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Loundras, Eleni-Anna. "The foot-and-mouth disease virus replication complex : dissecting the role of the viral polymerase (3Dpol) and investigating interactions with phosphatidylinositol-4-kinase (PI4K)." Thesis, University of Leeds, 2017. http://etheses.whiterose.ac.uk/19452/.
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Replication of many positive-strand RNA viruses have been shown to occur within intracellular membrane-associated compartments termed replication complexes. Replication of viral RNA occurs within these intracellular compartments as a way for the virus to concentrate the structural and non-structural components into a small area to facilitate replication as well as protecting the virus components from host cell pathogen recognition and innate immune responses. Using immunofluorescent confocal and electron microscopy, foot-and-mouth disease virus (FMDV) has been shown to dysregulate Golgi and ER-derived membranes, but to date, no distinct membrane-bound replication complex comprised of viral RNA, structural and nonstructural proteins, and host-cell proteins have yet to be identified for FMDV. The FMDV RNA-dependent RNA polymerase, 3Dpol, is the primary protein involved in virus genome replication and has been previously shown to form higher-order fibril like structures in vitro in the presence of RNA. These 3Dpol fibril structures could act to ‘scaffold’ replication complex formation. Here, several mutations were made in 3Dpol to assess their role in higher-order complex formation. The ability for the different 3Dpol mutations to function was assessed biochemically, structurally and in cell culture. The results point towards the necessity for a fully functional (catalytically active) polymerase in the formation of the higher-order structures. Furthermore, complementation studies indicate that 3Dpol has two distinct functions necessary for replication within cells. Additionally, it was pertinent to investigate the role of membrane-associated kinases,such as PI4K, as a number of related viruses utilise this cellular pathway to form an optimal environment within which viral replication can occur by upregulating the formation of lipids used in the building of intracellular membranes. Investigation of translation and replication of FMDV RNA within cells show that FMDV does not appear to utilise the PI4K pathway. These results highlight differences between FMDV and other related picornaviruses and provide a basis to investigate alternative methods for replication complex formation.
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Krinke, Onďrej. "Rôle de la signalisation phospholipidique dans la voie de réponse à l'acide salicyclique chez Arabidopsis thaliana." Paris 6, 2007. https://tel.archives-ouvertes.fr/tel-00808969.
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Chez les plantes, l’acide salicylique (SA) a un rôle central dans la réponse à de nombreuses contraintes environnementales et lors du développement. Cependant les événements de signalisation précoces qu’il déclenche sont peu connus. Nous montrons, par marquage métabolique au 33Pi sur une suspension cellulaire d’Arabidopsis thaliana, que le SA induit une diminution rapide et précoce d’un pool de phosphatidylinositol (PI). Celle-ci est accompagnée d’une accumulation de PI 4-phosphate et PI 4,5-bisphosphate. Ces changements sont inhibés par de la wortmannine à 30 μM mais pas à 1 μM, ce qui implique une activation de PI 4-kinase de type III. C’est pourquoi une étude des effets de la wortmannine sur les modifications de transcriptome par le SA a été menée à l’aide de la puce « Complete Arabidopsis Transcriptome MicroArray » (CATMA). Sur 773 gènes régulés par le SA, 112 sont sensibles à 30 μM de wortmannine. En parallèle, nous voyons que l’acide phosphatidique issu de la phospholipase D (PLD) est important pour la réponse génique précoce au SA. Une expérience de puces menée pour identifier les gènes régulés par la PLD en réponse au SA a révélé que parmi 1327 gènes régulés par le SA, 97 gènes sont régulés positivement, et 117 gènes négativement, par la PLD. Les régulons de la voie sensible à la wortmannine et de la voie PLD se chevauchent fortement, ce qui suggère que les deux activités agissent en synergie dans la même voie de signalisation en réponse au SASalicylic acid (SA) has a pivotal role in many plant stress and developmental responses but little is known about the early signalling events triggered by this molecule. Using Arabidopsis thaliana suspension cells, it was shown by in vivo metabolic phospholipid labelling with 33Pi that SA induced rapid and early decrease in a pool of phosphatidylinositol (PI). The decrease was accompanied by an increase in PI 4-phosphate and PI 4,5-bisphosphate contents. These changes could be inhibited by 30 M wortmannine, but not by 1 μM wortmannine, implying that a type III PI 4-kinase was activated in response to SA. Therefore, a study of wortmannin effects on SA transcriptome was undertaken. Using the Complete Arabidopsis Transcriptome MicroArray (CATMA) chip, 773 SA-regulated genes were identified. Among these, the SA response of 112 was inhibited by 30 M wortmannine, but not by 1 M wortmannin. In parallel, it was discovered that phospholipase D (PLD) derived phosphatidic acid was important for the early SA-regulated gene expression. Microarray experiment aimed to identify genes regulated by PLD in response to SA revealed that out of 1327 genes regulated by SA, 97 genes were positively and 117 genes were negatively regulated by PLD. The wortmannin-sensitive pathway and PLD pathway regulons share an important overlap implying that the two enzyme activities act synergistically in the same signalling pathway in response to SA. Key words: Arabidopsis thaliana, phosphatidylinositol 4-kinase, ph
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BIANCO, ANNALISA. "Virus-host interactions in hepatitis C virus infection: implications for pathogenesis and therapy." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2012. http://hdl.handle.net/10281/29914.
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Virus-host interactions are crucial for the pathogenesis of Hepatitis C. Disease progression and response to therapy depends from viral and host factors and from their mutual interactions. The study of host and viral factors is also of primary importance for the development of new antiviral therapies.
The goal of this work was to investigate some of the most relevant viral and host factors in order to improve their knowledge and the possibility to translate this knowledge to a useful clinical application.
CHAPTER 2: Metabolism of Phosphatidylinositol 4-Kinase IIIα-Dependent PI4P is Subverted by HCV and Is Targeted by a 4-Amino Quinazoline with Antiviral Activity
The enzymatic activity of PI4KIIIα is required for efficient HCV RNA Replication and the direct activation of this lipid kinase by HCV is critical for the integrity of the viral replication complex.
Since we demonstrated that the anti-HCV compound AL-9 is an inhibitor of PI4KIIIα, this kinase is a suitable antiviral target for the treatment of HCV.
CHAPTERS 3-4: Unraveling host responses to the emergence of hepatitis C virus particles with defective RNA genomes
HCV particles with defective RNA genomes have been recently identified in the serum of some patients with chronic HCV infection and represent a significant proportion of viral load.
In order to investigate whether HCV defective genomes could play a role in any of the hepatic disease manifestations associated with chronic HCV infection, or affect response to antiviral therapy, we adopted a two-fold ex vivo/in vitro approach.
On one hand, we performed a retrospective screening campaign aiming at assessing the presence of defective genomes in the serum of HCV-infected individuals stratified according to disease severity as well as response to PEG-IFNα/RBV combination therapy (CHAPTER 3).
On another hand, we studied the direct role of defective HCV genomes in hepatocyte injury using an infectivity model system in vitro (CHAPTER 4).
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Jetté, Abriana. "Pink houses." Thesis, Boston University, 2012. https://hdl.handle.net/2144/12432.
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Thesis (M.F.A.)--Boston University
PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you.
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Cross, Alison Danielle. "Early marine growth and consumption demand of juvenile pink salmon in Prince William Sound and the northern coastal Gulf of Alaska /." Thesis, Connect to this title online; UW restricted, 2006. http://hdl.handle.net/1773/5314.
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Parker, Samuel Tovarisch. "The Pink Passenger." Digital Archive @ GSU, 2010. http://digitalarchive.gsu.edu/art_design_theses/59.
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The work I have created during my time as a graduate student is a reflection of the dialogues I have engaged in with other artists and acquaintances both in and outside of the academic arena. Stylistically this work is derivative of my involvement with graffiti, Tattooing, and underground comics. I have developed the icon of the rider to represent the agency and responsibility of myself as an artist in reflecting these various contexts.
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CARVALHO, RODRIGO PEREIRA. "PICK S THEOREM." PONTIFÍCIA UNIVERSIDADE CATÓLICA DO RIO DE JANEIRO, 2015. http://www.maxwell.vrac.puc-rio.br/Busca_etds.php?strSecao=resultado&nrSeq=25845@1.
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PONTIFÍCIA UNIVERSIDADE CATÓLICA DO RIO DE JANEIROCOORDENAÇÃO DE APERFEIÇOAMENTO DO PESSOAL DE ENSINO SUPERIOR
O estudo de geometria, em particular área de polígonos simples, é pouco trabalhado em sala de aula, sendo assim o presente trabalho tem como finalidade apresentar o Teorema de Pick, com algumas demonstrações, como ferramenta de cálculo de área. Atenção especial é necessária para polígonos simples mas não necessariamente convexos. Além disso discutimos outros Teoremas relacionados, como Jordan e Euler. Espera-se que esta pesquisa se some a outras no sentido de contribuir para o ensino de matemática de forma qualitativa, podendo se utilizar de técnicas aqui abordadas ou ainda serem adaptadas às diversas realidades para o seu melhor aproveitamento.
The study of plane geometry, in particular the computation of areas of simple polygons, is little explored in the classroom. Our aim here is to state and prove Pick s Theorem. We also present sever al examples and more than one proof. Simple polygons (which are not necessarily convex) receive special attention. We also consider some related results, such as the theorems of Jordan and Euler. It is hoped that this re e arch will contribute to the teaching of mathematics in a qualitative way.
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Sotomayor, Ponte José Carlos Manuel. "Teorema de Pick." Bachelor's thesis, Pontificia Universidad Católica del Perú, 2020. http://hdl.handle.net/20.500.12404/20195.
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Los polígonos enteros, en particular los politopos enteros en el plano, pueden ser descritos por vértices de puntos enteros. Por supuesto, estos puntos no son necesariamente los únicos con la cualidad de ser enteros dentro del polígono. A cada punto entero dentro de estos objetos podemos asignarle un peso, de acuerdo con el rol que cumpla en el mismo: vértice, lado o interior. A la suma ponderada de los puntos de coordenadas enteras del polígono se le asigna un nombre conocido por todos: es en realidad el área. Podría ser una forma poco intuitiva de hallar el área, pero gracias a ella también podemos obtener propiedades que se pueden considerar poco intuitivas, pero no por ello menos importantes. Sin embargo, esta propiedad es única y exclusivamente para polígonos en el plano. Por ejemplo, el tetraedro de Reeve nos encara con una obstrucción para efectuar el mismo trabajo en el espacio R3. La teoría de Ehrhart ayuda a resolver cuestiones análogas en dimensiones mayores a 2.Trabajo de investigación
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Blagg, Caroline. "The Pink Papers." Thesis, University of North Texas, 2003. https://digital.library.unt.edu/ark:/67531/metadc4270/.
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The Pink Papers is a collection of three short stories and a novel in progress consisting of four chapters. Each piece is a work of original fiction. The preface addresses the female writer and the female voice in fiction. "Broken Clock" and "Pink Paper" are the stories of two girls coping with endometriosis. "Normal Capacity" looks at the loss of a dream through the eyes of a first-year law student. The novel in progress, titled Blanchard, OK, is set in a rural farming town in Oklahoma. The novel tells the stories of 24-year-old Robin, her Aunt Paula, and Paula's boyfriend, Sam.
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Dickerson, Bobette Ray. "Reproductive success in wild pink salmon, Oncorhynchus gorbuscha /." Thesis, Connect to this title online; UW restricted, 2003. http://hdl.handle.net/1773/5337.
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Strandberg, Mitra. "Semi-Supervised Domain Adaptation for Pick Classification in Pick and Place Machines." Thesis, KTH, Skolan för elektroteknik och datavetenskap (EECS), 2019. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-254977.
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Pick and Place (PnP) machines collect and use large amounts of image data of Printed Circuit Board (PCB) components. The data is used to train automated image analysis methods to improve the decisions in the mounting process. Previous work with Neural Networks has shown promising results in the classification of the component status. However, the characteristics of the data changes over time as new PCBs, components, and PnP machines are deployed. This work applies a Semi-supervised Domain Adaptation method named Associative Domain Adaptation to enable learning of a new and unlabeled data set. The networks reach high performance despite skew class distributions, but the final results do not outperform the current classification algorithm in the PnP machines. However, ensembling of different methods can make use of the strengths from both the current classification system and the method proposed in this thesis, where the ability to learn from unlabeled data is a promising advantage.Inom fabrikstillverkning av kretskort (PCB) används automatiserade monteringslinjer med Pick and Place-maskiner. Dessa maskiner plockar upp komponenter och avgör sedan om de bör monteras eller förkastas. Genom att utveckla analysen av en plockad komponent kan användandet av material och resurser effektiviseras. Stora mängder av bilder på plockade komponenter har möjliggjort tillämpningar med neurala närtverk för att avgöra om en komponent är lämplig att montera. I och med att industrin hela tiden utvecklar nya komponenter och Pick and Place-maskiner så förändras utseendet av bilderna som nätverket ska klassificera. För att ett nätverk med övervakad inlärning (Supervised Learning) ska kunna anpassas till det senaste datat behöver experter hela tiden lägga ner tid på att tilldela etiketter (labels) till de nya bilderna. För att göra det möjligt för neurala nätverk att använda ny data som saknar etiketter så tillämpar detta arbete semi-övervakad inlärning för domänanpassning (Semi-Supervised Domain Adaptation). Ett ytterligare problem med datat är att felaktiga komponenter är ovanliga. Den valda metoden, Associativ domänanpassning (Associative Domain Adaptation), lyckas justera den inlärda fördelningen till den nya domänen trots att datamängdernas klasser har skev fördelning. De slutgiltiga nätverken når hög precision men överträffar inte befintliga beslutssystem. Däremot finns det potential att utnyttja styrkorna i båda klassificeringssystemen genom att kombinera dem, där nätverkens kapacitet att lära från data utan etiketter har en lovande potential.
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Hubert, Brian N. 1973. "Pick-and-place nanoassembly." Thesis, Massachusetts Institute of Technology, 2001. http://hdl.handle.net/1721.1/8139.
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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Mechanical Engineering, 2001.Leaves 148 and 149 blank.
Includes bibliographical references (leaves 144-147).
A new all-additive method for direct fabrication of nanometer-scale planar and multilayer structures using the probe tip of an atomic force microscope (AFM) and a material reservoir is proposed. The process, which is called Pick-and-Place NanoAssembly, enables true "pick-and-place" retrieval and deposition of materials with a wide range of electrical, chemical, and mechanical properties. The silicon tip of an AFM is used to discretely pick up molecules from a reservoir, transfer them to a construction zone, and then weld them to a surface. Unlike the prior art, this assembly method offers high-resolution direct patterning of a variety of materials, many of which are not amenable to patterning using current probe-based or conventional lithography methods. Metal nanoparticles, polymers, inks, solvents, and organics have been deposited onto a variety of substrates with resolutions approaching 1 million dots per inch (1 trillion dots per square inch). Lines of nanoparticles have been deposited with line widths of less than 17 nm. These materials can be assembled using reservoirs of viscous liquids, non-viscous liquids, and soft solids. Deposited volumes span a range of 10 orders of magnitude from 10-24 to 10-14 liters. Structures with dimensions of 60 to 100 nm are common.
he patterning process is capable of creating structures with height-to-width aspect ratios of better than 1-to-2, and is relatively insensitive to fluctuations in temperature (3 - 30 C) and humidity (0% - 90%). Methods for the fabrication of multi-layer structures and routes towards true three-dimensional structures are also introduced. It is anticipated that Pick-and-Place NanoAssembly will be suitable for precision deposition and direct patterning of a wide range of useful materials including semiconductors and biological compounds such as DNA. This technique promises to be an enabling tool for biological, chemical, and molecular electronics applications throughout the field of nanotechnology. Near-term applications may include the fabrication of ultra-high density gene chips, high-capacity nano-patterned magnetic disk drives, and single electron transistors.
Brian N. Hubert.
Ph.D.
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Balakrishnan, Sanjeevi. "Establishing a biological role for class II phosphoinositide 3-kinase (PI3K) enzyme PI3K-C2??" Thesis, Imperial College London, 2012. http://hdl.handle.net/10044/1/39135.
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Phosphoinositide 3-Kinase (PI3K) enzymes control a variety of cellular processes and their deregulation has been extensively investigated in disease conditions including renal disease, autoimmunity and chronic inflammation. Whilst PI3K enzymes have been the subject of intense research activity, the precise biological role of PI3K-C2?? enzyme remains unclear. PI3K-C2??-/- mice developed focal segmental glomerulosclerosis, damaging podocyte morphology and affecting function. My thesis explored the contribution of the PI3K-C2?? enzyme in the pathology of chronic diseases. PI3K-C2??flx/+ mice were mated with ??-actin cre mice, and the resulting F1 progeny, PI3K-C2??flx/- mice were backcrossed to produce PI3K-C2??-/- mice. Analysis of PI3K-C2??-/- mice revealed slightly elevated proteinuria and mild hyperglycaemia. Histological examination of their kidneys showed an increase in glomerular volume, intraglomerular nuclei, mesangial matrix expansion and an infiltration of T cell subsets in the glomeruli compared to control mice. In vitro, mesangial cells derived from PI3K-C2??-/- mice proliferated twice as fast as mesangial cells from control animals, without any stimulus. PI3K-C2??-/- mice exhibited an increase in the levels of leukocytes and displayed augmented proliferation, in presence of mitogenic stimuli. Wild type (WT) mice mesangial cells cultured in PI3K-C2??-/- mice splenocyte conditioned medium, exhibited a dose dependent increase in their proliferation. Induction of glomerulonephritis (GN) using a sub-nephritogenic dose of nephrotoxic serum (NTS) in PI3K-C2??-/- mice, resulted in impaired renal function and aggravated renal tissue damage. PI3K-C2??-/- mice had a greater influx of T cells and macrophages in the diseased glomeruli, but also of activated macrophage functions compared to WT mice. During GN, PI3K-C2??-/- mice developed splenomegaly leading to extramedullary haematopoiesis and increased splenocyte proliferation. PI3K-C2??-/- mice may mediate GN by polarising their cytokine effects via a Th1 pathway. PI3K-C2??-/- mice exhibit a delay in the repair of dermal injury during cutaneous wound healing. PI3K-C2??-/- mice recruit fewer macrophages to the wound site which affects re-epithelialisation, myofibroblast differentiation, angiogenesis and fibroblast mediated remodelling. Delayed wound healing in PI3K-C2??-/- mice might be a consequence of the failure to upregulate pro-inflammatory cytokines at the wound site, which are potential modulators for the recruitment of various cell types to the wound site to accelerate the healing process. To complement these in vivo studies, biochemical analysis on the putative Ras binding domain present in PI3K-C2?? and PI3K-C2?? enzymes was performed by expressing as recombinant proteins. The binding ability of the recombinant proteins to Ras family GTPases was tested. Although this approach initially proved unsuccessful, two putative binding partners, eEF1?? and eEF1?? were identified and have been shown to immunoprecipitate with full length enzymes. My data is the first study to demonstrate a role for the intracellular signalling enzyme, PI3K-C2?? in pathological conditions involving chronic inflammation. Agonist mediated activation of PI3K-C2?? enzyme might serve as a potential therapeutic target to treat chronic diseases.
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Meneses, Paulo de Oliveira. "Teorema de Pick e teorema espacial tipo-Pick: demonstraÃÃes e aplicaÃÃes no ensino mÃdio." Universidade Federal do CearÃ, 2016. http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=17239.
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CoordenaÃÃo de AperfeÃoamento de Pessoal de NÃvel SuperiorEstudos mostram que o desempenho do aluno em MatemÃtica nÃo à satisfatÃrio, pois apenas uma pequena parcela desses alunos tem os conhecimentos necessÃrios para prosseguir nos estudos. O presente trabalho visa criar ferramentas que possam auxiliar e melhorar as prÃticas em sala de aula, mais precisamente nos estudos de Geometria. Apresentaremos o Teorema de Pick, que visa calcular a Ãrea de um polÃgono simples usando contagem, analisando os pontos do bordo e do interior da figura em uma rede fixada, tornando-se uma ferramenta de uso simples e poderosa para a compreensÃo do estudo de Ãreas. Logo em seguida, mostraremos o Teorema de Reeve que, de modo anÃlogo a Pick, calcula o volume de um poliedro convexo contando os seus pontos de rede, trabalhando em uma rede secundÃria de pontos Z3n, realizando um elo entre Geometria e contagem.
Studies show that the performance of students in Mathematics is not satisfactory, since only a small portion of these students has the knowledge needed to pursue studies. The present work aims to create tools that can assist and improve classroom practices, more precisely in the studies of Geometry. We will present by counting Pick's Theorem, which calculates the area of a simple polygon by counting the points of the boundary and of the interior of the figure on a fixed lattice, making it a powerful tool of simple use for the understanding of the study of areas. Then we will present Reeve's Theorem that, similarly to Pick's, calculates the volume of a convex polyhedron by counting their lattice points, working on a secondary lattice of points Z3n, making a link between Geometry and counting.
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Meneses, Paulo de Oliveira. "Teorema de Pick e teorema espacial tipo-Pick: demonstrações e aplicações no ensino médio." reponame:Repositório Institucional da UFC, 2016. http://www.repositorio.ufc.br/handle/riufc/17972.
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MENESES, Paulo de Oliveira. Teorema de Pick e teorema espacial tipo-Pick: demonstrações e aplicações no ensino médio. 2016. 84 f. Dissertação (Mestrado em Matemática em Rede Nacional) – Centro de Ciências, Universidade Federal do Ceará, Fortaleza, 2016.Submitted by Rocilda Sales (rocilda@ufc.br) on 2016-06-27T13:14:24Z No. of bitstreams: 1 2016_dis_pomeneses.pdf: 8880492 bytes, checksum: 2116f6152464950d6130404a0eb876d9 (MD5)
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Studies show that the performance of students in Mathematics is not satisfactory, since only a small portion of these students has the knowledge needed to pursue studies. The present work aims to create tools that can assist and improve classroom practices, more precisely in the studies of Geometry. We will present by counting Pick's Theorem, which calculates the area of a simple polygon by counting the points of the boundary and of the interior of the figure on a fixed lattice, making it a powerful tool of simple use for the understanding of the study of areas. Then we will present Reeve's Theorem that, similarly to Pick's, calculates the volume of a convex polyhedron by counting their lattice points, working on a secondary lattice of points Z3n, making a link between Geometry and counting.
Estudos mostram que o desempenho do aluno em Matemática não é satisfatório, pois apenas uma pequena parcela desses alunos tem os conhecimentos necessários para prosseguir nos estudos. O presente trabalho visa criar ferramentas que possam auxiliar e melhorar as práticas em sala de aula, mais precisamente nos estudos de Geometria. Apresentaremos o Teorema de Pick, que visa calcular a área de um polígono simples usando contagem, analisando os pontos do bordo e do interior da figura em uma rede fixada, tornando-se uma ferramenta de uso simples e poderosa para a compreensão do estudo de áreas. Logo em seguida, mostraremos o Teorema de Reeve que, de modo análogo a Pick, calcula o volume de um poliedro convexo contando os seus pontos de rede, trabalhando em uma rede secundária de pontos Z3n, realizando um elo entre Geometria e contagem.
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Betzold, Nancy. "Pink discoloration of mozzerella cheese." Menomonie, WI : University of Wisconsin--Stout, 2004. http://www.uwstout.edu/lib/thesis/2004/2004betzoldn.pdf.
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Peters, Friedrich Ernst. "Hinnerk Pick und der Steernkieker." Universität Potsdam, 2012. http://opus.kobv.de/ubp/volltexte/2012/5889/.
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"Hinnerk Pick und der Steernkieker" ist ein poetischer Text, der sich mit dem Astronomen J. J. Sievers, der an der Altonaer Sternwarte tätig war, befasst. J. J. Sievers (1804-1881) stammte aus Stafstedt (Kreis Rendsburg-Eckernförde), einem Dorf in der Nähe von Luhnstedt, dem Heimatdorf von F. E. Peters. Er wird beschrieben als märchenhaft geheimnisvolle Gestalt und zugleich liebenswerter Sonderling, in dessen Augen sich eine Pascalsche Scheu vor der Unendlichkeit des Raumes widerspiegelt. "Immer aber wird mir der Steernkieker teuer bleiben als ein Zeugnis dafür, dass aus der Enge eines holsteinischen Dorfes zum Geist geführt werden kann, wen der Geist gerufen hat. Am Ende ist eines Menschen Drang ins Weite doch vergeblich, wenn er sie nach unruhigen Jahren des Suchens nicht findet in sich selbst."
In den Mund des Astronomen Sievers ("de ool Steernkieker", "de ool Klooksnacker") legt Peters am Anfang der "Baasdörper Krönk" die berühmte Beschreibung von Baasdorp und der Anlage des Dorfes in drei sozial definierte konzentrische Kreise (reiche Bauern; Halbhufner und kleine Bauern; schließlich Handwerker und Katenbauern).
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Thekkiam, Sruthi Sridhar. "PINK LOTUS MOTORBOAT: BANGALORE STORIES." Bowling Green State University / OhioLINK, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=bgsu1174880961.
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Bergstrand, Henrik, and Johanna Sjöström. "Light or Voice – make your choice! : Plocktekniker för tillverkningsföretag." Thesis, Linnéuniversitetet, Institutionen för informatik (IK), 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:lnu:diva-37023.
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Companies constantly strive for the perfect order which enables them to satisfy and retain their customers. This is a difficult process that can be facilitated by using different picking technologies. In this study, a research of the picking technologies Pick-to-Light and Pick-to-Voice have been made to investigate when each technology is suited.In order to collect relevant information and data to be able to answer the question formulation, a qualitative study with interviews have been made. The purpose of this essay was to investigate Pick-to-Light and Pick-to-Voice to see when each technology is best suited and to see what the differences between the technologies are. With our essay we wanted to help manufacturing companies to make the right decisions when implementing a picking technology.The results showed that those picking technologies give companies a higher picking quality and an increased work efficiency since the order picking is faster to perform, and that picking errors are reduced. Through the interviews conducted, the result showed that Pick-to-Light and Pick-to-Voice are best suited at different types of areas. Pick-to-Light is optimal in small areas with high picking frequency while Pick-to-Voice is optimal in large areas with low picking frequency. Companies that are thinking of expanding in the future and use a picking technology on a much larger area, was recommended to implement Pick-to-Voice since this technology is more cost effective. Both of these technologies have multiple positive effects that are similar. Examples on these positive effects are that the operator has an overview of the items to be picked, the technologies are easy to learn and ergonomics are enhanced significantly when all paper handling is eliminated.Obviously, there are also differences between the techniques and also some disadvantages of each technique. The main differences are that the operator with Pick-to-Light can see which articles to be picked with the help of the luminous lights while the operator with Pick-to-Voice is voice guided to the items to be picked. Another major difference is that Pick-to-Voice is a wireless technology unlike Pick-to-Light and the ability to pick multiple orders at the same time is only possible with Pick-to-Voice. When it comes to maintenance costs, Pick-to-Light is more costly, both in time and money, since lights and cable must be replaced periodically. Likewise, an expanding with Pick-to-Light is more comprehensive since more cables and lamps must be purchased and installed. With Pick-to-Voice the only needed adjustment to make is in the system.Depending on the available conditions on the companies, the technologies are best suitable in different ways. Companies can use the technologies to secure the quality of the picking, reducing picking errors, and streamline the picking process. These technologies create the opportunity for companies to achieve the perfect order.
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Kho, Pik Fang. "Genetic epidemiology of endometrial cancer." Thesis, Queensland University of Technology, 2021. https://eprints.qut.edu.au/211383/1/Pik%20Fang_Kho_Thesis.pdf.
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Endometrial cancer is the fifth most common cancer diagnosed in women in developed countries. This research used genetics to assess relationships between endometrial cancer and, previously identified and novel, risk factors. This work brings new insights by providing evidence that HDL and LDL cholesterol levels are linked to endometrial cancer risk. Further, I have shown that two gynaecological diseases, which are comorbid with endometrial cancer, also share genetic risk architecture with endometrial cancer. This work also advances the understanding of biological mechanisms of endometrial cancer by identifying candidate susceptibility genes.
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Biles, Leslie. "Pink flamingos and the two queens." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape8/PQDD_0015/MQ47980.pdf.
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Janoff, Douglas. "Pink blood queer-bashing in Canada /." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp03/MQ52091.pdf.
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Hale, Benjamin G. "Influenza A viruses and PI3K signalling." Thesis, University of St Andrews, 2007. http://hdl.handle.net/10023/483.
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The influenza A virus non-structural (NS1) protein is multifunctional, and during virus-infection NS1 interacts with several factors in order to manipulate host-cell processes. This study reports that NS1 binds directly to p85β, a regulatory subunit of phosphoinositide 3-kinase (PI3K), but not to the related p85α. Expression of NS1 was sufficient to activate PI3K and cause the phosphorylation of a downstream mediator of PI3K signalling, Akt. However, in virus-infected MDCK cells, the kinetics of Akt phosphorylation did not correlate with NS1 expression, and suggested that negative regulation of this signalling pathway occurs subsequent to ~8h post-infection. Mapping studies showed that the NS1:p85β interaction is primarily mediated by the NS1 C-terminal domain and the p85β inter-SH2 (Src homology 2) domain. Additionally, the highly conserved tyrosine at residue 89 (Y89) of NS1 was found to be important for binding and activating PI3K in a phosphorylation-independent manner. The inter-SH2 domain of p85β is a coiled-coil structure that acts as a scaffold for the p110 catalytic subunit of PI3K. As NS1 does not displace p110 from the inter-SH2 domain, a model is proposed whereby NS1 forms an active heterotrimeric complex with PI3K, and disrupts the ability of p85β to control p110 function. Biological studies revealed that a mutant influenza A virus (Udorn/72) expressing NS1 with phenylalanine substituted for tyrosine-89 (Y89F) exhibited a small-plaque phenotype, and grew more slowly in MDCK cells than wild-type virus. Unexpectedly, another mutant influenza A virus strain (WSN/33) expressing NS1-Y89F was not attenuated in MDCK cells, yet appeared to be less pathogenic than wild-type in vivo. Overall, these data indicate a role for NS1-mediated PI3K activation in efficient influenza A virus replication. The potential application of this work to the design of novel anti-influenza drugs and vaccine production is discussed.
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Bento, Carina Alexandra dos Reis. "Don't think pink : comunicar no feminino." Master's thesis, FEUC, 2011. http://hdl.handle.net/10316/14618.
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Dissertação de mestrado em Marketing, apresentada à Faculdade de Economia da Universidade de Coimbra.Longe vão os tempos em que o lugar da mulher era em casa. O papel da mulher na sociedade tem vindo a tomar contornos diferentes. Mais sofisticadas, mais cultas, mais independentes – social e economicamente - mais participativas na comunidade e com uma presença crescente no mercado de trabalho, são o resultado das suas conquistas, em especial nos últimos 50 anos. Pretende- se com o presente trabalho analisar uma realidade evidente, salientar que as mulheres são uma maioria emergente e não uma minoria que se pode facilmente ignorar. A riqueza tem vindo a passar das mãos dos homens para a das mulheres (através de divórcios, viuvez, heranças milionárias e, prioritariamente, por mérito próprio), e elas nunca tiveram tanto poder de compra, como agora. Desde sempre que as mulheres são associadas ao shopping, algumas chegam mesmo a dizer que o seu passatempo preferido é ir às compras. Se as empresas querem vender, porque não aproveitar ao máximo este facto? Se por um lado temos mulheres que não se importam de gastar, ou melhor, adoram comprar, por outro temos empresas à beira da falência que procuram escoar os seus produtos. Porquê estes dois mundos não se encontram? Ao longo deste trabalho, procura-se ainda estudar e dar linhas orientadoras que desvendem o que se passa na mente da consumidora moderna. Pretende-se igualmente reflectir e chamar a atenção para este mercado, aproveitar oportunidades, desenvolver tendências, integrar disciplinas, observando a realidade que nos rodeia. As consumidoras estão lá, o que acontece é que parece que ninguém sabe ou quer olhar para elas atentamente. A consumidora não quer os mesmos serviços que os homens, já não se trata apenas em apresentar o produto numa versão cor-de-rosa, mas antes adorná-los com uma componente mais emocional. A abordagem desta dissertação consiste em amputar o pensamento tipicamente pink, e apresentar insights relevantes para o sucesso de produtos e serviços dirigidos com especial enfoque nas senhoras. No trabalho salientam-se e desmistificam-se alguns conceitos. Para desvendar a mulher recorremos à ajuda e contribuições das várias ciências, de forma a apresentar com uma vertente científica que, homens e mulheres não são iguais. Objectivos Por se tratar de umaPor se tratar de uma temática ainda pouco explorada, do ponto de vista empresarial, o objectivo que nos propomos centra-se em estudar a mulher enquanto consumidora – com o suporte da ciência - e analisar as questões que elas mais valorizam, quer nos produtos, quer na própria comunicação destes. De uma forma neutra, apresentamos o perfil da mulher consumidora de modo a responder ao que elas querem e desejam, como gostam de ser tratadas e os aspectos que as empresas devem melhorar para alcançar as consumidoras portuguesas e adaptar a sua oferta. De seguida, apresentam-se os objectivos que pretendemos destacar e dar resposta ao longo deste projecto: # Demonstrar que as mulheres têm necessidades e preferências distintas; # Evidenciar as diferenças de género; # Estudar a mulher enquanto consumidora; # Alertar para a importância do público feminino no mercado; #Mostrar que as mulheres requerem abordagens de marketing diferenciadas.
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Hale, Benjamin G. "Influenza A viruses and PI3K signalling /." St Andrews, 2008. http://hdl.handle.net/10023/483.
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Smiley, Elizabeth G. "Many Ways to Pick a Stock." Thesis, The University of Arizona, 2014. http://hdl.handle.net/10150/321943.
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Wilson, F. Douglas, Jayne L. Szaro, and Benny R. Stapp. "Antibiosis in Cotton to Pink Bollworm." College of Agriculture, University of Arizona (Tucson, AZ), 1987. http://hdl.handle.net/10150/204497.
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Ninety-nine germplasm lines and a resistant check line of cotton, Gossypium hirsutum L., were infested artificially in the field with eggs of pink bollworm (PBW), Pectinophora gossypiella (Saunders), and evaluated for an antibiosis type of resistance to the insect and also for yield potential. All 99 lines came from crosses of well -adapted cultivars, or the nectariless, or nectariless-okra-leaf versions of those cultivars, with previously identified sources of antibiosis (a type of resistance that affects the growth and development of the insect once inside the boll). Twenty-three of the 99 were selected for low PBW damage or for a combination of high lint yield and low damage.
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Chu, C. C., and T. J. Henneberry. "Cultural Control and Pink Bollworm Populations." College of Agriculture, University of Arizona (Tucson, AZ), 1996. http://hdl.handle.net/10150/210914.
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A cotton management program in the Imperial Valley, CA was designed to reduce pink bollworm, Pectinophora gossypiella (Saunders), populations. The program established I March as the earliest planting date, 1 September for defoliant or plant growth regulator application and 1 November for cotton stalk destruction and plowdown. In-season gossyplure-baited pink bollworm male moth activity monitoring and immature green cotton boll inspections for larval infestation were encouraged as decision making aids to determine the need for additional control action. Male pink bollworm moth catches in gossyplure-baited Lingren and delta sticky traps were significantly reduced each year from 1990 to 1994 following the initiation of the management program in 1989. Fewer larvae per cotton boll occurred in the years from 1990 to 1992. Fiber quality of commercial cotton sampled was also improved from 1989 to 1994, as compared to the 1984 to 1988 average. Cotton production, in general, was reduced during 1989 to 1994 in areas surrounding Imperial Valley and may have contributed partially to reduced populations in Imperial Valley.
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Tamari, Márcio Eiji. "O teorema de Pick e aplicações." reponame:Repositório Institucional da UFABC, 2013.
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Price-Rhea, Kelly. "Does Golf Have a Pink Problem?" Digital Commons @ East Tennessee State University, 2019. https://dc.etsu.edu/etsu-works/5535.
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I love my pink glove. My last bag was pink. I am glad I had the pink option when I purchased these items. But the question remains, why must golf continue to place such deep division within many of its product lines which continues to fuel the gendering (and arguably sexism) of golf?
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Ahmed, F. (Furqan). "CrowdPickUp:task pick-up in the wild." Master's thesis, University of Oulu, 2016. http://jultika.oulu.fi/Record/nbnfioulu-201612073211.
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Abstract. This thesis investigates the feasibility and performance of different types of crowdsourcing tasks picked-up in the wild i.e., situated, location-based and general through the implementation and evaluation of the CrowdPickUp crowdsourcing platform.
We describe in detail the implementation process of CrowdPickUp, which we then used in a study where workers could earn coins on the basis of task completion and use their earned coins to buy different available items of their own choice using CrowdPickUp’s web shop integrated within our system. During the study, we recorded the average completion time and accuracy of different crowdsourcing tasks. The key findings show that our platform was able to generate high quality contributions in a composite environment.
Finally, we conclude the thesis by discussing the importance and usefulness of different crowdsourcing tasks designed for our crowdsourcing system and our possible future work within the area of crowdsourcing task-pickup system.Tiivistelmä. Tämä diplomityö tutkii joukkouttamisen suorituskykyä ja mahdollisuuksia erityyppisten tehtävien avulla. Tehtävät jaetaan työntekijöille luonnollisissa olosuhteissa paikkasidonnaisesti työssä kehitetyn CrowdPickUp-alustan avulla.
Työ kuvailee yksityiskohtaisesti kehitetyn alustan sovelluskehitysprosessin. Tämän jälkeen valmista alustaa käytettiin käyttäjäkokeissa, joissa työntekijät pystyivät ansaitsemaan virtuaalivaluuttaa, jolla pystyi ostamaan erilaisia palkintoja. Kokeen aikana tutkimme ja tallensimme monenlaista tietoa, kuten esimerkiksi suoritetun työn tarkkuutta ja keskimääräistä tehokkuutta. Työn päälöydökset osoittavat, että alustamme kykeni tuottamaan korkealaatuista työtä luonnollisissa olosuhteissa ja ilman tutkijoiden jatkuvaa läsnäoloa.
Lopuksi diplomityö keskustelee löydösten ja kehitystyön tärkeyttä sekä soveltuvuutta erilaisten tehtävien suorittamisalustaksi. Lisäksi esittelemme ideoita, joilla työtä voi kehittää eteenpäin entistä hyödyllisemmäksi tutkimusinstrumentiksi.
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White, Angela R. "Shared PI3K signaling abnormalities in brain tumors and epilepsy: PI3K inhibition in PTEN-deficient disorders of the brain." University of Cincinnati / OhioLINK, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1603712831970142.
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Pederzoli, Marco. "Dimensionamento di un pick & place veloce." Bachelor's thesis, Alma Mater Studiorum - Università di Bologna, 2013. http://amslaurea.unibo.it/4852/.
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Castel, Morales Pau. "Molecular mechanisms of resistance to PI3K inhibitors." Doctoral thesis, Universitat de Barcelona, 2016. http://hdl.handle.net/10803/396640.
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The development of high-throughput sequencing technologies has prompted the evaluation of large cohorts of different tumor types. The results from these comprehensive genomic studies have revealed the most commonly mutated genes across human cancers, providing further understanding of the pathogenesis, molecular classification, and therapeutic strategies for this disease.
PIK3CA, the gene encoding the PI3Kα isoform, is among the most frequently mutated genes in breast, head and neck, colorectal, and lung cancer, among others. Activating mutations in PIK3CA promote hyperactivation of the PI3K/AKT pathway, leading to increased proliferation, cell growth, survival, and metabolism.
Current efforts are aimed to develop PI3K inhibitors as an effective therapy for PIK3CA mutated cancers and, despite promising clinical responses, the emergence of drug resistance is a clear limitation. In this doctoral thesis, we have explored these mechanisms of resistance in order to provide a better understanding of tumor evolution upon therapy, define subpopulations of patients that are likely to respond to PI3K inhibitors, and provide novel pharmacological combinations to overcome therapy refractoriness.
The loss of the tumor suppressor PTEN was found to play an important role in the resistance of PI3Kα inhibitors in preclinical models and patients, mainly by reactivating the PI3K/AKT pathway as a result of an increased dependency on the PI3Kβ isoform. Our work also demonstrated the notion of tumor evolution and phenotypic convergent evolution in response to therapeutic pressure.
Moreover, we have established that intrinsic resistance to PI3Kα inhibitors occurs as a result of incomplete inhibition of the mammalian target of rapamycin complex 1 (mTORC1), a downstream effector of the PI3K/AKT pathway. PI3Kα inhibitor-resistant cells could be re-sensitized through the blockade of phosphoinositide-dependent kinase (PDK1), a constitutively active kinase, using genetic or pharmacologic inhibition. Further experiments showed that the downstream effector of PDK1 is the serum and glucocorticoid-induced kinase 1 (SGK1), which promotes cell survival through the
phosphorylation of key proteins such as FOXO3 and TSC2. Accordingly, the resistant phenotype could be also reverted by inhibiting SGK1, a novel pharmacological approach that has revealed interesting roles of this kinase in tumor biology.
Genetically engineered mouse models represent reliable tools for investigating the etiology, biology, and progression of human diseases, as well as for exploring novel therapeutic approaches. By serendipity, we discovered the role of PIK3CA mutations in the genesis of venous malformations, an aberration of normal venous development that currently lacks effective treatments. Our mouse models recapitulated the histopathologic features of the disease and provided an experimental platform to test novel pharmacological approaches. PI3Kα inhibitors were effective at reducing the morbidity and mortality of mice carrying venous malformations.
The results from this thesis highlight the importance of defining the molecular determinants of sensitivity and resistance to PI3K inhibitors, a therapy that will most likely benefit PIK3CA mutant patients.El desenvolupament de noves tècniques de seqüenciació massiva ha fomentat l’estudi d’un gran nombre de mostres de diversos tipus tumorals. Els resultats d’aquests estudis genòmics exhaustius ha revelat els gens que es troben mutats en major prevalença, contribuint a una millor comprensió dels processos de patogènesis, classificació molecular i estratègies terapèutiques per a aquesta malaltia. PIK3CA, el gen que codifica per a la isoforma PI3Kα, es troba entre els gens mes freqüentment mutats en el carcinoma de mama, cap i coll, colorectal, pulmó, entre d’altres. Les mutacions activadores a PIK3CA promouen la hiperactivació de la via de senyalització de PI3K/AKT, donant lloc a un increment en la proliferació, la supervivència, i el metabolisme de les cèl·lules tumorals. Els esforços actuals es centren en el desenvolupament d’inhibidors de l’enzim PI3K com a una possible teràpia efectiva en tumors que presenten mutacions a PIK3CA. Tot i que els assajos clínics inicials son prometedors, l’emergència de resistència a aquestes teràpies és una clara limitació. En aquesta tesis doctoral s’han explorat els possibles mecanismes de resistència per intentar entendre com els tumors evolucionen enfront d’aquest fàrmacs, poder definir les subpoblacions de pacients que respondran als inhibidors de PI3K i proporcionar noves combinacions farmacològiques per combatre el fenomen de la resistència. Hem demostrat que la pèrdua del supressor tumoral PTEN juga un paper important en la resistència als inhibidors de PI3Kα, tant en models preclínics com en pacients, mitjançant la reactivació de la via de PI3K/AKT que és resultat d’un increment en la dependència de la isoforma PI3Kβ. El nostre treball també ha evidenciat la noció d’evolució tumoral i ha demostrat el concepte d’evolució convergent fenotípica en resposta a la pressió terapèutica. També s’ha demostrat que la resistència intrínseca als inhibidors de PI3Kα es pot donar com a resultat d’una inhibició incompleta del complex 1 de mTOR (mTORC1), un efector clau de la via de PI3K/AKT. Cèl·lules resistents a inhibidors de PI3Kα es van poder sensibilitzar amb el bloqueig genètic o farmacològic de PDK1, una quinasa constitutivament activa. Experiments addicionals van poder demostrar que l’efector molecular de PDK1 era la quinasa SGK1, la qual promou la supervivència cel·lular a través de la fosforilació de proteïnes clau com FOXO3 i TSC2. El fenotip resistent es va poder revertir mitjançant la inhibició farmacològica d’aquesta proteïna, una aproximació terapèutica que ha revelat un rol interessant en la biologia tumoral. Els models murins modificats genèticament representen una eina segura per a l’estudi de la etiologia, biologia i progressió de malalties humanes, així com per explorar noves aproximacions terapèutiques. Com a resultat d’un descobriment imprevist, també hem pogut revelar el rol de les mutacions de PIK3CA en la formació de malformacions venoses, una aberració del desenvolupament normal de les venes que actualment no tenen un tractament específic. El nostre model animal de malformació venosa recapitula les característiques histopatològigues de la malaltia i proporciona una plataforma experimental única per a l’estudi de noves teràpies. En aquests models animals, els inhibidors de PI3Kα han demostrat ser efectius en la reducció de la morbiditat de les malformacions venoses.
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Figueiredo, Ana Raquel Martins. "Role of PI3K in pericytes during angiogenesis." Doctoral thesis, Universitat de Barcelona, 2017. http://hdl.handle.net/10803/404276.
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Pericytes (PCs) are important regulators of the vascular development promoting vessel growth and stabilization. They have recently emerged as a therapeutic target to promote or inhibit angiogenesis. Therefore, advancing our basic understanding on PCs biology and its molecular regulators during physiological angiogenesis is essential to develop PC-related therapies. One of the major pathways leading to cellular proliferation, migration, and survival is relayed by PI3K. Data from our laboratory and others have demonstrated isoform selectivity stimulating PI3K signalling in the regulation of both, the ECs and vSMCs. Interestingly, in these two cell populations’ p110α seems to be the major isoform.
By using pharmacological and genetic tools together with cultured PCs and retinal systems we have found that PCs pass through different states during vessel development, and that PI3K signalling regulates these cells in an isoform-specific manner. We have seen that immature and active PCs promote vessel growth while, mature and quiescent PCs result in vascular stabilization and remodelling. Moreover and unexpectedly, our results have identified p110β as the key regulator of PCs proliferation and growth. Inactivation of p110β in PCs, but not p110α, results in PC proliferation arrest and in several morphological changes, which resemble a more mature PC. Lack of p110β in PCs also leads to a more mature vascular plexus. We observed reduced vessel density, EC proliferation arrest and increased deposition of collagen IV. Furthermore, PTEN seems to be the regulator of PI3K in PCs, opposing the p110β effects and, leading to a more mature and stable PC and subsequently also more mature vasculature.
Since p110β-PI3K controls PC growth and proliferation, it suggests that target therapy directed to p110β in cancer could affect PCs. Using a pancreatic neuroendocrine tumour mouse model (RIP1-Tag2) we have seen that pharmacological inhibition of p110β impacts on tumour progression and in PCs growth. However, it also results in a slight reduction in the overall survival of the animal, without affecting their metastatic potential. Therefore, other studies are needed to further investigate p110β as a possible PC-specific target therapy.
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Toscano, Sarah. "Functional characterisation of PIP4K in Drosophila melanogaster." Thesis, University of Cambridge, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.609822.
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Pick, Sebastian [Verfasser]. "Absatzmarktorientierte Konzepte effizienter mobiler Arbeitsmaschinen / Sebastian Pick." München : Verlag Dr. Hut, 2015. http://d-nb.info/1067708812/34.
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Fedrigo, Carlos Alexandre. "Inibição da via PI3K-Akt em gliomas." Pontifícia Universidade Católica do Rio Grande do Sul, 2012. http://hdl.handle.net/10923/4518.
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Previous issue date: 2012Glioblastoma multiforme (GMB) is the most malignant and common type of all astrocytic tumours. Current standard treatment for GBM patients involves maximum surgical resection of the tumour, followed by radiotherapy and chemotherapy, usually containing the alkylating agent Temozolomide (TMZ). Despite this aggressive combination therapy, the survival rate of GBM patients is still low. This work consisted in investigating the cytotoxic effects of Akt-inhibition by MK-2206 with irradiation (RT) and TMZ on in vitro human malignant glioma. Seven malignant glioma cell lines were cultured and tested for clonogenic survival, invasion inhibition, tumour spheroid growth and proliferation. The Akt-inhibitor MK-2206 and TMZ were added at different time treatments and in varying doses. Cultures were irradiated with single dose and with fractionated γ-irradiation. Cellular modulation of Akt and p-Akt were assessed by Western blot analysis. MK-2206 reduced the levels of phospho- Akt key protein in the PI3Kinase-Akt pathway, decreased cell survival, and inhibited invasion, proliferation and cell growth. The combination of MK-2206 and RT lead to enhanced inhibition of cell proliferation and invasion, which is not observed with RT alone. The radioenhancing effect of MK-2206 was most striking in inhibition of spheroid volume growth by fractionated RT; the radiosensitizing effect of MK-2206 was stronger than that of TMZ. MK-2206 enhanced the in vitro effects of RT and TMZ in terms of decreased cell survival, invasion, proliferation and growth in malignant glioma. Effects could be ascribed to inhibition of PI3K-Akt pathway.
O Glioblastoma multiforme (GBM) é o tipo mais maligno e mais comum de todos tumores astrocíticos. O tratamento atual para pacientes de GBM envolve máxima remoção cirúrgica, seguida de radio e quimioterapia, normalmente com o agente alquilante Temozolamida (TMZ). Apesar da agressividade da terapia combinada, o tempo de sobrevivência dos pacientes ainda é baixo. Este trabalho procurou investigar os efeitos citotóxicos do inibidor de Akt MK-2206 em combinação com irradiação (RT) e TMZ em um painel de células de gliomas humanos. Sete linhagens de glioma foram cultivadas e testadas em ensaio de sobrevivência clonogênica, inibição de invasão, e modelos de proliferação e crescimento de volume em esferóides. O inibidor MK-2206 e TMZ foram adicionados em diferentes tempos de tratamento e diferentes doses. As culturas foram irradiadas com doses únicas ou em terapias fracionadas com irradiação γ. A modulação celular de Akt e fosfo-Akt foi checada via Western Blot. O composto MK-2206 reduziu a fosforilação da proteína chave Akt na via PI3K, diminuindo a sobrevivência celular e inibindo invasão, proliferação e crescimento celular. A combinação de MK-2206 com RT levou a uma maior inibição de invasão e proliferação, o que não é observado somente com a RT. O efeito radiosensível de MK-2206 foi ainda maior na inibição do volume dos esferóides em terapia combinada com RT fracionada, sendo ainda maior do que o efeito combinado com TMZ. MK-2206 aumentou os efeitos in vitro de RT e TMZ em termos de redução de sobrevivência celular, invasão, proliferação e crescimento celular em gliomas malignos. Os efeitos podem ser atribuídos a inibição da via PI3KAkt.
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Ramos, Delgado Carmen Fernanda. "Exploring PI3K signalling dynamics in pancreatic cancer." Thesis, Toulouse 3, 2020. http://www.theses.fr/2020TOU30152.
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Les PI3K sont des enzymes qui phosphorylent le groupe hydroxyl en position 3 des phosphatidylinositols comme le PIP2 ou le PI. Ces lipides sont impliqués dans de nombreux processus cellulaires tels que la croissance, la prolifération, la motilité, l'autophagie et le trafic cellulaire. Chez les mammifères, il y a 8 isoformes de PI3K et elles sont regroupées en trois classes (I, II et III) en fonction de leur structure et spécificité du substrat. Les PI3K de classe I sont les mieux caractérisées et impliquées dans le cancer. Les rôles oncogéniques des PI3K de classe II et III restent méconnus. La voie PI3K/Akt est fréquemment suractivée dans les cancers et est corrélée à un mauvais pronostic, particulièrement dans l'adénocarcinome canalaire pancréatique (PDAC). La mutation oncogénique de Kras est détectée dans plus de 90% des cas de PDAC et induit l'activation des voies effectrices, y compris de la voie PI3K. Le PDAC est l'un des cancers les plus mortels, caractérisé par un diagnostic tardif, une progression rapide et des options thérapeutiques limitées. Des études antérieures de l'équipe ont démontré que la PI3Kalpha, une PI3K de classe I, est cruciale dans les étapes précoces du PDAC. Néanmoins, son rôle dans la progression du PDAC reste inconnu. Ma thèse vise à élucider la dynamique de signalisation des PI3K dans le PDAC. J'ai commencé par caractériser le rôle de la PI3Kalpha dans la progression du PDAC et j'ai déterminé sa pertinence en tant que cible thérapeutique. Enfin, je montre des données préliminaires sur le rôle de Vps34, une PI3K de classe III, dans la physiologie des cellules acineuses et son rôle éventuel dans la cancérogenèse pancréatique. L'inactivation pharmacologique et génétique de PI3Kalpha in vitro démontre que cette PI3K contrôle les paramètres cellulaires qui régulent la progression des cellules tumorales pancréatiques, et ce quelles que soient leurs mutations génétiques. Ces résultats ont été validés in vivo dans le modèle murin appelé KPC. Ainsi, des souris KPC avec des taux élevés de cfDNA (cell free DNA, marqueur d'inflammation) et une tumeur détectée par échographie ont été traitées avec l'inhibiteur spécifique de PI3Kalpha, BYL-719. J'ai également comparé l'inhibition pharmacologique de PI3Kalpha avec l'inactivation génétique de PI3Kalpha dans l'épithélium pancréatique de souris KPC (réalisé avec des souris génétiquement modifiées). L'inhibition de la PI3Kalpha in vivo, diminue le volume tumoral, prolonge la survie et retarde la dissémination métastatique. L'effet anti-métastatique des inhibiteurs de PI3Kalpha a été validé par une injection de cellules cancéreuse pancréatiques dans la veine caudale avec ou sans traitement avec du BYL-719. L'inhibition de la PI3Kalpha a également diminué l'infiltration des macrophages protumoraux, suggérant un rôle dans la réponse immunitaire, facteur connu de progression du PDAC. [...]PI3Ks are enzymes that catalyse the phosphorylation of inositol phospholipids in the 3-position of the inositol ring. These substrates and products are involved in multiple cellular processes such as cell growth, proliferation, cell motility and cellular trafficking. In mammals, there are 8 isoforms of PI3Ks and they are grouped into three classes (class I, II and III) depending on their structure and substrate specificity. Class I PI3Ks are the best characterised and the most commonly implicated in cancer. Current evidence on the oncogenic roles of class II and class III PI3Ks is limited. The PI3K/Akt signalling pathway is frequently hyperactivated in cancers and is usually correlated to a poor prognosis, particularly in pancreatic ductal adenocarcinoma (PDAC). More than 90% of PDAC cases are driven by activating mutations in Kras, which then activate downstream effector-signalling pathways, including the PI3K pathway. PDAC is one of the most lethal cancers, characterised by a late-stage diagnosis, a rapid progression and limited therapeutic options. There is a dire need to find new biomarkers and to design novel therapeutics for PDAC management. Previous studies from the team demonstrated that PI3Kalpha, a class I PI3K, is crucial in the initial stages of PDAC. Nonetheless, its role during PDAC progression remains unknown. My PhD aims to elucidate PI3K signalling dynamics in PDAC. I focused on characterising the role of PI3Kalpha in PDAC progression and on determining its suitability as a therapeutic target. Additionally, I show preliminary data on the role of Vps34, a class III PI3K, in acinar cell physiology and its possible role in pancreatic carcinogenesis. The pharmacological and genetic inactivation of PI3Kalpha in vitro demonstrate that this PI3K isoform regulates parameters that drive pancreatic tumour cell progression regardless of oncogenic mutations. These effects are organ-specific; depending on the organ context, another class I PI3K isoform could drive the cancer progression. These results were then validated in vivo in the KPC mouse model used for preclinical testing of PDAC. KPC mice with high levels of cfDNA and a detected tumour via ultrasound imaging were treated with the PI3Kalpha-specific inhibitor, BYL-719. Likewise, I compared the pharmacological inhibition of PI3Kalpha with the genetic inactivation of PI3Kalpha in the pancreatic epithelium of KPC mice. Targeting PI3Kalpha in vivo, pharmacologically and genetically, decreases tumour volume, increases life expectancy and delays metastatic dissemination. To further support the anti-metastatic effect of PI3Kalpha, a tail vein assay was performed and the mice were also given BYL-719. This last experiment reproduced the previous results obtained with the other mouse models, reinforcing the role of PI3Kalpha in decreasing metastatic dissemination. Besides delaying metastatic dissemination, PI3Kalpha also decreased the infiltration of protumoral macrophages, suggesting a role for this isoform in shaping the immune response. [...]
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Karnes, Jonathan Burgess. "PI3K Class IIalpha Is Required for Autophagy." Thesis, Van Andel Research Institute, 2017. http://pqdtopen.proquest.com/#viewpdf?dispub=10268645.
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Autophagy is a cellular recycling process in which cytoplasmic proteins and organelles are sequestered in a double membrane vesicle, delivered to the lysosome, and degraded following fusion of the two vesicles. A key part of the initiation signaling for autophagy is the generation of phosphoinositol 3-phosphate (P13P) by class III phosphoinositol 3-kinase also knows as Vps 34. In humans there are eight P13K isoforms divided into three classes, four class I enzymes, three class II enzymes, and a single class III enzyme. Of these eight enzymes, only the class III isoform is thought to participate directly in autophagic signaling. A quantitative microscopy based, loss-of-function survey of all eight P13K isoforms was used to determine their relative contribution to autophagic signaling, as measured by LC3 positive autophagic vesicles. As predicted, knockdown of P13K-class III reduced the number of autophagic vesicles in cells. Interestingly, knockdown of the P13K-class IIα isoform had an even more potent effect on reducing the number of autophagic vesicles than knockdown of P13K-class III. In follow up studies, knockdown of P13K-class IIα reduced endogenous LC3 conversion, caused the accumulation of p62 and lipid droplets, and colocalized with endosomal markers. These results suggest P13K-class IIα may act to promote autophagy through the shuttling of endosomal vesicles into the autophagic pathway and approaches to test this hypothesis will be discussed. The requirement of P13K-class IIα for autophagy is an important finding as it indicates a role for class II P13Ks in autophagy.
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Zunder, Eli Richard. "A yeast screen for PI3K inhibitor resistance." Diss., Search in ProQuest Dissertations & Theses. UC Only, 2009. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3339211.
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Sims, Maria A., Timothy J. Dennehy, Laura Shriver, Danny Holley, Yves Carrière, Bruce Tabashnik, Larry Antilla, and Mike Whitlow. "Susceptibility of Arizona Pink Bollworm to Cry1Ac." College of Agriculture, University of Arizona (Tucson, AZ), 2002. http://hdl.handle.net/10150/197706.
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Genetically modified cotton expressing the Cry1Ac toxin has been used in Arizona since 1996 with exceptionally positive results in terms of economic returns to growers and reductions in insecticide use in cotton. Since 1995, average insecticide use in Arizona cotton has declined from greater than six applications per acre to less than two in 2000. Bt cotton has contributed greatly to these savings to growers, as have insect growth regulators used for whitefly control. Collections of pink bollworm, Pectinophora gossypiella, made in 1997 and subsequently exposed to Cry1Ac in the laboratory from 1998 to 2000, yielded a laboratory strain with susceptibility to Cry1Ac reduced 1,000 to 3,000- fold, relative to highly susceptible field populations. Unparalleled measures have been taken to detect and manage this resistance. In this report we summarize results of statewide monitoring of pink bollworm susceptibility to Cry1Ac conducted from 1997 to 2000, and results of field evaluations of the effectiveness of Bt cotton from 1995 to 2001. Susceptibility of Arizona pink bollworm to Cry1Ac, increased from 1997 to 2000. Mean corrected mortality in 1μg/ml Cry1Ac assays was 57.4% in 1997, 90.6% in 1998, 97.9% in 1999 and 97.4% in 2000. Mean corrected mortality in bioassays of 10 μg/ml also increased: it was 94.1% in 1997, 99.9% in 1998, 100% in 1999 and 100 % in 2000. Field performance of Bt cotton in 2000 continued to be excellent at 39 locations throughout Arizona cotton at which paired Bt and non-Bt fields were evaluated. Whereas non-Bt cotton fields had mean infestations of over 15% infested bolls, Bt cotton fields averaged less than 0.15% infested bolls. Thus, after six years of intensive use of Bt cotton in Arizona, pink bollworm populations show no signs of being resistant to Bollgard cotton. Indeed, for reasons that are not understood at this time, they have been found to be significantly more susceptible to the Bt toxin in Bollgard cotton at the end of the 2000 season than they were in 1997.
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Brown, P., R. Huber, and L. Moore. "Planting Date and Susceptibility to Pink Bollworm." College of Agriculture, University of Arizona (Tucson, AZ), 1990. http://hdl.handle.net/10150/208313.
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The susceptibility of cotton to spring emergence of pink bollworm (PBW) was evaluated for a variety of planting dates in Pinal Maricopa, LaPaz and Yuma counties using historical climate records and heat-unit-based models that predict PBW emergence and cotton development. Early planted cotton proved most susceptible to the PBW emergence, however, cotton type (shoe vs. long staple) and springtime weather conditions both played an important role in overall susceptibility.
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Brown, P., J. Silvertooth, and L. Moore. "Planting Date and Susceptibility to Pink Bollworm." College of Agriculture, University of Arizona (Tucson, AZ), 1991. http://hdl.handle.net/10150/208347.
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The susceptibility of cotton to spring emergence of pink bollworm (PBW) was evaluated for a variety of planting dates in Pinal, Maricopa, LaPaz and Yuma counties using historical climate records and heat - unit -based models that predict PBW emergence and cotton development. Early planted cotton proved most susceptible to the PBW emergence, however, springtime weather conditions also played an important role in determining overall susceptibility. Growers wishing to incorporate planting date as one aspect of PBW management should keep abreast of early season weather conditions.
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Wagstaff, Jessica. "Little Pink Pills: A History of Placebos." Thesis, The University of Arizona, 2012. http://hdl.handle.net/10150/244843.
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Why is it that folk remedies have endured the test of time? This review of the placebo effect begins with definitions of placebo and placebo effect. It delves into the history of the placebo and the placebo effects, from Cro-Magnon times up through current advances in medicine. Placebos were present in Ancient Rome and Greece, the Bible, Renaissance Europe. Many difference substances were used as placebos, including boiled dung, lizard blood, mold and unicorn horn. Current studies on depression and Parkinson's disease have shown the powerful responses placebos can produce. Future research is need to unveil the mechanisms and mediators involved in the placebo effect.
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Norton, Rachael M. "Pick interpolation, displacement equations, and W*-correspondences." Diss., University of Iowa, 2017. https://ir.uiowa.edu/etd/5586.
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The classical Nevanlinna-Pick interpolation theorem, proved in 1915 by Pick and in 1919 by Nevanlinna, gives a condition for when there exists an interpolating function in H∞(D) for a specified set of data in the complex plane. In 1967, Sarason proved his commutant lifting theorem for H∞(D), from which an operator theoretic proof of the classical Nevanlinna-Pick theorem followed. Several competing noncommutative generalizations arose as a consequence of Sarason's result, and two strategies emerged for proving generalized Nevanlinna-Pick theorems: via a commutant lifting theorem or via a resolvent, or displacement, equation.
We explore the difference between these two approaches. Specifically, we compare two theorems: one by Constantinescu-Johnson from 2003 and one by Muhly-Solel from 2004. Muhly-Solel's theorem is stated in the highly general context of W*-correspondences and is proved via commutant lifting. Constantinescu-Johnson's theorem, while stated in a less general context, has the advantage of an elegant proof via a displacement equation. In order to make the comparison, we first generalize Constantinescu-Johnson's theorem to the setting of W*-correspondences in Theorem 3.0.1. Our proof, modeled after Constantinescu-Johnson's, hinges on a modified version of their displacement equation. Then we show that Theorem 3.0.1 is fundamentally different from Muhly-Solel's. More specifically, interpolation in the sense of Muhly-Solel's theorem implies interpolation in the sense of Theorem 3.0.1, but the converse is not true. Nevertheless, we identify a commutativity assumption under which the two theorems yield the same result.
In addition to the two main theorems, we include smaller results that clarify the connections between the notation, space of interpolating maps, and point evaluation employed by Constantinescu-Johnson and those employed by Muhly-Solel. We conclude with an investigation of the relationship between Theorem 3.0.1 and Popescu's generalized Nevanlinna-Pick theorem proved in 2003.
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Vinberg, Karl, Jacob Holm, and Amer Basic. "Från periodisk inventering utan Pick By Voice till rullande inventering med Pick By Voice : En fallstudie på Företag X." Thesis, Linnéuniversitetet, Institutionen för ekonomistyrning och logistik (ELO), 2020. http://urn.kb.se/resolve?urn=urn:nbn:se:lnu:diva-96750.
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Titel: Från periodisk inventering utan Pick By Voice till rullande inventering med Pick By Voice - En fallstudie på Företag X Bakgrund och problem: Företag X har valt att implementera plocktekniken Pick By Voice, samtidigt som företaget ser över möjligheten att implementera en rullande inventering i samband med detta. Frågor som uppstår är vad lagar och praxis säger för området samt hur en möjlig implementering av rullande inventering bör se ut. Syfte: Syftet med uppsatsen är att genom en kvalitativ studie undersöka behovet av en ny inventeringsmetod genom en förstudie och därefter utveckla en inventeringsprocess passande efter Företag X förutsättningar. Denna inventeringsprocess ska kunna användas i samspel med Pick By Voice. Vidare är också att uppmuntra andra företag inom likartad bransch att se över sin nuvarande inventeringsmetod och om de kan implementera en liknande förändring av rullande inventering med Pick By Voice. Metod: Denna studie är en kvalitativ fallstudie. Insamlingen av empiri har skett genom utförandet av semistrukturerade och ostrukturerade intervjuer med företag och revisionsbyråer. Slutsats: En nu 65 år gammal skattelag säger att företag måste inventera sina lager minst en gång om året. Som en otillräcklig beskrivning av hur detta ska göras, samtidigt som lagerhanteringssystemet får ny utveckling, har detta lagt större vikt vid nuvarande praxis. Detta är särskilt så när ett företag implementerar en rullande inventeringsmetod. Viktiga steg i implementeringsprocessen bekräftas vara avgörande för företag att uppfylla. Dels för att lyckas med implementeringen, men också för att säkerställa en tillfredsställande inventeringsprocess och undvika att både misstag i implementerings- och inventeringssprocessen uppstår. Att kombinera den rullande inventeringen med röstplocktekniken Pick By Voice anses även det vara betydande för att reducera ytterligare misstag som förekommer eller kan förekomma i inventeringsprocessen. Hur frekvent företag bör inventera grundar sig i; vilken typ av marknad företaget är verksamt på, andelen misstag som uppstår i inventeringsprocessen och om fler antal inventeringar kan bidra till fler besparingar för företaget.Title: From periodic inventory without Pick By Voice to continuous inventory with Pick By Voice - A case study at Company X Background and problem: Company X has chosen to implement the Pick By Voice picking technology, while at the same time considering the possibility of implementing a continuous inventory in connection with this. Questions that arise are what the laws and practices say for this area and what a possible implementation of continuous inventory should look like. Purpose: The purpose of this thesis is to investigate the need for a new inventory method through a pilot study and then develop an inventory process suitable for Company X conditions. This inventory process should be used in interaction with Pick By Voice. Furthermore, other companies in similar industries are also encouraged to review their current inventory method and whether they can implement a similar change of continuous inventory with Pick By Voice. Method: This study is a qualitative case study. The collection of empirical data has been carried out through the conduct of semi structured and unstructured interviews with companies and accounting firms. Conclusion: A now 65 years old tax law says that companies need to count their inventory at least once a year. As there is an insufficient description of how this should be done, while also warehouse management system get new development, this has placed greater emphasis on current practice. This so, especially when a company is implementing a continuous inventory method with Pick By Voice. Important steps in the implementation process have been confirmed to be crucial to fulfil by the company. Especially in order to achieve a successful implementation of the process, ensure that the process fulfil its required satisfaction level and to avoid occurrence of mistakes in the implementation process as well as in the inventory process. The combination of continuous inventory and Pick By Voice is considered to be significant in the reduction of further mistakes that occur or can occur in the inventory process. The determination of the inventory frequency is dependent on; type of market that the company operates in, number of occurring mistakes in the inventory process and if an increase in number of inventory occasions can contribute to an increase in the savings.
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Duarte, Andressa. "Participação da via PI3K/AKT na produção de óxido nítrico por macrófagos peritoneais." Universidade de São Paulo, 2013. http://www.teses.usp.br/teses/disponiveis/17/17147/tde-21102013-112320/.
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A imunidade inata é responsável pela resposta inicial aos microrganismos, uma vez que impede, controla ou elimina a infecção. Esse sistema consiste em barreiras epiteliais, proteínas plasmáticas e células circulantes e teciduais. Dentre esses componentes, os macrófagos possuem grande importância, sendo capazes de controlar e eliminar agentes patogênicos através da fagocitose e produção de espécies reativas de oxigênio e nitrogênio. A ativação de PRRs por constituintes oriundos dos patógenos em macrófagos desencadeia eventos da resposta imune inata, ativados por diversas vias de sinalização intracelular. A via das PI3Ks é conhecida por regular várias funções nas células, como a regulação do ciclo celular, migração e produção de espécies reativas de oxigênio e nitrogênio. O NO é um mediador central na imunidade inata que, após estímulos inflamatórios, é produzido em altas quantidades através da iNOS. Macrófagos deficientes em PI3K produzem menos NO e apresentam prejudicado controle da infecção quando infectados por T. cruzi. O objetivo do presente trabalho foi investigar o papel da via PI3K na produção de NO por macrófagos peritoneais estimulados com LPS. Os macrófagos empregados no estudo, WT e PI3K-/-, possuem o mesmo fenótipo. Observamos que macrófagos PI3K-/- possuem uma menor produção de NO e expressam menos iNOS. A reduzida expressão de iNOS, após estímulo com LPS, é também observada quando macrófagos WT são tratados com inibidores seletivos da PI3K e AKT. Além disso, demonstramos que, concomitantemente à menor expressão da iNOS, ocorre deficiência na fosforilação da AKT e diminuição da ativação do fator de transcrição NF-kB, sugerindo que a PI3K participa da ativação do NF-kB. Foi observado ainda que o tratamento com PTX também diminui a expressão da iNOS. No entanto, macrófagos PAFR-/- expostos ao LPS presentam maior expressão da iNOS, enquanto os macrófagos CCR2-/- apresentam menor expressão dessa enzima nessas condições. Para investigar a implicação da via PI3K in vivo foi administrado LPS i.v., como modelo de choque endotoxemico, no qual observamos maior sobrevida em animais PI3K-/- comparado aos animais WT e menores níveis de nitrito no soro. Nossos dados sugerem que a enzima PI3K é crítica para expressão de iNOS e produção de NO pelos macrófagos, possivelmente através da ativação do receptor CCR2, estando envolvida na fisiopatologia do choque induzido por LPS.Innate immunity is the initial response to microorganisms, since it prevents, controls and eliminates infection. This system consists in epithelial barriers, plasma proteins and circulating and tissue cells. Among these components, macrophages have great importance, being capable of control and eliminate pathogen agents through phagocytosis and production of reactive oxygen and nitrogen species. Activation of PRRs by pathogens constituents in macrophages triggers events of the innate immune response, activated by various intracellular signaling pathways. PI3Ks pathway is known to regulate several functions in the cell, such as regulation of the cell cycle, migration and production of reactive oxygen and nitrogen species. NO is a central mediator in innate immunity, which after inflammatory stimuli, is produced in high levels by iNOS. PI3K-deficient macrophages produce less NO and exhibit impaired control of infection when infected by T. cruzi. The aim of the present study is to investigate the role of PI3K pathway in NO production by LPS-estimulated peritoneal macrophages. The macrophages used in this study, WT and PI3K- / -, have the same phenotype. We observed that PI3K- / - macrophages have a lower NO production and express less iNOS. The low expression of iNOS after stimulation with LPS was also observed in WT macrophages treated with selective inhibitors of PI3K and AKT. Furthermore, we demonstrate that, along to lower iNOS expression, there is deficiency in AKT phosphorylation and decreased activation of the transcription factor NF-kB, suggesting that PI3K participates of the NF-kB activation. It was also observed that PTX treatment has decreased iNOS expression. However, LPS-exposed PFAR-/- macrophages present greater expression of iNOS, while CCR2-/- macrophage exhibit lower expression of this enzyme under these conditions. To investigate involvement of the PI3K pathway has \"in vivo\",LPS was administered i.v., as an endotoxic model, in which we observed a higher survival in PI3K- / - animals compared to WT animals and lower nitrite levels in serum. Our data suggest that PI3K enzyme is critical to iNOS expression and NO production by macrophages, possibly through activation of the CCR2 receptor, being involved in the LPS-induced shock pathophysiology
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Chu, Ying Ying Julia. "Apoptosis is promoted by unconventional FcγR-PI3KCdc42-Pak-Mek-Erk signalling in the human neutrophil." Thesis, University of Edinburgh, 2017. http://hdl.handle.net/1842/28813.
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Neutrophils form a first line of defence against infections. These short-lived, terminally differentiated cells perform many important functions, including chemotaxis, degranulation, reactive oxygen species (ROS) release and cytokine production. Whilst neutrophils are essential for host immunity, their inappropriate recruitment, activation and/or removal can contribute to excessive inflammation and host damage, as exemplified in autoimmune diseases such as rheumatoid arthritis. It is therefore essential that neutrophil function is tightly regulated. Neutrophils are activated by a range of stimuli, including immune complexes. Neutrophil functions are tightly regulated by intracellular signalling events that are induced by the ligation of cell surface receptors, for example, the binding of immune complexes to Fc receptors. Phosphoinositide 3-kinase (PI3K) and extracellular signal-regulated kinase (Erk) are key signalling intermediates that act downstream of many cell surface receptors. They are involved in the regulation of numerous biological processes in the neutrophil. Using pharmacological interventions, I analysed PI3K signalling in immune complex-stimulated human neutrophils and uncovered a previously uncharacterised, noncanonical signalling pathway, PI3K-Cdc42-Pak-Mek-Erk. This represents an unusual situation where Pak acts as the MAP3K downstream of Cdc42 in a PI3K-dependent fashion. By performing a range of functional experiments, I showed that this unconventional signalling pathway promotes apoptosis in human neutrophils by regulating the ratio between anti- and pro-apoptotic members of the Bcl-2 family proteins. No other immune complex-induced, PI3K-dependent neutrophil function tested depended on PI3K-Cdc42-Pak-Mek-Erk signalling. Mouse knock-outs of all components of this signalling pathway have been described. Immune complex-induced apoptosis was also PI3K-dependent in mouse neutrophils, but experiments performed with inhibitors showed that, in contrast to human neutrophils, this was not dependent on PI3K-Cdc42-Pak-Mek-Erk signalling. The myeloid leukaemia cell line, PLB-985 is amenable to knock-down and can be differentiated to become neutrophil-like. These cells are not notably activated by immune complexes, perhaps because they do not express the major Fcγ receptor, CD16. Since retroviral expression of CD16 in PLB985 cells did not improve their response to activation by immune complexes, I was not able to confirm my observations with human neutrophils genetically. Collectively, I showed that a novel, pro-apoptotic signalling pathway operates downstream of Fcγ receptors in the human neutrophil. The fact that this signalling pathway appears to regulate apoptosis specifically suggests uncoupling pro- and anti-inflammatory effects induced by immune complexes might be possible. This may be helpful in the design of improved therapies of autoimmune diseases such as rheumatoid arthritis, in which immune complex-driven neutrophilic inflammation contributes to disease pathogenesis and where neutrophil apoptosis is disturbed.
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Killip, Marian J. "RNA virus modulation of IFN, PI3K and apoptosis." Thesis, St Andrews, 2009. http://hdl.handle.net/10023/777.
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