一类带有阈的神经网络模型的全局稳定性

利用分析技巧,获得了一类带有阈的神经网络模型全局稳定性的判据,去掉了文「１」相应结果的一个较强条件∫＾∞０ｓｋ（ｓ）ｄｓ〈＋∞。     

Gene network inference using continuous time Bayesian networks: a comparative study and application to Th17 cell differentiation

Background

Dynamic aspects of gene regulatory networks are typically investigated by measuring system variables at multiple time points. Current state-of-the-art computational approaches for reconstructing gene networks directly build on such data, making a strong assumption that the system evolves in a synchronous fashion at fixed points in time. However, nowadays omics data are being generated with increasing time course granularity. Thus, modellers now have the possibility to represent the system as evolving in continuous time and to improve the models’ expressiveness.

Results

Continuous time Bayesian networks are proposed as a new approach for gene network reconstruction from time course expression data. Their performance was compared to two state-of-the-art methods: dynamic Bayesian networks and Granger causality analysis. On simulated data, the methods comparison was carried out for networks of increasing size, for measurements taken at different time granularity densities and for measurements unevenly spaced over time. Continuous time Bayesian networks outperformed the other methods in terms of the accuracy of regulatory interactions learnt from data for all network sizes. Furthermore, their performance degraded smoothly as the size of the network increased. Continuous time Bayesian networks were significantly better than dynamic Bayesian networks for all time granularities tested and better than Granger causality for dense time series. Both continuous time Bayesian networks and Granger causality performed robustly for unevenly spaced time series, with no significant loss of performance compared to the evenly spaced case, while the same did not hold true for dynamic Bayesian networks. The comparison included the IRMA experimental datasets which confirmed the effectiveness of the proposed method. Continuous time Bayesian networks were then applied to elucidate the regulatory mechanisms controlling murine T helper 17 (Th17) cell differentiation and were found to be effective in discovering well-known regulatory mechanisms, as well as new plausible biological insights.

Conclusions

Continuous time Bayesian networks were effective on networks of both small and large size and were particularly feasible when the measurements were not evenly distributed over time. Reconstruction of the murine Th17 cell differentiation network using continuous time Bayesian networks revealed several autocrine loops, suggesting that Th17 cells may be auto regulating their own differentiation process.     

Reconstruction of Gene Regulatory Networks Based on Two-Stage Bayesian Network Structure Learning Algorithm

In the post-genomic biology era,the reconstruction of gene regulatory networks from microarray gene expression data isvery important to understand the underlying biological system,and it has been a challenging task in bioinformatics.TheBayesian network model has been used in reconstructing the gene regulatory network for its advantages,but how to determinethe network structure and parameters is still important to be explored.This paper proposes a two-stage structure learning algorithmwhich integrates immune evolution algorithm to build a Bayesian network.The new algorithm is evaluated with the use ofboth simulated and yeast cell cycle data.The experimental results indicate that the proposed algorithm can find many of theknown real regulatory relationships from literature and predict the others unknown with high validity and accuracy.     

一类带有肝炎B病毒感染的数学模型的全局稳定性分析（英文）

本文主要分析了一类具有肝炎B病毒感染且带有治愈率的典型的数学模型（HBV）.通过稳定性分析,得到了该模型的无病平衡点与地方病平衡点全局稳定的充分条件,并且证明了当基本再生数R0〈1, HBV感染消失;当R0〉1,HBV感染持续.     

Gene Network Polymorphism Is the Raw Material of Natural Selection: The Selfish Gene Network Hypothesis

Population genetics, the mathematical theory of modern evolutionary biology, defines evolution as the alteration of the frequency of distinct gene variants (alleles) differing in fitness over the time. The major problem with this view is that in gene and protein sequences we can find little evidence concerning the molecular basis of phenotypic variance, especially those that would confer adaptive benefit to the bearers. Some novel data, however, suggest that a large amount of genetic variation exists in the regulatory region of genes within populations. In addition, comparison of homologous DNA sequences of various species shows that evolution appears to depend more strongly on gene expression than on the genes themselves. Furthermore, it has been demonstrated in several systems that genes form functional networks, whose products exhibit interrelated expression profiles. Finally, it has been found that regulatory circuits of development behave as evolutionary units. These data demonstrate that our view of evolution calls for a new synthesis. In this article I propose a novel concept, termed the selfish gene network hypothesis, which is based on an overall consideration of the above findings. The major statements of this hypothesis are as follows. (1) Instead of individual genes, gene networks (GNs) are responsible for the determination of traits and behaviors. (2) The primary source of microevolution is the intraspecific polymorphism in GNs and not the allelic variation in either the coding or the regulatory sequences of individual genes. (3) GN polymorphism is generated by the variation in the regulatory regions of the component genes and not by the variance in their coding sequences. (4) Evolution proceeds through continuous restructuring of the composition of GNs rather than fixing of specific alleles or GN variants.     

一类带有肝炎B病毒感染的数学模型的全局稳定性分析

本文主要分析了一类具有肝炎B病毒感染且带有治愈率的典型的数学模型(HBV).通过稳定性分析,得到了该模型的无病平衡点与地方病平衡点全局稳定的充分条件,并且证明了当基本再生数R0＜1,HBV感染消失;当R0＞1,HBV感染持续.     

肾肿瘤相关基因的共表达网络构建与分析

作为泌尿系统常见的肿瘤之一,肾肿瘤发病率在逐年上升。针对Affymetrix hgu133b的基因芯片数据进行差异表达基因筛选,应用加权基因共表达网络分析算法构建肾肿瘤差异表达基因的共表达网络。分析肾部正常组织和肿瘤组织差异表达基因之间的关联模式;选取与肿瘤发生关联程度最高的模块,筛选枢纽基因。最后,针对枢纽基因进行基因本体富集分析。细胞衰老是抑制肿瘤发生的主要机制之一,分析结果显示枢纽基因PLA2R1和TBX3与细胞衰老有关,可能对肾肿瘤的形成具有重要影响。该结果与基因PLA2R1通过促进细胞衰老抑制肾部肿瘤发生的研究结论一致。     

基于IRES序列的多基因共表达载体构建

目的:构建一个IRES序列介导的多基因共表达载体,实现两个目的基因和筛选标记基因共用一个启动子高效表达,提高多基因稳定共表达细胞株的筛选效率。方法:以实验室前期构建的载体pLV-MCS-Puro为骨架,设计并全基因合成双基因克隆表达元件,连接到骨架载体,构建多基因共表达载体pLV-2MCS-Puro,以DsRed2和EGFP荧光蛋白基因验证该载体用于多基因稳定共表达细胞株筛选的效率。结果:成功构建了pLV-2MCS-Puro载体以及DsRed2和EGFP共表达重组质粒pLV-DsRed2-EGFP-Puro。瞬时转染实验证明该载体能介导多基因共表达。抗性筛选获得了MDCK和HeLa两种细胞的多基因稳定共表达细胞池。细胞池涂片荧光显微镜观察和计数表明抗性细胞池DsRed2和EGFP双阳率接近100%。基因组和转录水平PCR及蛋白质免疫印迹实验表明,DsRed2和EGFP稳定整合到抗性细胞基因组,并且两种蛋白质表达水平较为一致。结论:成功构建了多基因共表达载体pLV-2MCS-Puro,实现了两个目的基因和抗性基因串联共表达,并且具有高效的多基因稳定共表达细胞株筛选效率。该载体在研究蛋白质相互作用及工程细胞构建等方面具有一定的应用前景。     

Network Pharmacology and Molecular Docking Combined to Analyze the Molecular and Pharmacological Mechanism of Pinellia ternata in the Treatment of Hypertension

Hypertension is a cardiovascular disease that causes great harm to health and life, affecting the function of important organs and accompanied by a variety of secondary diseases, which need to be treated with drugs for a long time. P. ternata alone or combination with western medicine has played an important role in traditional Chinese medicine. Although P. ternata is used clinically to treat hypertension, its functional molecular mechanism and pharmacological mechanism have not been elucidated. Therefore, in this study, the potentially effective components, and targets of P. ternata in the treatment of hypertension were screened by the method of network pharmacology, and the mechanism of P. ternata in the treatment of hypertension was analyzed by constructing a component-target relationship network, PPI interaction network, targets’ function analysis, and molecular docking. In the study, 12 potentially effective components and 88 targets were screened, and 3 potential protein modules were found and analyzed after constructing a PPI network using targets. In addition, 10 targets were selected as core targets of the PPI network. After that, the targets were analyzed by Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Finally, the molecular docking method is used to study the interaction between the targets and the active components. The above evidence shows that the mechanism of P. ternata in the treatment of hypertension is complicated, as it acts in many ways, mainly by affecting nerve signal transmission, cell proliferation, and apoptosis, calcium channels, and so on. The binding between targets and active components mainly depends on Pi bonds and hydrogen bonds. Using the method of network pharmacology and molecular docking to analyze the mechanism of P. ternata in the treatment of hypertension will help to provide a better scientific basis for the combined use of traditional Chinese medicine and western medicine, and will better help to improve the quality of P. ternata and point out its direction.     

不稳定EGFP细胞模型的构建及其在基因编辑体系评价中的应用*

目的:为了更好地评价基因编辑效率,满足高通量筛选应用中快速、高效的检测要求,在细胞上建立一个原位检测方法具有重要的意义。通过检测荧光蛋白信号强度的变化可以评价CRISPR系统在细胞中的基因编辑情况,然而这一方法的效率受限于荧光蛋白较长的半衰期。方法:将鸟氨酸脱羧酶降解结构域(含PEST序列)与EGFP融合,通过慢病毒系统感染HEK-293T细胞,获得了表达单拷贝、EGFP-PEST报告基因的稳转细胞系。结果:与EGFP相比,EGFP-PEST在细胞内的降解速度明显加快,荧光水平在4 h内显著降低。利用该模型比较了3种商品化脂质体介导的CRISPR/Cas9基因编辑效率,能够在2~4 d实现定性和定量评价。结论:这一模型能够快速、灵敏地指示基因编辑效果,可以用于不同CRISPR系统或新递送工具的高通量筛选和评价。     

用于鉴定microRNA靶基因的新型双萤光素酶报告基因系统的构建及应用

目的:构建用于鉴定microRNA靶基因的报告基因系统。方法:在pGL3-Basic载体的luc基因上游插入CMV启动子,下游插入用于克隆靶基因3’UTR的多克隆位点,构建报告基因载体pMIR-luciferase;将pMIR-lu-ciferase载体的luc基因替换成Rluc基因,构建内参载体pMIR-control;将补体因子H(CFH)的3’UTR插入pMIR-luciferase载体的多克隆位点处,构建含有CFH 3’UTR的报告基因载体;用pIRES2-EGFP载体构建microRNA146a真核表达载体;将含有CFH 3’UTR的报告基因载体、microRNA146a真核表达载体及内参载体共转染HepG2细胞,进行报告基因的活性检测。结果:构建了报告基因载体、内参载体和microRNA146a真核表达载体,经酶切和测序鉴定正确;microRNA146a真核表达载体转染细胞72 h后,经荧光显微镜观察确认载体转染及表达;用实时定量PCR检测,microRNA146a的表达水平显著上调(P<0.01);用构建的报告基因系统检测,结果表明microRNA146a显著地抑制了含CFH 3’UTR的报告基因的活性(P<0.05)。结论:构建了一种新型的报告基因载体系统,该系统可用于miRNA靶基因的鉴定。     

Analysis of Novel Nonviral Gene Transfer Systems for Gene Delivery to Cells of the Musculoskeletal System

The aim of the present study was to evaluate the efficacy of novel nonviral gene delivery systems in cells of musculoskeletal origin. Primary cultures of lapine skeletal muscle cells, lapine articular chondrocytes, human cells from fibrous dysplasia and cell lines established from human osteosarcoma (SAOS-2), chondrosarcoma (CS-1), murine skeletal myoblasts (L8) and fibroblasts (NIH 3T3) were transfected with the P. pyralis luc or the E. coli lacZ genes using Nanofectin 1 and 2, Superfect, JetPEI, GeneJammer, Effectene, TransPass D2, FuGENE 6, Lipofectamine 2000, Dreamfect, Metafectene, Escort III, and calcium phosphate. Maximal transfection efficiency in lapine skeletal muscle cells was of 60.8 ± 21.2% using Dreamfect, 38.9 ± 5.0% in articular chondrocytes using Gene Jammer, 5.2 ± 8.0% in human cells from fibrous dysplasia using Lipofectamine 2000, 12.7 ± 16.2% in SAOS-2 cells using FuGENE 6, 29.9 ± 3.5% in CS-1 cells using Lipofectamine 2000, 70.7 ± 8.6% in L8 cells using FuGENE 6, and 48.9 ± 13.0% in NIH 3T3 cells using Metafectene. When the cells were transfected with a human IGF-I gene, significant amounts of the IGF-I protein were secreted. These results indicate that relatively high levels of transfection can be achieved using novel nonviral gene transfer methods.     

Global Network Analysis of Lipid-Raft-Related Proteins Reveals Their Centrality in the Network and Their Roles in Multiple Biological Processes

Lipid rafts are specialized cholesterol-enriched microdomains in the cell membrane. They have been known as a platform for protein-protein interactions and to take part in multiple biological processes. Nevertheless, how lipid rafts influence protein properties at the proteomic level is still an open question for researchers using traditional biochemical approaches. Here, by annotating the lipid raft localization of proteins in human protein-protein interaction networks, we performed a systematic analysis of the function of proteins related to lipid rafts. Our results demonstrated that lipid raft proteins and their interactions were critical for the structure and stability of the whole network, and that the interactions between them were significantly enriched. Furthermore, for each protein in the network, we calculated its “lipid raft dependency (LRD),” which indicates how close it is topologically associated with lipid rafts, and we then uncovered the connection between LRD and protein functions. Proteins with high LRD tended to be essential for mammalian development, and malfunction of these proteins was inclined to cause human diseases. Coordinated with their neighbors, high-LRD proteins participated in multiple biological processes and targeted many pathways in diseases pathogenesis. High-LRD proteins were also found to have tissue specificity of expression. In summary, our network-based analysis denotes that lipid raft proteins have higher centrality in the network, and that lipid-raft-related proteins have multiple functions and are probably concerned with many biological processes in disease development.     

Human male infertility may be due to a decrease of the protamine P2 content in sperm chromatin

Basic chromosomal proteins were extracted from the sperm of fertile and infertile human males. The relative proportions of protamine 1, 2, and 3 were determined by scanning microdensitometry following electrophoresis of total protamine in polyacrilamide gels. The findings were as follows: (1) The proportion of protamine P(2 + 3) in sperm obtained from infertile males was lower than that in fertile males. (2) Protamine P(2 + 3) in infertile human males showed reduced affinity to DNA. The possibility that some cases of human male infertility may be due to mutation within the protamine P2 gene is discussed. © 1993 Wiley-Liss, Inc.     

Reconstruction of ancestral sequences by the inferential method,a tool for protein engineering studies

This paper describes the inferential method, an approach for reconstructing protein and nucleotide sequences of ancestral species, starting from known, homologous, contemporary sequences. The method requires knowledge of the topology of the phylogenetic tree, whose nodes are the species to whom the reconstructed sequences belong.The method has been tested by computer simulation of speciation and nucleotide substitutions, starting from a single ancestral sequence, and by subsequent reconstruction of nodal sequences. Results have shown that reconstructions obtained by the inferential method are affected by limited error frequencies, which (1) are proportional to the squares of nucleotide substitution rates and of internodal distances, and (2) are little influenced by non-uniformity of transformation rates of nucleotides.Furthermore, good agreement of the results has been obtained by comparing protein-sequence reconstructions carried out with the inferential method with those obtained using the maximum parsimony method in two different cases: e.g., a reconstruction of simulated sequences and a reconstruction of mammalian ribonuclease sequences.Abbreviations used MP maximum parsimony method - ML maximum likelihood method - IM inferential method - MY millions of years - N-tree natural-like phylogenetic tree - E-tree equibranched phylogenetic tree - EA percentage number of erroneous amino acids in a reconstructed sequence - EC percentage number of erroneous codons in a reconstructed sequence - t _n time interval between a P- and its - F-sequence nucleotides and amino acids are indicated by their I.U.B. codes (N.C.-I.U.B., 1985) Correspondence to: A. Di Donato     

Saving Our Planet's Flora, the Contribution of the French National Natural History Museum to the Implementation of the Global Strategy for Plant Conservation

The National Natural History Museum plays a key role in the implementation of the GSPC through its botanical gardens,the Conservatoire Botanique National du Bassin Parisien,the Herbarium,and also by providing expertise on all areas of the Strategy(botany,conservation,ethonobotany,article 8j,substainable use),etc.For 2 of the goals of GSPC(conserving plant diversity,Understanding and Documenting Plant Diversity),the Muséum has developed activities all over the world,including compilation of various flora and...     

Phylogenetic Reconstruction Using an Unsupervised Growing Neural Network That Adopts the Topology of a Phylogenetic Tree

We propose a new type of unsupervised, growing, self-organizing neural network that expands itself by following the taxonomic relationships that exist among the sequences being classified. The binary tree topology of this neutral network, contrary to other more classical neural network topologies, permits an efficient classification of sequences. The growing nature of this procedure allows to stop it at the desired taxonomic level without the necessity of waiting until a complete phylogenetic tree is produced. This novel approach presents a number of other interesting properties, such as a time for convergence which is, approximately, a lineal function of the number of sequences. Computer simulation and a real example show that the algorithm accurately finds the phylogenetic tree that relates the data. All this makes the neural network presented here an excellent tool for phylogenetic analysis of a large number of sequences. Received: 14 May 1996 / Accepted: 6 August 1996     

西南山地红外相机监测网络建设进展

中国西南山地是全球生物多样性热点区。西南山地红外相机监测网络是我国生物多样性监测的区域性红外相机网络之一。该网络由北京大学牵头, 始建于2002年, 合作单位包括科研院所、高校、保护组织、政府部门、保护地管理机构等。网络主要覆盖青藏高原东缘大横断山区域的秦岭、岷山、邛崃山、相岭、凉山、沙鲁里山、云岭7大山系。网络内目前共有41个监测样区, 包括自然保护区、社区保护地、林场等多种类型。网络内监测样区均采用标准的网格化布设规程, 采取统一数据结构与数据库结构、建立离散式数据库进行分散管理的总体架构, 所有监测样区的数据库保持一致的结构和统一的核心字段, 由每个监测样区建立并维护各自独立的数据库。截至2019年12月, 网络内布设有效调查/监测位点5,738个, 已处理数据中调查工作量(以有效相机日计)合计约120.74万天, 积累红外相机照片/视频(删除连续空拍后) 302.59万份, 另有111.16万份待处理。共记录到分属7目21科的63种野生哺乳动物与分属10目35科的182种野生鸟类物种, 其中国家一、二级重点保护野生动物分别有18与39种。西南山地网络今后的重点工作方向包括: (1)基于通用元数据结构建立统一的在线数据库平台; (2)加强网络内保护地数据管理与分析能力建设; (3)为区域内生物多样性保护与保护地管理提供持续支持; (4)针对野生动物种间关系、群落构建机制以及大型食肉动物的生态功能开展深入的动物生态学研究。     

Global Potential Energy Minima of SPC/E Water Clusters without and with Induced Polarization Using a Genetic Algorithm

The global minimum potential energy structures of water clusters, (H₂O) _n , n = 2-14, have been calculated for the SPC/E (Simple Point Charge/Extended) model and a recent fluctuating charge version of the latter using a simple genetic algorithm. The SPC/E cluster geometries are in good agreement with previous TIP3P (Transferable Intermolecular Potential-3 Point) and TIP4P (Transferable Intermolecular Potential-4 Point) calculations as well as the interpretation of experimental measurements. In contrast to this, the polarizable version of the SPC/E model, which is based on the fluctuating charge approach, deviates rather strongly for n=6 with few exceptions. However, comparing the polarizable model to ab initio results for identical cluster geometries we find reasonable agreement for the magnitude of the average molecular dipole moment, the corresponding energy per molecule, and the average oxygen-oxygen distance as functions of n.Electronic Supplementary Material available.