From Large Scale Rearrangements to Mode Coupling Phenomenology

We consider the equilibrium dynamics of Ising spin models with multi-spin interactions on sparse random graphs (Bethe lattices). Such models undergo a mean field glass transition upon increasing the graph connectivity or lowering the temperature. Focusing on the low temperature limit, we identify the large scale rearrangements responsible for the dynamical slowing-down near the transition. We are able to characterize exactly the dynamics near criticality by analyzing the statistical properties of such rearrangements. Our approach can be generalized to a large variety of glassy models on sparse random graphs, ranging from satisfiability to kinetically constrained models.Comment: 4 pages, 4 figures, minor corrections, accepted versio

P35. Intratumoral patterns of clonal evolution in meningiomas

Núm. a Art Públic: 1815Digitalitzat per Tecnodo

Accumulation of driver and passenger mutations during tumor progression

Major efforts to sequence cancer genomes are now occurring throughout the world. Though the emerging data from these studies are illuminating, their reconciliation with epidemiologic and clinical observations poses a major challenge. In the current study, we provide a novel mathematical model that begins to address this challenge. We model tumors as a discrete time branching process that starts with a single driver mutation and proceeds as each new driver mutation leads to a slightly increased rate of clonal expansion. Using the model, we observe tremendous variation in the rate of tumor development - providing an understanding of the heterogeneity in tumor sizes and development times that have been observed by epidemiologists and clinicians. Furthermore, the model provides a simple formula for the number of driver mutations as a function of the total number of mutations in the tumor. Finally, when applied to recent experimental data, the model allows us to calculate, for the first time, the actual selective advantage provided by typical somatic mutations in human tumors in situ. This selective advantage is surprisingly small, 0.005 +- 0.0005, and has major implications for experimental cancer research

On Embeddability of Buses in Point Sets

Set membership of points in the plane can be visualized by connecting corresponding points via graphical features, like paths, trees, polygons, ellipses. In this paper we study the \emph{bus embeddability problem} (BEP): given a set of colored points we ask whether there exists a planar realization with one horizontal straight-line segment per color, called bus, such that all points with the same color are connected with vertical line segments to their bus. We present an ILP and an FPT algorithm for the general problem. For restricted versions of this problem, such as when the relative order of buses is predefined, or when a bus must be placed above all its points, we provide efficient algorithms. We show that another restricted version of the problem can be solved using 2-stack pushall sorting. On the negative side we prove the NP-completeness of a special case of BEP.Comment: 19 pages, 9 figures, conference version at GD 201

Predicting the Response to Combination Antiretroviral Therapy: Retrospective Validation of geno2pheno-THEO on a Large Clinical Database

BackgroundExpert-based genotypic interpretation systems are standard methods for guiding treatment selection for patients infected with human immunodeficiency virus type 1. We previously introduced the software pipeline geno2pheno-THEO (g2p-THEO), which on the basis of viral sequence predicts the response to treatment with a combination of antiretroviral compounds by applying methods from statistical learning and the estimated potential of the virus to escape from drug pressure MethodsWe retrospectively validated the statistical model used by g2p-THEO in ∼7600 independent treatment-sequence pairs extracted from the EuResist integrated database, ranging from 1990 to 2007. Results were compared with the 3 most widely used expert-based interpretation systems: Stanford HIVdb, ANRS, and Rega ResultsThe difference in receiver operating characteristic curves between g2p-THEO and expert-based approaches was significant (P<.001; paired Wilcoxon test). Indeed, at 80% specificity, g2p-THEO found 16.2%-19.8% more successful regimens than did the expert-based approaches. The increased performance of g2p-THEO was confirmed in a 2001-2007 data set from which most obsolete therapies had been removed ConclusionFinding drug combinations that increase the chances of therapeutic success is the main reason for using decision support systems. The present analysis of a large data set derived from clinical practice demonstrates that g2p-THEO solves this task significantly better than state-of-the-art expert-based systems. The tool is available at http://www.geno2pheno.or

More Legal Transformations for Locality

Distinguished paper award Commercial link : http://www.springerlink.de ALCHEMY/http://www.springer.comProgram transformations are one of the most valuable compiler techniques to improve data locality. However, restructuring compilers have a hard time coping with data dependences. A typical solution is to focus on program parts where the dependences are simple enough to enable any transformation. For more complex problems is only addressed the question of checking whether a transformation is legal or not. In this paper we propose to go further. Starting from a transformation with no guarantee on legality, we show how we can correct it for dependence satisfaction with no consequence on its locality properties. Generating code having the best locality is a direct application of this result

On the dynamics of the glass transition on Bethe lattices

The Glauber dynamics of disordered spin models with multi-spin interactions on sparse random graphs (Bethe lattices) is investigated. Such models undergo a dynamical glass transition upon decreasing the temperature or increasing the degree of constrainedness. Our analysis is based upon a detailed study of large scale rearrangements which control the slow dynamics of the system close to the dynamical transition. Particular attention is devoted to the neighborhood of a zero temperature tricritical point. Both the approach and several key results are conjectured to be valid in a considerably more general context.Comment: 56 pages, 38 eps figure

Differential expression of DHHC9 in microsatellite stable and instable human colorectal cancer subgroups

Microarray analysis on pooled samples has previously identified ZDHHC9 (DHHC9) to be upregulated in colon adenocarcinoma compared to normal colon mucosa. Analyses of 168 samples from proximal and distal adenocarcinomas using U133plus2.0 microarrays validated these findings, showing a significant two-fold (log 2) upregulation of DHHC9 transcript (P<10(−6)). The upregulation was more striking in microsatellite stable (MSS), than in microsatellite instable (MSI), tumours. Genes known to interact with DHHC9 as H-Ras or N-Ras did not show expression differences between MSS and MSI. Immunohistochemical analysis was performed on 60 colon adenocarcinomas, previously analysed on microarrays, as well as on tissue microarrays with 40 stage I–IV tumours and 46 tumours from different organ sites. DHHC9 protein was strongly expressed in MSS compared to MSI tumours, readily detectable in premalignant lesions, compared to the rare expression seen in normal mucosa. DHHC9 was specific for tumours of the gastrointestinal tract and localised to the Golgi apparatus, in vitro and in vivo. Overexpression of DHHC9 decreased the proliferation of SW480 and CaCo2 MSS cell lines significantly. In conclusion, DHHC9 is a gastrointestinal-related protein highly expressed in MSS colon tumours. The palmitoyl transferase activity, modifying N-Ras and H-Ras, suggests DHHC9 as a target for anticancer drug design