The Egyptian Cardiothoracic Surgeon (ECTS - E-Journal)
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Multiplex Eukaryotic Transcription (In) activation: Timing, Bursting and Cycling of a Ratchet Clock Mechanism
No full textActivation of eukaryotic transcription is an intricate process that relies on a multitude of regulatory proteins forming complexes on chromatin. Chromatin modifications appear to play a guiding role in protein-complex assembly on chromatin. Together, these processes give rise to stochastic, often bursting, transcriptional activity. Here we present a model of eukaryotic transcription that aims to integrate those mechanisms. We use stochastic and ordinary differential-equation modeling frameworks to examine various possible mechanisms of gene regulation by multiple transcription factors. We find that the assembly of large transcription factor complexes on chromatin via equilibrium-binding mechanisms is highly inefficient and insensitive to concentration changes of single regulatory proteins. An alternative model that lacks these limitations is a cyclic ratchet mechanism. In this mechanism, small protein complexes assemble sequentially on the promoter. Chromatin modifications mark the completion of a protein complex assembly, and sensitize the local chromatin for the assembly of the next protein complex. In this manner, a strict order of protein complex assemblies is attained. Even though the individual assembly steps are highly stochastic in duration, a sequence of them gives rise to a remarkable precision of the transcription cycle duration. This mechanism explains how transcription activation cycles, lasting for tens of minutes, derive from regulatory proteins residing on chromatin for only tens of seconds. Transcriptional bursts are an inherent feature of such transcription activation cycles. Bursting transcription can cause individual cells to remain in synchrony transiently, offering an explanation of transcriptional cycling as observed in cell populations, both on promoter chromatin status and mRNA levels
Identification and characterization of novel associations in the CASP8/ALS2CR12 region on chromosome 2 with breast cancer risk
No full textPrevious studies have suggested that polymorphisms in CASP8 on chromosome 2 are associated with breast cancer risk. To clarify the role of CASP8 in breast cancer susceptibility, we carried out dense genotyping of this region in the Breast Cancer Association Consortium (BCAC). Single-nucleotide polymorphisms (SNPs) spanning a 1 Mb region around CASP8 were genotyped in 46 450 breast cancer cases and 42 600 controls of European origin from 41 studies participating in the BCAC as part of a custom genotyping array experiment (iCOGS). Missing genotypes and SNPs were imputed and, after quality exclusions, 501 typed and 1232 imputed SNPs were included in logistic regression models adjusting for study and ancestry principal components. The SNPs retained in the final model were investigated further in data from nine genome-wide association studies (GWAS) comprising in total 10 052 case and 12 575 control subjects. The most significant association signal observed in European subjects was for the imputed intronic SNP rs1830298 in ALS2CR12 (telomeric to CASP8), with per allele odds ratio and 95% confidence interval [OR (95% confidence interval, CI)] for the minor allele of 1.05 (1.03-1.07), P = 1 x 10(-5). Three additional independent signals from intronic SNPs were identified, in CASP8 (rs36043647), ALS2CR11 (rs59278883) and CFLAR (rs7558475). The association with rs1830298 was replicated in the imputed results from the combined GWAS (P = 3 x 10(-6)), yielding a combined OR (95% CI) of 1.06 (1.04-1.08), P = 1 x 10(-9). Analyses of gene expression associations in peripheral blood and normal breast tissue indicate that CASP8 might be the target gene, suggesting a mechanism involving apoptosis
CHO: Towards a Benchmark Suite for OpenCL FPGA Accelerators
No full textProgramming FPGAs with OpenCL-based high-level synthesis frameworks is gaining attention with a number of commercial and research frameworks announced. However, there are no benchmarks for evaluating these frameworks. To this end, we present CHO benchmark suite an extension of CHStone, a commonly used C-based high-level synthesis benchmark suite, for OpenCL. We characterise CHO at various levels and use it to investigate compiling non-trivial software to FPGAs. CHO is work in progress and more benchmarks will be added with time
Epigenetic activation of a cryptic TBC1D16 transcript enhances melanoma progression by targeting EGFR.
No full textMetastasis is responsible for most cancer-related deaths, and, among common tumor types, melanoma is one with great potential to metastasize. Here we study the contribution of epigenetic changes to the dissemination process by analyzing the changes that occur at the DNA methylation level between primary cancer cells and metastases. We found a hypomethylation event that reactivates a cryptic transcript of the Rab GTPase activating protein TBC1D16 (TBC1D16-47 kDa; referred to hereafter as TBC1D16-47KD) to be a characteristic feature of the metastatic cascade. This short isoform of TBC1D16 exacerbates melanoma growth and metastasis both in vitro and in vivo. By combining immunoprecipitation and mass spectrometry, we identified RAB5C as a new TBC1D16 target and showed that it regulates EGFR in melanoma cells. We also found that epigenetic reactivation of TBC1D16-47KD is associated with poor clinical outcome in melanoma, while conferring greater sensitivity to BRAF and MEK inhibitors
Applying the Wiener-Hopf Monte Carlo simulation technique for Lévy processes to path functionals
No full textSuicidality and posttraumatic stress disorder (PTSD) in adolescents: a systematic review and meta-analysis
No full textFollowing families over time and across studies
No full textThe e-Stat project (which ran from September 2009 until December 2012) was one of the eight nodes of ESRC’s Digital Social Research Programme, whose aim is to use the recent advances in digital technologies to augment the impact of research in the social sciences. The project resulted from collaboration between the universities of Bristol, Stirling, Southampton and Manchester and brought together social scientists, statisticians and programmers. Its goals were to empower users of quantitative social science by developing tools that enable collaborative research, in terms of streamlining access and interoperability between advanced statistical packages, but also by developing tools that improve the documentation and sharing of research processes, results and techniques across the social science community.This paper presents the outcomes of a feasibility study within the e-STAT project whose goal was to design a transferable concept of family composition to be used in research that, for example, focuses on children's development; to explore its potential for use with the main UK longitudinal studies; and to discuss its implementation in two key longitudinal studies (the British Household Panel Survey and the Millennium Cohort Study)
'The Coagulate' and 'Not Simply a Case:’ The Development of Form, Style and the Mentally Ill ‘I’ in Frank Bidart’s ‘Herbert White’ and ‘Ellen West’
No full text‘The Coagulate’ and ‘Not Just a Case: The Development of Form, Style and the Mentally Ill ‘I’ in Frank Bidart’s ‘Herbert White’ and ‘Ellen West’ Crystal Lee AndersonUniversity of ManchesterCreative Writing PhDJanuary 2015This doctoral thesis involves two components, a book length collection of poems and a critical study of ‘Herbert White’ and ‘Ellen West’ by Frank Bidart. The collection of poems, The Coagulate, consists of four parts: 1) Semi-personal poems focusing on nature both in a general sense and in specific reference to the natural British landscape. 2) Poems that explore the nature-based myths and contemporary social idiosyncrasies of Japan.3) Poems that explore the social perception of mental illness and the individual voices that exist in spite psychological classification.4) Poems by an alter-ego named Lee Cole, a completely foreign perspective to my own. These poems were written with the intent to adhere to Frank Bidart’s concept of Herbert White as ‘all that I was not.’ However, unlike Bidart, these poems attempt to remove the presence of the poet and forgo the use of a feint. The collection is organised with contexture in mind rather than chronology. Poems build upon one another and one section flows into the next causing the book to have a fluid quality. The critical component examines Bidart’s treatment of two mentally ill characters in respect to the establishment of the form, style, and voice that would become a hallmark of his poetry. Chapter 1 looks at the first poem of Bidart’s first book, ‘Herbert White.’ This chapter examines how Bidart’s unique use of white space, voice, Freudian theory, and the sharing of the poet’s history contributed to the crafting of a mentally ill character. It suggests that the inclusion of the poet, a stable presence in comparison to White, allows the reader to recognise certain universal human personality traits in a character that seems inhuman. Chapter 2 examines how Bidart crafted ‘Ellen West,’ a character just as unlike Bidart as ‘Herbert White.’ Central to this analysis is the examination on how to construct a character struggling with identity. It also examines the use of dramatic monologues and how ‘Ellen West’ fits into a form with a flexible definition. As with Chapter 1, Chapter 2 examines how Bidart uses the poet’s self to add to a fictional narrative and how that reflects upon his personal poetry, indicating that Bidart’s use of the self is a redirection from how the Confessional poets used first-person
