Zinc finger nucleases (ZFNs) induce double-strand DNA breaks at specific recognition sites. ZFNs can dramatically increase the efficiency of incorporating desired insertions, deletions, or substitutions in living cells. These tools have revolutionized the field of genome engineering in several model organisms and cell types including zebrafish, rats, and human pluripotent stem cells. There have been numerous advances in ZFN engineering and characterization strategies, some of which are detailed in this work. The central theme of this dissertation is improving the activity and specificity of engineered zinc finger nucleases with the ultimate goal of increasing the safety and efficacy of these tools for human therapy. As a first step, I undertook a large-scale effort to demonstrate that the modular assembly method of ZFN synthesis has a significantly higher failure rate than previously reported in the literature. This strongly suggested that engineering of ZFNs should better account for context-dependent effects among zinc fingers. The second advance reported in this dissertation is a method for biasing repair of zinc finger protein-induced DNA breaks toward homology-driven rather than error-prone repair in the presence of a donor template. Catalytically inactivating one monomer of a ZFN dimer results in a zinc finger nickase (ZFNickase) whose cleavage preference is directed at only one DNA strand. In human cell reporter assays, these ZFNickases exhibit a higher likelihood of repair by homology-driven processes, albeit with reduced absolute rates of correction. With further optimization, zinc finger nickases could provide a safer alternative to ZFNs in the context of gene correction therapies. Third, realizing there was no robust method for determining off-target cleavage sites of ZFNs in a genome-wide manner, I validated a collaborator’s novel in vitro selection system in human cells by identifying eight new potential off-target cleavage sites for a ZFN pair currently being used in clinical trials. Although it is unlikely these low-frequency mutations would be deleterious to patients, these results demonstrated that ZFNs induced more off-target effects than had been appreciated by previous work in the field. Collectively, the findings of this dissertation have contributed to more robust strategies for designing and evaluating ZFNs.

Purpose – Previously, modularity has mainly been studied in a production context. This paper highlights the opportunities and challenges of a modular strategy in an internationalisation context. It identifies which module components become active when entering new markets and suggests a model for how a modular internationalisation architecture can be designed. Design/methodology/approach – Results from a single case study of a multinational corporation in the vehicle industry, where managers of different departments involved in the internationalisation process support the possibility to create a modular internationalisation architecture. Findings – The findings suggest that the most important opportunities arising from modularity when entering new markets are the clear structure and shorter time to market. The main challenges to overcome are the risk of loss of flexibility and the issues of designing a modular architecture. Based on the key components in the case firm, one initial project-based departmentalised matrix structure is designed which can also help overcome the issues of choosing between standardisation and adaptation. Practical implications – The modular internationalisation architecture may help managers in multinational corporations who are already working with modularity in production to also organise the internal structure of their internationalisation process. Originality/value – This study includes a new model for multinational corporations entering new markets – the modular internationalisation architecture – which makes it possible to structure processes depending on internationalisation factors. The model should be seen as an initial suggestion of how a modular internationalisation architecture can be designed, but it may need to be further developed and tested. Keywords – International business, Internationalisation strategy, Organisational structure, Modularity, Modular processes, Modules, Components Paper type – Master’s thesis

The goal of this thesis is two-fold. First, it gives an efficient method for calculating the action of Hecke operators in terms of "Manin" symbols, otherwise known as "M-symbols," in the first homology group of Bianchi spaces. Second, it presents data that may be used to understand and better state an unpublished conjecture of Fukaya, Kato, and Sharifi concerning the structure of Bianchi Spaces modulo Eisenstein ideals [5]. Swan, Cremona, and others have studied the homology of Bianchi spaces characterized as certain quotients of hyperbolic 3-space [3], [13]. The first homology groups are generated both by modular symbols and a certain subset of them: the Manin symbols. This is completely analogous to the study of the homology of modular curves. For modular curves, Merel developed a technique for calculating the action of Hecke operators completely in terms of "Manin" symbols [10]. For Bianchi spaces, Bygott and Lingham outlined methods for calculating the action of Hecke operators in terms of modular symbols [2], [9]. This thesis generalizes the work of Merel to Bianchi spaces. The relevant Bianchi spaces are characterized by imaginary quadratic fields K. The methods described in this thesis deal primarily with the case that the ring of integers of K is a PID. Let p be an odd prime that is split in K. The calculations give the F_p-dimension of the homology modulo both p and an Eisenstein ideal. Data is given for primes less than 50 and the five Euclidean imaginary quadratic fields Q(√-1), Q(√-2), Q(√-3), Q(√-7), and Q(√-11). All of the data presented in this thesis comes from computations done using the computer algebra package Magma.

Pateikiami trys modulinių laukiamojo baldų variantai. Pagrindinė medžiaga, iš kurios padaryti baldai, yra plastikas. Plastikiniai baldai patogūs, juos paprasta prižiūrėti, lengva pernešti iš vienos vietos į kitą, ir jie yra pigesni. Norint pakeisti baldų išdėstymą nekils problemų. Šiame projekte nėra prisirišama prie plano, moduliniai baldai projektuoti oro uosto laukiamojo salei. Tačiau juos galima pritaikyti ir kitose viešose erdvėse kaip traukinių, autobusų stotis ir t.t. Atrinktos penkios idėjos, iš kurių trys galutinai išplėtotos. Visuose trijuose variantuose suprojektuotas šviečiantis modulis, centrinis akcentas su vandeniu, ir galimybe atsisėsti. Pirmajį variantą sudaro šviečiantis elementas bukam kampui, metalinis elementas stačiam kampui, plastikinis elementas smailiam kampui, plastikinė kilpa, šiukšliadėžė, centrinis akcentas. Centrinis akcentas jungia grindis ir lubas, jame įrengtas LED apšvietimas, tekančio vandens atkarpa. Antrajį variantą sudaro koriuko formos elementai – elementas atsisėsti be atlošo, šviečiantis elementas atsisėsti su atlošu, elementas su jame pasėta žole, šiukšliadėžė, centrinis akcentas. Centrinis akcentas suprojektuotas iš skirtingų dydžių korio formos marmuro plokštumų, jame įrengtas apšvietimas ir vandens telkinys. Trečiajį variantą sudaro sėdimoji dalis, šviečiantis elementas, šiukšliadėžė, centrinis akcentas. Centriniame akcente įrengtas fontanas, padaryti platesni fontano kraštai, kad būtų galima prisėsti. Po sėdimosios dalies... [toliau žr. visą tekstą] / Three variations of the modular lounge furniture are presented. The main material used to make furniture is plastic. Plastic furniture is comfortable and cheaper. It is easy to handle and move from one place to another. Therefore the change of furniture arrangement does not cause any problems. This project does not accurately follow the plan; modular furniture was designed for the airport departue lounge, but it can be adjusted to use in other public space, such as ralway or bus station, etc. Five ideas were chosen and three of them were developed till the end. All three variations include a luminous module as a central part with water and sitting possibility designed. The first variation consists of luminous element for a blunt corner, metal element for a sharp corner, plastic element for an acute corner, plastic loop, litterbin and a central part. Central part ties in a floor with a ceiling, it includes LED ilumination and running water segment installed. The second variation consists of the comb form elements – sitting element without a backrest, luminous sitting element with a backrest, element with a grass inside it, litterbin and a central part. Central part is designed using different sizes of the comb form marble flats with illumination and water body installed. The third variation consists of the sitting part, luminous element, litterbin and central part. Central part includes a fountain with wide edges to sit on. Illumination is installed under the sitting part.

The ongoing search for energy conservation in built structures and during the construction process prompted this thesis work to explore the use of sustainable technologies for floor heating systems. The thesis work explores the use of thermoplastic material as a sustainable substitute material for future floor heating systems. Concrete materials are presently used extensively for floor heating systems. Thermoplastic materials are seldom used for floor heating and the primary focus of this thesis is to explore the suitability & adaptability of thermoplastics as an innovative energy saving floor heating material. A thorough study of energy demands and the impact on environment due to greenhouse gas emissions has been done. Thermoplastic materials are environmental friendly and light weight. They exhibit high thermal conductivity which is favourable for the floor heating systems. A design technique has been developed for the use of thermoplastic materials as an energy efficient floor heating material. The present technique creates a new modular floor heating system. The design technique uses thermoplastic material of size 2.4m x1.2m with embedded electric heaters. Thermoplastic foam panels act as a single building block. A numerical simulation has been carried out to study the heat transfer characteristics of the proposed material. Limited experiments were conducted to verify the validity of the simulation results. The results from the experiments indicate good agreement with simulation results. The energy savings from the thermoplastic floor heating systems have been compared with that of electrical floor heating systems. The adaptability of the new floor heating system in terms of energy savings and cost benefit analysis is also discussed. / sustainable floor heating system

The Escherichia coli O9a and O8 antigen serotypes represent model systems for the ABC transporter-dependent synthesis of bacterial polysaccharides. Their O-antigens are linear mannose homopolymers containing conserved reducing termini (the primer-adaptor), a variable repeat-unit domain, and a non-glycan terminator. Synthesis of these glycans occurs on the polyisoprenoid lipid acceptor, undecaprenyl pyrophosphoryl-β-GlcNAc, due to the sequential activities of two conserved mannosyltransferases, WbdC and WbdB, and a serotype-specific mannosyltransferase, WbdA. The work reported in this doctoral thesis establishes a model for biosynthesis of the O8 and O9a antigens using a combination of in vivo (mutant complementation) experiments and in vitro strategies with purified enzymes and synthetic acceptors. WbdC and WbdB synthesize the adaptor region, where they transfer one and two α-(1,3)-linked mannose residues, respectively. The WbdA enzymes are solely responsible for forming the repeat-unit domains. WbdAO9a polymerizes a tetrasaccharide repeat unit containing two α-(1,3)- and two α-(1,2)-linked mannose residues, while WbdAO8 polymerizes trisaccharide repeat units containing single α-(1,3), α-(1,2), and β-(1,2)-mannoses. Consistent with the multifunctional nature of the WbdA mannosyltransferases, two separable domains were identified in WbdAO9a and three in WbdAO8. Results from mutation of the catalytic site motifs of WbdAO9a and in vitro assays with synthetic acceptors demonstrated that the N-terminal domain of WbdAO9a possesses α-(1,2)-mannosyltransferase activity. Therefore, these studies form a framework to investigate the hypothesis that each domain of WbdA is a catalytically active mannosyltransferase module, possessing one of the activities associated with the enzyme. The O8 and O9a systems provide examples where a unique combination of single domain mannosyltransferases, one of which is capable of adding two mannose residues in succession, and a multidomain polymerizing mannosyltransferase is exploited to build a single glycan. The information gained from this project is expected to extend to other bacteria that utilize similar pathways for biogenesis of cell surface glycopolymers. / Natural Sciences and Engineering Research Council of Canada

The high and ever growing demand for electricity coupled with environmental concerns and a worldwide desire to shed petroleum dependence, all point to a shift to utilization of renewable sources of energy. The under developed nature of truly renewable energy sources such as, wind and solar, along with their limitations on the areas of applicability and the energy output calls for a renaissance in nuclear energy. In this second nuclear era, deliberately small reactors are poised to play a major role with a number of Small Modular Reactors (SMRs) currently under development in the U.S. In this work, an SMR model of the Integral Pressurized Water Reactor (IPWR) type is created, analyzed and optimized to meet the publically available performance criteria of the mPower SMR from B&W. The Monte Carlo codes MCNP5/MCNPX are used to model the core. Fuel enrichment, core inventory, core size are all variables optimized to meet the set goals of core lifetime and fuel utilization (burnup). Vital core behavior characteristics such as delayed neutron fraction and reactivity coefficients are calculated and shown to be typical of larger PWR systems, which is necessary to ensure the inherent safety and to achieve rapid deployment of the reactor by leveraging the vast body of operational experience amassed with the larger commercial PWRs. Inherent safety of the model is analyzed with the results of an analytical single channel analysis showing promising behavior in terms of axial and radial fuel element temperature distributions, the critical heat flux, and the departure from nucleate boiling ratio. The new fleet of proposed SMRs is intended to have increased proliferation resistance (PR) compared to the existing fleet of operating commercial PWRs. To quantify this PR gain, a PR analysis is performed using the Proliferation Resistance Analysis and Evaluation Tool for Observed Risk (PRAETOR) code developed by the Nuclear Science and Security Policy Institute at Texas A&M University. The PRAETOR code uses multi-attribute utility analysis to combine 63 factors affecting the PR value of a facility into a single metric which is easily comparable. The analysis compared hypothetical spent fuel storage facilities for the SMR model spent fuel assembly and one for spent fuel from a Westinghouse AP1000. The results showed that from a fuel material standpoint, the SMR and AP1000 had effectively the same PR value. Unable to analyze security systems and methods employed at specific nuclear power plant sites, it is premature to conclude that the SMR plants will not indeed show increased PR as intended.

No description available.

No description available.

Chapter 0 In this introductory chapter, certain notational and terminological conventions are established and a summary given of background results that are needed in subsequent chapters. Chapter 1 In this chapter, the notion of a "weak conguence formula" [Tay72], [BB75] is introduced and used to characterize both subdirectly irreducible algebras and essential extensions. Special attention is paid to the role they play in varieties with definable principal congruences. The chapter focuses on residually small varieties; several of its results take their motivation from the so-called "Quackenbush Problem" and the "RS Conjecture". One of the main results presented gives nine equivalent characterizations of a residually small variety; it is largely due to W. Taylor. It is followed by several illustrative examples of residually small varieties. The connections between residual smallness and several other (mostly categorical) properties are also considered, e.g., absolute retracts, injectivity, congruence extensibility, transferability of injections and the existence of injective hulls. A result of Taylor that establishes a bound on the size of an injective hull is included. Chapter 2 Beginning with a proof of A. Day's Mal'cev-style characterization of congruence modular varieties [Day69] (incorporating H.-P. Gumm's "Shifting Lemma"), this chapter is a self-contained development of commutator theory in such varieties. We adopt the purely algebraic approach of R. Freese and R. McKenzie [FM87] but show that, in modular varieties, their notion of the commutator [α,β] of two congruences α and β of an algebra coincides with that introduced earlier by J. Hagemann and C. Herrmann [HH79] as well as with the geometric approach proposed by Gumm [Gum80a],[Gum83]. Basic properties of the commutator are established, such as that it behaves very well with respect to homomorphisms and sufficiently well in products and subalgebras. Various characterizations of the condition "(x, y) Є [α,β]” are proved. These results will be applied in the following chapters. We show how the theory manifests itself in groups (where it gives the familiar group theoretic commutator), rings, modules and congruence distributive varieties. Chapter 3 We define Abelian congruences, and Abelian and affine algebras. Abelian algebras are algebras A in which [A2, A2] = idA (where A2 and idA are the greatest and least congruences of A). We show that an affine algebra is polynomially equivalent to a module over a ring (and is Abelian). We give a proof that an Abelian algebra in a modular variety is affine; this is Herrmann's Funda- mental Theorem of Abelian Algebras [Her79]. Herrmann and Gumm [Gum78], [Gum80a] established that any modular variety has a so-called ternary "difference term" (a key ingredient of the Fundamental Theorem's proof). We derive some properties of such a term, the most significant being that its existence characterizes modular varieties. Chapter 4 An important result in this chapter (which is due to several authors) is the description of subdirectly irreducible algebras in a congruence modular variety. In the case of congruence distributive varieties, this theorem specializes to Jόnsson's Theorem. We consider some properties of a commutator identity (Cl) which is a necessary condition for a modular variety to be residually small. In the main result of the chapter we see that for a finite algebra A in a modular variety, the variety V(A) is residually small if and only if the subalgebras of A satisfy (Cl). This theorem of Freese and McKenzie also proves that a finitely generated congruence modular residually small variety has a finite residual bound, and it describes such a bound. Thus, within modular varieties, it proves the RS Conjecture. Conclusion The conclusion is a brief survey of further important results about residually small varieties, and includes mention of the recently disproved (general) RS Conjecture. / Thesis (M.Sc.)-University of Natal, Durban, 2000.