Dissertations / Theses on the topic 'Spontaneous prose'

Elementary teachers' spontaneous (unaided) and cued identifications of key concepts in narrative prose were examined. Measures of the influences of exposure to research and attitudes toward the importance of prior knowledge on their cued identifications were investigated. Data were analyzed to determine the degree to which elementary teachers identified cued key concepts and primary teachers' identifications were compared to those of intermediate teachers. Separate and combined measures of teachers' exposure to reading research and attitudes were compared to their cued key concept identifications. A post hoc exploratory content analysis of the spontaneous key concept identifications was undertaken to discover possible patterns or phenomena in the data. Results of the analyses of cued concept identifications indicated: a) teachers were unable to successfully identify key concepts in narrative prose; b) there were no significant differences between primary and intermediate teachers' identifications; and c) exposure to reading research and attitudes towards the importance and use of prior knowledge and concept development influenced teachers' ability to identify key concepts. An examination of spontaneous key concept identifications showed that: a) there was a lack of teacher consensus as to definition of a key concept; and b) teachers were unable to identify passage-relevant key concepts when left to their own resources.
Education, Faculty of
Language and Literacy Education (LLED), Department of
Graduate

Thirty thousand feet above the Pacific Ocean—somewhere between Sydney and Los Angeles—the narrator of “the lonely and the road” doesn’t really know where he is going, or why. His is a quest written spontaneously—‘on-the-go.’ It is a journey of uncertain motivation, of uncertain means, towards uncertain ends. From Los Angeles, to Vegas, to the Rocky Mountain states and beyond, the narrator travels with and learns from his friends, his family and even his ex-girlfriend as he searches for that which continues to elude him. But what is that exactly? Does it even exist? While the novel details a journey, the exegesis is a phenomenological account of the intersecting of my road with that taken by Jack Kerouac. It explores my experiences with the life and work of Kerouac—the creator of spontaneous prose—in relation to the development of my writing, up to and including this novel. In doing so, the exegesis is itself a quest that seeks to understand more fully the essence of Kerouac’s and my own representation of the quest motif in content and in form. Both the exegesis and the novel, then, constitute part of the search for my own artistic road, and aim to assist others in search of theirs.

With the publication of On the Road in 1957, Jack Kerouac became a cultural phenomenon. Crowned the "King" of the Beat Generation, Kerouac embodied the restlessness of Cold War-era America. What no one realized at the time, however, was that the movement that he supposedly led went against Kerouac's own beliefs. Rather than rebellion, Kerouac wanted to write in a way that no one had written before. Heavily influenced by, among others, Mark Twain, Fyodor Dostoevsky, Marcel Proust, Herman Melville, and, especially, James Joyce, Kerouac used the influence of his predecessors to formulate his own style of writing-spontaneous prose. The critics who label Kerouac as a cultural icon akin to James Dean fail to see Kerouac as a serious author. The removal of the cultural fanfare surrounding Kerouac shows the truth about his writing, his influences, and his influence on late-twentieth century literature, including the entire postmodern movement.

Il NM è una disturbo del movimento spontaneo caratterizzato da un sottoutilizzo dell’arto controlesionale in assenza di un deficit primario che migliora con il comando verbale. Per la sue caratteristiche è difficile da evocare in ambito clini-co e il suo riconoscimento si basa sull'osservazione dei sintomi. Le lesioni associate al NM sono diverse e i suoi mecca-nismi sono sconosciuti. La compromissione selettiva del movimento spontaneo suggerisce un coinvolgimento del si-stema motorio mediale. La ricerca ha lo scopo di studiare il NM con un nuovo metodo quantitativo, basato su actigra-fia, e di esplorare le basi neuroanatomiche. Due accelerometri erano posti su entrambi i polsi per 24 ore. 31 soggetti sani e 38 cerebrolesi, 6 con MN sono stati reclutati. In due casi abbiamo esplorato le lesioni. E’stato validato il nuovo indice di asimmetria AR24h. I MN mostravano un comportamento asimmetrico, simile agli emiplegici e diverso dai sani e dai pazienti non emiplegici. I pazienti mostravano una lesione del cingolo e putamen, parti del sistema motorio mediale, importante per le azioni volontarie. I risultati che l’actigrafia differenziale nel quantifica il movimento spontaneo e valuta il NM. Putamen e il cingolo causano una disfunzione del sistema motorio mediale e induce NM.
The MN is a movement disorder characterized by spontaneous underutilized contralesional limb in the absence of a primary deficit that improves with the verbal command. For its characteristics it is difficult to evoke in the clinical set-ting and its recognition is based on observation of symptoms. The lesions associated with NM are different and its mechanisms are unknown. The selective impairment of spontaneous movement suggests the involvement of the medi-al motor system. Research has the aim of studying the MN with a new quantitative method, based on the actigraphy, and to explore the neuroanatomical bases. Two accelerometers were placed on both wrists for 24 hours. Sog-31 jets and 38 brain-healthy, with 6 MN were recruited. In two cases we analysis lesions. It has been validated new asymmetry index AR24h. The MN showed an asymmetric behavior, similar to and different from the healthy and hemiplegic pa-tients not hemiplegic. Patients showed a lesion of the cingulate and putamen, parts of the medial motor system im-portant for voluntary actions. The differential actigraphy quantifies the spontaneous movement and evaluates the NM. Putamen and the track cause dysfunction of the motor system and causes medial NM.

This research project attempts to identify the genetic determinants of SHRSP/Gla phenotypes by using mRNA and micro(mi)RNA expression profiling data, in combination with the genome sequence of the SHRSP/Gla and WKY/Gla, to facilitate human translational studies for hypertension and vice versa.

Thesis (Ph.D.) - University of Glasgow, 2008.
Ph.D. thesis submitted to the Faculty of Medicine, Division of Cardiovascular and Medical Sciences, University of Glasgow, 2008. Includes bibliographical references. Print version also available.

The stroke-prone spontaneously hypertensive rat (SHRSP) is an inbred model of hypertension. Renal microarrays and functional genomic strategies investigated chromosome 2 candidate hypertension genes, focussing on the oxidative-stress defence gene, glutathione s-transferse mu type 1 (Gstm1). Ingenuity pathway analysis of renal microarrays in 5 and 16-week SHRSP, normotensive Wistar Kyoto (WKY) and chromosome 2 congenic rats identified differential expression of several glutathione cycling genes. The Gstm1 promoter was investigated by luciferase and Transfac bioinformatic analysis, implicating two polymorphism clusters and several transcription factors in reduced SHRSP Gstm1 expression. Recombinant adenoviruses expressing Gstm1 and short-hairpin RNA-interference sequences to reduce Gstm family expression were produced. In-vivo overexpression of Gstm1 did not improve endothelial nitric-oxide bioavailability in SHRSP carotid arteries. Bacterial artificial chromosome and linear expression constructs were purified for production of Gstm1 transgenic rats, putative transgenic rats were screened by PCR. The strategies developed in this project are an example of thorough functional genomic analysis in experimental hypertension research.

Essential hypertension (EH) is considered one of the major contributors to the present pandemic of cardiovascular disease (CVD). EH has a largely obscure aetiology, which lies upon both environmental risk factors and underlying genetic traits. The stroke-prone spontaneously hypertensive rat (SHRSP) is an excellent model of human EH and exhibits salt sensitivity. Two quantitative trait loci (QTL) for blood pressure (BP) regulation have been identified on rat chromosome 2 (chr.2). On this basis, previous work in our laboratory focused on construction of chr.2 congenic strains, on both the SHRSP and Wistar-Kyoto (WKY) genetic backgrounds. In combination with microarray gene expression profiling in kidney from salt-loaded rats, two positional candidate genes for salt-sensitive hypertension were identified. Sphingosine-1-phosphate receptor 1 (S1pr1) and vascular adhesion molecule (Vcam1) lie on the chr.2 congenic interval implicated in salt-sensitivity. Additionally, studies on vascular smooth muscle cells (VSMC) demonstrated enhanced S1PR1-mediated sphingosine signalling in SHRSP compared to WKY. Finally, glutathione S-transferase mu 1 (Gstm1) was identified as another chr.2 candidate gene for BP regulation, lying outside the region implicated in salt-sensitivity. This project attempts to comprehensively investigate the potential role of altered S1PR1 signalling in BP regulation and salt-sensitivity, through comparative proteomic and metabolomic profiling in WKY, SHRSP and chromosome 2 congenic and transgenic stains (WKY.SPGla2a, SP.WKYGla2a, SP.WKYGla2k and Gstm1-transgenic). Characterisation of S1PR1 expression in renal and vascular tissue from 21 week-old salt-loaded rats, demonstrated below detection protein levels across parental and congenic strains. To further investigate the effect of the congenic interval and Gstm1 on salt-sensitivity and BP regulation and identify putative biomarkers, high-throughput metabolomic screening of urine and plasma was conducted in parental, SP.WKYGla2k congenic and Gstm1-transgenic strains, on a normal-salt and high-salt diet. In both urine and plasma, salt-loading affected processes implicated in CVD, including inflammatory response, free radical scavenging and lipid metabolism. In urine, oleic acid, implicated in regulation of renin levels, was increased in the SHRSP and transgenic salt-sensitive strains compared to the WKY and 2k congenic salt-resistant strains, upon salt-loading. In plasma, known biomarkers of CVD were altered in SHRSP compared to the other three strains, at normal-salt, including L-proline and linoleic acid. Upon salt-loading, glutathione disulfide and sphingosine-1-phosphate (S1P) were identified in high levels in the salt-sensitive strains. However, at normal-salt S1P was decreased in SHRSP compared to WKY and 2k congenic strains. Therefore, characterisation of the impact of S1P/S1PR1 signalling in the vasculature across the different strains was further investigated. Initially, structure, mechanical properties and vascular reactivity of mesenteric resistance arteries (MRA) were studied in 16 week-old parental and reciprocal 2a congenic strains (WKY.SPGla2a and SP.WKYGla2a). There was no significant remodelling observed across the strains. However, SHRSP vessels were stiffer and this phenotype was under the control of the congenic segment. SHRSP exhibited hypercontractility, which was mediated by RhoA/Rock signalling pathway and was corrected by the transfer of the congenic interval in SP.WKYGla2a. SHRSP also displayed endothelial dysfunction, which was related to reduced nitric oxide (NO) bioavailability and was not improved by the congenic interval. The predominant regulatory mechanisms of contraction and relaxation in MRAs from WKY and WKY.SPGla2a were demonstrated to be different compared to SHRSP. Subsequently, representation of these physiological differences in MRAs, at the molecular level, was investigated along with the effect of S1P-signalling in HTN. Comprehensive, high-throughput proteome profiling of S1P-stimulated primary mesenteric VSMCs from parental and 2a-reciprocal congenic strains, was achieved through triple stable isotope labelling (SILAC), LC-MS/MS analysis and MaxQuant quantification. Detection of few abundant phosphorylated proteins was attributed to lack of enrichment for phosphoproteome. Therefore, focus was placed on proteins whose differential expression between SHRSP and WKY was genetically regulated. These proteins mapped to pathways implicated in BP-regulation, including oxidative stress, vascular tone regulation and vascular remodelling. Glutathione S-transferase mu 1 (GSTM1) was upregulated in SHRSP, as opposed to down-regulated NAD(P)H oxidase quinone 1 (NQO1) and heme oxygenase 1 (HMOX1), suggesting different antioxidant mechanisms in health and disease. Natriuretic peptide receptor C (NPR3) which is implicated in vascular relaxation was increased in SHRSP, along with activators of RhoA contractile mechanism, such as caveolin1 (CAV1). Furthermore, RhoA/Rock signalling pathway was highly altered in SHRSP. Finally, differentially expressed proteins were related to sphingosine signalling, including superoxide dismutase 2 (SOD2) and collagen type III, alpha 1 (COL3A1). To further investigate the metabolic effect of sphingosine signalling across the strains, and assess the contribution of the congenic interval, metabolomic profiling of primary mesenteric VSMCs from parental and SP.WKYGla2a congenic strains, was performed at basal conditions and upon S1P-stimulation. A labelling-free, untargeted approach was employed, using HILIC-MS analysis and data processing through IDEOM. The effect of the congenic interval on the metabolic profile of SP.WKYGla2a was more profound under basal conditions. S1P-stimulation induced greater responses in SHRSP than WKY, indicating altered signalling. Furthermore the responses were different in each strain, suggesting a combined effect of the genetic background and the congenic interval on S1P signalling regulation. Inosine, which is implicated in purine metabolism, was significantly decreased in SHRSP compared to SP.WKYGla2a, at basal conditions, but was increased upon-S1P stimulation, implying that this S1P effect depends on the congenic interval. Moreover, tyramine, which has vasodilatory properties, was increased in stimulated SHRSP compared to basal conditions, indicating potential relation of sphingosine signalling with BP-regulation. This study has combined high-throughput proteomic and metabolomic screenings with congenic and transgenic strains to capture a clearer picture of the pathophysiological processes that underlie HTN in SHRSP. Individual metabolites and proteins or pathways and processes identified to be altered in HTN, through this work, can be used for generation of new testable hypothesis towards the development of new therapeutic approaches against HTN.

Cette thèse consiste en une étude comparée de La Montagne de l’âme de Gao Xingjian et Sur la route de Jack Kerouac ayant « la quête » comme problématique centrale. Bien qu’à première vue les deux œuvres apparaissent fort différentes, selon l’esprit de la littérature comparée, elles méritent une confrontation minutieuse et nous estimons qu’elles possèdent quantité de points communs : Premièrement, il s’agit de deux romans foisonnants qui englobent bon nombre de genres romanesques et semblant relever simultanément de plusieurs catégories : roman autobiographique, roman-géographe, roman de pèlerinage, roman picaresque, roman de mœurs, roman de méditation, et enfin roman « froid » et « sans-isme ». Par leurs différents aspects, ces deux œuvres peuvent satisfaire aux attentes de divers lecteurs. Deuxièmement, au plan stylistique, La Montagne de l’âme et Sur la route sont deux romans insolites. L’innovation de La Montagne de l’âme se manifeste par la pratique d’un mode de narration inédit, la particularité linguistique, la singularité dans la structure, l’hétérogénéité du matériau romanesque, bref par une grande originalité formelle. Quant à Sur la route, sa nouveauté se manifeste d’abord par sa création fondamentale, à savoir la prose spontanée. Elle s’exprime aussi par la particularité de la construction romanesque, l’originalité de l’écriture et la singularité du contenu. Troisième parenté fondamentale : La Montagne de l’âme et Sur la route se présentent comme deux quêtes de l’espace. Montagne, chemin et maison sont trois motifs récurrents communs à ces deux romans qui sont également deux odes aux grands espaces. Les protagonistes relatent les itinéraires parcourus en Amérique et en Chine et l’on peut voir dans ces livres deux odes aux cultures nées dans les grands espaces. À l’intérieur de ces deux œuvres, les paysages romanesques se recommandent par leur caractère pictural et polysensoriel. L’espace typographique du texte est également aménagé avec art : les deux romans sont à la fois découpés et cousus. Enfin, considérés sous l’angle de la spiritualité, La Montagne de l’âme et Sur la route peuvent être dits romans de l’âme : de nombreuses questions spirituelles y sont intégrées, posées et approfondies. L’un et l’autre traitent la quête du sens de la vie, plus précisément, la quête de l’ego (identité, soi), la quête d’un mode de vie (fondé sur le présent, la liberté) et la quête métaphysique (destin, mort, croyance). Ces quatre similitudes correspondent à quatre quêtes que les deux oeuvres déploient à leur façon : la recherche d’un genre romanesque, d’une stylistique originale, d’un espace romanesque et enfin d’un sens de la vie
The thesis is about the comparative analysis which concern about the main concept of quest where from soul mountain of Gao Xingjian and On the Road of Jack Kerouac. Although these two books seem quite unlike, by the spiritual of comparative literature, they totally worth to be comparative studied carefully, and we think they have quite much in common.First, these two novels are both rich in connotation, they cover many of the novel categories, such as autobiographical novel, geographical novel, pilgrimage novel, picaresque novel, novel of manners, novel of meditation, the “cold” novel and non socialist novel. In different aspects, these two works can meet the needs of different readers.Secondly, in the stylistics, the soul mountain and on the road are two unusual novels. The innovation of the soul mountain is the practice of singularity of narration, the singularity of language characteristic, the singularity of structure, the heterogeneity of the material, the singularity of the form. As for on the road, the creativity of the novel based on many aspects, namely the spontaneous prose, also the singularity of characteristic of the construction, the way of writing, and the uniqueness of content.The third, the soul mountain and on the road two novels both relate as they quest the idea of space. Mountain, road and house are three common recurrent motifs which show up in these two novels, which are also odes of wide open spaces. The protagonists narrate the travel through America and China. We can discover from the two books both contain odes which point to the cultures cultivated from the spaces. In these two works, the narrations about landscapes are both pictorial and also polysensoriel. Spaces typographic of the two novels are also rearranged with art: both cut and sewn. Finally, from the perspective of the spiritual, the soul mountain and on the road can be regarded as novels of the soul: many spiritual questions are quested and thoroughly researched. The two novels both deal with the quest for the sense of life, and more specifically, the pursuit of the ego, (identity, soi), the quest for the way of life (present, liberty), the quest for the metaphysical (destiny, death, religion).These four similarities are corresponding to the four quests of these two novels: the quest of novel categories, stylistics, space, sense of life

During pregnancy, the maternal cardiovascular system undergoes major adaptation. One of these changes is a 40-50 % increase in circulating blood volume which requires a systemic remodelling of the vasculature in order to regulate maternal blood pressure and maximise blood supply to the developing placenta and fetus. These changes are broadly conserved between humans and rats making them an appropriate pre-clinical model in which to study the underlying mechanisms of pregnancy-dependent cardiovascular remodelling. Whilst women are normally protected against cardiovascular disease; pregnancy marks a period of time where women are susceptible to cardiovascular complications. Cardiovascular disease is the leading cause of maternal mortality in the United Kingdom; in particular hypertensive conditions are among the most common complications of pregnancy. One of the main underlying pathologies of these pregnancy complications is thought to be a failure of the maternal cardiovascular system to adapt. The remodelling of the uterine arteries, which directly supply the maternal-fetal interface, is paramount to a healthy pregnancy. Failure of the uterine arteries to remodel sufficiently can result in a number of obstetric complications such as preeclampsia, fetal growth restriction and spontaneous pregnancy loss. At present, it is poorly understood whether this deficient vascular response is due to a predisposition from existing maternal cardiovascular risk factors, the physiological changes that occur during pregnancy or a combination of both. Previous work in our group employed the stroke prone spontaneously hypertensive rat (SHRSP) as a model to investigate pregnancy-dependent remodelling of the uterine arteries. The SHRSP develops hypertension from 6 weeks of age and can be contrasted with the control strain, the Wistar Kyoto (WKY) rat. The phenotype of the SHRSP is therefore reflective of the clinical situation of maternal chronic hypertension during pregnancy. We showed that the SHRSP exhibited a deficient uterine artery remodelling response with respect to both structure and function accompanied by a reduction in litter size relative to the WKY at gestational day (GD) 18. A previous intervention study using nifedipine in the SHRSP achieved successful blood pressure reduction from 6 weeks of age and throughout pregnancy; however uterine artery remodelling and litter size at GD18 was not improved. We concluded that the abnormal uterine artery remodelling present in the SHRSP was independent of chronic hypertension. From these findings, we hypothesised that the SHRSP could be a novel model of spontaneously deficient uterine artery remodelling in response to pregnancy which was underpinned by other as yet unidentified cardiovascular risk factors. In Chapter 1 of this thesis, I have characterised the maternal, placental and fetal phenotype in pregnant (GD18) SHRSP and WKY. The pregnant SHRSP exhibit features of left ventricular hypertrophy in response to pregnancy and altered expression of maternal plasma biomarkers which have been previously associated with hypertension in human pregnancy. I developed a protocol for accurate dissection of the rat uteroplacental unit using qPCR probes specific for each layer. This allowed me to make an accurate and specific statement about gene expression in the SHRSP GD18 placenta; where oxidative stress related gene markers were increased in the vascular compartments. The majority of SHRSP placenta presented at GD18 with a blackened ring which encircled the tissue. Further investigation of the placenta using western blot for caspase 3 cleavage determined that this was likely due to increased cell death in the SHRSP placenta. The SHRSP also presented with a loss of one particular placental cell type at GD18: the glycogen cells. These cells could have been the target of cell death in the SHRSP placenta or were utilised early in pregnancy as a source of energy due to the deficient uterine artery blood supply. Blastocyst implantation was not altered but resorption rate was increased between SHRSP and WKY; indicating that the reduction in litter size in the SHRSP was primarily due to late (>GD14) pregnancy loss. Fetal growth was not restricted in SHRSP which led to the conclusion that SHRSP sacrifice part of their litter to deliver a smaller number of healthier pups. Activation of the immune system is a common pathway that has been implicated in the development of both hypertension and adverse pregnancy outcome. In Chapter 2, I proposed that this may be a mechanism of interest in SHRSP pregnancy and measured the pro-inflammatory cytokine, TNFα, as a marker of inflammation in pregnant SHRSP and WKY and in the placentas from these animals. TNFα was up-regulated in maternal plasma and urine from the GD18 SHRSP. In addition, TNFα release was increased from the GD18 SHRSP placenta as was the expression of the pro-inflammatory TNFα receptor 1 (Tnfr1). In order to investigate whether this excess TNFα was detrimental to SHRSP pregnancy, a vehicle-controlled intervention study using etanercept (a monoclonal antibody which works as a TNFα antagonist) was carried out. Etanercept treatment at GD0, 6, 12 and 18 resulted in an improvement in pregnancy outcome in the SHRSP with an increased litter size and reduced resorption rate. Furthermore, there was an improved uterine artery function in GD18 SHRSP treated with etanercept which was associated with an improved uterine artery blood flow over the course of gestation. In Chapter 3, I sought to identify the source of this detrimental excess of TNFα by designing a panel for maternal leukocytes in the blood and placenta at GD18. A population of CD3- CD161+ cells, which are defined as rat natural killer (NK) cells, were increased in number in the SHRSP. Intracellular flow cytometry also identified this cell type as a source of excess TNFα in blood and placenta from pregnant SHRSP. I then went on to evaluate the effects of etanercept treatment on these CD3- CD161+ cells and showed that etanercept reduced the expression of CD161 and the cytotoxic molecule, granzyme B, in the NK cells. Thus, etanercept limits the cytotoxicity and potential damaging effect of these NK cells in the SHRSP placenta. Analysing the urinary peptidome has clinical potential to identify novel pathways involved with disease and/or to develop biomarker panels to aid and stratify diagnosis. In Chapter 4, I utilised the SHRSP as a pre-clinical model to identify novel urinary peptides associated with hypertensive pregnancy. Firstly, a characterisation study was carried out in the kidney of the WKY and SHRSP. Urine samples from WKY and SHRSP taken at pre-pregnancy, mid-pregnancy (GD12) and late pregnancy (GD18) were used in the peptidomic screen. In order to capture peptides which were markers of hypertensive pregnancy from the urinary peptidomic data, I focussed on those that were only changed in a strain dependent manner at GD12 and 18 and not pre-pregnancy. Peptide fragments from the uromodulin protein were identified from this analysis to be increased in pregnant SHRSP relative to pregnant WKY. This increase in uromodulin was validated at the SHRSP kidney level using qPCR. Uromodulin has previously been identified to be a candidate molecule involved in systemic arterial hypertension but not in hypertensive pregnancy thus is a promising target for further study. In summary, we have characterised the SHRSP as the first model of maternal chronic hypertension during pregnancy and identified that inflammation mediated by TNFα and NK cells plays a key role in the pathology. The evidence presented in this thesis establishes the SHRSP as a pre-clinical model for pregnancy research and can be continued into clinical studies in pregnant women with chronic hypertension which remains an area of unmet research need.

MicroRNAs (miRs) are a group of short non-coding RNAs, on average 22 nucleotides in length, that form an important axis of post-transcriptional regulation of gene expression. They have been identified as major modulators of all biological processes including development, cell differentiation, growth and apoptosis as well as diseases such as cancer, diabetes and cardiovascular disease (CVD). In the developed world CVD remains the leading cause of morbidity and mortality, and a substantial burden on healthcare. Left ventricular hypertrophy (LVH) is defined as an increase in thickness of the myocardium and is an important risk factor in CVD. The stroke-prone spontaneously hypertensive rat (SHRSP) is an animal model of essential hypertension used in research of CVD together with a normotensive reference strain Wistar-Kyoto (WKY). The SHRSP animals exhibit an increase in the size of myocardium prior to the onset of hypertension and have established LVH at 16 weeks of age thus are a good model for investigating the genetics of this condition. The aim of this project was to identify signature expression patterns of novel and previously implicated microRNAs and to investigate their role in the development of LVH in the SHRSP. Furthermore, potential gene targets of candidate selected microRNAs were identified to investigate biological pathways involved in the disease process. MicroRNA microarray profiling was performed by Dr. McBride in the hearts of 5 week old SHRSP and WKY male rats using the LC Sciences (LCS) multispecies chip based on Sanger miRBase 11.0. The data were analysed (Drs. McBride and McClure) using Rank Product (RP) analysis method and evaluated in combination with the statistical analysis provided by LC Sciences (LCS). LCS data indicated 103 microRNAs differentially expressed at 5 weeks of age, 64 at 16 weeks of age, with 9 in common. The RP analysis identified 72 microRNAs differentially expressed between WKY and SHRSP at 5 weeks of age and 51 at 16 weeks of age, and 21 microRNAs were differentially regulated at both time points. Both methods identified a subset of 35 microRNAs in 5 week old hearts and 8 in 16 week old samples. TaqMan® microRNA assays were used to confirm these expression patterns. Based on these data and published literature candidate microRNAs – miR-195, miR-329 and miR-451 were selected for further experimental investigation. Expression of candidate microRNAs (miR-195, miR-329 and miR-451) in neonatal hearts of SHRSP and WKY rats was also investigated. It was found that all three candidate microRNAs were differentially expressed at this time point and there were significantly increased levels in the SHRSP compared to WKY. Cardiac cell line H9c2 AngII model of hypertrophy was used to investigate the effect of AngII on our candidate miRNA expression levels. A 96 hour stimulation of H9c2 cell with AngII resulted in a significant increase in cell size. Levels of miR-195 and miR-329 were not affected by addition of AngII; expression of miR-451 was significantly down-regulated immediately post stimulation, however levels were increased at the final assessment at 96 hours. Adenoviral vectors over-expressing miR-195, miR-329 and miR-451 were designed and generated. These vectors were used to investigate if overexpression of each individual miR could affect cell size in the selected in vitro model of cardiomyocyte hypertrophy. It was found that all candidate microRNAs reduced AngII mediated hypertrophic cell growth at higher doses. Identifying pathways and specific gene targets affected by changes in microRNA levels is of paramount importance. Availability of such data not only provides information about regulation of cardiac homeostasis, but also possible therapeutic approaches for treatment and prevention. Target prediction algorithms (DIANAmT, miRanda, miRDB, miRWalk, PICTAR5, PITA, RNA22, RNAhybrid and Targetscan) were used to identify potential gene targets for candidate microRNAs. To refine these lists to genes relevant to the experimental design Ingenuity Pathway analysis (IPA 9.0) software was used to overlay microRNA microarray data with results of heart mRNA gene expression data (M. McBride, personal communications) from the same cardiac tissue and to relate these to appropriate pathways and cellular functions. A list of 12 genes was generated: similar to CG4768-PA (RGD1309748), KN motif and ankyrin repeat domains 1 (Kank1), sterile alpha motif domain containing 4B (Samd4b), dual specificity phosphatase 10 (Dusp10), follistatin-like 3 (secreted glycoprotein) (Fstl3), jun D proto-oncogene (JunD), forkhead box M1 (Foxm1), SIN3 homolog A transcription regulator (yeast) (Sin3a), cyclin-dependent kinase 1 (Cdk1), kinesin family member 23 (Kif23), bone morphogenetic protein receptor type IA (Bmpr1a) and sestrin 1 (Sesn1). Expression of these candidate targets was assessed in heart tissues from neonates, 5 and 16 week old rats. Six out of ten of these targets were differentially expressed at one or more time points. To further investigate the proposed targeting of these genes by candidate microRNAs, expression levels were measured in each of the predicted targets in H9c2 cell transduced with miR over-expressing viruses. The expression patterns of Cdk1, Kif23, Kank1 and Sin3a were consistent with overexpression of the targeting microRNA, i.e. expression of each gene was down-regulated. In summary, data presented in this thesis elucidate the role of miR-195, miR-329 and miR-451 in the development of LVH in the SHRSP. Understanding the underlying cause for differential expression of these candidate microRNAs, confirming gene targets and identifying relevant pathways will improve the understanding of LVH at the molecular level. It will also help explain the pathophysiology of cardiovascular disease development in this rat model of human hypertension providing a basis for the development of novel therapeutic approaches to treat or prevent LVH.

Thesis (M.S.)--University of North Carolina at Chapel Hill, 2006.
Title from electronic title page (viewed Oct. 10, 2007). "... in partial fulfillment of the requirements for the degree of Master of Science in the Department of Environmental Sciences and Engineering." Discipline: Environmental Sciences and Engineering; Department/School: Public Health.

Stroke accounts for 9% of all deaths worldwide and is a major cause of severe disability (Donnan et al, 2008). Following ischaemic stroke, the penumbra represents tissue which is hypoperfused and functionally impaired but is not yet irreversibly damaged. However, the penumbra has a finite lifespan and will proceed to infarction in the absence of swift reperfusion. Therefore, the identification and potential salvage of penumbral tissue in acute ischaemic stroke is the ultimate goal for both clinicians and experimental stroke researchers. Positron emission tomography (PET) is the ‘gold standard’ imaging modality for identifying the penumbra, but the complex logistics of PET limit its widespread use. Magnetic Resonance Imaging (MRI) is widely used for penumbra imaging in both clinical and pre-clinical research. The MRI perfusion-diffusion mismatch model provides an approximation of the penumbra, where diffusion weighted imaging (DWI) identifies the core of ischaemic injury and perfusion weighted imaging (PWI) reveals the perfusion deficit. The mismatch between the DWI and PWI provides a measure of penumbral tissue. However, there is no consensus on the perfusion and diffusion thresholds used to identify mismatch tissue in clinical and preclinical stroke research. Furthermore, in rodent stroke models differences in the evolution of ischaemic injury between strains may limit the use of a single set of threshold values. Therefore, the first aim of this thesis was to establish strain specific perfusion and diffusion thresholds to compare penumbra volume in the clinically relevant spontaneously hypertensive stroke-prone rat (SHRSP) and the normotensive control strain, Wistar-Kyoto (WKY) using 3 different methods. The SHRSP strain is characterised by the progressive development of severe hypertension which is followed by a tendency to spontaneous stroke and an increased sensitivity to experimental stroke. Experimental stroke was induced by permanent middle cerebral artery occlusion (MCAO) by the intraluminal filament method. DWI and PWI were obtained every hour from 1-4 hours post-MCAO. Strain-specific diffusion and perfusion thresholds were established from final infarct at 24 hours post-MCAO, as defined by T2 weighted imaging. The calculated ADC thresholds were comparable between the strains but the absolute perfusion threshold was significantly higher in SHRSP compared to WKY. This may be indicative of an increased sensitivity to ischaemia in the hypertensive strain. Furthermore, application of these thresholds to the acute MRI data revealed that the volume of ischaemic injury and the perfusion deficit were significantly larger in SHRSP compared to WKY and this was also reflected in the significantly larger infarct volume observed in SHRSP at 24 hours post-MCAO. Interestingly, there was evidence of a temporal increase in the volume of the perfusion deficit in SHRSP and WKY. This may indicate that there is a progressive failure of collateral blood supply in both strains following stroke. Penumbra volume was then assessed in SHRSP and WKY rats using the mismatch method and also indirectly by examining the growth of the volume of ADC derived ischaemic injury. Mismatch volume was determined by arithmetic subtraction of the volume of ischaemic injury from the volume of perfusion deficit (volumetric method) and also by manual delineation of mismatch on each of 6 coronal slices (spatial method). There was a limited volume of mismatch tissue in either strain from as early as 1 hour post-MCAO and the volumetric method generated smaller mismatch volumes than the spatial mismatch method. Mismatch volume was comparable in SHRSP and WKY from 1-4 hours post-MCAO. Penumbra was also determined retrospectively by subtracting the volume of ischaemic injury at each time point from final infarct volume. Using this method, penumbra volume was significantly larger in WKY compared to SHRSP at 30 minutes post-MCAO but penumbra volume was comparable at all later time points. This suggests that there is reduced potential for tissue salvage in SHRSP compared to WKY within the first hour following MCAO but from 1 hour onwards, there is limited potential for penumbra salvage in both strains. In addition, there was evidence of ‘negative’ mismatch tissue in SHRSP and WKY rats, where the ADC derived lesion expanded beyond the boundary of the perfusion deficit. The volume of negative mismatch tissue was comparable between the strains and was persistent over the 4 hour time course. This phenomenon may arise from the spread of toxic mediators from the ischaemic core. Oxidative stress is a major mediator of cellular injury following ischaemic stroke and reactive oxygen species, like superoxide, have multiple deleterious effects on the components of the neurovascular unit. It is well established that NADPH oxidase is the principal source of superoxide in acute ischaemic stroke and is therefore a target for potential neuroprotective strategies (Moskowitz et al, 2010). Consequently, the second aim of this thesis was to evaluate the potential neuroprotective effect of NADPH oxidase inhibition with low and high dose apocynin following permanent or transient ischaemia. Rats were administered apocynin at a dose of 5mg/kg or 30mg/kg or vehicle, at 5 minutes post-MCAO. Apocynin treatment had no significant effect on infarct volume or functional outcome at 24 hours following permanent MCAO in WKY rats. However, both low and high dose apocynin treatment significantly reduced infarct volume at 72 hours post-MCAO by 60% following 1 hour of ischaemia in Sprague-Dawley rats. Furthermore, functional outcome was improved in the low dose apocynin treated group, although this did not reach the level of statistical significance. On the basis of these results, low dose apocynin treatment was evaluated in SHRSP rats following 1 hour of ischaemia. However, apocynin treatment had no effect on the acute evolution of ischaemic injury and failed to improve stroke outcome, where the mortality rate was high in both the apocynin treated and the vehicle treated group. The conflicting effects of apocynin may be attributable to a differential expression of NADPH oxidase subunits in normotensive and hypertensive rat strains. These findings may also explain the failure of neuroprotective drugs to translate from bench to bedside, as therapies which are neuroprotective in young healthy animals may not demonstrate the same efficacy in animal models with stroke co-morbidities. Therefore, potential therapeutic strategies should be extensively evaluated in animal models with stroke risk factors before proceeding to clinical trial.

Hypertensive disorders of pregnancy are an increasingly common disorder in modern society. The increasing prevalence of women with pre-eclampsia superimposed on a background of chronic hypertension is a significant burden in modern society and is profoundly detrimental to both mother and child; during pregnancy and beyond. Little is understood about the development of these multifactorial hypertensive disorders, however there is increasing evidence that the manifestation of hypertensive disorders during pregnancy is not solely due to placental-derived dysfunctions and has important maternally-driven components. The stroke-prone spontaneously hypertensive (SHRSP) rat is a well-established model of human essential hypertension. SHRSP dams remain hypertensive throughout pregnancy and demonstrate an abnormal uterine artery structure and function at term. This project aimed to more fully characterise pregnancy in the SHRSP rat. The objectives were to assess maternal responses and determine how maternal hypertension impacts maternal and fetal well-being as well as placental development; to investigate the underlying genetic mechanisms behind the eventual abnormal pregnancy-dependent uterine artery remodelling; and, finally, to increase the maternal cardiovascular load in SHRSP pregnancy to establish a model of superimposed pre-eclampsia. In vivo and ex vivo techniques were used to characterise cardiovascular function in the hypertensive SHRSP and normotensive WKY rats during gestation, as well as assess pregnancy outcomes. The SHRSP dams were found to have similar cardiac function compared to WKY, yet there was evidence of impaired systemic vascular structure and function in late gestation and placental abnormalities. Nevertheless, the SHRSP maintained similar litter sizes to WKY and did not demonstrate any major impact on fetal growth. Further similarities between SHRSP and WKY pregnancy were revealed with the assessment of uterine artery function in early gestation. However, using RNA sequencing to elucidate the transcriptomic profiles of the uterine arteries, SHRSP were found to have strikingly different responses to pregnancy at the transcript expression level, compared to WKY. Finally, a model of superimposed pre-eclampsia was established by increasing the cardiovascular stress in the dam using angiotensin II infusion during pregnancy in SHRSP. This model had a significantly higher systolic and diastolic blood pressure than the already hypertensive SHRSP. The pregnancy-dependent increase in cardiac output, observed in SHRSP, was negated by AngII infusion and was reduced in the highest treatment group. These major cardiovascular impairments were observed alongside increased proteinuria and reduced fetal growth; all phenotypes found in severely pre-eclamptic women. This work has provided information on systemic and uterine specific vascular responses to pregnancy in SHRSP and WKY rats alongside detail of underlying transcriptional differences. This study was the first to examine uterine artery gene expression changes during pregnancy. The different transcriptomic profiles of early pregnancy changes in the two strains make this an intriguing model to study maternal-driven vascular remodelling in hypertensive pregnancy. Furthermore, this work demonstrated that increasing the cardiovascular load during pregnancy in SHRSP successfully mimics superimposed pre-eclamptic phenotypes and could be used in the assessment of novel therapeutic strategies. To conclude, the SHRSP has the potential to aid our understanding of human pre-eclamptic conditions, especially when endeavouring to determine the impact of maternally-driven components of hypertensive disorders of pregnancy.

L’avortement spontané (AS) désigne la perte du produit de conception avant sa viabilité, c'est-à-dire avant la 22e semaine d’aménorrhée, ou un poids fœtal inférieur à 500 g. La cause génétique est à l’origine de plus des deux tiers des AS, les aneuploïdies autosomiques, représentant à elles seules jusqu’à 70% des pertes fœtales du 1er trimestre. Le caryotype présente une très bonne sensibilité en ce qui concerne le dépistage des trisomies autosomiques (13, 18 et 21) et des aneuploïdies affectant les chromosomes sexuels, mais il montre d’importantes limites, d’une part en raison des échecs de culture cellulaire et d’autre part en raison de l’existence de remaniements non détectables au caryotype standard. Actuellement plusieurs techniques moléculaires de dépistage rapides des aneuploïdies liées aux échecs de grossesses ont été vérifiées : 1°) la fluorescence in situ par hybridation (FISH) 2°) l’amplification multiplex de sondes nucléiques dépendant des ligatures (MLPA). Ces deux méthodes présentent l’avantage d’être réalisables, sans culture préalable, sur noyaux en interphase ou sur ADN extrait et de permettre la détection d’anomalies cryptiques. Notre étude repose sur l’étude cytogénétique des produits d’AS pour mettre en évidence les anomalies chromosomiques les plus fréquentes à l’origine de ces pertes fœtales et d’en mieux appréhender les mécanismes de survenue. Elle a été réalisée sur 220 patientes âgées de 19 à 45 ans, et était fondée sur l’analyse directe par FISH sur noyaux interphasiques (AneuVysionTM) de prélèvements de villosités choriales et sur l’analyse de l’ADN extrait de tissus fœtaux par MLPA afin de révéler d’éventuelles aneuploïdies et micro-remaniements. L’âge gestationnel au moment des prélèvements était compris entre 7 et 38 semaines d’aménorrhée. Sur un total de 151 échantillons analysés par AneuVysionTM, 10 anomalies chromosomiques ont été observées: 3 trisomies 21, 1 trisomie 18, 1 trisomie 13, 1 mosaïque 46,XX/47,XX+21, 3 triploïdies et 1 monosomie X (Turner). Par ailleurs, sur les 69 autres échantillons analysés par MLPA, 6 étaient ininterprétables. Les anomalies trouvées par cette technique étaient: 2 monosomies X. Pour les échantillons restants, la MLPA a été négative. Nous avons en parallèle réalisé une étude rétrospective fondée sur l’analyse comparative d’un échantillon recruté à Sidi Bel Abbès, de femmes ayant subi un AS et admises à la maternité del’hôpital Hassani Abdelkader de Sidi Bel Abbès et d’un échantillon recruté à Clermont-Ferrand de femmes ayant subi un AS et pour lesquelles un prélèvement pour établir le caryotype du produit de fausse-couche avait été adressé dans le service de cytogénétique du CHU Estaing de Clermont-Ferrand. Cette étude a couvert une période de six années, allant de janvier 2005 à décembre 2010. Les techniques de FISH et de MLPA représentent des outils simples, rapides et sensibles pour la détection des remaniements chromosomiques. Elles représentent une alternative très intéressante à la culture cellulaire, et permettent le diagnostic de désordres génomiques indécelables par les techniques conventionnelles
Spontaneous abortion (SA) is the loss of the product of fertilization before its viability, that is, before22 weeks of gestation or fetal weight less than 500 g. Genetic causes account for more than two thirds of SA, autosomal aneuploidies alone accounting for up to 70% fetal loss. Chromosomal cytogenetic techniques show significant limitations on the one hand because of the failures of cell culture, and secondly because of the existence of undetectable alterations to the standard karyotype. It was therefore planned to use molecular techniques :- Fluorescent in situ hybridization (FISH)- Multiplex ligation-dependent probe amplification (MLPA). Both techniques have the advantage of being achievable without prior culture of cores interphase or DNA extracted and to enable detection of cryptic abnormalities. The project is based on cytogenetic study of AS products to highlight the most frequent chromosomal abnormalities causing fetal losses, and to better understand their occurrence. Our study was performed on 220 patients from 19 to 45 years, and was based on the direct analysis by FISH on interphase nuclei (AneuVysionTM) of chorionic villus sampling and analysis of DNA extracted fetal tissue by MLPA to reveal any aneuploidy and rearrangements. The gestational age of the samples ranged from the 7th to the 38th week of gestation. In a total of 151 samples analyzed by AneuVysionTM, 10 chromosomal abnormalities were observed: three trisomies 21, one trisomy 18, one trisomy 13, one mosaic 46,XX/47,XX+21, 3 triploidies and one monosomy X (Turner). In addition, among the other 69 samples analyzed by MLPA, 6 were uninterpretable. The abnormalities found by this technique were 2 monosomies X. For the remaining samples, the MLPA was negative. We conducted a retrospective parallel study based on the analysis of a sample recruited in Sidi Bel Abbes, women who have had an AS and were admitted to the maternity hospital Abdelkader Hassani, Sidi Bel Abbes ; and a sample recruited in Clermont-Ferrand : women who underwent AS for which a levy to establish the karyotype product miscarriage had been addressed in the Department of Cytogenetics of CHU Estaing, Clermont-Ferrand. This study covered a period of six years, from January 2005 to December 2010. The techniques of FISH and MLPA are simple, rapid and sensitive tools for the detection of chromosomal rearrangements. They represent a very interesting alternative to cell culture and allow diagnosis for genomic disorders undetectable by conventional techniques

Une des caractéristiques les plus singulières de l’activité corticale est son degré élevé de variabilité. Ma thèse dedoctorat s’est focalisée sur l’étude de (i) l’irrégularité des intervalles entre potentiels d’action (PAs)successivement émis par un neurone, et (ii) la variabilité dans l’évolution temporelle de l’activité d’un ensemblede neurones. Premièrement, j’ai étudié l’irrégularité des neurones enregistrés dans le cortex moteur de singesmacaques performant une tâche d’estimation du temps et de préparation à l’action. J’ai montré que l’irrégularitén’est pas un paramètre libre de l’activité neuronale, contrairement au taux de PAs, mais est déterminée par lescontraintes structurelles des réseaux neuronaux. Deuxièmement, j’ai utilisé le modèle de Markov caché (MMC)pour analyser l’activité d’ensembles de neurones enregistrés dans plusieurs aires corticales, sensorielles etmotrices, de singes exécutant une tâche de discrimination tactile. J’ai montré que les processus sensoriels etdécisionnels sont distribués dans plusieurs aires corticales. Les résultats suggèrent que l’action et la décision surlaquelle elle est basée sont reliées par une cascade d’évènements non stationnaires et stochastiques. Finalement,j’ai utilisé le MMC pour caractériser l’activité spontanée d’un ensemble de neurones du cortex préfrontal d’unrat. Les résultats montrèrent que l’alternance entre les états UP et DOWN est un processus stochastique etdynamique. La variabilité apparaît donc aussi bien pendant l’activité spontanée que pendant le comportementactif et semble être contrainte par des facteurs structurels qui, à leur tour, contraignent le mode d’opération desréseaux neuronaux
A hallmark of cortical activity is its high degree of variability. The present work focused on (i) the variability ofintervals between spikes that single neurons emit, called spike time irregularity (STI), and (ii) the variability inthe temporal evolution of the collective neuronal activity. First, I studied the STI of macaque motor corticalneurons during time estimation and movement preparation. I found that although the firing rate of the neuronstransmitted information about these processes, the STI of a neuron is not flexible and is determined by thebalance of excitatory and inhibitory inputs. These results were obtained by means of an irregularity measure thatI compared to other existing measures. Second, I analyzed the neuronal ensemble activity of severalsomatosensory and motor cortical areas of macaques during tactile discrimination. I showed that ensembleactivity can be effectively described by the Hidden Markov Model (HMM). Both sensory and decision-makingprocesses were distributed across many areas. Moreover, I showed that decision-related changes in neuronalactivity rely on a noise-driven mechanism and that the maintenance of the decision relies on transient dynamics,subtending the conversion of a decision into an action. Third, I characterized the statistics of spontaneous UP andDOWN states in the prefrontal cortex of a rat, using the HMM. I showed that state alternation is stochastic andthe activity during UP states is dynamic. Hence, variability is prominent both during active behavior andspontaneous activity and is determined by structural factors, thus rending it inherent to cortical organization andshaping the function of neural networks

L’acquisition du lexique précoce est très importante dans le développement du langage dans la mesure où les mots sont constitutifs des énoncés signifiants de l’enfant mais également car leur développement préfigure dans une certaine mesure les habiletés langagières ultérieures. Il est aujourd’hui admis que l’acquisition du lexique se fait sur la base d’étapes communes mais au sein desquelles il existe de fortes variations inter-individuelles, qui selon les chercheurs seraient d’ordre linguistiques, sociales ou idiosyncrasiques. Cependant, il reste encore des zones d’ombre, notamment sur l’influence possible des méthodes d’évaluation sur les résultats ; et malgré le fait que certains chercheurs conseillent l’utilisation conjointe de plusieurs méthodes de collecte pour éviter cette influence liée à la méthodologie, cette préconisation est peu suivie.Cette thèse vise à étudier les trajectoires développementales du lexique en production et leurs variations selon les enfants ; plus spécifiquement, il s’agit de montrer l’apport de méthodes complémentaires et l’importance de l’exploration du contexte de production des mots lors des observations spontanées en milieu naturel pour mieux interpréter les différences inter-individuelles.Des questionnaires parentaux ont été remplis pour 10 enfants français monolingues de 8;16 à 32;27 mois, que nous avons régulièrement filmé en milieu naturel (corpus TOTAL). Globalement, le développement et la composition du vocabulaire des 10 enfants évalués par l’IFDC suivent les tendances observées dans la littérature. Nous nous sommes ensuite focalisés sur 4 de ces enfants pour les stades linguistiques 15-25 ; 50 ; 70-120 mots (corpus CIBLÉ). L’utilisation des deux méthodes – questionnaires parentaux et données spontanées – a permis d’évaluer le développement lexical de manière plus fiable et complète, les avantages d’une méthode permettant de combler les limites de l’autre. Afin de mieux comprendre les divergences de certains résultats entre ces deux méthodes, nous avons poursuivi nos investigations sur les données spontanées des 4 enfants en examinant les contextes situationnels et interactionnels. Nous avons défini et catégorisé les situations présentes dans les enregistrements du corpus TOTAL. Une variation dans les durées de ces diverses situations a été trouvée entre stades linguistiques et entre enfants du corpus CIBLÉ. Des analyses croisées sur la production du vocabulaire en fonction des situations ont permis de réinterpréter les différences inter-individuelles des 4 enfants du corpus CIBLÉ. Par exemple, il est apparu que les deux enfants dont les effectifs de mots sont les moins élevés au niveau des données spontanées ont été davantage filmés en situation ludique solitaire ; situation où les analyses révèlent que le nombre d’unités lexicales produites est le plus faible. Ensuite, un autre travail a consisté à décrire le contexte interactionnel et plus précisément à comprendre les implications des enfants dans les échanges interactionnels. Beaucoup de différences inter-individuelles sont apparues, dont certaines nous permettent de clarifier les données des enfants. Ainsi, chaque analyse apporte des informations complémentaires – du vocabulaire estimé des questionnaires parentaux, au vocabulaire en usage enregistré en milieu naturel. En dépit du nombre restreint d’enfants qui composent cet échantillon, ces résultats encouragent l’utilisation de méthodes complémentaires. L’analyse des contextes situationnels et interactionnels nous semble aussi cruciale pour comprendre les mesures lexicales des enfants et mieux interpréter les différences intra et inter-individuelles
The acquisition of early lexicon is very important for the development of language considering that it is the early lexicon that builds infants’ first significant utterances and that it prefigures to a certain extent infants’ future language skills. It is well established that lexical acquisition presents common developmental trends and milestones, nevertheless a great amount of individual variation exists. This variation comes from linguistic, social and/or idiosyncratic factors. Further research should be done to investigate the possible influence of evaluation procedures on the results. Although the use of a complementary approach could limit this bias, it has rarely been used in lexical acquisition research. This work aims at describing not only the common developmental trajectories of early lexicon in French monolingual children, but also the inter-individual differences. More specifically, we want to show the importance of applying a complementary approach and of exploring word production during spontaneous interactions in real-life settings to better interpret inter-individual differences. The parents of 10 French monolingual children aged from 8;16 to 32;27 months filled out a questionnaire (IFDC) regarding their child’s vocabulary. The same children were video-recorded at home (corpus TOTAL). Overall, the development and the composition of individual lexicon, evaluated through the IFDC, follow the trends already reported in the literature. As for the spontaneous vocabulary, we focused our study on 4 children at the 15-52; 50; 70-120 word linguistic stages (corpus CIBLÉ). The integration of two complementary approaches, i.e. parental questionnaires and spontaneous observations, proved to be efficient and allowed us to reliably evaluate the lexical development and to avoid the bias linked to the use of a single method. To better understand the results variations between the two methods, we explored the situational and interactional context on the corpus CIBLÉ. We defined and categorized the different situations in the corpus TOTAL, then we focused on the corpus CIBLÉ to calculate their duration and we found variations between situations. A Cross-analysis on word production as a function of the situation helped to understand the lexical measure on linguistic stages and enabled the reinterpretation of individual variations. For example, the two children with the smallest lexicon had the longest duration of solitary play. During this activity, the number of produced words was generally very low. Next, we describe the interactional context, and more particularly, the rate and the nature of the children exchanges. The analyses revealed an important variation between measures and differences in the exchange rate among children. To a certain degree, for some children the interactional measures provide a richer interpretation of lexical measures.Our work clearly shows the advantages of combining several types of data to evaluate the early lexical development and the differences between individuals and encourages this approach. The analysis of situational and interactional contexts shows that these are crucial for understanding children lexical measures and better interpreting intra- and inter-individual differences

碩士
國立陽明大學
生醫光電研究所
105
Pump-probe microscopy has become a common platform for imaging based on nonlinear optical processes, such as stimulated emission (SE), ground state depletion (GSD), and excited state depletion (ESD). The capacity includes molecular specificity, improved resolution, and enhanced penetration depth. In the past years, stimulated emission based pump-probe microscopy has demonstrated dark chromophore detection and fluorescence lifetime imaging. In this work, a pump-probe microscope is configured for the detection of stimulated gain and spontaneous loss. We have used a pulsed diode laser, λpu = 635 nm as the pump (excitation) beam and a mode-locked Ti-sapphire laser, λpr = 780 nm, as the probe (stimulation) beam. The time delay (τ) between the pump and probe pulses are precisely controlled by adjusting the length of the triggering cables and setting the delay generator. The probe beam pulses are passed through two 15-cm long dispersive glass rods (SF-6) for extending into a pulse width of 3.0 ps. Both beams are coupled into the scanner and focused on the sample by an objective lens (10X, NA=0.3). For stimulated gain, the pump beam is modulated at a frequency, f1, and the probe beam is demodulated accordingly to extract the signal in the transmission direction with a photodiode as the detector (PDA 36A, Thorlabs). For spontaneous loss, the probe beam is modulated at frequency, f2, the spontaneous loss signal is than demodulated from the fluorescence detected in the reflection mode by a PMT. In all cases, a high performance lock-in amplifier (HF2LI, Zurich Instruments) is used. The output signal of the lock-in amplifier is then fed to the A/D channel of the scanning unit for image reconstruction. The scan rate is set at a frequency 500 Hz, to match the time constant (1.99 ms) of the lock-in amplifier. By demodulating fluorescence signal, the fluorescence lifetime and optical section images can be obtained with greatly reduced background, in which shot noise is attributed. Additionally, this technique improves signal-to-noise ratio and enhances penetration depth like multiphoton microscopy, without expansive femtosecond lasers.

AFRIKAANS: Die navorsing handel oor die effek van SHIP® (Spontaneheling Intrasistemiese Proses) by adolessente tennisspelers en die waarde daarvan ten opsigte van die ontwikkeling van sielkundige potensiaal van spelers. Tradisioneel word Sportsielkunde vanaf ‘n kliniese konteks gevoed. Dit is ‘n dinamiese veld wat voordurend op soek is na nog verdere tegnologiese ontwikkeling. Die waarde van die studie is dat dit die eerste keer is dat ‘n hele kliniese intervensieprogram suiwer in ‘n sportkonteks toegepas word. Die doel van die studie is om te bepaal wat die moontlike sielkundige bydrae van SHIP® op die sielkunde van die tennisspeler is. Die intervensie SHIP® het tussen vier tot ses maande geduur met ‘n gemiddeld van tien sessies per speler waar ‘n sessie een uur lank duur. ‘n Totaal van tien adolessente tennisspelers wat verbonde is aan ‘n tennisskool is vir die studie gebruik. Die spelers wat aan die studie deelgeneem het bestaan uit vier manlike en ses vroulike tennisspelers. Die eksperimentele groep bestaan uit ses tennisspelers (twee manlik en vier vroulik) wat ‘n reeks psigometriese toetse afgelê het en deur SHIP® behandel is. Die kontrole groep bestaan uit vier tennisspelers (twee manlik en twee vroulik) wat nie deur SHIP® behandel is nie, maar wel die psigometriese toetse afgelê het. Die studie maak gebruik van ‘n tradisionele eksperimentele ontwerp wat van ‘n eksperimentele en kontrole groep gebruik maak. Verder leen die studie aspekte van Pieterse (2004) se enkelproefpersoonnavorsingsontwerp. Die ontwerp behels onderhoude wat met al die spelers gevoer is, voor die intervensie. Die onderhoude handel oor die spelers se sterkpunte, swakpunte en belewenis van angs en stres tydens tenniswedstryde. Na die intervensie is daar onderhoude met die afrigters en drie spelers gevoer om te bepaal of daar enige verandering by die spelers plaasgevind het. Die resultate van die studie toon ‘n afname in kognitiewe en liggaamlike angs van die eksperimentele groep met geen beduidende veranderinge by die kontrole groep nie. Al hierdie veranderinge is beduidend op die 5% peil van betekenis. Ten opsigte van selfvertroue het beide groepe ‘n statisties beduidende verandering getoon op die 10% peil van betekenis. Die eksperimentele groep het egter ‘n beduidende toename getoon terwyl die kontrole groep se tellings op die subskaal beduidend afgeneem het. Die spanning-angs toetstellings van die kontrole groepe was beduidend hoër as die eksperimentele groep. Hierdie verskil was beduidend op die 10% peil van betekenis. Die depressie en woede-vyandigheid toetstellings van die kontrole groep was ook statisties hoër as die eksperimentele groep na die intervensie. Hierdie verskille was beduidend op die 5% peil van betekenis. Die resultate van die analise binne groepe, toon dat die vigortellings van die eksperimentele groep beduidend toegeneem het, terwyl die afname in die kontrole groep se tellings nie beduidend was nie. Hierdie statisties beduidende veranderinge in die eksperimentele groep was beduidend op die 5% peil van betekenis. Die afgematheid telling van die eksperimentele groep het beduidend afgeneem oor die tyd met geen beduidende verandering in die kontrole groep nie. Hierdie verandering was beduidend op die 10% peil van betekenis. Die verwarringtellings van die eksperimentele groep het beduidend afgeneem, met geen beduidende veranderings in die kontrole groep nie. Die verandering was beduidend op die 5% peil van betekenis. Die outonomiteitssubskaaltelling van die eksperimentele groep het statisties beduidend toegeneem. Die verandering was beduidend op die 10% peil van betekenis. Geen beduidende verandering het ten opsigte van hierdie subskaal by die kontrole groep plaasgevind nie. Die kontrole groepe het ‘n statisties beduidende afname in die positiewe verhoudingssubskaal getoon. Ten opsigte van entiteitsingesteldheid het die kontrole groep ‘n beduidende toename in die tellings getoon. Hierdie toename was beduidend op die 10% peil van betekenis alhoewel die eksperimentele groep se tellings ook toegeneem het, was dit nie statisties beduidend nie. Uit die onderhoude met die spelers en afrigters na die intervensie is dit duidelik dat die eksperimentele groep gegroei het ten opsigte van aandag en konsentrasiebeheer, die hantering van stres en angs en genot tydens tenniswedstryde. ENGLISH: This study examines the effect of SHIP® (Spontaneous Healing Intrasystemic Process) on adolescent tennis players and its advantages in accordance with the development of the players’ potential. Traditionally Sport Psychology has evolved from a clinical context. It is a dynamic field that is always open to further technological development. The value of the study lies in the fact that it is the first time that an entire clinical intervention programme is applied in a purely sports context. The goal of the study is to determine the possible psychological effects that SHIP® might have on the psychology of tennis players. The SHIP® intervention lasted between four to six months, with an average of ten sessions per player, and each session lasting one hour. A total of ten adolescent tennis players who attend a tennis school participated in the study. Of these players, four were male and six female. The experimental group consisted of six tennis players (two male and four female) who completed a battery of psychometric tests and went through SHIP®. The control group consisted of four tennis players (two male and two female) who completed the psychometric tests, but were not put through SHIP® . The study made use of a traditional experimental design, consisting of an experimental and a control group. In addition, the study also employed aspects of Pieterse’s (2004) single subject design. Specific aspects of this design that were applied, include interviews conducted with all the players prior to the intervention. The interviews focused on the players’ strong points, weak points and their experience of anxiety and stress during tennis matches. Follow-up interviews were conducted with three players and their coaches after the intervention, to determine if the players had experienced any change. The results of the study point toward a decrease in the cognitive and physical anxiety of the experimental group, with no significant changes manifesting in the control group. All these changes are significant on the 5%-level of significance. With regard to self-confidence, both groups showed a statistically meaningful change on the 10%-level of significance. The experimental group scores showed a significant increase, while the control group scores on this subscale decreased significantly. The stress-anxiety test scores of the control group were significantly higher than those of the experimental group. This difference was meaningful on the 10%-level of significance. The depression and anger test scores of the control group were statistically higher than those of the experimental group after the intervention. These changes were meaningful on the 5%-level of significance. The results of the analysis within groups, showed that the vigor scores of the experimental group had increased significantly, while the decrease in the control group scores was of no significance. These statistical changes in the experimental group were meaningful on the 5%-level of significance. The fatigue scores of the experimental group decreased significantly over time, with no significant changes in the control group. These changes were meaningful on the 10%-level of significance. The confusion scores of the experimental group decreased significantly, with no significant changes in the control group. This change was meaningful on the 5%-level of significance. The autonomy subscale scores of the experimental group increased statistically significantly. This change was meaningful on the 10%-level of significance. No significant change occurred in the control group with regard to this subscale. The control group showed a statistically significant decrease in the positive relationship subscale. This change was meaningful on the 10%-level of significance. The experimental group showed no significant change with regard to this scale. With regard to the entity mindset, the control group showed a significant increase in scores. This increase was meaningful on the 10%-level of significance. Although the experimental group scores also increased, the scores were not statistically significant. From the interviews with the players and coaches after the intervention, it became clear that the experimental group had grown in terms of attention and concentration control, coping with stress and anxiety, and pleasure experienced during tennis matches.
Thesis (DPhil)--University of Pretoria, 2009.
Biokinetics, Sport and Leisure Sciences
unrestricted

碩士
輔仁大學
營養科學系
100
Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that affects various organs. It has been associated with interactions between the endocrine system , the environment, and genetic factors, but the pathogenesis is not yet fully understood. Conventionally, immunosuppressive agents such as steroids have been used to treat SLE patients. However, due to severe adverse effects of immunosuppressive agents, alternative treatments instead of traditional medication are now under development. According to our preliminary studies, the extracts of Poria cocos (PC) play beneficial roles in attenuating the progression of asthma on mouse models, and it may through its anti-inflammatory effects, probably. Both pathological mechanisms of asthma and SLE were related of shifting the immune status from Th1-dominant to Th2-dominant immune responses, therefore, we would like to explore whether PC contributes to the remission of SLE. Spontaneous SLE prone female NZB/W F1 mice were divided into the control group and the other three experimental groups (N = 8/group), which been fed with 0.1, 0.5, or 2.5 mg PC per kg body weight per day, respectively, for five weeks. Collected data showed that the experimental groups had showed significantly decreased levels of sera IgA and IgG, and fewer CD5+ B lymphocytes in Peyer's patches than those of the control group. Besides, the experimental group with the highest dosage of PC treatment represented the highest total cell number of B and T lymphocytes, as well as total leukocytes in the splenocytes among the experimental groups on two-week-fed's interval. In summary, PC may modulate the generation of white blood cells and B lymphocytes in lupus-like mice. In our study, when we fed NZB/W F1 mice with the highest dosage of PC (2.5 mg PC per kg body weight per day) for 5 weeks, accumulated data suggested that PC had no disadvantageous response to the innate immunity. The role of PC in immunoregulation still needs further investigation.