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The colorectal adenoma-carcinoma sequence has provided a paradigmatic framework for understanding the successive somatic genetic changes and consequent clonal expansions that lead to cancer.sup.1. However, our understanding of the earliest phases of colorectal neoplastic changes--which may occur in morphologically normal tissue--is comparatively limited, as for most cancer types. Here we use whole-genome sequencing to analyse hundreds of normal crypts from 42 individuals. Signatures of multiple mutational processes were revealed; some of these were ubiquitous and continuous, whereas others were only found in some individuals, in some crypts or during certain periods of life. Probable driver mutations were present in around 1% of normal colorectal crypts in middle-aged individuals, indicating that adenomas and carcinomas are rare outcomes of a pervasive process of neoplastic change across morphologically normal colorectal epithelium. Colorectal cancers exhibit substantially increased mutational burdens relative to normal cells. Sequencing normal colorectal cells provides quantitative insights into the genomic and clonal evolution of cancer. Genome sequencing of hundreds of normal colonic crypts from 42 individuals sheds light on mutational processes and driver mutations in normal colorectal epithelial cells., Author(s): Henry Lee-Six [sup.1] , Sigurgeir Olafsson [sup.1] , Peter Ellis [sup.1] , Robert J. Osborne [sup.1] , Mathijs A. Sanders [sup.1] [sup.2] , Luiza Moore [sup.1] , Nikitas Georgakopoulos [...]

Haematopoietic stem cells drive blood production, but their population size and lifetime dynamics have not been quantified directly in humans. Here we identified 129,582 spontaneous, genome-wide somatic mutations in 140 single-cell-derived haematopoietic stem and progenitor colonies from a healthy 59-year-old man and applied population-genetics approaches to reconstruct clonal dynamics. Cell divisions from early embryogenesis were evident in the phylogenetic tree; all blood cells were derived from a common ancestor that preceded gastrulation. The size of the stem cell population grew steadily in early life, reaching a stable plateau by adolescence. We estimate the numbers of haematopoietic stem cells that are actively making white blood cells at any one time to be in the range of 50,000-200,000. We observed adult haematopoietic stem cell clones that generate multilineage outputs, including granulocytes and B lymphocytes. Harnessing naturally occurring mutations to report the clonal architecture of an organ enables the high-resolution reconstruction of somatic cell dynamics in humans.Analysis of blood from a healthy human show that haematopoietic stem cells increase rapidly in numbers through early life, reaching a stable plateau in adulthood, and contribute to myeloid and B lymphocyte populations throughout life., Author(s): Henry Lee-Six [sup.1] , Nina Friesgaard Øbro [sup.2] , Mairi S. Shepherd [sup.2] , Sebastian Grossmann [sup.1] , Kevin Dawson [sup.1] , Miriam Belmonte [sup.2] , Robert J. Osborne [...]

This paper summarises some of the key characteristics of access to and participation in higher education. In particular, it focuses on the key social characteristics of participation and the interaction with migration to study outside Northern Ireland. Key policy areas relating to student finance and widening access are also considered. The paper also reports on qualitative research conducted with Protestant and Catholic pupils from less well-off backgrounds about attitudes to further and higher education. The paper concludes by suggesting higher education policy issues for a newly restored devolved administration.

Transmembrane chloride ion conductance in skeletal muscle increases during early postnatal development. A transgenic mouse model of myotonic dystrophy type 1 (DM1) displays decreased sarcolemmal chloride conductance. Both effects result from modulation of chloride channel 1 (CLCN1) expression, but the respective contributions of transcriptional vs. posttranscriptional regulation are unknown. Here we show that alternative splicing of CLCN1 undergoes a physiological splicing transition during the first 3 wk of postnatal life in mice. During this interval, there is a switch to production of CLCN1 splice products having an intact reading frame, an upregulation of CLCN1 mRNA encoding full-length channel protein, and an increase of CLCN1 function, as determined by patch-clamp analysis of single muscle fibers. In a transgenic mouse model of DM1, however, the splicing transition does not occur, CLCN1 channel function remains low throughout the postnatal interval, and muscle fibers display myotonic discharges. Thus alternative splicing is a posttranscriptional mechanism regulating chloride conductance during muscle development, and the chloride channelopathy in a transgenic mouse model of DM1 results from a failure to execute a splicing transition for CLCN1. chloride channel 1; nonsense-mediated decay; alternative splicing; CUG repeats; developmental regulation; muscular dystrophy; ion channel

This paper seeks to examine some aspects of the early operation of the Northern Ireland Assembly and in particular the role of the Statutory Committees. The particular issue that is used to explore these matters is the review of student finances which the Higher and Further Education, Training and Employment Committee (HFETEC) undertook as its first major investigation. It should be noted here that the Department of Higher and Further Education, Training and Employment changed its name to the Department of Employment and Learning during 2000. The Committee also changed its name to the Employment and Learning Committee. Since the issues discussed took place prior to these changes the original name has been used here. Specifically, the paper examines the Review of Student Finances launched by the Department of Higher and Further Education, Training and Employment (DHFETE), how the Committee tackled the issue, tensions within the Committee, the relationship between the Committee and the Minister, between the Minister and the Department, the public debate, how the Committee Report was subsequently dealt with in the Assembly and the Minister's response. It is suggested that this example provides some insights into the operation of the distinctive devolved institutions in Northern Ireland and some early evidence of how such Statutory Committees may develop.