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Disorders of sexual development (DSD) refer to the congenital abnormalities of chromosomes, gonads, or gender anatomy. Children with DSD usually experience more stress. The present study aims to evaluate the mental health status of children with DSD, and to explore the potential relevant factors. We included 30 children with DSD and 30 age- and gender-matched children without DSD as the control group. All the children and their parents completed the scales of the Hamilton Anxiety Scale (HAMA). Children over 8 years old (n = 22) completed the Screen Scale for Child Anxiety Related Emotional Disorders (SCARED), the Depression Self-rating Scale for Children (DSRSC), and the Egna Minnen av Barndoms Uppfostran-own memories of parental rearing practices in childhood. DSD children had significantly higher somatic anxiety, mental anxiety, and total anxiety scores than the control group (p < 0.001). The scores of the SCARED, anxiety, and depression subscales of DSD children were higher than those of control children (p < 0.05 and p < 0.001, respectively). The correlation analysis showed that the score of generalized anxiety was positively related to age and entertainment. The regression analysis showed that age was a major factor that affected generalized anxiety in DSD children, and neuroticism was a major factor of anxiety disorder and separation anxiety in DSD children. Children with DSD have obvious anxiety problems, which are associated with family environmental factors (entertainment, success, and conflicts) and age. It is important to focus emphasis on emotional stability in children with DSD for detecting anxiety-related emotional disorders early.

The increased burden of nonalcoholic fatty liver disease (NAFLD) parallels the increased incidence of overweight and metabolic syndrome worldwide. Because of the close relationship between metabolic disorders and fatty liver disease, a new term, metabolic-related fatty liver disease (MAFLD), was proposed by a group of experts to more precisely describe fatty liver disease resulting from metabolic disorders. According to the definitions, MAFLD and NAFLD populations have considerable discrepancies, but overlap does exist. This new definition has a nonnegligible impact on clinical practices, including diagnoses, interventions, and the risk of comorbidities. Emerging evidence has suggested that patients with MAFLD have more metabolic comorbidities and an increased risk of all-cause mortality, particularly cardiovascular mortality than patients with NAFLD. In this review, we systemically summarized and compared the risk and underlying mechanisms of cardiovascular disease (CVD) in patients with NAFLD or MAFLD.

BackgroundWhether early pharmacologic cardioversion is necessary for recent-onset atrial fibrillation is still controversial. Current meta-analyses were limited to evaluating the effects within 24 h without sufficient considering longer follow-up outcomes. We aimed to compare the effect of early pharmacologic cardioversion and non-early cardioversion in patients with recent-onset atrial fibrillation within 4-weeks of follow-up.MethodsWe searched the Cochrane Library, EMBASE, MEDLINE, PubMed, Web of Science, ClinicalTrials.gov, and Clinicaltrialsregister. eu for randomized controlled trials (RCTs) published before November 2021 comparing early pharmacologic cardioversion and non-early cardioversion in recent-onset atrial fibrillation and synthesized data in accordance with PRISMA-Systematic Reviews and Network Meta-Analysis (NMA). Early pharmacological cardioversion referred to immediate cardioversion with antiarrhythmic drugs (i.e., amiodarone, propafenone, flecainide, tedisamil, vernakalant, vanoxerine, and sotalol) upon admission, while non-early cardioversion involved the administration of rate-control or placebo medication without immediate cardioversion.Results16 RCTs with 2,395 patients were included. Compared to non-early cardioversion, a systematic review showed that early pharmacologic cardioversion resulted in a higher probability of sinus rhythm maintenance within 24 h (odds ratios [OR] 2.50, 95% credible interval [CrI] 1.76 to 3.54) and 1-week (2.50, 1.76 to 3.54), however, there was no significant difference in sinus rhythm maintenance within 4-weeks (1.37, 0.90 to 2.09). In subgroup analysis, the Bayesian NMA revealed that vernakalant may be successful in sinus rhythm maintenance within both 24 h (3.55, 2.28 to 5.55) and 1-week (2.72, 1.72 to 4.31). The results were consistent with the frequentist NMA.ConclusionsNon-early pharmacologic cardioversion may not be inferior to early cardioversion within a 4-week follow-up period in patients with recent-onset atrial fibrillation. The evidence remains insufficient to determine which antiarrhythmic agent is optimal in the longer run. Further high-quality relevant RCTs are necessary.Clinical Trial RegistrationPROSPERO CRD42020166862.

Abstract Background Bifidobacteria are important probiotics; some of the beneficial effects of bifidobacteria are achieved by the hydrolysis of glycans in the human gut. However, because the diet of breastfed infants typically lacks plant-derived glycans, in the gut environment of mothers and their breastfed infants, the mother will intake a variety of plant-derived glycans, such as from onions and bananas, through her diet. Under this assumption, we are interested in whether the same species of bifidobacteria isolated from mother-infant pairs present a distinction in their hydrolysis of plant-derived carbohydrates. Results Among the 36 Bifidobacterium strains, bifidobacterial carbohydrate utilization showed two trends related to the intestinal environment where the bacteria lived. Compared with infant-type bifidobacterial strains, adult-type bifidobacterial strains preferred to use plant-derived glycans. Of these strains, 10 isolates, 2 Bifidobacterium pseudocatenulatum (B. pseudocatenulatum), 2 Bifidobacterium pseudolongum (B. pseudolongum), 2 Bifidobacterium bifidum (B. bifidum), 2 Bifidobacterium breve (B. breve), and 2 Bifidobacterium longum (B. longum), were shared between the mother-infant pairs. Moreover, the repetitive sequence-based polymerase chain reaction (rep-PCR) results illustrated that B. pseudolongum and B. bifidum showed genotypic similarities of 95.3 and 98.2%, respectively. Combined with the carbohydrate fermentation study, these results indicated that the adult-type strains have a stronger ability to use plant-derived glycans than infant-type strains. Our work suggests that bifidobacterial carbohydrate metabolism differences resulted in the selective adaptation to the distinct intestinal environment of an adult or breastfed infant. Conclusions The present study revealed that the different gut environments can lead to the differences in the polysaccharide utilization in the same strains of bifidobacterial strains, suggesting a further goal of investigating the exact expression of certain enzymes in response to specific carbon sources.

The Cramer-Rao bound (CRB) offers insights into the inherent performance benchmark of any unbiased estimator developed for a specific parametric model, which is an important tool to evaluate the performance of direction-of-arrival (DOA) estimation algorithms. In this paper, a closed-form stochastic CRB for a mixture of circular and noncircular uncorrelated Gaussian signals is derived. As a general one, it can be transformed into some existing representative results. The existence condition of the CRB is also analysed based on sparse arrays, which allows the number of signals to be more than the number of physical sensors. Finally, numerical comparisons are conducted in various scenarios to demonstrate the validity of the derived CRB.

BackgroundEmerging evidence suggests an association between remnant cholesterol (RC) and vascular damage and hypertension. However, this association has not been explored in a large-scale population in China, and a temporal relationship between RC and hypertension also needs to be investigated.MethodsWe conducted a retrospective cross-sectional study in 2,199,366 individuals and a longitudinal study in 24,252 individuals with repeated measurements of lipid profile and blood pressure in at least a 3-year follow-up. The logistic model was used to explore the association between lipid components and hypertension in the cross-sectional analysis. The Cox model was used to analyze the association between high RC (HRC) at baseline and the subsequent incidence of hypertension or the association between hypertension at baseline and incidence of HRC. The cross-lagged panel model was applied to analyze the temporal relationship between RC and hypertension.ResultsRC level as a continuous variable had the highest correlation with hypertension among lipid profiles, including RC, low-density lipoprotein cholesterol, total cholesterol, non-high-density lipoprotein cholesterol, and triglycerides, with an odds ratio of 1.59 (95% confidence interval: 1.58–1.59). In the longitudinal cohort, HRC at baseline was associated with incident hypertension. We further explored the temporal relationship between RC and hypertension using the cross-lagged analysis, and the results showed that RC increase preceded the development of hypertension, rather than vice versa.ConclusionsRC had an unexpected high correlation with the prevalence and incidence of hypertension. Moreover, RC increase might precede the development of hypertension, suggesting the potential role of RC in the development of hypertension.

Background and aimsMetabolic dysfunction-associated fatty liver disease (MAFLD) is a newly emerged term that is suggested to better reflect the pathogenesis of nonalcoholic fatty liver disease (NAFLD); however, the association between hyperuricemia and MAFLD has not been explored in the Chinese population. Meantime, this study also examined the temporal relationship between the two entities in a longitudinal cohort.MethodsWe conducted a retrospective cross-sectional study including 1,587,962 individuals from 19 health check-up centers in China from 2009-2017 and a longitudinal study with 16,112 individuals. A logistic regression model was applied to determine the association between hyperuricemia and MAFLD in a cross-sectional study. The Cox regression model was used to explore the association between hyperuricemia at baseline and subsequent onset of MAFLD or the association between the presence of MAFLD at baseline and the subsequent incidence of hyperuricemia. The cross-lagged analysis was applied to exam the temporal relationship between hyperuricemia and MAFLD.ResultsIn the cross-sectional study, hyperuricemia showed a strong positive association with MAFLD after controlled potential confounders. In the longitudinal cohorts, hyperuricemia at baseline was associated with the new-onset of MAFLD, with a hazard ratio (HR) of 1.765 (95% CI: 1.512, 2.060). Interestingly, baseline MAFLD was also associated with the subsequent incidence of hyperuricemia, with an HR of 1.245 (95% CI: 1.106, 1.400). The cross-lagged path analysis revealed a bidirectional relationship between hyperuricemia and MAFLD.ConclusionsThe results suggested that hyperuricemia and MAFLD form a vicious cycle, resulting in more deterioration of metabolic status.

Background The disease burden from ischaemic heart disease remains heavy in the Chinese population. Traditional risk scores for estimating long-term mortality in patients with acute myocardial infarction (AMI) have been developed without sufficiently considering advances in interventional procedures and medication. The goal of this study was to develop a risk score comprising clinical parameters and intervention advances at hospital admission to assess 5-year mortality in AMI patients in a Chinese population. Methods We performed a retrospective observational study on 2,722 AMI patients between January 2013 and December 2017. Of these patients, 1,471 patients from Changsha city, Hunan Province, China were assigned to the development cohort, and 1,251 patients from Xiangtan city, Hunan Province, China, were assigned to the validation cohort. Forty-five candidate variables assessed at admission were screened using least absolute shrinkage and selection operator, stepwise backward regression, and Cox regression methods to construct the C2ABS2-GLPK score, which was graded and stratified using a nomogram and X-tile. The score was internally and externally validated. The C-statistic and Hosmer-Lemeshow test were used to assess discrimination and calibration, respectively. Results From the 45 candidate variables obtained at admission, 10 potential predictors, namely, including Creatinine, experience of Cardiac arrest, Age, N-terminal Pro-Brain Natriuretic Peptide, a history of Stroke, Statins therapy, fasting blood Glucose, Left ventricular end-diastolic diameter, Percutaneous coronary intervention and Killip classification were identified as having a close association with 5-year mortality in patients with AMI and collectively termed the C2ABS2-GLPK score. The score had good discrimination (C-statistic = 0.811, 95% confidence intervals (CI) [0.786–0.836]) and calibration (calibration slope = 0.988) in the development cohort. In the external validation cohort, the score performed well in both discrimination (C-statistic = 0.787, 95% CI [0.756–0.818]) and calibration (calibration slope = 0.976). The patients were stratified into low- (≤148), medium- (149 to 218) and high-risk (≥219) categories according to the C2ABS2-GLPK score. The predictive performance of the score was also validated in all subpopulations of both cohorts. Conclusion The C2ABS2-GLPK score is a Chinese population-based risk assessment tool to predict 5-year mortality in AMI patients based on 10 variables that are routinely assessed at admission. This score can assist physicians in stratifying high-risk patients and optimizing emergency medical interventions to improve long-term survival in patients with AMI.

This paper presents a modified fifth-order WENO-HLLC Riemann solver for the transonic compressible viscous flows around the helicopter rotor in hover. The HLLC approximate Riemann solver is proposed to discrete the convection term involving grid velocity of the Navier-Stokes equations. In order to solve the interface flow accurately, a modified fifth-order WENO scheme is presented by designing the smoothness indicators based on L1 norm measurement. The improved WENO scheme can provide the optimal approximation order even at critical points. Numerical accuracy and robustness are validated by several benchmark inviscid flow problems. Then the numerical properties of the WENO-HLLC solver in conjunction with the implicit LU-SGS time integration method with high efficiency are further validated by simulating transonic viscous flows over RAE2822 airfoil and ONERA-M6 wing. The results show that the accuracy of calculating shock, discontinuity, and the vortex is significantly improved. Finally, the method is developed to compute the transonic vortex flow around the helicopter rotor with a domain discretized by overset grids. The results indicate that the proposed method is very robust and effective in acquiring high resolution for vortex wake.

Objective: High systolic blood pressure (HSBP) remains the leading risk factor for mortality worldwide; however, limited data have revealed all-cause and cause-specific burdens attributed to HSBP at global and regional levels. This study aimed to estimate the global burden and priority diseases attributable to HSBP by region, sex, and age.Methods: Based on data and evaluation methods from the Global Burden of Diseases, Injuries, and Risk Factors Study 2019, we estimated trends of age-standardized mortality rate (ASMR), the age-standardized rate of disability-adjusted life years (ASDRs), and the age-standardized rate of years lived with disability (ASYRs) attributable to HSBP during 1990-2019. Further, we analyzed cause-specific burdens attributable to HSBP by sex, age, year, and region.Results: Globally, a significant downtrend was found in the ASMR attributed to HSBP while ASYRs did not change substantially during 1990-2019. The majority of HSBP burden has shifted from high-middle sociodemographic index (SDI) regions to lower SDI regions. All-cause and most cause-specific burdens related to HSBP were improved in high SDI regions but the downtrends have stagnated in recent years. Although many cause-specific deaths associated with HSBP declined, chronic kidney disease (CKD) and endocarditis associated deaths were aggravated globally and ischemic heart disease (IHD), atrial fibrillation and flutter, aortic aneurysm (AA), and peripheral artery disease (PAD) associated deaths were on the rise in low/low-middle/middle SDI regions. Additionally, males had higher disease burdens than females. Middle-aged people with CVDs composed the major subgroup affected by HSBP while older people had the highest ASMRs associated with HSBP.Conclusions: This study revealed the global burden and priority diseases attributable to HSBP with wide variation by region, sex, and age, calling for effective and targeted strategies to reduce the prevalence and mortality of HSBP, especially in low/low-middle/middle SDI regions.

Metabolic-associated fatty liver disease (MAFLD) is a new disease definition, and this nomenclature MAFLD was proposed to renovate its former name, non-alcoholic fatty liver disease (NAFLD). MAFLD/NAFLD have shared and predominate causes from nutrition overload to persistent liver damage and eventually lead to the development of liver fibrosis and cirrhosis. Unfortunately, there is an absence of effective treatments to reverse MAFLD/NAFLD-associated fibrosis. Due to the significant burden of MAFLD/NAFLD and its complications, there are active investigations on the development of novel targets and pharmacotherapeutics for treating this disease. In this review, we cover recent discoveries in new targets and molecules for antifibrotic treatment, which target pathways intertwined with the fibrogenesis process, including lipid metabolism, inflammation, cell apoptosis, oxidative stress, and extracellular matrix formation. Although marked advances have been made in the development of antifibrotic therapeutics, none of the treatments have achieved the endpoints evaluated by liver biopsy or without significant side effects in a large-scale trial. In addition to the discovery of new druggable targets and pharmacotherapeutics, personalized medication, and combinatorial therapies targeting multiple profibrotic pathways could be promising in achieving successful antifibrotic interventions in patients with MAFLD/NAFLD.

Objective: Internet addiction has emerged as a growing concern worldwide. This study aimed to compare the prevalence of Internet addiction between left-behind children (LBC) and non-left-behind children (non-LBC), and explore the role of paternal and maternal parent-child communication on LBC.Methods: We conducted a cross-sectional survey in rural areas in Anhui, China. The complete data were available from 699 LBC and 740 non-LBC. Multivariable logistic regression was used to examine 1) whether LBC were more likely to develop Internet addiction, and 2) the association between parent-child communication and Internet addiction among LBC.Results: LBC had a higher likelihood to report Internet addiction when compared to non-LBC (OR = 2.03, 95%CI = 1.43–2.88, p < 0.001). Among LBC, parent-child communication (both mother-child and father-child) was protective factor for children’s Internet addiction. The role of mother-child communication played well among male LBC.Conclusions: The lack of parental supervision may lead to Internet addiction. It is highly recommended for migrant parents to improve the quality of communication with their children. Also, gender-matching effects should be considered in the relationship between children’s behavior and parental factors.

Parents’ knowledge, attitudes, and beliefs about attention-deficit/hyperactivity disorder (ADHD) are crucial in the selection of the treatment strategy and how to care for children with ADHD. However, little is known about parents’ conception in mainland China. A semi-structured questionnaire was used to assess this information with 25 true/false questions regarding ADHD, and other questions investigating the methods of acquiring ADHD-related information, treatment preference, and concerns about ADHD treatment strategy. We found that the average score of all the participants was 17.42 ± 2.69 (total of 25 points) for the questionnaire on knowledge, attitudes, and beliefs about ADHD. This indicated that the parents had insufficient knowledge of this disease profile. They always accessed specialized information through mobile internet. For the treatment options, the investigated parents chose psychotherapy treatment rather than medications, in that they worried about the side effects of medication and expected to find alternative treatment strategies. The present investigation demonstrated that most parents lack knowledge about ADHD in treatment decision making in China. Medical professionals should provide parents with evidence-based ADHD-related information to help them understand this disease.

The existing research on deep learning for radar signal intra–pulse modulation classification is mainly based on supervised leaning techniques, which performance mainly relies on a large number of labeled samples. To overcome this limitation, a self–supervised leaning framework, contrastive learning (CL), combined with the convolutional neural network (CNN) and focal loss function is proposed, called CL––CNN. A two–stage training strategy is adopted by CL–CNN. In the first stage, the model is pretrained using abundant unlabeled time–frequency images, and data augmentation is used to introduce positive–pair and negative–pair samples for self–supervised learning. In the second stage, the pretrained model is fine–tuned for classification, which only uses a small number of labeled time–frequency images. The simulation results demonstrate that CL–CNN outperforms the other deep models and traditional methods in scenarios with Gaussian noise and impulsive noise–affected signals, respectively. In addition, the proposed CL–CNN also shows good generalization ability, i.e., the model pretrained with Gaussian noise–affected samples also performs well on impulsive noise–affected samples.

Objective Lung cancer is the most common malignancy worldwide and exhibits both high morbidity and mortality. In recent years, scientists have made substantial breakthroughs in the early diagnosis and treatment of lung adenocarcinoma (LUAD), however, patient prognosis still shows vast individual differences. In this study, bioinformatics methods were used to identify and analyze ferroptosis-related genes to establish an effective signature for predicting prognosis in LUAD patients. Methods The gene expression profiles of LUAD patients with complete clinical and follow-up information were downloaded from two public databases, univariate Cox regression and multivariate Cox regression analysis were used to obtain ferroptosis-related genes for constructing the prognos tic risk model, AUC and calibration plot were used to evaluate the predictive accuracy of the FRGS and nomogram. Results A total of 74 ferroptosis-related differentially expressed genes (DEGs) were identi fied between LUAD and normal tissues from The Cancer Genome Atlas (TCGA) database. A five-gene panel for prediction of LUAD prognosis was established by multivariate regression and was verified using the GSE68465 cohort from the Gene Expression Omnibus (GEO) database. Patients were divided into two different risk groups according to the median risk score of the five genes. Based on Kaplan-Meier (KM) analysi, the OS rate of the high-risk group was markedly worse than that of the low-risk group. We also found that risk score was an independent prognostic indicator. The receiver operating characteristic ROC curve showed that the proposed model had good prediction ability. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional analyses indicated that risk score was prominently enriched in ferroptosis processes. Moreover, at the score of immune-associated gene sets, significant differences were found between the two risk groups. Conclusions This study demonstrated that ferroptosis-related gene signatures can be used as a potential predictor for the prognosis of LUAD, thus providing a novel strategy for individualized treatment in LUAD patients.

Objectives To examine primary care physicians’ (PCPs) perception of patients’ trust and associated factors for enhancing perceived trust in rural China.Design A cross-sectional questionnaire study.Setting All township health centres (primary care facilities in rural areas of China) in both developed and less developed counties of Zhejiang province, China, were chosen as the study sites.Participants A total of 849 questionnaires were distributed from December 2019 to January 2020, and 673 PCPs working in township health centres completed the questionnaires. The response rate was 79.3%.Outcome measures PCPs’ perceived patients’ trust in them, PCPs’ practices to meet patients’ expectations and PCPs’ perceived conflicting patient and employer interests were measured by a self-designed and verified questionnaire. Confirmatory factor analysis was applied to verify the measurement model of PCPs’ practices. Multivariable logistic regression analyses were performed to explore the association between clinical practice characteristics, discordant patient and employer interests and perceived patient trust after controlling for social–demographic characteristics.Results Among all participants, 572 (85.0%) PCPs often/always perceived patients’ trust in their clinical competence, and over two-thirds of PCPs reported ever perceived patient worries about overprescriptions. After adjustment for social-demographic characteristics, regression model results indicated that, among PCPs’ clinical practices characteristics, emotional support (OR=1.23, 95% CI=1.06 to 1.42) and accurate diagnosis and treatment (OR=1.35, 95% CI=1.17 to 1.55) were positively associated with PCPs’ perceived patients’ trust in their clinical competence. A strong association was found between accurate diagnosis and treatment (OR=1.20, 95% CI=1.08 to 1.34, p

Objective The survival benefit of using mechanical circulatory support (MCS) in patients with acute myocardial infarction (AMI) is still controversial. It is necessary to explore the impact on clinical outcomes of MCS in patients with AMI undergoing stenting.Design Systematic review and meta-analysis.Data sources Embase, Cochrane Library, Medline, PubMed, Web of Science, ClinicalTrials.gov and Clinicaltrialsregister.eu databases were searched from database inception to February 2021.Eligibility criteria Randomised clinical trials (RCTs) on MCS use in patients with AMI undergoing stent implantation were included.Data extraction and synthesis Data were extracted and summarised independently by two reviewers. Risk ratios (RRs) and 95% CIs were calculated for clinical outcomes according to random-effects model.Results Twelve studies of 1497 patients with AMI were included, nine studies including 1382 patients compared MCS with non-MCS, and three studies including 115 patients compared percutaneous ventricular assist devices (pVADs) versus intra-aortic balloon pump (IABP). Compared with non-MCS, MCS was not associated with short-term (within 30 days) (RR=0.90; 95% CI 0.57 to 1.41; I2=46.8%) and long-term (at least 6 months) (RR=0.82; 95% CI 0.57 to 1.17; I2=37.6%) mortality reductions. In the subset of patients without cardiogenic shock (CS) compared with non-MCS, the patients with IABP treatment significantly had decreased long-term mortality (RR=0.49; 95% CI 0.27 to 0.90; I2=0), but without the short-term mortality reductions (RR=0.51; 95% CI 0.22 to 1.19; I2=17.9%). While in the patients with CS, the patients with MCS did not benefit from the short-term (RR=1.09; 95% CI 0.67 to 1.79; I2=46.6%) or long-term (RR=1.00; 95% CI 0.75 to 1.33; I2=22.1%) survival. Moreover, the application of pVADs increased risk of bleeding (RR=1.86; 95% CI 1.15 to 3.00; I2=15.3%) compared with IABP treatment (RR=1.86; 95% CI 1.15 to 3.00; I2=15.3%).Conclusions In all patients with AMI undergoing stent implantation, the MCS use does not reduce all-cause mortality. Patients without CS can benefit from MCS regarding long-term survival, while patients with CS seem not.

We study the asymptotic behavior of solutions of a Fisher equation with free boundaries and the nonlocal term (an integral convolution in space). This problem can model the spreading of a biological or chemical species, where free boundaries represent the spreading fronts of the species. We give a dichotomy result, that is, the solution either converges to $1$ locally uniformly in $\mathbb{R}$, or to $0$ uniformly in the occupying domain. Moreover, we give the sharp threshold when the initial data $u_0=\sigma \phi$, that is, there exists $\sigma^*>0$ such that spreading happens when $\sigma>\sigma^*$, and vanishing happens when $\sigma\leq \sigma^*$.

Abstract Background The microbial transglutaminase (MTG) is inactive when only the mature sequence is expressed in Pichia pastoris. Although co-expression of MTG and its N-terminal pro-peptide can obtain the active MTG, the enzyme activity was still low. One of the basic steps for strain improvement is to ensure a sufficient level of transcription of the heterologous gene, based on promoter strength and gene copy number. To date, high-copy-number recombinants of P. pastoris are achievable only by cloning of gene concatemers, so methods for rapid and reliable multicopy strains are therefore desirable. Results The coexpression strains harboring different copies mtg were obtained successfully by stepwise increasing Zeocin concentration based on the rDNA sequence of P. pastoris. The genome of coexpression strains with the highest enzyme activity was analyzed by real-time fluorescence quantitative PCR, and three copies of mtg gene (mtg-3c) was calculated according to the standard curve of gap and mtg genes (gap is regarded as the single-copy reference gene). The maximum enzyme activity of mtg-3c was up to 1.41 U/mL after being inducted for 72 h in 1 L flask under optimal culture conditions, and two protein bands were observed at the expected molecular weights (40 kDa and 5 kDa) by Western blot. Furthermore, among the strains detected, compared with mtg-2c, mtg-6c or mtg-8c, mtg-3c is the highest expression level and enzyme activity, implying that mtg-3c is the most suitable for co-expression pro-peptide and MTG. Conclusions This study provides an effective strategy for improving the expression level of active MTG by directional increasing of mtg copies in P. pastoris.

This study was designed to investigate the impact of blood tumor mutational burden (bTMB) on advanced NSCLC in Southwest China. The relationship between the tTMB estimated by next-generation sequencing (NGS) and clinical outcome was retrospectively analyzed in tissue specimens from 21 patients with advanced NSCLC. Furthermore, the relationship between the bTMB estimated by NGS and clinical outcome was retrospectively assessed in blood specimens from 70 patients with advanced NSCLC. Finally, 13 advanced NSCLC patients were used to evaluate the utility of bTMB assessed by NGS in differentiating patients who would benefit from immunotherapy. In the tTMB group, tTMB ≥ 10 mutations/Mb was related to inferior progression-free survival (PFS) (hazard ratio [HR], 0.30; 95% CI, 0.08-1.17; log-rank P = 0.03) and overall survival (OS) (HR, 0.30; 95% CI, 0.08-1.16; log-rank P = 0.03). In the bTMB group, bTMB ≥ 6 mutations/Mb was associated with inferior PFS (HR, 0.32; 95% CI, 0.14-1.35; log-rank P < 0.01) and OS (HR, 0.31; 95% CI, 0.14-0.7; log-rank P < 0.01). In the immunotherapy section, bTMB ≥ 6 mutations/Mb was related to superior PFS (HR, 0.32; 95% CI, 0.14-1.35; log-rank P < 0.01) and objective response rates (ORRs) (bTMB < 6: 14.2%; 95% CI, 0.03-1.19; bTMB ≥ 6: 83.3%; 95% CI, 0.91-37.08; P = 0.02). These findings suggest that bTMB is a validated predictive biomarker for determining the clinical outcome of advanced NSCLC patients and may serve as a feasible predictor of the clinical benefit of immunotherapies (anti-PD-1 antibody) in the advanced NSCLC population in Yunnan Province.

ObjectiveQujing City, Yunnan Province, China, has a high incidence of lung cancer and related mortality. The etiology of NSCLC in Qujing area and distribution of associated molecular aberrations has not been fully elucidated. This study aimed to reveal the profile of driver gene mutations in patients with non-small-cell lung cancer (NSCLC) in Qujing and explore their relationships with clinicopathological characteristics.MethodsIn this study, the mutation profiles of NSCLC driver genes, including EGFR, ALK, ROS1, KRAS, BRAF, RET, MET, HER2, NRAS, and PIK3CA, were investigated in patients with NSCLC from Qujing and compared with those from other regions in Yunnan Province. The associations between molecular mutations and clinicopathological characteristics were further analyzed.ResultsA distinct profile of driver gene mutations was discovered in patients with NSCLC from Qujing. Interestingly, a higher proportion of EGFR compound mutations, including G719X + S768I (19.65% vs 3.38%, P < 0.0001) and G719X + L861Q (21.10% vs 2.82%, P < 0.0001), was observed in patients with NSCLC in Qujing compared with patients in non-Qujing area, besides significantly different distributions of EGFR (46.01% vs. 51.07%, P = 0.0125), ALK (3.17% vs. 6.97%, P = 0.0012), ROS1 (0.5% vs. 2.02%, P = 0.0113), and KRAS (23.02% vs. 7.85%, P < 0.0001). Further, EGFR compound mutations were more likely associated with the occupation of patients (living/working in rural areas, e.g., farmers). Moreover, KRAS G12C was the dominant subtype (51.11% vs 25.00%, P = 0.0275) among patients with NSCLC having KRAS mutations in Qujing.ConclusionsPatients with NSCLC in Qujing displayed a unique profile of driver gene mutations, especially a higher prevalence of EGFR compound mutations and dominant KRAS G12C subtype, in this study, indicating a peculiar etiology of NSCLC in Qujing. Therefore, a different paradigm of therapeutic strategy might need to be considered for patients with NSCLC in Qujing.

Background: Pyroptosis is a form of cell death triggered by proinflammatory signals. Recent studies have reported that oxidized phospholipids function as caspase-11 agonists to induce noncanonical inflammasome activation in immune cells. As the levels of oxidized phospholipids derived from ox-LDL are largely elevated in atherosclerotic lesions, this study sought to determine whether oxidized lipids trigger pyroptosis and subsequent inflammation in the pathogenesis of atherosclerosis.Methods and Results: In our current study, after integrating transcriptomic data available from the Gene Expression Omnibus with data from hyperlipidemic mice and ox-LDL-treated peritoneal macrophages, we discovered that caspase-4/11-gasdermin D-associated inflammatory signaling was significantly activated. Consistently, the mRNA expression of caspase-4 and gasdermin D was upregulated in peripheral blood mononuclear cells from patients with coronary heart disease. In particular, the expression of caspase-4 was closely associated with the severity of lesions in the coronary arteries. An in vivo study showed that caspase-11-gasdermin D activation occurred in response to a high-fat/high-cholesterol (HFHC) diet in ApoE−/− mice, while caspase-11 deletion largely attenuated the volume and macrophage infiltration of atherosclerotic lesions. An in vitro mechanistic study showed that caspase-11-mediated inflammation occurred partly via gasdermin D-mediated pyroptosis in macrophages. Suppressing gasdermin D in HFHC-fed ApoE−/− mice via delivery of an adeno-associated virus markedly decreased lesion volume and infiltrating macrophage numbers.Conclusion: Caspase-11-gasdermin D-mediated pyroptosis and the subsequent proinflammatory response in macrophages are involved in the pathogenesis of atherosclerosis. Therefore, targeting the caspase 11-gasdermin D may serve as an alternative strategy for the treatment of atherosclerosis.

Major challenges have been encountered regarding the development of highly efficient subunit malaria vaccines, and so whole-parasite vaccines have regained attention in recent years. The whole-killed blood-stage vaccine (WKV) is advantageous as it can be easily manufactured and efficiently induced protective immunity against a blood-stage challenge, as well as inducing cross-stage protection against both the liver and sexual-stages. However, it necessitates a high dose of parasitized red blood cell (pRBC) lysate for immunization, and this raises concerns regarding its safety and low immunogenicity. Knowledge of the major components of WKV that can induce or evade the host immune response, and the development of appropriate human-compatible adjuvants will greatly help to optimize the WKV. Therefore, we argue that the further development of the WKV is worthwhile to control and potentially eradicate malaria worldwide.

Objective To examine the clinical effects of revision endoscopic frontal sinus surgery (RESS) through modified agger nasi (MAN)–middle turbinate resection on refractory chronic rhinosinusitis (CRS). Methods We reviewed 156 patients who were treated for refractory CRS from February 2012 to August 2014. These patients had been diagnosed with refractory CRS by computed tomography and endoscopy and had received several surgical and medical treatments in the past, but their condition had not been cured. They were divided into the observation group (RESS through MAN–middle turbinate resection, n = 78) and the control group (endoscopic sinus surgery, n = 78). Complete or partial control of the patient’s symptoms and signs suggested that the treatment was effective, and no improvement in the symptoms and signs indicated that the treatment was ineffective. Results The 6-month treatment efficacy rate was significantly higher in the observation group (91.03%) than in the control group (71.79%). The observation group had a significantly lower complication rate (7.69%) and recurrence rate (3.85%) than the control group (17.95% and 12.82%, respectively). Conclusion RESS through MAN–middle turbinate resection together with adequate perioperative preparation has a significant effect on the outcome of refractory CRS and is worthy of clinical promotion.

Background: Cadmium is the most prevalent form of heavy metal contaminant globally and its exposure rises serious health concern. Chronic exposure to cadmium causes immune disturbances. However, few studies have addressed how it affects circulating immune cells, one of the most essential elements for the host defense system, at both population and molecular level. Therefore, this is the first single-cell transcriptomic analysis of the response of the human circulating immune system to plasma cadmium level. Methods: We conducted a cross-sectional study in Hunan province, which has the highest level of cadmium land contamination in China. A total of 3283 individuals were eligible for analyzing the association between plasma cadmium levels and the monocyte counts and its subgroups. Another 780 individuals were assigned for validation. Thirty propensity-matched individuals without chronic disease from the lowest- and highest-quartile groups according to serum cadmium levels were selected for single-cell RNA sequencing (scRNA-seq) and flow cytometry analyses. Moreover, the monocyte phenotypic alterations in the heavy metal-exposed population were validated with a cecal ligation and puncture sepsis mouse model. Results: From August 2016 to July 2017, we conducted a cross-sectional study to identify phenotypic alterations in peripheral immune cells in cadmium polluted areas in China. Monocyte percentages were negatively associated with plasma cadmium levels in multivariable linear regression analysis. Peripheral blood mononuclear cell scRNA-seq revealed that the CD14+ monocyte subset was dramatically reduced in the highest-quartile cadmium-exposed group. Moreover, we assessed different hallmarks of immune cell dysfunction—such as host defense capability, apoptotic signaling, cellular diversity and malignant gene expression in monocytes. Importantly, cadmium induced phenotypic alterations in the immune system were validated in the cecal ligation and puncture sepsis mouse model, in which chronic exposure to cadmium not only increased the death rate but also decreased monocyte numbers and the ability to clear bacterial infections. Conclusion: This transcriptomic analysis provides molecular information about how the most important hallmarks of immune cell dysfunction are affected by plasma cadmium level. The significant phenotypic alterations in monocytes serving as early indicators of increased susceptibility to infectious and malignant diseases.

Background ADRB1 (adrenergic receptor beta 1) responds to neuroendocrine stimulations, which have great implications in hypertension. GRK2 (G protein‐coupled receptor kinase 2) is an essential regulator for many G protein‐coupled receptors and subsequent cell signaling cascades, but its role as a regulator of ADRB1 and associated cardiac hypertrophy in hypertension remains to be elucidated. Methods and Results In this study, we found the expressions of GRK2 and ADRB1 in peripheral blood mononuclear cells were positively associated with blood pressure levels in hypertensive patients and with their expression in heart. In vitro evidence showed a direct interaction in ADRB1 and GRK2 and genetic depletion of GRK2 blocks epinephrine‐induced upregulation of hypertrophic and fibrotic genes in cardiomyocytes. Meanwhile, we discovered a selective serotonin reuptake inhibitor paroxetine specifically blockades GRK2 and ADRB1 interaction. In vivo, paroxetine treatment ameliorates hypertension‐induced cardiac hypertrophy, dysfunction, and fibrosis in animal models. We found that paroxetine suppressed sympathetic overdrive and increased the adrenergic receptor sensitivity to catecholamines. Paroxetine treatment also blocks epinephrine‐induced upregulation of hypertrophic and fibrotic genes as well as ADRB1 internalization in cardiomyocytes. Coadministration of paroxetine further potentiates metoprolol‐induced reductions in blood pressure and heart rate, further attenuating cardiac hypertrophy in spontaneously hypertensive rats. Furthermore, in patients with hypertension accompanied with depression, we observed that cardiac remodeling was less severe in those with paroxetine treatment compared with those with other types of anti‐depressive agents. Conclusions Paroxetine promotes ADRB1 sensitivity and attenuates cardiac hypertrophy partially via blocking GRK2‐mediated ADRB1 activation and internalization in the context of hypertension.

Background: Postoperative sleep disorder is common in elderly surgery patients, and it often worsens their recovery after surgery. This study aimed to explore the effect of intraoperative dexmedetomidine dose on postoperative sleep quality.Methods: Based on information regarding dexmedetomidine use during surgery from an electronic medical record system, 4,349 elderly surgery patients were divided into three groups: 1,374 without intraoperative use of dexmedetomidine (Non-DEX), 917 with dexmedetomidine 0.1–0.2 μg/kg/h (Low-DEX), and 2,058 with dexmedetomidine >0.2 μg/kg/h (High-DEX). The numerical rating scale (NRS) for sleep disturbance during the first night after surgery was recorded, and the incidence of NRS ≥ 6 was considered the primary outcome.Results: NRS (P < 0.001) and incidence of severe sleep disturbance (P < 0.001) were lower in patients receiving intraoperative dexmedetomidine than in those without the intraoperative use of dexmedetomidine. Patients in the Low-DEX group had the lowest incidence, followed by those in the High-DEX and Non-DEX groups (6.7% vs. 13.7% vs. 19.5%). After propensity score matching, 906 pairs of elderly surgery patients were included in the Low-DEX and High-DEX groups, and the Low-DEX group had lower NRS (2.7 ± 2.1 vs. 3.1 ± 2.4, P < 0.001) than the High-DEX group. The incidence of severe sleep disturbance was lower in the Low-DEX group than in the High-DEX group (6.6% vs. 12.8%) with an odds rate of 0.48 (95% confidence interval, 0.35 to 0.67).Conclusions: For elderly patients, intraoperative dexmedetomidine use can significantly improve the quality of the first night sleep after surgery. Low-dose (0.1–0.2 μg/kg/h) dexmedetomidine can have an improvement effect on sleep quality, and it is recommended to improve the quality of postoperative sleep.

High-mobility group box-1 (HMGB1), a ubiquitous nuclear protein, acts as a late mediator of lethality when released extracellularly during sepsis. The major source of circulating HMGB1 in sepsis is hepatocytes. However, the mechanism of HMGB1 release of hepatocytes during sepsis is not very clear. We have previously shown that bacterial endotoxin [lipopolysaccharide (LPS)] sensing pathways, including Toll-like receptor (TLR)4 and caspase-11, regulate hepatocyte HMGB1 release in response to LPS. Here, we report the novel function of caspase-11 and gasdermin D (GsdmD) in LPS-induced active HMGB1 released from hepatocytes. HMGB1 release during endotoxemia was caspase-11/GsdmD dependent via an active way in vivo and in vitro. Caspase-11/GsdmD was responsible for HMGB1 translocation from nucleus to the cytoplasm via calcium changing-induced phosphorylation of calcium-calmodulin kinase kinase (camkk)β during endotoxemia. Cleaved GsdmD accumulated on the endoplasmic reticulum, suggesting this may lead to calcium leak and intracellular calcium increase. Furthermore, we investigated that exosome was an important pathway for HMGB1 release from hepatocytes; this process was dependent on TLR4, independent of caspase-11 and GsdmD in vivo and in vitro. These findings provide a novel mechanism that TLR4 signaling results in an increase in caspase-11 expression, as well as increased exosome release, while caspase-11/GsdmD activation/cleavage leads to accumulation of HMGB1 in the cytoplasm through a process associated with the release of calcium from the endoplasmic reticulum and camkkβ activation.

The data volume and computation task of MIMO radar is huge; a very high-speed computation is necessary for its real-time processing. In this paper, we mainly study the time division MIMO radar signal processing flow, propose an improved MIMO radar signal processing algorithm, raising the MIMO radar algorithm processing speed combined with the previous algorithms, and, on this basis, a parallel simulation system for the MIMO radar based on the CPU/GPU architecture is proposed. The outer layer of the framework is coarse-grained with OpenMP for acceleration on the CPU, and the inner layer of fine-grained data processing is accelerated on the GPU. Its performance is significantly faster than the serial computing equipment, and satisfactory acceleration effects have been achieved in the CPU/GPU architecture simulation. The experimental results show that the MIMO radar parallel simulation system with CPU/GPU architecture greatly improves the computing power of the CPU-based method. Compared with the serial sequential CPU method, GPU simulation achieves a speedup of 130 times. In addition, the MIMO radar signal processing parallel simulation system based on the CPU/GPU architecture has a performance improvement of 13%, compared to the GPU-only method.

Background/Aims: We investigated the correlation between toll-like receptor 4 (TLR4) and β-catenin for disclosing the potential pathogenesis of hepatocellular carcinoma (HCC). Methods: Immunohistochemical toolkit was implemented to measure the expression of TLR4 and β-catenin in 98 cases of HCC tissues and adjacent tissues. After setting up the HepG2.2.15 hepatitis B virus (HBV) related HCC cell line, we divided the cells into the control group, TLR4 siRNA group, β-catenin siRNA group, and pcDNA.3.1 TLR4 + β-catenin siRNA group. Western blot, CCK-8 method, Transwell and flow cytometry were used to detect protein expression, cell proliferation, cell migration and invasion as well as cell apoptosis, respectively. Nude mice tumor model was established to observe the effects of TLR4 and β-catenin on the progression of HBV-related HCC in vivo. Results:The positive rates of TLR4 and β-catenin were higher in HCC tissues compared with normal tissues. Both the TLR4 siRNA group and β-catenin siRNA group exhibited a decreased expression of β-catenin. The proliferation, migration and invasion of tumor cells in the above two groups were suppressed, while the cell apoptosis appeared to be stimulated. As suggested by the results from in vivo and in vitro experiments, the up-regulation of TLR4 could antagonize the corresponding effect of β-catenin siRNA. Conclusions: TLR4 can affect the expression of β-catenin and hence influence the progression of HBV-related HCC.

Abstract The inflammatory pathways that drive the development of intimai hyperplasia (IH) following arterial injury are not fully understood. We hypothesized that the lysosomal cysteine protease cathepsin L activates processes leading to IH after arterial injury. Using a mouse model of wire-induced carotid artery injury, we showed that cathepsin L activity peaks at d 7 and remains elevated for 28 d. Genetic deletion of cathepsin L prevented IH and monocyte recruitment in the carotid wall. The injury-induced increases in cathepsin L mRNA and activity were mitigated in mice with myeloid-specific deletion of toll-like receptor 4 (TLR4) or myeloid differentiation primary response gene 88 (MyD88). We further discovered that the HIV protease inhibitor saquinavir (SQV), which is known to block recombinant mouse cathepsin L activity in vitro, prevented IH after arterial injury. SQV also suppressed LPS (TLR4 agonist)-induced monocyte adhesion to endothelial monolayers. These findings establish cathepsin L as a critical regulator of the inflammation that leads to IH and that the TLR4-MyD88 pathway in myeloid lineages regulates cathepsin L expression in the vessel wall following wire injury. The Food and Drug Administration-approved drug SQV blocks IH though mechanisms that may include the suppression of cathepsin L.

A new type of network-combination synchronization is proposed between two drive networks, small-world and scale-free, and one response community network based on the model of multiple system combination. According to Lyapunov Stability Theorem, combined controllers are designed to control three disparate networks with different topological structures. A realistic combination model of multiple inhomogeneous networks and a universal controller are devised in the combination design. The paper is characterized by two parts of one response community network loaded from the combined signals of two drive networks. Numerical simulations are presented to show the full and partial control of the proposed method.

Background/Aims: The primary objective of this study was to investigate the role of miR-146a in inducing the inflammatory infiltration of macrophages in polymyositis/dermatomyositis (PM/DM) through targeting TNF receptor associated factor 6 (TRAF6), which may further down-regulate the Interleukin-17 (IL-17)/Intercellular Adhesion Molecule 1 (ICAM-1) pathway. Methods: Biopsies were collected from PM/DM patients and healthy volunteers. PM/DM model establishment and macrophage isolation were performed on Sprague Dawley (SD) rats. Model rats and macrophages were treated with anti-IL-17, anti-ICAM-1, miR-146a mimics, miR-146a inhibitors, and TRAF6 siRNAs. Serum creatine phosphokinase (S-CK) expression was assessed using double antibody sandwich enzyme-linked immunosorbent assay (ELISA) assay, and immunohistochemistry assay was performed to analyze CD163 expression in muscle samples. Furthermore, we used transwell assay to test cell migration; RT-PCR and western blot were carried out to determine the expression of miR-146a, TRAF6, IL-17, and ICAM-1. Results: The S-CK, TRAF6, IL-17 and ICAM-1 levels were higher in PM/DM patients compared with healthy controls and were down-regulated after the conventional treatment. Treatment with miR-146a mimics, anti-IL-17 and anti-ICAM-1 decreased the expression of IL-17 and ICAM-1, whereas miR-146a inhibitors exerted the opposite effects. The effects of miR-146a inhibitors were suppressed by treatment with TRAF6 siRNA. In addition, the luciferase reporter assay validated the targeting relationship between miR-146a and TRAF6. Conclusions: MiR-146a regulates inflammatory macrophage infiltration in PM/DM by targeting TRAF6 and affecting the IL-17/ICAM-1 pathway.

Background Regulator of G protein signaling 6 (RGS6) is an important member of the RGS family and produces pleiotropic regulatory effects on cardiac pathophysiology. However, the role of RGS6 protein in cardiomyocytes during angiotensin II– and pressure overload–induced cardiac hypertrophy remain unknown. Methods and Results Here, we used a genetic approach to study the regulatory role of RGS6 in cardiomyocytes during pathological cardiac hypertrophy. RGS6 expression was significantly increased in failing human hearts and in hypertrophic murine hearts. The extent of aortic banding–induced cardiac hypertrophy, dysfunction, and fibrosis in cardiac‐specific RGS6 knockout mice was alleviated, whereas the hearts of transgenic mice with cardiac‐specific RGS6 overexpression exhibited exacerbated responses to pressure overload. Consistent with these findings, RGS6 also facilitated an angiotensin II–induced hypertrophic response in isolated cardiomyocytes. According to the mechanistic studies, RGS6 mediated cardiac hypertrophy by directly interacting with apoptosis signal–regulating kinase 1, which further activates the P38‐c‐JUN N‐terminal kinase 1/2 signaling pathway. Conclusions Based on our findings, RGS6 aggravates cardiac hypertrophy, and the RGS6‐apoptosis signal–regulating kinase 1 pathway represents a potential therapeutic target to attenuate pressure overload–driven cardiac remodeling.

Purpose: This paper investigates the influence of channel structures and channel coordination on the supplier, the retailer and the entire supply chain in the context of two different kinds of marketing models: The common retailer and the exclusive shop.Methodology: With suppliers who manufacture the alternative commodities and retailers in the dual-channel supply chains as the object of the research, this paper compares suppliers' profits, consumer utility without coordination and contrasts suppliers' and retailers' profits with coordination to determine the range of the revenue sharing rates and which parameters are related.Findings: The analysis suggests the preference lists of the supplier and the retailer over channel structures with and without coordination are different, and depend on parameters like channel basic demand, channel cost and channel substitutability.Originality/value: In this research, new sales model for two suppliers should choose the same retailer or the exclusive retailers to sell their commodities.

In this paper we investigate a logistic equation with a new free boundary condition appearing in ecology, we aim to describe the spreading of a new or invasive species by studying the asymptotic behavior of the radially symmetric solutions of the problem. We will obtain a trichotomy result: spreading (the solution converges to a stationary solution defined on the half–line), transition (the solution converges to a stationary solution with compact support) and vanishing (the solution converges to 0 within a finite time). Besides we can also obtain a dichotomy result (either spreading or vanishing happens). Moreover, in the spreading case, we give the sharp estimate of the asymptotic spreading speed of the free boundary.

Postoperative cognitive dysfunction (POCD) is a common complication after surgery, especially for elderly patients. Administration of RNase has been reported to exhibit neuroprotective effects in acute stroke. However, the potential role of RNase on POCD is unknown. Therefore, we sought to investigate whether RNase treatment could mitigate unilateral nephrectomy induced-cognitive deficit in aged mice. In the present study, twelve-month-old mice were administered RNase or an equal amount of normal saline perioperatively. All mice underwent Morris Water Maze (MWM) training 3 times per day for 7 days to acclimatize them to the water maze before surgical operation, and testing on days 1, 3 and 7 after surgery. We found that perioperative administration of RNase: 1) attenuated unilateral nephrectomy-induced cognitive impairment at day 3 after surgery; 2) reduced the hippocampal cytokines mRNA production and serum cytokines protein production at day 1 and day 7 (for MCP-1) after surgery, and; 3) inhibited hippocampal apoptosis as indicated by cleaved caspase-3 western blot and TUNEL staining at day 1 after surgery. In addition, a trend decrease of total serum RNA levels was detected in the RNase treated group after surgery compared with the untreated group. Further, our protocol of RNase administration had no impact on the arterial blood gas analysis right after surgery, kidney function and mortality rate at the observed days postoperatively. In conclusion, perioperative RNase treatment attenuated unilateral nephrectomy-induced cognitive impairment in aged mice.

Age, hypertension, dyslipidemia and diabetes are common cardiovascular risk factors (CVRFs) that contribute to the development of atherosclerosis in cardiovascular system including carotid artery disease. However, the impact of these risk factors on the increased carotid intima-media thickness (cIMT) and degree of carotid severity remains to be further clarified. This study aims to evaluate the relationship between CVRFs and degree of carotid severity and cIMT in high-risk subjects.Four thousand and three hundred ninety-four subjects with one or more risk factors were retrospectively reviewed in this study. Patients were divided into different groups based on age, the type and quantity of CVRFs. cIMT and degree of carotid artery stenosis were measured and analyzed based on carotid ultrasound imaging with findings compared to the CVRFs to determine the correlation between these variables.Aging was significantly associated with degree of severity (P < 0.05) and cIMT was significantly increased with age (P < 0.05). Individual CVRF analysis shows that hypertension was more related to the degree of severity than dyslipidemia and diabetes with corresponding abnormal cIMT rates being 79.39%, 72.98% and 32.37%, respectively. The prevalence of carotid atherosclerosis were 20.06%, 22.88% and 28.63%, respectively corresponding to patients with zero, one and more than one chronic diseases. The percentage of abnormal cIMT in hypertensive patient group with dyslipidemia is significantly higher than the other groups (P< 0.05).This study shows a direct correlation between the degree of carotid severity and cIMT and cardiovascular risk factors, especially with age and hypertension. Carotid atherosclerosis is closely related to the number of cardiovascular risk factors.

The two major intracellular protein degradation systems, the ubiquitin-proteasome system (UPS) and autophagy, work collaboratively in many biological processes including development, apoptosis, aging, and countering oxidative injuries. We report here that, in human retinal pigment epithelial cells (RPE), ARPE-19 cells, proteasome inhibitors, clasto-lactacystinβ-lactone (LA) or epoxomicin (Epo), at non-lethal doses, increased the protein levels of autophagy-specific genes Atg5 and Atg7 and enhanced the conversion of microtubule-associated protein light chain (LC3) from LC3-I to its lipidative form, LC3-II, which was enhanced by co-addition of the saturated concentration of Bafilomycin A1 (Baf). Detection of co-localization for LC3 staining and labeled-lysosome further confirmed autophagic flux induced by LA or Epo. LA or Epo reduced the phosphorylation of the protein kinase B (Akt), a downstream target of phosphatidylinositol-3-kinases (PI3K), and mammalian target of rapamycin (mTOR) in ARPE-19 cells; by contrast, the induced changes of autophagy substrate, p62, showed biphasic pattern. The autophagy inhibitor, Baf, attenuated the reduction in oxidative injury conferred by treatment with low doses of LA and Epo in ARPE-19 cells exposed to menadione (VK3) or 4-hydroxynonenal (4-HNE). Knockdown of Atg7 with siRNA in ARPE-19 cells reduced the protective effects of LA or Epo against VK3. Overall, our results suggest that treatment with low levels of proteasome inhibitors confers resistance to oxidative injury by a pathway involving inhibition of the PI3K-Akt-mTOR pathway and activation of autophagy.

We study a free boundary problem for a reaction diffusion equation modeling the spreading of a biological or chemical species. In this model, the free boundary represents the spreading front of the species. We discuss the asymptotic behavior of bounded solutions and obtain a trichotomy result: spreading (the free boundary tends to +∞ and the solution converges to a stationary solution defined on [0+∞)), transition (the free boundary stays in a bounded interval and the solution converges to a stationary solution with positive compact support), and vanishing (the free boundary converges to 0 and the solution tends to 0 within a finite time).

Using a specially constructed cone and the fixed point index theory, this work shows existence and nonexistence results of positive solutions for fourth-order boundary value problem with two different parameters in Banach spaces.