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Search Results: 1 - 10 of 38599 matches for " Nick ST Thomas "
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A meta-analysis of single base-pair substitutions in translational termination codons ('nonstop' mutations) that cause human inherited disease
Stephen E Hamby, Nick ST Thomas, David N Cooper, Nadia Chuzhanova
Human Genomics , 2011, DOI: 10.1186/1479-7364-5-4-241
Abstract: There are currently in excess of 60,000 missense and nonsense mutations (in nearly 4,000 different genes) listed in the Human Gene Mutation Database (HGMD) that are known to cause, or to be associated with, human inherited disease [1]. In addition, there are 119 examples of mutations (in 87 different genes) that occur within stop codons, a category of mutation which therefore constitutes ~0.2% per cent of codon-changing mutations [1]. Such lesions have been termed 'nonstop', 'nostop' or 'readthrough' mutations on the basis that the loss of the normal translational termination (stop) codon is likely to lead to continued translation of the mRNA further downstream into the 3'-untranslated region (UTR).Although many authors tacitly assume that the normal open reading frame will simply be extended until the next in-frame stop codon is encountered, too few human nonstop mutations have so far been characterised to allow any general conclusions to be drawn as to their likely phenotypic consequences at either the mRNA or the protein level. In three reported cases, however (namely, those nonstop mutations in the gene encoding ribosomal protein S19 [RPS19], causing Diamond-Blackfan anaemia,[2] the F10 gene causing factor X deficiency [3] and the foxhead box E3 [FOXE3] gene causing anterior segment dysgenesis [4]), the levels of the mutant mRNA transcripts were found to be dramatically lower than those of their wild-type counterparts. By contrast, the mRNA level associated with a nonstop mutation in the 3-beta-hydroxy-delta-5-steroid dehyrogenase (HSD3B2) gene causing adrenal hyperplasia was found to be near normal, although both HSD3B2 enzymatic activity and antigen (associated with a predicted 467 amino-acid protein, extended by 95 residues beyond the wild-type length) were found to be dramatically reduced [5]. Similarly, in the case of a nonstop mutation in the thymidine phosphorylase (TYMP) gene responsible for mitochondrial neurogastrointestinal encephalomyopathy, the mRNA
The Human Gene Mutation Database: 2008 update
Peter D Stenson, Matthew Mort, Edward V Ball, Katy Howells, Andrew D Phillips, Nick ST Thomas, David N Cooper
Genome Medicine , 2009, DOI: 10.1186/gm13
Abstract: The Human Gene Mutation Database (HGMD?) [1] records the first report of a disease-causing mutation or disease-associated/functional polymorphism and provides these data in a readily accessible form to all interested parties, whether they are from an academic, a clinical or a commercial background. HGMD has become the de facto central disease-associated mutation database available to the scientific community. The data comprise single base-pair substitutions in coding, regulatory and splicing-relevant regions of human nuclear genes, micro-deletions and micro-insertions, combined insertions/deletions (indels), repeat expansions, gross lesions (deletions, insertions and duplications) and complex rearrangements (including inversions). These categories of mutation data are summarized in Table 1.Mutation and polymorphism data are obtained by means of a combination of manual and computerized search procedures. Thus, online library screening, the PubMed database and publicly available locus-specific mutation databases (LSDBs) are all used to optimize data acquisition. Each mutation or disease-associated/functional polymorphism is entered into HGMD only once under its earliest literature citation. Silent mutations within the coding region that do not alter the encoded amino acid are not recorded unless there is clear evidence of altered splicing and/or a direct disease association. Mutations that have not been adequately or unambiguously described in the corresponding literature report are also excluded unless full details can subsequently be obtained from the authors. Disease-associated/functional polymorphisms (see below) are excluded if the published data are deemed to be of insufficient quality (either because of the description provided or because of a tenuous/non-significant association with a clinical or laboratory phenotype). HGMD does not include somatic lesions or mitochondrial genome mutations. These are well covered by COSMIC [2] and MITOMAP [3], respectively.Mut
LP=>: Extending LP with a strong conditional operator
Nick Thomas
Mathematics , 2013,
Abstract: We augment LP with a strong conditional operator, to yield a logic we call "strong LP," or LP=>. The resulting logic can speak of consistency in more discriminating ways, but introduces new possibilities for trivializing paradoxes.
On the comprehension schema in LP=>
Nick Thomas
Mathematics , 2013,
Abstract: We construct a model of the comprehension schema in the logic LP=>.
Der Wandel in der wissenschaftlichen Informationsvermittlung: das Beispiel Google Book Search
St?ber, Thomas
Zeitenblicke , 2006,
Report on Excavations at Sedgeford, Norfolk 1996
Nick Cook,Andrew Gardner,Gabor Thomas
Papers from the Institute of Archaeology , 1997, DOI: 10.5334/pia.113
Abstract: Excavations were undertaken as part of the ongoing work of the Sedgeford Hall Archaeological Research Project, which was set up in 1995 with the aim of investigating the archaeological history of the parish of Sedgeford, west Norfolk.
The Roles of Dehumanization and Moral Outrage in Retributive Justice
Brock Bastian, Thomas F. Denson, Nick Haslam
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0061842
Abstract: When innocents are intentionally harmed, people are motivated to see that offenders get their “just deserts”. The severity of the punishment they seek is driven by the perceived magnitude of the harm and moral outrage. The present research extended this model of retributive justice by incorporating the role of offender dehumanization. In three experiments relying on survey methodology in Australia and the United States, participants read about different crimes that varied by type (child molestation, violent, or white collar – Studies 1 and 2) or severity (Study 3). The findings demonstrated that both moral outrage and dehumanization predicted punishment independently of the effects of crime type or crime severity. Both moral outrage and dehumanization mediated the relationship between perceived harm and severity of punishment. These findings highlight the role of offender dehumanization in punishment decisions and extend our understanding of processes implicated in retributive justice.
Phenomenology of the Top Mass in Realistic Extended Technicolor Models
Thomas Appelquist,Nick Evans,Stephen B. Selipsky
Physics , 1996, DOI: 10.1016/0370-2693(96)00149-9
Abstract: Extended technicolor (ETC) theories typically require ETC gauge bosons lighter than of order 1 TeV, to perturbatively generate the $t$ quark mass. We point out that explicit models of $t-b$ mass splitting also typically contain additional TeV scale ETC gauge bosons transforming in the {\it adjoint} of technicolor, leading to large weak-isospin-breaking effects observable in the $\rho$ parameter. Viable ETC models may thus require a lowest ETC scale of order 10 TeV, with relatively strong and finely tuned couplings to generate $m_t$. Such models do not generate observable corrections to the $Zb{\bar b}$ vertex.
Quantile Mechanics II: Changes of Variables in Monte Carlo methods and GPU-Optimized Normal Quantiles
William T. Shaw,Thomas Luu,Nick Brickman
Quantitative Finance , 2009,
Abstract: This article presents differential equations and solution methods for the functions of the form $Q(x) = F^{-1}(G(x))$, where $F$ and $G$ are cumulative distribution functions. Such functions allow the direct recycling of Monte Carlo samples from one distribution into samples from another. The method may be developed analytically for certain special cases, and illuminate the idea that it is a more precise form of the traditional Cornish-Fisher expansion. In this manner the model risk of distributional risk may be assessed free of the Monte Carlo noise associated with resampling. Examples are given of equations for converting normal samples to Student t, and converting exponential to hyperbolic, variance gamma and normal. In the case of the normal distribution, the change of variables employed allows the sampling to take place to good accuracy based on a single rational approximation over a very wide range of the sample space. The avoidance of any branching statement is of use in optimal GPU computations as it avoids the effect of {\it warp divergence}, and we give examples of branch-free normal quantiles that offer performance improvements in a GPU environment, while retaining the best precision characteristics of well-known methods. We also offer models based on a low-probability of warp divergence. Comparisons of new and old forms are made on the Nvidia Quadro 4000, GTX 285 and 480, and Tesla C2050 GPUs. We argue that in single-precision mode, the change-of-variables approach offers performance competitive with the fastest existing scheme while substantially improving precision, and that in double-precision mode, this approach offers the most GPU-optimal Gaussian quantile yet, and without compromise on precision for Monte Carlo applications, working twice as fast as the CUDA 4 library function with increased precision.
An Improved Protocol for Sequencing of Repetitive Genomic Regions and Structural Variations Using Mutagenesis and Next Generation Sequencing
Botond Sipos, Tim Massingham, Adrian M. Stütz, Nick Goldman
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0043359
Abstract: The rise of Next Generation Sequencing (NGS) technologies has transformed de novo genome sequencing into an accessible research tool, but obtaining high quality eukaryotic genome assemblies remains a challenge, mostly due to the abundance of repetitive elements. These also make it difficult to study nucleotide polymorphism in repetitive regions, including certain types of structural variations. One solution proposed for resolving such regions is Sequence Assembly aided by Mutagenesis (SAM), which relies on the fact that introducing enough random mutations breaks the repetitive structure, making assembly possible. Sequencing many different mutated copies permits the sequence of the repetitive region to be inferred by consensus methods. However, this approach relies on molecular cloning in order to isolate and amplify individual mutant copies, making it hard to scale-up the approach for use in conjunction with high-throughput sequencing technologies. To address this problem, we propose NG-SAM, a modified version of the SAM protocol that relies on PCR and dilution steps only, coupled to a NGS workflow. NG-SAM therefore has the potential to be scaled-up, e.g. using emerging microfluidics technologies. We built a realistic simulation pipeline to study the feasibility of NG-SAM, and our results suggest that under appropriate experimental conditions the approach might be successfully put into practice. Moreover, our simulations suggest that NG-SAM is capable of reconstructing robustly a wide range of potential target sequences of varying lengths and repetitive structures.
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