<p dir="ltr">UBE2C is upregulated in castration-resistant prostate cancer and shows strong correlation with high tumor grade. Currently, the scarcity of UBE2C inhibitors is alarming. This study is the first to report UBE2C post-translational modulation mediated by LIMK2 kinase. A proteome-wide screen previously conducted in the Shah lab has identified UBE2C as a direct substrate of LIMK2 using an innovative chemical genetic approach. LIMK2 regulates UBE2C in a variety of ways. First, LIMK2 directly associates with UBE2C in cells. Second, LIMK2 phosphorylates UBE2C at S123 and increases its stability at the protein level. Third, LIMK2 upregulates UBE2C mRNA and protein expression levels in cells. Contrary to its well-established function as an enzyme involved in the ubiquitin-proteosome pathway, UBE2C stabilizes LIMK2 protein expression in a reciprocal loop. This study is the first to show UBE2C stabilizing its substrate. Likewise, UBE2C increases LIMK2 mRNA and protein levels; however, the mechanism is to be elucidated. LIMK2-UBE2C loop is extremely oncogenic creating CRPC pathogenesis <i>in vivo</i>. Targeting LIMK2 is a suitable approach to effectively degrade both UBE2C and LIMK2 which leads to significant inhibition of tumor formation, cancer stem cell phenotype and epithelial to mesenchymal transition <i>in vivo</i>. Additionally, CDK1 for the longest time was thought to be the only protein of the cyclin dependent kinase family which binds to and is activated by cyclin B1 to regulate cell cycle progression. We first showed CDK5 activity in cell division and its importance in maintaining mitotic fidelity. We first established the activation of CDK5 by cyclin B1 <i>in vitro</i>. The phospho-mimetic CDK5 was observed to be less active when bound to cyclin B1 than its wild-type counterpart.</p>

<p>Från och med den 1 januari 2002 har närstående till en person som dödats genom en skadeståndsgrundande handling en i lag (5 kap 2 § skadeståndslagen) reglerad rätt till skadestånd för personskada som har åsamkats dem till följd av dödsfallet. Lagstiftaren har lagt ett stort ansvar på rättstillämparen gällande inte minst då det gäller att avgränsa gruppen ersättningsberättigade. Här tvingas jurister göra svåra bedömningar som ej är att beteckna som strikt juridiska, till exempel att avgöra vem som ”stod den avlidne särskilt nära”. I uppsatsen presenteras en arbetsmodell som utgår från de fyra kriterierna blodsband, hushållsgemenskap, tidsaspekt och förhållandet personerna emellan i övrigt. I och med nyttjandet av arbetsmodellen möjliggörs den nyanserade bedömning som lagstiftaren efterfrågar. De fyra kriterierna skall vägas samman vid bedömningen och de olika kriteriernas tyngd vid denna sammanvägning kan variera. Metoden erbjuder en utgångspunkt för hur bedömningen på ett metodiskt sätt kan genomföras och den är dessutom tillämpbar på de flesta situationer. På så sätt kommer vi ifrån den begränsande metoden att strikt följa typfall.Uppsatsen innehåller även en sammanställning av relevant praxis på området och en katalog med personkategorier som kan komma ifråga för ersättning.</p> / <p>From January 1st 2002 there is a statutory right for a deceased (culpa or dolus) person’s relatives, or more correctly persons with a close relationship to the desceased) to claim damages for their own emotional suffering. The legislator has put a huge responsibility on courts of law and insurance companies by letting these decide who is to be considered close and therefore entitled to damages. This report introduces a method to help them with this task. The Method is built on a test consisting of four different criteria: blood-relationship, household/cohabiting, time aspect and the relationship as such.</p>

Från och med den 1 januari 2002 har närstående till en person som dödats genom en skadeståndsgrundande handling en i lag (5 kap 2 § skadeståndslagen) reglerad rätt till skadestånd för personskada som har åsamkats dem till följd av dödsfallet. Lagstiftaren har lagt ett stort ansvar på rättstillämparen gällande inte minst då det gäller att avgränsa gruppen ersättningsberättigade. Här tvingas jurister göra svåra bedömningar som ej är att beteckna som strikt juridiska, till exempel att avgöra vem som ”stod den avlidne särskilt nära”. I uppsatsen presenteras en arbetsmodell som utgår från de fyra kriterierna blodsband, hushållsgemenskap, tidsaspekt och förhållandet personerna emellan i övrigt. I och med nyttjandet av arbetsmodellen möjliggörs den nyanserade bedömning som lagstiftaren efterfrågar. De fyra kriterierna skall vägas samman vid bedömningen och de olika kriteriernas tyngd vid denna sammanvägning kan variera. Metoden erbjuder en utgångspunkt för hur bedömningen på ett metodiskt sätt kan genomföras och den är dessutom tillämpbar på de flesta situationer. På så sätt kommer vi ifrån den begränsande metoden att strikt följa typfall.Uppsatsen innehåller även en sammanställning av relevant praxis på området och en katalog med personkategorier som kan komma ifråga för ersättning. / From January 1st 2002 there is a statutory right for a deceased (culpa or dolus) person’s relatives, or more correctly persons with a close relationship to the desceased) to claim damages for their own emotional suffering. The legislator has put a huge responsibility on courts of law and insurance companies by letting these decide who is to be considered close and therefore entitled to damages. This report introduces a method to help them with this task. The Method is built on a test consisting of four different criteria: blood-relationship, household/cohabiting, time aspect and the relationship as such.

Les travaux présentés s’axent autour de 2 chapitres indépendants : - le 1er concerne l’étude rhéologique d’une formulation pour SMC sans fibres. Cette étude permet d’élaborer des lois de comportement rhéologique. Ces lois sont ensuite insérées dans un code de calcul de simulation numérique afin de prédire les efforts mis en jeu lors d’une compression. Ces données simulées sont comparées avec des données de compression obtenues expérimentalement. - le 2ème se penche sur l’étude d’un comportement rhéologique rare : la rhéopexie négative. La viscosité de l’échantillon dépend de l’histoire de cisaillement qui lui est appliquée. Ce comportement est très sensible à la composition du mélange, et fait intervenir 4 constituants. Dès lors que l’un d’eux est retiré, le phénomène disparaît. Le mélange étudié est constitué de produits classiquement utilisés pour la production de SMC. / The research presented is divided into 2 independents chapters: - the 1st one focuses on the rheological study of a fibreless formulation for SMC. This study allows us to write constitutive equations of the formulation. These equations are in turn implemented in a numerical simulation program, in order to predict the forces generated during a compression experiment. These simulated data are eventually compared with experimental data obtained during compression.- the 2nd chapter concerns the study of a rare rheological behaviour: the negative rheopexy. The viscosity of the sample depends on its shear history, in a very different way than a thixotropic sample’s viscosity would. This rheological behaviour is very component sensitive, and results from the interactions between 4 components. As soon as one of them is missing, the negative rheopexy disappears. The mixture studied is constituted of products traditionally used for the production of SMC.

Ce mémoire présente l'implémentation d'un nouveau langage de programmation nommé Typer. Typer est un langage fonctionnel orienté vers la méta programmation. Il a été conçu pour augmenter la productivité du programmeur et lui permettre d'écrire des applications plus fiables grâce à son système de types. Pour arriver à ses fins, Typer utilise l'inférence de types et implémente un puissant système de macros. L'inférence de types permet à l'utilisateur d'omettre certains éléments, le système de macros, quant à lui, permet de compléter le programme pendant la compilation lorsque l'inférence n'est pas suffisante ou pour générer du code. Typer utilise les types dépendants pour permettre à l'utilisateur de créer des types très expressifs pouvant même être utilisés pour représenter des preuves formelles. De plus, l'expressivité des types dépendants permet au compilateur d'effectuer des vérifications plus approfondies pendant la compilation même. Ces mécaniques permettent au code source d'être moins verbeux, plus concis et plus simple à comprendre, rendant, ainsi l'écriture de programmes ou/et de preuves plus plaisante. Ces fonctionnalités sont implémentées dans l'étape que nous appelons l'élaboration, à l'intérieur de laquelle de nombreuses transformations du code source ont lieu. Ces transformations incluent l'élimination des aides syntaxiques, la résolution des identificateurs, l'expansion des macros, la propagation et l'inférence des types. / This dissertation present the implementation of a new programming language named Typer Typer is a functional programming language oriented towards meta programming. It has been created to increase the programmer productivity and enable him to write safer programs thanks to his type system. To achieve his goal, Typer use type inference and a powerful macro system. Type inference enable to user to elide some elements while the macro system enable us to complete the program during compilation. Typer use dependent type which enable the user to create very expressive types which can even be used to represent formal proofs. Furthermore, dependent type's expressivity enable the compiler to perform a in-depth checks during compilation. Those mechanics enable the source code to be less verbose, shorter and easier to understand, making the writing of new programmes more enjoyable. Those functionalities are implemented during the step we call the elaboration in which numerous transformations occur. Those transformations include the removal of syntactic sugar, identifier resolution, macro expansion and the propagation and the inference of types.

Structural integrity assessment of nuclear components assessed using the R6 Failure Assessment Diagram approach requires an understanding of the limiting condition in terms of both fracture and plastic collapse. For ductile materials, such as stainless steels used for nuclear components, including the primary pipe-work of a Pressurised Water Reactor (PWR), the limiting condition defined by plastic collapse is likely to occur prior to the initiation of fracture. This is due to the relatively low yield stress of the material and the high fracture toughness. If this is the case, structural integrity may be solely assessed on plastic collapse criteria, with little or no reference to fracture toughness; thus considerably simplifying the assessment procedure, whilst maintaining the integrity of the plant. Nevertheless, an in-depth understanding of fracture under plastic collapse conditions is required to make a robust case for single parameter assessments based on a plastic collapse criterion alone. The challenge in this project lay in understanding and predicting ductile fracture initiation under large-scale yielding conditions, i.e. outside the normal validity limits of conventional elastic-plastic fracture mechanics as plastic collapse conditions are achieved. The approach developed in this research has explored three fracture assessment methods: (a) two parameter fracture mechanics based on the J-integral and a refined Q-parameter calculated closer to the crack-tip under widespread plasticity than is conventionally the case, (b) two local approach methods based on critical void growth ratio defined by Rice and Tracey, and (c) a local approach method based on the critical work of fracture. All three methodologies were found to adequately describe failure across a range of constraint conditions. The fracture toughness constraint dependence of 304(L) stainless steel was studied experimentally and analytically. Significant constraint loss was shown to occur in nominally high constraint fracture toughness specimens due to extensive plastic deformation at fracture initiation. Furthermore, significant fracture toughness constraint dependence was observed experimentally. An analytical method using local approach criteria was developed to predict high constraint fracture toughness, required for structural integrity assessments, and to quantify the constraint dependence fracture toughness as a function of two parameter fracture mechanics based on the J-integral and the refined Q-parameter. The influence of constraint on the prediction of failure in a stainless steel pipe containing a fully circumferential crack of various depths was investigated analytically for a range of loading conditions. A refined constraint independent failure assessment methodology was developed using local approach analyses. Using this methodology, the pipe component was shown to consistently fail by plastic collapse irrespective of the crack depth or loading condition. The conservatism of the conventional structural integrity assessment was quantified and shown to vary with crack depth and with loading conditions. This research has suggested that failure in a 304(L) stainless steel pipe will be by plastic collapse prior to ductile initiation for a limited range of defects and loading conditions. Further analytical studies and experimental work will be required to demonstrate whether this observation is general for a wider range of defects and loading conditions.

This master thesis is focused for design, respectively for creating counterproposal of existing structure of Motorway Bridge located at D1 motorway between Jánovce and Jablonov in district Levoča in Slovakia. This bridge is over a local road. The main aim of this thesis is design, analysis and assessment of bearing elements of bridge deck. For purposes of this thesis was created three variants of bridge deck. Detailed analysis was performed on bearing construction from post-tensioned precast beam with monolithing concrete slab. Two mathematic models were used for analysis of chosen variant. First model was spatial 3D shell construction. The purpose of this model was determinate cross spreading line of other constant load and live load. Second, flat 2D model, was for determination creep and shrinkage appeared from long-term load. These effects were observed in at advanced defined time nodes. Outcomes from upper mentioned model were used from design and assessment of bearing elements of bridge deck, design prestressed reinforcement cables and concrete reinforcement rods.

The demand for automated home solutions is growing and it has created a market for automated blinds. For now most of these solutions seem to focus on fully opening and closing, either rolling blinds or slat blinds, with different electronic solutions. There doesn’t seem to be many solutions for continuously regulating light inlet based on ambient light. This project examined the possibilities of continuously regulating the amount of natural light let through a window. This was tested by measuring ambient light on one side of the blind with light dependant resistors (LDR’s) and regulating a Venetian blind based on measured light intensity. A feed-forward controller was implemented, programmed on an Arduino Uno board, to control sensors and actuators that regulate the blind. A prototype unit was built on a window-resembling wooden frame to evaluate the performance of the controller. The light sensitivity of LDR’s were sufficient for measuring differences in ambient light in different conditions where an automated blind could be used. The final prototype could be set to adjust light inlet in increments for changes in ambient light, thereby opening up to uses beyond simply closing and opening a light inlet. Future improvements could be to implement a feedback controller (e.g. a PID controller). The controller could be set to a certain reference as preferred ambient lighting in a room, thereby letting the controller adjust the blinds towards that reference value while conditions outside and inside change during the day. This could also be implemented in already existing smart home solutions. / Efterfrågan på automatiserade hemmalöningar är växande och det har skapat en marknad för automatiserade persienner. För nuvarande verkar det de flesta lösningarna fokusera på att helt öppna eller stänga, antingen rullgardiner eller persienner, med olika elektriska lösningar. Det verkar inte finnas många lösningar med kontinuerlig justering av inkommande omgivningsljus. Detta projekt utforskar möjligheterna för kontinuerlig justering av mängden naturligt ljus som släpps igenom ett fönster. Detta gjordes genom att mäta omgivande ljus på ena sidan av persiennen med fotoresistorer och reglera persiennen baserat på den uppmätta ljusintensiteten. Framkopplad styrning implementerades, programmerad på en Arduino Uno, för att styra sensorer och ställdon som reglerar persiennen. En prototypenhet byggdes på en fönsterliknande träram för att utvärdera prestandan av styrenheten.  Ljuskänsligheten i fotoresistorerna var tillräcklig för att mäta skillnader i omgivningsljus för de olika förhållanden där automatiserade persienner skulle kunna användas. Den slutgiltiga prototypen kunde ställas in att justera ljusinsläppet stegvis för skillnader i omgivningsljus, vari nya användningsområden öppnas upp utöver att endast stänga och öppna ett ljusinsläpp.  Framtida förbättringar skulle kunna vara att implementera en återkopplande styrning (t.ex. PID-styrning). Styrenheten skulle kunna ställas in till ett specifikt referensvärde på önskat omgivande ljus i ett rum, vari kontrollern justerar persiennerna för att hålla det önskade referensvärdet medan förhållanden utomhus och inomhus varierar under dagen. Detta skulle även kunna implementeras i redan befintliga smarta lösningar för hemmet.

Les leucémies aigües lymphobastiques (LAL) représentent un tiers des leucémies et constituent le cancer pédiatrique le plus fréquent chez l’enfant. Les LAL de type T (LAL-T)sont caractérisées par l’expansion anormale de progéniteurs de lymphocytes T. Aujourd’hui,la réponse curative aux traitements est proche de 80% chez l’enfant et 50% chez l’adulte. La rechute reste donc fréquente et souvent de mauvais pronostic. Pour ces raisons,l’identification de nouvelles voies de signalisation en vue de développer de nouvelles stratégies thérapeutiques est cruciale afin d’améliorer le traitement des LAL-T.Les résultats précédents du laboratoire ont révélé l’activation soutenue de la voie calcineurine (Cn)/NFAT dans des échantillons humains de lymphomes et de LAL, ainsi que dans des modèles murins de ces pathologies. Le laboratoire a ensuite montré que Cn est intrinsèquement requise pour la capacité des cellules leucémiques de LAL-T à propager la maladie (activité LIC « Leukemia Initiating Cells ») dans un modèle murin de LAL-T induit parun allèle activé de NOTCH1 (ICN1). Puisque l’inhibition pharmacologique de Cn induit de nombreux effets secondaires, la recherche de cibles thérapeutiques en aval de Cn constitue un axe de recherche important. J’ai participé à une étude du laboratoire montrant que l’expression à la surface cellulaire de CXCR4 est régulée par Cn et requise pour la migration des cellules de LAL-T, mais non suffisante pour rétablir le potentiel de ré-initiation suggérant que d’autres effecteurs doivent être impliqués dans cette activité.Les facteurs de transcription NFAT (NFAT1, NFAT2 et NFAT4) sont des effecteurs importants de Cn en réponse à la signalisation calcique lors du développement des thymocytes, mais également dans les lymphocytes T. L’essentiel de ce travail de thèse a utilisé des LAL-T induites par ICN1 dans lesquelles l’inactivation génique des trois facteurs NFAT par recombinaison homologue. Nous avons ainsi montré que (i) les facteurs NFAT sont requis en aval de Cn pour le potentiel LIC des LAL-T-ICN1 in vivo, (ii) leur inactivation altère la survie, la prolifération et la migration des cellules de LAL-T in vitro, (iii) NFAT1,NFAT2 et NFAT4 ont une fonction largement redondante dans les LAL-T. Nous avons également par une approche transcriptomique identifié deux gènes dont l’expression estsous contrôle des facteurs NFAT et impliqués dans la régulation de la survie et de la prolifération des LAL-T in vitro : CDKN1A et MAFB.Tout comme la voie Cn/NFAT, les CaMKs sont des protéines kinases activées en aval de la signalisation calcique dans les lymphocytes T. Nous avons montré par une approche pharmacologique que l’inhibition des CaMKs dans les LAL-T-ICN1 in vitro altère la survie etla prolifération des cellules leucémiques. L’inhibition spécifique par une approche d’ARN interférence de deux isoenzymes CaMKIIγ et CaMKIIδ suggèrent que ces protéines jouent dans le maintien des cellules leucémiques in vitro. / T cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy of T cell progenitors. Despite initial response to chemotherapy, relapses remain frequent in children and adults. Previous results identify sustained activation of Calcineurin (Cn)/NFAT signaling pathway in human T-ALL and murine T-ALL models. Importantly, they also demonstrated Cn is essential for T-ALL Leukemia Initiating Cells (LIC) activity in a murine model of T-ALL induced by an activated allele of NOTCH1 (ICN1). Since pharmacologic inhibition of Cn induces side effects, we aim to identify downstream effectors involved in T-ALL. NFAT (Nuclear Factor of Activated T cells) factors play crucial roles downstream Cn during development and activation of T cells. To address their role in T-ALL, we generated mouse ICN1-induced T-ALL in which NFAT genes can be inactivated either single or in combination following Cre-mediated gene deletion. We demonstrated that (i) NFAT factors are required downstream Cn for LIC activity in T-ALL in vivo (ii) ex vivo NFAT factors deletion alters survival, proliferation and migration of T-ALL (iii) NFAT1, 2 and 4 have a largely redundant function in T-ALL. Moreover, the NFAT-dependant transcriptome allowed to identify important targets (CDKN1A, MAFB) involved in T-ALL survival and proliferation in vitro. Calmodulin-dependant kinases (CaMK) are kinases activated by calcium signaling in T cells. We showed that pharmacologic inhibition of CaMKs in ICN1-induced T-ALL alters survival and proliferation of T-ALL in vitro. Beside, specific inhibition by RNA interference of CaMKIIg and CaMKIId suggests a putative role of these kinases in T-ALL maintenance.

A cryogenic (325-80 K) ion mobility-mass spectrometer was designed and constructed in order to improve the analytical figures-of-merit for the chemical analysis of small mass analytes using ion mobility-mass spectrometry. The instrument incorporates an electron ionization source, a quadrupole mass spectrometer, a uniform field drift cell spectrometer encased in a cryogenic envelope, and an orthogonal geometry time-of-flight mass spectrometer. The analytical benefits of low temperature ion mobility are discussed in terms of enhanced separation ability, ion selectivity and sensitivity. The distinction between resolving power and resolution for ion mobility is also discussed. Detailed experimental designs and rationales are provided for each instrument component. Tuning and calibration data and methods are also provided for the technique. Proof-of-concept experiments for an array of analytes including rare gases (argon, krypton, xenon), hydrocarbons (acetone, ethylene glycol, methanol), and halides (carbon tetrachloride) are provided in order to demonstrate the advantages and limitations of the instrument for obtaining analytically useful information. Trendline partitioning of small analyte ions based on chemical composition is demonstrated as a novel chemical analysis method. The utility of mobility-mass analysis for mass selected ions is also demonstrated, particularly for probing the ion chemistry which occurs in the drift tube for small mass ions. As a final demonstration of the separation abilities of the instrument, the electronic states of chromium and titanium (ground and excited) are separated with low temperature. The transition metal electronic state separations demonstrated here are at the highest resolution ever obtained for ion mobility methods. The electronic conformational mass isomers of methanol (conventional and distonic) are also partially separated at low temperature. Various drift gases (helium, neon, and argon) are explored for the methanol system in order to probe stronger ion-neutral interaction potentials and effectuate higher resolution separations of the two isomeric ions. Finally, two versatile ion source designs and a method for axially focusing ions at low pressure (1-10 torr) using electrostatic fields is presented along with some preliminary work on the ion sources.