Dynamic response mechanism and precursor characteristics of gneiss rockburst under different initial burial depths

To investigate the influence mechanism of geostress on rockburst characteristics,three groups of gneiss rockburst experiments were conducted under different initial geostress conditions.A high-speed photography system and acoustic emission(AE)monitoring system were used to monitor the entire rockburst process in real time.The experimental results show that when the initial burial depth increases from 928 m to 1320 m,the proportion of large fracture scale in rockburst increases by 154.54%,and the AE energy increases by 565.63%,reflecting that the degree and severity of rockburst increase with the increase of burial depth.And then,two mechanisms are proposed to explain this effect,including(i)the increase of initial geostress improves the energy storage capacity of gneiss,and then,the excess energy which can be converted into kinetic energy of debris ejection increases,consequently,a more pronounced violent ejection phenomenon is observed at rockburst;(ii)the increase of initial geostress causes more sufficient plate cracks of gneiss after unloading ofσh,which provides a basis for more severe ejection of rockburst.What’s more,a precursor with clear physical meaning for rockburst is proposed under the framework of dynamic response process of crack evolution.Finally,potential value in long term rockburst warning of the precursor obtained in this study is shown via the comparison of conventional precursor.

Investigation of granite failure precursor under axial load using modified LSTM framework

Granite is usually composed of quartz,biotite,feldspar,and cracks,and the variation characteristics of these components could reflect the deformation and failure process of rock well.Taking granite as an example,the video camera was used to record the deformation and failure process of rock.The distribution of meso-components in video images was then identified.The meso-components of rock failure precursors were also discussed.Moreover,a modified LSTM(long short-term memory method)based on SSA(sparrow search algorithm)was proposed to estimate the change of meso-components of rock failure precursor.It shows that the initiation and expansion of cracks are mainly caused by feldspar and quartz fracture,and when the quartz and feldspar exit the stress framework,rock failure occurs;the second large increase of crack area and the second large decrease of quartz or feldspar area may be used as a precursor of rock failure;the precursor time of rock failure based on meso-scopic components is about 4 s earlier than that observed by the naked eye;the modified LSTM network has the strongest estimation ability for quartz area change,followed by feldspar and biotite,and has the worst estimation ability for cracks;when using the modified LSTM network to predict the precursors of rock instability and failure,quartz and feldspar could be given priority.The results presented herein may provide reference in the investigation of rock failure mechanism.

Stabilizing perovskite precursors with the reductive natural amino acid for printable mesoscopic perovskite solar cells

Solution processability significantly advances the development of highly-efficient perovskite solar cells.However,the precursor solution tends to undergo irreversible degradation reactions,impairing the device performance and reproducibility.Here,we utilize a reductive natural amino acid,Nacetylcysteine(NALC),to stabilize the precursor solution for printable carbon-based hole-conductorfree mesoscopic perovskite solar cells.We find that I_(2) can be generated in the aged solution containing methylammonium iodide(MI) in an inert atmosphere and speed up the MA-FA^(+)(formamidinium) reaction which produces large-size cations and hinders the formation of perovskite phase.NALC effectively stabilizes the precursor via its sulfhydryl group which reduces I_(2) back to I^(-)and provides H^(+).The NALC-stabilized precursor which is aged for 1440 h leads to devices with a power conversion efficiency equivalent to 98% of that for devices prepared with the fresh precursor.Furthermore,NALC improves the device power conversion efficiency from 16.16% to 18.41% along with enhanced stability under atmospheric conditions by modifying grain boundaries in perovskite films and reducing associated defects.

Precursor engineering enables high-performance all-inorganic CsPbIBr_(2) perovskite solar cells with a record efficiency approaching 13%

All-inorganic CsPbIBr_(2) perovskite has attracted widespread attention in photovoltaic and other optoelectronic devices because of its superior thermal stability.However,the deposition of high-quality solutionprocessed CsPbIBr_(2) perovskite films with large thicknesses remains challenging.Here,we develop a triple-component precursor(TCP) by employing lead bromide,lead iodide,and cesium bromide,to replace the most commonly used double-component precursor(DCP) consisting of lead bromide and cesium iodide.Remarkably,the TCP system significantly increases the solution concentration to 1.3 M,leading to a larger film thickness(~390 nm) and enhanced light absorption.The resultant CsPbIBr_(2) films were evaluated in planar n-i-p structured solar cells,which exhibit a considerably higher optimal photocurrent density of 11.50 mA cm^(-2) in comparison to that of DCP-based devices(10.69 mA cm^(-2)).By adopting an organic surface passivator,the maximum device efficiency using TCP is further boosted to a record efficiency of 12.8% for CsPbIBr_(2) perovskite solar cells.

Disinfection Byproducts and Their Precursors in Drinking Water Sources:Origins,Influencing Factors,and Environmental Insights

Tracing the contamination origins in water sources and identifying the impacts of natural and human processes are essential for ecological safety and public health.However,current analysis approaches are not ideal,as they tend to be laborious,time-consuming,or technically difficult.Disinfection byproducts(DBPs)are a family of well-known secondary pollutants formed by the reactions of chemical disinfectants with DBP precursors during water disinfection treatment.Since DBP precursors have various origins(e.g.,natural,domestic,industrial,and agricultural sources),and since the formation of DBPs from different precursors in the presence of specific disinfectants is distinctive,we argue that DBPs and DBP precursors can serve as alternative indicators to assess the contamination in water sources and identify pollution origins.After providing a retrospective of the origins of DBPs and DBP precursors,as well as the specific formation patterns of DBPs from different precursors,this article presents an overview of the impacts of various natural and anthropogenic factors on DBPs and DBP precursors in drinking water sources.In practice,the DBPs(i.e.,their concentration and speciation)originally present in source water and the DBP precursors determined using DBP formation potential tests—in which water samples are dosed with a stoichiometric excess of specific disinfectants in order to maximize DBP formation under certain reaction conditions—can be considered as alternative metrics.When jointly used with other water quality parameters(e.g.,dissolved organic carbon,dissolved organic nitrogen,fluorescence,and molecular weight distribution)and specific contaminants of emerging concern(e.g.,certain pharmaceuticals and personal care products),DBPs and DBP precursors in drinking water sources can provide a more comprehensive picture of water pollution for better managing water resources and ensuring human health.

Numerical Simulation of the Mechanical Stirring Process in a Tannin-Based Foaming Precursor Resin

Tannin foam is a new functional material.It can be widely applied to the automobile industry,construction industry,and packaging industry due to its wide range of raw materials,renewable,easily degraded,low cost and almost no pollution.Preparing tannin foam is a very complex process that includes high temperature,two phases,mechanical agitation,and phase change.To investigate the influence of the stirring velocity and paddle shape,simulation was calculated by making use of the volume of fluid(VOF)method and multiple reference frame(MRF)method in a three-dimensional flow field of tannin-based foaming precursor resin.The gas holdup and velocity magnitude were analysed with various conditions of mechanical velocities and paddle shape in the stirring flow field.The result shows the higher the velocity,the greater the disturbance and paddle shape between the eggbeater and the Rushton turbine,obviously the paddle shape of the eggbeater with a wider range of agitation,which can entrap more air into the tannin-based foaming precursor resin in a short time.Especially when the speed is 1500 rpm,the flow field of the Rushton turbine comes out of a ditch,which decreases the efficiency of mass transfer;there is less air to mix into the tannin-based foaming precursor resin,which causes unevenness.At the same time,the eggbeater shows the marvelous capability of hybrid as it has two vortexes and multiple cycles that make a difference from the Rushton turbine,which has only one vortex and two upper and lower loops;the structure makes the flow field more stable allowed evenness of flow field tannin-based foaming precursor resin.The results reveal that it is beneficial for tannin-based foaming precursor resin to use an eggbeater with a speed of 1500 rpm to reduce the consumption of resources while obtaining a uniform flow field.

Highly Defective Dark TiO_(2) Modified with Pt: Effects of Precursor Nature and Preparation Method on Photocatalytic Properties

The study focused on the modification with platinum of dark defective titania obtained via pulsed laser ablation. Both the method of Pt introduction and the nature of the Pt precursor were varied. All samples exhibited similar phase compositions, specific surface areas, and Pt contents. High-resolution transmission electron microscopy coupled with pulsed CO adsorption revealed increased dispersity when photoreduction and the hydroxonitrate complex (Me _(4) N) _(2) [Pt _(2) (OH) _(2) (NO _(3) ) _(8) ] were used. The sample featured a high content of single-atom species and subnano-sized Pt clusters. The X-ray photoelectron spectroscopy results showed that the photoreduction method facilitated the appearance of a larger number of Pt ^(2+) states, which appeared owing to the strong metal-support interaction (SMSI) eff ect of the transfer of electron density from the electron-saturated defects on the TiO _(2) surface to Pt ^(4+) . In the hydrogen evolution reaction, samples with a significant fraction of the Pt ^(2+) ionic component, capable of generating short-lived Pt^(0) single-atom sites under irradiation due to the SMSI eff ect, exhibited the highest photocatalytic activity. The 0.5Pt(C)/TiO_(2) -Ph sample exhibited the highest hydrogen yield with a quantum efficiency of 0.53, retaining its activity even after 8 h of operation.

Pyrolysis mechanism of ZrC precursor and fabrication of C/C-ZrC composites by precursor infiltration and pyrolysis

C/C-ZrC composites were prepared by precursor infiltration and pyrolysis using the organic zirconium as precursor.The conversion mechanisms of the precursors such as the thermal behavior,structural evolution,phase composition,microstructure,composition of the precursors and products were analyzed by thermal gravimetric analyzer,Fourier transform infrared spectrometer,X-ray diffraction and scanning electron microscope.The results indicate that the ZrC precursor transforms to inorganic ZrO2 from room temperature to 1200 ℃,then reduces to ZrC at 1600 ℃ through the carbothermal reduction reaction.The microstructure of the C/C-ZrC composites was also investigated.The composites exhibit an interesting structure,a coating composed of ZrC ceramic covers the exterior of the composite,and the ZrC ceramic is embedded in the pores of the matrix inside the composite.

Precursor solution prepared by evaporation deamination complex method for solvent separation of Mo and W by H_2O_2-complexation

An novel method on preparation of precursor solution for solvent separation of molybdenum （Mo） and tungsten （W） by hydrogen peroxide （H2O2）-complexation from the ammonium tungstate solution containing high Mo was studied. The precursor solution was obtained via evaporation deamination and H202-complex transformation processes. Then it was extracted with a mixture extractant of tri-alkyl phosphine oxide （TRPO） and tributyl phosphate （TBP） to separate Mo and W. The results indicated that the evaporation deamination complex method reduced the acid consumption by more than 90% in comparison with the traditional directly acid regulation complex method. The transformation rates of W and Mo were higher than 95% and the decomposition rate of H202 was less than 15% at a 1.8-1.9 times H202 dosage, 45-50 ℃, initial pH of 1.80-1.90, and transformation volume ratio of 100% for 60 min in the H2O2-complexation transformation process. The minimum extraction rate of W was 2%, the maximum extraction rate of Mo was 82.6% and the highest separation coefficient was 76.7 in a single-stage extraction.

Shape-controlled synthesis of novel precursor for fibrous Ni-Co alloy powders

A novel precursor of nickel-cobalt alloy powders with an appropriate Ni to Co molar ratio was prepared under selectively synthetic conditions. The composition and morphology of the precursor were characterized by X-ray diffractometry （XRD）, scanning electron microscopy （SEM）, Fourier transform infrared spectrometry （FT-IR） and energy dispersive spectrometry （EDS）. The effects of pH value, reaction temperature, metal ion concentrations and surfactant on the morphology and the dispersion of precursor were investigated. The results show that the morphology of precursor depends on ammonia content in the precursor. A fibriform precursor is a complicated ammonia-containing nickel-cobalt oxalate. The uniform shape-controlled fibrous precursor is obtained under the following optimum conditions： ammonia as complex agent as well as pH adjustor, oxalate as coprecipitator, 50-65 °C of reaction temperature, 0.5-0.8 mol/L of total concentration of Ni2＋ and Co2＋, PVP as dispersant, and pH 8.0-8.4.

Thermodynamic analysis on synthesis of fibrous Ni-Co alloys precursor and Ni/Co ratio control

According to the principles of simultaneous equilibrium and mass equilibrium, a series of thermodynamic equilibrium equations in Ni（II）-Co（II）-C2O4^2--NH3-NH4^＋-H2O system at ambient temperature were deduced. The diagrams of logarithm ion concentrations versus pH values at different solution compositions were drawn. The results show that Ni^2＋ and Co^2＋ can completely precipitate at pH less than 5.0 and the predefined Ni/Co ratios can be well kept in the precursor. The precursor morphology is granular aggregation. However, rod aggregation precursor is obtained in the pH range of 5.0-8.0, and fibre-shape precursor is got at pH value higher than 8.0. The Ni/Co ratios in the above two precursors are not reproduced as that in the feed due to the formhtion of multi-coordinated Ni（NH3）n^2＋ and Co（NH3）n^2＋ （n=1-6）. Modification of precipitation medium is favorable for the precursors to keep the predefined Ni/Co ratios of the feed in the pH range of 2.0-8.6. Meanwhile, the precursors with fibrous morphology can be obtained.

家蚕孤雌生殖差异脂蛋白30K lipoprotein precursor基因的克隆与生物信息学分析

应用二维凝胶电泳（2-DE）技术分离家蚕孤雌生殖蚁蚕总蛋白，并和正常蚁蚕总蛋白进行比较，得到46个可能与家蚕孤雌生殖相关的差异蛋白点。对这些差异蛋白点进行胶内酶解后基质辅助激光解吸电离串联飞行时间质谱（MALDI-TOF-TOFMS）分析，经数据库搜索鉴定，确定其中一个差异蛋白点为脂蛋白30Klipoprotein precursor（30KLPP）。通过5′-RACE技术克隆到30KLPP脂蛋白的全长cDNA序列。生物信息学分析显示该差异蛋白基因全长917bp。编码261个氨基酸，理论分子质量为30．013kD，等电点为7．193；结构域和三级结构预测显示该蛋白包含1个Lipoprotein_11结构域和12个β-折叠。预测其信号肽概率为1．000，定位在1～20aa区域，即可能存在信号肽。细胞定位预测显示该蛋白可能分泌到胞外（SP值为0．934）。分析结果有助于进一步研究30KLPP脂蛋白结构与功能的关系。

脯氨酰羟化酶2抑制剂cpd17对小鼠成骨前体细胞的影响

背景:脯氨酰羟化酶2抑制剂能够调节骨代谢,改善卵巢切除大鼠骨质疏松。cpd17是中国药科大学最新研发的一款小分子口服脯氨酰羟化酶2抑制剂,用于治疗肾性贫血疗效肯定,不良反应小,但是对骨形成和骨吸收的作用还不清楚。目的:探讨脯氨酰羟化酶2抑制剂cpd17对成骨前体细胞的影响。方法:采用cpd17处理C57BL/6小鼠成骨前体细胞,检测碱性磷酸酶活性和细胞外基质矿化程度,检测成骨、破骨相关标志物以及脯氨酰羟化酶2、低氧诱导因子1α的表达水平。使用低氧诱导因子1α通路抑制剂LW6抑制低氧诱导因子1α通路后,再次检测碱性磷酸酶活性和细胞外基质矿化程度,以及成骨和破骨分化相关标志物以及脯氨酰羟化酶2、低氧诱导因子1α的表达水平。结果与结论:cpd17能显著增强碱性磷酸酶活性和基质矿化程度,上调成骨分化相关标志物的表达,下调破骨分化相关标志物的表达,并上调低氧诱导因子1α表达,下调脯氨酰羟化酶2的表达。而LW6能明显减弱cpd17的作用。结果表明,脯氨酰羟化酶2抑制剂cpd17可通过激活低氧诱导因子1α信号通路促进成骨分化和抑制破骨分化。

Observation of amyloid precursor protein cleavage and Aβ generation in living cells by using multiphoton laser scanning microscopy

Objective To investigate the proteolytic mechanism of amyloid precursor protein （APP） and to explore amyloidbeta （Aβ） generation in living neurons. Methods DNA fragments were amplified by PCR or synthesized. The four fragments, CFP, 54bp, YFP and C99 were ligated into pcDNA3.0 vector to construct the recombinant plasmids pcDNA3.0-CFP-54bp- YFP and pcDNA3.0-CFP-54bp-YFP-C99. The SH-SY5Y cells were transiently transfected with pcDNA3.0-CFP-54bp-YFP or pcDNA3.0-CFP-54bp-YFP-C99. The expression of fusion gene was examined under a multiphoton laser scanning microscope. Fluorescence resonance energy transfer （FRET） was used to measure the β cleavage and γ cleavage of APE Aβ generation was confirmed by immunocytochemistry and multiphoton laser scanning microscopy. Cell viability was tested by MTT assay at different time points. Results （1） The double restriction endonuclease digestion and sequencing analysis confirmed the authenticity of the recombinant plasmids pcDNA3.0-CFP-54bp-YFP and pcDNA3.0-CFP-54bp- YFP-C99. （2） Blue and yellow fluorescences were detected in the transfected cells. （3） FRET occurred in pcDNA3.0-CFP- 54bp-YFP-transfected cells but not in pcDNA3.0-CFP-54bp-YFP-C99-transfected cells. （4） Aβ was produced in the pcDNA3.0- CFP-54bp-YFP-C99 transfected cells. （5） Aβ-deposition was widespread in the cell. （6） Cell viability decreased along with the intracellular Aβ deposition. Conclusion C99 is important for the APP β cleavage. Aβ may be generated and deposited in cells at the early stage of Alzheimer＇s disease. Intracellular Aβ accumulation brings deleterious effects on cells.

Cloning and Sequence Analysis of 5′ Flanking Region and Exon of Inhibin α Precursor Gene in Goats

[Objective] The aim of this study was to reveal the relationship between inihibin （INH） α precursor gene and seasonal reproduction of goats, and investigate the evolutionary conservation of INHα precursor gene. [ Method] Cloning and sequence analysis of 5＇ flanking region and exon of inihibinα （INHE） precursor gene in twenty ewes between non-seasonal estrous breed （Haimen goats） and seasonal estrous breed （Anhui white goats） was analyzed in this study. [ Result] Compared with Anhui white goats, INHα precursor gene in Haimen goats had three SNP but no amino acid change, while its nucleotide homology was 99.7% and amino acid homology was 100%. The nucleotide homology of INHα precursor gene in goat, cattle, pig, person, chicken, horse, rat and dog ranged from 12.7% to 96.5%. [ Conclusion] INHα precursor gene tends to be highly conserved in species, and any change of nucleotide and amino acid maybe directly influence the function of the whole gene coding and regulation.

Effect of Three Precursors on Accumulation of Principal Volatile Oil Constituents in Tissue Culture Plantlets of Atractylodes lancea (Thunb.) DC.

[Objective] This study was to explore the effect of three precursors on the accumulation of principal volatile oil constituents in tissue culture plantlets of Atractylodes lancea （Thunb.） DC. with the aim to provide references for the improvement of artificial cultivated A. lancea quality. [Method] Three precursors were added into the MS rooting medium for A. lancea tissue culture plantlets and the volatile oil was extracted by ultrasonication after cultured for several days. The content of atractylon, atractylol, β-eucalyptol and atractydin in the volatile oil were determined by using gas chromatography method. [Result] The addition of xylose, isoprene and tetrahydrofuran impacted the growth indicators, yield of volatile oil and relative percentage content of the four constituents of A. lancea tissue culture plantlets. In the 6 g/L xylose optimized medium, the atractylon and β-eucalyptol content reached up to 4.23% and 56.34%, respectively, 1.41% and 1.66% higher than the control; although the addition of isoprene into medium raised the atractylon content, the accumulation of total volatile oil was inhibited that it decreased by 23.67%, 31.06% and 7.10% to the control; for the tetrahydrofuran optimized medium, the content of atractylon, atractylol and atractydin all increased, and the total volatile oil content increased by 49.97% to the control when the concentration of tetrahydrofuran was 0.07 g/L. [Conclusion] The addition of xylose and tetrahydrofuran promoted the accumulation of principal constituents of the volatile oil, whereas the addition of isoprene inhibited the accumulation.

Emerging structures and dynamic mechanisms ofγ-secretase for Alzheimer’s disease

γ-Secretase,called“the proteasome of the membrane,”is a membrane-embedded protease complex that cleaves 150+peptide substrates with central roles in biology and medicine,including amyloid precursor protein and the Notch family of cell-surface receptors.Mutations inγ-secretase and amyloid precursor protein lead to early-onset familial Alzheimer’s disease.γ-Secretase has thus served as a critical drug target for treating familial Alzheimer’s disease and the more common late-onset Alzheimer’s disease as well.However,critical gaps remain in understanding the mechanisms of processive proteolysis of substrates,the effects of familial Alzheimer’s disease mutations,and allosteric modulation of substrate cleavage byγ-secretase.In this review,we focus on recent studies of structural dynamic mechanisms ofγ-secretase.Different mechanisms,including the“Fit-Stay-Trim,”“Sliding-Unwinding,”and“Tilting-Unwinding,”have been proposed for substrate proteolysis of amyloid precursor protein byγ-secretase based on all-atom molecular dynamics simulations.While an incorrect registry of the Notch1 substrate was identified in the cryo-electron microscopy structure of Notch1-boundγ-secretase,molecular dynamics simulations on a resolved model of Notch1-boundγ-secretase that was reconstructed using the amyloid precursor protein-boundγ-secretase as a template successfully capturedγ-secretase activation for proper cleavages of both wildtype and mutant Notch,being consistent with biochemical experimental findings.The approach could be potentially applied to decipher the processing mechanisms of various substrates byγ-secretase.In addition,controversy over the effects of familial Alzheimer’s disease mutations,particularly the issue of whether they stabilize or destabilizeγ-secretase-substrate complexes,is discussed.Finally,an outlook is provided for future studies ofγ-secretase,including pathways of substrate binding and product release,effects of modulators on familial Alzheimer’s disease mutations of theγ-secretase-substrate complexes.Comprehensive understanding of the functional mechanisms ofγ-secretase will greatly facilitate the rational design of effective drug molecules for treating familial Alzheimer’s disease and perhaps Alzheimer’s disease in general.

miRNA-21-5p is an important contributor to the promotion of injured peripheral nerve regeneration using hypoxia-pretreated bone marrow-derived neural crest cells

Our previous study found that rat bone marrow–derived neural crest cells(acting as Schwann cell progenitors)have the potential to promote long-distance nerve repair.Cell-based therapy can enhance peripheral nerve repair and regeneration through paracrine bioactive factors and intercellular communication.Nevertheless,the complex contributions of various types of soluble cytokines and extracellular vesicle cargos to the secretome remain unclear.To investigate the role of the secretome and extracellular vesicles in repairing damaged peripheral nerves,we collected conditioned culture medium from hypoxia-pretreated neural crest cells,and found that it significantly promoted the repair of sensory neurons damaged by oxygen-glucose deprivation.The mRNA expression of trophic factors was highly expressed in hypoxia-pretreated neural crest cells.We performed RNA sequencing and bioinformatics analysis and found that miR-21-5p was enriched in hypoxia-pretreated extracellular vesicles of neural crest cells.Subsequently,to further clarify the role of hypoxia-pretreated neural crest cell extracellular vesicles rich in miR-21-5p in axonal growth and regeneration of sensory neurons,we used a microfluidic axonal dissociation model of sensory neurons in vitro,and found that hypoxia-pretreated neural crest cell extracellular vesicles promoted axonal growth and regeneration of sensory neurons,which was greatly dependent on loaded miR-21-5p.Finally,we constructed a miR-21-5p-loaded neural conduit to repair the sciatic nerve defect in rats and found that the motor and sensory functions of injured rat hind limb,as well as muscle tissue morphology of the hind limbs,were obviously restored.These findings suggest that hypoxia-pretreated neural crest extracellular vesicles are natural nanoparticles rich in miRNA-21-5p.miRNA-21-5p is one of the main contributors to promoting nerve regeneration by the neural crest cell secretome.This helps to explain the mechanism of action of the secretome and extracellular vesicles of neural crest cells in repairing damaged peripheral nerves,and also promotes the application of miR-21-5p in tissue engineering regeneration medicine.

Regulator of G protein signaling 6 mediates exercise-induced recovery of hippocampal neurogenesis,learning,and memory in a mouse model of Alzheimer’s disease

Hippocampal neuronal loss causes cognitive dysfunction in Alzheimer’s disease.Adult hippocampal neurogenesis is reduced in patients with Alzheimer’s disease.Exercise stimulates adult hippocampal neurogenesis in rodents and improves memory and slows cognitive decline in patients with Alzheimer’s disease.However,the molecular pathways for exercise-induced adult hippocampal neurogenesis and improved cognition in Alzheimer’s disease are poorly understood.Recently,regulator of G protein signaling 6(RGS6)was identified as the mediator of voluntary running-induced adult hippocampal neurogenesis in mice.Here,we generated novel RGS6fl/fl;APP_(SWE) mice and used retroviral approaches to examine the impact of RGS6 deletion from dentate gyrus neuronal progenitor cells on voluntary running-induced adult hippocampal neurogenesis and cognition in an amyloid-based Alzheimer’s disease mouse model.We found that voluntary running in APP_(SWE) mice restored their hippocampal cognitive impairments to that of control mice.This cognitive rescue was abolished by RGS6 deletion in dentate gyrus neuronal progenitor cells,which also abolished running-mediated increases in adult hippocampal neurogenesis.Adult hippocampal neurogenesis was reduced in sedentary APP_(SWE) mice versus control mice,with basal adult hippocampal neurogenesis reduced by RGS6 deletion in dentate gyrus neural precursor cells.RGS6 was expressed in neurons within the dentate gyrus of patients with Alzheimer’s disease with significant loss of these RGS6-expressing neurons.Thus,RGS6 mediated voluntary running-induced rescue of impaired cognition and adult hippocampal neurogenesis in APP_(SWE) mice,identifying RGS6 in dentate gyrus neural precursor cells as a possible therapeutic target in Alzheimer’s disease.

Treadmill exercise in combination with acousto-optic and olfactory stimulation improves cognitive function in APP/PS1 mice through the brain-derived neurotrophic factor-and Cygb-associated signaling pathways

A reduction in adult neurogenesis is associated with behavioral abnormalities in patients with Alzheimer's disease.Consequently,enhancing adult neurogenesis represents a promising therapeutic approach for mitigating disease symptoms and progression.Nonetheless,nonpharmacological interventions aimed at inducing adult neurogenesis are currently limited.Although individual non-pharmacological interventions,such as aerobic exercise,acousto-optic stimulation,and olfactory stimulation,have shown limited capacity to improve neurogenesis and cognitive function in patients with Alzheimer's disease,the therapeutic effect of a strategy that combines these interventions has not been fully explored.In this study,we observed an age-dependent decrease in adult neurogenesis and a concurrent increase in amyloid-beta accumulation in the hippocampus of amyloid precursor protein/presenilin 1 mice aged 2-8 months.Amyloid deposition became evident at 4 months,while neurogenesis declined by 6 months,further deteriorating as the disease progressed.However,following a 4-week multifactor stimulation protocol,which encompassed treadmill running(46 min/d,10 m/min,6 days per week),40 Hz acousto-optic stimulation(1 hour/day,6 days/week),and olfactory stimulation(1 hour/day,6 days/week),we found a significant increase in the number of newborn cells(5'-bromo-2'-deoxyuridine-positive cells),immature neurons(doublecortin-positive cells),newborn immature neurons(5'-bromo-2'-deoxyuridine-positive/doublecortin-positive cells),and newborn astrocytes(5'-bromo-2'-deoxyuridine-positive/glial fibrillary acidic protein-positive cells).Additionally,the amyloid-beta load in the hippocampus decreased.These findings suggest that multifactor stimulation can enhance adult hippocampal neurogenesis and mitigate amyloid-beta neuropathology in amyloid precursor protein/presenilin 1 mice.Furthermore,cognitive abilities were improved,and depressive symptoms were alleviated in amyloid precursor protein/presenilin 1 mice following multifactor stimulation,as evidenced by Morris water maze,novel object recognition,forced swimming test,and tail suspension test results.Notably,the efficacy of multifactor stimulation in consolidating immature neurons persisted for at least 2weeks after treatment cessation.At the molecular level,multifactor stimulation upregulated the expression of neuron-related proteins(NeuN,doublecortin,postsynaptic density protein-95,and synaptophysin),anti-apoptosis-related proteins(Bcl-2 and PARP),and an autophagyassociated protein(LC3B),while decreasing the expression of apoptosis-related proteins(BAX and caspase-9),in the hippocampus of amyloid precursor protein/presenilin 1 mice.These observations might be attributable to both the brain-derived neurotrophic factor-mediated signaling pathway and antioxidant pathways.Furthermore,serum metabolomics analysis indicated that multifactor stimulation regulated differentially expressed metabolites associated with cell apoptosis,oxidative damage,and cognition.Collectively,these findings suggest that multifactor stimulation is a novel non-invasive approach for the prevention and treatment of Alzheimer's disease.