Objective: The cytotoxic property of anti-EGFR-1 monoclonal-antibody nimotuzumab modified with nuclear localization sequence and radiolabeled with 111In was evaluated in trastuzumab-resistant breast cancer cells. Methods: 111In-nimotuzumab-NLS was constructed and its immunoreactivity was determined. Cellular and nuclear uptake was evaluated by cell fractionation. Finally, the cytotoxicity of conjugates (111In-nimotuzumab/111In-nimotuzumab-NLS) was studied by clonogenic assays. Results: The immunoreactivity of 111In-nimotuzumab-NLS was conserved. 111In-nimotuzumab-NLS exhibited 2-fold higher nuclear translocation as compared to 111In-nimotuzumab in MDA-MB-468 cells. Nuclear importation of 111In-nimotuzumab-NLS in MDA-MB-468 cells was 4-fold and 6-fold higher than moderate and low EGFR expressing cell lines, respectively. Clonogenic survival (CS) for MDA-MB-468 cells showed 111In-nimotuzumab-NLS to be 10-folds and 60-folds more potent than 111In-nimotuzumab and nimotuzumab, respectively. Moderate killing for TrR1 and MDA-MB-231 was observed. 111In-hEGF showed significantly higher cytotoxicity and 2-fold higher γ-H2AX foci integrated density/nuclear-area as compared to 111In-nimotuzumab-NLS. Preserved selectivity of 111In-nimotuzumab-NLS makes it an excellent drug for treating cancers.

The recent discovery of Cr4AlB4, a laminated ternary metal boride belonging to the family of layered MAB-phases, where the transition metal boride layers are interleaved by an A layer, has spurred theoretical investigation for novel M4AlB4 phases. In this study, first-principles calculations were applied in order to investigate the thermodynamical stability and mechanical properties of M4AB4 where M = Cr, Hf, Mo, Nb, Ta, Ti, V, W, Zr while the A layer was kept fixed as Al. The thermodynamical stability calculations validate the recently discovered Cr4AlB4 phase’s stability and suggest the neighboring phase Mo4AlB4 to be stable. Additionally, the phases Mo3AlB4, Mo2AlB2, Ti4AlB4 and Ti2AlB2 indicates phases close to stable with a formation enthalpy within the range of 0 < ∆H < 25 meV per atom compared to competing phases. Hence dynamical stability investigations were carried out, which indicates Mo4AlB4 to be dynamically stable. The stability of Mo4AlB4 does encourage synthesizing attempts to be kept in mind as a future project. Phase stability trends of the 111, 212, 314 and 414 compositions were discovered, where a 212, 314 and 414 composition is seen to be more stable for an M-element with lower electron configuration. Furthermore, the mechanical properties of the 414 compositions were investigated by systematically straining the unit cell in different directions. The bulk-, shear- and Young’s-modulus were derived and are presented, where Ti4AlB4 demonstrates values similar to the commended Ti2AlC MAX-phase. Finally, ductility plots are presented which purposes a linear trend between the elements of group IV, V and VI. Based on the results, further studies with a focus on the temperature and magnetization’s impact on the stability and mechanical properties are suggested.

Sex determination is a key developmental process in several species regulated by sexrelated transcription factors. In many species a gene called doublesex and mab-3 related transcription factor 1 (dmrt1), plays an important role in sexual differentiation. I used African clawed frogs (Xenopus) to examine function of dmrt1 in two species: a diploid species, X. tropicalis, and an allotetraploid species, X. laevis. In both species, dmrt1 is an autosomal gene; Xenopus tropicalis has one copy of dmrt1 and X. laevis has two homeologous copies that by definition are derived from whole genome duplication: dmrt1.L and dmrt1.S in X. laevis. We generated knockouts of each of these genes to further examine their function in sexual differentiation. Histological examination showed testicular dysgenesis in X. tropicalis dmrt1 and X. laevis dmrt1.L null males whereas dmrt1.S null males presented no obvious difference in sperm density compared to wildtype males. X. tropicalis dmrt1 and X. laevis dmrt1.L null females were found to completely lack reproductive organs and are infertile whereas dmrt1.S null females appeared unaffected. The contrasting results between dmrt1.L and dmrt1.S in X. laevis provides evidence of both neofunctionalization and subfunctionalization following gene duplication and suggest that gene duplication is a major contributor to evolutionary change. Additional investigation of the transcriptome of these frogs and the role of dmrt1 in the secondary sex characteristic vocalization provides further evidence of the role of dmrt1 in development. Comprehensively, this investigation provides further knowledge of the role of dmrt1 and homeologs of this gene in sexual differentiation and introduces a novel aspect of this gene in female development. Future efforts are focused on generating double knockouts for dmrt1.L and dmrt1.S, further examining the role of dmrt1.S in somatic cell function and developing additional mutant lines in other Xenopus for comparative analysis. / Thesis / Master of Science (MSc) / In many species sexual differentiation is a crucial developmental event. Surprisingly, however, the systems orchestrating sexual differentiation are highly variable among species. The doublesex and mab-3 related transcription factor 1 (dmrt1) gene plays a role in sexual differentiation in many groups, but its specific roles in this process are incompletely characterized and potentially diverse. We used genetic engineering in two species of African clawed frog (Xenopus) to disable function of dmrt1 in order to explore effects on gonadal development and the development of secondary sex characteristics. We found that dmrt1 is required for normal ovary or testis development in both Xenopus species, and that functional divergence occurred following duplication of dmrt1 by whole genome duplication. Taken together, these findings identify previously uncharacterized roles of dmrt1 in Xenopus and provide evidence of dynamic functional evolution of this important gene.

A promising approach in combatting infections from antibiotic resistant bacteria/fungi is using therapeutic monoclonal antibodies (mAbs) that can bind the outer surfaces of microbes. We have developed a synthetic vaccine platform that can rapidly generate mAbs against surface glycans from desired strains, such as lipopolysaccharides and capsular polysaccharides. To create therapeutic antibodies against Ruminococcus gnavus, Burkholderia multivorans, and Staphylococcus aureus, we synthesize glycan antigens from each strain that are necessary for use in our glycoconjugate vaccine platform. Blooms of the Gram-positive bacterium Ruminococcus gnavus have been correlated with inflammatory bowel disease, and recently a polysaccharide produced by this organism was shown to stimulate release of inflammatory cytokines. This stimulation was proposed to signal through toll-like receptor 4. We have synthesized the pentasaccharide repeating unit of this polysaccharide and showed that it stimulates TNF-α and IL-6 release from bone marrow-derived dendritic cells in a TLR4-dependent manner. A related glycan does not stimulate significant cytokine release, demonstrating TLR4 selectivity in glycan recognition. Ceragenins are a class of antimicrobials that have broad-spectrum activity against many antimicrobial resistant strains of fungi, Gram-negative bacteria, and Gram-positive bacteria. Previous work has shown that ceragenins can tolerate large structural modifications without loss of activity, such as incorporation of long polyethylene glycol linkers and other domains with selective binding activities. Here we perform structure activity relationship studies of the tail domain of ceragenins to bind hydroxyapatite to combat bone infection, copper for preventing implant related infections, and as a bioresorbable antimicrobial for use in bioresorbable medical devices.

Flera kommuner runt om i Sverige rapporterar om att man har bostadsbrist. Orsaker tillatt det finns en bostadsbrist i Sverige är dels den höga byggkostnaden delsbefolkningsökning som sker. För att kunna möta upp bristen samt ökningen har detproducerats bostäder i en stor volym. Samtidigt som man bygger en stor mängd bostäder,går det att ifrågasätta hur många av dessa som håller viktiga kvaliteter som krävs förbostäder ska kunna uppnå trivsel och hemkänsla.Bostadsbristen som vi befinner oss i nu kan liknas med den bostadsbrist som Sverigebefann sig i på 50- och 60-talet. Det ledde då till att miljonprogrammet startades undermitten av 60-talet till mitten av 70-talet. Då byggdes mycket på kort tid och därefterupptäcktes brister i kvalitén och utförande. För att undvika bristerna i kvalitet är detviktigt att beakta grundfaktorer som skapar trivsel. Några av dessa grundfaktorer är de“omätbara värdena” som i samverkan med varandra skapar hemkänsla och trivsel i enbostad.Att skapa trivsamma bostäder och byggnader är en väldigt komplex uppgift i form av attman kan missa vissa grundfaktorer som främjar trivsel i bostäder. Därför behövs studiergöras för att se om dessa grundfaktorer finns med i dagens nyproduktion av bostäder.Detta på grund av att dagens byggindustri kan glömma viktiga punkter i sin projekteringoch bara tänker på kostnader och tid. Vilket gör att många viktiga parametrar kanglömmas bort och därför skapas en mindre trivsam bostad.Syftet med arbetet är att undersöka planlösningar för att kunna få en insikt i hur kvaliteteni nya lägenheter i flerbostadshus är. Arbetet granskar planlösningar från fyra kommunersom är slumpmässigt utvalda. För att avgöra kvaliteten i bostäderna utgår arbetet frånboken “Bostadens omätbara värden” av Ola Nylander samt “Manual för analys avBostadskvalitet” som är framtagen av forskare vid Chalmers.Den valda metoden är en fallstudie av stickprovskaraktär. I studien har de utvaldaplanlösningarna granskats och analyserats baserat på fyra parametrar om omätbara värdensamt en parameter med mätbart värde. De fyra omätbara värdena är rundgång, axialitet,dagsljus och rumsorganisation. Det mätbara värdet är Potential för kvarboende.Resultatet av arbetet redovisas genom figurer på planlösningarna där tydligt visas de olikaparametrar i figurer. Gruppen har gått igenom olika bostadsstorlekar från de fyra olikakommunerna. Storlekarna på bostäderna är 2 ROK, 3 ROK och 4 ROK.Slutsatsen av studien är att nya bostäder som byggs överlag uppfyller kraven uppställda i”Bostadens omätbara värden” samt ”Manual för analys av Bostadskvalitet”. Vidprojektering av bostäderna visas det i denna studie att arkitekter och projektörer har tänktpå de omätbara och mätbara värdena när lägenheterna tagits fram. Storleken på bostadenhar stor betydelse, eftersom det går att få med flera och bättre parametrar i bostaden omde innehåller flera rum. I mindre bostäder finns i vissa fall, brister i antal parametrar somsänker kvaliteten. Parametern från Manual för analys av Bostadskvalitét (MAB),Potential för kvarboende, gick att finna i planlösningarna på ett tydligt sätt. / Several municipalities around Sweden report that they have a housing shortage. Reasonswhy there is a housing shortage in Sweden are partly the high construction costs andpartly the population increase that is taking place. In order to meet the shortage as well asthe increase, housing has been produced in a large volume. At the same time as a largeamount of housing is being built, it is possible to question how many of these meet theimportant qualities required for housing to be able to achieve comfort and a sense offeeling of home.The housing shortage that we are in now can be compared to the housing shortage thatSweden was in in the 50s and 60s. That then led to the million program being started inthe mid-60s to the mid-70s. Back then, a lot was built in a short time and then flaws in thequality and execution were discovered. In order to avoid deficiencies in quality, it isimportant to consider basic factors that create well-being. Some of these basic factors arethe "immeasurable values" which, in cooperation with each other, create a sense of homeand well-being in a home.Creating pleasant homes and buildings is a very complex task and therefore it is easy tomiss certain basic factors that promote well-being in homes. Therefore, studies need to bedone to see if these basic factors are included in today's new housing production. This isbecause today's construction industry can forget important points in its planning and onlythinks about costs and time. Which means that many important parameters can beforgotten and therefore create a less pleasant home.The purpose of the work is to investigate floor plans in order to gain an insight into thequality of new apartments in apartment buildings. The work examines planning solutionsfrom four municipalities that are randomly selected. In order to determine the quality ofthe housing, the work is based on the book "The home ́s immeasurable value" by OlaNylander and "Manual for analysis of housing quality" developed by research scientist atChalmers.The chosen method is a random sample study. In the study, the selected floor plans havebeen reviewed and analyzed based on four parameters of immeasurable values and oneparameter with measurable value. The four immeasurable values are movement, axiality,daylight and room organization. The measurable value is Potential for remainingresidents.The result of the work is shown through figures on the floor plans where the variousparameters are clearly shown in figures. The group has gone through different housingsizes from the four different municipalities. The sizes of the homes are 2 RAK, 3 RAKand 4 RAK.The conclusion of the study is that new homes that are built generally meet therequirements set out in "The immeasurable values of housing" and "Manual for analysisof housing quality". When designing the homes, it is shown in this study that architectsand designers have thought about the immeasurable and measurable values when theapartments were designed. The size of the home is of great importance, as it is possible toget more and better parameters in the home if they contain several rooms. In smallerhomes there are, in some cases, deficiencies in the number of parameters that lower thequality. The parameter from the Manual for Analysis of Housing Quality (MAB),Potential for remaining residents, could be found in the floor plans in a clear way.

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

vi ABSTRACT IL-2 has been used in cancer therapy and also for other applications like treatment of chronic viral infections or as an adjuvant for vaccines. However, treatment with IL-2 is rather difficult due to its severe side effects. These toxicities, associated with high-dose treatment necessary for IL-2 to function, have been found the most limiting factor for IL- 2 applications. Further, particular anti-IL-2 monoclonal antibodies (mAb) can actually increase biological activity of IL-2 rather than block it. Binding of IL-2 to anti-IL-2 mAb creates a superagonistic immunocomplexes which have dramatically higher and selective biological activity in comparison to free IL-2 in vivo. Such approach may finally over- come the difficulties associated with administration of IL-2, thus opening brand new scopes for IL-2 and its application not only in the field of tumor therapy. We have shown that IL-2 immunocomplexes composed of IL-2 and anti-IL-2 mAb S4B6 (IL-2/S4B6) stimulate predominantly cells expressing CD122 and CD132 (dimeric IL-2 receptor), i.e. NK and MP CD8+ T cells, with Treg,  T and NKT cells being expanded as well. IL-2/S4B6 are able to drive the expansion of activated naive CD8+ T cells into functional memory-like CD8+ T cells. Moreover, these immunocomplexes exert therapeu- tical potential alone...

In this thesis, we address several generic problems concerned with procurement of tasks from a crowd that consists of strategic workers with uncertainty in their qualities. These problems assume importance as the quality of services in a service marketplace is known to degrade when there is (unchecked) information asymmetry pertaining to quality. Moreover, crowdsourcing is increasingly being used for a wide variety of tasks these days since it offers high levels of flexibility to workers as well as employers. We seek to address the issue of quality uncertainty in crowdsourcing through mechanism design and machine learning. As the interactions in web-based crowdsourcing platform are logged, the data captured could be used to learn unknown parameters such as qualities of individual crowd workers. Further, many of these platforms invite bids by crowd workers for available tasks but the strategic workers may not bid truthfully. This warrants the use of mechanism design to induce truthful bidding. There ensues a complex interplay between machine learning and mechanism design, leading to interesting technical challenges. We resolve some generic challenges in the context of the following problems. Design of a quality eliciting mechanism with interdependent values We consider an expert sourcing problem, where a planner seeks opinions from a pool of experts. Execution of the task at an assured quality level in a cost effective manner turns out to be a mechanism design problem when the individual qualities are private information of the experts. Also, the task execution problem involves interdependent values, where truthfulness and efficiency cannot be achieved in an unrestricted setting due to an impossibility result. We propose a novel mechanism that exploits the special structure of the problem and guarantees allocative efficiency, ex-post incentive compatibility and strict budget balance for the mechanism, and ex-post individual rationality for the experts. Design of an optimal dimensional crowdsourcing auction We study the problem faced by an auctioneer who gains stochastic rewards by procuring multiple units of a service from a pool of heterogeneous strategic workers. The reward obtained depends on the inherent quality of the worker; the worker’s quality is fixed but unknown. The costs and capacities are private information of the workers. The auctioneer is required to elicit costs and capacities (making the mechanism design dimensional) and further, has to learn the qualities of the workers as well, to enable utility maximization. To solve this problem, we design a dimensional multi-armed bandit auction that maximizes the expected utility of the auctioneer subject to incentive compatibility and individual rationality while simultaneously learning the unknown qualities of the agents. Design of a multi-parameter learning mechanism for crowdsourcing We investigate the problem of allocating divisible jobs, arriving online, to workers in a crowd-sourcing platform. Each job is split into a certain number of tasks that are then allocated to workers. These tasks have to meet several constraints that depend on the worker performance. The performance of each worker in turn is characterized by several intrinsic stochastic parameters. In particular, we study a problem where each arriving job has to be completed within a deadline and each task has to be completed, honouring a lower bound on quality. The job completion time and quality of each worker are stochastic with fixed but unknown means. We propose a learning mechanism to elicit the costs truthfully while simultaneously learning the stochastic parameters. Our proposed mechanism is dominant strategy incentive compatible and ex-post individually rational with asymptotically optimal regret performance.

Philosophiae Doctor - PhD / The domesticated apple (Malus x domestica Borkh.) has been distributed into diverse climatic conditions worldwide for commercial production of fruit. Apple trees need exposure to cold temperatures, referred to as chill unit (CU) accumulation during winter, in order for budbreak to occur promptly and uniformly after winter. In warmer production areas the application of dormancy breaking chemicals has enabled successful production of high chilling requiring apple cultivars in suboptimal environmental conditions. In the Western Cape region of South Africa it is common orchard practice to apply dormancy breaking chemicals after winter in order to stimulate vegetative growth. If this is not done prolonged dormancy symptoms (PDS) are experienced which include extended rest, less synchronised breaking of buds and reduced branching. An increasing awareness of both global warming and the negative effects associated with the use of chemical sprays (for both pest and disease resistance and growth regulation) has resulted in the need to breed cultivars better adapted to current and future environmental conditions. The breeding of new cultivars using conventional breeding methods is a time consuming process, especially in perennial tree species with a long juvenile phase such as apple. The implementation of marker-assistedbreeding (MAB) and selection (MAS) will enable the selection of favourable genotypes at a very early seedling stage. Although markers linked to genes involved in disease resistance for a variety of known apple pathogens have been identified and are already in use in breeding programs, the genetic determinants of dormancy related characteristics residing within the bud itself iii (endodormancy) are poorly understood. This hampers the genetic improvement of such characters. Although this study focused on time of initial vegetative budbreak IVB, there are various other characteristics that can be associated with dormancy, such as position and number of budbreak and budbreak duration.

La connaissance des effets et modes d’action des QTL (Quantitative Trait Loci) de résistance des plantes aux maladies est un enjeu majeur pour l’exploitation durable des résistances génétiques en agriculture. Dans le pathosystème pois/Aphanomyces euteiches, présentant une importance économique majeure, l’objectif de la thèse a consisté à valider les effets de QTL de résistance, seuls ou en combinaison, et à connaitre leurs modes d’action sur les étapes du cycle de l’agent pathogène. Un total de 157 NILs (Near Isogenic Lines) de pois issues d’un programme de Back-cross Assisté par Marqueurs, porteuses d’aucun, un, deux ou trois des sept principaux QTL de résistance préalablement identifiés, a été génotypé à l’aide d’une puce 15K SNPs et évalué pour la résistance. Les NILs porteuses de QTL à effets majeurs, seuls ou en combinaison avec des QTL à effets mineurs,ont présenté des niveaux accrus de résistance partielle en conditions contrôlées et au champ par rapport aux NILs dépourvues de QTL, dans différents fonds génétiques. Certaines NILs comportant des QTL individuels ou combinés à effets mineurs ont également montré un niveau réduit de sévérité de la maladie dans l’une ou les deux conditions de test. La plupart des QTL a présenté des effets significatifs sur le ralentissement de l’infection et/ou de la quantité d’ADN pathogène ayant colonisé la racine pendant sept jours après inoculation. Cette thèse fournit des outils et éléments de choix de QTL à combiner en sélection pour augmenter l’efficacité de la résistance partielle à A. euteiches dans les futures variétés de pois / Knowledge of the effects and action modes of resistance QTL to plant diseases is a major challenge for the durable use of genetic resistances in agriculture. In the pea/Aphanomyces euteiches pathosystem, which has a major economic importance, the aim of this study was to validate the single or combined effects of main resistance QTL, and study their action modes on steps of the pathogen life cycle. A total of 157 pea NILs (Near Isogenic Lines) created by Marker-Assisted Back-crossing and carrying no, one, two or three of the seven main resistance QTL previously identified, was genotyped using a 15K SNPs array and evaluated for resistance. The NILs carrying major-effect QTL, individually or in combination with minor-effect QTL, had increased levels of partial resistance in controlledconditions and in the field compared to NILs without QTL, in different genetic backgrounds. Several NILs carrying single or multiple minor-effect QTL also showed reduced levels of disease severity in one or the two test conditions. Most of the QTL had significant effects on slowing down infection and/or pathogen DNA quantity which had colonized the root for seven days after inoculation. This study gives tools and information for the choice of resistance QTL to use in pyramiding breeding strategies for increasing partial levels of resistance to A. euteiches in future pea varieties.