Genetic changes acquired in the pigment producing cells of the skin, called melanocytes, can lead to formation of the deadly cancer melanoma. Mutations or amplifications leading to the activation of the RAS/MAPK pathway occur in more than 90% of melanomas. Melanocyte development and survival requires the stimulation of this pathway by the receptor tyrosine kinase (RTK) KIT. In ~2% of melanomas, oncogenic KIT mutations drive tumor formation; however, the majority of melanomas lose wild-type KIT expression, suggesting that KIT could suppress melanoma formation. In human melanoma patients of The Cancer Genome Atlas (TCGA), we found an association between BRAFV600E mutations and low KIT mRNA expression, so we tested whether KIT loss would affect BRAFV600E-driven tumor onset by crossing a kit(lf) mutant allele into melanoma-prone Tg(mitfa:BRAFV600E); p53(lf) zebrafish. We observed that kit(lf)-mutant zebrafish experienced accelerated tumor onset and their tumors had increased RAS/MAPK pathway activation. In BRAFV600E-mutant melanoma cells, KIT activity reduced RAS/MAPK signaling by promoting activation of wild-type BRAF (BRAFWT). Furthermore, we found that overexpression of BRAFWT delayed tumor onset in Tg(mitfa:BRAFV600E); p53(lf); mitfa(lf) zebrafish, but had no effect in kit(lf); Tg(mitfa:BRAFV600E); p53(lf); mtifa(lf) zebrafish and a cohort of TCGA BRAFV600E-mutant melanoma patients with high KIT expression and high BRAFWT allele ratios experienced a reduced likelihood of metastasis and extended overall survival. These studies indicate that wild-type KIT acts to suppress melanoma formation through activation of BRAFWT, causing reduced signaling output of BRAFV600E-mutant cells.

Water is essential to life. Three general forms of water exist: pre-formed water that is available in food, metabolic water that is created as a byproduct of life processes (e.g., metabolism of fat or breakdown of carbohydrates), and free water (i.e., water available for drinking). As humans settle arid environments, the addition of man-made free water sources (e.g., sewage ponds, catchment ponds) often occurs. In addition, a tool commonly used to increase the abundance or distribution of wildlife species in desert environments is the addition of water sources, usually specifically designed to benefit game species like bighorn sheep (Ovis canadensis), mule deer (Odocoileus hemionus), and chukar partridge (Alectoris chukar). In recent decades, some scientists have argued that adding water sources to deserts may have little to no effect on desert species because they are adapted to living in desert conditions, and have thus evolved to obtain their water needs in preformed and/or metabolic form. Scientists have also suggested that adding water sources to desert environments may actually harm some individual species and alter the arraignments of groups of similarly related species, known as communities. I conducted four studies at the U.S. Army Dugway Proving Ground to determine if man-made water sources have an influence on the rodent community, jackrabbits, and the canid community at the U.S. Army Dugway Proving Ground, Utah. I found that turning off water sources had no effect on abundance of rodent communities or jackrabbits. I found that a portion of coyotes used water sources and coyotes were only slightly less common near water sources once they were turned off. In addition, a portion of coyotes rarely or never drink from water sources and that coyotes did not leave their territories if water sources accessible to them were turned off. My final study revealed that turning off water sources did not influence kit fox survival or abundance, and that kit fox territories differed from areas associated with water sources in several key environmental characterizes, which may suggest that areas associated with water sources were not historically used by kit foxes. In summary, these findings suggest that water developments have little impact on the species that I studied.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19368号 / 医博第4045号 / 新制||医||1011(附属図書館) / 32382 / 新制||医||1011 / 京都大学大学院医学研究科医学専攻 / (主査)教授 髙折 晃史, 教授 吉村 長久, 教授 山田 泰広 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Can a house be a product? This thesis sets out to form a set of basic elements for a minimum house in light of this question that is both functional and aesthetic. The goal is to develop an efficient prefabricated system of construction analogous to a chart of chemical elements. The modular system is then applied to the most basic footprint for a house - a 400 square foot Accessory Dwelling Unit (ADU). Through studying the fundamental parts of a house, a level of understanding emerges, which allows for a projection of the idea as a whole. The ideal of prefabrication posits the possibility of architecture as a system. This idea has attracted architects for decades, despite what appears to be an inherent tension between architecture as a system and the poetic iconicity of the house as a type. A study of the systemic introduced by considerations of prefabrication can offer a deeper understanding of the complex nature of architecture. Finally, can the essence of architecture endure amidst the necessary limitations of factory production and manufacturing in our post-industrial age? / Master of Architecture / This thesis consists of a system-generated 400 square foot prefabricated house, a catalog of the house's elements, an expanded catalog of small houses, and a series of studies conducted while traveling through Europe and upon return. The system utilizes a series of functional pods and frames the 'served' with panelized elemental compounds such as walls, floors, and roofs to meet the programmatic requirements of a house. By applying this limited catalog, the feasibility of production can be explored through an expanded catalog. Ultimately, the whole must be greater than the sum of its parts; through tectonic articulation, functional clarity and an additive approach, this can be achieved while meeting the strict constraints that prefabrication demands.

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No description available.

The mammalian hippocampus is responsible for many crucial brain functions such as learning, memory, and neurogenesis in adults. Its degeneration is a pathology associated with the early stages of Alzheimer’s disease. A variety of genes have been associated with both neuroprotection and neurogenesis in the brain, some of which include progesterone membrane component 1 (Pgrmc1) and kit ligand (KitL). Pgrmc1 is recognized for mediating hormonal functions in both the ovary and neuroendocrine regions such as the anteroventral periventricular nucleus (AVPV), but its functions in the hippocampus are not well known. Both Pgrmc1 and KitL share downstream targets, the most strongly supported being genes in the Janus kinase (Jak)/signal transducer and activator of transcription (Stat) pathway. I hypothesized that Pgrmc1 regulates neural targets through KitL/c-Kit signaling. To investigate this hypothesis I used a variety of in vivo and in vitro techniques. These techniques included mapping both KitL and receptor c-Kit in the adult female rat brain using in situ hybridization. I used Pgrmc1 silencing with siRNA in hippocampal-derived mHe-18 cells and Pgrmc1/2 double conditional knock out mouse brains to study Pgrmc1 regulation of KitL synthesis. To determine common downstream targets of KitL and Pgrmc1 I then treated mHe-18 cells with soluble KitL protein. Finally, to determine whether c-Kit mediated effects of Pgrmc1, I treated cells with both Pgrmc1 siRNA and AG-1296, a c-Kit inhibitor. The results show that Pgrmc1 regulates KitL expression, as well as downstream targets Pias1, 2, 3, and 4. However, AG-1296 did not abrogate Pgrmc1 regulation of the downstream targets, demonstrating regulation independent of KitL signaling. Taken together, these results suggest that while Pgrmc1 alters KitL expression and regulates the same genes as KitL/c-Kit, the mechanism of action likely differs. Considering that these two genes are involved in neurogenesis and neuroprotection, as well as memory and learning, a better understanding of the pathways may help lead the way in treating neurodegenerative diseases in the future.

Data Plane Development Kit is a highly used library for creating network applications that can be run on all hardware. Data Plane Development Kit has a component called Service Cores, which allows the main applications to create services that will run independently. These services are manually mapped to specific CPU cores, and are scheduled in a round-robin method. Because of the manual mapping, and the scheduling, the different load for each service can impact the start time for each service. By having services not run when supposed to, the throughput will degrade. In this thesis, we investigate and try to solve the issue by implementing a basic load balancer into the Service Core component. Our results show that an basic load balancer, that will balance upon reaching a CPU upper threshold, will increase the throughput of services while decreasing the delay between each service run.

Les mastocytes (MCs) sont issus des cellules hématopoïétiques multipotentes non engagées, CD34+, et jouent un rôle important dans l’initiation de la réponse immunitaire innée et adaptative, ainsi que dans les réactions allergiques IgE-dépendantes. Les mastocytoses sont des néoplasies myéloïdes caractérisées par une accumulation anormale et l'activation fréquente de mastocytes dans divers organes. Les organes généralement atteints sont la moelle osseuse, la peau, le foie et le tractus gastro-intestinal. Elles sont caractérisées dans l’immense majorité des cas par la présence de mutations acquises de la structure du récepteur KIT (plus particulièrement KIT D816V) qui induisent l’activation constitutive de ce récepteur à activité tyrosine kinase intrinsèque. Le traitement actuel de ces pathologies est décevant car la mutation KIT D816V résiste à la plupart des inhibiteurs de tyrosine kinases (ITKs).Dès le début de ma thèse, nous avons pu établir, à partir de cellules souches hématopoïétiques de sang de cordon humain normal cultivées à long terme en présence de stem cell factor (SCF), une nouvelle lignée mastocytaire humaine stable, dénommée ROSA KIT WT, restant strictement dépendante pour sa survie et sa prolifération du SCF, exprimant le récepteur de haute affinité aux IgE (FcεRI), et présentant un récepteur KIT de structure normale. Cette lignée, facile à cultiver en grandes quantités, permet d’envisager l’étude approfondie des évènements intracellulaires menant à l’activation mastocytaire IgE-dépendante et la mise au point de tests de criblage à haut débit dans le domaine de la thérapeutique anti-allergique et/ou anti-inflammatoire.Par ailleurs, afin de pouvoir étudier le rôle transformant des mutants de KIT retrouvés au cours des mastocytoses, nous avons transfecté les cellules ROSA KIT WT par des vecteurs lentiviraux apportant une construction codant pour le KIT muté en D816V ou le KIT muté Delta 417-419 insY. Nous avons ainsi obtenu deux nouvelles lignées mastocytaires humaines SCF-indépendantes, ROSA KIT D816V et ROSA KIT Delta 417-419 insY, pour lesquelles nous avons montré qu’il existe une activation constitutive de KIT, mais aussi de STAT5 et d’AKT. Ces deux lignées de pourront être utilisées soit pour étudier l’impact des mutations de KIT sur la signalisation intracellulaire, soit pour le criblage molécules à activité antiproliférative potentielle dirigées soit contre KIT muté, soit contre l'une ou l’autre des molécules intracellulaires impliquées dans la transduction du signal KIT muté / Mast cells are cells with ubiquitous tissue distribution, derived from CD34 + multipotent hematopoietic cells. These cells play a fundamental role in the initiation of innate and adaptive immune response and in IgE-dependent allergic reactions or in various inflammatory reactions.Mastocytosis is defined as a myeloproliferative neoplastic disorder, caused by an abnormal accumulation of mast cells in one or more organ systems. Mastocytosis presents in cutaneous and systemic forms. In patients with systemic mastocytosis, the most frequent point mutation is KIT D816V, whereas in pediatric patients, where the disease is usually restricted to the skin, different KIT defects have been detected, mostly in the extracellular portion of KIT.In a primary culture of mast cells made from precursors of one cord blood, we have successfully isolated a new human mast cell line called ROSA KIT WT with a phenotype and reactivity comparable to those of normal mast cells. This cell line is dependent on SCF for growth and expresses the KIT receptor wild. It is easy to grow in large quantities, to freeze and to activate by IgE-anti IgE couple or a couple of allergen and corresponding specific IgE. This cell line can be used to study pathophysiologic mechanisms of allergy and to develop and use high-throughput screening tests of molecules in search of anti-allergic properties.In addition, we transfected these cells by lentiviral vectors providing constructs encoding the mutated KIT D816V or the mutated KIT Delta 417-419 insY, two KIT abnormalities encountered in the course of mastocytosis. This allowed us to establish two new cell lines independent of SCF for proliferation, ROSA KIT D816V and ROSA KIT Delta417-419 insY, which are particularly easy to grow in large quantities, and whose phenotype is similar to that of abnormal mast cells during mastocytosis. These two cell lines can be used for pathophysiologic studies on mastocytosis and for high throughput screening of molecules in search of antiproliferative effects specifically directed against the mutated KIT or against one or other of the intracellular molecules involved in signal transduction induced by mutant KIT.

Thesis (Ph. D.)--Ohio State University, 2006. / Title from first page of PDF file. Includes bibliographical references (p. 130-142).