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Using creativity to promote recreational services is crucial. Accordingly, creative linguistic landscapes (CLLs) are being used to improve visitors' experiences in some recreational zones. However, relevant research is still in its early stages. Therefore, this study was conducted. It summarized the leisure function categories and function evaluation indicators of CLLs in recreational zones respectively based on image materials and related online reviews. The leisure function outcomes of all CLL types were ranked using the fuzzy PROMETHEE method; based on this ranking, a CLL configuration optimization mode was suggested. The findings reveal the following. (1) Currently, there are mainly nine leisure function types of CLL in practice, although the type structure is severely imbalanced; there are 12 primary corresponding function evaluation indicators, although each of them draws significantly different attention. (2) There are notable variations among the outcomes of different types of functions of CLL: mood adjustment is the most advantageous function of CLL for leisure services, followed by emotional guidance and cognitive building functions; (3) According to the study findings, in the configuration of CLL, which aims at leisure function optimization, the "function focusing and coordinating mode (the superior functions of CLL are focused on and its various functions are coordinated)" should be adopted. The results provide meaningful lessons for the establishment of rational and effective CLL in recreational zones.

This study aimed at investigating the feasibility of using the spatiotemporal image correlation (STIC) technology for prenatal cardiac screening, finding factors that influence the offline evaluation of reconstructed fetal heart, and establishing an optimal acquisition scheme.The study included 452 gravidae presenting for routine screening at 3 maternity centers at 20-38 gestational weeks. The factors influencing the quality of STIC volume data were evaluated using t test, chi-square test, and logistic regression analysis. The predictive power was evaluated using the receiver operating characteristic (ROC) curve.Among the 452 fetuses enrolled, 353 (78.1%) were identified as successful and 99 (21.9%) as failure of evaluation of the reconstructed fetal heart. The total success rate of qualified STIC images was 78.1%. The display rates of reconstructed cardiac views were 86.5% (four-chamber view), 92.5% (left ventricular outflow tract view), 92.7% (right ventricular outflow tract view), 89.9% (three-vessel trachea view), 63.9% (aortic arch view), 81.4% (ductal arch view), 81% (short-axis view of great vessels), 80.1% (long-cava view), and 86.9% (abdominal view). A logistic regression analysis showed that more than 28 gestational weeks [OR = 0.39 (CI 95% 0.16, 0.19), P = 0.035], frequent fetal movements [OR = 0.37 (CI 95% 0.16, 0.87), P = 0.022], shadowing [OR = 0.36 (CI 95% 0.19, 0.72), P = 0.004], spine location at 10-2 o'clock [OR = 0.08 (CI 95% 0.02, 0.27), P = 0.0], and original cardiac view [OR = 0.51 (0.25, 0.89), P = 0.019] had a significant impact on the quality of STIC. The area under the ROC curve was 0.775.Fetal cardiac-STIC seems a feasible tool for prenatal screening of congenital heart diseases. The influence factors on the quality of STIC images included the intensity of training, gestational age, fetal conditions and parameter settings. The optimal acquisition scheme may improve the application and widespread use of cardiac STIC.

Congenital heart disease (CHD) is the most prevalent type of birth defect in human, with high morbidity in infant. Several genes essential for heart development have been identified. GATA4 is a pivotal transcription factor that can regulate the cardiac development. Many GATA4 mutations have been identified in patients with different types of CHD.In this study, the NKX2-5, HAND1 and GATA4 coding regions were sequenced in a family spanning three generations in which seven patients had CHD. Disease-causing potential variation in this family was evaluated by bioinformatics programs and the transcriptional activity of mutant protein was analyzed by the dual luciferase reporter assay.A novel GATA4 mutation, c.C931T (p.R311W), was identified and co-segregated with the affected patients in this family. The bioinformatics programs predicted this heterozygous mutation to be deleterious and the cross-species alignment of GATA4 sequences showed that the mutation occurred within a highly conserved amino acid. Even though it resided in the nuclear localization signal domain, the mutant protein didn't alter its intracellular distribution. Nevertheless, further luciferase reporter assay demonstrated that the p.R311W mutation reduced the ability of GATA4 to activate its downstream target gene.Our study identified a novel mutation in GATA4 that likely contributed to the CHD in this family. This finding expanded the spectrum of GATA4 mutations and underscored the pathogenic correlation between GATA4 mutations and CHD.

Resting-state functional magnetic resonance imaging (fMRI) has been used to detect the alterations of spontaneous neuronal activity in various neurological and neuropsychiatric diseases, but rarely in hemifacial spasm (HFS), a nervous system disorder. We used resting-state fMRI with regional homogeneity (ReHo) analysis to investigate changes in spontaneous brain activity of patients with HFS and to determine the relationship of these functional changes with clinical features. Thirty patients with HFS and 33 age-, sex-, and education-matched healthy controls were included in this study. Compared with controls, HFS patients had significantly decreased ReHo values in left middle frontal gyrus (MFG), left medial cingulate cortex (MCC), left lingual gyrus, right superior temporal gyrus (STG) and right precuneus; and increased ReHo values in left precentral gyrus, anterior cingulate cortex (ACC), right brainstem, and right cerebellum. Furthermore, the mean ReHo value in brainstem showed a positive correlation with the spasm severity (r = 0.404, p = 0.027), and the mean ReHo value in MFG was inversely related with spasm severity in HFS group (r = -0.398, p = 0.028). This study reveals that HFS is associated with abnormal spontaneous brain activity in brain regions most involved in motor control and blinking movement. The disturbances of spontaneous brain activity reflected by ReHo measurements may provide insights into the neurological pathophysiology of HFS.

Ab initio assembly of transcriptome sequencing data has been widely used to identify large intergenic non-coding RNAs (lincRNAs), a novel class of gene regulators involved in many biological processes. To differentiate real lincRNA transcripts from thousands of assembly artifacts, a series of filtering steps such as filters of transcript length, expression level and coding potential, need to be applied. However, an easy-to-use and publicly available bioinformatics pipeline that integrates these filters is not yet available. Hence, we implemented sebnif, an integrative bioinformatics pipeline to facilitate the discovery of bona fide novel lincRNAs that are suitable for further functional characterization. Specifically, sebnif is the only pipeline that implements an algorithm for identifying high-quality single-exonic lincRNAs that were often omitted in many studies. To demonstrate the usage of sebnif, we applied it on a real biological RNA-seq dataset from Human Skeletal Muscle Cells (HSkMC) and built a novel lincRNA catalog containing 917 highly reliable lincRNAs. Sebnif is available at http://sunlab.lihs.cuhk.edu.hk/sebnif/.

BACKGROUND: Perimembranous ventricular septal defect (PMVSD) is a congenital heart aberration, which is surgically treated by patch or device closure, but also can heal without operation as spontaneous closure (SC). METHODS: We analyzed data from 1873 PMVSD patients admitted to our hospital during September 2001 and December 2009, in order to establish a Cox regression model for PMVSD SC probability prediction (derivative cohort). Initial contact age, ventricular septal defect (VSD) diameter, shunt flow, aneurysmal tissue of the ventricular membranous septum (ATVMS) development, associated complications, and left ventricular end-diastolic dimension (LVDD) were analyzed for correlations with SC. The derived scoring system based on the coefficients of the model was developed and applied to another cohort with 382 PMVSD patients to evaluate the validity for SC probability forecast (validation cohort). RESULTS: Multivariate Cox regression analysis revealed that SC of PMVSD was associated with age at first contact, defect size, diffuse shunt flow, ATVMS formation, associated complication, as well as increased LVDD, which were used to establish a new scoring system. The area under the receiver operating characteristic (ROC) curve of our predictive scaling was 0.831 (95% CI 0.804-0.858, p

Microrefugia at high altitudes or high latitudes are thought to play an important role in the post-glacial colonization of species. However, how populations in such microrefugia have responded to climate changes in alternating cold glacial and warm interglacial stages remain unclear. Here we present evidence to indicate the Rongbuk Valley of the Mt. Qomolangma (Mt. Everest) area, the highest region on earth, had microrefugia for Hippophae tibetana and discuss how this low shrub was adapted to the extreme climate fluctuations of the last 25,000 years by shifts. By integrating geological, glaciological, meteorological, and genetic information, we found that the Rongbuk Valley was not only a glacial microrefugium but also an interglacial microrefugium for H. tibetana: the former was located on the riverbank below 4800 m above sea level (asl) or lower area and the latter at ∼ 5000 m asl. Our results show that after the Last Glacial Maximum (LGM), H. tibetana in the valley has undergone upward and downward migrations around ∼ 5000 m driven by climate fluctuations and the population in the glacial microrefugium has suffered extinction or extreme contraction. Moreover, with the rise of temperature in the last four decades, the upper limit of H. tibetana has shifted at least 30 m upward. Combining population history and recent range shift of this species is important in predicting the fate of this endemic species to future climate changes.

DNA methylation, one of the most important epigenetic modifications, plays a crucial role in various biological processes. The level of DNA methylation can be measured using whole-genome bisulfite sequencing at single base resolution. However, until now, there is a paucity of publicly available software for carrying out integrated methylation data analysis. In this study, we implemented Methy-Pipe, which not only fulfills the core data analysis requirements (e.g. sequence alignment, differential methylation analysis, etc.) but also provides useful tools for methylation data annotation and visualization. Specifically, it uses Burrow-Wheeler Transform (BWT) algorithm to directly align bisulfite sequencing reads to a reference genome and implements a novel sliding window based approach with statistical methods for the identification of differentially methylated regions (DMRs). The capability of processing data parallelly allows it to outperform a number of other bisulfite alignment software packages. To demonstrate its utility and performance, we applied it to both real and simulated bisulfite sequencing datasets. The results indicate that Methy-Pipe can accurately estimate methylation densities, identify DMRs and provide a variety of utility programs for downstream methylation data analysis. In summary, Methy-Pipe is a useful pipeline that can process whole genome bisulfite sequencing data in an efficient, accurate, and user-friendly manner. Software and test dataset are available at http://sunlab.lihs.cuhk.edu.hk/methy-pipe/.

OBJECTIVE: To determine the pathogenesis of a patient born with congenital heart defects, who had appeared normal in prenatal screening. METHODS: In routine prenatal screening, G-banding was performed to analyse the karyotypes of the family and fluorescence in situ hybridization was used to investigate the 22q11.2 deletion in the fetus. After birth, the child was found to be suffering from heart defects by transthoracic echocardiography. In the following study, sequencing was used to search for potential mutations in pivotal genes. SNP-array was employed for fine mapping of the aberrant region and quantitative real-time PCR was used to confirm the results. Furthermore, other patients with a similar phenotype were screened for the same genetic variations. To compare with a control, these variations were also assessed in the general population. RESULTS: The child and his mother each had a region that was deleted in the beta-defensin repeats, which are usually duplicated in the general population. Besides, the child carried a SOX7-gene duplication. While this duplication was not detected in his mother, it was found in two other patients with cardiac defects who also had the similar deletion in the beta-defensin repeats. CONCLUSION: The congenital heart defects of the child were probably caused by a SOX7-gene duplication, which may be a consequence of the partial haplotype of beta-defensin regions at 8p23.1. To our knowledge, this is the first congenital heart defect case found to have the haplotype of beta-defensin and the duplication of SOX7.

A Content, Context, Connection and Researching, Reasoning, Reflecting (3C3R) model is a conceptual framework for problem-based learning (PBL) problem design. We introduced the 3C3R-PBL method into a pediatric teaching plan, and evaluated its effectiveness and feasibility. The 3C3R model was applied in a pediatric problem design teaching plan "why the lips turn purple when a baby is crying". All students were assigned either into a traditional PBL course or into a 9-step 3C3R model PBL course (3C3R-PBL). The performance outcomes of both groups were compared. For the PBL group, the proportion of students scoring ≥4 for content, context, and problem design connection, was 90.8%, 80.3%, and 64.5% respectively, while for tutors, it was 71.4%, 71.4%, and 28.6%; for researching, reasoning, and reflecting, the proportion of students scoring ≥4 was 81.6%, 55.3%, and 40.8%, while for tutors, it was 71.4%, 100%, and 57.1%. The learning difficulty was not considered high with only 31.6% of students and 42.9% of tutors rating the task as difficult. For the 3C3R-PBL group, the proportion of students scoring content, context, and connection, ≥4 was 100%, 98.4%, and 90.5%, while for tutors it was 100%, 100%, 83.3%; for researching, reasoning, and reflecting, the proportion of students scoring ≥4 was 95.2%, 88.9%, and 76.2%, while for tutors it was 100% for all 3 R components. Students and tutors were convinced by the content, case context, research process and reasoning process of both teaching plans, while scores for connection and reflecting were significantly improved when the PBL plan was amended by a 3C3R model (p

Gram-negative bacteria have evolved sophisticated secretion machineries specialized for the secretion of macromolecules important for their life cycles. The Type VI secretion system (T6SS) is the most widely spread bacterial secretion machinery and is encoded by large, variable gene clusters, often found to be essential for virulence. The latter is true for the atypical T6SS encoded by the Francisella pathogenicity island (FPI) of the highly pathogenic, intracellular bacterium Francisella tularensis. We here undertook a comprehensive analysis of the intramacrophage secretion of the 17 FPI proteins of the live vaccine strain, LVS, of F. tularensis. All were expressed as fusions to the TEM β-lactamase and cleavage of the fluorescent substrate CCF2-AM, a direct consequence of the delivery of the proteins into the macrophage cytosol, was followed over time. The FPI proteins IglE, IglC, VgrG, IglI, PdpE, PdpA, IglJ and IglF were all secreted, which was dependent on the core components DotU, VgrG, and IglC, as well as IglG. In contrast, the method was not directly applicable on F. novicida U112, since it showed very intense native β-lactamase secretion due to FTN_1072. Its role was proven by ectopic expression in trans in LVS. We did not observe secretion of any of the LVS substrates VgrG, IglJ, IglF or IglI, when tested in a FTN_1072 deficient strain of F. novicida, whereas IglE, IglC, PdpA and even more so PdpE were all secreted. This suggests that there may be fundamental differences in the T6S mechanism among the Francisella subspecies. The findings further corroborate the unusual nature of the T6SS of F. tularensis since almost all of the identified substrates are unique to the species.

microRNAs (miRNAs) are non-coding RNAs that regulate gene expression post-transcriptionally, and mounting evidence supports the prevalence and functional significance of their interplay with transcription factors (TFs). Here we describe the identification of a regulatory circuit between muscle miRNAs (miR-1, miR-133 and miR-206) and Yin Yang 1 (YY1), an epigenetic repressor of skeletal myogenesis in mouse. Genome-wide identification of potential down-stream targets of YY1 by combining computational prediction with expression profiling data reveals a large number of putative miRNA targets of YY1 during skeletal myoblasts differentiation into myotubes with muscle miRs ranking on top of the list. The subsequent experimental results demonstrate that YY1 indeed represses muscle miRs expression in myoblasts and the repression is mediated through multiple enhancers and recruitment of Polycomb complex to several YY1 binding sites. YY1 regulating miR-1 is functionally important for both C2C12 myogenic differentiation and injury-induced muscle regeneration. Furthermore, we demonstrate that miR-1 in turn targets YY1, thus forming a negative feedback loop. Together, these results identify a novel regulatory circuit required for skeletal myogenesis and reinforce the idea that regulatory circuitries involving miRNAs and TFs are prevalent mechanisms.

BackgroundIntervertebral disc degeneration (IDD) is a progressive chronic condition that commonly causes low back pain. Cancer is among the primary reasons for deaths worldwide. Our purpose was to identify the characteristic genes of IDD and explore the potential association between IDD and cancer.MethodsImmune cell infiltration and differentially expressed analysis were conducted utilizing data from the GSE124272 database. Enrichment analysis of differentially expressed genes (DEGs) was performed to explore the possible mechanisms underlying IDD development. Moreover, weighted gene correlation network analysis (WGCNA) was applied to select IDD-related hub genes. The immune-related key genes were determined by intersecting DEGs, IDD-related hub genes, and immune genes. Subsequently, machine learning models based on these genes were built to identify and verify the characteristic genes. RNA sequencing and clinical data of 33 carcinoma categories were obtained from the Cancer Genome Atlas (TCGA). The association between NAIP expression and prognosis was calculated using the Kaplan-Meier analysis. To gain a deeper understanding of the impact of NAIP in tumor immunotherapy, the association between NAIP and immune infiltration and two immunotherapeutic biomarkers were explored. Ultimately, the association between NAIP and immunotherapeutic response was investigated utilizing two independent cohorts.ResultsNAIP was identified as an immune-related characteristic gene between IDD and normal intervertebral disc tissue. In certain carcinoma categories, NAIP expression levels were elevated (4/33) and significantly correlated to the respective tumor stage (4/21). Survival analysis revealed that the expression levels of NAIP have prognostic significance in different cancer types. Generally, NAIP presented a strong association with immune cell infiltration and modulators. NAIP may influence immunotherapy effects through tumor mutational burden and microsatellite instability. No remarkable association between NAIP and immunotherapy response was found in either cohort.ConclusionOur study is the first to identify NAIP as an immune-related characteristic gene. Pan-cancer analysis revealed that NAIP could serve as a novel clinical prognostic marker and therapeutic target for a variety of carcinoma categories, reducing the risk of IDD in tumor patients.

As the most common type of neurodegenerative diseases (NDDs), Alzheimer's disease (AD) is thought to be caused mainly by the excessive aggregation of β-amyloid protein (Aβ). However, a growing number of studies have found that reactive oxygen species (ROS) play a key role in the onset and progression of AD. The present study aimed to probe the neuroprotective effect of high-frequency low-intensity pulsed electric field (H-LIPEF) for SH-SY5Y cells against hydrogen peroxide (H2O2) and Aβ-induced cytotoxicity. By looking in a systematic way into the frequency- and amplitude-dependent neuroprotective effect of pulsed electric field (PEF), the study finds that H-LIPEF at 200 Hz produces the optimal protective effect for SH-SY5Y cells. The underlying mechanisms were confirmed to be due to the activation of extracellular signal-regulated kinase (ERK) pathway and the downstream prosurvival and antioxidant proteins. Because the electric field can be modified to focus on specific area in a non-contact manner, the study suggests that H-LIPEF holds great potential for treating NDDs, whose effect can be further augmented with the administering of drugs or natural compounds at the same time.