggests that gut microbiota dysbiosis may significantly contribute to the severity of SLE,and the normalization of the gut microbiota through methods such as fecal microbiota transplantation presents new opportunities for effective treatment of SLE.

摘要：Tumor vaccines are a promising avenue in cancer immunotherapy.Despite the progress in targeting specific immune epitopes,tumor cells lacking these epitopes can evade the treatment.Here,we aimed to construct an efficient in situ tumor vaccine called Vac-SM,utilizing shikonin(SKN)to induce immunogenic cell death(ICD)and Mycobacterium smegmatis as an immune adjuvant to enhance in situ tumor vaccine efficacy.SKN showed a dose-dependent and time-dependent cytotoxic effect on the tumor cell line and induced ICD in tumor cells as evidenced by the CCK-8 assay and the detection of the expression of relevant indicators,respectively.Compared with the control group,the in situ Vac-SM injection in mouse subcutaneous metastatic tumors significantly inhibited tumor growth and distant tumor metastasis,while also improving survival rates.Mycobacterium smegmatis effectively induced maturation and activation of bone marrow-derived dendritic cells(DCs),and in vivo tumor-draining lymph nodes showed an increased maturation of DCs and a higher proportion of effector memory T-cell subsets with the Vac-SM treatment,based on flow cytometry analysis results.Collectively,the Vac-SM vaccine effectively induces ICD,improves antigen presentation by DCs,activates a specific systemic antitumor T-cell immune response,exhibits a favorable safety profile,and holds the promise for clinical translation for local tumor immunotherapy.

摘要：The extensive spread of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)throughout China in late 2022 has underscored the correlation between this virus and severe psychiatric disorders.However,there remains a lack of reported clinical and pathological features.Accordingly,we retrospectively reviewed the electronic medical records of psychiatric inpatients for seven days from early January 2023.Twenty-one inpatients who developed first-episode psychiatric disorders within two weeks after SARS-CoV-2 infection were recruited,while 24 uninfected first-episode psychiatric inpatients were selected as controls.Comparative analyses of clinical manifestations,routine laboratory tests,and imaging examinations were performed.Our investigation demonstrated a 330%increase in the incidence of first-episode psychiatric inpatients after SARS-CoV-2 infection in 2023,compared with the preceding year without SARS-CoV-2 infections.Most cases exhibited psychiatric symptoms within one week of SARS-CoV-2 infection,which resolved after approximately two weeks,with no residual symptoms after three months.One-way ANOVA demonstrated a significant difference in the highest fever temperature between inpatients with and without psychotic symptoms.Infected inpatients displayed elevated levels of interleukin-4,interleukin-8,and interferon-α,but decreased levels of eosinophils and basophils.These findings suggest that SARS-CoV-2 may contribute to the development of psychiatric disorders,likely mediated by the virus-induced inflammatory response and neuronal dysfunction in the context of psychological distress.

摘要：Nocardiosis manifests as an opportunistic infection,primarily affecting individuals who are immunocompromised and susceptible to the infection.We present a case study of one patient with nephrotic syndrome and membranous nephropathy,who underwent treatment with prednisone and cyclosporine in 2016.In early 2017,the patient was diagnosed with a"fungal infection"and discontinued the use of cyclosporine.After one month of anti-infection therapy,a cranial magnetic resonance imaging scan showed multiple abscesses in the right temporal region.The diagnosis of nocardiosis was confirmed based on the presence of metastatic abscess masses,multiple lung and brain lesions,and a positive culture of Nocardia in the drainage.We changed the anti-infection therapy to a combination of trimethoprim-sulfamethoxazole(TMP-SMX),minocycline,and voriconazole.However,the patient experienced a sudden cardiac arrest and subsequently recovered after cardiopulmonary resuscitation.During the five-month follow-up period following the discharge,the patient displayed an enhanced nutritional status and stable renal function.The focal infection ultimately resolved during the subsequent three years.Neuro-infection caused by Nocardia should be considered in immunocompromised patients,and TMP-SMX is the preferred initial therapy;however,because of the high mortality rate,a long-term combination therapy with imipenem,cefotaxime,amikacin,and TMP-SMX is suggested.

摘要：Immune-related adverse events(irAEs)represent an increasingly concerning challenge in the assessment of biopharmaceutical products.In contrast to historically rare allergic reactions associated with small chemical drugs,contemporary biotherapeutics exhibit a significantly higher morbidity of irAEs,because of their complex structure and comprehensive mechanisms of action.While the immunogenicity of protein-based compounds is associated with the induction of anti-drug antibodies,the pathogenesis of irAEs in advanced biologics,such as cell and gene therapy,remains to be further delineated.In the current study,I present an updated profile regarding the untoward immune effects of medications,covering various material categories systematically,with the underlying mechanisms to inspire risk mitigation in biopharmaceutical development and application.

摘要：Epidemiological data are scarce regarding the association of exposure to mixtures of per-and polyfluoroalkyl substances(PFASs)with liver injury in the general population.In the current study,therefore,we examined data from the National Health and Nutrition Examination Survey(2009-2018).The PFAS exposure levels were defined by the serum concentrations of PFASs with over 70%detection in samples,namely perfluorooctanoic acid,perfluorononanoic acid,perfluorohexane sulfonic acid,perfluorodecanoic acid,and perfluorooctane sulfonic acid(PFOS).We evaluated liver injury from two aspects:first,the degree of liver inflammation was determined based on levels of the serum alanine aminotransferase,aspartate aminotransferase,glutamyltransferase,and total bilirubin;second,the degree of liver fibrosis was determined based on the fibrosis-4 index.We assessed the associations of individual or total PFAS exposure with these liver injury outcomes using multivariable linear and logistic regression models,restricted cubic splines,and weighted quantile sum regression.Among the samples of 7 484 American adults,the median concentration of PFOS was the highest,followed by perfluorooctanoic acid and perfluorohexane sulfonic acid.Using multivariable linear regression,we observed positive correlations between all PFAS exposure and liver enzyme levels,such as alanine aminotransferase,aspartate aminotransferase,and total bilirubin.Additionally,the weighted quantile sum model indicated an overall positive association between exposure to the five PFASs and liver injury risk.For liver function biomarkers and liver fibrosis,perfluorononanoic acid and PFOS were the most heavily weighted chemicals,respectively.Our findings provide new epidemiological evidence indicating potential associations between PFAS exposure and adverse effects on liver injury biomarkers,highlighting the potentially harmful effects of PFAS exposure on human liver health.

摘要：The prevalence of stunting in Indonesian children under five years of age is approximately 20%.Chronic maternal malnutrition contributes to the risk of stunting by affecting global DNA methylation.In the present study,we aimed to evaluate the levels of 5-methyl-cytosine(5mC)as a surrogate marker of global DNA methylation in buccal swabs and its potential association with the risk of stunting and cognitive performance.The levels of 5mC were measured using an enzyme-linked immunosorbent assay.The Wechsler Preschool and Primary Scale of Intelligence(WPPSI)was used to measure cognitive function.Buccal swab DNA samples and anthropometric data were collected from a total of 231 children aged zero to five years.In this cross-sectional cohort,the prevalence of stunting was 37%in 138 children aged zero to two years and 30%in 93 children aged over two years.The univariable analysis revealed that the levels of 5mC in buccal swab DNA were significantly lower in severely stunted children(median,2.84;interquartile range[IQR],2.39-4.62)and children aged less than two years(median,2.81;IQR,2.53-4.62)than those in normal children(median,3.75;IQR,2.80-4.74;P-value,0.028)and children aged over four years(median,4.01;IQR,3.39-4.87;P-value<0.001),respectively.We also found that the average cognitive scores tended to be low in boys and stunted children,although the differences were not statistically significant.Furthermore,the levels of 5mC found in buccal swab and mouthwash DNA were not associated with cognitive scores.

摘要：Inconsistent findings have been reported regarding the associations between hypertensive disorders in pregnancy(HDP)and infant neurodevelopment.Leveraging data from the Jiangsu Birth Cohort,in the present study,we re-visited such associations in one-year-old infants from 2 576 singleton pregnancies and 261 twin pregnancies.We first assessed infant neurodevelopment by the Bayley Scales of Infant and Toddler Development Screening Test(the Third Edition),and then estimated its association with maternal HDP using general linear regression models and Poisson regression models.In singleton pregnancies,compared with mothers unexposed to HDP,infants born to mothers with chronic hypertension exhibited a lower score(β,-0.67;95%confidence interval[CI],-1.19--0.15)and a higher risk of"non-optimal"gross motor development(risk ratio[RR],2.21;95%CI,1.02-4.79);in twin pregnancies,infants born to mothers with HDP exhibited lower scores in cognition(β,-0.49;95%CI,-0.96--0.01),receptive communication(β,-0.55;95%CI,-1.03--0.06),and gross motor(β,-0.44;95%CI,-0.86--0.03),and at a higher risk of"non-optimal"gross motor development(RR,2.12;95%CI,1.16-3.88).These findings indicate that infants born to mothers with HDP may have inferior neurodevelopment outcomes at the age of one year.

摘要：Dear Editor, Renal calculosis is one of the most common urological disorders worldwide,with a prevalence ranging from 1％ to 13％ across different regions[1].Renal stones are crystal concretions that form on the inner surface of the kidney,resulting from disruptions in the metabolism,the excretion of stone constituents,or the formation of Randall's plaques and plugs. These stones are a result of various endogenous factors,such as age,sex,and genetic makeup as well as various exogenous factors like geography,weather conditions,and dietary factors[2].

摘要：Aberrant alternative polyadenylation(APA)events play an important role in cancers,but little is known about whether APA-related genetic variants contribute to the susceptibility to bladder cancer.Previous genome-wide association study performed APA quantitative trait loci(apaQTL)analyses in bladder cancer,and identified 17 955 single nucleotide polymorphisms(SNPs).We found that gene symbols of APA affected by apaQTL-associated SNPs were closely correlated with cancer signaling pathways,high mutational burden,and immune infiltration.Association analysis showed that apaQTL-associated SNPs rs34402449 C>A,rs2683524 C>T,and rs11540872 C>G were significantly associated with susceptibility to bladder cancer(rs34402449:OR=1.355,95%confidence interval[CI]:1.159-1.583,P=1.33×10-4;rs2683524:OR=1.378,95%CI:1.164-1.632,P=2.03×10-4;rs11540872:OR=1.472,95%CI:1.193-1.815,P=3.06×10-4).Cumulative effect analysis showed that the number of risk genotypes and smoking status were significantly associated with an increased risk of bladder cancer(Ptrend=2.87×10-12).We found that PRR13,being demonstrated the most significant effect on cell proliferation in bladder cancer cell lines,was more highly expressed in bladder cancer tissues than in adjacent normal tissues.Moreover,the rs2683524 T allele was correlated with shorter 3′ untranslated regions of PRR13 and increased PRR13 expression levels.Collectively,our findings have provided informative apaQTL resources and insights into the regulatory mechanisms linking apaQTL-associated variants to bladder cancer risk.