An empirical study on perceptive teaching in junior middle school English in China

Although the middle school English teaching has gotten a lot of achievements in China, some problems still exist, such as too much emphasis on words, grammars and structures. Perceptive teaching can be helpful for English teaching from a new perspective. There are three teaching procedures in the perceptive teaching: eliciting to acquire text meaning, creating situation to experience and comprehending to get the internal values in individuals. This thesis did the experimental research on English perspective teaching in middle school in China. The results show that in perceptive teaching, learners’ cognitive abilities can be improved; learners can show great interests in learning and shape positive attitudes; their learning methods can greatly be promoted. For different level learners, it shows that middle level learners can gain more benefit than the high level or low level learners in English perceptive teaching

Disruption of mitochondrial and lysosomal functions by human CACNA1C variants expressed in HEK 293 and CHO cells

ObjectiveTo investigate the pathogenesis of three novel de novo CACNA1C variants (p.E411D, p.V622G, and p.A272V) in causing neurodevelopmental disorders and arrhythmia.MethodsSeveral molecular experiments were carried out on transfected human embryonic kidney 293 (HEK 293) and Chinese hamster ovary (CHO) cells to explore the effects of p.E411D, p.V622G, and p.A272V variants on electrophysiology, mitochondrial and lysosomal functions. Electrophysiological studies, RT-qPCR, western blot, apoptosis assay, mito-tracker fluorescence intensity, lyso-tracker fluorescence intensity, mitochondrial calcium concentration test, and cell viability assay were performed. Besides, reactive oxygen species (ROS) levels, ATP levels, mitochondrial copy numbers, mitochondrial complex I, II, and cytochrome c functions were measured.ResultsThe p.E411D variant was found in a patient with attention deficit-hyperactive disorder (ADHD), and moderate intellectual disability (ID). This mutant demonstrated reduced calcium current density, mRNA, and protein expression, and it was localized in the nucleus, cytoplasm, lysosome, and mitochondria. It exhibited an accelerated apoptosis rate, impaired autophagy, and mitophagy. It also demonstrated compromised mitochondrial cytochrome c oxidase, complex I, and II enzymes, abnormal mitochondrial copy numbers, low ATP levels, abnormal mitochondria fluorescence intensity, impaired mitochondrial fusion and fission, and elevated mitochondrial calcium ions. The p.V622G variant was identified in a patient who presented with West syndrome and moderate global developmental delay. The p.A272V variant was found in a patient who presented with epilepsy and mild ID. Both mutants (p.V622G and p.A272V) exhibited reduced calcium current densities, decreased mRNA and protein expressions, and they were localized in the nucleus, cytoplasm, lysosome, and mitochondria. They exhibited accelerated apoptosis and proliferation rates, impaired autophagy, and mitophagy. They also exhibited abnormal mitochondrial cytochrome c oxidase, complex I and II enzymes, abnormal mitochondrial copy numbers, low ATP, high ROS levels, abnormal mitochondria fluorescence intensity, impaired mitochondrial fusion and fission, as well as elevated mitochondrial calcium ions.ConclusionThe p.E411D, p.V622G and p.A272V mutations of human CACNA1C reduce the expression level of CACNA1C proteins, and impair mitochondrial and lysosomal functions. These effects induced by CACNA1C variants may contribute to the pathogenesis of CACNA1C-related disorders

In situ correction of various β-thalassemia mutations in human hematopoietic stem cells

β-thalassemia (β-thal) is the most common monogenic disorder caused by various mutations in the human hemoglobin β (HBB) gene and affecting millions of people worldwide. Electroporation of Cas9 and single-guide RNA (sgRNA)–ribonucleoprotein (RNP) complex-mediated gene targeting in patient-derived hematopoietic stem cells (HSCs), followed by autologous transplantation, holds the promise to cure patients lacking a compatible bone marrow donor. In this study, a universal gene correction method was devised to achieve in situ correction of most types of HBB mutations by using validated CRISPR/sgRNA–RNP complexes and recombinant adeno-associated viral 6 (rAAV6) donor-mediated homology-directed repair (HDR) in HSCs. The gene-edited HSCs exhibited multi-lineage formation abilities, and the expression of β-globin transcripts was restored in differentiated erythroid cells. The method was applied to efficiently correct different mutations in β-thal patient-derived HSCs, and the edited HSCs retained the ability to engraft into the bone marrow of immunodeficient NOD-scid-IL2Rg−/− (NSI) mice. This study provides an efficient and safe approach for targeting HSCs by HDR at the HBB locus, which provides a potential therapeutic approach for treating other types of monogenic diseases in patient-specific HSCs

Synaptopathology Involved in Autism Spectrum Disorder

Autism spectrum disorder (ASD) encompasses a group of multifactorial neurodevelopmental disorders characterized by impaired social communication, social interaction and repetitive behaviors. ASD affects 1 in 59 children, and is about 4 times more common among boys than among girls. Strong genetic components, together with environmental factors in the early stage of development, contribute to the pathogenesis of ASD. Multiple studies have revealed that mutations in genes like NRXN, NLGN, SHANK, TSC1/2, FMR1, and MECP2 converge on common cellular pathways that intersect at synapses. These genes encode cell adhesion molecules, scaffolding proteins and proteins involved in synaptic transcription, protein synthesis and degradation, affecting various aspects of synapses including synapse formation and elimination, synaptic transmission and plasticity. This suggests that the pathogenesis of ASD may, at least in part, be attributed to synaptic dysfunction. In this article, we will review major genes and signaling pathways implicated in synaptic abnormalities underlying ASD, and discuss molecular, cellular and functional studies of ASD experimental models

Neurological Diseases With Autism Spectrum Disorder: Role of ASD Risk Genes

Autism spectrum disorder (ASD) is frequently comorbid with other neurological disorders such as intellectual disability (ID) or global development delay (GDD) and epilepsy. The pathogenesis of ASD is complex. So far, studies have identified more than 1000 ASD risk genes. Most of them were also reported to relate with other neurological diseases, and only several of them have been confirmed as pathogenic genes for autism. Little is known about the roles of these risk genes in neurological diseases with ASD. In the present study, we recruited a cohort of 158 neurological disorder probands with 163 variants of 48 ASD risk genes. Of these, 50 individuals (31.6%) were diagnosed with ASD. In the ASD patient subset, we identified several rarely reported candidate genes including DOLK, USH2A, and HUWE1. In a comparison of patients with neurological disorders with and without ASD, we found that ID/GDD was frequently comorbid with ASD whereas epilepsy was more common in the non-ASD group. Statistical analyses of all possible risk factors implicated that variants in synaptic genes, especially non-voltage-gated ion channel genes and in transcriptional and chromosome genes were related to ASD, but none of the investigated environmental factors was. Our results are useful for the future diagnosis and prognosis of patients with neurological disorders and emphasize the utility of genetic screening

Electronically phase separated nano-network in antiferromagnetic insulating LaMnO3/PrMnO3/CaMnO3 tricolor superlattice

Strongly correlated materials often exhibit an electronic phase separation (EPS) phenomena whose domain pattern is random in nature. The ability to control the spatial arrangement of the electronic phases at microscopic scales is highly desirable for tailoring their macroscopic properties and/or designing novel electronic devices. Here we report the formation of EPS nanoscale network in a mono-atomically stacked LaMnO3/CaMnO3/PrMnO3 superlattice grown on SrTiO3 (STO) (001) substrate, which is known to have an antiferromagnetic (AFM) insulating ground state. The EPS nano-network is a consequence of an internal strain relaxation triggered by the structural domain formation of the underlying STO substrate at low temperatures. The same nanoscale network pattern can be reproduced upon temperature cycling allowing us to employ different local imaging techniques to directly compare the magnetic and transport state of a single EPS domain. Our results confirm the one-to-one correspondence between ferromagnetic (AFM) to metallic (insulating) state in manganite. It also represents a significant step in a paradigm shift from passively characterizing EPS in strongly correlated systems to actively engaging in its manipulation

Tremella fuciformis polysaccharide reduces obesity in high-fat diet-fed mice by modulation of gut microbiota

Obesity is a metabolic disease associated with gut microbiota and low-grade chronic inflammation. Tremella fuciformis is a medicinal and edible fungus; polysaccharide (TP) is the main active component, which has a variety of biological activities, such as hypoglycemic and hypolipidemic. However, the anti-obesity effects and potential mechanisms of TP have never been reported. This study was conducted to elucidate the inhibitory effect of TP on high-fat diet (HFD)-induced obesity in mice. Mice were split into five groups: normal chow diet (NCD) group, NCD_TP_H group, HFD group, HFD_TP_L group and HFD_TP_H group. Our study showed that TP inhibited high-fat diet-induced weight gain and fat accumulation in mice and reduced blood glucose, hyperlipidemia and inflammation. TP also improved gut microbiota disorders by reducing the Firmicutes/Bacteroidetes ratio and modulating the relative abundance of specific gut microbiota. We also found that the anti-obesity and gut microbiota-modulating effects of TP could be transferred to HFD-fed mice via faecal microbiota transplantation (FMT), confirming that the gut microbiota was one of the targets of TP for obesity inhibition. Further studies showed that TP increased the production of short-chain fatty acids and the secretion of intestinal hormones. Our studies showed that TP inhibited obesity by modulating inflammation and the microbe-gut-brain axis, providing a rationale for developing TP to treat obesity and its complications

Rare Copy Number Variations and Predictors in Children With Intellectual Disability and Epilepsy

Introduction: The concurrence of intellectual disability/global developmental delay and epilepsy (ID/GDD-EP) is very common in the pediatric population. The etiologies for both conditions are complex and largely unknown. The predictors of significant copy number variations (CNVs) are known for the cases with ID/GDD, but unknown for those with exclusive ID/GDD-EP. Importantly, the known predictors are largely from the same ethnic group; hence, they lack replication.Purpose: We aimed to determine and investigate the diagnostic yield of CNV tests, new causative CNVs, and the independent predictors of significant CNVs in Chinese children with unexplained ID/GDD-EP.Materials and methods: A total of 100 pediatric patients with unexplained ID/GDD-EP and 1,000 healthy controls were recruited. The American College of Medical Genetics guideline was used to classify the CNVs. Additionally, clinical information was collected and compared between those with significant and non-significant CNVs.Results: Twenty-eight percent of the patients had significant CNVs, 16% had variants of unknown significance, and 56% had non-significant CNVs. In total, 31 CNVs were identified in 28% (28/100) of cases: 25 pathogenic and 6 likely pathogenic. Eighteen known syndromes were diagnosed in 17 cases. Thirteen rare CNVs (8 novel and 5 reported in literature) were identified, of which three spanned dosage-sensitive genes: 19q13.2 deletion (ATP1A3), Xp11.4-p11.3 deletion (CASK), and 6q25.3-q25.3 deletion (ARID1B). By comparing clinical features in patients with significant CNVs against those with non-significant CNVs, a statistically significant association was found between the presence of significant CNVs and speech and language delay for those aged above 2 years and for those with facial malformations, microcephaly, congenital heart disease, fair skin, eye malformations, and mega cisterna magna. Multivariate logistic regression analysis allowed the identification of two independent significant CNV predictors, which are eye malformations and facial malformations.Conclusion: Our study supports the performance of CNV tests in pediatric patients with unexplained ID/GDD-EP, as there is high diagnostic yield, which informs genetic counseling. It adds 13 rare CNVs (8 novel), which can be accountable for both conditions. Moreover, congenital eye and facial malformations are clinical markers that can aid clinicians to understand which patients can benefit from the CNV testing and which will not, thus helping patients to avoid unnecessary and expensive tests