No description available.

Noonan syndrome (NS) is one of several autosomal dominant “RASopathies” caused by mutations in components of the RAS-RAF-MEK-ERK MAPK pathway. Germ line mutations in RAF1 (encoding the serine-threonine kinase for MEK1/2) account for ~3-5% of NS, and unlike other NS alleles, RAF1 mutations that confer increased kinase activity are highly associated with hypertrophic cardiomyopathy (HCM). Notably, some NS-associated RAF1 mutations show normal or decreased kinase activity. To explore the pathogenesis of such mutations, I generated “knock-in” mice that express kinase-activating (L613V) or -impaired (D486N) Raf1 mutants, respectively. Knock-in mice expressing the kinase-activated allele Raf1L613V developed typical NS features (short stature, facial dysmorphia, haematological abnormalities), as well as HCM. As expected, agonist-evoked Mek/Erk activation was enhanced in multiple cell types expressing Raf1L613V. Moreover, postnatal Mek inhibition normalized the growth, facial, and cardiac defects in L613V/+ mice, showing that enhanced Mek/Erk activation by Raf1 mutant is critical for evoking NS phenotypes. D486N/+ female mice exhibited a mild growth defect. Male and female D486N/D486N mice developed concentric cardiac hypertrophy and incompletely penetrant, but severe, growth defects. Remarkably, Mek/Erk activation was enhanced in Raf1D486N-expressing cells compared with controls. In both mouse and human cells, RAF1D486N, as well as other kinase-impaired RAF1 mutants, show increased heterodimerization with BRAF, which is necessary and sufficient to promote increased MEK/ERK activation. Furthermore, kinase-activating RAF1 mutants also require heterodimerization to enhance MEK/ERK activation. Our results suggest that increased heterodimerization ability is the common pathogenic mechanism for NS-associated RAF1 mutations.

<p>The Ras family of small GTPases, comprised of the KRAS, NRAS, and HRAS genes, are mutated to encode constitutively-active, GTP-bound, oncogenic proteins in upwards of one quarter or more of all human cancers, which is well established to promote tumorigenesis. Despite the prominent role these genes play in human cancer, the encoded proteins have proven difficult to pharmacologically inhibit. Therefore, it is important to understand how Ras proteins are activated. </p><p>RAS proteins cycle between a GDP-bound inactive state and a GTP-bound active state through guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs). GEFs facilitate the GDP-to-GTP exchange of RAS and promote RAS activation. Similar to GEFs, reactive oxygen/nitrogen species can also promote RAS activation through reactions with the thiol residue of cysteine 118 (C118). This residue may therefore play a role in RAS activation in cancer. To test this possibility, I investigated the effect of mutating C118 to serine (C118S) in Kras on (1) carcinogen-induced lung tumorigenesis, and (2) xenograft tumor growth of HRAS12V-transformed cells.</p><p>To explore the impact of the C118S mutation in Kras on carcinogen-induced lung tumorigenesis, I introduced a C118S mutation into the endogenous murine Kras allele and exposed the resultant mice to the carcinogen urethane, which induces Kras mutation-positive lung tumors. Kras+/C118S and KrasC118S/C118S mice developed fewer and smaller lung tumors than Kras+/+ mice. Although the KrasC118S allele did not appear to affect tumorigenesis when the remaining Kras allele was conditionally oncogenic (KrasG12D), there was a moderate imbalance of oncogenic mutations favoring the native Kras allele in tumors from Kras+/C118S mice treated with urethane. Therefore, mutating C118 of Kras impedes urethane-induced lung tumorigenesis.</p><p>To explore the the impact of the C118S mutation in Kras on xenograft tumor growth of HRAS12V-transformed cells, I tested and found that redox-dependent reactions with cysteine 118 (C118) and activation of wild type KRAS are critical for oncogenic HRAS-driven tumorigenesis. Such redox-dependent activation of KRAS affected both PI3K-AKT and RAF-MEK-ERK pathways. These findings were confirmed in the endogenous mouse Kras gene. Speicfically, oncogenic HRAS-transformed KrasC118S/C118S MEFs grew in soft agar and as xenograft tumors more slowly than similarly transformed Kras+/+ MEFs, suggesting that redox-dependent reactions with C118 of Kras promotes transformation and tumorigenesis. </p><p>Taken together, I have demonstrated a critical role of redox-dependent reactions with Kras C118 in tumorigenesis.</p> / Dissertation

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

No description available.

Denna studie berör hur Fattigvårdsstyrelsens föreställningar om resande tog sig i uttryck i Tattarutredningen. Materialet består av Tattarutredningen och 36 monografier, ett opublicerat underlag till utredningen, som alla är inhämtade från Arkivhuset i Jönköping. Studiens syfte är att undersöka föreställningarna om resande och vilka egenskaper, utseenden och beteenden som tillskrevs dessa människor med utgångspunkt i den så kallade Tattarutredningen. Metoden som använts för att besvara detta är en CDA, kritisk diskursanalys. Studiens teoretiska ramverk är inspirerat av diskursanalysen, forskningen om ”bilden av den andre” och begrepp som etnicitet och ras.   Materialet har analyserats med hjälp av Norman Faircloughs CDA, där studiens teoretiska ramverk har styrt analysen. Dessa analysverktyg har möjliggjort en kvalitativ kritisk studie av språket i materialet. I studien identifierades olika mönster i materialet som har delats in i fem olika teman. ”Tattare” är inte som svenskarna, ”Tattare” är mindre begåvade, ”Tattare” är våldsamma, ”Tattare” är lata och ”Tattare” är orena. Dessa teman går att koppla till de föreställningar som Fattigvårdsstyrelsen hade om resande utifrån studiens metod, teori och den tidigare forskningen. Studiens resultat visar att resande tillskrevs olika egenskaper, utseenden och beteenden som byggde på föreställningar och fördomar. Resultatet visar också att det fanns en önskan om att särskilja resande och svenskar från varandra. / This study views how Fattigvårdsstyrelsen conceptions about Travelers where expressed in Tattarutredningen. The material in this study is based on Tattarutredningen and 36 monographs, all of which have been obtained from Arkivhuset in Jönköping. The purpose of this study is to investigate the conceptions about Travelers and the characteristics, appearances and behaviors that was attributed to these people on the basis of the so-called Tattarutredningen. The method used to answer this is CDA, critical discourse analysis. The theoretical framework is based on the CDA, the image of the other and concepts such as ethnicity and race.   The material has been analyzed with the help of Norman Fairclough’s CDA, where the study’s framework has guided the analysis. These analytics tools have made it possible to do a qualitative critical study of the language of the material. In the study, various patterns have been identified in the material that have been divided into five different themes. “Tattare” are not as Swedes, “Tattare” are less talented, “Tattare” are violent, “Tattare” are lazy and “Tattare” are dirty. The most essential theme is that Travelers are not as Swedes, where Fattigvårdsstyrelsens conceptions about Travelers is exemplified trough out the study. The study’s results shows that the attributes characteristics, appearances and behaviors were based on beliefs and perceptions. The result also shows that there was an underlying desire to distinguish Travelers and Swedes from each other.

Currently the Iowa Flood Center (IFC) of the University of Iowa is working in conjunction with the Iowa Department of Natural Resources (IDNR) to create statewide floodplain maps. The IFC has set up a four year plan to construct flood inundation maps for 85 of the 99 counties within the state of Iowa, with the final goal of creating maps acceptable by FEMA. High resolution statewide LiDAR information provides a base dataset from which floodplain maps are produced. Stream centerline data is extracted from a DEM produced by the LiDAR dataset. The centerline information is used in both this project and as a replacement for the USGS NHD streamline for the state. Stream flow estimation for a range of annual exceedance discharges are produced through a USGS recommended combination of regional regression analysis weighted by gage influence. Water surface elevations are produced for each of the annual exceedance discharges through the use of a HEC-RAS one dimensional steady flow model. Flood boundaries are the final product created by HEC-GeoRAS though a comparison of a TIN produced from the water surface elevations and the ground surface DEM. Final FEMA acceptable DFIRM's are produce by the IDNR and submitted to FEMA for adoption into the NFIP.

The Iowa Flood Center (IFC), a unit of The University of Iowa's IIHR - Hydroscience & Engineering, and the Iowa Department of Natural Resources are developing a statewide floodplain boundary dataset to provide information that is critical to proper flood mitigation planning. During flooding, soil loss from agricultural land, in addition to inundation, can have a substantial economic impact on an agricultural state like Iowa. The ability to identify areas with a high potential to experience scour during flooding could assist farmers and land owners in making better land management decisions. Currently, the IFC statewide floodplain mapping program is creating annual exceedance probability floodplain data for all Iowa streams. The effort described herein has developed methods to take advantage of this large dataset, applying uniform open channel flow theory to spatially characterize scour potential using custom tools created with GIS model builder. The results of this thesis are being used by the Iowa Natural Heritage Foundation (INHF) and the IFC to develop a program through which certified crop consultants can help farmers make more informed land management decisions based on risk of flood related soil loss.

Thesis (M. Phil.)--University of Hong Kong, 2006. / Title proper from title frame. Also available in printed format.