Sorl1 knockout inhibits expression of brain-derived neurotrophic factor:involvement in the development of late-onset Alzheimer's disease

Sortilin-related receptor 1(SORL1)is a critical gene associated with late-onset Alzheimer’s disease.SORL1 contributes to the development and progression of this neurodegenerative condition by affecting the transport and metabolism of intracellularβ-amyloid precursor protein.To better understand the underlying mechanisms of SORL1 in the pathogenesis of late-onset Alzheimer s disease,in this study,we established a mouse model of SorI1 gene knockout using cluste red regularly inters paced short palindro mic repeats-associated protein 9 technology.We found that Sorl1-knocko ut mice displayed deficits in learning and memory.Furthermore,the expression of brain-derived neurotrophic factor was significantly downregulated in the hippocampus and co rtex,and amyloidβ-protein deposits were observed in the brains of 5orl1-knockout mice.In vitro,hippocampal neuronal cell synapses from homozygous Sorl1-knockout mice were impaired.The expression of synaptic proteins,including Drebrin and NR2B,was significantly reduced,and also their colocalization.Additionally,by knocking out the Sorl1 gene in N2a cells,we found that expression of the N-methyl-D-aspartate receptor,NR2B,and cyclic adenosine monophosphate-response element binding protein was also inhibited.These findings suggest that SORL1 participates in the pathogenesis of late-onset Alzheimer s disease by regulating the N-methyl-D-aspartate receptor NR2B/cyclic adenosine monophosphate-response element binding protein signaling axis.

Determination of full-scale pore size distribution of Gaomiaozi bentonite and its permeability prediction

Gaomiaozi(GMZ)bentonite is a potential buffer/backfill material for a deep geological disposal of highlevel radioactive waste.It has a wide pore size distribution(PSD)with sizes ranging from several nanometers to more than one hundred microns.Thus,properly characterizing the pore structures of GMZ bentonite is a challenging issue.In this study,pressure-controlled porosimetry(PCP),ratecontrolled porosimetry(RCP),and scanning electron microscopy(SEM)were used to investigate the PSD of GMZ bentonite,The results indicate that each method has its limitation,and a combined use of PCP and RCP is suitable to obtain the full-scale PSD of GMZ bentonite.Moreover,we also compared the full-scale PSD with nuclear magnetic resonance(NMR)result.It is found that there is no significant difference in the range of PSD characterization between NMR and mercury intrusion method(PCP and RCP).However,in a ce rtain range,the detection accuracy of NMR is higher than that of mercury injection method.Finally,permeability prediction based on PCP and SEM data was conducted,and both of the two methods were found to be able to predict the permeability.The combined method is effective to obtain the full-scale PSD of GMZ bentonite,which is the key to estimation of the sealing ability of bentonite buffer.

Quantitative two/three-dimensional spatial characterization and fluid transport prediction of macro/micropores in Gaomiaozi bentonite

The sealing performance of a bentonite barrier is highly dependent on its seepage characteristics, which are directly related to the characteristics of its pore structure. Based on scanning electron microscopy(SEM) and focused ion beam-SEM(FIB-SEM), the pore structure of bentonite was characterized at different scales. First, a reasonable gray threshold was determined through back analysis, and the image was binarized based on the threshold. In addition, binary images were used to analyze bentonite’s pore structure(porosity and pore size distribution). Furthermore, the effects of different algorithms on the pore structure characterization were evaluated. Then, permeability calculations were performed based on the previous pore structure characteristics and a modified permeability prediction model. For permeability prediction based on the three-dimensional model, the effect of pore tortuosity was also considered. Finally, the accuracy of numerical calculations was verified by conducting macroscopic gas and alcohol permeability experiments. This approach provides a better understanding of the microscale mechanism of gas transport in bentonite and the importance of pore structures at different scales in determining its seepage characteristics.

Investigation of Photocatalytic Degradation of Methyl Orange by Using Nano-Sized ZnO Catalysts

Nano-sized ZnO catalysts were prepared by a direct precipitation method under the optimal conditions (cal-cination of precursors at 550?C for 120 min). The as-synthesized ZnO catalysts were characterized by X-ray diffraction (XRD), scanning electron microscope (SEM) and UV-Vis spectroscopy. The photocatalytic prop-erties of ZnO nanoparticles were investigated via methyl orange (MO) as a model organic compound under UV light irradiation. The influence of operating parameters on MO degradation including the amount of ZnO catalysts, pH value of solutions, and the photodegradation temperature was thoroughly examined. In addition, the kinetic process of photocatalytic degradation of MO using nano-sized ZnO catalyst was also examined, and the degradation of MO follow the first order kinetics.

Analysis and Discussion on Subway Construction Accidents from Geological Perspective

Several cave-in accidents often occur in subway construction,causing personnel and economic losses.This paper has carried on the statistics and analysis of some typical subway construction accidents in recent years.Taking the collapse accident of a subway station in Hangzhou as the engineering background,the causes of the collapse of the foundation pit were analyzed.The analysis found that groundwater,earthwork over-excavation,weak support design and inadequate monitoring are the main reasons.These factors should be highlighted in the construction of similar projects in the future to avoid similar tragedies.

Targeting complement hyperactivation:a novel therapeutic approach for severe pneumonia induced by influenza virus/staphylococcus aureus coinfection

Dear Editor,Infections by the influenza virus are a significant and widespread global health threat,as these infections have an annual death toll ranging from 290,000 to 650,000.1 A significant proportion of these fatalities are attributed to secondary bacterial pneumonia,a severe complication commonly caused by ubiquitous respiratory pathogens such as Staphylococcus aureus(S.aureus).2 Of particular concern is the increased morbidity and mortality rates in individuals infected simultaneously with influenza virus and methicillin-resistant S.aureus(MRSA).3 The concurrent presence of bacteria and influenza virus usually causes acute respiratory distress syndrome(ARDS),which is associated with acute lung injury(ALI),severe lung tissue edema,and widespread inflammation.Nevertheless,determining the complex mechanisms underlying the synergistic interplay will require further investigation with a suitable coinfection mouse model.In our previous study,we utilized different sequential coinfections at various time points to model influenza A virus and MRSA coinfection.

野生建兰根系共生真菌群落结构及生物学功能

【目的】为探究建兰Cymbidium ensifolium根系共生真菌群落结构及生物学功能。【方法】利用高通量测序技术和FunGulid数据库,对来自湖南省(HN)、福建省(FJ)、贵州省(GZ)和云南省(YN)的4个样品的野生建兰根围土壤、根表和根内3个生态位的共生真菌种群结构与功能进行鉴定和预测。【结果】建兰根系共生真菌分布在12门44纲103目241科432属中,优势门类为担子菌门Basidiomycota(49.51%)、子囊菌门Ascomycota(27.39%)和被孢霉门Mortierellomycota(20.22%),在属水平上,被孢霉属(Mortierella)(11.75%)、Saitozyma(11.45%)和Papiliotrema(7.93%)为优势属。不同建兰样品的真菌营养类型相差较大,但每个样品在根围土壤和根表间的真菌营养类型相似度高,根内菌均以腐生型为绝对优势类型(50.11%–85.98%),其中FJ样品较为特殊,3个生态位均以腐生营养型占绝对优势(85.98%–94.76%)。根围土壤和根表都以病理-腐生-共生混合型真菌为主,除此之外GZ样品的共生营养型,YN样品的腐生型、共生型,HN样品的腐生型也均为各自的优势营养类型。【结论】建兰根系共生真菌种类多样性丰富,各样品和各生态位点间的共生真菌群落结构均存在极显著差异。建兰根系共生真菌存在的潜在有益真菌包括被孢霉属、红菇属(Russula)、Saitozyma、Papiliotrema、Cladophialophora等。该研究为揭示建兰根部与真菌的共生关系,以及为建兰共生真菌的开发利用提供了理论基础。

Gefitinib and fostamatinib target EGFR and SYK to attenuate silicosis:a multi-omics study with drug exploration

Silicosis is the most prevalent and fatal occupational disease with no effective therapeutics,and currently used drugs cannot reverse the disease progress.Worse still,there are still challenges to be addressed to fully decipher the intricated pathogenesis.Thus,specifying the essential mechanisms and targets in silicosis progression then exploring anti-silicosis pharmacuticals are desperately needed.In this work,multi-omics atlas was constructed to depict the pivotal abnormalities of silicosis and develop targeted agents.By utilizing an unbiased and time-resolved analysis of the transcriptome,proteome and phosphoproteome of a silicosis mouse model,we have verified the significant differences in transcript,protein,kinase activity and signaling pathway level during silicosis progression,in which the importance of essential biological processes such as macrophage activation,chemotaxis,immune cell recruitment and chronic inflammation were emphasized.Notably,the phosphorylation of EGFR(p-EGFR)and SYK(pSYK)were identified as potential therapeutic targets in the progression of silicosis.To inhibit and validate these targets,we tested fostamatinib(targeting SYK)and Gefitinib(targeting EGFR),and both drugs effectively ameliorated pulmonary dysfunction and inhibited the progression of inflammation and fibrosis.Overall,our drug discovery with multi-omics approach provides novel and viable therapeutic strategies for the treatment of silicosis.