New lead discovery for novel M_1 agonists:pharmacophore model based on DISCO computation and virtual screening

To discover new lead compounds for M1 agonists. Ten typical M1 agonists were superimposed to build a M1 agonists 3D-pharmacophore model using distance-comparisons （DISCO） method without the previous knowledge of the three-dimensional structure of M1 receptor. Virtual screening strategy was used to analyze the Available Chemicals Directory-Screening Compounds （ACD-SC） to identify possible new hits. Twenty-two compounds which fit the pharmacophore model well and are not similar with known M1 agonists were purchased in order to evaluate their M1 receptor agonist activity. One of them shows M1 receptor agonist activity with EC50 of 4.90 μmol/L and maximum response. Multiple of 10.0 which shows it worthy of further study as a new lead compound for M1 agonists.

Divalent metal transporter 1 expression and iron deposition in the substantia nigra of a rat model of Parkinson's disease

Extensive iron deposition has been observed in the midbrain substantia nigra （SN） of Parkinson＇s disease （PD） patients, but the mechanisms of iron deposition in the SN remain poorly understood. The present study investigated the relationship between dopaminergic neuronal damage, iron content changes, and divalent metal transporter 1 （DMT1） in the midbrain SN of PD rats to explore the relationship between time of iron deposition and DMT1 expression. Frozen midbrain SN sections from model rats were stained with Perls＇ iron. Results showed massive loss of tyrosine hydroxylase （TH）-positive cells in the SN and increased DMT1 expression in model group rats. No obvious iron deposition was observed in the SN during early stages after damage, but significant iron deposition was detected at 8 weeks post-injury. Results demonstrate that the loss of TH-positive cells in the SN appeared simultaneously with increased DMT1 expression. Extensive iron deposition occurred at 8 weeks post injury, which could be regarded as an early time window of iron deposition.

Outlook of PINK1/Parkin signaling in molecular etiology of Parkinson's disease,with insights into Pink1 knockout models

Parkinson’s disease(PD)relates to defective mitochondrial quality control in the dopaminergic motor network.Genetic studies have revealed that PINK1 and Parkin mutations are indicative of a heightened propensity to PD onset,pinpointing mitophagy and inflammation as the culprit pathways involved in neuronal loss in the substantia nigra(SNpc).In a reciprocal manner,LRRK2 functions in the regulation of basal flux and inflammatory responses responsible for PINK1/Parkin-dependent mitophagy activation.Pharmacological intervention in these diseasemodifying pathways may facilitate the development of novel PD therapeutics,despite the current lack of an established drug evaluation model.As such,we reviewed the feasibility of employing the versatile global Pink1knockout(KO)rat model as a self-sufficient,spontaneous PD model for investigating both disease etiology and drug pharmacology.These rats retain clinical features encompassing basal mitophagic flux changes with PD progression.We demonstrate the versatility of this PD rat model based on the incorporation of additional experimental insults to recapitulate the proinflammatory responses observed in PD patients.

Effects of natural-cerebrolysin-containing serum on neurotoxicity and synaptogenesis in amyloid-beta 1-40-induced Alzheimer's disease in vitro models

BACKGROUND： Neuronal loss, synapse mutilation, and increasing malnourished axons are pathologically related to Alzheimer＇s disease. Microtubule-associated protein 2 （MAP2） is of importance for neuronal, axonal, and dendritic generation, extension, and stabilization, as well as for the regulation of synaptic plasticity. OBJECTIVE： To investigate the antagonistic effects of natural-cerebrolysin-containing serum on beta amyloid protein 1-40 （Aβ1-40）-induced neurotoxicity from the standpoints of cell proliferation, synaptogenesis, and cytoskeleton formation （MAP2 expression）. DESIGN, TIME AND SETTING： A paralleled, controlled, neural cell, and molecular biology experiment was performed at the Institute of Integrated Chinese and Western Medicine, Shenzhen Hospital, Southern Medical University between February 2006 and April 2008. MATERIALS： PC12 cells, derived from the rat central nervous system, were purchased from Shanghai Institute of Cell Biology, Chinese Academy of Sciences, China. A β1-40 was provided by Sigma, USA. Natural-cerebrolysin was provided by Shenzhen Institute of Integrated Chinese and Western Medicine, China. The natural-cerebrolysin was predominantly composed of Renshen （Radix Ginseng）, Tianma （Rhizoma Gastrodiae）, and Yixingye （Ginkgo Leaf） in a proportion of 1：2：2. Following conventional water extraction technology, an extract （1：20） was prepared. Each gram of extract equaled 20 grams of crude drug. In a total of 12 adult male New Zealand rabbits, six underwent intragastric administration of natural-cerebrolysin extract for 1 month to prepare natural-cerebrolysin-containing serum, and the remaining six rabbits received intragastric administration of physiological saline to prepare normal blank serum. METHODS： An AIzheimer＇s disease in vitro model was induced in PC12 cells using Aβ1-40. The cells were incubated with varying doses of natural-cerebrolysin-containing serum （2.5%, 5%, and 10%）. Normal blank serum-treated PC12 cells served as a blank control group. MAIN OUTCOME MEASURES： Through the use of inverted phase contrast microscope, cell morphology and neurite growth were observed, neurite length was measured, and the percentage of neurite-positive cells was calculated. Cell proliferation rate was determined by MTT assay, and MAP 2 expression was detected by fluorescent immunocytochemistry. RESULTS： Following Aβ1-40 treatments, some PC12 cells were apoptotic/dying, and only a few short neurites were observed. Following interventions with natural-cerebrolysin-containing serum, the PC12 cells proliferated, there was an increased number of neurites, and neurite length was enhanced. After middle- and high-dose natural-cerebrolysin treatments, the percentage of neurite-positive cells, as well as the average length of neurites, was significantly greater than the normal blank serum-treated PC12 cells （P 〈 0.05 or P 〈 0.01）. Compared with the blank control group, MAP2 expression in the Aβ1-40-treated PC12 cells was significantly inhibited, and the cell proliferation rate was significantly decreased （P 〈 0.01）. Following incubations with natural-cerebrolysin-containing serum, MAP2 expression and cell proliferation rate in the PC12 cells were significantly increased in a dose-dependent manner, compared with treatments with blank control serum （P 〈 0.05 or P 〈 0.01 ）. CONCLUSION： Natural-cerebrolysin exhibited antagonistic effects on neurotoxicity in Aβ1-40 induced Alzheimer＇s disease in vitro models. These effects were likely related to cell proliferation and the upregulation of intracellular MAP2 expression.

Cow milkα_(s1)-casein induces allergic responses in a mouse model of atopy

α_(s1)-Casein is a potential allergen to induce hypersensitivity in cow milk.We had identifiedα_(s1)-casein and its epitopes in previous studies.The present study aimed to evaluate the allergic mechanism ofα_(s1)-casein in a BALB/c mouse model.The levels of specific IgE,mast cell proteinase,histamine and cytokines in sensitized mice were determined,and the clinical and pathological observation were evaluated.Results showed that the levels of specific IgE,mast cell proteinase,histamine,IL-4,IL-5,IL-10 increased significantly with a dose-dependent trend.The local alveolar septum collapsed or thickened,and lymphatic foci were produced in the spleen and thymus,and the inflammatory cells infiltrated in small intestinal mucosa mesenchyme.In conclusion,the levels of specific IgE,mast cell proteinase,histamine,IL-4,IL-5,IL-10 and some inflammatory factors could possibly serve as allergic biomarkers ofα_(s1)-casein,however,additional studies on signal transduction and gene expression are necessary in future.

S＝1伊辛模型临界温度的METROPOLIS动力学标度计算

考察了平方晶格上自旋Ｓ＝１伊辛模型的两种组态按时序ｍｅｔｒｏｐｏｌｉｓ动力学规则随时间的演化，并分析给出两组态之间的Ｄａｍａｇｅ量。采用动力学有限尺寸标度计算技术，得到了模型的临界点。

中药Ⅰ号方对APP/PS1双转基因模型小鼠APP代谢的影响

目的研究中药I号方对APP/PS1双转基因模型小鼠APP代谢的影响。方法将5月龄APP/PS1双转基因模型小鼠随机分为模型组(vehicle)、中药Ⅰ号方低剂量组(0.6 g/kg)、中剂量组(1.2 g/kg)和高剂量组(2.4 g/kg),并以同窝阴性小鼠作为正常对照组(wild-type,WT),每组16只,雌雄各半。给药小鼠每天灌胃一次,模型组和正常对照组分别给予等体积的双蒸水灌胃。给药四个月后,用免疫组化和Western blot检测淀粉样前体蛋白(APP)及其代谢产物和分解酶的变化。结果 Western blot结果显示,与模型组相比,治疗组低剂量、中剂量和高剂量给药组能显著降低APP分解酶(ADAM10和BACE1)(P<0.01)及APP的分解产物的量,如:β-CTF(C99)、α-CTF(C83)、s APPα、s APPβ(P<0.01)。结论中药I号方通过影响APP的分解过程减少淀粉样蛋白(β-amyloid peptide,Aβ)的生成,减少脑内老年斑的沉积。

通信受限下T-S模糊网络控制系统L_(1)动态输出反馈控制

针对通信受限的非线性网络控制系统,为兼顾系统性能和节约利用网络资源,引入事件触发通信机制(ETCM),利用时延建模方法和并行分布补偿(PDC)技术,将连续控制系统建模为一个采样数据误差依赖的非线性网络化系统模型;构建保守性低的时滞依赖和模糊基依赖的Lyapunov-Krasovskii泛函,给出增广系统稳定性和鲁棒性结果,得到鲁棒控制器存在的充分条件,提出一种基于线性矩阵不等式(LMIs)的事件触发参数,以及全局模糊L 1动态输出反馈控制器参数的协同设计方法。采用永磁同步电动机模型仿真验证,结果表明该设计方法可减少网络资源占用,达到闭环控制系统的性能要求。

混合自旋─1/2─自旋─S伊辛模型临界温度的自由费密近似解

本文考虑正方晶格上混合自旋─１／２─自旋─Ｓ伊辛模型。运用自由费密近似方法对该模型进行了求解，计算得到了临界温度的自由费密近似解，并与Ｙｏｕｓｉｆ和Ｂｏｗｅｒｓ的高温级数解结果进行比较。

Noether's theorem for non-conservative Hamilton system based on El-Nabulsi dynamical model extended by periodic laws

This paper focuses on the Noether symmetries and the conserved quantities for both holonomic and nonholonomic systems based on a new non-conservative dynamical model introduced by E1-Nabulsi. First, the E1-Nabulsi dynamical model which is based on a fractional integral extended by periodic laws is introduced, and E1-Nabulsi-Hamilton＇s canoni- cal equations for non-conservative Hamilton system with holonomic or nonholonomic constraints are established. Second, the definitions and criteria of E1-Nabulsi-Noether symmetrical transformations and quasi-symmetrical transformations are presented in terms of the invariance of E1-Nabulsi-Hamilton action under the infinitesimal transformations of the group. Fi- nally, Noether＇s theorems for the non-conservative Hamilton system under the E1-Nabulsi dynamical system are established, which reveal the relationship between the Noether symmetry and the conserved quantity of the system.

Inhibiting effect of antisense oligonucleotides phosphorthioate on gene expression of TIMP-1 in rat liver fibrosis

AIM: To observe the inhibition of antisense oligonucleotides (asON) phosphorthioate to the tissue inhibitors metalloproteinase-1 (TIMP-1) gene and protein expression in the liver tissue of immunologically induced hepatic fibrosis rats. The possibility of reversing hepatic fibrosis through gene therapy was observed. METHODS: Human serum albumin (HSA) was used to attack rats, as hepatic fibrosis model, in which asONs were used to block the gene and protein expressing TIMP-1. According to the analysis of modulator, structure protein, coding series of TIMP-1 genome, we designed four different asONs. These asONs were injected into the hepatic fibrosis models through coccygeal vein. The results was observed by RT-PCR for measuring TIMP-1 mRNA expression, immunohistochemistry and in situ hybridization for collagen I, II, special staining of collagen fiber, and electron microscopic examination. RESULTS: Hepatic fibrosis could last within 363 days in our modified model. The expressing level of TIMP-1 was high during hepatic fibrosis process. It has been proved by the immunohistochemical and the electron microscopic examination that the asON phosphorthioate of TIMP-1 could exactly express in vivo. The effect of colchicine was demonstrated to inhibit the expressing level of mRNA and the content of collagen I, III in the liver of experimental hepatic fibrosis rats. However, the electron microscopy research and the pathologic grading of hepatic fibrosis showed that there was no significant difference between the treatment group and the model group (P】 0.05). CONCLUSION: The experimental rat model of hepatic fibrosis is one of the preferable models to estimate the curative effect of anti-hepatic fibrosis drugs. The asON phosphorthioate of TIMP-1 could block the gene and protein expression of TIMP-1 in the liver of experimental hepatic fibrosis rats at the mRNA level. It is possible to reverse hepatic fibrosis, and it is expected to study a new drug of antihepatic fibrosis on the genetic level. Colchicine has very limited therapeutic effect on hepatic fibrosis, furthermore, its toxicity and side effects are obvious.

Demage Spreading in the Ising Model with a special Metropolis Dynamics Approach

The time evolution of the Hamming distance (damage spreading) for the and Ising models on the square lattice is performed with a special metropolis dynamics algorithm. Two distinct regimes are observed according to the temperature range for both models: a low-temperature one where the distance in the long-time limit is finite and seems not to depend on the initial distance and the system size; a high-temperature one where the distance vanishes in the long-time limit. Using the finite size scaling method, the dynamical phase transition (damage spreading transition) temperature is obtained as for the Ising model.

SIRT1 facilitates amyloid beta peptide degradation by upregulating lysosome number in primary astrocytes

Previous studies have shown that sirtuin 1（SIRT1） reduces the production of neuronal amyloid beta（Aβ） and inhibits the inflammatory response of glial cells, thereby generating a neuroprotective effect against Aβ neurotoxicity in animal models of Alzheimer＇s disease. However, the protective effect of SIRT1 on astrocytes is still under investigation. This study established a time point model for the clearance of Aβ in primary astrocytes. Results showed that 12 hours of culture was sufficient for endocytosis of oligomeric Aβ, and 36 hours sufficient for effective degradation. Immunofluorescence demonstrated that Aβ degradation in primary astrocytes relies on lysosome function. Enzymatic agonists or SIRT1 inhibitors were used to stimulate cells over a concentration gradient. Aβ was co-cultured for 36 hours in medium. Western blot assay results under different conditions revealed that SIRT1 relies on its deacetylase activity to promote intracellular Aβ degradation. The experiment further screened SIRT1 using quantitative proteomics to investigate downstream, differentially expressed proteins in the Aβ degradation pathway and selected the ones related to enzyme activity of SIRT1. Most of the differentially expressed proteins detected are close to the primary astrocyte lysosomal pathway. Immunofluorescence staining demonstrated that SIRT1 relies on its deacetylase activity to upregulate lysosome number in primary astrocytes. Taken together, these findings confirm that SIRT1 relies on its deacetylase activity to upregulate lysosome number, thereby facilitating oligomeric Aβ degradation in primary astrocytes.

区域一维速度模型对地震定位的定量影响——以2017年九寨沟M_(S)7.0地震序列为例

利用2017年8月1日至2017年12月31日四川地震台网和甘肃地震台网记录到的发生在青藏高原东缘的731个地震事件的9 284条Pg震相到时数据,首先反演了该地区的"最小一维速度模型",并将该模型和选取的速度模型建立对比模型,以九寨沟地震序列为研究目标,定量讨论了两种速度模型分别在绝对定位和相对定位方法中对定位结果的影响。所得定位结果表明:反演获得的"最小一维速度模型"在重定位中可以有效地减小地震走时均方根残差;绝对定位比相对定位更加依赖于一维速度模型,一维速度模型会直接影响绝对定位结果中的震源分布形态,但在相对定位结果中仅起到调整地震事件相对位置的作用;在地震绝对定位中,震级越大的地震对于速度模型越敏感,而这一特点在相对定位中表现得并不明显。通过本项研究可知,在地震定位研究中,联合采用绝对定位和相对定位方法是最佳策略。

SU(3)_L×U(1)模型

1967到1968年,Weinberg与Salam利用自发破缺的Higgs机制提出了完整的SU(2)×U(1)弱电统一规范理论(W—S模型)。本文重新构造了一个非标准的SU(3)_L×U(1)模型,结果与W—S模型相容。

Union Jack晶格上混合自旋-1/2—自旋-S伊辛模型临界温度的自由费米近似解

考虑Union Jack晶格上各向异性二体耦合相互作用的混合自旋-1/2—自旋-S伊辛模型,运用自由费米近似方法对模型进行了求解,得到了模型临界温度的自由费米近似解.

■Ω and ■^(*)Ω Dibaryons in SC7(3)Chiral Quark Model

The binding energy of the six quark system with strangeness s=-5 is investigated by the SU(3)chiral constituent quark model.The single ■^(*)Ω channel calculation with spin S=Q and the coupled ■Ω-■^(*)Ω channel calculation with spin S=1 are considered.It is shown that in the spin S=0 case,the binding energy of ■^(*)Ω is ranged from 80.0 to 92.4MeV,while in the S=1 case,the additional ■^(*)Ω channel increases the binding energy of ■Ω to a range of 26.2-32.9 MgV.

Generating Li-Yorke chaos in a stable continuous-time T-S fuzzy model via time-delay feedback control

This paper investigates the chaotification problem of a stable continuous-time T S fuzzy system. A simple nonlinear state time-delay feedback controller is designed by parallel distributed compensation technique. Then, the asymptotically approximate relationship between the controlled continuous-time T-S fuzzy system with time-delay and a discrete-time T-S fuzzy system is established. Based on the discrete-time T-S fuzzy system, it proves that the chaos in the discrete- time T-S fuzzy system satisfies the Li-Yorke definition by choosing appropriate controller parameters via the revised Marotto theorem. Finally, the effectiveness of the proposed chaotic anticontrol method is verified by a practical example.

A hybrid method integrating Green's function Monte Carlo and projected entangled pair states

This paper introduces a hybrid approach combining Green’s function Monte Carlo(GFMC)method with projected entangled pair state(PEPS)ansatz.This hybrid method regards PEPS as a trial state and a guiding wave function in GFMC.By leveraging PEPS’s proficiency in capturing quantum state entanglement and GFMC’s efficient parallel architecture,the hybrid method is well-suited for the accurate and efficient treatment of frustrated quantum spin systems.As a benchmark,we applied this approach to study the frustrated J_(1)–J_(2) Heisenberg model on a square lattice with periodic boundary conditions(PBCs).Compared with other numerical methods,our approach integrating PEPS and GFMC shows competitive accuracy in the performance of ground-state energy.This paper provides systematic and comprehensive discussion of the approach of our previous work[Phys.Rev.B 109235133(2024)].

BH-1灵巧手运动学和动力学建模研究

通过对ＢＨ－１灵巧手结构的分析，建立了其运动学和动力学模型，并对其运动姿态进行了仿真研究。