An efficient pseudomedian filter for tiling microrrays

<p>Abstract</p> <p>Background</p> <p>Tiling microarrays are becoming an essential technology in the functional genomics toolbox. They have been applied to the tasks of novel transcript identification, elucidation of transcription factor binding sites, detection of methylated DNA and several other applications in several model organisms. These experiments are being conducted at increasingly finer resolutions as the microarray technology enjoys increasingly greater feature densities. The increased densities naturally lead to increased data analysis requirements. Specifically, the most widely employed algorithm for tiling array analysis involves smoothing observed signals by computing pseudomedians within sliding windows, a <it>O</it>(<it>n</it>²log<it>n</it>) calculation in each window. This poor time complexity is an issue for tiling array analysis and could prove to be a real bottleneck as tiling microarray experiments become grander in scope and finer in resolution.</p> <p>Results</p> <p>We therefore implemented Monahan's HLQEST algorithm that reduces the runtime complexity for computing the pseudomedian of <it>n </it>numbers to <it>O</it>(<it>n</it>log<it>n</it>) from <it>O</it>(<it>n</it>²log<it>n</it>). For a representative tiling microarray dataset, this modification reduced the smoothing procedure's runtime by nearly 90%. We then leveraged the fact that elements within sliding windows remain largely unchanged in overlapping windows (as one slides across genomic space) to further reduce computation by an additional 43%. This was achieved by the application of skip lists to maintaining a sorted list of values from window to window. This sorted list could be maintained with simple <it>O</it>(log <it>n</it>) inserts and deletes. We illustrate the favorable scaling properties of our algorithms with both time complexity analysis and benchmarking on synthetic datasets.</p> <p>Conclusion</p> <p>Tiling microarray analyses that rely upon a sliding window pseudomedian calculation can require many hours of computation. We have eased this requirement significantly by implementing efficient algorithms that scale well with genomic feature density. This result not only speeds the current standard analyses, but also makes possible ones where many iterations of the filter may be required, such as might be required in a bootstrap or parameter estimation setting. Source code and executables are available at <url>http://tiling.gersteinlab.org/pseudomedian/</url>.</p

Resource Control for Synchronous Cooperative Threads

We develop new methods to statically bound the resources needed for the execution of systems of concurrent, interactive threads. Our study is concerned with a \emph{synchronous} model of interaction based on cooperative threads whose execution proceeds in synchronous rounds called instants. Our contribution is a system of compositional static analyses to guarantee that each instant terminates and to bound the size of the values computed by the system as a function of the size of its parameters at the beginning of the instant. Our method generalises an approach designed for first-order functional languages that relies on a combination of standard termination techniques for term rewriting systems and an analysis of the size of the computed values based on the notion of quasi-interpretation. We show that these two methods can be combined to obtain an explicit polynomial bound on the resources needed for the execution of the system during an instant. As a second contribution, we introduce a virtual machine and a related bytecode thus producing a precise description of the resources needed for the execution of a system. In this context, we present a suitable control flow analysis that allows to formulte the static analyses for resource control at byte code level

Preliminary experiences with contact endoscopy of the larynx

Nine patients with laryngeal polyps, four with Reinke’s edema, three with leukoplakia, one with papilloma and one with malignant tumor were studied by means of laryngeal contact endoscopy during microlaryngoscopy. This technique allowed in vivo and in situ visualization of the superficial layer of the laryngeal epithelium after staining with methylene blue. Cell structures evaluated were the size and color of the nuclei, the nucleus/cytoplasm ratio, nuclear and cytoplasmic contours, the presence of nucleoli, mitoses and keratoses, as well as the microvascular network of the mucosa and superficial cellular changes from normal to pathological. The normal squamous epithelium of the vocal cord showed a homogeneous cellular population with regular nuclear and cytoplasmic morphological characteristics and a uniform nucleus-to-cytolasm ratio. Specific cellular epithelial pat- terns and several alterations of the vascular distribution were found in different pathological conditions. Cytological pictures obtained at contact endoscopy were consistent with histological findings in all the patients studie

Whole-genome association studies on alcoholism comparing different phenotypes using single-nucleotide polymorphisms and microsatellites

Alcoholism is a complex disease. As with other common diseases, genetic variants underlying alcoholism have been illusive, possibly due to the small effect from each individual susceptible variant, gene × environment and gene × gene interactions and complications in phenotype definition. We conducted association tests, the family-based association tests (FBAT) and the backward haplotype transmission association (BHTA), on the Collaborative Study of the Genetics of Alcoholism (COGA) data provided by Genetic Analysis Workshop (GAW) 14. Efron's local false discovery rate method was applied to control the proportion of false discoveries. For FBAT, we compared the results based on different types of genetic markers (single-nucleotide polymorphisms (SNPs) versus microsatellites) and different phenotype definitions (clinical diagnoses versus electrophysiological phenotypes). Significant association results were found only between SNPs and clinical diagnoses. In contrast, significant results were found only between microsatellites and electrophysiological phenotypes. In addition, we obtained the association results for SNPs and microsatellites using COGA diagnosis as phenotype based on BHTA. In this case, the results for SNPs and microsatellites are more consistent. Compared to FBAT, more significant markers are detected with BHTA

Hinge Atlas: relating protein sequence to sites of structural flexibility

<p>Abstract</p> <p>Background</p> <p>Relating features of protein sequences to structural hinges is important for identifying domain boundaries, understanding structure-function relationships, and designing flexibility into proteins. Efforts in this field have been hampered by the lack of a proper dataset for studying characteristics of hinges.</p> <p>Results</p> <p>Using the Molecular Motions Database we have created a Hinge Atlas of manually annotated hinges and a statistical formalism for calculating the enrichment of various types of residues in these hinges.</p> <p>Conclusion</p> <p>We found various correlations between hinges and sequence features. Some of these are expected; for instance, we found that hinges tend to occur on the surface and in coils and turns and to be enriched with small and hydrophilic residues. Others are less obvious and intuitive. In particular, we found that hinges tend to coincide with active sites, but unlike the latter they are not at all conserved in evolution. We evaluate the potential for hinge prediction based on sequence.</p> <p>Motions play an important role in catalysis and protein-ligand interactions. Hinge bending motions comprise the largest class of known motions. Therefore it is important to relate the hinge location to sequence features such as residue type, physicochemical class, secondary structure, solvent exposure, evolutionary conservation, and proximity to active sites. To do this, we first generated the Hinge Atlas, a set of protein motions with the hinge locations manually annotated, and then studied the coincidence of these features with the hinge location. We found that all of the features have bearing on the hinge location. Most interestingly, we found that hinges tend to occur at or near active sites and yet unlike the latter are not conserved. Less surprisingly, we found that hinge residues tend to be small, not hydrophobic or aliphatic, and occur in turns and random coils on the surface. A functional sequence based hinge predictor was made which uses some of the data generated in this study. The Hinge Atlas is made available to the community for further flexibility studies.</p

Ex vivo determination of bone tissue strains for an in vivo mouse tibial loading model

AbstractPrevious studies introduced the digital image correlation (DIC) as a viable technique for measuring bone strain during loading. In this study, we investigated the sensitivity of a DIC system in determining surface strains in a mouse tibia while loaded in compression through the knee joint. Specifically, we examined the effect of speckle distribution, facet size and overlap, initial vertical alignment of the bone into the loading cups, rotation with respect to cameras, and ex vivo loading configurations on the strain contour maps measured with a DIC system.We loaded tibiae of C57BL/6 mice (12 and 18 weeks old male) up to 12N at 8N/min. Images of speckles on the bone surface were recorded at 1N intervals and DIC was used to compute strains. Results showed that speckles must have the correct size and density with respect to the facet size of choice for the strain distribution to be computed and reproducible. Initial alignment of the bone within the loading cups does not influence the strain distribution measured during peak loading, but bones must be placed in front of the camera with the same orientation in order for strains to be comparable. Finally, the ex vivo loading configurations with the tibia attached to the entire mouse, or to the femur and foot, or only to the foot, showed different strain contour maps.This work provides a better understanding of parameters affecting full field strain measurements from DIC in ex vivo murine tibial loading tests

Learning from the Success of MPI

The Message Passing Interface (MPI) has been extremely successful as a portable way to program high-performance parallel computers. This success has occurred in spite of the view of many that message passing is difficult and that other approaches, including automatic parallelization and directive-based parallelism, are easier to use. This paper argues that MPI has succeeded because it addresses all of the important issues in providing a parallel programming model.Comment: 12 pages, 1 figur

Spatial relationship between bone formation and mechanical stimulus within cortical bone: Combining 3D fluorochrome mapping and poroelastic finite element modelling

Bone is a dynamic tissue and adapts its architecture in response to biological and mechanical factors. Here we investigate how cortical bone formation is spatially controlled by the local mechanical environment in the murine tibia axial loading model (C57BL/6). We obtained 3D locations of new bone formation by performing ‘slice and view’3D fluorochrome mapping of the entire bone and compared these sites with the regions of high fluid velocity or strain energy density estimated using a finite element model, validated with ex-vivo bone surface strain map acquired ex-vivo using digital image correlation. For the comparison, 2D maps of the average bone formation and peak mechanical stimulus on the tibial endosteal and periosteal surface across the entire cortical surface were created. Results showed that bone formed on the periosteal and endosteal surface in regions of high fluid flow. Peak strain energy density predicted only the formation of bone periosteally. Understanding how the mechanical stimuli spatially relates with regions of cortical bone formation in response to loading will eventually guide loading regime therapies to maintain or restore bone mass in specific sites in skeletal pathologies