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Gestational cadmium exposure increases the risk of preeclampsia. Placenta mitophagy was activated in preeclampsia. The aim of present study was to explore the mechanism of cadmium-induced mitophagy activation and its association with preeclampsia. Mitophagy markers expression levels were detected by quantitative real-time PCR, Western blot, immunofluorescence and immunochemistry in preeclampsia placenta. JEG3 cells were treated with CdCl2, iopanoic acid (IOP), 3-methyladenine and PGC1α SiRNA to verify mechanism of cadmium-induced mitophagy. Mitophagy marker LC3BII/I and P62 expression were increased and mitochondrial membrane receptor protein TOM20 and FUNDC1 expression were decreased in preeclampsia placenta as compared with that in normotension control. Mitophagy marker LC3BII/I and P62 expression were increased and TOM20 and FUNDC1 expression was decreased in CdCl2-treated JEG3 cells. Meanwhile, mitochondrial biogenesis regulator, PGC1α expression was decreased in preeclampsia and CdCl2-treated JEG3 cells. The expressions of LC3B and P62 were increased and the expressions of TOM20, FUNDC1 and PGC1α were decreased in IOP-treated cell. PGC1α SiRNA transfection led to increased expression of LC3BII/I and P62 and decreased expression of TOM20 and FUNDC1. The expression of sFlt1 was increased in preeclampsia placenta, CdCl2-treated cells, in IOP-treated cells and in PGC1α SiRNA transfected cells. 3-methyladenine treatment protected the increased expression of sFlt1 in CdCl2-treated cells, in IOP-treated cells and in PGC1α SiRNA transfected cells. Meanwhile, co-treatment of cadmium and IOP or PGC1αSiRNA led to a reduce expressions of OPA1, MFN1, MFN2 and FUNDC1 as compared to cadmium-treated, IOP-treated and PGC1α SiRNA-treated cells. These results elucidated that maternal cadmium exposure activated placenta mitophagy through downregulation of thyroid hormone receptor signal mediated decreased expression of PGC1α and was associated with the occurrence of preeclampsia.

Rehmannia glutinosa, a crucial medicinal plant native to China, is extensively cultivated across East Asia. We used high-throughput sequencing to identify viruses infecting R. glutinosa with mosaic, leaf yellowing, and necrotic symptoms. A novel Torradovirus, which we tentatively named “Rehmannia torradovirus virus” (ReTV), was identified. The complete sequences were obtained through reverse-transcription polymerase chain reaction (RT-PCR), 5′ and 3′ rapid amplification of cDNA ends, and Sanger sequencing. The amino acid sequence alignment between the ReTV-52 isolate and known Torradovirus species in the Pro-Pol and coat protein regions were 51.3–73.3% and 37.1–68.1%, respectively. Meanwhile, the amino acid sequence alignment between the ReTV-8 isolate and known Torradovirus species in the Pro-Pol and coat protein regions were 52.7–72.8% and 36.8–67.5%, respectively. The sequence analysis classified ten ReTV strains into two variants. The ReTV-52 genome has two RNA segments of 6939 and 4569 nucleotides, while that of ReTV-8 consists of two RNA segments containing 6889 and 4662 nucleotides. Sequence comparisons and phylogenetic analysis showed ReTV strains clustered within the Torradovirus, exhibiting the closet relation to the squash chlorotic leaf spot virus. The RT-PCR results showed a 100% ReTV detection rate in all 60 R. glutinosa samples. Therefore, ReTV should be classified as a novel Torradovirus species. ReTV is potentially dangerous to R. glutinosa, and necessitating monitoring this virus in the field.

Septic encephalopathy (SE) represents a severe inflammatory syndrome linked to elevated septic mortality rates, lacking specific therapeutic interventions, and often resulting in enduring neurological sequelae. The present investigation endeavors to elucidate the involvement of C-X-C Motif Chemokine Receptor 2 (CXCR2) in the pathogenesis of SE and to explore the potential of CXCR2 modulation as a therapeutic avenue for SE. Employing a murine SE model induced by lipopolysaccharide (LPS) administration, CXCR2 knockout mice and the CXCR2 inhibitor SB225002 were utilized to assess neutrophil recruitment, endothelial integrity, and transendothelial migration. Our findings substantiate that either CXCR2 deficiency or its inhibition curtails neutrophil recruitment without impacting their adhesion to cerebral endothelial cells. This phenomenon is contingent upon endothelial CXCR2 expression rather than CXCR2’s presence on neutrophils. Furthermore, the CXCR2 blockade preserves the integrity of tight junction protein ZO-1 and mitigates F-actin stress fiber formation in cerebral endothelial cells following septic challenge. Mechanistically, CXCL1-mediated CXCR2 activation triggers cerebral endothelial actin contraction via Rho signaling, thereby facilitating neutrophil transmigration in SE. These observations advocate for the potential therapeutic efficacy of CXCR2 inhibition in managing SE.

Rehmannia glutinosa is one of the most important medicinal plants in China and is affected by viral diseases. In this study, a new virus tentatively named Rehmannia Allexivirus virus (ReAV) was identified through high-throughput sequencing, reverse-transcription polymerase chain reaction (RT-PCR), and Sanger sequencing. The complete genome length was 7297 nt and it contained five open reading frames (ORFs) encoding replicase, triple gene block 1(TGB1), TGB2, TGB3, and coat protein (CP). The replicase and CP presented nucleotide homology ranges of 59.9–65.2% and 47.5–55.5% between the nine ReAV isolates and the other 12 species of the genus Allexivirus. In the nine isolates, ReAV-20 and ReAV-31 isolates showed breakpoints in the replicase and CP regions, respectively. The other isolates shared 87.2–96.5% nt with the whole genome nucleotide identity. The phylogenetic tree showed that seven ReAV isolates based on replicase, CP, and whole genome sequences were clustered in the same branch and were related to the genus Allexivirus. The ReAV detection rates for 60 R. glutinosa samples were 73.3–81.7% through RT-PCR using primers targeting the replicase or CP genes. These results demonstrate that ReAV is the dominant virus in R. glutinosa. This study provides important evidence for understanding viruses infecting R. glutinosa and for establishing efficient strategies to prevent viral spread.

Generally, transition metal-catalyzed stereodivergent transfer semihydrogenation of alkynes realized regulation of stereoselectivity by a Z to E isomerization process. Here, authors report a Ni-catalyzed stereodivergent transfer semihydrogenation of alkynes with a base-assisted metal species modulation mechanism, delivering both olefinic isomers smoothly in orthogonal catalytic pathways using cheap and nontoxic catalysts and additives

Bending angle is an important parameter in multi-pass roll forming. However, in actual manufacturing, there is still a lack of theoretical guidance; hence, rebound defects are commonly observed. In this paper, a bending angle distribution function with an optimized segmented boundary combination is proposed to improve the forming quality and reduce the rebound defects in multi-pass roll forming. For cap-shaped sheets, COPRA, a roll-bending simulation software, is used to investigate the bending angle distribution to optimize the process of cap-shaped roll-bending. Furthermore, the stress and strain distributions in the sheets after each forming pass is analyzed using finite element simulation. The influence law of different bending angle parameters on the quality of sheets is obtained. The finite element simulation is verified by comparing the experimental results of the change law of rebound defects of cap-shaped parts under different bending angle distribution conditions. Based on the segmented boundary combination of bending angle optimization functions, the stress and strain distributions in the sheets during roll-bending forming of the cap-shaped parts are improved, the rebound defects in the bending area are smaller, and the forming quality is better than the other bending angle distribution methods.

Current chemotherapy strategies used in clinic appear with lots of disadvantages due to the low targeting effects of drugs and strong side effects, which significantly restricts the drug potency, causes multiple dysfunctions in the body, and even drives the emergence of diseases. Immunotherapy has been proved to boost the body’s innate and adaptive defenses for more effective disease control and treatment. As a trace element, selenium plays vital roles in human health by regulating the antioxidant defense, enzyme activity, and immune response through various specific pathways. Profiting from novel nanotechnology, selenium nanoparticles have been widely developed to reveal great potential in anticancer, antibacterial, and anti-inflammation treatments. More interestingly, increasing evidence has also shown that functional selenium nanoparticles can be applied for potential immunotherapy, which would achieve more effective treatment efficiency as adjunctive therapy strategies for the current chemotherapy. By directly interacting with innate immune cells, such as macrophages, dendritic cells, and natural killer cells, selenium nanoparticles can regulate innate immunity to intervene disease developments, which were reported to boost the anticancer, anti-infection, and anti-inflammation treatments. Moreover, selenium nanoparticles can also activate and recover different T cells for adaptive immunity regulations to enhance their cytotoxic to combat cancer cells, indicating the potential of selenium nanoparticles for potential immunotherapy strategy development. Here, aiming to enhance our understanding of the potential immunotherapy strategy development based on Se NPs, this review will summarize the immunological regulation effects of selenium nanoparticles and the application of selenium nanoparticle-based immunotherapy strategies. Furthermore, we will discuss the advancing perspective of selenium nanoparticle-based potential immunotherapy as a kind of novel adjunctive therapy to enhance the efficiency of current chemotherapies and also introduce the current obstacles for the development of selenium nanoparticles for potential immunotherapy strategy development. This work is expected to promote the future research on selenium nanoparticle-assisted immunotherapy and finally benefit the more effective disease treatments against the threatening cancer and infectious and chronic diseases.

Oseltamivir is a widely used influenza virus neuraminidase (NA) inhibitor that prevents the release of new virus particles from host cells. However, oseltamivir-resistant strains have emerged, but effective drugs against them have not yet been developed. Elucidating the binding mechanisms between NA and oseltamivir may provide valuable information for the design of new drugs against NA mutants resistant to oseltamivir. Here, we conducted large-scale (353.4 μs) free-binding molecular dynamics simulations, together with a Markov State Model and an importance-sampling algorithm, to reveal the binding process of oseltamivir and NA. Ten metastable states and five major binding pathways were identified that validated and complemented previously discovered binding pathways, including the hypothesis that oseltamivir can be transferred from the secondary sialic acid binding site to the catalytic site. The discovery of multiple new metastable states, especially the stable bound state containing a water-mediated hydrogen bond between Arg118 and oseltamivir, may provide new insights into the improvement of NA inhibitors. We anticipated the findings presented here will facilitate the development of drugs capable of combating NA mutations.

Abstract Background It is significant to model clinical activities for process mining, which assists in improving medical service quality. However, current process mining studies in healthcare pay more attention to the control flow of events, while the data properties and the time perspective are generally ignored. Moreover, classifying event attributes from the view of computers usually are difficult for medical experts. There are also problems of model sharing and reusing after it is generated. Methods In this paper, we presented a constraint-based method using multi-perspective declarative process mining, supporting healthcare personnel to model clinical processes by themselves. Inspired by openEHR, we classified event attributes into seven types, and each relationship between these types is represented in a Constrained Relationship Matrix. Finally, a conformance checking algorithm is designed. Results The method was verified in a retrospective observational case study, which consists of Electronic Medical Record (EMR) of 358 patients from a large general hospital in China. We take the ischemic stroke treatment process as an example to check compliance with clinical guidelines. Conformance checking results are analyzed and confirmed by medical experts. Conclusions This representation approach was applicable with the characteristic of easily understandable and expandable for modeling clinical activities, supporting to share the models created across different medical facilities.

Abstract Background With the character of high incidence, high prevalence and high mortality, stroke has brought a heavy burden to families and society in China. In 2009, the Ministry of Health of China launched the China national stroke screening and intervention program, which screens stroke and its risk factors and conducts high-risk population interventions for people aged above 40 years old all over China. In this program, stroke risk factors include hypertension, diabetes, dyslipidemia, smoking, lack of exercise, apparently overweight and family history of stroke. People with more than two risk factors or history of stroke or transient ischemic attack (TIA) are considered as high-risk. However, it is impossible for this criterion to classify stroke risk levels for people with unknown values in fields of risk factors. The missing of stroke risk levels results in reduced efficiency of stroke interventions and inaccuracies in statistical results at the national level. In this paper, we use 2017 national stroke screening data to develop stroke risk classification models based on machine learning algorithms to improve the classification efficiency. Method Firstly, we construct training set and test sets and process the imbalance training set based on oversampling and undersampling method. Then, we develop logistic regression model, Naïve Bayesian model, Bayesian network model, decision tree model, neural network model, random forest model, bagged decision tree model, voting model and boosting model with decision trees to classify stroke risk levels. Result The recall of the boosting model with decision trees is the highest (99.94%), and the precision of the model based on the random forest is highest (97.33%). Using the random forest model (recall: 98.44%), the recall will be increased by about 2.8% compared with the method currently used, and several thousands more people with high risk of stroke can be identified each year. Conclusion Models developed in this paper can improve the current screening method in the way that it can avoid the impact of unknown values, and avoid unnecessary rescreening and intervention expenditures. The national stroke screening program can choose classification models according to the practice need.

Abstract Background Sympathetic overactivation and inflammation are two major mediators to post-myocardial ischemia-reperfusion (I/R)-induced ventricular arrhythmia (VA). The vicious cycle between microglia and sympathetic activation plays an important role in sympathetic hyperactivity related to cardiovascular diseases. Recently, studies have shown that microglial activation might be attenuated by light-emitting diode (LED) therapy. Therefore, we hypothesized that LED therapy might protect against myocardial I/R-induced VAs by attenuating microglial and sympathetic activation. Methods Thirty-six male anesthetized rats were randomized into four groups: control group (n = 6), LED group (n = 6), I/R group (n = 12), and LED+I/R group (n = 12). I/R was generated by left anterior descending artery occlusion for 30 min followed by 3 h reperfusion. ECG and left stellate ganglion (LSG) neural activity were recorded continuously. After 3 h reperfusion, a programmed stimulation protocol was conducted to test the inducibility of VA. Furthermore, we extracted the brain tissue to examine the microglial activation, and the peri-ischemic myocardium to examine the expression of NGF and inflammatory cytokines (IL-1β, IL-18, IL-6, and TNF-α). Results As compared to the I/R group, LED illumination significantly inhibited the LSG neural activity (P

Abstract Excessive organic acids in grape juice will not only result in poor taste but will also cause turbidity and sedimentation. Tartaric acid exerts the most significant acidity among all organic acids in grape juice. In this study, we used tartaric acid as the main target and anion‐exchange resin to remove tartaric acid from concentrated grape juice. Factors influencing the removal process were optimized by liquid chromatography with ultraviolet detection and statistical analysis for optimal deacidification of concentrated grape juice. Use of the anion‐exchange resin 335 treat the concentrated grape juice at a ratio of 1:6 (2:11.98) at 15.57°C for 4.35 hr. The tartaric acid removal rate reached 69.01%; the anion‐exchange resin 335 demonstrated the best removal effect.

Abstract Background In recent years, the increasing incidence and prevalence of stroke has brought a heavy economic burden on families and society in China. The Ministry of Health of the Peoples’ Republic of China initiated the national stroke screening and intervention program in 2011 for stroke prevention and control. In the screening, only those who have been classified to “potential high-risk” group in preliminary screening need further examination and physician confirmation to determine the risk level of stroke in rescreening. However, at the beginning of the program, the “potential high-risk” classification method in the preliminary screening are determined by experts based on their experience. The primary aim of this study is to study the causality of stroke and risk factors in middle-aged population using the cohort data, and to explore whether the stroke screening and intervention program should include more precise “potential high-risk” evaluation criteria for this age group in preliminary screening. Method We use the cohort data of screening between 2013 and 2017 in this study. After data cleaning, the cohort consists of 48,007 people aged from 40 to 59 who are free of stroke at baseline. We use Bayesian networks to develop models. Result The results show that the stroke incidence in middle-aged population with certain two risk factors is higher than some of that with three factors, which is in keeping with our previous study results. We can take the ratio of the stroke incidence with combinations of risk factors and incidence without any of the risk factors as a variable threshold. By adjusting the threshold, we can get precise stroke preliminary screening criteria to achieve a balance between economy and efficiency. Conclusion We find that the criteria used in preliminary screening are not reasonable enough. There is a need for national stroke screening and intervention program to further include some more important risk factors or combinations of two risk factors as classification criteria in the preliminary screening. The results of the study can directly guide stroke screening program in China to make the screening more accurate and efficient.

Because of the significant environmental pollution produced by human activities, there is an ongoing need to develop transportable, simple, and reliable techniques for determining trace contaminants on the spot. This work reported a colorimetric detection method for aqueous Cr(VI) sensing by maleic acid-functionalized gold nanoparticles with high sensitivity and selectivity. The wine-red color of the probe solution can change to gray even in the presence of 1.0 µg L−1 of aqueous Cr(VI). Moreover, with the assistance of a smartphone installed with a commercially available color scan application software, its concentration of could be readily quantified on the spot without the help of UV-Vis spectrometer. The detection limit could reach as low as 0.1 µg L−1 with linear range from 0.2 to 2.0 µg L−1. Most importantly, the coefficient variation of the proposed smartphone-based method was equivalent to that of colorimetry, demonstrating the high accuracy of the proposed method for accurate detection of Cr(VI) in resource-constrained countries. Conclusively, with the help of the smartphone, this nanomaterials-based probe demonstrated the potential in the field of environment monitoring for on-site quantitative detection of any pollutants in resource-constrained countries.

Recently, biosensing based on weak coupling in plasmon-emitter hybrid nanostructures exhibits the merits of simplicity and high sensitivity, and attracts increasing attention as an emerging nano-sensor. In this study, we propose an innovative plasmon-regulated fluorescence resonance energy transfer (plasmon-regulated FRET) sensing strategy based on a plasmon-emitter hybrid nanostructure of gold nanorod-quantum dots (Au NR-QDs) by partially modifying QDs onto the surfaces of Au NRs. The Au NR-QDs showed good sensitivity and reversibility against refractive index change. We successfully employed the Au NR-QDs to fabricate nano-sensors for detecting a cancer biomarker of alpha fetoprotein with a limit of detection of 0.30 ng/mL, which displays that the sensitivity of the Au NR-QDs nano-sensor was effectively improved compared with the Au NRs based plasmonic sensing. Additionally, to demonstrate the universality of the plasmon-regulated FRET sensing strategy, another plasmon-emitter hybrid nano-sensor of Au nano-prism-quantum dots (Au NP-QDs) were constructed and applied for detecting a myocardial infarction biomarker of cardiac troponin I. It was first reported that the change of absorption spectra of plasmonic structure in a plasmon-emitter hybrid nanostructure was employed for analytes detection. The plasmon-regulated FRET sensing strategy described herein has potential utility to develop general sensing platforms for chemical and biological analysis.

Saliva contains important personal physiological information that is related to some diseases, and it is a valuable source of biochemical information that can be collected rapidly, frequently, and without stress. In this article, we reported a new and simple localized surface plasmon resonance (LSPR) substrate composed of polyaniline (PANI)-gold hybrid nanostructures as an optical sensor for monitoring the pH of saliva samples. The overall appearance and topography of the substrates, the composition, and the wettability of the LSPR surfaces were characterized by optical and scanning electron microscope (SEM) images, infrared spectra, and contact angles measurement, respectively. The PANI-gold hybrid substrate readily responded to the pH. The response time was very short, which was 3.5 s when the pH switched from 2 to 7, and 4.5 s from 7 to 2. The changes of visible-near-infrared (NIR) spectra of this sensor upon varying pH in solution showed that—for the absorption at given wavelengths of 665 nm and 785 nm—the sensitivities were 0.0299 a.u./pH (a.u. = arbitrary unit) with a linear range of pH = 5–8 and 0.0234 a.u./pH with linear range of pH = 2–8, respectively. By using this new sensor, the pH of a real saliva sample was monitored and was consistent with the parallel measurements with a standard laboratory method. The results suggest that this novel LSPR sensor shows great potential in the field of mobile healthcare and home medical devices, and could also be modified by different sensitive materials to detect various molecules or ions in the future.

Abstract Background Extensive local invasion of glioblastoma (GBM) cells within the central nervous system (CNS) is one factor that severely limits current treatments. The aim of this study was to uncover genes involved in the invasion process, which could also serve as therapeutic targets. For the isolation of invasive GBM cells from non-invasive cells, we used a three-dimensional organotypic co-culture system where glioma stem cell (GSC) spheres were confronted with brain organoids (BOs). Using ultra-low input RNA sequencing (ui-RNA Seq), an invasive gene signature was obtained that was exploited in a therapeutic context. Methods GFP-labeled tumor cells were sorted from invasive and non-invasive regions within co-cultures. Ui-RNA sequencing analysis was performed to find a gene cluster up-regulated in the invasive compartment. This gene cluster was further analyzed using the Connectivity MAP (CMap) database. This led to the identification of SKF83566, an antagonist of the D1 dopamine receptor (DRD1), as a candidate therapeutic molecule. Knockdown and overexpression experiments were performed to find molecular pathways responsible for the therapeutic effects of SKF83566. Finally, the effects of SKF83566 were validated in orthotopic xenograft models in vivo. Results Ui-RNA seq analysis of three GSC cell models (P3, BG5 and BG7) yielded a set of 27 differentially expressed genes between invasive and non-invasive cells. Using CMap analysis, SKF83566 was identified as a selective inhibitor targeting both DRD1 and DRD5. In vitro studies demonstrated that SKF83566 inhibited tumor cell proliferation, GSC sphere formation, and invasion. RNA sequencing analysis of SKF83566-treated P3, BG5, BG7, and control cell populations yielded a total of 32 differentially expressed genes, that were predicted to be regulated by c-Myc. Of these, the UHRF1 gene emerged as the most downregulated gene following treatment, and ChIP experiments revealed that c-Myc binds to its promoter region. Finally, SKF83566, or stable DRD1 knockdown, inhibited the growth of orthotopic GSC (BG5) derived xenografts in nude mice. Conclusions DRD1 contributes to GBM invasion and progression by regulating c-Myc entry into the nucleus that affects the transcription of the UHRF1 gene. SKF83566 inhibits the transmembrane protein DRD1, and as such represents a candidate small therapeutic molecule for GBMs.

Abstract Background Valtrate, a natural compound isolated from the root of Valeriana, exhibits antitumor activity in many cancers through different mechanisms. However, its efficacy for the treatment of glioblastoma (GBM), a tumor type with a poor prognosis, has not yet been rigorously investigated. Methods GBM cell lines were treated with valtrate and CCK-8, colony formation and EdU assays, flow cytometry, and transwell, 3D tumor spheroid invasion and GBM-brain organoid co-culture invasion assays were performed to assess properties of proliferation, viability, apoptosis and invasion/migration. RNA sequencing analysis on valtrate-treated cells was performed to identify putative target genes underlying the antitumor activity of the drug in GBM cells. Western blot analysis, immunofluorescence and immunohistochemistry were performed to evaluate protein levels in valtrate-treated cell lines and in samples obtained from orthotopic xenografts. A specific activator of extracellular signal-regulated kinase (ERK) was used to identify the pathways mediating the effect. Results Valtrate significantly inhibited the proliferation of GBM cells in vitro by inducing mitochondrial apoptosis and suppressed invasion and migration of GBM cells by inhibiting levels of proteins associated with epithelial mesenchymal transition (EMT). RNA sequencing analysis of valtrate-treated GBM cells revealed platelet-derived growth factor receptor A (PDGFRA) as a potential target downregulated by the drug. Analysis of PDGFRA protein and downstream mediators demonstrated that valtrate inhibited PDGFRA/MEK/ERK signaling. Finally, treatment of tumor-bearing nude mice with valtrate led to decreased tumor volume (fivefold difference at day 28) and enhanced survival (day 27 vs day 36, control vs valtrate-treated) relative to controls. Conclusions Taken together, our study demonstrated that the natural product valtrate elicits antitumor activity in GBM cells through targeting PDGFRA and thus provides a candidate therapeutic compound for the treatment of GBM.

IntroductionSafranal is an active component of the traditional Tibetan medicine (TTM) saffron, which has potential anticancer activity.Methods and resultsHere, we studied the therapeutic effect and mechanism of safranal on GBM. CCK-8, GBM-brain organoid coculture experiments and 3D tumour spheroid invasion assays showed that safranal inhibited GBM cell proliferation and invasion in vitro. Network pharmacology, RNA-seq, molecular docking analysis, western blotting, apoptosis, and cell cycle assays predicted and verified that safranal could promote GBM cell apoptosis and G2/M phase arrest and inhibit the PI3K/AKT/mTOR axis. In vivo experiments showed that safranal could inhibit GBM cell growth alone and in combination with TMZ.ConclusionThis study revealed that safranal inhibits GBM cell growth in vivo and in vitro, promotes GBM cell apoptosis and G2/M phase arrest, inhibits the PI3K/AKT/mTOR axis and cooperate with TMZ.

Abstract Background The tripartite motif (TRIM) family of proteins plays a key role in the developmental growth and therapeutic resistance of many tumors. However, the regulatory mechanisms and biological functions of TRIM proteins in human glioblastoma (GBM) are not yet fully understood. In this study, we focused on TRIM56, which emerged as the most differentially expressed TRIM family member with increased expression in GBM. Methods Western blot, real-time quantitative PCR (qRT-PCR), immunofluorescence (IF) and immunohistochemistry (IHC) were used to study the expression levels of TRIM56 and cIAP1 in GBM cell lines. Co-immunoprecipitation (co-IP) was used to explore the specific binding between target proteins and TRIM56. A xenograft animal model was used to verify the tumor promoting effect of TRIM56 on glioma in vivo. Results We observed elevated expression of TRIM56 in malignant gliomas and revealed that TRIM56 promoted glioma progression in vitro and in a GBM xenograft model in nude mice. Analysis of the Human Ubiquitin Array and co-IPs showed that cIAP1 is a protein downstream of TRIM56. TRIM56 deubiquitinated cIAP1, mainly through the zinc finger domain (amino acids 21–205) of TRIM56, thereby reducing the degradation of cIAP1 and thus increasing its expression. TRIM56 also showed prognostic significance in overall survival of glioma patients. Conclusions TRIM56-regulated post-translational modifications may contribute to glioma development through stabilization of cIAP1. Furthermore, TRIM56 may serve as a novel prognostic indicator and therapeutic molecular target for GBM.

Abstract Background Existing evidence has shown that negative parenting style elevates the risk of school bullying victimization in children and adolescents. Resilience may play as a mediating factor in this association. However, this hypothesis has not been investigated. Methods In this cross-sectional study, a total of 4582 Chinese children and adolescents had been surveyed by self-administered questionnaire. The Chinese version of Egna Minnen av. Barndoms Uppfostra (s-EMBU-C), the Olweus Bully/Victim Questionnaire (OBVQ) and the Resilience Scale for Chinese Adolescents (RSCA) were used to collect relevant information. Univariate and multiple logistic regression models were used to estimate the crude and adjusted associations between parenting style, resilience, and bullying victimization. Path analysis was used to estimate the mediation via resilience in the association between parenting style and bullying victimization. Results After adjustment for possible covariates, the results of multivariate binary logistic regression model suggested that among all dimensions of parenting style, mother’s and father’s rejection were significantly associated with school bullying victimization. Path analysis revealed a statistically significant mediation of resilience in the association between parental rejection and bullying victimization, and among the five dimensions of resilience, emotion regulation, family support and interpersonal assistance accounted for the highest proportions of mediation. Conclusions For children and adolescents who suffered from parental rejection, building up resilience, especially those measures aiming at improving emotion regulation ability and consolidating family and peer support, might be effective in reducing risk of school bullying victimization.

Abstract Background Childhood maltreatment (CM) has been associated with suicidal ideation (SI) in children and adolescents, yet the mediating role of mindfulness in this association remains unclear. This study aims to test the mediation of mindfulness in CM-SI association among a large sample of Chinese children and adolescents. Methods A population-based cross-sectional study of 3455 children and adolescents aged 10–17 years from southwest China Yunnan province was conducted. Information from the participants was collected by using a comprehensive self-administered questionnaire. The Chinese version of the Childhood Trauma Questionnaire (CTQ), Five Facet Mindfulness Questionnaire (FFMQ), and the Beck Scale for Suicidal Ideation (BSSI) were used to measure CM, mindfulness and SI. Univariate and multivariate binary logistic regression models were used to estimate the crude and adjusted associations between CM, mindfulness and SI (one-week, one-year, lifetime). Pathway analysis was subsequently performed to test the mediation of mindfulness in CM-SI association. Results The findings showed that mindfulness, CM and SI were significantly correlated with each other (p

Abstract Background School bullying victimization is associated with increased risk of anxiety in children and adolescents. However, little is known about the role of resilience in this association. The purpose of this study was to investigate the possible mediation by resilience in this association in a large group of Chinese children and adolescents. Methods A population-based cross-sectional study adopting two-stage simple random cluster sampling was implemented in Yunnan province, southwestern China. A comprehensive questionnaire was used to collect information from the participants. Among all the participants, 4624 were included in the final analysis. Descriptive statistics were used to present general characteristics of the study participants. Univariate and multivariate logistic regression models were adopted to estimate crude and adjusted associations among bullying victimization, anxiety, and resilience. A path model was used to analyze the hypothesized mediation by resilience in the association between bullying victimization and anxiety. Results Analytical results of multivariate logistic regression models suggested that bullying victimization was significantly associated with anxiety in Chinese children and adolescents; compared with individuals who had not been bullied, victims of bullying were more likely to experience anxiety symptoms, with an adjusted odds ratio (OR) of 3.02 (95% CI 2.46–3.71). Path analysis revealed a prominent mediating effect of resilience in the association between bullying victimization and anxiety, accounting for 31.89% of the total association. Further analysis indicated that, among the five dimensions of resilience, emotional regulation, interpersonal assistance, and family support were significant mediators, accounting for 30.34%, 10.79%, and 8.35% of the total association. Conclusions Our major findings highlighted the promising role of resilience-based intervention measures in reducing the risk of anxiety associated with school bullying victimization in Chinese children and adolescents.

Abstract Background SMC5/6 complex plays a vital role in maintaining genome stability, yet the relationship with human diseases has not been described. Methods SMC5 variation was identified through whole‐exome sequencing (WES) and verified by Sanger sequencing. Immunoprecipitation, cytogenetic analysis, fluorescence activated cell sorting (FACS) and electron microscopy were used to elucidate the cellular consequences of patient's cells. smc5 knockout (KO) zebrafish and Smc5K371del knock‐in mouse models were generated by CRISPR‐Cas9. RNA‐seq, quantitative real‐time PCR (qPCR), western blot, microquantitative computed tomography (microCT) and histology were used to explore phenotypic characteristics and potential mechanisms of the animal models. The effects of Smc5 knockdown on mitotic clonal expansion (MCE) during adipogenesis were investigated through Oil Red O staining, proliferation and apoptosis assays in vitro. Results We identified a homozygous in‐frame deletion of Arg372 in SMC5, one of the core subunits of the SMC5/6 complex, from an adult patient with microcephalic primordial dwarfism, chromosomal instability and insulin resistance. SMC5 mutation disrupted its interaction with its interacting protein NSMCE2, leading to defects in DNA repair and chromosomal instability in patient fibroblasts. Smc5 KO zebrafish showed microcephaly, short length and disturbed glucose metabolism. Smc5 depletion triggers a p53‐related apoptosis, as concomitant deletion of the p53 rescued growth defects phenotype in zebrafish. An smc5K371del knock‐in mouse model exhibited high mortality, severe growth restriction and fat loss. In 3T3‐L1 cells, the knockdown of smc5 results in impaired MCE, a crucial step in adipogenesis. This finding implies that defective cell survival and differentiation is an important mechanism linking growth disorders and metabolic homeostasis imbalance.

With the characteristics of high incidence, high prevalence and high mortality, stroke has a serious impact on residents' health and imposes a heavy ecomomic burden on China. In order to simulate the economic burden of stroke in the next 20 years, we construct a simulation platform for Chinese stroke economic burden based on the national stroke screening data. We use the Leslie model for population prediction and the equilibrium model to simulate the stroke economic burden in the platform. The platform constructed in this study can dynamically simulate the stroke economic burden during 2020-2040 by computing the incidence, prevelance and mortality rates from the national stroke screening data or as customized by the user. Based on this platform, we can further develop a warning mechanism at the national level, and provide a guide for the planning and allocation of national health resources. [ABSTRACT FROM AUTHOR]

Float glass installed with frame supports is broadly exploited in building construction. In a fire environment, the breakage of float glass significantly influences the dynamic development of the fire within the building space. The thermal rupture behavior of the frame-supported float glass subjected to thermal loading is carefully examined using a self-built experimental system. The designed system is aimed at capturing crucial behavioral parameters. The experimental study reveals that the main reason for the breakage of the frame-supported float glass is the temperature difference on the glass surface, with a critical temperature difference of approximately 65 °C. The crack starts at the edge of the glass surface where the temperature difference is maximum and then rapidly expands. By intersecting the cracks, a crack island is configured, which is not dislodged under the stress of the supporting frame and the surrounding glass. A thermomechanical and micro-geometric model of the frame-supported float glass is developed based on the PFC2D program to show further the micro-crack expansion pattern of the frame-supported float glass under thermal loading. This scrutiny provides theoretical guidance for installing and using frame-supported float glass in construction projects and identifying fire evidence.

BackgroundStudies indicated that bullying victimization (BV) is an important risk factor for self-harm in children and adolescents. However, it is unclear whether perceived social support significantly mediates this association. This study aimed to examine the association between BV and self-harm, with a particular focus on the mediating role of perceived social support.MethodsA population-based cross-sectional study of 4,627 Chinese students aged from 10 to 17 years was conducted in southwestern China Yunnan province. A two-stage simple random cluster sampling method was used to choose study subjects. The adjusted associations between school BV, perceived social support, and self-harm were examined by using the multivariate logistic regression models. The mediation of perceived social support in the association between BV and self-harm was evaluated by using a path model.ResultsAfter controlling potential covariates, BV was associated with a prevalence of increased self-harm, with an adjusted odds ratio of 1.90 (95% CI: 1.57, 2.32). Among all sources of perceived social support, only parental support played a prominent mediating role in the association between BV and self-harm, accounting for 20.73% of the explained variance. The mediation of parental support was comparable between boys and girls. As for different types of bullying victimization, path analyses indicated that only the association between physical victimization and self-harm was significantly mediated by parental support.ConclusionOur study results highlighted the promising interventional benefit of parental support in BV-associated self-harm risk for children and adolescents. For victims of bullying, especially physical bullying, promoting parental support might be effective in reducing self-harm risk. Longitudinal studies are warranted to further corroborate these findings.

Liver cancer is a major public health challenge. Few published studies reported temporal trend and geographical distribution of liver cancer mortality in China, especially in less developed southwest regions with higher liver cancer incidence. In the current study, we obtained liver cancer mortality data from population-based death surveillance system in Yunnan province in 2015–2019. The mortality of liver cancer was analyzed by using the joinpoint regression model. The space distribution of liver cancer mortality in 129 counties and districts in Yunnan province was illustrated by using the ArcGIS software. Moran's I method was used to estimate the global and local spatial autocorrelation of liver cancer mortality. Analytical results revealed that from 2015 to 2019, the average mortality rate of liver cancer in Yunnan province was 12.96/100,000, with an average annual growth rate of 6.26% (p < 0.05). Higher liver cancer mortality was found in rural areas and in males. Moreover, people aged 45–50 years experienced a steep increase in liver cancer mortality rate. High-high cluster was mainly consisted of areas with higher hepatitis virus infection rate or severe intravenous drug use problem. Our study results suggest a heavy burden of liver cancer in southwest China Yunnan province. Comprehensive intervention measures need to be developed and implemented.

BackgroundPublished studies in comparing pre and post the COVID-19 pandemic depression and anxiety levels among children and adolescents yielded incongruent results. Therefore, there is a necessity to perform a timely meta-analysis to synthesize existing evidence.MethodsA total of 10 digital databases (PubMed, Web of Science, PsycINFO, the Cochrane Library, Embase, Scopus, ScienceDirect, CNKI, WanFang, CQVIP) were fully searched for eligible studies published before November 6, 2021. Based on quality assessment results, relevant data were extracted for eligible studies of higher quality. We combined standardized mean difference (SMD) or prevalence ratio (RR) for anxiety and depression pre and post the COVID-19 pandemic by using random-effects models. Sensitivity analysis was further performed to evaluate heterogeneity of included studies.Results14,508 articles were preliminarily identified, and after stepwise screening process, 8 articles were included eventually. The results showed that the SMD for post COVID-19 anxiety score measured by GAD-7 was 0.12 (95% CI: 0.08, 0.17), an significant increase compared with pre COVID-19 period; the SMDs and 95% CIs for post COVID-18 depression scores measured by PHQ-9, PHQ-8, and MFQ were 0.17 (95% CI: 0.10, 0.24), 0.23 (95% CI: 0.08, 0.38), and 0.11 (95% CI: 0.06, 0.17), respectively, also significantly increased compared with pre COVID-19 period. The RR for depression was 2.54 (95% CI: 2.48, 2.60) in post COVID-19 period when compared with pre-pandemic.ConclusionsChildren and adolescents reported deteriorated anxiety and depression levels after the COVID-19 pandemic. More attention should be paid to this vulnerable group. Effective, expedient, and practical intervention measures which are compatible with COVID-19 prevention and control policies should be developed and implemented to maintain mental health wellbeing of the youths.

A positive connection has been established between personality traits and suicidal ideation (SI). However, the possible mediation of resilience within this association has never been thoroughly discussed. In this study, we aimed to investigate this topic by using population-based cross-sectional survey data of 4,489 Chinese children and adolescents. A self-administered questionnaire was used to collect information from the participants. Univariate and multivariate logistic regression models were adopted to measure the crude and adjusted associations between personality traits, SI, and resilience. Path analysis was performed to evaluate the mediation of resilience in the association between personality traits and SI. For 4,489 study subjects, the mean age was 13.4 years, ethnic minorities accounted for 71.8%, and over a half (54.6%) were middle school students. The reported prevalence rates for 1-week, 1-year, and lifetime SI were 27.6% (95% CI: 24.9%, 30.0%), 35.5% (95% CI: 30.8%, 41.0%), and 56.7% (95% CI: 52.3%, 61.0%), respectively. Girls reported a significantly higher prevalence of SI than boys. Path analysis results revealed a prominent mediation of resilience; moreover, for different dimensions of personality traits, the proportion of mediation by resilience varied. Our major findings suggest that resilience-based intervention measures could be considered in preventing personality traits related to suicidal risk among youngsters. For children and adolescents, the measuring of personality dimensions may also be helpful in targeting key subpopulations of intervention priority.

Resibufogenin (RB) is a major active ingredient in the traditional Chinese medicine Chansu and has garnered considerable attention for its efficacy in the treatment of cancer. However, the anticancer effects and underlying mechanisms of RB on glioblastoma (GBM) remain unknown. Here, we found that RB induced G2/M phase arrest and inhibited invasion in a primary GBM cell line, P3#GBM, and two GBM cell lines, U251 and A172. Subsequently, we demonstrated that RB-induced G2/M phase arrest occurred through downregulation of CDC25C and upregulation of p21, which was caused by activation of the MAPK/ERK pathway, and that RB inhibited GBM invasion by elevating intercellular Ca2+ to suppress the Src/FAK/Paxillin focal adhesion pathway. Intriguingly, we confirmed that upon RB binding to ATP1A1, Na+-K+-ATPase was activated as a receptor and then triggered the intracellular MAPK/ERK pathway and Ca2+-mediated Src/FAK/Paxillin focal adhesion pathway, which led to G2/M phase arrest and inhibited the invasion of GBM cells. Taken together, our findings reveal the antitumor mechanism of RB by targeting the ATP1A1 signaling cascade and two key signaling pathways and highlight the potential of RB as a new class of promising anticancer agents.

Introduction: In atherosclerotic lesions, extensive inflammation of the vessel wall contributes to plaque instability. Long noncoding RNAs (lncRNAs) play important roles in diverse biological processes in atherosclerosis. Objectives: Here, we aim to identify the functional role and regulatory mechanisms of lncRNA hypoxia-inducible factor 1 alpha-antisense RNA 2 (HIF1A-AS2) in atherosclerotic inflammation. Methods: An atherosclerotic mouse model was induced in ApoE-/- mice by high fat diet (HFD). Endothelial cells (ECs), human aortic smooth muscle cells (SMCs) or human coronary artery endothelial cells (HCAECs) were exposed to ox-LDL to develop the in vitro model. The effects of lncRNA HIF1A-AS2 on inflammation were evaluated by determining levels of inflammatory factors tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) and levels of adhesion molecules vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), and macrophage cationic peptide 1 (MCP-1). Results: It was established that lncRNA HIF1A-AS2 and ATF2 were highly expressed in atherosclerotic ApoE-/- mice. Downregulating lncRNA HIF1A-AS2 in ox-LDL-exposed ECs, SMCs and HCAECs inhibited inflammation by reducing levels of pro-inflammatory factors and adhesion molecules. LncRNA HIF1A-AS2 bound to the transcription factor USF1 to elevate ATF2 expression. USF1 overexpression counteracted the suppressive effect of lncRNA HIF1A-AS2 silencing on ox-LDL-induced inflammation. Knockdown of lncRNA HIF1A-AS2 or ATF2 could also attenuate inflammation in atherosclerotic mice. Collectively, the present study demonstrates that downregulation of lncRNA HIF1A-AS2 represses the binding of USF1 to the ATF2 promoter region and then inhibits ATF2 expression, thereby suppressing atherosclerotic inflammation. Conclusion: This study suggests lncRNA HIF1A-AS2 as an promising therapeutic target for atherosclerosis.

BackgroundAndrogen insensitivity syndrome (AIS) is a rare X-linked genetic disease and one of the causes of 46,XY disorder of sexual development. The unstraightforward diagnosis of AIS and the gender assignment dilemma still make a plague for this disorder due to the overlapping clinical phenotypes.MethodsPeripheral blood mononuclear cells (PBMCs) of partial AIS (PAIS) patients and healthy controls were separated, and RNA-seq was performed to investigate transcriptome variance. Then, tissue-specific gene expression, functional enrichment, and protein–protein interaction (PPI) network analyses were performed; and the key modules were identified. Finally, the RNA expression of differentially expressed genes (DEGs) of interest was validated by quantitative real-time PCR (qRT-PCR).ResultsIn our dataset, a total of 725 DEGs were captured, with functionally enriched reproduction and immune-related pathways and Gene Ontology (GO) functions. The most highly specific systems centered on hematologic/immune and reproductive/endocrine systems. We finally filtered out CCR1, PPBP, PF4, CLU, KMT2D, GP6, and SPARC by the key gene clusters of the PPI network and manual screening of tissue-specific gene expression. These genes provide novel insight into the pathogenesis of AIS in the immune system or metabolism and bring forward possible molecular markers for clinical screening. The qRT-PCR results showed a consistent trend in the expression levels of related genes between PAIS patients and healthy controls.ConclusionThe present study sheds light on the molecular mechanisms underlying the pathogenesis and progression of AIS, providing potential targets for diagnosis and future investigation.

A mesh flexible spoke non-pneumatic tire is designed to avoid tire burst and other hidden dangers in the traditional pneumatic tires, and improve driving safety. The purpose of this study is to explore the fatigue performance and fatigue life prediction method of the non-pneumatic tire and analyze the influence of structural parameters on the fatigue life of non-pneumatic tire. Based on the crack propagation method of energy release rate by J-integral, the fatigue life of the meshed flexible spoke non-pneumatic tire is predicted. Using numerical simulation method, the influence of key structural parameters, such as the curvature, unit angle and thickness of the lateral spoke and the tread thickness, on tire fatigue life is studied. The results show that the fatigue life prediction method proposed can be used to predict the fatigue life of flexible spoke non-pneumatic tire, and the fatigue life of non-pneumatic tire with flexible spoke can be improved by selecting appropriate structural parameters, which could provide some reference for the structural optimization design of the fatigue performance of the non-pneumatic tire.

Gloiopeltis furcata (Postels et Ruprecht) J. Agardh is a commercial red alga with high value in nutraceuticals and pharmaceuticals. To enrich information on its life history, the early developmental process of G. furcata from northern China was investigated using free-hand section and microexamination methods. Early life stage development includes the formation of carpogonial branch, spermatangia, cystocarp tetrasporangia, and spores germination. Results showed that one auxiliary cell and one adjacent supporting cell constituted an ampulla. Auxiliary cell was usually near the basal part of the ampulla and generated several two to three celled carpogonial branches. One spermatangial mother cell originated in the superficial cortical cell and produced single spermatangia. After fertilization, carpogonium formed a connecting filament which fused with the auxiliary cell ultimately. Many branched gonimoblast filaments were produced from auxiliary cell and generated into carpospores. Mature cystocarps protruded on the thalli surface showing some subspherical-shaped structures. Tetrasporangium developed from the inner cortical cell generated four tetrasporangia by cruciform division. Mature tetraspores and carpospores were released, attached to the bottom of Petri dishes through the stickum within 12 h, and then divided through regular binary fission. Undergoing a month of cultivation, the spores grew up to discoid crusts with diameters ranging from 55 to 60 µm. Growth of G. furcata was initiated with the domeshaped apical cell division to form the central axial structure, being the first to confirm the occurrence of apical growth of this species. [ABSTRACT FROM AUTHOR]