Thèse doctorat : Biochimie : INSA LYON : 2001. / Titre provenant de l'écran-titre. Bibliogr. p. 161-198.

Thesis (Ph. D.)--University of Missouri--Columbia, 2001. / "May 2001." Typescript. Vita. Includes bibliographical references (leaves 180-198). Also available on the Internet.

Thesis (Ph. D.)--University of Washington, 2001. / Vita. Includes bibliographical references (leaves 152-175).

Syftet är att få en fördjupad förståelse av hur man på organisationsnivå kan stimulera utveck­lingen av lärarnas undervisningsformer så de gynnar elever i läs- och skrivsvårigheter och vilka möjligheter och/eller hinder som kan uppstå. I studien utgår vi från är en kvalitativ ansats där vi använder halvstrukturerade intervjuer som datainsamlingsteknik. Åtta rektorer/biträdan­de rektorer och fem speciallärare/specialpedagoger intervjuas om sin syn på vilka faktorer som påverkar möjligheterna att stimulera lärare till användning av alternativa verktyg i sin under­visning. Resultatet i vår studie visar att rektorers förutsättningar för att stimulera lärare i användningen av datorn som kompensatoriskt stöd för elever i läs- och skrivsvårigheter är begränsade. Delvis beror svårigheterna på att inga tydliga IT-planer funnits, varken på förvaltningsnivå eller lokal skolnivå. Osäker nätuppkoppling och bristande teknisk funktion har också orsakat problem på skolorna. Den viktigaste faktorn, enligt speciallärare/special­pedagoger, för att stimulera lärarna i användningen av kompensatoriskt stöd, var möjligheter till utbildning i de stödprogram som används. Rektorer och speciallärare/specialpedagoger anser att den största utmaningen är att hitta tiden för att samordna utbildningsinsatsen. Vi kom fram till att implementeringen av 1:1-datorer i den studie vi gjort inte var genomtänkt, eftersom planer för användning och utveckling av IT saknades. Det i sin tur ledde till att skolledningen och speciallärare/specialpedagoger inte fick tillräckliga förutsättningarna att skapa en gynnsam lärmiljö för elever i allmänhet och för elever i läs- och skrivsvårigheter i synnerhet.

Approximately two-thirds of US adults are overweight or obese, and obesity is also becoming more prevalent in children and adolescents. Similar to adults, obese children are at a higher risk of developing health problems due in part to dysfunctional immune surveillance. Obesity has been shown reduce the generation of new T-cells by accelerating thymic aging in an adult mouse. This study therefore aimed at determining whether similar diet induced obesity (DIO) changes can be induced in a young mouse. Comparisons made between lean and DIO C57Bl/6 mice showed a significant increase in thymic weight, decrease in thymic cellularity and thymic output, and impaired T-cell development at the double negative stage. We associate these alterations with changes in thymic architecture and accumulation of lipid droplets within the thymic cortex and medulla of the obese mice. The above observations indicate that DIO can induce fat accumulation and reduce thymic function at a young age. Resveratrol, a natural polyphenolic compound, was then used to regulate fat metabolism in an attempt to reduce these DIO changes we observed. Resveratrol induces fat oxidation via 5' adenosine monophosphate-activated protein kinase (AMPK), and its reciprocal regulation of glycerol-3-phosphate acyltransferase-1 (GPAT-1) and carnitine palmitoyltransferase-1 (CPT-1), the rate-limiting enzymes required for glycerophospholipid biosynthesis and oxidation, respectively. Through resveratrol feeding, we were able to prevent the effects of DIO on thymic architecture and thymic T-cell proliferation. This was achieved by manipulating AMPK into inhibiting GPAT-1 and enhancing CPT-1 activity. Since the expression of GPAT-1 was upregulated in the obese mice, we investigated whether deleting GPAT-1 altogether might prevent the thymic involution, by inhibiting synthesis of glycerophospholipids and triacylglycerol. Instead, we found that GPAT-1 deletion slowed thymic growth and reduced cellularity in young mice, which we associated with impaired thymic T-cell function and development, suggesting that the deleterious effects of GPAT-1 deficiency may be due to perturbations in thymic T-cell activation and signaling. These data provide a novel link between lipid metabolism and T-cell development, and identify the use of the naturally-occurring resveratrol to reduce lipid accumulation within the involution-prone thymus, thus providing a useful approach to preventing a decline in thymic function in childhood. / text

Den föreliggande studien är en kvalitativ fallstudie med syftet att undersöka lärares kompetensutveckling i samband med 1-till-1-satsningar (en dator per elev).  Studiens frågeställning kretsar kring följande två frågor; Hur har lärarna uppfattat kompetensutvecklingen de erhållit i samband med kommunens 1-till-1-satsning? Hur har lärarnas kompetensutveckling i användandet av nya läroverktyg (MacBook Air) påverkat lärarnas didaktiska tillvägagångssätt? Höstterminen 2012 påbörjades en sådan 1-till-1-satsning i en av norra skånes kommuner. Baserat utifrån ett fenomenologiskt perspektiv kunde studien ge information kring lärarnas upplevda erfarenheter och belysa problematiken kring 1-till-1.

- / Background: Endothelin-1 (ET-1), a strong vasoconstrictive substance acting via stimulation of specific receptors (ET-A and ET-B), has been implicated in the development of renal scarring. Activation of endothelin system was observed in experimental models of glomerular diseases and this was attributed to the toxic action of proteinuria to the tubular epithelial cells. However, we have not enough information about the role of endothelin system in human glomerular diseases and in renal diseases without proteinuria like obstructive nephropathy. The aim of this study was to examine the endothelin system in patients with primary glomerular diseases and in experimental animals with unilateral ureteric obstruction. Patients and Methods: Thirty-seven patients with different types of primary glomerulonephritides and 14 controls were included in the study. Patients presented by either nephrotic syndrome (n=25) or mild proteinuria (<1g/24h, n=12). The expression of ET-A and ET-B receptors in the renal tissue was examined immunohistochemically. At the time of biopsy, urinary ET-1 was determined by RIA. Experimental animals and Methods: Twenty –day old opossum pups (n=6) underwent surgical ligation of the left ureter. Sham operated animals, non-operated controls and normal human kidneys were also used. Animals were sacrificed at 2 (n=2), 3 (n=1), 4 (n=1), 5(n=1) and 8 (n=1) weeks post surgery and their kidneys were examined. Sham operation was performed at equivalent times in pups that served as control. The expression of ET-A and ET-B receptors in the renal tissue was examined immunohistochemically. Results: The expression of both receptors was mainly localized within tubular epithelial cells and was significantly higher in patients with glomerulonephritides compared to controls. The expression of ET-B receptors was higher in nephrotic compared to non-nephrotic patients while no difference was observed in the expression of ET-A receptors. Urinary excretion of ET-1 was increased in patients compared to healthy subjects (579±146 ng/24h vs. 410±78 ng/24h, p<0.01) and it was higher in nephrotic compared to non-nephrotic patients (617±167 ng/24h vs. 485±71 ng/24h, p<0.05). A significant positive correlation of the excreted ET-1 with the degree of proteinuria (r= 0.338, p<0.05) and the extent of immunostaining for ET-B receptors (r=0.427, p<0.05) was observed. The expression of ET-B receptors and the excretion of ET-1 were significantly decreased in patients who present remission of the nephrotic syndrome under immunosuppressive therapy. In tubular epithelial cells of the experimental animals there was a temporal increase in the expression of ET-A receptors with duration of obstruction while there was no significant difference between the expression of ET-B receptors in obstructed kidneys and controls. Conclusions: this study provides evidence that the endothelin system is activated in renal diseases and proteinuria seems to be related only in part to this activation. Further investigation is needed to ascertain if the activation of endothelin system has a causative role in the progression of renal diseases.

The purpose of this explanatory single-case case study was to investigate teachers' perceptions of a principal's leadership behavior associated with the integration of a one-to-one laptop program in a parochial secondary school. The sample included the school principal and teachers who have had at least one year of teaching experience at the parochial school with laptop computers. Owing to a mixed methods case study approach, data was collected from four sources: a semi-structured personal interview with the school principal, semi-structured personal interviews with teachers, a focus group interview with teachers, and teachers' completion with an electronic version of the Principal Leadership Questionnaire. These multiple forms of data were collected to support data-rich triangulation on the same set of research questions. SPSS was used to assist with data analysis of the electronic survey. Cronbach's alpha was used to determine the reliability of the instrument. Themes were extracted from the semi-structured personal interviews and focus group. The findings from this study provided teachers' perceptions of a principal's leadership behaviors associated with the integration of a one-to-one laptop program for students in a parochial secondary school.

Myeloid Cell Leukemia-1 (Mcl-1) is a widely expressed anti-apoptotic member of the Bcl-2 family that is elevated in a variety of tumour types including breast cancer. Mcl-1 promotes tumour cell survival and drug resistance and was a mechanism of resistance to first generation Bcl-2 family inhibitors. To determine the significance of Mcl-1 in breast cancer, we evaluated the regulation of Mcl-1 by signalling via the epidermal growth factor receptors (EGFRs). EGFR signalling is frequently deregulated in breast cancer and leads to increased proliferation and survival of tumour cells. We aimed to determine whether Mcl-1 is a critical downstream effector of this pathway and therefore an important therapeutic target. We found that Mcl-1 protein and messenger RNA levels were rapidly induced upon stimulation of breast cancer cells with epidermal growth factor. This induction was blocked by inhibitors of the Ras/Raf/Mek/Erk signalling cascade and was dependent upon activation of the transcription factor Elk-1. We found Mcl-1 to be an essential survival protein, as targeted knock-down with small interfering RNA alone was sufficient to induce apoptosis. Mcl-1 may be critical for the survival advantage conferred by EGFR activation, as prevention of its up-regulation by Mek/Erk inhibitors significantly reduced the drug resistance conferred by EGF. Furthermore, we found a correlation between phosphorylated Elk-1 and Mcl-1 protein levels in breast tumour samples. Therefore, we conclude that Mcl-1 is an important downstream effector of survival and drug resistance mediated by elevated EGF signalling, making it an important therapeutic target in breast cancer.

The highly unstructured interferon regulated transcription factor IRF-1 is a tumour suppressor protein that plays vital roles in the antiviral and DNA damage response pathways. To identify interacting factors that regulate IRF-1 function and expand on the available limited information on its interactome, an in vitro screen was developed using peptide-aptamer affinity chromatography coupled with mass spectrometry. Discrete identified which bind to a number of potential transcriptional regulators including NPM1, YB-1 and TRIM28. The screen also proved useful in identifying binding proteins to the C-terminal Mf1 domain, which is vital for IRF-1-mediated growth suppression and Cdk2 repression, and additionally regulates IRF-1 stability. Thus, an LXXLL motif in the MF1 domain was found to be required for the binding of Hsp70 family members and cooperation with Hsp90 to regulated IRF-1 turnover and activity. These conclusions were supproted by the finding the Hsp90 inhibitors suppressed IRF-1-dependent transcription shortly after treatment, whilst at later time points inhibition of Hsp90 led to an Hsp70-dependent depletion of nuclear IRF-1. Conversely, the half-life of IRF-1 was increase by Hsp90 in an ATPase-dependent manner leading to the accumulation of nuclear, but not cytoplasmic, IRF-1. Additionally, a stress specific interaction between IRF-1 and the Hsp70-associated ubiquitin E3 ligase CHIP, that targets Hsp70/Hsp90 clients for proteasomal degradation, was demonstrated. Consequently, decreases in IRF-1 protein levels in cells exposed to heat stress or heavy metal ions were accompanied by the formation of IRF-1:CHIP complexes. Based on observations that CHIP ubiquitination of IRF-1 occurred both in the presence and absence of Hsp70, a model was proposed wherein Hsp70 serves as a factor that recruits CHIP to its substrates and its dissociation from the complex allosterically activates CHIP-dependent substrate ubiquitination. In support of this model, in vitro and biophysical evidence is presented, showing that CHIP in complex with Hsp70 is less flexible and less effective as an E3 ligase that CHIP alone. Thus, in agreement with recent studies, the work done in this thesis highlights the importance of conformational flexibility and of direct binding or 'docking' of CHIP to its substrate(s) in its mechanism of action.