Alzheimer's disease (AD) is the most prevalent neurodegenerative disease worldwide, characterized by progressive neuron degeneration or loss due to excessive accumulation of β-amyloid (Aβ) peptides, ...formation of neurofibrillary tangles (NFTs), and hyperphosphorylated tau. The treatment of AD has been only partially successful as the majority of the pharmacotherapies on the market may alleviate some of the symptoms. In the occurrence of AD, increasing attention has been paid to neurodegeneration, while the resident glial cells, like microglia are also observed. Microglia, a kind of crucial glial cells associated with the innate immune response, functions as double-edge sword role in CNS. They exert a beneficial or detrimental influence on the adjacent neurons through secretion of both pro-inflammatory cytokines as well as neurotrophic factors. In addition, their endocytosis of debris and toxic protein like Aβ and tau ensures homeostasis of the neuronal microenvironment. In this review, we will systematically summarize recent research regarding the roles of microglia in AD pathology and latest microglia-associated therapeutic targets mainly including pro-inflammatory genes, anti-inflammatory genes and phagocytosis at length, some of which are contradictory and controversial and warrant to further be investigated.
Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disorder clinically characterized by cognitive impairment, abnormal behavior, and social deficits, which is intimately ...linked with excessive β-amyloid (Aβ) protein deposition along with many other misfolded proteins, neurofibrillary tangles formed by hyperphosphorylated tau protein aggregates, and mitochondrial damage in neurons, leading to neuron loss. Currently, research on the pathological mechanism of AD has been elucidated for decades, still no effective treatment for this complex disease was developed, and the existing therapeutic strategies are extremely erratic, thereby leading to irreversible and progressive cognitive decline in AD patients. Due to gradually mental dyscapacitating of AD patients, AD not only brings serious physical and psychological suffering to patients themselves, but also imposes huge economic burdens on family and society. Accordingly, it is very imperative to recapitulate the progress of gene editing-based precision medicine in the emerging fields. In this review, we will mainly focus on the application of CRISPR/Cas9 technique in the fields of AD research and gene therapy, and summarize the application of CRISPR/Cas9 in the aspects of AD model construction, screening of pathogenic genes, and target therapy. Finally, the development of delivery systems, which is a major challenge that hinders the clinical application of CRISPR/Cas9 technology will also be discussed.
The adverse use of alcohol is a serious global public health problem. Maternal alcohol consumption during pregnancy usually causes prenatal alcohol exposure (PAE) in the developing fetus, leading to ...a spectrum of disorders known as fetal alcohol spectrum disorders (FASD) and even fetal alcohol syndrome (FAS) throughout the lifelong sufferers. The prevalence of FASD is approximately 7.7 per 1,000 worldwide, and is even higher in developed regions. Generally, Ethanol in alcoholic beverages can impair embryonic neurological development through multiple pathways leading to FASD. Among them, the leading mechanism of FASDs is attributed to ethanol-induced neuroinflammatory damage to the central nervous system (CNS). Although the underlying molecular mechanisms remain unclear, the remaining multiple pathological mechanisms is likely due to the neurotoxic damage of ethanol and the resultant neuronal loss. Regardless of the molecular pathway, the ultimate outcome of the developing CNS exposed to ethanol is almost always the destruction and apoptosis of neurons, which leads to the reduction of neurons and further the development of FASD. In this review, we systematically summarize the current research progress on the pathogenesis of FASD, which hopefully provides new insights into differential early diagnosis, treatment and prevention for patents with FASD.
Fluoride exposure has a detrimental effect on neurodevelopment, while the underlying processes remain unknown. The goal of this study was to investigate how fluoride impacts synaptogenesis, with a ...focus on the phosphorylation of Creb1 (p-Creb1)-brain-derived neurotrophic factor (BDNF)-tyrosine kinase B (TrkB) pathway. We generated a sodium fluoride (NaF) model using C57 BL/6 J mice exposed to 100 mg/L NaF from gestation day 1 (GD1) to GD20. It was identified that NaF treatment impaired the learning and memory abilities of the male offspring, reduced dendritic spine density, lowered postsynaptic density protein-95 (PSD95) and synaptophysin (SYN) expression in the male offspring's hippocampus, indicating that synaptic dysfunction may contribute to the cognitive impairment in the NaF model. In addition, in vivo experiment demonstrated that the protein abundance of BDNF and the ratio of p-Creb1 to Creb1 were increased in the hippocampus of NaF offspring, while the level of TrkB was reduced. Similarly, PC12 cells treated with NaF also showed increased expression of BDNF and decreased levels of TrkB. Notably, fluoride treatment increased p-Creb1 in vitro, while inhibiting p-Creb1 by 66615 significantly alleviated the effects of NaF exposure, indicating that p-Creb1 exerts a regulatory function in the BDNF-TrkB pathway. Altogether, these results demonstrated prenatal fluoride exposure triggered neurotoxicity in the male offspring hippocampus was linked to synaptogenesis damage caused by activating p-Creb1, which disrupted the BDNF-TrkB pathway.
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•Pregnant mice were exposed to environmentally relevant doses of sodium fluoride from GD1 to GD20.•Exposure to sodium fluoride resulted in structural and functional impairments in male offspring mouse hippocampus.•The activation of P-Creb1 signaling pathway played a role in sodium fluoride-induced cognitive impairment.•We provided new insight into the mechanisms of sodium fluoride-induced developmental toxicity.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The paper gives an applicable model called colored balanced traveling salesman problem (CBTSP), it is utilized to model optimization problems with partially overlapped workspace such as the ...scheduling and deploying of the resources and goods. CBTSP is NP-hard problem, the traditional nature-inspired algorithms, such as genetic algorithm (GA), hill-climbing GA and simulated annealing GA, are easy to fall into local optimum. In order to improve it, the paper proposes a novel genetic algorithm (NGA) based on ITÖ process to solve CBTSP. First of all, NGA utilizes the dual-chromosome coding to represent solution of this problem, and then updates the solution by the crossover and mutation operator. During the process of crossover operator, the length of crossover can be affected by activity intensity, which is directly proportional to environmental temperature and inversely proportional to particle radius. The experiments verify that NGA can demonstrate better solution quality than the compared algorithms for large scale CBTSP.
•This paper provides colored balanced traveling salesman problem (CBTSP).•The large scale optimization for CBTSP is studied.•A novel genetic algorithm is proposed for large scale CBTSP.•Experiments show the superiority of the proposed algorithm.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
It is well-known that ultra-fine particles, especially those with oxidized surface, are difficult to float using conventional methods. Flotation of oxidized ultra-fine particles has been a serious ...problem which should be well solved as the demand for energy is increasing. In this investigation, the flotation behaviors of fresh and oxidized fine coal (<45 μm) and the effect of mixing with coarse particles (250–500 μm) in equal proportions were discussed. Zeta potential and contact angle results indicated the surface hydrophobicity of oxidized fine coal was much lower than that of fresh fine coal. When floating alone, yields of fresh, moderately oxidized, deeply oxidized and very deeply oxidized fine coal were 77.88%, 62.36%, 34.66% and 16.67%, respectively. However, the yields for the above four fine coals were increased to 82.83%, 87.04%, 82.72% and 50.07%, respectively when mixed with coarse particles. The yield improvement indicator values for the four fine coals were 4.95%, 24.68%, 48.06% and 33.40%, respectively. Obviously, the yield improvement indicator values for oxidized fine coals were much higher than fresh fine coal. A similar trend was also observed in the experiments without collector. Throughout this research, mixing with hydrophobic coarse coal is proved to be an effective method to improve the flotation behavior of oxidized fine coal.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Coloured travelling salesman problem (CTSP) is an extended model of multiple travelling salesman problems (MTSPs), as one kind of problem in combination optimisation problems, which has been applied ...to many real-world planning problems such as multi-machine engineering system (MES). Population-based algorithms such as genetic algorithm (GA) and simulated annealing (SA) algorithm are only used to solve small- or medium-scale cases in which the city number is <2000. Furthermore, in term of the convergence speed and solution quality, their performances have further improvement space. Since many real-world problems can be modelled by large-scale CTSP, it is necessary to study better algorithms to solve large-scale CTSP. Since artificial bee colony algorithm (ABC) can show good performance in solving combination optimisation problems, and therefore this study applied improved ABC algorithms to solve large-scale CTSP. The modified ABC algorithms use generating neighbourhood solution (GNS) to improve ABC for this problem, two limitation and optimisation conditions are applied into GNS during the process of reinserting cities. The extensive experiments verify that the improved algorithms can demonstrate better solution quality than the compared algorithms for large-scale CTSP.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Traditional algorithms, such as genetic algorithm and simulated annealing, have greatly attracted a lot of research studies due to their simplicity and flexibility to solve coloured travelling ...salesman problem (CTSP). However, their performance is limited in solution quality and convergence speed. To improve these limitations, this study presents a fast and effective ant colony optimisation (FEACO) algorithm. In the proposed FEACO, a new pheromone updating mechanism is incorporated into the traditional ant colony optimisation (ACO) to improve its performance. Furthermore, a multi-task cooperative learning approach is employed to solve CTSP. In it, multiple tasks in a shared city set are cooperatively carried out by all salesmen, but each task in exclusive city sets is independently performed by an appointed salesman. In ACO and FEACO, feasible solutions can be found for CTSP by cooperative learning, which is carried out by the cooperation of a set of ants. During the process, ants can cooperate to find good solutions by utilising the pheromone deposited on the paths while ants pass them. Compared with state-of-the-art algorithms, the experimental results on both small scale and larger scale show that the proposed method has potential to provide an improvement in solution quality and convergence speed.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Accumulating evidence suggests that prenatal stress (PNS) increases offspring susceptibility to depression, but the underlying mechanisms remain unclear. We constructed a mouse model of prenatal ...stress by spatially restraining pregnant mice from 09:00-11:00 daily on Days 5-20 of gestation. In this study, western blot analysis, quantitative real-time PCR (qRT‒PCR), immunofluorescence, immunoprecipitation, chromatin immunoprecipitation (ChIP), and mifepristone rescue assays were used to investigate alterations in the GR/P300-MKP1 and downstream ERK/CREB/TRKB pathways in the brains of prenatally stressed offspring to determine the pathogenesis of the reduced neurogenesis and depression-like behaviors in offspring induced by PNS. We found that prenatal stress leads to reduced hippocampal neurogenesis and depression-like behavior in offspring. Prenatal stress causes high levels of glucocorticoids to enter the fetus and activate the hypothalamic‒pituitary‒adrenal (HPA) axis, resulting in decreased hippocampal glucocorticoid receptor (GR) levels in offspring. Furthermore, the nuclear translocation of GR and P300 (an acetylation modifying enzyme) complex in the hippocampus of PNS offspring increased significantly. This GR/P300 complex upregulates MKP1, which is a negative regulator of the ERK/CREB/TRKB signaling pathway associated with depression. Interestingly, treatment with a GR antagonist (mifepristone, RU486) increased hippocampal GR levels and decreased MKP1 expression, thereby ameliorating abnormal neurogenesis and depression-like behavior in PNS offspring. In conclusion, our study suggested that the regulation of the MKP1 signaling pathway by GR/P300 is involved in depression-like behavior in prenatal stress-exposed offspring and provides new insights and ideas for the fetal hypothesis of mental health.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
In view of the problem that it is difficult to accurately determine the maximum subsidence value of the surface of the fully mechanized caving face, according to the characteristics of movement, ...deformation and damage of overburden in goaf and the law of mine pressure appearance, it is proposed that the height of the remaining free space of the overburden is equal to the maximum subsidence of the surface. Through the analysis of the spatial transformation relationship between the residual free space height of overburden and the mining height, the height of caving zone and the residual swelling height of caving rock mass, the calculation model of the maximum subsidence value of the working face to be mined is established. Taking the S2S2 working face of Daping Mine as an example, the maximum subsidence value of the surface obtained by the calculation model is 11.17 m, and the maximum subsidence value obtained by the actual measurement is 11.07 m. The relative error between the calculation result and the actual
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