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Abstract In a multicenter case–control investigation, we assessed the efficacy of the Electrooculogram Signal Analysis (EOG-SA) method, which integrates attention-related visual evocation, electrooculography, and nonlinear analysis, for distinguishing between intellectual and developmental disabilities (IDD) and typical development (TD) in children. Analyzing 127 participants (63 IDD, 64 TD), we applied nonlinear dynamics for feature extraction. Results indicated EOG-SA’s capability to distinguish IDD, with higher template thresholds and Correlation Dimension values correlating with clinical severity. The template threshold proved a robust indicator, with higher values denoting severe IDD. Discriminative metrics showed areas under the curve of 0.91 (template threshold) and 0.85/0.91 (D2), with sensitivities and specificities of 77.6%/95.9% and 93.5%/71.0%, respectively. EOG-SA emerges as a promising tool, offering interpretable neural biomarkers for early and nuanced diagnosis of IDD.

ABSTRACTCritical-size defects (CSDs) are challenging oral clinical issues that need to be solved. Adipose-derived mesenchymal stem cells (ADSCs) and gene therapy offer a new target to solve these issues. Consequently, ADSCs attract more and more attention because of advantages such as easy obtainability and no ethical concerns. TNF receptor-associated factor 6 (TRAF6) is a significant binding protein both of tumour necrosis factor superfamily and of the toll/interleukin-1 receptor superfamily. Evidence is accumulating that TRAF6 inhibited osteoclast formation and promoted the proliferation of multiple myeloma cell lines and bone resorption. Here, we reported that overexpression of TRAF6 enhanced the proliferation, migration and osteogenesis of ADSCs through Raf-Erk-Merk-Hif1a pathway. Cell sheet of ADSCs combined with TRAF6 accelerated the healing of CSDs. In a word, TRAF6 enhanced osteogenesis, migration and proliferation through Raf-Erk-Merk-Hif1a pathway.

During acute reperfusion, the expression profiles of long noncoding RNAs in adult rats with focal cerebral ischemia undergo broad changes. However, whether long noncoding RNAs are involved in neuroprotective effects following focal ischemic stroke in rats remains unclear. In this study, RNA isolation and library preparation was performed for long noncoding RNA sequencing, followed by determining the coding potential of identified long noncoding RNAs and target gene prediction. Differential expression analysis, long noncoding RNA functional enrichment analysis, and co-expression network analysis were performed comparing ischemic rats with and without ischemic postconditioning rats. Rats were subjected to ischemic postconditioning via the brief and repeated occlusion of the middle cerebral artery or femoral artery. Quantitative real-time reverse transcription-polymerase chain reaction was used to detect the expression levels of differentially expressed long noncoding RNAs after ischemic postconditioning in a rat model of ischemic stroke. The results showed that ischemic postconditioning greatly affected the expression profile of long noncoding RNAs and mRNAs in the brains of rats that underwent ischemic stroke. The predicted target genes of some of the identified long noncoding RNAs (cis targets) were related to the cellular response to ischemia and stress, cytokine signal transduction, inflammation, and apoptosis signal transduction pathways. In addition, 15 significantly differentially expressed long noncoding RNAs were identified in the brains of rats subjected to ischemic postconditioning. Nine candidate long noncoding RNAs that may be related to ischemic postconditioning were identified by a long noncoding RNA expression profile and long noncoding RNA-mRNA co-expression network analysis. Expression levels were verified by quantitative real-time reverse transcription-polymerase chain reaction. These results suggested that the identified long noncoding RNAs may be involved in the neuroprotective effects associated with ischemic postconditioning following ischemic stroke. The experimental animal procedures were approved by the Animal Experiment Ethics Committee of Kunming Medical University (approval No. KMMU2018018) in January 2018.

Abstract Background Intensive evidence has highlighted the effect of aberrant alternative splicing (AS) events on cancer progression when triggered by dysregulation of the SR protein family. Nonetheless, the underlying mechanism in breast cancer (BRCA) remains elusive. Here we sought to explore the molecular function of SRSF1 and identify the key AS events regulated by SRSF1 in BRCA. Methods We conducted a comprehensive analysis of the expression and clinical correlation of SRSF1 in BRCA based on the TCGA dataset, Metabric database and clinical tissue samples. Functional analysis of SRSF1 in BRCA was conducted in vitro and in vivo. SRSF1-mediated AS events and their binding motifs were identified by RNA-seq, RNA immunoprecipitation-PCR (RIP-PCR) and in vivo crosslinking followed by immunoprecipitation (CLIP), which was further validated by the minigene reporter assay. PTPMT1 exon 3 (E3) AS was identified to partially mediate the oncogenic role of SRSF1 by the P-AKT/C-MYC axis. Finally, the expression and clinical significance of these AS events were validated in clinical samples and using the TCGA database. Results SRSF1 expression was consistently upregulated in BRCA samples, positively associated with tumor grade and the Ki-67 index, and correlated with poor prognosis in a hormone receptor-positive (HR+) cohort, which facilitated proliferation, cell migration and inhibited apoptosis in vitro and in vivo. We identified SRSF1-mediated AS events and discovered the SRSF1 binding motif in the regulation of splice switching of PTPMT1. Furthermore, PTPMT1 splice switching was regulated by SRSF1 by binding directly to its motif in E3 which partially mediated the oncogenic role of SRSF1 by the AKT/C-MYC axis. Additionally, PTPMT1 splice switching was validated in tissue samples of BRCA patients and using the TCGA database. The high-risk group, identified by AS of PTPMT1 and expression of SRSF1, possessed poorer prognosis in the stage I/II TCGA BRCA cohort. Conclusions SRSF1 exerts oncogenic roles in BRCA partially by regulating the AS of PTPMT1, which could be a therapeutic target candidate in BRCA and a prognostic factor in HR+ BRCA patient.

Erythropoietin has been researched for its neuroprotective effects in ischemic stroke for over 30 years. Although erythropoietin can cause side effects that need to be controlled, it has been suggested to be effective in enhancing the prognosis of patients who are out of the therapeutic time window and have not received recombinant tissue plasminogen activator therapy. Studies on the mechanism of the function of erythropoietin have shown that it has various protective effects in ischemic brain injury after stroke, including promoting neurogenesis. In this review, we discuss the effects of erythropoietin on neurogenesis after ischemic brain injury and provide references for effective treatments for ischemic stroke, which is one of the leading causes of death worldwide.

Background: Four single nucleotide polymorphisms (SNPs) in the modulator recognition factor 2/AT-rich interaction domain 5B (MRF2/ARID5B) gene located at chromosome 10q21.2 have been shown to be associated with both type 2 diabetes mellitus (T2DM) and coronary artery disease in a Japanese cohort. This study aimed to investigate the relationship between these SNPs (rs2893880, rs10740055, rs7087507, rs10761600) and new-onset T2DM and lipid metabolism in a Northern Chinese population. Methods: This was a case-control study. The rs2893880, rs10740055, rs7087507, and rs10761600 genetic variants were genotyped by SNPscan and analyzed in relation to T2DM susceptibility in 2000 individuals (999 with newly diagnosed T2DM and 1001 controls without diabetes mellitus). Associations between the MRF2/ARID5B genetic models and T2DM were determined by multivariate logistic regression. Results: Regarding the rs10740055 SNP, AA was associated with a higher risk of T2DM compared with codominant-type CC (adjusted by sex, age, and body mass index [BMI], P= 0.041, odds ratio [OR] = 1.421, 95% confidence interval [CI] 1.014–1.991). Meanwhile, AA individuals were at increased risk of presenting with T2DM compared with individuals with CC or a single C (adjusted by sex, age, and BMI, P= 0.034, OR = 1.366, 95% CI 1.023–1.824). With respect to rs10761600, AT contributed to a higher risk of T2DM compared with AA (adjusted by sex, age, and BMI, P= 0.013, OR = 1.585, 95% CI 1.101–2.282), while TT also increased the risk of presenting with T2DM compared with AA or A (adjusted by sex, age, and BMI, P= 0.004, OR = 1.632, 95% CI 1.166–2.284). High-density lipoprotein cholesterol (HDL-C) levels were significantly different among the three genotypes of rs7087507 in the controls (P = 0.048) (GG>GA). Conclusions: The present results identified MRF2/ARID5B as a potential susceptibility gene for new-onset T2DM in a Northern Chinese population, while the rs7087507 SNP was associated with HDL-C levels. Further larger studies are required to validate these findings.

It is of great importance to optimize the schemes of long through-type bus lines to adapt to the urban rail transit network. Focusing on the long through-type bus lines close to metro stations, a bilevel programming model on the adjustment schemes of bus lines is proposed, taking the impacts of urban rail transit network into account. The upper level model aims at adjusting the setting decisions of stop stations and vehicle headways of bus lines to minimize the passenger travel cost and maximize the benefits of bus operators. The lower level model is a passenger flow assignment model based on Logit-SUE considering the crowding perception of passengers in bus vehicles. Moreover, the constraint of average load factor of the bus line sections is considered. Then the genetic algorithm is applied to solve the proposed model, and a numerical example is conducted to verify the effectiveness. Results show that the value of the objective function of the model is improved by 27.2%, in comparison with the original scheme. Even though the average travel cost of passengers increases slightly, the bus line operation cost and the imbalance degree of load factors are reduced by 46.1% and 18.6%, respectively. The sensitivity analyses show that it is better to divide the long through-type bus line into several separate bus lines with independent operation, respectively, under the condition of unbalanced passenger flow distribution. Meanwhile, the multiple bus lines are more adapted to the unbalanced passenger flow distribution when the weight of the benefits of the bus operators in the total objective function is bigger. Besides, the lower time value that the passengers perceive, the more passengers willing to take bus than metro trains. As the increment of the passenger time value, the combination of feeder bus lines and a longer bus line is better for passengers’ trip demand than the long through-type bus line.

Background: Polymorphisms of microRNA (miRNA), as a novel mechanism, are closely associated with disease states by interfering with miRNA function. Direct correlations have been identified between single-nucleotide polymorphisms (SNPs) in miRNA, but the effect on type 2 diabetes mellitus (T2DM) onset among Chinese population remains unclear. Therefore, the aim of this study was to identify correlations between common SNPs in miR-27a, miR-146a, and miR-124a with T2DM among a Chinese population, as well as to explore diabetic pathological mechanisms and the impact of environmental factors. Methods: SNPscan technology was used to genotype 995 patients newly diagnosed with T2DM and 967 controls. Logistic regression analysis was performed to compare mutation frequencies between cases and controls. Results: We found no significant correlations between all genotypes of these miRNAs and T2DM in our research. However, stratification analysis identified a lower risk of T2DM associated with the rs531564GC genotype among younger subjects (age < 45 years) (adjusted P = 0.043; odds ratio [OR] = 0.73; 95% confidence interval [CI] = 0.54-0.99). Furthermore, the rs895819CC genotype in overweight people (24 ≤ body mass index [BMI] < 28) was significantly associated with an increased risk of T2DM (adjusted P = 0.042; OR = 1.73; 95% CI = 1.02-2.94), while the rs2910164 genotype in miR-146a was not significantly correlated with T2DM. The genetic risk score was calculated based on the number of risk alleles of the three SNPs and was found to be correlated to total cholesterol (adjusted P = 0.021). Conclusions: The rs531564GC genotype acted as a protective factor to decrease the risk of T2DM in younger subjects (age < 45 years), while the presence of the rs895819CC genotype increased the risk of illness among overweight subjects (24 ≤ BMI < 28 kg/m 2 ). The presence of SNPs in miRNA might promote disease by affecting miRNA expression and gene function. Thus, miRNA mimics or inhibitors that directly regulate miRNA expression present novel and promising therapeutic targets.