Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive memory loss along with neuropsychiatric symptoms and a decline in activities of daily life. Its main pathological ...features are cerebral atrophy, amyloid plaques, and neurofibrillary tangles in the brains of patients. There are various descriptive hypotheses regarding the causes of AD, including the cholinergic hypothesis, amyloid hypothesis, tau propagation hypothesis, mitochondrial cascade hypothesis, calcium homeostasis hypothesis, neurovascular hypothesis, inflammatory hypothesis, metal ion hypothesis, and lymphatic system hypothesis. However, the ultimate etiology of AD remains obscure. In this review, we discuss the main hypotheses of AD and related clinical trials. Wealthy puzzles and lessons have made it possible to develop explanatory theories and identify potential strategies for therapeutic interventions for AD. The combination of hypometabolism and autophagy deficiency is likely to be a causative factor for AD. We further propose that fluoxetine, a selective serotonin reuptake inhibitor, has the potential to treat AD.
Demand for electricity is a key bottleneck for the development of remote areas. Grid extension to remote areas has previously been constrained due to difficult terrain for construction and vast ...investment. Fast development of decentralized renewable energy production technologies provides opportunity for tackling the challenges. The study aims to demonstrate the techno-economic feasibility of off-grid hybrid renewable energy system for remote rural electrification, via a case study of a village in West China by performing simulation, optimization and sensitivity analysis. Daily and seasonal characteristics of energy supply as well as demand sizes and patterns of remote rural areas are considered. Different combinations of PV panels, wind turbine and biogas generator are modeled and optimized in Hybrid Optimization Model for Electric Renewables (HOMER). The most cost competitive configuration is determined whilst ensuring a reliable power supply featuring residential, community, commercial and agricultural demand of the village. Comparison of the off-grid hybrid power system and grid extension has been carried out. Results show that a hybrid power system comprising solar, wind and biomass is a reliable and cost-effective option for sustainable remote rural electrification whilst achieving environmental benefits.
Highly reactive metastable intermixed composites (MICs) have attracted much attention in the past decades. The MIC family of materials mainly includes traditional metal‐based nanothermites, novel ...core–shell‐structured, 3D ordered macroporous‐structured, and ternary nanocomposites. By applying special fabrication approaches, highly reactive MICs with uniformly dispersed reactants, “layer‐by‐layer” or “core–shell” structures, can be prepared. Thus, the combustion performance can be greatly improved, and the ignition characteristics and safety can be precisely controlled by using a certain preparation strategy. Here, the preparation and characterization of the MICs that have been developed during the past few decades are summarized. Traditional preparation methods for MICs generally include physical mixing, high‐energy ball milling, sol–gel synthesis, and vapor deposition, while the novel methods include self‐assembly, electrophoretic deposition, and electrospinning. Various preparation procedures and the ignition and combustion performance of different MIC reactive systems are compared and discussed. In particular, the advantages of novel structured MICs in terms of safety and combustion efficiency are clarified, based on which suggestions regarding the possible future research directions are proposed.
Highly reactive metastable intermixed composites (MICs) prepared by different strategies show various characteristics and properties. By applying special fabrication approaches, highly reactive MICs with uniformly dispersed reactants, assembled in either layer‐by‐layer or core–shell structure, can be prepared. Thus, the improved and desired performances can be achieved by using a certain preparation strategy.
Objective
Neurodevelopmental diseases are common disorders caused by the disruption of essential neurodevelopmental processes. Recent human exome sequencing and genome‐wide association studies have ...shown that mutations in the subunits of the SWI/SNF (BAF) complex are risk factors for neurodevelopmental diseases. Clinical studies have found that ARID1A (BAF250a) is the most frequently mutated SWI/SNF gene and its mutations lead to mental retardation and microcephaly. However, the function of ARID1A in brain development and its underlying mechanisms still remain elusive.
Methods
The present study used Cre/loxP system to generate an Arid1a conditional knockout mouse line. Cell proliferation, cell apoptosis and cell differentiation of NSPCs were studied by immunofluorescence staining. In addition, RNA‐seq and RT‐PCR were performed to dissect the molecular mechanisms of Arid1a underlying cortical neurogenesis. Finally, rescue experiments were conducted to evaluate the effects of Neurod1 or Fezf2 overexpression on the differentiation of NSPCs in vitro.
Results
Conditional knockout of Arid1a reduces cortical thickness in the developing cortex. Arid1a loss of function inhibits the proliferation of radial glial cells, and increases cell death during late cortical development, and leads to dysregulated expression of genes associated with proliferation and differentiation. Overexpression of Neurod1 or Fezf2 in Arid1a cKO NSPCs rescues their neural differentiation defect in vitro.
Conclusions
This study demonstrates for the first time that Arid1a plays an important role in regulating the proliferation and differentiation of NSPCs during cortical development, and proposes several gene candidates that are worth to understand the pathological mechanisms and to develop novel interventions of neurodevelopment disorders caused by Arid1a mutations.
Although Arid1a mutations are closely related to mental retardation and microcephaly, the function of Arid1a in brain development and its underlying mechanisms still remain elusive. The present study demonstrates for the first time that Arid1a plays an important role in regulating the proliferation and differentiation of neural stem/progenitor cells during cortical development, and proposes several gene candidates that are worth to understand the pathological mechanisms and to develop novel interventions of neurodevelopment disorders caused by Arid1a mutations.
Histone lysine crotonylation (Kcr), an evolutionarily conserved and widespread non‐acetyl short‐chain lysine acylation, plays important roles in transcriptional regulation and disease processes. ...However, the genome‐wide distribution, dynamic changes, and associations with gene expression of histone Kcr during developmental processes are largely unknown. In this study, we find that histone Kcr is mainly located in active promoter regions, acts as an epigenetic hallmark of highly expressed genes, and regulates genes participating in metabolism and proliferation. Moreover, elevated histone Kcr activates bivalent promoters to stimulate gene expression in neural stem/progenitor cells (NSPCs) by increasing chromatin openness and recruitment of RNA polymerase II (RNAP2). Functionally, these activated genes contribute to transcriptome remodeling and promote neuronal differentiation. Overall, histone Kcr marks active promoters with high gene expression and modifies the local chromatin environment to allow gene activation.
Synopsis
Histone lysine crotonylation (Kcr) is an active epigenetic mark with diverse functions during neural development. Kcr regulates neural stem cell fate decisions by activating developmentally primed bivalent promoters.
Histone crotonylation marks active promoters of genes participating in metabolism and proliferation.
Histone crotonylation also activates bivalent promoters to stimulate gene expression in neural stem/progenitor cells.
Crotonate promotes differentiation of neural stem/progenitor cells by increasing histone crotonylation.
Histone lysine crotonylation (Kcr) is an active epigenetic mark with diverse functions during neural development. Kcr regulates neural stem cell fate decisions by activating developmentally primed bivalent promoters.
Mutations in AT‐rich interactive domain‐containing protein 1A (ARID1A) cause Coffin‐Siris syndrome (CSS), a rare genetic disorder that results in mild to severe intellectual disabilities. However, ...the biological role of ARID1A in the brain remains unclear. In this study, we report that the haploinsufficiency of ARID1A in excitatory neurons causes cognitive impairment and defects in hippocampal synaptic transmission and dendritic morphology in mice. Similarly, human embryonic stem cell‐derived excitatory neurons with deleted ARID1A exhibit fewer dendritic branches and spines, and abnormal electrophysiological activity. Importantly, supplementation of acetate, an epigenetic metabolite, can ameliorate the morphological and electrophysiological deficits observed in mice with Arid1a haploinsufficiency, as well as in ARID1A‐null human excitatory neurons. Mechanistically, transcriptomic and ChIP‐seq analyses demonstrate that acetate supplementation can increase the levels of H3K27 acetylation at the promoters of key regulatory genes associated with neural development and synaptic transmission. Collectively, these findings support the essential roles of ARID1A in the excitatory neurons and cognition and suggest that acetate supplementation could be a potential therapeutic intervention for CSS.
Synopsis
Mutations in ARID1A cause Coffin‐Siris syndrome (CSS), a rare genetic disorder with severe neurodevelopmental deficits. This study investigates the genetic basis of the pathophysiological role of ARID1A in CSS and proposes a potential therapeutic intervention.
Arid1a haploinsufficiency in mouse excitatory neurons leads to spatial memory defects.
ARID1A is required for neuron dendritic and synapse growth in mice and humans.
Acetate supplementation rescues the neuronal deficits by increasing H3K27 acetylation levels at the promoters of neuronal genes in both Arid1a haploinsufficient mice and ARID1A KO hESC‐derived neurons.
Mutations in ARID1A cause Coffin‐Siris syndrome (CSS), a rare genetic disorder with severe neurodevelopmental deficits. This study investigates the genetic basis of the pathophysiological role of ARID1A in CSS and proposes a potential therapeutic intervention.
Salvia miltiorrhiza Burge (Danshen) is an eminent medicinal herb that possesses broad cardiovascular and cerebrovascular protective actions and has been used in Asian countries for many centuries. ...Accumulating evidence suggests that Danshen and its components prevent vascular diseases, in particular, atherosclerosis and cardiac diseases, including myocardial infarction, myocardial ischemia/reperfusion injury, arrhythmia, cardiac hypertrophy and cardiac fibrosis. The published literature indicates that lipophilic constituents (tanshinone I, tanshinone IIa, tanshinone IIb, cryptotanshinone, dihydrotanshinone, etc) as well as hydrophilic constituents (danshensu, salvianolic acid A and B, protocatechuic aldehyde, etc) contribute to the cardiovascular protective actions of Danshen, suggesting a potential synergism among these constituents. Herein, we provide a systematic up-to-date review on the cardiovascular actions and therapeutic potential of major pharmacologically active constituents of Danshen. These bioactive compounds will serve as excellent drug candidates in small-molecule cardiovascular drug discovery. This article also provides a scientific rationale for understanding the traditional use of Danshen in cardiovascular therapeutics.
This paper explores the relationship between college students’ consumption views and their consumption views under Civic Education in the context of multiple datasets. Secondly, a multi-agent, ...multi-source heterogeneous data collection model is used to collect data on consumption view and Civic Education. A CNN model is designed to study the correlation between consumption view and Civic Education. The CNN and LSTM multi-grain data classification models are used to fuse the features of consumer outlook and Civic Education, respectively. Then, build an online learning platform for college students’ consumerism. Finally, the platform’s fusion effect and learning results for college students were analyzed and studied. The average JS index of data fusion was 93.32%, and the fusion effect was good. The total score of students’ pre and post-test consumerism scores increased from 86 to 100, and the effect of college students’ consumerism education was positive.
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