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Abstract Background Tight junctions (TJ) are multi-protein complexes that hold epithelial cells together and form structural and functional barriers for maintaining proper biological activities. Dual specificity phosphatase 3 (DUSP3), a suppressor of multiple protein tyrosine (Tyr) kinases, is decreased in lung cancer tissues. Here we demonstrated the role of DUSP3 in regulation of epithelial TJ. Methods Barrier functions of TJ were examined in wild-type or DUSP3-deficient lung epithelial cells. Animal and clinical data were analyzed for the association between DUSP3 deficiency and lung cancer progression. Proximity ligation assay, immunoblotting, and phosphatase assay were performed to study the effect of DUSP3 on the TJ protein occludin (OCLN). Mutations of Tyr residues on OCLN showed the role of Tyr phosphorylation in regulating OCLN. Results Compared to those of the DUSP3-expressing cells, we found the expression and distribution of ZO-1, a TJ-anchoring molecule, were abnormal in DUSP3-deficient cells. OCLN had an increased phosphorylation level in DUSP3-deficient cells. We identified that OCLN is a direct substrate of DUSP3. DUSP3 regulated OCLN ubiquitination and degradation through decreasing OCLN tyrosine phosphorylation directly or through suppressing focal adhesion kinase, the OCLN kinase. Conclusion Our study revealed that DUSP3 is an important TJ regulatory protein and its decrease may be involved in progression of epithelial cancers.

IntroductionDiabetic sarcopenia (DS) is characterized by muscle atrophy, slower nerve conduction, reduced maximum tension generated by skeletal muscle contraction, and slower contraction rate. Hence, DS can cause limb movement degeneration, slow movement, reduced balance, reduced metabolic rate, falls, fractures, etc. Moreover, the relevant early biological metabolites and their pathophysiological mechanism have yet to be characterized.MethodThe current cross-sectional study employed serum metabolomics analysis to screen potential noninvasive biomarkers in patients with diabetic sarcopenia. A total of 280 diabetic patients were enrolled in the study (n = 39 sarcopenia [DS], n = 241 without sarcopenia [DM]). Ten patients were randomly selected from both groups. Non-targeted metabolomic analysis was performed by ultra-high-performance liquid chromatography-electrospray ionization tandem mass spectrometry.ResultsA total of 632 differential metabolites were identified, including 82 that were significantly differentially abundant (P < 0.05, VIP > 1, FC > 1.2 or FC < 0.8). Compared with the DM group, the contents of pentadecanoic acid, 5'-methylthioadenosine (5'-MTA), N,N-dimethylarginine (asymmetric dimethylarginine, ADMA), and glutamine in the DS group were significantly increased, while that of isoxanthohumol was decreased.DiscussionBased on receiver operating characteristic curve analysis, pentadecanoic acid, 5'-MTA, ADMA, and glutamine may serve as potential biomarkers of DS. Moreover, ATP-binding cassette (ABC) transporters and the mammalian target of the rapamycin signaling pathway were found to potentially have important regulatory roles in the occurrence and development of DS (P < 0.05). Collectively, the differential metabolites identified in this study provide new insights into the underlying pathophysiology of DS and serve as a basis for therapeutic interventions.

Background: The signal transducer and activator of transcription (STAT) gene family have been widely found to regulate cell proliferation, differentiation, apoptosis, and angiogenesis through complex signaling pathways, and thus impacting tumor formation and development in different types of tumor. However, the roles of STATs on prognostic prediction and therapeutic guidance in pan-cancer remain unexplored.Materials and Methods: The dataset of 33 types of TCGA tumor, para-carcinoma and normal tissues, was obtained from the UCSC Xena database, including the gene expression profiles in the formats of FPKM value, demographic characteristics, clinical information, and survival data of STATs. Differential expression and co-expression analyses, WGCNA, clinical relevance analysis, immune subtype analysis, tumor stemness analysis, tumor purity analysis, immune infiltration analysis, immunotherapy related analysis, tumor mutation related analysis, and drug sensitivity analysis were performed by R software.Results: Differential expression of STAT1 was found between normal and BRCA tissues (p < 0.001, log2FC = 0.895). Additionally, the strongest correlation among STATs lied between STAT1 and STAT2 (correlation coefficient = 0.6). Moreover, high expression levels of STAT1 (p = 0.031) were revealed to be notably correlated with poor prognosis in KIRP. In addition, STAT1 expressed the highest value in immune subtypes C1, C2, C3, and C6 in LUAD. What’s more, strong negative correlations were demonstrated between expression of STAT6 and mDNAss and mRNAss of TGCT. Additionally, STAT4 expression was characterized to be significantly negatively correlated with tumor purity of the majority of cancer types. Moreover, STAT1 and STAT3 were shown to be generally high-expressed in pan-cancer myeloid cells, and STATs all had positive correlation with the infiltration of the majority of immune cells. In addition, STATs were revealed to be closely linked with immunotherapy response. What’s more, STAT4 expression was identified to have a strong negative correlation with TMB value in DLBC. Last but not least, positive correlations were accessed between STAT5 and sensitivity of Nelarabine (cor = 0.600, p < 0.001).Conclusion: In the present study, we identified STATs as biomarkers for prognostic prediction and therapeutic guidance in pan-cancer. Hopefully our findings could provide a valuable reference for future STATs research and clinical applications.

The standard rate‐and‐state friction (RSF) has extensively captured frictional behaviors, but it fails to explain the velocity dependence of frictional stability transition and widespread slow‐slip events (SSEs) in experiments and nature adequately. An alternative microphysical Chen‐Niemeijer‐Spiers (CNS) model can well describe the velocity dependence of frictional behaviors of granular gouges. Using the original CNS model, standard RSF parameters can be quantified microphysically. However, some micro‐parameters are not easy to estimate quantitatively, making it difficult to extrapolate to natural and experimental conditions. Here, we simplify the microphysically‐derived RSF parameters including direct effect a, evolution effect b, and critical slip distance Dc, as well as equivalent values (aeq, beq, and Deq). The simplified friction parameters directly illustrate their velocity dependence, namely the essentially constant a, aeq, and Dc, negatively velocity‐dependent b and beq, as well as varying Deq for different laws. They are roughly consistent with experimental results in various fault gouges. A modified CNS model is further derived from the original CNS model, establishing a direct link between the standard RSF and CNS models. The modified CNS model exhibits virtually identical frictional behaviors to the original CNS, but differs from the standard RSF at large velocity perturbations. Moreover, the linearized stability analysis indicates that the critical stiffness for the modified CNS model is velocity‐dependent. Compared with the standard RSF, the modified CNS model not only explains the velocity dependence of frictional stability transition, but also exhibits a more gradual transition for SSEs with a broader range of stiffness ratios. Plain Language Summary: Geological observations have illustrated a growing body of slow fault slip events that radiate little or no seismic energy, but the underlying mechanisms are not fully understood. This study examines two widely‐used friction models, namely, an empirical friction model and a microphysically‐based model. Both of them have been employed to capture experimental and natural observations, but the microphysical model shows significant velocity dependence of friction and is able to interpret friction parameters of the empirical friction model microphysically. We further examine the microphysically‐derived friction parameters, omit some micro‐parameters that contribute negligibly, directly describe their velocity dependence, and derive a simple friction model. The modified friction model is roughly consistent with the microphysically‐based model. More importantly, the modified model can not only describe the velocity dependence of frictional stability transition, but also explain the widespread slow fault slip events in experiments and nature. Key Points: Microphysically‐derived rate‐and‐state friction parameters are simplifiedA modified Chen, Niemeijer, and Spiers (CNS) model is derived from the original microphysical modelThe modified CNS model captures a more gradual transition for slow‐slip events [ABSTRACT FROM AUTHOR]

Annonaceae, comprising approximately 107 genera and 2400 species, is the largest family among early-divergent Magnoliales. Previous studies have concentrated on the binding mechanism that holds together the four members of tetrads in Annonaceae. However, the development mechanisms of different tetrad types remain largely unknown. Mitrephora tomentosa was found to exhibit five permanent tetrad types, with two or three of them existing in the same microsporangium, which is ideal for studying the formation mechanisms of different permanent tetrad pollens in a single microsporangium and explaining the relationship between cytokinesis and pollen tetrad types. The ontogenetic development of the different tetrads in M. tomentosa was investigated using electron microscopy technologies, histochemical staining, and immunocytochemistry. During meiosis, pollen mother cells produce decussate and tetragonal tetrads by successive cytokinesis and produce tetrahedral and rhomboidal tetrads by simultaneous cytokinesis. Bidirectional callose deposition was observed in tetrahedral, tetragonal, rhomboidal, and decussate tetrads. The variations in the process of microsporogenesis randomly accumulate and manifest as different combinations of cytokinesis and callose deposition, leading to the formation of differently shaped tetrads. In mature permanent tetrad pollens, four microspores are connected by both simple cohesion and cytoplasmic channels, which also play an important role in maintaining the synchronization of the tetrad members.

Abstract The incidence and mortality of hepatocellular carcinoma (HCC) are gradually increasing during the past years. Recently, some studies have reported that malic enzyme (ME) plays an important role in cancer development, while the involvement of ME2 in HCC remains still undetermined. Here, we demonstrated that ME2 played an oncogenic role in HCC. ME2 was overexpressed in HCC tissues. TCGA database showed that the ME2 transcript level was inversely associated with the survival of HCC patients. Loss‐of‐function and gain‐of‐function assays showed that ME2 promoted HCC cell growth and migration. Furthermore, the xenografted tumorigenesis of MHCC97H cells was retarded by ME2 knockdown. ME2 silencing also suppressed the cell cycle process and induced apoptosis. Mechanistically, ME2 potentiated triglyceride synthesis, inhibition of which suppressed the proliferation and migration. We propose that ME2 promotes HCC progression by increasing triglyceride production.

BackgroundMuscle mass loss is common in long-standing rheumatoid arthritis (RA). The aim was to explore the prevalence and effects of RA disease characteristics in patients with early RA.MethodsThis cross-sectional study was carried out based on a Chinese RA cohort and control subjects. The body composition (BC) was assessed using bioelectric impedance analysis. Myopenia was defined by an appendicular skeletal muscle mass index of ≤ 7.0 kg/m2 in men and ≤ 5.7 kg/m2 in women. Physical dysfunction was defined as a health assessment questionnaire disability index > 1. Propensity score matching was performed to balance age and gender differences among patients with early RA (disease duration ≤ 12 months) and established RA, and controls (with 1:3:3 matching).ResultsIn total, 2017 controls and 1,008 patients with RA were recruited for this study. Among the patients with RA, there were 190 (18.8%) patients with early RA, with a median disease duration of 7 (4, 11) months. The matched patients with early RA (n = 160) showed a higher prevalence of myopenia than the matched controls (41.3 vs. 15.8%, P < 0.0167), but no difference was found in the matched patients with established RA (41.3 vs. 50.4%, P > 0.0167). Compared with the patients with established RA, the patients with early RA exhibited higher disease activity scores [disease activity score in 28 joints with four variables including C-reactive protein (DAS28-CRP): median 4.76 vs. 3.93, P < 0.001] and a higher prevalence of physical dysfunction (26.3 vs. 19.4%, P = 0.035). In the patients with early RA, patients with myopenia showed a higher prevalence of physical dysfunction than those without myopenia (41.3 vs. 15.5%, P < 0.001), among which walking and common daily activities were the most involved subdimensions. Multivariate logistic regression analysis showed that DAS28-CRP was positively associated with myopenia [adjusted odds ratio (AOR) 1.558, 95% CI (1.138–2.132)], and myopenia [AOR 2.983, 95% CI (1.192–7.465)] was independently associated with physical dysfunction in the patients with early RA.ConclusionOur data indicate the importance of early detection of muscle involvement in the early stage of RA and imply the significance of early aggressive control of disease activity for the prevention of myopenia and physical dysfunction in patients with early RA. Our study provides a new perspective on RA management.

CX-5461, a novel selective RNA polymerase I inhibitor, shows potential anti-inflammatory and immunosuppressive activities. However, the molecular mechanisms underlying the inhibitory effects of CX-5461 on macrophage-mediated inflammation remain to be clarified. In the present study, we attempted to identify the systemic biological processes which were modulated by CX-5461 in inflammatory macrophages. Primary peritoneal macrophages were isolated from normal Sprague Dawley rats, and primed with lipopolysaccharide or interferon-γ. Genome-wide RNA sequencing was performed. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes databases were used for gene functional annotations. Enrichment analysis was conducted using the ClusterProfiler package of R software. We found that CX-5461 principally induced a molecular signature related to cell cycle inhibition in primed macrophages, featuring downregulation of genes encoding cell cycle mediators and concomitant upregulation of cell cycle inhibitors. At the same concentration, however, CX-5461 did not induce a systemic anti-inflammatory transcriptional program, although some inflammatory genes such as IL-1β and gp91phox NADPH oxidase were downregulated by CX-5461. Our data further highlighted a central role of p53 in orchestrating the molecular networks that were responsive to CX-5461 treatment. In conclusion, our study suggested that limiting cell proliferation predominated in the inhibitory effects of CX-5461 on macrophage-mediated inflammation.

AIM:To build prediction model of dry eye with data mining techniques.METHODS: From March 2020 to January 2021, 218 patients(436 eyes)with dry eye were selected as dry eye group, and 212 patients(424 eyes)without dry eye were selected as control group. Schirmer Ⅰ test(SⅠt), fluorescein staining tear film break-up time(FBUT), non-contact tear film break-up time(NI-BUT), tear meniscus height(TMH), corneal fluorescein staining(FL)and meibomian gland function score(MG-SCORE)were performed in both groups. Totally 200 eyes of 100 samples were randomly selected from the dry eye group and the control group to form a test set of 400 eyes of 200 samples. The remaining 118 samples(236 eyes)in the dry eye group and 112 samples(224 eyes)in the control group were used as the training set. Correlation feature searching(CFS)feature selection algorithm was used to search the factors related to the detection of dry eye. C4.5, Random Forest, Rondom Tree, Naïve Bayes, KNN, SVM, Decision Stump and Bagging methods were used to construct the prediction model, respectively.RESULTS:By using CFS feature selection algorithm, an optimal sub-feature set including SⅠt, NI-BUT, TMH and FL were obtained. Based on the four features, eight machine learning algorithms were employed to build the prediction model, respectively. The results show that the prediction accuracies were all higher than 75%. Among the eight prediction models, the prediction accuracy model by using Random Forest is the highest, which achieved 91.8% and 88.3%, respectively. And the total prediction accuracy reached 90.1%. In addition, through the analysis of single factor modeling, we found that FL and NI-BUT had the highest prediction accuracy, which exceeded 74%.CONCLUSION: Random Forest could be considered as a stable and well generalization algorithm to build prediction model for dry eye with well generalization. NI-BUT and FL have a strong correlation with dry eye, which can be considered as the standard for clinical examination of dry eye.

Introduction Living with heart failure (HF), is a shared journey and arduous work for patients and their informal family caregivers. Given the key role and limited evidence of dyad illness management in improving dyad health in the context of HF, we developed a customisable, relationship focused, family online dynamic disease management programme—FOCUS programme—to improve dyad health for HF patients and their informal caregivers in China.Methods and analysis Based on the Theory of Dyadic Illness Management and the Systemic Transactional Model of Stress and Coping, the family customised online FOCUS programme has five modules: (1) family participatory; (2) open communication; (3) coping effectiveness; (4) uncertainty reduction and 5) shared dyad life stories. HF family dyads will be recruited in the cardiology wards of four university-affiliated hospitals in China. The dyads (N=142) will be randomly allocated to the intervention group that will receive the family customised online FOCUS programme, and the attention control group that will not receive elements of the FOCUS programme. Dyadic coping, HF somatic perception, self-care, anxiety and depression for patients and family caregivers and all-cause mortality and hospital admission for patients will be measured at baseline, 4 weeks (after the discharge, T1), 12 weeks (after the discharge, T2) and 24 weeks (after the discharge, T3). Statistical analysis will be performed using SPSS V. 22.0 software.Ethics and dissemination The study protocol was approved by the ethics committees of Tianjin Medical University (Reference number TMUHEC2019002) that covers all the centres enrolled in this study. The findings of this study will be published in scientific journals and will be presented at scientific conferences.Trial registration number ChiCTR2100053168.

People with hemophilia (PWH), especially severe hemophilia, often experience bleeding episodes, which occur mostly at major joints. Intramural hematoma of the gastrointestinal (GI) tract is a rare, potentially life-threatening clinical bleeding manifestation in PWH. Prompt identification and timely administration of clotting factor concentrates are of utmost importance for effective management and optimal patient outcomes. In this report, we present the case of a 48-year-old male with severe hemophilia A. The patient developed a spontaneous intramural hematoma of the jejunum, leading to signs of acute abdomen, bloody stool, and paralytic ileus. Conservative management with factor VIII (FVIII) infusion was successfully administered. However, within a span of three months, the patient suffered from a recurrent episode of intramural hematoma, which was again effectively treated with conservative therapy. Subsequently, prophylactic FVIII therapy was administered to the patient, resulting in the absence of recurrence for over three years. Inspired by this case, we conducted a comprehensive review of the relevant literature and gathered data from 79 reported cases of intramural hematoma that were documented between the years 1956 and 2022. We classified these cases based on the site affected within the gastrointestinal (GI) tract (spread across five different locations) and proceeded to conduct a simple pooling analysis on the data collected, which subsequently revealed that the overall mortality rate of intramural hematoma in people with hemophilia (PWH) was found to be 12.2%, while children have a higher mortality rate (23.3%) than adults (4.9%). We hope this case report and literature review increase awareness of this rare bleeding manifestation in PWH, the effectiveness of conservative treatment, and the possibility of prophylaxis against recurrence.

AIM:To explore the effects of recombinant human growth hormone(rHGH)on early rehabilitation in rabbit corneal epithelial wound. METHODS:Thirty-two New Zealand rabbits were selected to establish the corneal epithelial defects models. One eye was treated with normal saline(NC group)and the other eye was treated with 20nmol/L rHGH(rHGH group)in a randomized double-blinded way. The corneal healing process was monitored by the corneal fluorescein staining scores at 0h, 24h, 48h, and 72h after the surgery. The central corneal sensitivity was detected by Cochet-Bonnet corneal esthesiometer and the concentrations of inflammatory mediators interlecukin-1α(IL-1α), interlecukin-17(IL-17), interlecukin-21(IL-21), Leptin, matrix metalloproteinase-9(MMP-9)and tumor necrosis factor-α(TNF-α)in collected tears were measured by multiplex antibody microarray. RESULTS: The corneal epithelial healing rates of the NC group and rHGH group were(62.52±6.73)% and(79.62±10.62)%(P0.05).CONCLUSION: Topical application of rHGH can accelerate the early stage of rabbit corneal epithelial wound healing in vivo.

Abstract Circular RNA (circRNAs) functions vital in the pathogenesis and progression of hepatocellular carcinoma (HCC). However, the expressions and functions of certain circRNAs on metastasis and proliferation of that cancer is still unclear. Bioinformation analysis and qRT-PCR indicated that CircC16orf62 was prominent upregulated in HCC of which the expression level was positively associated to cancer’s malignant progression. Gain or loss-of-function studies indicated that the reduction of CircC16orf62 expression promotes the proliferation, invasion, and glycolysis of HCC in vitro and in vivo. The bioinformatic analysis found that miR-138-5p and PTK2 were the downstream target of CircC16or62. Then, the FISH(Fluorescence immunoin situ hybridization) and cell nucleoplasmic separation determined that CircC16orf62 located in the cell cytoplasm. Plasmid vectors or siRNAs were used to change the expression of CircC16orf62, miR-138-5p, and PTK2 in PC cell lines. CircC16orf62 functioned as a molecular sponge for miR-138-5p, and a competitive endogenous RNA for PTK2, promoting AKT/mTOR pathway activation. Our observations lead us to conclude that CircC16orf62 functions as an oncogene in HCC progression, behaving as a competitive endogenous RNA for miR-138-5p binding, thus activating the AKT/mTOR pathway. In conclusion, CircC16orf62 is an oncogene through the miR-138-5p/PTK2/Akt axis in HCC cells, indicating CircC16orf62 can be a therapeutic target with potentiality for liver cancer and a predictive marker for people with HCC.

ABSTRACT With the demographic changes, more and more elderly people have chosen to spend their retirement life in a senior care facility. The elderly people in senior care facility are commonly suffering from various geriatric syndromes, including declined daily living activities, cognitive dysfunction, frailty, comorbidities, and polypharmacy, which make them vulnerable to adverse effects, like hypoglycemia and fall. Therefore, layered management is necessary for this population with group disparities. However, the staff in senior care facility vary greatly in concepts and skills on management of senile diabetic population, which needs urgently to be standardized and improved. For this purpose, based on literature review and panel discussion, 28 recommendations are proposed in respect of the standardized management of blood glucose, covering the comprehensive assessment, layered management and grouping, exercise, nutrition, glucose monitoring, identification and treatment of severe hyperglycemia, identification of macrovascular and microvascular complications, management of hypoglycemic drugs, falls and choking and other common problems, blood glucose screening, hypoglycemia prevention, and blood glucose management in major public health events or serious natural disasters. This guideline aims to standardize management skills of medical staff and caregivers in senior care facility for the blood glucose of elderly people and improve their quality of life.

ObjectiveThis study examined the association of lifetime experiences, measured by a cognitive reserve (CR) composite score composed of years of education, literacy, and vocabulary measures, to level and rate of change in white matter microstructure, as assessed by diffusion tensor imaging (DTI) measures. We also examined whether the relationship between the proxy CR composite score and white matter microstructure was modified by participant age, APOE-ε4 genetic status, and level of vascular risk.MethodsA sample of 192 non-demented (n = 166 cognitively normal, n = 26 mild cognitive impairment) older adults [mean age = 70.17 (SD = 8.5) years] from the BIOCARD study underwent longitudinal DTI (mean follow-up = 2.5 years, max = 4.7 years). White matter microstructure was quantified by fractional anisotropy (FA) and radial diffusivity (RD) values in global white matter tracts and medial temporal lobe (MTL) white matter tracts.ResultsUsing longitudinal linear mixed effect models, we found that FA decreased over time and RD increased over time in both the global and MTL DTI composites, but the rate of change in these DTI measures was not related to level of CR. However, there were significant interactions between the CR composite score and age for global RD in the full sample, and for global FA, global RD, and MTL RD among those with normal cognition. These interactions indicated that among participants with a lower baseline age, higher CR composite scores were associated with higher FA and lower RD values, while among participants with higher age at baseline, higher CR composite scores were associated with lower FA and higher RD values. Furthermore, these relationships were not modified by APOE-ε4 genotype or level of vascular risk.ConclusionThe association between level of CR and DTI measures differs by age, suggesting a possible neuroprotective effect of CR among late middle-aged adults that shifts to a compensatory effect among older adults.

Growing evidence has demonstrated that hypertension was associated with dysbiosis of intestinal flora. Since intestinal microbes could critically regulate neurofunction via the intestinal–brain axis, the study aimed to reveal the role and prediction value of intestinal flora alteration in hypertension-associated cognitive impairment. A cohort of 97 participants included 63 hypertension patients and 34 healthy controls. The structure of intestinal flora was analyzed by V3–V4 16S rRNA amplicon sequencing. The cognitive function was assessed using the Montreal Cognitive Assessment (MoCA) scale, and 31 patients were considered to have cognitive impairment (MoCA < 26). Patients with cognitive impairment had considerable alterations in intestinal flora structure, composition, and function compared with normal-cognitive patients. In particular, the abundance of LPS-containing taxa (Proteobacteria, Gammaproteobacteria, Enterobacterales, Enterobacteriaceae, and Escherichia–Shigella) and SCFA-producing taxon (Prevotella) significantly changed in cognition-impaired patients. Tax4Fun predication results showed downregulation of glycan biosynthesis and metabolism in hypertension patients with cognitive impairment. Additionally, the pathway was demonstrated to be significantly correlated with LPS-containing taxa (Proteobacteria, Gammaproteobacteria, Enterobacterales, Enterobacteriaceae, and Escherichia–Shigella) and SCFA-producing taxon Prevotella. Furthermore, the taxa-based multiple joint prediction model (9×) was demonstrated to have excellent diagnostic potential for cognitive impairment of hypertension patients (AUC = 0.944). The current study revealed the involvement of intestinal microbiota dysbiosis in cognition-impaired hypertension patients and provided an objective predictive index for this cognition disorder.

Abstract Background Despite the substantial burden of caring schizophrenic patients, primary caregivers can also experience posttraumatic growth (PTG) which may buffer their negative experience. Influencing factors of PTG and their functional pathways among primary caregivers of schizophrenic patients remain unclear. This study is designed to test the simple and serial mediating roles of coping styles and resilience in the relationship between perceived social support and PTG among those primary caregivers. Methods A cross-sectional study was conducted from October 2018 to January 2019, and 365 primary caregivers (self-reported) of schizophrenic patients were analyzed. Measures used to assess their perceived social support, coping styles, resilience, and PTG were the Perceived Social Support Scale, the Simplified Coping Style Questionnaire, the Connor-Davidson Resilience Scale, and the Posttraumatic Growth Inventory, respectively. Structural equation modeling was used to run the analysis. Results The average scores of PTG (range: 0–5), perceived social support (range: 1–7), positive coping style (range: 0–3), negative coping style (range: 0–3), resilience (range: 0–4) reported by primary caregivers was (2.91 ± 0.99), (4.80 ± 1.26), (1.79 ± 0.65), (1.49 ± 0.56), and (2.46 ± 0.66), respectively. The fitness indices of measurement and structural models were satisfactory. Three indirect pathways totally explained 55.56% variance of the PTG. The indirect effect of positive coping style between perceived social support and PTG was 0.20 [95% confidence interval (CI) 0.05 to 0.37], and this simple mediation pathway explained 27.78% variance of PTG. The indirect effect of resilience between perceived social support and PTG was 0.11 [95% CI 0.01 to 0.20], and this simple mediation pathway explained 15.28% variance of PTG. The indirect effect of positive coping style and then resilience between perceived social support and PTG was 0.09 [95% CI 0.01 to 0.17], and this serial mediation pathway explained 12.50% variance of PTG. Conclusions Both simple and serial mediation roles of positive coping style and resilience are established in the relationship between perceived social support and PTG among primary caregivers of schizophrenic patients. Positive coping style and resilience are two important targets for future interventional studies, and interventions on them may bring the synergistic effect on improving PTG.

Depression is the most common mental health problem affecting adolescents globally, wherein its increasing prevalence together with the negative health impacts escalates the need for further research in this area. This work determined the prevalence and factors associated with depressive symptoms among young adolescents in Malaysia. A total of 1350 adolescent aged 13 to 14 years in school across nine secondary schools in Selangor state, Malaysia participated in a cross-sectional study. Independent variables were examined using the using the Global School-Based Student Health Survey included age, gender, ethnicity, alcohol intake, smoking and illicit drug use, loneliness, bullying, parental marital status, income and supervision; and the Health Literacy and Stigma questionnaire examined mental health literacy levels. Depressive symptoms were the dependent variable which was examined using the Center for Epidemiology Study Depression (CESD) instrument. Prevalence of depressive symptoms among all participants was 19 % (95% CI [16.9, 21.2]), with a higher prevalence of depressive symptoms being reported among females 26.3% (95% CI [23.0, 29.8]) compared to males 11.7% (95% CI [9.4, 14.4]). Determinants namely females (AOR = 3.83; 95% CI [2.66, 5.52]), smoking (AOR = 6.16; 95% CI [3.15, 12.05]), been bullied (AOR = 3.70; 95% CI [2.51, 5.47]), felt lonely (AOR = 10.46; 95% CI [7.09, 15.42]) and having no parental supervision (AOR = 1.79; 95% CI [1.26, 2.53]) significantly increased the odds of depressive symptoms among all adolescents in the multivariate model. In addition, feeling lonely, being bullied and smoking were identified as common significant determinants of depressive symptoms across both genders. Feeling lonely (65% to 71%) and being bullied (10% to 19%) were ranked as the most important determinants of depressive symptoms among young adolescents. Tackling these factors would be instrumental in helping decision makers formulate depression prevention strategies and activities for adolescents.

CX-5461 is a first-in-class selective RNA polymerase I inhibitor. Previously we found that CX-5461 had anti-inflammatory activities. In this study we characterized potential immunosuppressive effects of CX-5461 and explored the underlying mechanisms. Allogeneic skin transplantation model (BALB/c to C57BL/6 mice) and heterotopic heart transplantation model (F344 to Lewis rats) were used. We showed that CX-5461 was a potent inhibitor of alloimmunity which prevented acute allograft rejections. CX-5461 treatment was invariably associated with expansion of the regulatory T cell population. In vitro, CX-5461 inhibited agonists-induced T cell activation. CX-5461 consistently inhibited the expression of interferon-γ and interleukin − 2, key mediators of T cell-mediated alloimmunity. Mechanistically, CX-5461-induced immunosuppression was, at least partly, dependent on the p53-DUSP5 (dual-specificity phosphatase 5) axis and subsequent antagonism of the Erk1/2 mitogen-activated protein kinase pathway. In conclusion, our results suggest that CX-5461 is a promising candidate of a novel class of immunosuppressant which may be used as an alternative to the currently approved anti-rejection therapies.

Background: Exposure to metals lead (Pb), mercury (Hg), and cadmium (Cd) and trace elements selenium (Se) and manganese (Mn) has been linked to the developmental origins of cardiometabolic diseases, but the mechanisms are not well-understood. Objective: Conduct a metabolome-wide association study to understand how in utero exposure to Pb, Hg, Cd, Se, and Mn affects the metabolic programming of fetuses. Methods: We used data from the Boston Birth Cohort, which enrolled mother-child pairs from Boston, MA. We measured metals and trace elements in maternal red blood cells (RBCs) collected 24–72 h after delivery, and metabolites in cord blood collected at birth. We used multivariable linear regression to examine associations of metals and trace elements with metabolites and Bonferroni correction to account for multiple comparisons. We assessed non-linear associations of metals and trace elements with metabolites using restricted cubic spline plots. Results: This analysis included 670 mother-child pairs (57% non-Hispanic Black and 24% Hispanic). After Bonferroni correction, there were 25 cord metabolites associated with at least one of the metals or trace elements. Pb was negatively associated with the xenobiotic piperine, Cd was positively associated with xenobiotics cotinine and hydroxycotinine, and Hg was associated with 8 lipid metabolites (in both directions). Se and Mn shared associations with 6 metabolites (in both directions), which mostly included nucleotides and amino acids; Se was additionally associated with 7 metabolites (mostly amino acids, nucleotides, and carnitines) and Mn was additionally associated with C36:4 hydroxy phosphatidylcholine. Restricted cubic spline plots showed that most associations were linear. Discussion: Maternal RBC metal and trace element concentrations were associated in a dose-dependent fashion with cord blood metabolites. What remains to be determined is whether these metals- and trace elements-associated changes in cord metabolites can influence a child’s risk of cardiometabolic diseases.

Abstract Objective Examine whether cognitive reserve moderates the association of 1) vascular risk factors and 2) white matter hyperintensity burden with risk of clinical progression and longitudinal cognitive decline. Methods BIOCARD Study participants were cognitively normal and primarily middle‐aged (M = 57 years) at baseline and have been followed with annual cognitive and clinical assessments (M = 13 years). Baseline cognitive reserve was indexed with a composite score combining education with reading and vocabulary scores. Baseline vascular risk (N = 229) was assessed with a composite risk score reflecting five vascular risk factors. Baseline white matter hyperintensity load (N = 271) was measured with FLAIR magnetic resonance imaging. Cox regression models assessed risk of progression from normal cognition to onset of clinical symptoms of Mild Cognitive Impairment. Longitudinal mixed effects models measured the relationship of these variables to cognitive decline, using a global composite score, and executive function and episodic memory sub‐scores. Results Both vascular risk and white matter hyperintensities were associated with cognitive decline, particularly in executive function. Higher vascular risk, but not white matter hyperintensity burden, was associated with an increased risk of progression to Mild Cognitive Impairment. Higher cognitive reserve was associated with a reduced risk of symptom onset and higher levels of baseline cognition but did not modify the associations between the vascular risk score and white matter hyperintensities with clinical progression or cognitive decline. Interpretation Although cognitive reserve has protective effects on clinical and cognitive outcomes, it does not mitigate the negative impact of vascular risk and small vessel cerebrovascular disease on these same outcomes.

The physical/chemical properties and synthesis methods of nanoparticles were briefly introduced, and then the type and principle of the self-assembly of nanoparticles were discussed in detail. The research progress in the application of the nanoparticle self-assembly in lithium-ion batteries was summarized, and the existing problems such as the low production efficiency and high pollution in this field were also pointed out. The future works will be focused on developing approp-riate building blocks, disclosing the self-organization mechanisms and simplifying the fabrication processes, and the simultaneous yet effective adjustion of the self-assembly processes in the materials synthesis stage for advanced battery components with hierarchical structures or functions is one of the most important approaches.

Abstract Background Low-dose mercury (Hg) exposure has been associated with cardiovascular diseases, diabetes, and obesity in adults, but it is unknown the metabolic consequence of in utero Hg exposure. This study aimed to investigate the association between in utero Hg exposure and child overweight or obesity (OWO) and to explore if adequate maternal folate can mitigate Hg toxicity. Methods This prospective study included 1442 mother-child pairs recruited at birth and followed up to age 15 years. Maternal Hg in red blood cells and plasma folate levels were measured in samples collected 1–3 days after delivery (a proxy for third trimester exposure). Adequate folate was defined as plasma folate ≥ 20.4 nmol/L. Childhood OWO was defined as body mass index ≥ 85% percentile for age and sex. Results The median (interquartile range) of maternal Hg levels were 2.11 (1.04–3.70) μg/L. Geometric mean (95% CI) of maternal folate levels were 31.1 (30.1–32.1) nmol/L. Maternal Hg levels were positively associated with child OWO from age 2–15 years, independent of maternal pre-pregnancy OWO, diabetes, and other covariates. The relative risk (RR = 1.24, 95% CI 1.05–1.47) of child OWO associated with the highest quartile of Hg exposure was 24% higher than those with the lowest quartile. Maternal pre-pregnancy OWO and/or diabetes additively enhanced Hg toxicity. The highest risk of child OWO was found among children of OWO and diabetic mothers in the top Hg quartile (RR = 2.06; 95% CI 1.56–2.71) compared to their counterparts. Furthermore, adequate maternal folate status mitigated Hg toxicity. Given top quartile Hg exposure, adequate maternal folate was associated with a 34% reduction in child OWO risk (RR = 0.66, 95% CI 0.51–0.85) as compared with insufficient maternal folate. There was a suggestive interaction between maternal Hg and folate levels on child OWO risk (p for interaction = 0.086). Conclusions In this US urban, multi-ethnic population, elevated in utero Hg exposure was associated with a higher risk of OWO in childhood, and such risk was enhanced by maternal OWO and/or diabetes and reduced by adequate maternal folate. These findings underscore the need to screen for Hg and to optimize maternal folate status, especially among mothers with OWO and/or diabetes.

Objectives: There is no analytical method for simultaneous monitoring of warfarin and novel direct oral anticoagulants (NOACs) in human urine samples in a single run in the clinics. Although several studies have reported their measurements in human blood samples, but its sample collection is more invasive and time-consuming, thereby challenging to monitor frequently. Methods: In this work, we developed a fast microextraction technique (ultrasound-assisted salt-induced liquid-liquid microextraction, USA-SI-LLME) coupled with high-performance liquid chromatography-tandem mass spectrometry (HPLC–MS/MS) to rapidly quantify four commonly used NOACs drugs (apixaban, dabigatran, edoxaban, and rivaroxaban) and warfarin in human urine samples. USA-SI-LLME conditions were optimized using a water-miscible organic solvent as an extraction solvent, high salt concentrations, sample pH, and extraction time (∼5.5 min). Results and conclusions: The analytical method showed excellent linearities from 0.5 to 500 μg/L for apixaban, edoxaban, rivaroxaban, warfarin, and 1 ∼ 500 μg/L for dabigatran. Intra- and inter-day precision values were 0.99 for all analytes. Limits of detection ranged between 0.07 ∼ 0.18 μg/L, and relative recoveries ranged between 92.18 and 110.15%. This method was successfully applied to analyze 15 one-spot urine samples from 15 clinical patients who regularly took warfarin or NOACs, and high accuracy was found. We concluded that this method could be used as a non-invasive high-throughput and rapid monitoring of NOACs and warfarin in human urine in clinical settings and could provide timely analysis during emergency care.

Pulmonary fibrosis, a chronic lung disease caused by progressive deterioration of lung tissue, is generated by several factors including genetic and environmental ones. In response to long-term exposure to environmental stimuli, aberrant tissue repair and epithelial cell-to- mesenchymal cell transition (EMT) trigger the subsequent progression of pulmonary fibrotic diseases. The Aryl hydrocarbon receptor (AhR) is a transcription factor that is activated by ligands providing lung dysfunction when activated by environmental toxins, such as polycyclic aromatic hydrocarbons. Our previous study demonstrated that AhR mediates α-SMA expression by directly binding to the α-SMA (fibroblast differentiation marker) promoter, suggesting the role of AhR in mediating fibrogenic progression. Here we follow the hypothesis that macrophage infiltrated microenvironments may trigger inflammation and subsequent fibrosis. We studied the expression of cytokines in RAW 264.7 cells by AhR activation through an ELISA assay. To investigate molecular events, migration, western blotting and zymography assays were carried out. We found that AhR agonists such as TCDD, IP and FICZ, promote the migration and induce inflammatory mediators such as TNF-α and G-CSF, MIP-1α, MIP-1β and MIP-2. These cytokines arbitrate EMT marker expression such as E-cadherin, fibronectin, and vimentin in pulmonary epithelial cells. Expression of proteins of MMPs in mouse macrophages was determined by zymography, showing the caseinolytic activity of MMP-1 and the gelatinolytic action of MMP-2 and MMP-9. Taken together, the present study showed that AhR activated macrophages create an inflammatory microenvironment which favours the fibrotic progression of pulmonary epithelial cells. Such production of inflammatory factors was accomplished by affecting the Wnt/β-catenin signalling pathway, thereby creating a microenvironment which enhances the epithelial-mesenchymal transition, leading to fibrosis of the lung.

This article aims to explore the impact of the punch structure (number of grooves, area ratio of grooves, depth of grooves and flaring angle) on the loading, torque and metal flow during the rotary extrusion (RE) process via finite element simulation (FEM) software. In order to further verify the simulation results, physical experiments were carried out and the microstructure of Mg-Gd-Y-Zn-Zr alloy after RE deformation was characterized and analyzed. The FEM results indicated that increasing the groove number will increase the amount of shear deformation and promote the metal at the bottom of the punch to flow rapidly to the cylinder wall. The increase in the groove depth would continue to reduce the forming load and increase the strain. However, if the groove depth exceeded 6 mm, an excessive flow-velocity difference would be formed, resulting in the formation of folding defects. The time of metal flow from the bottom of the punch to the cylinder wall would be shortened with the increase in flaring angle. Therefore, a groove number of 8, an area ratio of 64.49%, a groove depth of 6 mm and a flaring angle ranging from 7° to 9° were the optimal parameters of the punch structure to form the Mg-Gd-Y-Zn-Zr cylindrical parts via the RE technique. In addition, the cylinder parts could be formed with good quality according to the optimized FEM results. The cylinder wall from inner region to outer region exhibited gradient microstructure owing to the different metal flow and strain during the RE process.