A whole-genome massively parallel sequencing analysis of BRCA1 mutant oestrogen receptor-negative and -positive breast cancers

BRCA1 encodes a tumour suppressor protein that plays pivotal roles in homologous recombination (HR) DNA repair, cell-cycle checkpoints, and transcriptional regulation. BRCA1 germline mutations confer a high risk of early-onset breast and ovarian cancer. In more than 80% of cases, tumours arising in BRCA1 germline mutation carriers are oestrogen receptor (ER)-negative; however, up to 15% are ER-positive. It has been suggested that BRCA1 ER-positive breast cancers constitute sporadic cancers arising in the context of a BRCA1 germline mutation rather than being causally related to BRCA1 loss-of-function. Whole-genome massively parallel sequencing of ER-positive and ER-negative BRCA1 breast cancers, and their respective germline DNAs, was used to characterize the genetic landscape of BRCA1 cancers at base-pair resolution. Only BRCA1 germline mutations, somatic loss of the wild-type allele, and TP53 somatic mutations were recurrently found in the index cases. BRCA1 breast cancers displayed a mutational signature consistent with that caused by lack of HR DNA repair in both ER-positive and ER-negative cases. Sequencing analysis of independent cohorts of hereditary BRCA1 and sporadic non-BRCA1 breast cancers for the presence of recurrent pathogenic mutations and/or homozygous deletions found in the index cases revealed that DAPK3, TMEM135, KIAA1797, PDE4D, and GATA4 are potential additional drivers of breast cancers. This study demonstrates that BRCA1 pathogenic germline mutations coupled with somatic loss of the wild-type allele are not sufficient for hereditary breast cancers to display an ER-negative phenotype, and has led to the identification of three potential novel breast cancer genes (ie DAPK3, TMEM135, and GATA4).

Design and test of a bit parallel 2nd order IIR filter structure

Test procedures for a pipelined bit-parallel IIR filter chip which maximally exploit its regularity are described. It is shown that small modifications to the basic architecture result in significant reductions in the number of test patterns required to test such chips. The methods used allow 100% fault coverage to be achieved using less than 1000 test vectors for a chip which has 12 bit data and coefficients.

Ixaru's Extended Frequency Dependent Quadrature Rules for Slater Integrals: Parallel Computation Issues

We describe recent progress of an ongoing research programme aimed at producing computational science software that can exploit high performance architectures in the atomic physics application domain. We examine the computational bottleneck of matrix construction in a suite of two-dimensional R-matrix propagation programs, 2DRMP, that are aimed at creating virtual electron collision experiments on HPC architectures. We build on Ixaru's extended frequency dependent quadrature rules (EFDQR) for Slater integrals and examine the challenge of constructing Hamiltonian matrices in parallel across an m-processor compute node in a block cyclic distribution for subsequent diagonalization by ScaLAPACK.

Formal Analysis of MPI-based Parallel Programs

Most parallel computing applications in highperformance computing use the Message Passing Interface (MPI) API. Given the fundamental importance of parallel computing to science and engineering research, application correctness is paramount. MPI was originally developed around 1993 by the MPI Forum, a group of vendors, parallel programming researchers, and computational scientists. However, the document defining the standard is not issued by an official standards organization but has become a de facto standard © 2011 ACM.

Parallel and nonparallel ecological, morphological and genetic divergence in lake-stream stickleback from a single catchment

Parallel phenotypic evolution in similar environments has been well studied in evolutionary biology; however, comparatively little is known about the influence of determinism and historical contingency on the nature, extent and generality of this divergence. Taking advantage of a novel system containing multiple lake-stream stickleback populations, we examined the extent of ecological, morphological and genetic divergence between three-spined stickleback present in parapatric environments. Consistent with other lake-stream studies, we found a shift towards a deeper body and shorter gill rakers in stream fish. Morphological shifts were concurrent with changes in diet, indicated by both stable isotope and stomach contents analysis. Performing a multivariate test for shared and unique components of evolutionary response to the distance gradient from the lake, we found a strong signature of parallel adaptation. Nonparallel divergence was also present, attributable mainly to differences between river locations. We additionally found evidence of genetic substructuring across five lake-stream transitions, indicating that some level of reproductive isolation occurs between populations in these habitats. Strong correlations between pairwise measures of morphological, ecological and genetic distance between lake and stream populations supports the hypothesis that divergent natural selection between habitats drives adaptive divergence and reproductive isolation. Lake-stream stickleback divergence in Lough Neagh provides evidence for the deterministic role of selection and supports the hypothesis that parallel selection in similar environments may initiate parallel speciation.

Parsing parallel evolution:Ecological divergence and differential gene expression in the adaptive radiations of thick-lipped Midas cichlid fishes from Nicaragua

The study of parallel evolution facilitates the discovery of common rules of diversification. Here, we examine the repeated evolution of thick lips in Midas cichlid fishes (the Amphilophus citrinellus species complex) - from two Great Lakes and two crater lakes in Nicaragua - to assess whether similar changes in ecology, phenotypic trophic traits and gene expression accompany parallel trait evolution. Using next-generation sequencing technology, we characterize transcriptome-wide differential gene expression in the lips of wild-caught sympatric thick- and thin-lipped cichlids from all four instances of repeated thick-lip evolution. Six genes (apolipoprotein D, myelin-associated glycoprotein precursor, four-and-a-half LIM domain protein 2, calpain-9, GTPase IMAP family member 8-like and one hypothetical protein) are significantly underexpressed in the thick-lipped morph across all four lakes. However, other aspects of lips' gene expression in sympatric morphs differ in a lake-specific pattern, including the magnitude of differentially expressed genes (97-510). Generally, fewer genes are differentially expressed among morphs in the younger crater lakes than in those from the older Great Lakes. Body shape, lower pharyngeal jaw size and shape, and stable isotopes (dC and dN) differ between all sympatric morphs, with the greatest differentiation in the Great Lake Nicaragua. Some ecological traits evolve in parallel (those related to foraging ecology; e.g. lip size, body and head shape) but others, somewhat surprisingly, do not (those related to diet and food processing; e.g. jaw size and shape, stable isotopes). Taken together, this case of parallelism among thick- and thin-lipped cichlids shows a mosaic pattern of parallel and nonparallel evolution. © 2012 Blackwell Publishing Ltd.

Autonomic management of non-functional concerns in distributed & parallel application programming

An approach to the management of non-functional concerns in massively parallel and/or distributed architectures that marries parallel programming patterns with autonomic computing is presented. The necessity and suitability of the adoption of autonomic techniques are evidenced. Issues arising in the implementation of autonomic managers taking care of multiple concerns and of coordination among hierarchies of such autonomic managers are discussed. Experimental results are presented that demonstrate the feasibility of the approach.

Kinematic Analysis and Dimensional Synthesis of Exechon Parallel Kinematic Machine for Large Volume Machining

A parallel kinematic machine (PKM) topology can only give its best performance when its geometrical parameters are optimized. In this paper, dimensional synthesis of a newly developed PKM is presented for the first time. An optimization method is developed with the objective to maximize both workspace volume and global dexterity of the PKM. Results show that the method can effectively identify design parameter changes under different weighted objectives. The PKM with optimized dimensions has a large workspace to footprint ratio and a large well-conditioned workspace, hence justifies its suitability for large volume machining.