Cette étude porte sur l'impact du processus de paix en Irlande du Nord sur les partis politiques de la Province jusqu'à présent considérés comme radicaux : le D.U.P. et le Sinn Féin. Il s'agit d'identifier et d'analyser les changements stratégiques et politiques survenus au sein du D.U.P. et du Sinn Féin pendant le processus de paix afin d'aboutir à une entente politique en mai 2007, date de formation de l'Assemblée nord-irlandaise. Ainsi, nous tentons, d'une part, de démontrer comment le D.U.P. est passé du radicalisme politique et religieux à la modération, et, d'autre part, comment le Sinn Féin s'est distancé de la lutte armée de l'I.R.A. pour s'engager dans un combat exclusivement politique. Cette étude propose, dans un premier temps, d'identifier le statut du D.U.P. et du Sinn Féin sur la scène politique nord-irlandaise avant le processus de paix pour ensuite mettre en exergue les difficultés liées à la mise en place des accords de paix dans la province, compte tenu des divergences idéologiques de ces deux partis. Le rôle, les stratégies et le discours politique de ces deux partis pendant le processus de paix sont analysés afin de mieux comprendre leur perception des accords de paix mais également leur succès auprès des électeurs nord-irlandais. En effet, il est démontré que la stratégie politique du D.U.P. et du Sinn Féin pendant le processus de paix s'est avérée être efficace sur le plan électoral et a donc été synonyme de nouveaux enjeux politiques. En devenant les acteurs principaux des négociations sur l'avenir politique de l'Irlande du Nord, le D.U.P. et le Sinn Féin ont ainsi été contraints de participer, ensemble et de manière constructive, à la vie politique nord-irlandaise. Cette étude entend donc démontrer quels mécanismes diplomatiques et politiques ont contribué à transformer ces deux partis pour finalement les amener à partager le pouvoir politique en Irlande du Nord. / The present work is an attempt to examine the impact of the northern irish peace process on the DUP and Sinn Féin, since these two parties used to be considered as being radical ones. The author consequently analyses the political and strategic transformation of these two parties during the peace process which eventually permitted the formation of a mandatory coalition in May 2007 as well as the restoration of devolution in the Province. The aim of this study is therefore to demonstrate how the DUP shifted from political and religious radicalism to moderation and how the Republican Party dissociated itself from the IRA's armed struggle to embark on exclusively political activities. Three questions underlie our analysis: Considering their radical political beliefs, which role did these two parties play in northern irish politics before the peace process? What was their interpretation of the different peace treaties and what enabled them to appeal to the northern irish electorate? Finally, following their political success, how did they manage to deal with their new political responsibilities, namely sharing power in Northern Ireland? This study thus intends to reveal the diplomatic and strategic mechanisms that contributed to the transformation of these two parties over the last decades and how they succeded in sharing political power.

<p>To ensure genomic integrity, the genome must be accurately duplicated once and only once per cell division. DNA replication is tightly regulated by replication licensing mechanisms which ensure that origins only initiate replication once per cell cycle. Disruption of replication licensing mechanisms may lead to re-replication and genomic instability. </p><p>DNA licensing involves two steps including the assembly of the pre-replicative compelx at origins in G1 and the activation of pre-RC in S-phase. Cdt1, also known as Double-parked (Dup) in <italic> Drosophila Menalogaster </italic>, is a key regulator of the assembly of pre-RC and its activity is strictly limited to G1 by multiple mechanisms including Cul4<super>Ddb1</super> mediated proteolysis and inhibitory binding by geminin. Previous studies have indicated that when the balance between Cdt1 and geminin is disrupted, re-replication occurs but the genome is only partially re-replicated. The exact sequences that are re-replicated and the mechanisms contributing to partial re-replication are unknown. To address these two questions, I assayed the genomic consequences of deregulating the replication licensing mechanisms by either RNAi depletion of geminin or Dup over-expression in cultured Drosophila Kc167 cells. In agreement with previously reported re-replication studies, I found that not all sequences were sensitive to geminin depletion or Dup over-expression. Microarray analysis and quantitative PCR revealed that heterochromatic sequences were preferentially re-replicated when Dup was deregulated either by geminin depletion or Dup over-expression. The preferential re-activation of heterochromatic replication origins was unexpected because these origins are typically the last sequences to be duplicated during normal S-phase. </p><p>In the case of geminin depletion, immunofluorescence studies indicated that the re-replication of heterochromatin was regulated not at the level of pre-RC activation, but rather due to the restricted formation of the pre-RC to the heterochromatin. Unlike the global assembly of the pre-RC that occurs throughout the genome in G1, in the absence of geminin, limited pre-RC assembly was restricted to the heterochromatin. Elevated cyclin A-CDK activity during S-phase could be one mechanism that prevents pre-RC reassembly at euchromatin when geminin is absent. These results suggest that there are chromatin and cell cycle specific controls that regulate the re-assembly of the pre-RC outside of G1.</p><p>In contrast to the specific re-replication of heterochromatin when geminin is absent, re-replication induced by Dup over-expression is not restricted to heterochromatin but rather includes re-activation of origins throughout the genome, although there is a slight preference for heterochromatin when re-replication is initiated. Surprisingly, Dup over-expression in G2 arrested cells result in a complete endoreduplication. In contrast to the ordered replication of euchromatin and heterochromatin during early and late S-phase respectively, endoreduplication induced by Dup over-expression does not exhibit any temporal order of replication initiation from these two types of chromatin, suggesting replication timing program may be uncoupled from local chromatin environment. Taken together, these findings suggest that the maintenance of proper levels of Dup protein is critical for genome integrity.</p> / Dissertation

No description available.

Daily undulating periodization is a growing trend in the exercise science literature. Flexible daily undulating periodization allows for athletes to have some autonomy within a periodized training cycle and is a relatively new and unstudied concept. The comparison of a flexible and traditional daily undulating periodization program using trained males has not been examined in the literature. The purpose of this study was to compare the effects of Flexible and Traditional Daily Undulating Periodization models on powerlifting performance in trained males. 25 resistance-trained males (23±6 years; 79±22 kg) completed a 9-week resistance-training program and were randomly assigned to one of two groups: Flexible Daily Undulating Periodization (FDUP; N=14) or Daily Undulating Periodization (DUP; N=11). All subjects possessed a minimum of 6 months of resistance training experience & were required to squat 125% their bodyweight, bench press their bodyweight, and deadlift 150% their bodyweight. Dependent variables (DV) included bench press 1RM, squat 1RM, deadlift 1RM, Powerlifting total, and Wilk's Coefficient. Each DV was assessed at baseline and after the 9-week training program. The DUP group performed a hypertrophy workout on Monday, a power workout on Wednesday, and a strength workout on Friday. The FDUP group completed the exact same workouts in a given week, but were allowed to choose the order of the workouts. Data for each DV were analyzed via a 2x2 between-within factorial repeated measures ANOVA. The alpha criterion for significance was set at 0.05. There were no significant differences in total volume or intensity between groups. There was a main effect for time (p < 0.001) for 1RM Squat (FDUP pre = 132 ± 34 kg, FDUP Post = 148 ± 33 kg; DUP pre = 147 ± 31 kg, DUP post = 165 ± 25 kg), 1RM Bench Press (FDUP pre = 96 ± 20 kg, FDUP post = 102 ± 19 kg; DUP pre = 147 ± 31 kg, DUP post = 165 ± 25 kg), 1RM Deadlift (FDUP pre = 166 ± 41 kg, FDUP post: 181 ± 37 kg; DUP pre = 174 ± 25 kg, DUP post = 188 ± 29 kg), Powerlifting Total (FDUP pre = 394 ± 90 kg, FDUP post = 431 ± 84; DUP pre = 439 ± 71 kg, DUP post = 480 ± 69 kg), and Wilk's Coefficient (FDUP pre = 147 ± 25 kg, FDUP post = 304 ± 51; DUP pre = 299 ± 41, DUP post = 325 ± 38). There were no interaction effects between the FDUP and DUP for any of the variables assessed. 9 weeks of Flexible DUP leads to comparable gains in powerlifting performance when compared to a Traditional DUP program in trained males. This may be attributed to the fact that both groups performed similar volumes of work throughout the study. Specifically, FDUP improved squat 1RM by 12%, bench press 1RM by 7%, deadlift 1RM by 9%, powerlifting total by 9%, & Wilk's coefficient by 9%. Similarly, DUP improved squat 1RM by 12%, bench press 1RM by 8%, deadlift 1RM by 8%, powerlifting total by 9%, & Wilk's coefficient by 9%.

No description available.

The non-peptidic angiotensin II receptor subtype selective antagonists, DuP 753 and PD123177, were used to characterize angiotensin II receptor binding sites in the rat brain. Competitive receptor autoradiography with 125I-Sar1-Ile8 angiotensin II defined a regional distribution of binding sites that were sensitive to either DuP 753 (designated AIIα subtype) or PD123177 (designated AIIβ subtype). Whereas most brain nuclei could be assigned to a category containing a predominant subtype, a multiple receptor subtype analysis indicated that some regions are homogeneous, while others contain a mixture of both AIIα and AIIβ subtypes.

The non-peptide angiotensin II (AII) receptor subtype selective antagonist, DuP 753, was used to characterize AII receptor binding sites in the rat brain. DuP 753 competed for specific 125I-[Sar1, Ile8]AII (125I-SIAII) binding in many brain nuclei (IC50 = 20-30 nM), but was a weak competitor at remaining sites (IC50 > 10-4 M). DuP 753 sensitive binding sites (designated AIIα subtype) correspond with areas where binding is inhibited by sulfhydryl reducing agents, whereas DuP 753 insensitive sites (AIIβ) correspond with areas where binding is not inhibited by sulfhydryl reducing agents.

The retinoic acid induced 1 (RAI1) gene maps within the Smith-Magenis syndrome (SMS) region on chromosome 17p11.2. Interstitial deletion of 17p11.2 including RAI1 or mutation of RAI1 results in SMS, while duplication of 17p11.2, including RAI1, results in the dup(17)(p11.2) syndrome. Smith-Magenis syndrome is a complex disorder characterized by a constellation of ~30 features that includes mental retardation, sleep disturbance, craniofacial defects, neurological and behavioral anomalies, and variable systemic features. Dup(17)(p11.2) syndrome is characterized by mental retardation, craniofacial defects, developmental delay, failure to thrive, and hyperactivity. We hypothesized that RAI1 is a dosage-sensitive gene with specific roles in SMS and dup(17)(p11.2) syndrome. To understand the clinical consequences of haploinsufficiency of RAI1 in humans, 60 SMS patients were evaluated by fluorescent in situ hybridization and/or sequencing of RAI1 to identify 17p11.2 deletions or intragenic mutations. Phenotypic comparison between patients with deletions and those with RAI1 mutations show that 21 of 30 SMS features are the result of haploinsufficiency of RAI1. Other features such as cardiac and renal anomalies, speech and motor delay, chronic respiratory and ear infections, hypotonia, short stature, and ear and eye anomalies are associated with 17p11.2 deletions rather than RAI1 mutations (P <0.05). Mouse models were evaluated using both qualitative and quantitative methodologies for phenotypic consequences due to altered Rai1 dosage. To this extent, BAC transgenic mice overexpressing Rai1 1.5-fold (hemizygous) or 2-fold (homozygous) and Rai1-targeted heterozygous (Rai1+/-) mice with 0.5-fold dosage were utilized. Compared to wild type littermates, Rai1 overexpressing mice have growth retardation, increased locomotor activity, gait abnormalities, and abnormal anxiety-related behavior, while Rai1+/- mice are obese and hypoactive. Analyses of homozygous BAC transgenic mice revealed a dosage-dependent exacerbation of the phenotype. Both the Rai1-overexpressors and Rai1-haploinsufficient mice showed neurological deficits. To identify target genes altered due to haploinsufficiency of RAI1, RNA-interference-based knockdown (~50%) of RAI1 was achieved in HEK293T cell lines. Genome-wide gene expression profiling showed that ~60 genes were upregulated and ~200 genes were downregulated due to RAI1 haploinsufficiency. Real-time qPCR not only confirmed the gene expression profile in HEK293 cells but also in lymphoblastoid cell lines obtained from SMS patients with 17p11.2 deletion. Further, our analysis has identified several RAI1 downstream genes, implicated in circadian activity, growth regulation, lipid biosynthesis, and neuronal regulation, which are potential candidate genes for non-deletion/non-RAI1-mutation cases of SMS and SMS-like phenotypes. These results show that Rai1 dosage has major consequences on molecular processes involved in growth, development, circadian rhythm, and neurological and behavioral functions, thus providing evidence for several dosage-thresholds for phenotypic manifestations causing dup(17p11.2) syndrome or Smith-Magenis syndrome in humans.

Smith-Magenis syndrome (SMS) is a complex disorder caused by haploinsufficiency of RAI1 and characterized by sleep disturbances, behavioral abnormalities, mental retardation, and obesity in teens and adults. Rai1+/- mice are obese after 20 weeks. Dup(17)(p11.2) syndrome is a complex disorder associated with overexpression of RAI1. A transgenic mouse model of dup(17)(p11.2) syndrome overexpresses Rai1 and results in a mouse that is growth delayed. In order to characterize the obese phenotypes of mouse models of SMS and the role of RAI1 in obesity, daily food intake and serum levels of insulin, glucose, PPY, and leptin were measured; adiposity was studied by characterizing fat deposition; and gene expression was studied in the hypothalamus. These studies show that Rai1+/- mice are hyperphagic, consume more during the inactive light phase, and have altered satiety genes in the hypothalamus. Adiposity studies have shown WT females have a higher body fat content and visceral fat proportion than males, but Rai1-Tg and Rai1+/- females have similar fat deposition patterns as WT males. Hypothalamic gene expression studies show that many genes and pathways are affected by Rai1 and Rai1 dosage, including many genes associated with obesity and satiety.

The subcellular mechanism and site of action of linopirdine or DuP 996 (3,3‐bis(4‐pyridinylmethyl)‐1‐phenylindolin‐2‐one) was investigated at the frog neuromuscular junction, using miniature endplate potential (m.e.p.p.) counts and a new method for obtaining unbiased estimates of n (number of functional release sites), p (probability of release), and varsp (spatial variance in p). DuP 996 produced an increase in m (no. of quanta released), which was due to an increase in n and p. The increase in m was concentration‐dependent over a range of 0.1–100 μm and completely reversible with 15 min of wash. There was a saturation in the increase in p, but not in the increase in m and n, for [DuP 996] >10 μm. By contrast, there was no major change in varsp. Block of presynaptic Na+‐ and Ca2+‐channels with 3 μm tetrodotoxin and 1.8 mm Co2+prevented the m.e.p.p. frequency increase to DuP 996, and this effect was completely reversed by washing. Application of the neuronal Ca2+‐channel blocker, ω‐conotoxin GVIA (1 μm) brought about a rapid and profound decrease in the m.e.p.p. frequency increase produced by DuP 996. The effect of the toxin was not reversed by prolonged washing. Block of voltage‐gated K+‐channels with 100 μm 4‐aminopyridine (4‐AP) resulted in only a small (28%) increase in m. The combination of 4‐AP (100 μm) and DuP 996 (10 μm) produced an increase in m (189%) which was much greater than the sum of the responses to each agent alone. This increase in m was due solely to an increase in n, as p and varsp were unchanged. For [DuP 996] up to 100 μm, there was no apparent change in the mean size, amplitude distribution, or time course of m.e.p.ps, signifying that it had no anticholinesterase activity. It is concluded that DuP 996 increases the release of quantal transmitter but not the postsynaptic response to the quanta. This appears to involve an effect at the nerve terminal membrane, most likely an increase in Ca2+‐conductance, and not an action to block K+‐conductance or to release Ca2+from intraterminal organelles. 1994 British Pharmacological Society