Macroautophagy (referred to as autophagy hereafter) is a major intracellular lysosomal degradation pathway that is responsible for the degradation of misfolded/damaged proteins and organelles. Previous studies showed that autophagy protects against acetaminophen (APAP)-induced injury (AILI) via selective removal of damaged mitochondria and APAP protein adducts. The lysosome is a critical organelle sitting at the end stage of autophagy for autophagic degradation via fusion with autophagosomes. In the present study, we showed that transcription factor EB (TFEB), a master transcription factor for lysosomal biogenesis, was impaired by APAP resulting in decreased lysosomal biogenesis in mouse livers. Genetic loss-of and gain-of function of hepatic TFEB exacerbated or protected against AILI, respectively. Mechanistically, overexpression of TFEB increased clearance of APAP protein adducts and mitochondria biogenesis as well as SQSTM1/p62-dependent non-canonical nuclear factor erythroid 2-related factor 2 (NRF2) activation to protect against AILI. We also performed an unbiased cell-based imaging high-throughput chemical screening on TFEB and identified a group of TFEB agonists. Among these agonists, salinomycin, an anticoccidial and antibacterial agent, activated TFEB and protected against AILI in mice. In conclusion, genetic and pharmacological activating TFEB may be a promising approach for protecting against AILI.

Objective·To analyze and explore the influencing factors that lead to cognitive deterioration in individuals with elevated fasting blood glucose(FBG)and the metabolic clues associated with changes in the risk of cognitive deterioration.Methods·Data from the Alzheimer's Disease Neuroimaging Initiative(ADNI)database were downloaded,and the samples with FBG and follow-up data were selected from the database.Clinical information,including age,gender,body mass index,education years,apolipoprotein E4(APOE4)genotype and race,and corresponding metabolic indicator data,including amino acids,fatty acids,proteins and others were obtained.Based on the FBG levels and diagnosis of cognitive impairment stages in Alzheimer's disease,the subjects were categorized into four groups:normal FBG without/with cognitive deterioration,and elevated FBG without/with cognitive deterioration.The univariate analysis method,the Cox proportional hazards model,orthogonal projections to latent structures discriminant analysis(OPLSDA),and Spearman correlation analysis were employed for data analysis.Results·A total of 1 317 subjects were included,among which 1 153 had normal FBG level(>3.9 mmol/L and<6.1 mmol/L)and 164 had elevated FBG level(≥6.1 mmol/L).In the normal FBG group,275 subjects showed cognitive deterioration,while in the elevated FBG group,53 subjects showed cognitive deterioration.Univariate analysis revealed significant differences in gender and race between the normal FBG and elevated FBG group,and significant differences in age,gender,and APOE4 genotype between the groups with and without cognitive deterioration(all P<0.05).Cox regression analysis indicated that primary influencing factors for cognitive deterioration were APOE4 positivity,elevated FBG,and increasing age in order(HR=2.22,HR=1.38,HR=1.02;all P<0.05).In the analysis of baseline metabolic indicators in the groups without and with cognitive deterioration,as well as metabolic indicators before and after cognitive deterioration at different FBG levels,the results of the analysis of variance revealed that in the cognitively deteriorated population,the ratio of phospholipids carried by high-density lipoproteins(HDL)to total lipids was significantly higher;low-density lipoprotein(LDL)particle concentration and the lipids carried by LDL were significantly higher after cognitive deterioration.Correlation analysis showed that valine and leucine were significantly correlated not only with FBG level but also with phosphorylated tau(pTau)level in the plasma in the cognitively deteriorated population.Cholesterol and the ratio of phospholipids to total lipids carried by HDL were significantly correlated with pTau levels in cerebrospinal fluid(CSF).Conclusion·Compared to the individuals with normal FBG level,those with high FBG level have a significantly higher risk of cognitive deterioration.Additionally,different metabolic indicators show significant differences between the groups without and with cognitive deterioration,as well as metabolic indicators before and after cognitive deterioration at different FBG levels.Overall,LDL and its lipid content,and HDL-carried phospholipids show an increasing trend during cognitive deterioration,and the branched-chain amino acids valine and leucine are significantly correlated with pTau levels in CSF and plasma,suggesting that these metabolic markers may play an important role in cognitive deterioration.

Objective To investigate the correlations of the expression levels of plasma long non-coding RNA plasmacytoma variant translocation 1 (LncRNA PVT1) and microRNA-143-3p (miR-143-3p) with disease activity and prognosis in patients with rheumatoid arthritis (RA). Methods A total of 129 RA patients admitted to our hospital from April 2021 to April 2023 were selected as disease group. According to the 28-joint disease activity scores (DAS28), the patients were divided into stable disease group (n=28), mildly active group (n=42), moderately active group (n=35), and severely active group (n=24). According to the prognosis of the patients after 6 months of treatment, they were divided into good prognosis group (n=88) and poor prognosis group (n=41), and 110 healthy people who underwent physical examinations in our hospital during the same period were included as control group. The expression levels of plasma LncRNA PVT1 and miR-143-3p were detected using quantitative real-time fluorescent polymerase chain reaction (qRT-PCR). The targeting relationship between LncRNA PVT1 and miR-143-3p was predicted using the Target Scan Human website. Multivariate Logistic regression analysis was conducted to explore the factors influencing the prognosis of RA patients. Receiver operating characteristic (ROC) curve was performed to assess the predictive value of plasma LncRNA PVT1 and miR-143-3p for the prognosis of RA patients. Results The plasma LncRNA PVT1 level in the disease group was higher than that in the control group, while the plasma miR-143-3p level was lower (P < 0.05). The plasma LncRNA PVT1 levels decreased sequentially in the severe activity, moderate activity, mild activity, and disease stable groups, while the plasma miR-143-3p levels increased sequentially (P < 0.05).The proportion of patients positive for human leukocyte antigen-DR4 (HLA-DR4), DAS28, and plasma LncRNA PVT1 expression level were higher in the poor prognosis group than in the good prognosis group, while the plasma miR-143-3p level was lower (P < 0.05). Plasma LncRNA PVT1, miR-143-3p expression, HLA-DR4 positivity, and DAS28 were factors influencing the prognosis of RA patients (P < 0.05). LncRNA PVT1 and miR-143-3p had targeted binding sites, and there was a negative correlation between them (P < 0.05). The area under the curve (AUC) for the combined prediction of plasma LncRNA PVT1 and miR-143-3p for prognosis of RA patients was 0.914, which was superior to the individual diagnosis of LncRNA PVT1 or miR-143-3p (Z=2.159, P=0.031; Z=2.108, P=0.035). The sensitivity and specificity of the combined diagnosis were 95.12% and 78.41%, respectively. Conclusion The plasma LncRNA PVT1 level gradually increases, while the plasma miR-143-3p level gradually decreases with increasing RA disease activity. The combined detection of the two biomarkers has high predictive value for the prognosis of RA patients.

Background::Hepatic ischemia-reperfusion injury (HIRI) remains a common complication during liver transplantation (LT) in patients. As a key downstream effector of the Hippo pathway, Yes-associated protein (YAP) has been reported to be involved in various physiological and pathological processes. However, it remains elusive whether and how YAP may control autophagy activation during ischemia-reperfusion.Methods::Human liver tissues from patients who had undergone LT were obtained to evaluate the correlation between YAP and autophagy activation. Both an in vitro hepatocyte cell line and in vivo liver-specific YAP knockdown mice were used to establish the hepatic ischemia-reperfusion models to determine the role of YAP in the activation of autophagy and the mechanism of regulation. Results::Autophagy was activated in the post-perfusion liver grafts during LT in patients, and the expression of YAP positively correlated with the autophagic level of hepatocytes. Liver-specific knockdown of YAP inhibited hepatocytes autophagy upon hypoxia-reoxygenation and HIRI ( P <0.05). YAP deficiency aggravated HIRI by promoting the apoptosis of hepatocytes both in the in vitro and in vivo models ( P <0.05). Attenuated HIRI by overexpression of YAP was diminished after the inhibition of autophagy with 3-methyladenine. In addition, inhibiting autophagy activation by YAP knockdown exacerbated mitochondrial damage through increasing reactive oxygen species ( P <0.05). Moreover, the regulation of autophagy by YAP during HIRI was mediated by AP1 (c-Jun) N-terminal kinase (JNK) signaling through binding to the transcriptional enhanced associate domain (TEAD). Conclusions::YAP protects against HIRI by inducing autophagy via JNK signaling that suppresses the apoptosis of hepatocytes. Targeting Hippo (YAP)-JNK-autophagy axis may provide a novel strategy for the prevention and treatment of HIRI.

Background::Although overnight fasting is recommended prior to endoscopic retrograde cholangiopancreatography (ERCP), the benefits and safety of high-carbohydrate fluid diet (CFD) intake 2 h before ERCP remain unclear. This study aimed to analyze whether high-CFD intake 2 h before ERCP can be safe and accelerate patients’ recovery.Methods::This prospective, multicenter, randomized controlled trial involved 15 tertiary ERCP centers. A total of 1330 patients were randomized into CFD group ( n = 665) and fasting group ( n = 665). The CFD group received 400 mL of maltodextrin orally 2 h before ERCP, while the control group abstained from food/water overnight (>6 h) before ERCP. All ERCP procedures were performed using deep sedation with intravenous propofol. The investigators were blinded but not the patients. The primary outcomes included postoperative fatigue and abdominal pain score, and the secondary outcomes included complications and changes in metabolic indicators. The outcomes were analyzed according to a modified intention-to-treat principle. Results::The post-ERCP fatigue scores were significantly lower at 4 h (4.1 ± 2.6 vs. 4.8 ± 2.8, t = 4.23, P <0.001) and 20 h (2.4 ± 2.1 vs. 3.4 ± 2.4, t= 7.94, P <0.001) in the CFD group, with least-squares mean differences of 0.48 (95% confidence interval [CI]: 0.26–0.71, P <0.001) and 0.76 (95% CI: 0.57–0.95, P <0.001), respectively. The 4-h pain scores (2.1 ± 1.7 vs. 2.2 ± 1.7, t = 2.60, P = 0.009, with a least-squares mean difference of 0.21 [95% CI: 0.05–0.37]) and positive urine ketone levels (7.7% [39/509] vs. 15.4% [82/533], χ2 = 15.13, P <0.001) were lower in the CFD group. The CFD group had significantly less cholangitis (2.1% [13/634] vs. 4.0% [26/658], χ2 = 3.99, P = 0.046) but not pancreatitis (5.5% [35/634] vs. 6.5% [43/658], χ2 = 0.59, P = 0.444). Subgroup analysis revealed that CFD reduced the incidence of complications in patients with native papilla (odds ratio [OR]: 0.61, 95% CI: 0.39–0.95, P = 0.028) in the multivariable models. Conclusion::Ingesting 400 mL of CFD 2 h before ERCP is safe, with a reduction in post-ERCP fatigue, abdominal pain, and cholangitis during recovery.Trail Registration::ClinicalTrials.gov, No. NCT03075280.

The prevention and treatment of cardiovascular diseases have always been a focus of attention in re-lated fields.This paper discusses the application and mechanism of exogenous and endogenous supplementation with β-hy-droxybutyrate in the prevention and treatment of cardiovascular diseases such as myocardial ischemia,myocardial infarc-tion,diabetic cardiomyopathy,hypertension,myocardial inflammation,hypertrophic cardiomyopathy and heart failure.Exogenous β-hydroxybutyrate supplementation can quickly and directly provide substitute energy for the heart and thus prevent and treat heart injury.The comprehensive effect of exogenous β-hydroxybutyrate supplementation is significantly better than that of endogenous β-hydroxybutyrate.Endogenous fatty acid,obtained through a ketogenic diet,needs to be oxidized to β-hydroxybutyrate in vivo for energy supply,which is greatly influenced by glucose and lipid metabolism under the conditions of the basic disease itself.At present,ketogenic diet is not recommended for use in the prevention and treat-ment of myocardial ischemia or myocardial infarction,and in the treatment of diabetic cardiomyopathy or hypertension.

Objective To study the diagnostic and therapeutic value of endoscopic irrigation for uncomplicated acute colonic diverticulitis.Methods From June 2021 to March 2022,4 patients suspected uncomplicated acute colonic diverticulitis who then underwent colonoscopy,and endoscopic irrigation treatment was performed after confirming.The endoscopic imaging of acute colonic diverticulitis was summarized.The changes of abdominal pain symptoms and prognosis of the patients were evaluated.The levels of white blood cell(WBC)and C-reactive protein(CRP)in serum before and after treatment were measured.Results 4 patients were diagnosed as uncomplicated acute colonic diverticulitis underwent colonoscopy.Two cases were located in the ascending colon and the other two in the cecum.Endoscopic imaging characteristics included mucosal hyperemia and swelling of diverticular orifice and nearby area,purulent secretions,purulent fur and fecalith at the diverticular orifice.After treatment,the symptom of abdominal pain was relieved,the levels of WBC and CRP in serum were lower than before treatment.Conclusion Endoscopic irrigation has a useful diagnostic and therapeutic value for uncomplicated acute diverticulitis of the colon.It is worthy of further clinical study.

Objective:To explore the latent categories of outpatient nurses' conflict management styles and analyze their influencing factors.Methods:A total of 408 outpatient nurses from six hospitals of Jiangsu Province were selected as study participants by convenience sampling. Data were collected using a general information questionnaire, the Rahim Organizational Conflict Inventory Scale, the Nurse Burnout Scale, the Caring Ability Inventory Scale and the Wong and Law Emotional Intelligence Scale. Latent profile analysis was used to classify the conflict management styles of outpatient nurses, and logistic regression analysis was applied to identify the influencing factors of different categories.Results:A total of 408 questionnaires were distributed, and 372 valid responses were received, with an effective response rate of 91.18%. Outpatient nurses' conflict management styles were divided into two categories: the "Integration-Concession Group" and the "Dominance-Avoidance Group." Logistic regression analysis showed that being an only child, receiving interpersonal communication training, nurse burnout, humanistic care ability, and emotional intelligence were significant influencing factors of the latent categories of conflict management styles ( P<0.05) . Conclusions:There is heterogeneity in outpatient nurses' conflict management styles. It is recommended that nursing administrators adopt a comprehensive approach, conduct thorough assessments of nurses' general conditions and personality traits, guide nurses toward adopting positive conflict management methods, and enhance their abilities in problem-solving and conflict resolution. This can improve interpersonal relationships and work efficiency in medical settings, stabilize the outpatient nursing workforce, and improve the overall quality of nursing services.

The aim of this study was to investigate the effects of high-intensity interval training(HIIT)on lipopolysaccharide(LPS)-induced septic myocardial injury in mice and the roles of NLRP3 inflammasome and macrophage M1 polarization in the process.C57BL/6 male mice were randomly divided into 4 groups:control(CON)group,LPS(L)group,HIIT+saline injection(E)group,and HIIT+LPS(EL)group.Six weeks of HIIT intervention was followed by intraperitoneal injection of LPS,and cardiac function indexes were measured by echocardiography 12 hours post the injection.Hematoxylin-eosin(HE)staining was used to evaluate the morphology and pathological characteristics of myocardium for assessing myocardial damage score;enzyme-linked immunosorbent assay(ELISA)was used to test the content of myocardial damage indicators(AST,CK-MB,LDH);RT-PCR was used to detect the relative mRNA levels of NLRP3 inflammasome(NLRP3,Caspase-1),atrial natriuretic peptide(ANP),brain natriuretic peptide(BNP),myeloperoxidase(MPO)and macrophage M1-associated inflammasome factors(IL-1β,TNF-α,IL-6);Western blot was applied to measure the protein expression of inducible nitric oxide synthase(iNOS)and apoptosis-associated speck-like protein containing a caspase recruitment domain(ASC)in cardiac tissues;immunofluorescence staining was used to detect the protein expression of NLRP3 inflammasome,ASC,IL-18 and iNOS.Compared with the CON group,mice in the LPS group showed obvious decrease in body weight,a significant decrease in EF and FS,a significant increase in LVESD and LVEDD,obvious pathological damage in myocardial tissue,a significant increase in myocardial damage fraction,a significant increase in serum myocardial damage indexes,and a significant increase in the expression levels of BNP,MPO,NLRP3 inflammasome,iNOS,IL-1β,IL-6 and TNF-α.HIIT treatment could reverse these changes mentioned above in model mice.In conclusion,6 weeks of HIIT inhibits the activation of LPS-induced NLRP3 inflammasome and suppressed macrophage M1-type polarization,thereby combating septic myocardial injury.

Objective:To evaluate the efficacy of allogeneic hematopoietic stem cell transplantation for the treatment of combined immunodeficiency (CID) and explore prognostic risk factors.Methods:In this retrospective cohort study, clinical characteristics, laboratory tests and prognosis of 73 CID children who underwent allogeneic hematopoietic stem cell transplantation from February 2014 to April 2022 in the Children′s Hospital of Fudan University were analyzed. Based on the subtypes of diseases, all patients were divided into severe combined immunodeficiency disease (SCID) group and other CID group. Based on the types of donors, all patients were divided into matched sibling donor group, matched unrelated donor group, unrelated cord blood group, and haploidentical donor group. Kaplan-Meier method and Log-Rank test were used to analyze the survival data. Cox regression was used to analyze prognostic factors.Results:Among the 73 patients, there were 61 (84%) males and 12 (16%) females. Fifty-five (75%) patients were SCID, and 18 (25%) patients were other CID. Donor source included 2 (3%) matched sibling donors (MSD), 3 (4%) matched unrelated donors (MUD), 64 (88%) unrelated cord blood (UCB), and 4 (5%) haploidentical donors. The age at transplant was 10.7 (5.9, 27.5) months, and the follow-up time was 36.2 (2.5, 62.9) months. The 3-year overall survival rate of 73 patients with CID was (67±6) %. No significant difference was found in the 3-year overall survival rates between patients with SCID (55 cases) and other CID (18 cases) ((64±7) % vs. (78±10) %, χ2=1.31, P=0.252). And no significant difference was found in the 3-year overall survival rates among patients who received MSD or MUD (5 cases), UCB (64 cases), and haploidentical donor (4 cases) transplant (100% vs. (66±6)% vs. (50±25) %, χ2=2.30, P=0.317). Cox regression analysis showed that the medical history of sepsis ( HR=2.55, 95% CI 1.05-6.20, P=0.039) and hypoalbuminemia at transplant ( HR=2.96, 95% CI 1.14-7.68, P=0.026) were independent risk factors for the prognosis of allogeneic hematopoietic stem cell transplantation in pediatric patients with CID. Conclusions:Allogeneic hematopoietic stem cell transplantation is an effective treatment for CID. The medical history of sepsis and hypoalbuminemia at transplant were risk factors for prognosis. Enhancing infection prevention and nutritional intervention before transplant can improve patient prognosis.