Cosmic Flows on 100 Mpc/h Scales: Standardized Minimum Variance Bulk Flow, Shear and Octupole Moments

The low order moments, such as the bulk flow and shear, of the large scale peculiar velocity field are sensitive probes of the matter density fluctuations on very large scales. In practice, however, peculiar velocity surveys are usually sparse and noisy, which can lead to the aliasing of small scale power into what is meant to be a probe of the largest scales. Previously, we developed an optimal ``minimum variance'' (MV) weighting scheme, designed to overcome this problem by minimizing the difference between the measured bulk flow (BF) and that which would be measured by an ideal survey. Here we extend this MV analysis to include the shear and octupole moments, which are designed to have almost no correlations between them so that they are virtually orthogonal. We apply this MV analysis to a compilation of all major peculiar velocity surveys, consisting of 4536 measurements. Our estimate of the BF on scales of ~ 100 Mpc/h has a magnitude of |v|= 416 +/- 78 km/s towards Galactic l = 282 degree +/- 11 degree and b = 6 degree +/- 6 degree. This result is in disagreement with LCDM with WMAP5 cosmological parameters at a high confidence level, but is in good agreement with our previous MV result without an orthogonality constraint, showing that the shear and octupole moments did not contaminate the previous BF measurement. The shear and octupole moments are consistent with WMAP5 power spectrum, although the measurement noise is larger for these moments than for the BF. The relatively low shear moments suggest that the sources responsible for the BF are at large distances.Comment: 13 Pages, 7 figures, 4 tables. Some changes to reflect the published versio

A preliminary dictionary of Maori gainwords compiled on historical principles

This thesis is a preliminary dictionary of Maori gainwords compiled on historical principles. It will serve as the starting point for a fully fledged historical dictionary of Maori gainwords. The sources are a selection of all those Maori language publications printed between the dates 1815 and 1899. A large number of source items were photocopied from other institutions, and the binding and subsequent availability of these was not always in the order wished for. The research therefore has its limitations (clearly indicated by the use of the word 'preliminary' in the thesis title). Full coverage of all printed Maori publications between 1815 and 1899 has not been possible. Despite this, this preliminary dictionary offers a good indication of the extent of new gainword vocabulary introduced within the time frame. This thesis suggests that the terms loanword and borrowing should be replaced by the new term gainword or gain, and that the process by which new items of vocabulary enter a language should be known as gaining .. 'Gaining' is a positive process, and the word 'gainword' is normally devoid of any negative connotations or implications of cultural imperialism. This thesis is the first extended scholarly research into Maori gainword lexicography. Although 'preliminary', the dictionary is the first devoted solely to Maori gainwords - previous dictionaries of Maori have had gainwords as appendices, or have listed small numbers of gainwords in their general corpus. This dictionary builds on those earlier dictionaries by giving gainwords their own dictionary. This thesis will indicate that nearly all new items of vocabulary introduced into Maori language during the period researched were introduced by English-speaking Pakeha. English-speaking (and some few French-speaking) Pakeha controlled the printed word for some considerable time - up until the first Maori-controlled publication, Te Hokioi in 1861, in fact most gainwords were therefore imposed. The frequency count for Maori-driven gains done for this thesis will give only some slight indication of Maori use and acceptance of gains between 1815 and 1899

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes

Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans

Drug discovery in advanced prostate cancer: translating biology into therapy.

Castration-resistant prostate cancer (CRPC) is associated with a poor prognosis and poses considerable therapeutic challenges. Recent genetic and technological advances have provided insights into prostate cancer biology and have enabled the identification of novel drug targets and potent molecularly targeted therapeutics for this disease. In this article, we review recent advances in prostate cancer target identification for drug discovery and discuss their promise and associated challenges. We review the evolving therapeutic landscape of CRPC and discuss issues associated with precision medicine as well as challenges encountered with immunotherapy for this disease. Finally, we envision the future management of CRPC, highlighting the use of circulating biomarkers and modern clinical trial designs