Sample records for cd28-enhanced nanospatial coclustering

  1. Relational multimanifold coclustering. (United States)

    Li, Ping; Bu, Jiajun; Chen, Chun; He, Zhanying; Cai, Deng


    Coclustering targets on grouping the samples (e.g.,documents and users) and the features (e.g., words and ratings) simultaneously. It employs the dual relation and the bilateral information between the samples and features. In many real-world applications, data usually reside on a submanifold of the ambient Euclidean space, but it is nontrivial to estimate the intrinsic manifold of the data space in a principled way. In this paper, we focus on improving the coclustering performance via manifold ensemble learning, which is able to maximally approximate the intrinsic manifolds of both the sample and feature spaces. To achieve this, we develop a novel coclustering algorithm called relational multimanifold coclustering based on symmetric nonnegative matrix trifactorization, which decomposes the relational data matrix into three submatrices. This method considers the intertype relationship revealed by the relational data matrix and also the intratype information reflected by the affinity matrices encoded on the sample and feature data distributions. Specifically, we assume that the intrinsic manifold of the sample or feature space lies in a convex hull of some predefined candidate manifolds. We want to learn a convex combination of them to maximally approach the desired intrinsic manifold. To optimize the objective function, the multiplicative rules are utilized to update the submatrices alternatively. In addition, both the entropic mirror descent algorithm and the coordinate descent algorithm are exploited to learn the manifold coefficient vector. Extensive experiments on documents, images, and gene expression data sets have demonstrated the superiority of the proposed algorithm compared with other well-established methods.

  2. Co-clustering models, algorithms and applications

    CERN Document Server

    Govaert, Gérard


    Cluster or co-cluster analyses are important tools in a variety of scientific areas. The introduction of this book presents a state of the art of already well-established, as well as more recent methods of co-clustering. The authors mainly deal with the two-mode partitioning under different approaches, but pay particular attention to a probabilistic approach. Chapter 1 concerns clustering in general and the model-based clustering in particular. The authors briefly review the classical clustering methods and focus on the mixture model. They present and discuss the use of different mixture

  3. Anomaly Detection in Microblogging via Co-Clustering

    Institute of Scientific and Technical Information of China (English)

    杨武; 申国伟; 王魏; 宫良一; 于焱; 董国忠


    Traditional anomaly detection on microblogging mostly focuses on individual anomalous users or messages. Since anomalous users employ advanced intelligent means, the anomaly detection is greatly poor in performance. In this paper, we propose an innovative framework of anomaly detection based on bipartite graph and co-clustering. A bipartite graph between users and messages is built to model the homogeneous and heterogeneous interactions. The proposed co-clustering algorithm based on nonnegative matrix tri-factorization can detect anomalous users and messages simultaneously. The homogeneous relations modeled by the bipartite graph are used as constraints to improve the accuracy of the co-clustering algorithm. Experimental results show that the proposed scheme can detect individual and group anomalies with high accuracy on a Sina Weibo dataset.

  4. Co-clustering for Weblogs in Semantic Space

    DEFF Research Database (Denmark)

    Zong, Yu; Xu, Guandong; Dolog, Peter


    interest and content preference simultaneously. In this paper we will present a novel web co-clustering algorithm named Co-Clustering in Semantic space (COCS) to simultaneously partition web users and pages via a latent semantic analysis approach. In COCS, we first, train the latent semantic space...... of weblog data by using Probabilistic Latent Semantic Analysis (PLSA) model, and then, project all weblog data objects into this semantic space with probability distribution to capture the relationship among web pages and web users, at last, propose a clustering algorithm to generate the co......-aggregates of web users and pages which are closely related....

  5. A Fuzzy Co-Clustering approach for Clickstream Data Pattern

    CERN Document Server

    Rathipriya, R


    Web Usage mining is a very important tool to extract the hidden business intelligence data from large databases. The extracted information provides the organizations with the ability to produce results more effectively to improve their businesses and increasing of sales. Co-clustering is a powerful bipartition technique which identifies group of users associated to group of web pages. These associations are quantified to reveal the users' interest in the different web pages' clusters. In this paper, Fuzzy Co-Clustering algorithm is proposed for clickstream data to identify the subset of users of similar navigational behavior /interest over a subset of web pages of a website. Targeting the users group for various promotional activities is an important aspect of marketing practices. Experiments are conducted on real dataset to prove the efficiency of proposed algorithm. The results and findings of this algorithm could be used to enhance the marketing strategy for directing marketing, advertisements for web base...

  6. Co-clustering : A versatile Tool for Data Analysis in Biomedical Informatics


    Yoon, Sungroh; Benini, Luca; De Micheli, Giovanni


    Co-clustering has not been much exploited in biomedical in- formatics, despite its success in other domains. Most of the previous applications were limited to analyzing gene expression data. We performed co-clustering analysis on other types of data and obtained promising results, as summarized in this paper.

  7. Non-parametric co-clustering of large scale sparse bipartite networks on the GPU

    DEFF Research Database (Denmark)

    Hansen, Toke Jansen; Mørup, Morten; Hansen, Lars Kai


    Co-clustering is a problem of both theoretical and practical importance, e.g., market basket analysis and collaborative filtering, and in web scale text processing. We state the co-clustering problem in terms of non-parametric generative models which can address the issue of estimating the number...... of row and column clusters from a hypothesis space of an infinite number of clusters. To reach large scale applications of co-clustering we exploit that parameter inference for co-clustering is well suited for parallel computing. We develop a generic GPU framework for efficient inference on large scale......-life large scale collaborative filtering data and web scale text corpora, demonstrating that latent mesoscale structures extracted by the co-clustering problem as formulated by the Infinite Relational Model (IRM) are consistent across consecutive runs with different initializations and also relevant...

  8. Bayesian coclustering of Anopheles gene expression time series: Study of immune defense response to multiple experimental challenges


    Heard, Nicholas A.; Holmes, Christopher C.; Stephens, David A.; Hand, David J.; Dimopoulos, George


    We present a method for Bayesian model-based hierarchical coclustering of gene expression data and use it to study the temporal transcription responses of an Anopheles gambiae cell line upon challenge with multiple microbial elicitors. The method fits statistical regression models to the gene expression time series for each experiment and performs coclustering on the genes by optimizing a joint probability model, characterizing gene coregulation between multiple experiments. We compute the mo...

  9. Co-clustering Analysis of Weblogs Using Bipartite Spectral Projection Approach

    DEFF Research Database (Denmark)

    Xu, Guandong; Zong, Yu; Dolog, Peter


    and content preference simultaneously. In this paper we will present an algorithm using bipartite spectral clustering to co-cluster Web users and pages. The usage data of users visiting Web sites is modeled as a bipartite graph and the spectral clustering is then applied to the graph representation of usage...... data. The proposed approach is evaluated by experiments performed on real datasets, and the impact of using various clustering algorithms is also investigated. Experimental results have demonstrated the employed method can effectively reveal the subset aggregates of Web users and pages which......Web clustering is an approach for aggregating Web objects into various groups according to underlying relationships among them. Finding co-clusters of Web objects is an interesting topic in the context of Web usage mining, which is able to capture the underlying user navigational interest...

  10. Co-clustering directed graphs to discover asymmetries and directional communities. (United States)

    Rohe, Karl; Qin, Tai; Yu, Bin


    In directed graphs, relationships are asymmetric and these asymmetries contain essential structural information about the graph. Directed relationships lead to a new type of clustering that is not feasible in undirected graphs. We propose a spectral co-clustering algorithm called di-sim for asymmetry discovery and directional clustering. A Stochastic co-Blockmodel is introduced to show favorable properties of di-sim To account for the sparse and highly heterogeneous nature of directed networks, di-sim uses the regularized graph Laplacian and projects the rows of the eigenvector matrix onto the sphere. A nodewise asymmetry score and di-sim are used to analyze the clustering asymmetries in the networks of Enron emails, political blogs, and the Caenorhabditis elegans chemical connectome. In each example, a subset of nodes have clustering asymmetries; these nodes send edges to one cluster, but receive edges from another cluster. Such nodes yield insightful information (e.g., communication bottlenecks) about directed networks, but are missed if the analysis ignores edge direction.

  11. Nano-spatial parameters from 3D to 2D lattice dimensionality by organic variant in [ZnCl4]- [R]+ hybrid materials: Structure, architecture-lattice dimensionality, microscopy, optical Eg and PL correlations (United States)

    Kumar, Ajit; Verma, Sanjay K.; Alvi, P. A.; Jasrotia, Dinesh


    The nanospatial morphological features of [ZnCl]- [C5H4NCH3]+ hybrid derivative depicts 28 nm granular size and 3D spreader shape packing pattern as analyzed by FESEM and single crystal XRD structural studies. The organic moiety connect the inorganic components through N-H+…Cl- hydrogen bond to form a hybrid composite, the replacement of organic derivatives from 2-methylpyridine to 2-Amino-5-choloropyridine results the increase in granular size from 28nm to 60nm and unit cell packing pattern from 3D-2D lattice dimensionality along ac plane. The change in optical energy direct band gap value from 3.01eV for [ZnCl]- [C5H4NCH3]+ (HM1) to 3.42eV for [ZnCl]- [C5H5ClN2]+ (HM2) indicates the role of organic moiety in optical properties of hybrid materials. The photoluminescence emission spectra is observed in the wavelength range of 370 to 600 nm with maximum peak intensity of 9.66a.u. at 438 nm for (HM1) and 370 to 600 nm with max peak intensity of 9.91 a.u. at 442 nm for (HM2), indicating that the emission spectra lies in visible range. PL excitation spectra depicts the maximum excitation intensity [9.8] at 245.5 nm for (HM1) and its value of 9.9 a.u. at 294 nm, specify the excitation spectra lies in UV range. Photoluminescence excitation spectra is observed in the wavelength range of 280 to 350 nm with maximum peak intensity of 9.4 a.u. at 285.5 nm and 9.9 a.u. at 294 and 297 nm, indicating excitation in the UV spectrum. Single crystal growth process and detailed physiochemical characterization such as XRD, FESEM image analysis photoluminescence property reveals the structure stability with non-covalent interactions, lattice dimensionality (3D-2D) correlations interweaving into the design of inorganic-organic hybrid materials.

  12. Method for spectral co-clustering documents and words based on morphology%基于形态学的单词一文档谱聚类方法

    Institute of Scientific and Technical Information of China (English)

    刘娜; 肖智博; 鲁明羽


    本文利用形态学的方法确定聚类数目,并对单词一文档谱聚类方法进行改进.确定聚类数目主要分三个步骤:第一步将单词一文档谱聚类方法中产生的矩阵转换成可视化聚类趋势分析方法(visual assessment of tendency,VAT)灰度图,第二步利用灰度形态学、图像二值化、距离转换等图像处理技术过滤产生的VAT灰度图,第三步对过滤后的VAT灰度图建立信号图,并进行平滑处理,通过平滑后的信号图的波峰波谷数目确定文档集的聚类数目.实验表明,该方法能够提高单词一文档谱聚类方法的聚类效果.%One of the major problems in spectral co-clustering analysis is the determination of the number of clusters in datasets, which is a basic input for most spectral co-clustering algorithms. In this paper, we propose a new method for automatically estimating the number of clusters in datasets and modify spectral co-clustering documents and words, which is based on an existing algorithm for visual assessment of tendency (VAT) of a data set, using several common image and signal processing techniques. The method determining the number of clusters includes three main steps. First, the input matrix generated by spectral co-clustering documents and words is created into reordered dissimilarity gray image, from the image it is better able to highlight the potential cluster structure in dataset. We generate gray image use the VAT algorithm. Then, sequential image processing operations are used to segment the regions of interest in the gray image and to convert the filtered image into a distance- transformed image. These processing operations consist of gray morphology, image binarization, distance transform. Finally, we project the transformed image onto the diagonal axis, which yields a one dimensional signal,from which we can extract the number of clusters by major peaks and valleys after smoothing signal. When the number of

  13. Co-clustering Algorithm for Heterogeneous Data Based on Resistive Network%基于电阻网络的异构数据协同聚类算法

    Institute of Scientific and Technical Information of China (English)

    刘琰琼; 张文生; 李益群; 杨柳


    As traditional cluster methods focusing on the homogeneous data can not meet the need of simultaneous clustering of heterogeneous data, the precious is low, and the readability of the labels is poor, this paper presents a co-clustering algorithm for heterogeneous data based on resistive network.In the algorithm, the heterogeneous related data is transformed into a resistive network with multi-part graph structure for the following computing of eigenvalue and clustering.After co-clustering, a clustering result structure can be obtained, that in the structure one class includes multiple heterogeneous data which can be each other's label, and the readability of the labels is high.Experimental results prove that the data clustering algorithm is achievable and effective.%传统聚类方法处理的是同构数据,无法满足异构数据同时聚类的应用需求,聚类结果的准确率较低,标签可读性较差.针对上述问题,提出一种基于电阻网络的异构数据协同聚类算法.该算法将异构关联数据抽象为多部图形式的电阻网络,进行特征计算及聚类.在对异构数据进行协同聚类后,可以得到一种聚类结构,其中每一类包含多种异构数据,它们之间可以互为标签,标签可读性高.实验结果证明,该方法是一种切实可行且效果优异的数据聚类算法.


    Directory of Open Access Journals (Sweden)



    Full Text Available In a Wireless Sensor Network a large number of sensors are deployed for the purpose of sensing data and then to bring the data back securely to nearby base stations. The base stations then perform thecostly computation on behalf of the sensors to analyze the data sensed by the sensors. Due to resource limitations of the nodes and also due to the vulnerability of physical captures of the nodes, the traditional cryptographic techniques are very complex and should not fit for energy constrained environments. Data mining techniques can be applied to find the malicious behavior of the nodes of the SensorNetwork. By analyzing the traffic patterns one can differentiate the normal behavior from malicious behaviour.Those techniques are used to identify various attacks. This paper addresses the issue of Attacks using data mining techniques. There exist two types of attacks: (i external and (ii internal. External attacks are those in which an attacker manipulates the communication between pairs of trusted nodes and causes the nodes to de-synchronize. Internal attacks are those in which internal attackers report false clock references to their neighboring nodes proposed an approach to develop a protocol. The protocol not only finds malicious node(s but also counts them withinthe group using data mining clustering techniques.

  15. Neutrophil adhesion to E-selectin under shear promotes the redistribution and co-clustering of ADAM17 and its proteolytic substrate L-selectin. (United States)

    Schaff, Ulrich; Mattila, Polly E; Simon, Scott I; Walcheck, Bruce


    E-selectin is expressed by the vascular endothelium and binds flowing neutrophils in the blood to facilitate their recruitment into the underlying tissue at sites of inflammation. L-selectin on neutrophils is engaged by E-selectin and undergoes rapid clustering and then coalescence in the trailing edge of polarizing cells. These processes are believed to increase the valency and capacity of L-selectin to signal CD18 integrin activity. Neutrophils, upon exiting the microvasculature, down-regulate their surface L-selectin through ectodomain shedding by a disintegrin and metalloprotease 17 (ADAM17). We reasoned that neutrophil tethering and rolling on E-selectin might initiate a coordinate change in the membrane distribution of ADAM17 as well. We found that ADAM17 indeed underwent a dramatic cell surface redistribution to the trailing edge of neutrophils rolling on purified E-selectin when activated by a chemoattractant under shear flow; however, its lateral migration occurred at a slower rate than L-selectin. ADAM17 and L-selectin also redistributed in the same manner in neutrophils attached to IL-1beta-stimulated HUVEC under shear flow. In contrast, the coalescence of L-selectin on the surface of neutrophils by antibody cross-linking did not promote the redistribution of ADAM17, suggesting that these molecules do not constitutively associate in the plasma membrane. Together, our findings reveal that neutrophil activation upon E-selectin adhesion initiates active transport of ADAM17 and L-selectin to the cell uropod, thus providing additional insight into the molecular mechanisms that regulate L-selectin during leukocyte extravasation.

  16. Fuzzy co-clustering algorithm for high-order heterogeneous data%高阶异构数据模糊联合聚类算法

    Institute of Scientific and Technical Information of China (English)

    黄少滨; 杨欣欣; 申林山; 李艳梅



  17. 基于最小平方和残差的高阶模糊联合聚类算法%A Minimum Sum-squared Residue for High-order Fuzzy Co-clustering Algorithm

    Institute of Scientific and Technical Information of China (English)

    黄少滨; 杨欣欣



  18. Protein interacting with C kinase 1 (PICK1) reduces reinsertion rates of interaction partners sorted to Rab11-dependent slow recycling pathway

    DEFF Research Database (Denmark)

    Madsen, Kenneth Lindegaard; Thorsen, Thor Seneca; Rahbek-Clemmensen, Troels;


    of PICK1 co-clusters in Rab11-positive compartments. Furthermore, PICK1 inhibited Rab11-mediated recycling of the receptor in a BAR and PDZ domain-dependent manner. In contrast, transfer of the DAT C terminus to the δ-opioid receptor, which sorts to degradation, did not result in PICK1 co-clusters or any...... primarily sorts to degradation upon internalization, did not form perinuclear clusters with PICK1, and PICK1 did not affect DAT internalization/recycling. However, transfer of the PICK1-binding DAT C terminus to the β(2)-adrenergic receptor, which sorts to recycling upon internalization, led to formation...... change in internalization/recycling. Further support for a role of PICK1 determined by its PDZ cargo was obtained for the PICK1 interaction partner prolactin-releasing peptide receptor (GPR10). GPR10 co-localized with Rab11 and clustered with PICK1 upon constitutive internalization but co...

  19. Exogenous glycosyl phosphatidylinositol-anchored CD59 associates with kinases in membrane clusters on U937 cells and becomes Ca(2+)-signaling competent



    CD59, an 18-20-kD complement inhibitor anchored to the membrane via glycosyl phosphatidylinositol (GPI), can induce activation of T cells and neutrophils upon cross-linking with antibody. GPI-anchored molecules cocluster in high mol wt detergent-resistant complexes containing tyrosine kinases that are implicated in the signaling pathway. Exogenous, incorporated GPI-anchored molecules are initially unable to induce activation, presumably because they are not associated with kinases. Here we de...

  20. SparRec: An effective matrix completion framework of missing data imputation for GWAS (United States)

    Jiang, Bo; Ma, Shiqian; Causey, Jason; Qiao, Linbo; Hardin, Matthew Price; Bitts, Ian; Johnson, Daniel; Zhang, Shuzhong; Huang, Xiuzhen


    Genome-wide association studies present computational challenges for missing data imputation, while the advances of genotype technologies are generating datasets of large sample sizes with sample sets genotyped on multiple SNP chips. We present a new framework SparRec (Sparse Recovery) for imputation, with the following properties: (1) The optimization models of SparRec, based on low-rank and low number of co-clusters of matrices, are different from current statistics methods. While our low-rank matrix completion (LRMC) model is similar to Mendel-Impute, our matrix co-clustering factorization (MCCF) model is completely new. (2) SparRec, as other matrix completion methods, is flexible to be applied to missing data imputation for large meta-analysis with different cohorts genotyped on different sets of SNPs, even when there is no reference panel. This kind of meta-analysis is very challenging for current statistics based methods. (3) SparRec has consistent performance and achieves high recovery accuracy even when the missing data rate is as high as 90%. Compared with Mendel-Impute, our low-rank based method achieves similar accuracy and efficiency, while the co-clustering based method has advantages in running time. The testing results show that SparRec has significant advantages and competitive performance over other state-of-the-art existing statistics methods including Beagle and fastPhase.

  1. Initial precipitation and hardening mechanism during non-isothermal aging in an Al–Mg–Si–Cu 6005A alloy

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Wenchao, E-mail: [School of material Science and Engineering, Central South University, Changsha, 410083 (China); Brunel Centre for Advanced Solidification Technology (BCAST), Brunel University, Uxbridge, UB8 3PH (United Kingdom); Ji, Shouxun [Brunel Centre for Advanced Solidification Technology (BCAST), Brunel University, Uxbridge, UB8 3PH (United Kingdom); Huang, Lanping [State Key Laboratory of Powder Metallurgy, Central South University, Changsha, 410083 (China); Sheng, Xiaofei; Li, Zhou; Wang, Mingpu [School of material Science and Engineering, Central South University, Changsha, 410083 (China)


    The characterization of precipitation and hardening mechanism during non-isothermal aging had been investigated using high resolution transmission electron microscopy for an Al–Mg–Si–Cu 6005A alloy. It was proposed that the needle-shaped β″ precipitates with a three-dimension coherency strain-field and an increased number density in the Al matrix provided the maximum strengthening effect for the Al–Mg–Si–Cu 6005A alloy. Simultaneously, it was also found that the formation and evolution of clusters in the early precipitation were associated with the vacancy binding energy, during which Si atoms played an important role in controlling the numbers density of Mg/Si co-clusters, and the excess Si atoms provided the increased number of nucleation sites for the subsequent precipitates to strengthen and improve the precipitation rate. Finally, based on the experimental observation and theoretical analysis, the precipitation sequence during the early precipitation in the Al–Mg–Si–Cu 6005A alloy was proposed as: supersaturated solid solution → Si-vacancy pairs, Mg-vacancy pairs and Mg clusters → Si clusters, and dissolution of Mg clusters → Mg atoms diffusion into the existing Si clusters → Mg/Si co-clusters → GP zone. - Highlights: • β″ precipitates provide the maximum strengthening effect for the 6005A alloy. • Si atoms play an important role in controlling the numbers of Mg/Si co-clusters. • The early aging sequence is deduced based on the solute-vacancy binding energy.

  2. Towards stable catalysts by controlling collective properties of supported metal nanoparticles (United States)

    Prieto, Gonzalo; Zečević, Jovana; Friedrich, Heiner; de Jong, Krijn P.; de Jongh, Petra E.


    Supported metal nanoparticles play a pivotal role in areas such as nanoelectronics, energy storage/conversion and as catalysts for the sustainable production of fuels and chemicals. However, the tendency of nanoparticles to grow into larger crystallites is an impediment for stable performance. Exemplarily, loss of active surface area by metal particle growth is a major cause of deactivation for supported catalysts. In specific cases particle growth might be mitigated by tuning the properties of individual nanoparticles, such as size, composition and interaction with the support. Here we present an alternative strategy based on control over collective properties, revealing the pronounced impact of the three-dimensional nanospatial distribution of metal particles on catalyst stability. We employ silica-supported copper nanoparticles as catalysts for methanol synthesis as a showcase. Achieving near-maximum interparticle spacings, as accessed quantitatively by electron tomography, slows down deactivation up to an order of magnitude compared with a catalyst with a non-uniform nanoparticle distribution, or a reference Cu/ZnO/Al2O3 catalyst. Our approach paves the way towards the rational design of practically relevant catalysts and other nanomaterials with enhanced stability and functionality, for applications such as sensors, gas storage, batteries and solar fuel production.

  3. Signal Transduction in T Cell Activation and Tolerance (United States)


    nMunnol, 7, 175-207 26. Allison, J.P and Raulet, D.H (1990) The immunobiology of gamma delta+ T cells Seinin. InitunoI.f, 2, 59-65. 27. Blumberg, R S ... Janeway , C.A., Jr and Swain, S L. (1987) Coclustering of CD4 (L3T4) molecule with the T-cell receptor is induced by specific direct interaction of...rl ease; distribution is unl imi ted 4. PERFORMING ORGANIZATION REPORT NUMBER( S ) S . MONITORING ORGANIZATION REPORT NUMBER( S ) NMRI 93-49 6a. NAME OF

  4. Anti-glycosyl antibodies in lipid rafts of the enterocyte brush border: a possible host defense against pathogens

    DEFF Research Database (Denmark)

    Hansen, Gert Helge; Pedersen, Esben D K; Immerdal, Lissi;


    The pig small intestinal brush border is a glycoprotein- and glycolipid-rich membrane that functions as a digestive/absorptive surface for dietary nutrients as well as a permeability barrier for pathogens. The present work was performed to identify carbohydrate-binding (lectinlike) proteins...... a major part of the immunoglobulins at the lumenal surface of the gut. The antibodies were associated with lipid rafts at the brush border, and they frequently (52%) coclustered with the raft marker galectin 4. A lactose wash increased the susceptibility of the brush border toward lectin peanut agglutin...... the lipid raft microdomains of the brush border against pathogens....

  5. Research fronts analysis : A bibliometric to identify emerging fields of research (United States)

    Miwa, Sayaka; Ando, Satoko

    Research fronts analysis identifies emerging areas of research through observing co-clustering in highly-cited papers. This article introduces the concept of research fronts analysis, explains its methodology and provides case examples. It also demonstrates developing research fronts in Japan by looking at the past winners of Thomson Reuters Research Fronts Awards. Research front analysis is currently being used by the Japanese government to determine new trends in science and technology. Information professionals can also utilize this bibliometric as a research evaluation tool.

  6. NSOM/QD-Based Visualization of GM1 Serving as Platforms for TCR/CD3 Mediated T-Cell Activation

    Directory of Open Access Journals (Sweden)

    Liyun Zhong


    Full Text Available Direct molecular imaging of nanoscale relationship between T-cell receptor complexes (TCR/CD3 and gangliosidosis GM1 before and after T-cell activation has not been reported. In this study, we made use of our expertise of near-field scanning optical microscopy(NSOM/immune-labeling quantum dots- (QD-based dual-color imaging system to visualize nanoscale profiles for distribution and organization of TCR/CD3, GM1, as well as their nanospatial relationship and their correlation with PKCθ signaling cascade during T-cell activation. Interestingly, after anti-CD3/anti-CD28 Ab co-stimulation, both TCR/CD3 and GM1 were clustered to form nanodomains; moreover, all of TCR/CD3 nanodomains were colocalized with GM1 nanodomains, indicating that the formation of GM1 nanodomains was greatly correlated with TCR/CD3 mediated signaling. Specially, while T-cells were pretreated with PKCθ signaling inhibitor rottlerin to suppress IL-2 cytokine production, no visible TCR/CD3 nanodomains appeared while a lot of GM1 nanodomains were still observed. However, while T-cells are pretreated with PKCαβ signaling inhibitor GÖ6976 to suppress calcium-dependent manner, all of TCR/CD3 nanodomains were still colocalized with GM1 nanodomains. These findings possibly support the notion that the formation of GM1 nanodomains indeed serves as platforms for the recruitment of TCR/CD3 nanodomains, and TCR/CD3 nanodomains are required for PKCθ signaling cascades and T-cell activation

  7. Discovering Patterns in Time-Varying Graphs: A Triclustering Approach

    CERN Document Server

    Guigourès, Romain; Rossi, Fabrice


    This paper introduces a novel technique to track structures in time varying graphs. The method uses a maximum a posteriori approach for adjusting a three-dimensional co-clustering of the source vertices, the destination vertices and the time, to the data under study, in a way that does not require any hyper-parameter tuning. The three dimensions are simultaneously segmented in order to build clusters of source vertices, destination vertices and time segments where the edge distributions across clusters of vertices follow the same evolution over the time segments. The main novelty of this approach lies in that the time segments are directly inferred from the evolution of the edge distribution between the vertices, thus not requiring the user to make any a priori quantization. Experiments conducted on artificial data illustrate the good behavior of the technique, and a study of a real-life data set shows the potential of the proposed approach for exploratory data analysis.

  8. Role of the catalyst in the growth of single-wall carbon nanotubes. (United States)

    Balbuena, Perla B; Zhao, Jin; Huang, Shiping; Wang, Yixuan; Sakulchaicharoen, Nataphan; Resasco, Daniel E


    Classical molecular dynamics simulations are carried out to analyze the physical state of the catalyst, and the growth of single-wall carbon nanotubes under typical temperature and pressure conditions of their experimental synthesis, emphasizing the role of the catalyst/substrate interactions. It is found that a strong cluster/substrate interaction increases the cluster melting point, modifying the initial stages of carbon dissolution and precipitation on the cluster surface. Experiments performed on model Co-Mo catalysts clearly illustrate the existence of an initial period where the catalyst is formed and no nanotube growth is observed. To quantify the nature of the Co-Mo2C interaction, quantum density functional theory is applied to characterize structural and energetic features of small Co clusters deposited on a (001) Mo2C surface, revealing a strong attachment of Co-clusters to the Mo2C surface, which may increase the melting point of the cluster and prevent cluster sintering.

  9. New insight into molecular phylogeny and epidemiology of Sporothrix schenckii species complex based on calmodulin-encoding gene analysis of Italian isolates. (United States)

    Romeo, Orazio; Scordino, Fabio; Criseo, Giuseppe


    In this study, we investigated phylogenetic relationships among Italian Sporothrix schenckii isolates, by comparing their partial calmodulin sequences. In this analysis, we used 26 environmental strains of S. schenckii, plus two autochthonous clinical isolates. The results showed that our clinical strains grouped with S. schenckii sensu stricto isolates, whereas all 26 environmental isolates co-clustered with Sporothrix albicans (now regarded as a synonym of Sporothrix pallida), a non-pathogenic species closely related to S. schenckii. Furthermore, the group of environmental strains was found to be quite heterogeneous and further subdivided into two subgroups. The data reported here also showed that molecular methods, for specific identification of S. schenckii, developed before the description of its closely related species should be used with caution because of the possibility of false positive results, which could lead to inappropriate antifungal therapy. This study improves our understanding of the distribution of these new closely related Sporothrix species which also showed significant differences in antifungal susceptibilities.

  10. Leptin and the obesity receptor (OB-R) in the small intestine and colon: a colocalization study

    DEFF Research Database (Denmark)

    Hansen, Gert H; Niels-Christiansen, Lise-Lotte; Danielsen, E Michael


    Leptin is a hormone that plays an important role in overall body energy homeostasis, and the obesity receptor, OB-R, is widely distributed in the organism. In the intestine, a multitude of leptin actions have been reported, but it is currently unclear to what extent the hormone affects...... the intestinal epithelial cells by an endocrine or exocrine signaling pathway. To elucidate this, the localization of endogenous porcine leptin and OB-R in enterocytes and colonocytes was studied. By immunofluorescence microscopy, both leptin and OB-R were mainly observed in the basolateral membrane...... of enterocytes and colonocytes but also in the apical microvillar membrane of the cells. By electron microscopy, coclustering of hormone and receptor in the plasma membrane and localization in endosomes was frequently detected at the basolateral surface of the epithelial cells, indicative of leptin signaling...

  11. A PAC-Bayesian Analysis of Graph Clustering and Pairwise Clustering

    CERN Document Server

    Seldin, Yevgeny


    We formulate weighted graph clustering as a prediction problem: given a subset of edge weights we analyze the ability of graph clustering to predict the remaining edge weights. This formulation enables practical and theoretical comparison of different approaches to graph clustering as well as comparison of graph clustering with other possible ways to model the graph. We adapt the PAC-Bayesian analysis of co-clustering (Seldin and Tishby, 2008; Seldin, 2009) to derive a PAC-Bayesian generalization bound for graph clustering. The bound shows that graph clustering should optimize a trade-off between empirical data fit and the mutual information that clusters preserve on the graph nodes. A similar trade-off derived from information-theoretic considerations was already shown to produce state-of-the-art results in practice (Slonim et al., 2005; Yom-Tov and Slonim, 2009). This paper supports the empirical evidence by providing a better theoretical foundation, suggesting formal generalization guarantees, and offering...

  12. Weblog Clustering in Multilinear Algebra Perspective

    CERN Document Server

    Mirzal, Andri


    This paper describes a clustering method to group the most similar and important weblogs with their descriptive shared words by using a technique from multilinear algebra known as PARAFAC tensor decomposition. The proposed method first creates labeled-link network representation of the weblog datasets, where the nodes are the blogs and the labels are the shared words. Then, 3-way adjacency tensor is extracted from the network and the PARAFAC decomposition is applied to the tensor to get pairs of node lists and label lists with scores attached to each list as the indication of the degree of importance. The clustering is done by sorting the lists in decreasing order and taking the pairs of top ranked blogs and words. Thus, unlike standard co-clustering methods, this method not only groups the similar blogs with their descriptive words but also tends to produce clusters of important blogs and descriptive words.

  13. Lipid raft-mediated Fas/CD95 apoptotic signaling in leukemic cells and normal leukocytes and therapeutic implications. (United States)

    Gajate, Consuelo; Mollinedo, Faustino


    Plasma membrane is now recognized to contain tightly packed cholesterol/sphingolipid-rich domains, known as lipid or membrane rafts, which are more ordered than the surrounding lipid bilayer. Lipid rafts are crucial for the compartmentalization of signaling processes in the membrane, mostly involved in cell survival and immune response. However, in the last 15 years, a large body of evidence has also identified raft platforms as scaffolds for the recruitment and clustering of death receptor Fas/CD95 and downstream signaling molecules, leading to the concept of death-promoting lipid rafts. This raft-Fas/CD95 coclustering was first described at the early 2000s as the underlying mechanism for the proapoptotic action of the alkylphospholipid analog edelfosine in leukemic cells, hence facilitating protein-protein interactions and conveying apoptotic signals independently of Fas/CD95 ligand. Edelfosine induces apoptosis in hematologic cancer cells and activated T-lymphocytes. Fas/CD95 raft coclustering is also promoted by Fas/CD95 ligand, agonistic Fas/CD95 antibodies, and additional antitumor drugs. Thus, death receptor recruitment in rafts is a physiologic process leading to cell demise that can be pharmacologically modulated. This redistribution and local accumulation of apoptotic molecules in membrane rafts, which are usually accompanied by displacement of survival signaling molecules, highlight how alterations in the apoptosis/survival signaling balance in specialized membrane regions modulate cell fate. Membrane rafts might also modulate apoptotic and nonapoptotic death receptor signaling. Here, we discuss the role of lipid rafts in Fas/CD95-mediated apoptotic cell signaling in hematologic cancer cells and normal leukocytes, with a special emphasis on their involvement as putative therapeutic targets in cancer and autoimmune diseases.

  14. Coalescence of B cell receptor and invariant chain MHC II in a raft-like membrane domain. (United States)

    Hauser, Julian T; Lindner, Robert


    The BCR binds antigen for processing and subsequent presentation on MHC II molecules. Polyvalent antigen induces BCR clustering and targeting to endocytic processing compartments, which are also accessed by Ii-MHC II. Here, we report that clustered BCR is able to team up with Ii-MHC II already at the plasma membrane of mouse B-lymphocytes. Colocalization of BCR and Ii-MHC II on the cell surface required clustering of both types of molecules. The clustering of only one type did not trigger the recruitment of the other. Ii-bound MIF (a ligand of Ii) also colocalized with clustered BCR upon oligomerization of MIF on the surface of the B cell. Abundant surface molecules, such as B220 or TfnR, did not cocluster with the BCR. Some membrane raft-associated molecules, such as peptide-loaded MHC II, coclustered with the BCR, whereas others, such as GM1, did not. The formation of a BCR- and Ii-MHC II-containing membrane domain by antibody-mediated clustering was independent of F-actin and led to the coendocytosis of its constituents. With a rapid Brij 98 extraction method, it was possible to capture this membrane domain biochemically as a DRM. Ii and clustered BCR were present on the same DRM, as shown by immunoisolation. The coalescence of BCR and Ii-MHC II increased tyrosine phosphorylation, indicative of enhanced BCR signaling. Our work suggests a novel role for MIF and Ii-MHC II in BCR-mediated antigen processing.

  15. Coupling aging immunity with a sedentary lifestyle: has the damage already been done?--a mini-review. (United States)

    Simpson, Richard J; Guy, Keith


    The elderly population is at an unprecedented risk of infectious diseases and malignancy due to apparently inevitable age-related declines in immunity. The 'immune risk profile' (IRP) is an array of biomarkers that has been used to predict morbidity and mortality in older adults. As it is generally accepted that middle-aged and elderly individuals who habitually participate in moderate-intensity exercise are less likely to incur an infection than their sedentary counterparts, this review addresses current knowledge on the effects of regular exercise on aspects of adaptive immunity as they relate to the IRP. Findings from cross-sectional studies mostly show enhanced immunity in physically active compared to sedentary older adults. These include greater T-cell responsiveness to mitogens in vitro, a reduced frequency of antigen-experienced and senescent T-cells (i.e. CD45RO+/KLRG1+/CD57+/CD28-), enhanced IL-2 production and T-lymphocyte expression of the IL-2 receptor, longer chromosome telomere lengths in blood leukocytes and in vivo immune responses to vaccines and recall antigens. In contrast, the evidence from the available longitudinal studies that have used an exercise training intervention in previously sedentary elderly to improve similar immune responses is less compelling. Although this might indicate that exercise has limited immune restorative properties in previously sedentary elderly, there are still relatively few studies that have addressed specific IRP criteria and the large variation in experimental design among the longitudinal studies complicates the juxtaposition of these results. It is clear that a more substantial and focused research approach is required before physical exercise can be used in earnest as an effective immune restorative strategy in the elderly. This mini-review summarizes the major findings of these studies and proposes future avenues of research to investigate the effects of regular exercise on aspects of adaptive immunity in

  16. n-3 polyunsaturated fatty acids suppress CD4(+) T cell proliferation by altering phosphatidylinositol-(4,5)-bisphosphate [PI(4,5)P2] organization. (United States)

    Hou, Tim Y; Barhoumi, Rola; Fan, Yang-Yi; Rivera, Gonzalo M; Hannoush, Rami N; McMurray, David N; Chapkin, Robert S


    The mechanisms by which n-3 polyunsaturated fatty acids (n-3 PUFA), abundant in fish oil, exert their anti-inflammatory effects have not been rigorously defined. We have previously demonstrated that n-3 PUFA decrease the amount of phosphatidylinositol-(4,5)-bisphosphate, [PI(4,5)P2], in CD4(+) T cells, leading to suppressed actin remodeling upon activation. Since discrete pools of PI(4,5)P2 exist in the plasma membrane, we determined whether n-3 PUFA modulate spatial organization of PI(4,5)P2 relative to raft and non-raft domains. We used Förster resonance energy transfer (FRET) to demonstrate that lipid raft mesodomains in the plasma membrane of CD4(+) T cells enriched in n-3 PUFA display increased co-clustering of Lck(N10) and LAT(ΔCP), markers of lipid rafts. CD4(+) T cells enriched in n-3 PUFA also exhibited a depleted plasma membrane non-raft PI(4,5)P2 pool as detected by decreased co-clustering of Src(N15), a non-raft marker, and PH(PLC-δ), a PI(4,5)P2 reporter. Incubation with exogenous PI(4,5)P2 rescued the effects on the non-raft PI(4,5)P2 pool, and reversed the suppression of T cell proliferation in CD4(+) T cells enriched with n-3 PUFA. Furthermore, CD4(+) T cells isolated from mice fed a 4% docosahexaenoic acid (DHA)-enriched diet exhibited a decrease in the non-raft pool of PI(4,5)P2, and exogenous PI(4,5)P2 reversed the suppression of T cell proliferation. Finally, these effects were not due to changes to post-translational lipidation, since n-3 PUFA did not alter the palmitoylation status of signaling proteins. These data demonstrate that n-3 PUFA suppress T cell proliferation by altering plasma membrane topography and the spatial organization of PI(4,5)P2.

  17. JAM-A promotes neutrophil chemotaxis by controlling integrin internalization and recycling. (United States)

    Cera, Maria Rosaria; Fabbri, Monica; Molendini, Cinzia; Corada, Monica; Orsenigo, Fabrizio; Rehberg, Markus; Reichel, Christoph A; Krombach, Fritz; Pardi, Ruggero; Dejana, Elisabetta


    The membrane-associated adhesion molecule JAM-A is required for neutrophil infiltration in inflammatory or ischemic tissues. JAM-A expressed in both endothelial cells and neutrophils has such a role, but the mechanism of action remains elusive. Here we show that JAM-A has a cell-autonomous role in neutrophil chemotaxis both in vivo and in vitro, which is independent of the interaction of neutrophils with endothelial cells. On activated neutrophils, JAM-A concentrates in a polarized fashion at the leading edge and uropod. Surprisingly, a significant amount of this protein is internalized in intracellular endosomal-like vesicles where it codistributes with integrin beta1. Clustering of beta1 integrin leads to JAM-A co-clustering, whereas clustering of JAM-A does not induce integrin association. Neutrophils derived from JAM-A-null mice are unable to correctly internalize beta1 integrins upon chemotactic stimuli and this causes impaired uropod retraction and cell motility. Consistently, inhibition of integrin internalization upon treatment with BAPTA-AM induces a comparable phenotype. These data indicate that JAM-A is required for the correct internalization and recycling of integrins during cell migration and might explain why, in its absence, the directional migration of neutrophils towards an inflammatory stimulus is markedly impaired.

  18. Evolution of undissolved phases in high-zinc content super-high strength aluminum alloy during ageing

    Institute of Scientific and Technical Information of China (English)

    张坤; 刘志义; 叶呈武; 许晓嫦; 郑青春


    The evolution of undissolved phases in the high-zinc content super-high strength aluminum alloy during ageing was investigated by means of SEM and EIS. The results show that undissolved phases of Cu-rich M(AlZnMgCu) exist in the silver-free alloy at solid-solution state. With increasing the ageing time, the precipitation of agehardening precipitates MgZn2 stimulates Zn atoms within the undissolved phases to diffuse into the matrix, and thus the Cu content in the M(AlZnMgCu) phase increases relatively. For the silver-bearing alloy, small addition of Ag promotes the formation of Ag-rich M(A1ZnMgCuAg) undissolved phases and deteriorates mechanical properties of the alloy. At the early stage of ageing, Ag content within the M(AlZnMgCuAg) phases greatly decreases due to rapid diffusing of Ag atoms into the matrix and the co-clustering of Ag and Mg atoms. As the ageing time prolonging, the precipitation of MgZn2 results in the decrease of Zn content in the undissolved phases, and the relative increase of Ag and Mg contents.

  19. The fibroblast growth factor receptor acid box is essential for interactions with N-cadherin and all of the major isoforms of neural cell adhesion molecule. (United States)

    Sanchez-Heras, Elena; Howell, Fiona V; Williams, Gareth; Doherty, Patrick


    Interactions between the neural cell adhesion molecules NCAM and N-cadherin with the fibroblast growth factor receptor (FGFR) are important for a number of developmental events and have also been implicated in tumor progression. The factors regulating these interactions are not known. We have used co-immunoprecipitation and co-clustering paradigms to show that both adhesion molecules can interact with the 3Ig IIIC isoform of the FGFR1 in a number of cell types. Interestingly, whereas the interaction can be seen over most of the cell surface, it is not seen at points of cell-cell contact where the adhesion molecules accumulate at stable junctions. We also demonstrate for the first time that all of the major isoforms of NCAM can interact with the FGFR. Using deletion mutagenesis we have found that the adhesion molecule/FGFR interaction can withstand the removal of most of any one of the FGFR immunoglobulin-like domains (D1-D3). In contrast, the FGFR interaction with N-cadherin and NCAM (but not FGF) is absolutely dependant on the presence of the acid box motif that can be found in the linker region between D1 and D2. As this motif can be spliced out of all four FGFRs, it suggests that this is one mechanism that can regulate the interaction of the receptor with different ligand classes.

  20. SPARCoC: a new framework for molecular pattern discovery and cancer gene identification.

    Directory of Open Access Journals (Sweden)

    Shiqian Ma

    Full Text Available It is challenging to cluster cancer patients of a certain histopathological type into molecular subtypes of clinical importance and identify gene signatures directly relevant to the subtypes. Current clustering approaches have inherent limitations, which prevent them from gauging the subtle heterogeneity of the molecular subtypes. In this paper we present a new framework: SPARCoC (Sparse-CoClust, which is based on a novel Common-background and Sparse-foreground Decomposition (CSD model and the Maximum Block Improvement (MBI co-clustering technique. SPARCoC has clear advantages compared with widely-used alternative approaches: hierarchical clustering (Hclust and nonnegative matrix factorization (NMF. We apply SPARCoC to the study of lung adenocarcinoma (ADCA, an extremely heterogeneous histological type, and a significant challenge for molecular subtyping. For testing and verification, we use high quality gene expression profiling data of lung ADCA patients, and identify prognostic gene signatures which could cluster patients into subgroups that are significantly different in their overall survival (with p-values < 0.05. Our results are only based on gene expression profiling data analysis, without incorporating any other feature selection or clinical information; we are able to replicate our findings with completely independent datasets. SPARCoC is broadly applicable to large-scale genomic data to empower pattern discovery and cancer gene identification.

  1. Exploring the dominant role of Cav1 channels in signalling to the nucleus. (United States)

    Ma, Huan; Cohen, Samuel; Li, Boxing; Tsien, Richard W


    Calcium is important in controlling nuclear gene expression through the activation of multiple signal-transduction pathways in neurons. Compared with other voltage-gated calcium channels, Ca(V)1 channels demonstrate a considerable advantage in signalling to the nucleus. In this review, we summarize the recent progress in elucidating the mechanisms involved. Ca(V)1 channels, already advantaged in their responsiveness to depolarization, trigger communication with the nucleus by attracting colocalized clusters of activated CaMKII (Ca(2+)/calmodulin-dependent protein kinase II). Ca(V)2 channels lack this ability, but must work at a distance of >1 μm from the Ca(V)1-CaMKII co-clusters, which hampers their relative efficiency for a given rise in bulk [Ca(2+)](i) (intracellular [Ca(2+)]). Moreover, Ca(2+) influx from Ca(V)2 channels is preferentially buffered by the ER (endoplasmic reticulum) and mitochondria, further attenuating their effectiveness in signalling to the nucleus.

  2. Monitoring lipid anchor organization in cell membranes by PIE-FCCS. (United States)

    Triffo, Sara B; Huang, Hector H; Smith, Adam W; Chou, Eldon T; Groves, Jay T


    This study examines the dynamic co-localization of lipid-anchored fluorescent proteins in living cells using pulsed-interleaved excitation fluorescence cross-correlation spectroscopy (PIE-FCCS) and fluorescence lifetime analysis. Specifically, we look at the pairwise co-localization of anchors from lymphocyte cell kinase (LCK: myristoyl, palmitoyl, palmitoyl), RhoA (geranylgeranyl), and K-Ras (farnesyl) proteins in different cell types. In Jurkat cells, a density-dependent increase in cross-correlation among RhoA anchors is observed, while LCK anchors exhibit a more moderate increase and broader distribution. No correlation was detected among K-Ras anchors or between any of the different anchor types studied. Fluorescence lifetime data reveal no significant Förster resonance energy transfer in any of the data. In COS 7 cells, minimal correlation was detected among LCK or RhoA anchors. Taken together, these observations suggest that some lipid anchors take part in anchor-specific co-clustering with other existing clusters of native proteins and lipids in the membrane. Importantly, these observations do not support a simple interpretation of lipid anchor-mediated organization driven by partitioning based on binary lipid phase separation.

  3. Moesin is required for HIV-1-induced CD4-CXCR4 interaction, F-actin redistribution, membrane fusion and viral infection in lymphocytes. (United States)

    Barrero-Villar, Marta; Cabrero, José Román; Gordón-Alonso, Mónica; Barroso-González, Jonathan; Alvarez-Losada, Susana; Muñoz-Fernández, M Angeles; Sánchez-Madrid, Francisco; Valenzuela-Fernández, Agustín


    The human immunodeficiency virus 1 (HIV-1) envelope regulates the initial attachment of viral particles to target cells through its association with CD4 and either CXCR4 or CCR5. Although F-actin is required for CD4 and CXCR4 redistribution, little is known about the molecular mechanisms underlying this fundamental process in HIV infection. Using CD4(+) CXCR4(+) permissive human leukemic CEM T cells and primary lymphocytes, we have investigated whether HIV-1 Env might promote viral entry and infection by activating ERM (ezrin-radixin-moesin) proteins to regulate F-actin reorganization and CD4/CXCR4 co-clustering. The interaction of the X4-tropic protein HIV-1 gp120 with CD4 augments ezrin and moesin phosphorylation in human permissive T cells, thereby regulating ezrin-moesin activation. Moreover, the association and clustering of CD4-CXCR4 induced by HIV-1 gp120 requires moesin-mediated anchoring of actin in the plasma membrane. Suppression of moesin expression with dominant-negative N-moesin or specific moesin silencing impedes reorganization of F-actin and HIV-1 entry and infection mediated by the HIV-1 envelope protein complex. Therefore, we propose that activated moesin promotes F-actin redistribution and CD4-CXCR4 clustering and is also required for efficient X4-tropic HIV-1 infection in permissive lymphocytes.

  4. Tunneling magnetoresistance of C{sub 2}H{sub 2} molecules sandwiched between Co clusters

    Energy Technology Data Exchange (ETDEWEB)

    Zare-Kolsaraki, H. E-mail:; Micklitz, H


    The tunneling magnetoresistance (TMR) of samples containing well-defined Co clusters ({approx}4.5 nm mean diameter) embedded in C{sub 2}H{sub 2} matrices essentially is independent of Co-cluster volume fraction v{sub Co} and reveals a value of about 26% at T=2 K. This result is in contrast to that obtained for Co clusters embedded in C{sub 2}H{sub 4} matrices (Phys. Rev. B 67 (2003) 094433). In the latter system the TMR strongly decreased with increasing v{sub Co} indicating different possible orientation of the C{sub 2}H{sub 4} molecule sandwiched between the Co clusters. We, therefore, conclude that the C{sub 2}H{sub 2} molecules are sandwiched in a rather well-defined orientation between the Co clusters. They probably form double layers of C{sub 2}H{sub 2} molecules with the C-C bond axis parallel to the Co cluster surface.

  5. Genetic deletion of fibroblast growth factor 14 recapitulates phenotypic alterations underlying cognitive impairment associated with schizophrenia (United States)

    Alshammari, T K; Alshammari, M A; Nenov, M N; Hoxha, E; Cambiaghi, M; Marcinno, A; James, T F; Singh, P; Labate, D; Li, J; Meltzer, H Y; Sacchetti, B; Tempia, F; Laezza, F


    Cognitive processing is highly dependent on the functional integrity of gamma-amino-butyric acid (GABA) interneurons in the brain. These cells regulate excitability and synaptic plasticity of principal neurons balancing the excitatory/inhibitory tone of cortical networks. Reduced function of parvalbumin (PV) interneurons and disruption of GABAergic synapses in the cortical circuitry result in desynchronized network activity associated with cognitive impairment across many psychiatric disorders, including schizophrenia. However, the mechanisms underlying these complex phenotypes are still poorly understood. Here we show that in animal models, genetic deletion of fibroblast growth factor 14 (Fgf14), a regulator of neuronal excitability and synaptic transmission, leads to loss of PV interneurons in the CA1 hippocampal region, a critical area for cognitive function. Strikingly, this cellular phenotype associates with decreased expression of glutamic acid decarboxylase 67 (GAD67) and vesicular GABA transporter (VGAT) and also coincides with disrupted CA1 inhibitory circuitry, reduced in vivo gamma frequency oscillations and impaired working memory. Bioinformatics analysis of schizophrenia transcriptomics revealed functional co-clustering of FGF14 and genes enriched within the GABAergic pathway along with correlatively decreased expression of FGF14, PVALB, GAD67 and VGAT in the disease context. These results indicate that Fgf14−/− mice recapitulate salient molecular, cellular, functional and behavioral features associated with human cognitive impairment, and FGF14 loss of function might be associated with the biology of complex brain disorders such as schizophrenia. PMID:27163207

  6. A mathematical programming approach for sequential clustering of dynamic networks (United States)

    Silva, Jonathan C.; Bennett, Laura; Papageorgiou, Lazaros G.; Tsoka, Sophia


    A common analysis performed on dynamic networks is community structure detection, a challenging problem that aims to track the temporal evolution of network modules. An emerging area in this field is evolutionary clustering, where the community structure of a network snapshot is identified by taking into account both its current state as well as previous time points. Based on this concept, we have developed a mixed integer non-linear programming (MINLP) model, SeqMod, that sequentially clusters each snapshot of a dynamic network. The modularity metric is used to determine the quality of community structure of the current snapshot and the historical cost is accounted for by optimising the number of node pairs co-clustered at the previous time point that remain so in the current snapshot partition. Our method is tested on social networks of interactions among high school students, college students and members of the Brazilian Congress. We show that, for an adequate parameter setting, our algorithm detects the classes that these students belong more accurately than partitioning each time step individually or by partitioning the aggregated snapshots. Our method also detects drastic discontinuities in interaction patterns across network snapshots. Finally, we present comparative results with similar community detection methods for time-dependent networks from the literature. Overall, we illustrate the applicability of mathematical programming as a flexible, adaptable and systematic approach for these community detection problems. Contribution to the Topical Issue "Temporal Network Theory and Applications", edited by Petter Holme.

  7. Correlation functions quantify super-resolution images and estimate apparent clustering due to over-counting

    CERN Document Server

    Veatch, Sarah; Shelby, Sarah; Chiang, Ethan; Holowka, David; Baird, Barbara


    We present an analytical method to quantify clustering in super-resolution localization images of static surfaces in two dimensions. The method also describes how over-counting of labeled molecules contributes to apparent self-clustering and how the effective lateral resolution of an image can be determined. This treatment applies to clustering of proteins and lipids in membranes, where there is significant interest in using super-resolution localization techniques to probe membrane heterogeneity. When images are quantified using pair correlation functions, the magnitude of apparent clustering due to over-counting will vary inversely with the surface density of labeled molecules and does not depend on the number of times an average molecule is counted. Over-counting does not yield apparent co-clustering in double label experiments when pair cross-correlation functions are measured. We apply our analytical method to quantify the distribution of the IgE receptor (Fc{\\epsilon}RI) on the plasma membranes of chemi...

  8. Membrane distribution of the glycine receptor α3 studied by optical super-resolution microscopy. (United States)

    Notelaers, Kristof; Rocha, Susana; Paesen, Rik; Swinnen, Nina; Vangindertael, Jeroen; Meier, Jochen C; Rigo, Jean-Michel; Ameloot, Marcel; Hofkens, Johan


    In this study, the effect of glycine receptor (GlyR) α3 alternative RNA splicing on the distribution of receptors in the membrane of human embryonic kidney 293 cells is investigated using optical super-resolution microscopy. Direct stochastic optical reconstruction microscopy is used to image both α3K and α3L splice variants individually and together using single- and dual-color imaging. Pair correlation analysis is used to extract quantitative measures from the resulting images. Autocorrelation analysis of the individually expressed variants reveals clustering of both variants, yet with differing properties. The cluster size is increased for α3L compared to α3K (mean radius 92 ± 4 and 56 ± 3 nm, respectively), yet an even bigger difference is found in the cluster density (9,870 ± 1,433 and 1,747 ± 200 μm(-2), respectively). Furthermore, cross-correlation analysis revealed that upon co-expression, clusters colocalize on the same spatial scales as for individually expressed receptors (mean co-cluster radius 94 ± 6 nm). These results demonstrate that RNA splicing determines GlyR α3 membrane distribution, which has consequences for neuronal GlyR physiology and function.

  9. Lipid raft-dependent plasma membrane repair interferes with the activation of B lymphocytes. (United States)

    Miller, Heather; Castro-Gomes, Thiago; Corrotte, Matthias; Tam, Christina; Maugel, Timothy K; Andrews, Norma W; Song, Wenxia


    Cells rapidly repair plasma membrane (PM) damage by a process requiring Ca(2+)-dependent lysosome exocytosis. Acid sphingomyelinase (ASM) released from lysosomes induces endocytosis of injured membrane through caveolae, membrane invaginations from lipid rafts. How B lymphocytes, lacking any known form of caveolin, repair membrane injury is unknown. Here we show that B lymphocytes repair PM wounds in a Ca(2+)-dependent manner. Wounding induces lysosome exocytosis and endocytosis of dextran and the raft-binding cholera toxin subunit B (CTB). Resealing is reduced by ASM inhibitors and ASM deficiency and enhanced or restored by extracellular exposure to sphingomyelinase. B cell activation via B cell receptors (BCRs), a process requiring lipid rafts, interferes with PM repair. Conversely, wounding inhibits BCR signaling and internalization by disrupting BCR-lipid raft coclustering and by inducing the endocytosis of raft-bound CTB separately from BCR into tubular invaginations. Thus, PM repair and B cell activation interfere with one another because of competition for lipid rafts, revealing how frequent membrane injury and repair can impair B lymphocyte-mediated immune responses.

  10. The synaptic recruitment of lipid rafts is dependent on CD19-PI3K module and cytoskeleton remodeling molecules. (United States)

    Xu, Liling; Auzins, Arturs; Sun, Xiaolin; Xu, Yinsheng; Harnischfeger, Fiona; Lu, Yun; Li, Zhanguo; Chen, Ying-Hua; Zheng, Wenjie; Liu, Wanli


    Sphingolipid- and cholesterol-rich lipid raft microdomains are important in the initiation of BCR signaling. Although it is known that lipid rafts promote the coclustering of BCR and Lyn kinase microclusters within the B cell IS, the molecular mechanism of the recruitment of lipid rafts into the B cell IS is not understood completely. Here, we report that the synaptic recruitment of lipid rafts is dependent on the cytoskeleton-remodeling proteins, RhoA and Vav. Such an event is also efficiently regulated by motor proteins, myosin IIA and dynein. Further evidence suggests the synaptic recruitment of lipid rafts is, by principle, an event triggered by BCR signaling molecules and second messenger molecules. BCR-activating coreceptor CD19 potently enhances such an event depending on its cytoplasmic Tyr421 and Tyr482 residues. The enhancing function of the CD19-PI3K module in synaptic recruitment of lipid rafts is also confirmed in human peripheral blood B cells. Thus, these results improve our understanding of the molecular mechanism of the recruitment of lipid raft microdomains in B cell IS.

  11. Apoptosis of the teratocarcinoma cell line Tera-1 leads to the cleavage of HERV-K10gag proteins by caspases and/or granzyme B. (United States)

    Beyer, T D; Kolowos, W; Dumitriu, I E; Voll, R E; Heyder, P; Gaipl, U S; Kalden, J R; Herrmann, M


    Redistribution, post-translational modifications and coclustering with viral antigens contribute to the immunogenicity of apoptotic cell-derived autoantigens. Almost all known targets of the humoral autoimmune response in systemic lupus erythematosus (SLE) are cleaved by caspases or granzyme B during apoptosis. Antibodies against retroviral proteins can frequently be detected in the sera of SLE patients without overt retroviral infections. These antibodies may represent cross-reactive antibodies or may have been induced by proteins encoded by endogenous retroviral sequences. We used Tera-1 cells that abundantly express a group-specific antigen of human endogenous retroviruses, HERV-K10gag polyprotein, to investigate its processing during apoptosis. Tera-1 cells induced to undergo apoptosis showed an altered HERV-K10gag processing compared with viable cells. In addition, granzyme B was able to cleave HERV-K10gag isolated from viable Tera-1 cells. Similar to nuclear autoantigens, endogenous retroviral proteins are cleaved during the execution phase of apoptosis. These post-translational modifications may result in the generation of T-cell neoepitopes or a changed epitope hierarchy of retroviral proteins. Therefore, immunogenicity of retroviral antigens in SLE patients may result from a similar mechanism as described for nuclear autoantigens.

  12. Exploring the dominant role of Cav1 channels in signalling to the nucleus (United States)

    Ma, Huan; Cohen, Samuel; Li, Boxing; Tsien, Richard W.


    Calcium is important in controlling nuclear gene expression through the activation of multiple signal-transduction pathways in neurons. Compared with other voltage-gated calcium channels, CaV1 channels demonstrate a considerable advantage in signalling to the nucleus. In this review, we summarize the recent progress in elucidating the mechanisms involved. CaV1 channels, already advantaged in their responsiveness to depolarization, trigger communication with the nucleus by attracting colocalized clusters of activated CaMKII (Ca2+/calmodulin-dependent protein kinase II). CaV2 channels lack this ability, but must work at a distance of >1 μm from the CaV1-CaMKII co-clusters, which hampers their relative efficiency for a given rise in bulk [Ca2+]i (intracellular [Ca2+]). Moreover, Ca2+ influx from CaV2 channels is preferentially buffered by the ER (endoplasmic reticulum) and mitochondria, further attenuating their effectiveness in signalling to the nucleus. PMID:23088728

  13. Mechanisms controlling the artificial aging of Al-Mg-Si Alloys

    Energy Technology Data Exchange (ETDEWEB)

    Pogatscher, S., E-mail: [Institute of Nonferrous Metallurgy, Montanuniversitaet Leoben, Franz-Josef-Strasse 18, 8700 Leoben (Austria); Antrekowitsch, H. [Institute of Nonferrous Metallurgy, Montanuniversitaet Leoben, Franz-Josef-Strasse 18, 8700 Leoben (Austria); Leitner, H. [Department of Physical Metallurgy and Materials Testing, Montanuniversitaet Leoben, Franz-Josef-Strasse 18, 8700 Leoben (Austria); Ebner, T. [AMAG Rolling GmbH, Postfach 32, 5282 Ranshofen (Austria); Uggowitzer, P.J. [Laboratory of Metal Physics and Technology, Department of Materials, ETH Zurich, Wolfgang-Pauli-Strasse 10, 8093 Zurich (Switzerland)


    Highlights: > Artificial aging of Al-Mg-Si alloys in the range of 150 and 250 deg. C. > We study precipitation kinetics caused by various thermal histories. > Natural pre-aging affects kinetics at low artificial aging temperatures. > Natural pre-aging promotes kinetics at high artificial aging temperatures. > A vacancy-prison mechanism explains the effect of natural pre-aging. - Abstract: In this study the artificial aging behavior of the Al-Mg-Si alloy AA 6061 was investigated in the temperature range 150-250 deg. C using atom probe tomography, hardness and resistivity measurements for various thermal histories. It was found that the precipitation kinetics and age-hardening response of artificial aging at temperatures below 210 deg. C are lowered by prior natural aging but enhanced above this temperature. An analysis of hardness data was used to evaluate the temperature dependence of precipitation kinetics and dissolution processes. Supported by theoretical considerations, it is assumed that artificial aging of Al-Mg-Si alloys is controlled via the concentration of mobile vacancies. The 'vacancy-prison mechanism' proposed determines the mobile vacancy concentration in the case of natural pre-aging by temperature-dependent dissolution of co-clusters and solute-vacancy interactions.

  14. The origin of ferromagnetism of Co-doped TiO2 nanoparticles: Experiments and theory investigation (United States)

    Zhang, Suyin; Zhou, Zhongpo; Xiong, Rui; Shi, Jing; Lu, Zhihong; Wang, Haiying


    A series of Ti1-xCoxO2-δ (x = 0.01, 0.03, 0.05, 0.07) nanoparticles were synthesized by sol-gel method. The X-ray diffraction, transmission electron microscopy, Raman analysis and X-ray photoelectron spectroscopy ruled out the signatures of Ti3+, Co-clusters or any other oxides of Co. The ferromagnetic behavior was clearly observed at room temperature in doped samples with saturation magnetization (Ms) of the order of 0.008-0.035 emu/g depending on doping concentrations. The saturation magnetization is found to be increased with the Co contents increasing from 1% to 7%. From the plot of the M-T curve, we obtain the Tc as ˜515 K for 5% Co-doped TiO2. Oxygen vacancies were detected from the photoluminescence (PL) measurement. Magnetic properties analyses and PL analyses showed that oxygen vacancies probably played a major role in ferromagnetism of the Ti1-xCoxO2 system with Co substituting for Ti. The first-principles calculation was performed to investigate the magnetic properties of Co-doped TiO2 nanoparticles. It can be found that the major magnetic moment is from the 3d electron of Co. The experiment results are consistent with the first-principles calculation. The ferromagnetism derived from the spin-split of O-2p and Co-3d electron states caused by p-d orbit hybridization.

  15. Synthetic antigens reveal dynamics of BCR endocytosis during inhibitory signaling. (United States)

    Courtney, Adam H; Bennett, Nitasha R; Zwick, Daniel B; Hudon, Jonathan; Kiessling, Laura L


    B cells detect foreign antigens through their B cell antigen receptor (BCR). The BCR, when engaged by antigen, initiates a signaling cascade. Concurrent with signaling is endocytosis of the BCR complex, which acts to downregulate signaling and facilitate uptake of antigen for processing and display on the cell surface. The relationship between signaling and BCR endocytosis is poorly defined. Here, we explore the interplay between BCR endocytosis and antigens that either promote or inhibit B cell activation. Specifically, synthetic antigens were generated that engage the BCR alone or both the BCR and the inhibitory co-receptor CD22. The lectin CD22, a member of the Siglec family, binds sialic acid-containing glycoconjugates found on host tissues, inhibiting BCR signaling to prevent erroneous B cell activation. At low concentrations, antigens that can cocluster the BCR and CD22 promote rapid BCR endocytosis; whereas, slower endocytosis occurs with antigens that bind only the BCR. At higher antigen concentrations, rapid BCR endocytosis occurs upon treatment with either stimulatory or inhibitory antigens. Endocytosis of the BCR, in response to synthetic antigens, results in its entry into early endocytic compartments. Although the CD22-binding antigens fail to activate key regulators of antigen presentation (e.g., Syk), they also promote BCR endocytosis, indicating that inhibitory antigens can be internalized. Together, our observations support a functional role for BCR endocytosis in downregulating BCR signaling. The reduction of cell surface BCR levels in the absence of B cell activation should raise the threshold for BCR subsequent activation. The ability of the activating synthetic antigens to trigger both signaling and entry of the BCR into early endosomes suggests strategies for targeted antigen delivery.

  16. Coral: an integrated suite of visualizations for comparing clusterings

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    Filippova Darya


    Full Text Available Abstract Background Clustering has become a standard analysis for many types of biological data (e.g interaction networks, gene expression, metagenomic abundance. In practice, it is possible to obtain a large number of contradictory clusterings by varying which clustering algorithm is used, which data attributes are considered, how algorithmic parameters are set, and which near-optimal clusterings are chosen. It is a difficult task to sift though such a large collection of varied clusterings to determine which clustering features are affected by parameter settings or are artifacts of particular algorithms and which represent meaningful patterns. Knowing which items are often clustered together helps to improve our understanding of the underlying data and to increase our confidence about generated modules. Results We present Coral, an application for interactive exploration of large ensembles of clusterings. Coral makes all-to-all clustering comparison easy, supports exploration of individual clusterings, allows tracking modules across clusterings, and supports identification of core and peripheral items in modules. We discuss how each visual component in Coral tackles a specific question related to clustering comparison and provide examples of their use. We also show how Coral could be used to visually and quantitatively compare clusterings with a ground truth clustering. Conclusion As a case study, we compare clusterings of a recently published protein interaction network of Arabidopsis thaliana. We use several popular algorithms to generate the network’s clusterings. We find that the clusterings vary significantly and that few proteins are consistently co-clustered in all clusterings. This is evidence that several clusterings should typically be considered when evaluating modules of genes, proteins, or sequences, and Coral can be used to perform a comprehensive analysis of these clustering ensembles.

  17. The Neural Cell Adhesion Molecule (NCAM) Promotes Clustering and Activation of EphA3 Receptors in GABAergic Interneurons to Induce Ras Homolog Gene Family, Member A (RhoA)/Rho-associated protein kinase (ROCK)-mediated Growth Cone Collapse. (United States)

    Sullivan, Chelsea S; Kümper, Maike; Temple, Brenda S; Maness, Patricia F


    Establishment of a proper balance of excitatory and inhibitory connectivity is achieved during development of cortical networks and adjusted through synaptic plasticity. The neural cell adhesion molecule (NCAM) and the receptor tyrosine kinase EphA3 regulate the perisomatic synapse density of inhibitory GABAergic interneurons in the mouse frontal cortex through ephrin-A5-induced growth cone collapse. In this study, it was demonstrated that binding of NCAM and EphA3 occurred between the NCAM Ig2 domain and EphA3 cysteine-rich domain (CRD). The binding interface was further refined through molecular modeling and mutagenesis and shown to be comprised of complementary charged residues in the NCAM Ig2 domain (Arg-156 and Lys-162) and the EphA3 CRD (Glu-248 and Glu-264). Ephrin-A5 induced co-clustering of surface-bound NCAM and EphA3 in GABAergic cortical interneurons in culture. Receptor clustering was impaired by a charge reversal mutation that disrupted NCAM/EphA3 association, emphasizing the importance of the NCAM/EphA3 binding interface for cluster formation. NCAM enhanced ephrin-A5-induced EphA3 autophosphorylation and activation of RhoA GTPase, indicating a role for NCAM in activating EphA3 signaling through clustering. NCAM-mediated clustering of EphA3 was essential for ephrin-A5-induced growth cone collapse in cortical GABAergic interneurons, and RhoA and a principal effector, Rho-associated protein kinase, mediated the collapse response. This study delineates a mechanism in which NCAM promotes ephrin-A5-dependent clustering of EphA3 through interaction of the NCAM Ig2 domain and the EphA3 CRD, stimulating EphA3 autophosphorylation and RhoA signaling necessary for growth cone repulsion in GABAergic interneurons in vitro, which may extend to remodeling of axonal terminals of interneurons in vivo.

  18. Inhibitory synapse dynamics: coordinated presynaptic and postsynaptic mobility and the major contribution of recycled vesicles to new synapse formation. (United States)

    Dobie, Frederick A; Craig, Ann Marie


    Dynamics of GABAergic synaptic components have been studied previously over milliseconds to minutes, revealing mobility of postsynaptic scaffolds and receptors. Here we image inhibitory synapses containing fluorescently tagged postsynaptic scaffold Gephyrin, together with presynaptic vesicular GABA transporter (VGAT) or postsynaptic GABA(A) receptor γ2 subunit (GABA(A)Rγ2), over seconds to days in cultured rat hippocampal neurons, revealing modes of inhibitory synapse formation and remodeling. Entire synapses were mobile, translocating rapidly within a confined region and exhibiting greater nonstochastic motion over multihour periods. Presynaptic and postsynaptic components moved in unison, maintaining close apposition while translocating distances of several micrometers. An observed flux in the density of synaptic puncta partially resulted from the apparent merging and splitting of preexisting clusters. De novo formation of inhibitory synapses was observed, marked by the appearance of stably apposed Gephyrin and VGAT clusters at sites previously lacking either component. Coclustering of GABA(A)Rγ2 supports the identification of such new clusters as synapses. Nascent synapse formation occurred by gradual accumulation of components over several hours, with VGAT clustering preceding that of Gephyrin and GABA(A)Rγ2. Comparing VGAT labeling by active uptake of a luminal domain antibody with post hoc immunocytochemistry indicated that recycling vesicles from preexisting boutons significantly contribute to vesicle pools at the majority of new inhibitory synapses. Although new synapses formed primarily on dendrite shafts, some also formed on dendritic protrusions, without apparent interconversion. Altogether, the long-term imaging of GABAergic presynaptic and postsynaptic components reveals complex dynamics and perpetual remodeling with implications for mechanisms of assembly and synaptic integration.

  19. The population genetics of Pseudomonas aeruginosa isolates from different patient populations exhibits high-level host specificity.

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    Rosa van Mansfeld

    Full Text Available OBJECTIVE: To determine whether highly prevalent P. aeruginosa sequence types (ST in Dutch cystic fibrosis (CF patients are specifically linked to CF patients we investigated the population structure of P. aeruginosa from different clinical backgrounds. We first selected the optimal genotyping method by comparing pulsed-field gel electrophoresis (PFGE, multilocus sequence typing (MLST and multilocus variable number tandem-repeat analysis (MLVA. METHODS: Selected P. aeruginosa isolates (n = 60 were genotyped with PFGE, MLST and MLVA to determine the diversity index (DI and congruence (adjusted Rand and Wallace coefficients. Subsequently, isolates from patients admitted to two different ICUs (n = 205, from CF patients (n = 100 and from non-ICU, non-CF patients (n = 58, of which 19 were community acquired were genotyped with MLVA to determine distribution of genotypes and genetic diversity. RESULTS: Congruence between the typing methods was >79% and DIs were similar and all >0.963. Based on costs, ease, speed and possibilities to compare results between labs an adapted MLVA scheme called MLVA9-Utrecht was selected as the preferred typing method. In 363 clinical isolates 252 different MLVA types (MTs were identified, indicating a highly diverse population (DI  = 0.995; CI  = 0.993-0.997. DI levels were similarly high in the diverse clinical sources (all >0.981 and only eight genotypes were shared. MTs were highly specific (>80% for the different patient populations, even for similar patient groups (ICU patients in two distinct geographic regions, with only three of 142 ICU genotypes detected in both ICUs. The two major CF clones were unique to CF patients. CONCLUSION: The population structure of P. aeruginosa isolates is highly diverse and population specific without evidence for a core lineage in which major CF, hospital or community clones co-cluster. The two genotypes highly prevalent among Dutch CF patients appeared unique to CF patients

  20. Threonine 89 Is an Important Residue of Profilin-1 That Is Phosphorylatable by Protein Kinase A.

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    David Gau

    Full Text Available Dynamic regulation of actin cytoskeleton is at the heart of all actin-based cellular events. In this study, we sought to identify novel post-translational modifications of Profilin-1 (Pfn1, an important regulator of actin polymerization in cells.We performed in vitro protein kinase assay followed by mass-spectrometry to identify Protein Kinase A (PKA phosphorylation sites of Pfn1. By two-dimensional gel electrophoresis (2D-GE analysis, we further examined the changes in the isoelectric profile of ectopically expressed Pfn1 in HEK-293 cells in response to forskolin (FSK, an activator of cAMP/PKA pathway. Finally, we combined molecular dynamics simulations (MDS, GST pull-down assay and F-actin analyses of mammalian cells expressing site-specific phosphomimetic variants of Pfn1 to predict the potential consequences of phosphorylation of Pfn1.We identified several PKA phosphorylation sites of Pfn1 including Threonine 89 (T89, a novel site. Consistent with PKA's ability to phosphorylate Pfn1 in vitro, FSK stimulation increased the pool of the most negatively charged form of Pfn1 in HEK-293 cells which can be attenuated by PKA inhibitor H89. MDS predicted that T89 phosphorylation destabilizes an intramolecular interaction of Pfn1, potentially increasing its affinity for actin. The T89D phosphomimetic mutation of Pfn1 elicits several changes that are hallmarks of proteins folded into alternative three-dimensional conformations including detergent insolubility, protein aggregation and accelerated proteolysis, suggesting that T89 is a structurally important residue of Pfn1. Expression of T89D-Pfn1 induces actin:T89D-Pfn1 co-clusters and dramatically reduces overall actin polymerization in cells, indicating an actin-sequestering action of T89D-Pfn1. Finally, rendering T89 non-phosphorylatable causes a positive charge shift in the isoelectric profile of Pfn1 in a 2D gel electrophoresis analysis of cell extracts, a finding that is consistent with

  1. Correlation functions quantify super-resolution images and estimate apparent clustering due to over-counting.

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    Sarah L Veatch

    Full Text Available We present an analytical method using correlation functions to quantify clustering in super-resolution fluorescence localization images and electron microscopy images of static surfaces in two dimensions. We use this method to quantify how over-counting of labeled molecules contributes to apparent self-clustering and to calculate the effective lateral resolution of an image. This treatment applies to distributions of proteins and lipids in cell membranes, where there is significant interest in using electron microscopy and super-resolution fluorescence localization techniques to probe membrane heterogeneity. When images are quantified using pair auto-correlation functions, the magnitude of apparent clustering arising from over-counting varies inversely with the surface density of labeled molecules and does not depend on the number of times an average molecule is counted. In contrast, we demonstrate that over-counting does not give rise to apparent co-clustering in double label experiments when pair cross-correlation functions are measured. We apply our analytical method to quantify the distribution of the IgE receptor (FcεRI on the plasma membranes of chemically fixed RBL-2H3 mast cells from images acquired using stochastic optical reconstruction microscopy (STORM/dSTORM and scanning electron microscopy (SEM. We find that apparent clustering of FcεRI-bound IgE is dominated by over-counting labels on individual complexes when IgE is directly conjugated to organic fluorophores. We verify this observation by measuring pair cross-correlation functions between two distinguishably labeled pools of IgE-FcεRI on the cell surface using both imaging methods. After correcting for over-counting, we observe weak but significant self-clustering of IgE-FcεRI in fluorescence localization measurements, and no residual self-clustering as detected with SEM. We also apply this method to quantify IgE-FcεRI redistribution after deliberate clustering by

  2. 基于参考点的大规模本体分块与映射%Anchor-based large-scale ontologies partitioning and mapping

    Institute of Scientific and Technical Information of China (English)

    赖雅; 王润梅; 徐德智


    In order to solve the problem of low precision and low recall of large-scale ontology partitioning and mapping, this paper proposed a new anchor-based large-scale ontology partitioning and mapping method. This method used anchors to guide partitioning, and partitioned the two ontologies at the same time, which called co-clustering. Firstly,it preprocessed the two ontologies in order to normalize the entities' s name and turn them into tree structure, then used some simple methods to find anchors. At last, the anchors acted cluster centers to cluster the concepts in both ontology trees, and found block mappings at the same time. Theoretical analysis and experimental results show that this method both solves the large-scale ontologeis mapping problem and achieves good precision and recall.%针对大规模本体映射中存在查全率和查准率不高的问题,提出了一种新的基于参考点的大规模本体分块与映射的方法.该方法的主要思想是用参考点来指导分块,并同时对待映射的两个大规模本体同时分块,即联合分块.首先对大规模本体进行预处理,将本体中的实体名称归一化并将其表示成本体树的形式,然后采用一些简便的方法找到参考点,最后以参考点为聚类中心对两个本体树的概念进行聚类,并同时实现块映射.理论分析和实验结果表明,该方法能够有效地解决大规模本体映射问题,并能获得较好的查全率和查准率.

  3. The genome sequence of Caenorhabditis briggsae: a platform for comparative genomics.

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    Lincoln D Stein


    Full Text Available The soil nematodes Caenorhabditis briggsae and Caenorhabditis elegans diverged from a common ancestor roughly 100 million years ago and yet are almost indistinguishable by eye. They have the same chromosome number and genome sizes, and they occupy the same ecological niche. To explore the basis for this striking conservation of structure and function, we have sequenced the C. briggsae genome to a high-quality draft stage and compared it to the finished C. elegans sequence. We predict approximately 19,500 protein-coding genes in the C. briggsae genome, roughly the same as in C. elegans. Of these, 12,200 have clear C. elegans orthologs, a further 6,500 have one or more clearly detectable C. elegans homologs, and approximately 800 C. briggsae genes have no detectable matches in C. elegans. Almost all of the noncoding RNAs (ncRNAs known are shared between the two species. The two genomes exhibit extensive colinearity, and the rate of divergence appears to be higher in the chromosomal arms than in the centers. Operons, a distinctive feature of C. elegans, are highly conserved in C. briggsae, with the arrangement of genes being preserved in 96% of cases. The difference in size between the C. briggsae (estimated at approximately 104 Mbp and C. elegans (100.3 Mbp genomes is almost entirely due to repetitive sequence, which accounts for 22.4% of the C. briggsae genome in contrast to 16.5% of the C. elegans genome. Few, if any, repeat families are shared, suggesting that most were acquired after the two species diverged or are undergoing rapid evolution. Coclustering the C. elegans and C. briggsae proteins reveals 2,169 protein families of two or more members. Most of these are shared between the two species, but some appear to be expanding or contracting, and there seem to be as many as several hundred novel C. briggsae gene families. The C. briggsae draft sequence will greatly improve the annotation of the C. elegans genome. Based on similarity to C