Characterization of the mechanisms behind the alternative splicing of the mutually exclusive exons 18N and 18A in the sodium channel gene SCN8A and mutually exclusive exons 5N and 5A in the soldium channel gene SCN9A

Voltage-gated sodium channels are the primary molecules responsible for the rising phase of action potentials in electrically excitable cells. There are 10 distinct sodium channel isoforms Nav 1.1-1.8 (SCNIA-SCN5A and SCN8A-SCNIIA) and the majority of these undergo tissue and developmentally regulated alternative splicing. Two such examples are those of the SCN8A (Nav 1.6) and SCN9A (Nav 1.7) genes. SCN8A gene contains two mutually exclusive exons, 18N and 18A. Transcripts with exon 18N have a conserved inframe stop codon that predicts the synthesis of a truncated, non functional sodium channel. This protein is expressed in fetal brain and non-neuronal tissues. Once the exon 18A is included, the resulted protein will be a functional channel, that is expressed in adult neurons ofCNS and PNS. The SCN9A exon 5N is preferentially expressed in the PNS and CNS of adult tissues and significant usage of exon 5A was found only in DRG. These two isoforms differ in one amino acid in the S3 domain I (exons 5A and 5N). This change of one amino acid induced a small shift of activation to more hyperpolarized potentials forexon SA compared with exon SN. Analysis of SeNSA pre-mRNA splicing supports a model in which exon 18A exclusion in non-neuronal tissue is regulated primarily by the presence in the cell types of several hnRNPs proteins that function through an exonic splicing silencer (ESS) found in this exon together with the absence of neuron specific Fox-I protein. In neuronal cells the absence of these hnRNPs together with the presence of neuron specific Fox-l cause the exon to be included. The SeNSA exon 18N is included innon neuronal cells due to the SR proteins that function through an exonic splicing enhancer(ESE) found in this exon. In neuronal cells the lower levels of these SR proteins cause the exon 18N to be skipped. This type of control of mutually exclusive splicing through the proteome make-up of a cell type would appear to be influential in the temporal and tissue specific splicing of SeN8A, another member of the voltage gated sodium channels and may indeed represent a more general mechanism

Design of New Shopping Centres in Historic City Cores

The first chapter is a brief introduction to the original idea of the shopping conception by looking back to the Eastern bazaars and the 19th Century shopping arcades in the U.K. By giving some description regarding their layout as well as describing the factors acting as a major ingredient influencing their conception in general terms such as climatic conditions, and defining the shopping centre as one element in the texture. The second part is basically describing the evolution of the shopping centre's conception in three distinct stages which are as follows: the centres of the first stage (open mall) - the second stage centres (enclosed mall) - the third stage centres (multi-level centres) The next step consists mainly in classifying all types of shopping centres into three main categories and introducing the problems of out-of-town shopping centre development in the U.K. The aim of the first chapter is particularly to give a clear idea for the reader to understand as quickly as possible the historical background of the shopping centre development. The second chapter is divided into three distinct parts. The first part is mainly, looking and trying to explain the most important commercial factors which have a direct influence in attracting people more and more to the shopping centre as a place for retail. The second part is essentially focused on describing planning and architectural components which constitute the shopping centre in design terms and their characteristics in relation to each other. Also, trying to present fire safety and its impact in designing as well as introducing some U.K. regulation applied in this kind of development in order to keep the place safe for the shoppers as well as ensuring safety for the environment in case of fire. The third part consists of looking at the developer's and Local Authority's role in making the shopping centre happen. The third and fourth chapters consist of the case studies which are the most important sections in the thesis, supporting the previous chapters. The two examples are analysed deeply in visual terms, presenting photographs with comments and criticisms and in each case drawing up a conclusion. The two shopping centres are as below: 1. Carlisle Lanes Shopping Centre 2. York Coppergate Shopping Centre The reason for taking these two examples is mainly because each one represents a particular type of shopping centre. For example, the Lanes shopping centre is from an enclosed shopping centre group. The Coppergate shopping centre is included in the group of open mall shopping centres. Each of them has its own characteristics, different from the other one in terms of appearance in relation to the urban environment where it is located and inserted. The fifth chapter presents the conclusion of the whole thesis, leading to some important recommendations for the future concerning the inserted shopping centre design in a sensitive environment which planners, architects and designers are obliged to take into consideration, otherwise we will loose our heritage in the near future. The final chapter essentially consists of a proposal scheme with a detail study in terms of planning strategy towards the central area of Glasgow and the site analysis adding the proposal scheme with an urban design brief explaining the whole points which I mentioned before in the fifth chapter

Optimisation of automatic train protection systems.

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

The teaching of electronics in schools and further education: a case study in curriculum change.

This case study describes the development of Electronics within the curriculum in line with how both (Reid and Walker I975, Case Studies in Curriculum Change) and (Goodson I983, School Subjects and Curriculum Change) discussed changes in terms of theories of curriculum change. Alternative definitions of the term innovation are reviewed and for the purpose of this study a definition is adopted which includes syllabus change and major changes of scale and strategy. The study gives an outline of the major theories of innovation and implementation strategy. Features of centralisation and rationalisation are described insofar as these features led to current educational initiatives. An account Is given of how Electronics developed as a topic within ‘A’ level Physics, a subject within B.E.T.E.C. (previously O.N.C/T.E.C.) and as a separate G.C.E. subject. Data on examination entries In G.C.E. and C.S.E. Electronics are presented. These data are related to the- size of L.E.A.s, the type of centre, and also to explore the viability of G.C.E./G.C.S.E. provision in Electronics. Initiatives such as M.E.P., T.V.E.I., C.P.V.E., S.S.C.R. are described as they are expected to have a significant impact on the growth of Electronics. The position of Electronics within the curriculum and its educational value are discussed. Comment is made on the Systems and Components approaches to Electronics and on the importance of project work. Teacher difficulties with project work are noted and suggestions are made on the use and range of equipment available so that a suitable teaching style may be -developed