The prevalence of autism spectrum disorders in China: A comprehensive meta-analysis

There are conflicting prevalence estimates of autism spectrum disorders (ASDs) in mainland China (China thereafter). This study is a comprehensive meta-analysis of the pooled prevalence of ASDs in the general population in China. Study investigators independently conducted a systematic literature search of the following databases: PubMed, EMBASE, PsycINFO, China National Knowledge Infrastructure, Chinese biomedical literature service system, and Wan Fang. Studies reporting prevalence of ASDs and autism in Chinese population were identified and analysed using the Comprehensive Meta-Analysis program with the random effects model. Forty-four studies were included in the meta-analysis comprising 2,337,321 subjects of whom 46.66 % were females. The mean age of subjects ranged from 1.6 to 8 years. Based on diagnostic criteria the pooled prevalence of ASDs was 39.23 per 10,000 (95% CI: 28.44-50.03 per 10,000, I2=89.2%); specifically, the prevalence of autism was 10.18 per 10,000 (95% CI: 8.46-11.89 per 10,000, I2=92.5%). Subgroup analyses revealed significant difference in the prevalence of ASDs between genders (72.77 per 10,000 in males vs. 16.45 per 10,000 in females). In conclusion, the prevalence of ASDs and autism in China was found generally lower than those reported in other countries. Further studies are needed to clarify the variation in prevalence

'Obligate' anaerobic Salmonella strain YB1 suppresses liver tumor growth and metastasis in nude mice

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Adjunctive aripiprazole for antipsychotic-related hyperprolactinaemia in patients with first-episode schizophrenia: a meta-analysis.

Background(#br)Hyperprolactinaemia is a common antipsychotic (AP)-induced adverse effect, particularly in female patients.(#br)Aims(#br)This meta-analysis examined the efficacy and safety of adjunctive aripiprazole in preventing AP-related hyperprolactinaemia in patients with first-episode schizophrenia.(#br)Methods(#br)PubMed, PsycINFO, EMBASE, Cochrane Library, WanFang and China Journal Net databases were searched to identify eligible randomised controlled trials (RCTs). Primary outcomes were the reductions of serum prolactin level and prolactin-related symptoms. Data were independently extracted by two reviewers and analysed using RevMan (V.5.3). Weighted/standardised mean differences (WMDs/SMDs)±95% CIs were reported.(#br)Results(#br)In the five RCTs (n=400), the adjunctive aripiprazole (n=197) and the control groups (n=203) with a mean of 11.2 weeks of treatment duration were compared. The aripiprazole group had a significantly lower endpoint serum prolactin level in all patients (five RCTs, n=385; WMD: -50.43 ng/mL (95% CI: -75.05 to -25.81), p<0.00001; I2=99%), female patients (two RCTs, n=186; WMD: -22.58 ng/mL (95% CI: -25.67 to -19.49), p<0.00001; I2=0%) and male patients (two RCTs, n=127; WMD: -68.80 ng/mL (95% CI: -100.11 to -37.49), p<0.0001). In the sensitivity analysis for the endpoint serum prolactin level in all patients, the findings remained significant (p<0.00001; I2=96%). The aripiprazole group was superior to the control group in improving negative symptoms as assessed by the Positive and Negative Syndrome Scale (three RCTs, n=213; SMD: -0.51 (95% CI: -0.79 to -0.24), p=0.0002; I2=0%). Adverse effects and discontinuation rates were similar between the two groups.(#br)Conclusions(#br)Adjunctive aripiprazole appears to be associated with reduced AP-induced hyperprolactinaemia and improved prolactin-related symptoms in first-episode schizophrenia. Further studies with large sample sizes are needed to confirm these findings

Dissecting the effects of METTL3 on alternative splicing in prostate cancer

Although the role of METTL3 has been extensively studied in many cancers, its role in isoform switching in prostate cancer (PCa) has been poorly explored. To investigate its role, we applied standard RNA-sequencing and long-read direct RNA-sequencing from Oxford Nanopore to examine how METTL3 affects alternative splicing (AS) in two PCa cell lines. By dissecting genome-wide METTL3-regulated AS events, we noted that two PCa cell lines (representing two different PCa subtypes, androgen-sensitive or resistant) behave differently in exon skipping and intron retention events following METTL3 depletion, suggesting AS heterogeneity in PCa. Moreover, we revealed that METTL3-regulated AS is dependent on N6-methyladenosine (m6A) and distinct splicing factors. Analysis of the AS landscape also revealed cell type specific AS signatures for some genes (e.g., MKNK2) involved in key functions in PCa tumorigenesis. Finally, we also validated the clinical relevance of MKNK2 AS events in PCa patients and pointed to the possible regulatory mechanism related to m6A in the exon14a/b region and SRSF1. Overall, we characterize the role of METTL3 in regulating PCa-associated AS programs, expand the role of METTL3 in tumorigenesis, and suggest that MKNK2 AS events may serve as a new potential prognostic biomarker

CRISPR-Cas9 screens in human cells and primary neurons identify modifiers of C9ORF72 dipeptide-repeat-protein toxicity.

Hexanucleotide-repeat expansions in the C9ORF72 gene are the most common cause of amyotrophic lateral sclerosis and frontotemporal dementia (c9ALS/FTD). The nucleotide-repeat expansions are translated into dipeptide-repeat (DPR) proteins, which are aggregation prone and may contribute to neurodegeneration. We used the CRISPR-Cas9 system to perform genome-wide gene-knockout screens for suppressors and enhancers of C9ORF72 DPR toxicity in human cells. We validated hits by performing secondary CRISPR-Cas9 screens in primary mouse neurons. We uncovered potent modifiers of DPR toxicity whose gene products function in nucleocytoplasmic transport, the endoplasmic reticulum (ER), proteasome, RNA-processing pathways, and chromatin modification. One modifier, TMX2, modulated the ER-stress signature elicited by C9ORF72 DPRs in neurons and improved survival of human induced motor neurons from patients with C9ORF72 ALS. Together, our results demonstrate the promise of CRISPR-Cas9 screens in defining mechanisms of neurodegenerative diseases

Exome Sequencing Identifies ZNF644 Mutations in High Myopia

Myopia is the most common ocular disorder worldwide, and high myopia in particular is one of the leading causes of blindness. Genetic factors play a critical role in the development of myopia, especially high myopia. Recently, the exome sequencing approach has been successfully used for the disease gene identification of Mendelian disorders. Here we show a successful application of exome sequencing to identify a gene for an autosomal dominant disorder, and we have identified a gene potentially responsible for high myopia in a monogenic form. We captured exomes of two affected individuals from a Han Chinese family with high myopia and performed sequencing analysis by a second-generation sequencer with a mean coverage of 30× and sufficient depth to call variants at ∼97% of each targeted exome. The shared genetic variants of these two affected individuals in the family being studied were filtered against the 1000 Genomes Project and the dbSNP131 database. A mutation A672G in zinc finger protein 644 isoform 1 (ZNF644) was identified as being related to the phenotype of this family. After we performed sequencing analysis of the exons in the ZNF644 gene in 300 sporadic cases of high myopia, we identified an additional five mutations (I587V, R680G, C699Y, 3′UTR+12 C>G, and 3′UTR+592 G>A) in 11 different patients. All these mutations were absent in 600 normal controls. The ZNF644 gene was expressed in human retinal and retinal pigment epithelium (RPE). Given that ZNF644 is predicted to be a transcription factor that may regulate genes involved in eye development, mutation may cause the axial elongation of eyeball found in high myopia patients. Our results suggest that ZNF644 might be a causal gene for high myopia in a monogenic form

A multidimensional platform for the purification of non-coding RNA species

A renewed interest in non-coding RNA (ncRNA) has led to the discovery of novel RNA species and post-transcriptional ribonucleoside modifications, and an emerging appreciation for the role of ncRNA in RNA epigenetics. Although much can be learned by amplification-based analysis of ncRNA sequence and quantity, there is a significant need for direct analysis of RNA, which has led to numerous methods for purification of specific ncRNA molecules. However, no single method allows purification of the full range of cellular ncRNA species. To this end, we developed a multidimensional chromatographic platform to resolve, isolate and quantify all canonical ncRNAs in a single sample of cells or tissue, as well as novel ncRNA species. The applicability of the platform is demonstrated in analyses of ncRNA from bacteria, human cells and plasmodium-infected reticulocytes, as well as a viral RNA genome. Among the many potential applications of this platform are a system-level analysis of the dozens of modified ribonucleosides in ncRNA, characterization of novel long ncRNA species, enhanced detection of rare transcript variants and analysis of viral genomes.Singapore-MIT Alliance for Research and TechnologyNational Institute of Environmental Health Sciences (ES017010)National Institute of Environmental Health Sciences (ES002109

Virtual medical research mentoring

Background: Medical research is important for professional advancement, and mentoring is a key means by which students and early‐career doctors can engage in research. Contrasting international research collaborations, research mentoring programmes are often geographically limited. As the COVID‐19 pandemic has led to increased use of online technology for classes and conferences, a virtual, international approach to medical research mentoring may be valuable. Approach: We hereby describe our experience at the Cardiovascular Analytics Group, a virtual international medical research mentoring group established in 2015. We make use of virtual platforms in multi‐level mentoring with peer mentoring and emphasise active participation, early leadership, an open culture, accessible research support and a distributed research workflow. Evaluation: With 63 active members from 14 different countries, the Group has been successful in training medical students and early‐career medical graduates in academic medicine. Our members have led over 100 peer‐reviewed publications of original research and reviews since 2015, winning 13 research prizes during this time. Implications: Our accessible‐distributed model of virtual international medical research collaboration and multi‐level mentoring is viable and efficient and caters to the needs of contemporary healthcare. Others should consider building similar models to improve medical research mentoring globally

Modifiable Risk Factor Score and Fecundability in a Preconception Cohort in Singapore

Importance: Although multiple modifiable risk factors have been identified for reduced fecundability (defined as lower probability of conception within a menstrual cycle), no scoring system has been established to systematically evaluate fecundability among females who are attempting to conceive. Objective: To examine the association of a risk score based on 6 modifiable factors with fecundability, and to estimate the percentage reduction in incidence of nonconception if all study participants achieved a minimal risk score level. Design, Setting, and Participants: This population-based cohort study obtained data from the S-PRESTO (Singapore Preconception Study of Long-Term Maternal and Child Outcomes) prospective cohort study. Females of reproductive age who were trying to conceive were enrolled from February 2015 to October 2017 and followed for 1 year, ending in November 2018. Data were analyzed from March to May 2022. Exposures: A reduced fecundability risk score was derived by giving participants 1 point for each of the following factors: unhealthy body mass index, unhealthy diet, smoking, alcohol intake, folic acid supplement nonuser, and older maternal age. Total scores ranged from 0 to 6 and were classified into 5 levels: level 1 (score of 0 or 1), level 2 (score of 2), level 3 (score of 3), level 4 (score of 4), and level 5 (score of 5 or 6). Main Outcomes and Measures: Fecundability, measured by time to conception in cycles, was analyzed using discrete-time proportional hazards models with confounder adjustment. Results: A total of 937 females (mean [SD] age, 30.8 [3.8] years) were included, among whom 401 (42.8%) spontaneously conceived within 1 year of attempting conception; the median (IQR) number of cycles before conception was 4 (2-7). Compared with participants with a level 1 risk score, those with level 2, 3, 4, and 5 risk scores had reductions in fecundability of 31% (adjusted fecundability ratio [FR], 0.69; 95% CI, 0.54-0.88), 41% (FR, 0.59; 95% CI, 0.45-0.78), 54% (FR, 0.46; 95% CI, 0.31-0.69) and 77% (FR, 0.23; 95% CI, 0.07-0.73), respectively. Assessment of the population attributable fraction showed that all participants achieving a minimal (level 1) risk level would be associated with a reduction of 34% (95% CI, 30%-39%) in nonconception within a year. Conclusions and Relevance: Results of this study revealed the co-occurrence of multiple modifiable risk factors for lowered fecundability and a substantially higher conception rate among participants with no or minimal risk factors. The risk assessment scoring system proposed is a simple and potentially useful public health tool for mitigating risks and guiding those who are trying to conceive.publishedVersionPeer reviewe

Conserved Regulation of p53 Network Dosage by MicroRNA–125b Occurs through Evolving miRNA–Target Gene Pairs

MicroRNAs regulate networks of genes to orchestrate cellular functions. MiR-125b, the vertebrate homologue of the Caenorhabditis elegans microRNA lin-4, has been implicated in the regulation of neural and hematopoietic stem cell homeostasis, analogous to how lin-4 regulates stem cells in C. elegans. Depending on the cell context, miR-125b has been proposed to regulate both apoptosis and proliferation. Because the p53 network is a central regulator of both apoptosis and proliferation, the dual roles of miR-125b raise the question of what genes in the p53 network might be regulated by miR-125b. By using a gain- and loss-of-function screen for miR-125b targets in humans, mice, and zebrafish and by validating these targets with the luciferase assay and a novel miRNA pull-down assay, we demonstrate that miR-125b directly represses 20 novel targets in the p53 network. These targets include both apoptosis regulators like Bak1, Igfbp3, Itch, Puma, Prkra, Tp53inp1, Tp53, Zac1, and also cell-cycle regulators like cyclin C, Cdc25c, Cdkn2c, Edn1, Ppp1ca, Sel1l, in the p53 network. We found that, although each miRNA–target pair was seldom conserved, miR-125b regulation of the p53 pathway is conserved at the network level. Our results lead us to propose that miR-125b buffers and fine-tunes p53 network activity by regulating the dose of both proliferative and apoptotic regulators, with implications for tissue stem cell homeostasis and oncogenesis