58,248 research outputs found
The Talin Head Domain Reinforces Integrin-Mediated Adhesion by Promoting Adhesion Complex Stability and Clustering
Talin serves an essential function during integrin-mediated adhesion in linking integrins to actin via the intracellular adhesion complex. In addition, the N-terminal head domain of talin regulates the affinity of integrins for their ECM-ligands, a process known as inside-out activation. We previously showed that in Drosophila, mutating the integrin binding site in the talin head domain resulted in weakened adhesion to the ECM. Intriguingly, subsequent studies showed that canonical inside-out activation of integrin might not take place in flies. Consistent with this, a mutation in talin that specifically blocks its ability to activate mammalian integrins does not significantly impinge on talin function during fly development. Here, we describe results suggesting that the talin head domain reinforces and stabilizes the integrin adhesion complex by promoting integrin clustering distinct from its ability to support inside-out activation. Specifically, we show that an allele of talin containing a mutation that disrupts intramolecular interactions within the talin head attenuates the assembly and reinforcement of the integrin adhesion complex. Importantly, we provide evidence that this mutation blocks integrin clustering in vivo. We propose that the talin head domain is essential for regulating integrin avidity in Drosophila and that this is crucial for integrin-mediated adhesion during animal development
Pancancer analysis of DNA methylation-driven genes using MethylMix.
Aberrant DNA methylation is an important mechanism that contributes to oncogenesis. Yet, few algorithms exist that exploit this vast dataset to identify hypo- and hypermethylated genes in cancer. We developed a novel computational algorithm called MethylMix to identify differentially methylated genes that are also predictive of transcription. We apply MethylMix to 12 individual cancer sites, and additionally combine all cancer sites in a pancancer analysis. We discover pancancer hypo- and hypermethylated genes and identify novel methylation-driven subgroups with clinical implications. MethylMix analysis on combined cancer sites reveals 10 pancancer clusters reflecting new similarities across malignantly transformed tissues
Utilizing Protein Structure to Identify Non-Random Somatic Mutations
Motivation: Human cancer is caused by the accumulation of somatic mutations
in tumor suppressors and oncogenes within the genome. In the case of oncogenes,
recent theory suggests that there are only a few key "driver" mutations
responsible for tumorigenesis. As there have been significant pharmacological
successes in developing drugs that treat cancers that carry these driver
mutations, several methods that rely on mutational clustering have been
developed to identify them. However, these methods consider proteins as a
single strand without taking their spatial structures into account. We propose
a new methodology that incorporates protein tertiary structure in order to
increase our power when identifying mutation clustering.
Results: We have developed a novel algorithm, iPAC: identification of Protein
Amino acid Clustering, for the identification of non-random somatic mutations
in proteins that takes into account the three dimensional protein structure. By
using the tertiary information, we are able to detect both novel clusters in
proteins that are known to exhibit mutation clustering as well as identify
clusters in proteins without evidence of clustering based on existing methods.
For example, by combining the data in the Protein Data Bank (PDB) and the
Catalogue of Somatic Mutations in Cancer, our algorithm identifies new
mutational clusters in well known cancer proteins such as KRAS and PI3KCa.
Further, by utilizing the tertiary structure, our algorithm also identifies
clusters in EGFR, EIF2AK2, and other proteins that are not identified by
current methodology
A New Quartet Tree Heuristic for Hierarchical Clustering
We consider the problem of constructing an an optimal-weight tree from the
3*(n choose 4) weighted quartet topologies on n objects, where optimality means
that the summed weight of the embedded quartet topologiesis optimal (so it can
be the case that the optimal tree embeds all quartets as non-optimal
topologies). We present a heuristic for reconstructing the optimal-weight tree,
and a canonical manner to derive the quartet-topology weights from a given
distance matrix. The method repeatedly transforms a bifurcating tree, with all
objects involved as leaves, achieving a monotonic approximation to the exact
single globally optimal tree. This contrasts to other heuristic search methods
from biological phylogeny, like DNAML or quartet puzzling, which, repeatedly,
incrementally construct a solution from a random order of objects, and
subsequently add agreement values.Comment: 22 pages, 14 figure
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A Clustering System for Dynamic Data Streams Based on Metaheuristic Optimisation
open access articleThis article presents the Optimised Stream clustering algorithm (OpStream), a novel approach to cluster dynamic data streams. The proposed system displays desirable features, such as a low number of parameters and good scalability capabilities to both high-dimensional data and numbers of clusters in the dataset, and it is based on a hybrid structure using deterministic clustering methods and stochastic optimisation approaches to optimally centre the clusters. Similar to other state-of-the-art methods available in the literature, it uses “microclusters” and other established techniques, such as density based clustering. Unlike other methods, it makes use of metaheuristic optimisation to maximise performances during the initialisation phase, which precedes the classic online phase. Experimental results show that OpStream outperforms the state-of-the-art methods in several cases, and it is always competitive against other comparison algorithms regardless of the chosen optimisation method. Three variants of OpStream, each coming with a different optimisation algorithm, are presented in this study. A thorough sensitive analysis is performed by using the best variant to point out OpStream’s robustness to noise and resiliency to parameter changes
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Artificial Immune Systems - Models, algorithms and applications
Copyright © 2010 Academic Research Publishing Agency.This article has been made available through the Brunel Open Access Publishing Fund.Artificial Immune Systems (AIS) are computational paradigms that belong to the computational intelligence family and are inspired by the biological immune system. During the past decade, they have attracted a lot of interest from researchers aiming to develop immune-based models and techniques to solve complex computational or engineering problems. This work presents a survey of existing AIS models and algorithms with a focus on the last five years.This article is available through the Brunel Open Access Publishing Fun
A Spatial Simulation Approach to Account for Protein Structure When Identifying Non-Random Somatic Mutations
Background: Current research suggests that a small set of "driver" mutations
are responsible for tumorigenesis while a larger body of "passenger" mutations
occurs in the tumor but does not progress the disease. Due to recent
pharmacological successes in treating cancers caused by driver mutations, a
variety of of methodologies that attempt to identify such mutations have been
developed. Based on the hypothesis that driver mutations tend to cluster in key
regions of the protein, the development of cluster identification algorithms
has become critical.
Results: We have developed a novel methodology, SpacePAC (Spatial Protein
Amino acid Clustering), that identifies mutational clustering by considering
the protein tertiary structure directly in 3D space. By combining the
mutational data in the Catalogue of Somatic Mutations in Cancer (COSMIC) and
the spatial information in the Protein Data Bank (PDB), SpacePAC is able to
identify novel mutation clusters in many proteins such as FGFR3 and CHRM2. In
addition, SpacePAC is better able to localize the most significant mutational
hotspots as demonstrated in the cases of BRAF and ALK. The R package is
available on Bioconductor at:
http://www.bioconductor.org/packages/release/bioc/html/SpacePAC.html
Conclusion: SpacePAC adds a valuable tool to the identification of mutational
clusters while considering protein tertiary structureComment: 16 pages, 8 Figures, 4 Table
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