This thesis summarises the progress made in the design and synthesis of conformationally constrained β-strand peptidomimetic compounds using ring closing metathesis methodology under microwave irridation conditions. The best macrocycle were elaborated into an inhibitor for a specific protease target. Calpain was used as an example of protease targeting cataract disease. Chapter One introduces proteases in general centring on the general context of protease inhibitor design. The significant of the β-strand 'bioactive' conformation is discussed in details in particular the exploitation of conformationally constrained to potential lock the 'bioactive' conformation. Chapter Two illustrates in silico methods used to design a series of β-strand macrocycle 2.1-2.7. The analysis of these is performed using molecular modelling software Schrodinger suite (2005). A brief discussion of ring closing metathesis methodology is also included. Chapter Three describes the synthesis of the precursor required for RCM reactions (tripeptides dienes). Various types of allylated amino acid side chains were synthesised. The tripeptides were obtained using standard peptide coupling methodology utilising reagents such as HATU, EDC and HOAT. Chapter Four describes the application of ring closing metathesis for the synthesis of β-strand macrocycles. The development of a new reaction conditions to optimise the ring closing metathesis reaction is discussed. In particular the effect of the use of a Lewis acid (chlorodicyclohexylborane) additive in RCM reactions is investigated. Chapter Five discusses the mechanism of cataract formation, cataract treatment and the potential development of calpain inhibitors. One of the macrocycles synthesised in chapter 4 is elaborated into a calpain inhibitor. The in-vitro assay result of this is presented and this compound is currently undergoing in vivo evaluation.

Mining equipment are becoming very sophisticated and complex. At the same time, mining companies modernise its operation by increased mechanisation and automation (Dhillon, 2008). That requires well-developed and planned maintenance strategy. A proper maintenance strategy and appropriate maintenance actions, are essential to keep equipment safe & reliable, decrease the overall costs, and it helps to eliminate workplace hazards. Maintenance strategies and maintenance actions, in turn, are changed and developed more than any technology (Moubray, 1997). Changing and developing of the maintenance can be due to many factors, perhaps due to the complexity of the systems or due to the development of the technology. One of the best research (developed technology) that has been done in this area is the research by Nowlan and Heap about Reliability Centered Maintenance (RCM) in 1978. RCM is defined as, “a zero-based, structured process used to identify the failure management strategies required to ensure an asset meets its mission requirements in its operational environment in the safest and cost – effective manner” (Regan, 2012). The RCM is one of the best powerful asset management strategies. RCM can be applied to any asset, nuclear power plant, aeroplane, or truck ship. According to (Nowlan & Heap, 1978), the main goal of implementation an RCM process is to provide the stated function of the facility with required reliability and availability at the lowest cost. In this master thesis, an RCM analysis process has been described in details. Moreover, two types of implementation approaches of an RCM analysis process have also been described. The intention of describing these two approaches is to see what the differences between them are and which one can be recommended for using in mining. The first approach is according to (Hinchcliffe & Smith, 2004) and the second approach is according to (Regan, 2012). Moreover, in this master thesis, there are also two case studies that have been analysed. The intention of analysing these two case-studies is to see how the RCM has been implemented. As a result of the research carried out in this master thesis, some basic streamline RCM analysis process has been recommended for using in mining. This recommended RCM analysis process could be applicable to be used in every industry section. The result of this work can be summarised that RCM is an applicable tool which can be used in mining for selecting the right maintenance approach for different equipment, systems or subsystem. RCM analysis process is discussed from different perspective. In the discussion, the misconceptions about the implementation of an RCM analysis process have been discussed. Altogether, Reliability Centered Maintenance is one of the most powerful asset management strategies that can be used in every industry section. If the RCM is applied by right people and by the right way, the result can be profitable for the mining companies.

"Operational costs are of central importance for the economic health and sustainability of any organization. There are many contributors to these costs; some are industry specific, some are not. Factors such as organizational makeup and structure or general management and/or leadership practices all play a part, albeit, challenging to measure in terms of direct dollar correlation. Others, such as payroll, capital purchases, and asset management costs, to name a few have a more direct operational cost clearly linked to dollars and become the most practical place to look when trying to minimize operational costs. One of the critical aforementioned contributors to operational costs is that of capital asset management; in particular the issue of maintenance and repair of a company’s capital assets. More specifically, one can try to determine the best maintenance practice and schedule to use on varying systems in hopes of lowering maintenance costs and ultimately operational costs. One approach is to formulate a maintenance cost equation given the specific data and constraints available to solve a probabilistic problem through simulation. This study proposes a methodology that could be used as a tool to determine what maintenance practices to use on varying systems, sub-systems, and components. The focal point of this methodology is to formulate viable simulation logic. The logic takes into account maintenance costs that must be identified and defined. Additionally, coupled with this is the need to create a Weibull Distribution, which helps predict the next failure based on historical data. By matching the maintenance cost with the Weibull Distribution of each system, sub-system or component the simulation logic or equation is created. With this model in hand, simulations are run using Monte Carlo Simulation. In the end, an optimal schedule is determined based on the input. This thesis has three main deliverables. First, a maintenance methodology which assists in determining optimal component change out schedule based on historical data is created. Secondly, from the information gathered from Industrial Support Command Alameda*, ideal systems to target are identified. Thirdly, an implementation strategy is offered. Lastly, though not a primary deliverable, this study also offers some other maintenance related miscellaneous findings and/or recommendations. "

This thesis focuses on computatal problems regarding the allocation of resources within a data center that services a cloud. This problem is formally know as Resource Consolidation Managmenet (RCM). In this thesis we analyse current RCM methods from the literature with respect to computational problem defintions and propose a framework to allow the classification and comparison of RCM solutions. With a decade of research in the field, this framework should be intuitive such that any researcher can easily use it to define computational problems in the field of RCM and reverse engineer problem definitions from exisiting solutions for RCM Problems. Finally our framework should be extendable: as the field continues to grow, the framework should be able to adapt to meet future needs. Besides presenting the framework, we analyse computational problems obtained by the framework in terms of its classical complexity. We show several of those problems to be NP-complete and discuss variants that are solvable in polynomial time. A further contribution is the exploration of different comparison tools for solutions of RCM problems. / Graduate

This thesis summarises the progress made in the design and synthesis of conformationally constrained β-strand peptidomimetic compounds using ring closing metathesis methodology under microwave irridation conditions. The best macrocycle were elaborated into an inhibitor for a specific protease target. Calpain was used as an example of protease targeting cataract disease. Chapter One introduces proteases in general centring on the general context of protease inhibitor design. The significant of the β-strand 'bioactive' conformation is discussed in details in particular the exploitation of conformationally constrained to potential lock the 'bioactive' conformation. Chapter Two illustrates in silico methods used to design a series of β-strand macrocycle 2.1-2.7. The analysis of these is performed using molecular modelling software Schrodinger suite (2005). A brief discussion of ring closing metathesis methodology is also included. Chapter Three describes the synthesis of the precursor required for RCM reactions (tripeptides dienes). Various types of allylated amino acid side chains were synthesised. The tripeptides were obtained using standard peptide coupling methodology utilising reagents such as HATU, EDC and HOAT. Chapter Four describes the application of ring closing metathesis for the synthesis of β-strand macrocycles. The development of a new reaction conditions to optimise the ring closing metathesis reaction is discussed. In particular the effect of the use of a Lewis acid (chlorodicyclohexylborane) additive in RCM reactions is investigated. Chapter Five discusses the mechanism of cataract formation, cataract treatment and the potential development of calpain inhibitors. One of the macrocycles synthesised in chapter 4 is elaborated into a calpain inhibitor. The in-vitro assay result of this is presented and this compound is currently undergoing in vivo evaluation.

El texto completo de este trabajo no está disponible en el Repositorio Académico UPC por restricciones de la casa editorial donde ha sido publicado. / One of the main problems existing in manufacturing companies is the high frequency of machine breakdowns and their high repair time. Therefore, over time, various maintenance strategies seeking to more efficiently manage the scheduled jobs have been presented. However, these are not always as effective as expected, because they are not properly applied, the resources are not available, or the strategy is not aimed at directly solving the problem. Based on the aforementioned, this paper proposes an integral model of maintenance management based on the principles of total productive maintenance and reliability-centered maintenance methodologies in order to increase machine availability in a company in the manufacturing sector. To validate this proposal, a pilot project will be developed to measure the impact that is being sought.

Orientador: Ronaldo Aloise Pilli / Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Quimica / Made available in DSpace on 2018-08-10T13:11:39Z (GMT). No. of bitstreams: 1 Salvador_MayraBeloti_M.pdf: 2010457 bytes, checksum: 350e267c8a65621fe41d0da941852b62 (MD5) Previous issue date: 2007 / Resumo: Esta dissertação de mestrado trata da síntese da Criptomoscatona D2, uma lactona isolada pelo grupo de pesquisa dos Profs. Cavalheiro e Yoshida a partir da Cryptocarya moschata, planta encontrada em território brasileiro, cujas configurações relativa e absoluta ainda não foram determinadas. Além de auxiliar em sua elucidação estrutural a síntese desta molécula nos permitiria realizar estudos sobre sua atividade citotóxica, dando prosseguimento a estudos anteriores desenvolvidos em nosso laboratório com essa classe de compostos. Partindo-se do benziloxiacetaldeído obteve-se o álcool homoalílico quiral correspondente através de uma reação de alilação assimétrica com alilestanana e (S)-binaftol. Clivagem oxidativa da dupla ligação e reação de alilação mediada por InCl3 e estanho metálico na presença de brometo de alila forneceu uma mistura de álcoois homoalílicos sin/anti 1:1 cuja separação cromatográfica permitiu o prosseguimento da síntese racêmica com cada um dos diasteroisômeros. A reação de proteção das hidroxilas com o grupo TBS, seguida de clivagem oxidativa da dupla ligação e reação de alilação com BF3.Et2O e alilestanana forneceu o terceiro álcool homoalílico com mistura diastereoisomérica de cerca de 2:1 em ambas as rotas. Por fim, uma reação de esterificação do álcool remanescente na forma de acrilato seguida de reação de metátese de olefinas para formação do anel lactônico nos possibilitou o mapeamento de grande parte da rota sintética da Criptomoscatona D2 em sua forma racêmica / Abstract: This work describes the preliminary studies on the racemic and the asymmetric synthesis of Cryptomoscatone D2 based on sequential allylation reactions for the construction of its three stereogenic centers and ring-closing methatesis reaction to construct the lactone scaffold. Besides allowing the structure elucidation of the molecule isolated from a typical brazilian plant by the research groups of Profs. Cavalheiro and Yoshida, the synthesis of such a lactone would allow us to carry new cytotoxic studies which are being lately developed with this class of compound. The synthesis started with the allylation reaction of benzyloxyacetaldehyde under the conditions described by Keck and coworkers to furnish corresponding homoallylic alcohol. After an oxidative cleavage of the double bond, an InCl3 promoted allylation reaction allowed the preparation a 1:1 mixture of syn/anti homoallylic alcohols which were as the TBS ethers and submitted separately to double bond oxidative cleavages. These aldehydes were used as substrates for another allylation reaction with BF3.Et2O and allyltri-n-butyltin and the homolallylic alcohols (2:1 diatereoisomeric mixtures) were converted to the corresponding acrylates in order to carry out the planned RCM reaction. Several allylation reactions were tested and the homoallylic alcohols were prepared in 1:1 diasteroisomeric excesses. Efforts will be carried out in order to enhance the distereoselectivity of the allylation reactions for an efficient approach to Cryptomoscatone D2 (12) backbone / Mestrado / Quimica Organica / Mestre em Química

Notre projet s'inscrit dans le cadre de la lutte contre la résistance bactérienne et considère une approche radicalement opposée à tout ce qui a été fait jusqu'à présent dans le but de créer de nouveaux antibiotiques. En nous basant sur l'hypothèse qu'il existe d'autres façons pour obtenir un composé réactif que d'inclure le noyau beta-lactame dans une structure bicyclique très tendue (ou de l'activer par des effets électrocapteurs), nous avons imaginé une famille de molécules où l'adaptabilité conformationnelle pourrait être à l'origine de l'activité antibiotique. Il s'agit de beta–lactames bicycliques pontés obtenus au départ de l'acétoxy-azétidin-2-one commerciale, où les positions N1 et C3 sont connectées par des cycles de tailles variables (à partir de n et m = 1), incluant éventuellement des fonctions "activantes" de type carbonyle et/ou une double liaison C=C. La stratégie choisie fait intervenir la métathèse des oléfines (RCM) pour la formation du cycle pontant. Nos dérivés ont fait l'objet d'évaluations théoriques grâce à des modèles d'hydrolyses chimique et enzymatique, et expérimentales grâce à des suivis RMN-1H de l'hydrolyse en milieu basique et à des tests in vitro sur enzymes bactériennes et mammaliennes.

La siguiente propuesta de implementación está formada por cuatro capítulos, el primero describió el marco teórico necesario para desarrollar y sustentar la presente investigación. Se incluyeron temas como el proceso de generación eléctrica, estrategias de mantenimiento, así como la gestión de procesos aplicada al entorno del mantenimiento. En el segundo capítulo, se describió la situación de la empresa y su entorno en el mercado eléctrico nacional. Además, se describieron los objetivos estratégicos y los procesos de la compañía. También, se determinó la problemática actual del departamento de mantenimiento y se pudo determinar cuál es la causa raíz de este problema. En el tercer capítulo, se determinaron los objetivos y se propusieron las metas a alcanzar. Además, se seleccionó la mejor metodología para solucionar el problema para eliminar, controlar o mitigar las causas que lo originaron. Seguidamente, se comenzó a desarrollar de la metodología el RCM para los sistemas seleccionados. Con ello, se determinó los mejores planes y estrategias de mantenimiento y los recursos necesarios para poder eliminar y/o controlar adecuadamente fallas en los equipos más críticos garantizando la disponibilidad de la planta. En el Cuarto capítulo, se implementó un tablero de mando el cual controlará que los indicadores de mantenimiento se encuentren dentro de los límites establecidos. Esto permitirá medir y controlar los principales indicadores como la disponibilidad (D), tiempo medio entre fallas (TMEF) y tiempo medio para reparar (TMPR). Finalmente, se realizó el análisis económico del proyecto calculando el VAN, TIR para poder determinar su viabilidad. / The following implementation proposal is made up of four chapters, the first one describing the theoretical framework necessary to develop and sustain this research. Topics such as power generation process, maintenance strategies, as well as the management of processes applied to the maintenance environment were included. In the second chapter, the situation of the company and it’s environment in the national electricity market was described. In addition, the company's strategic objectives and processes were described. Also, the current problem of the maintenance department was settled, and the root cause of this problem could be determined. In the third chapter, the objectives were established and the goals to be achieved were proposed. In addition, the best methodology was selected to solve the problem to eliminate, control or mitigate the causes that originated it. Next, the RCM for the selected systems began to be developed from the methodology. With this, the best maintenance plans and strategies and the necessary resources were determined to be able to eliminate and / or adequately control failures in the most critical equipment guaranteeing the availability of the plant. In the Fourth chapter, a dashboard was implemented which will control that the maintenance indicators are within the established limits. This will allow measuring and controlling the main indicators such as availability (A), mean time between failures (MTBF) and average time to repair (MTTR). Finally, the economic analysis of the project was calculated by calculating the NPV, IRR in order to determine its viability. / Trabajo de Suficiencia Profesional

Cardiac diseases associated with mutations in Tn subunits include hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM) and restrictive cardiomyopathy (RCM). Altered calcium handling in these diseases is evidenced by changes in the Ca2+ sensitivity of contraction. Mutations were generated to increase/ decrease the Ca2+ sensitivity of skinned fibers, and create the classified effects of DCM, HCM and RCM. This study mimicked the changes in Ca2+ sensitivity and relaxation properties of the muscle to determine if this was sufficient to recreate the disease. Four mutants (A23Q, S37G, V44Q, L48Q) were identified with RCM-like properties; a large increase in Ca2+ sensitivity, increased basal force and loss of ATPase inhibition. Two mutations were identified (E40A, I61Q) with DCM properties; decreased Ca2+ sensitivity in skinned fibers, decreased force recovery (%), and decreased activation of the ATPase at high Ca2+ levels (pCa 6-4). Also, the functional effects of four newly identified cTnC mutations associated with HCM were reported. Three of these HCM mutations A8V, C84Y, and D145E displayed HCM characteristics, increased Ca2+ sensitivity in skinned fibers and ATPase and A8V and D145E increased the force recovery. Only, D145E significantly increased the ATPase activation of the reconstituted thin filament. Also, Ca2+ affinity measurements using IAANS fluorescence were performed. No significant changes were found for E134D. The C84Y IAANS fluorescence measurements revealed that cTnC Ca2+ affinity of the cTn complex was unaltered. The Ca2+ affinity increased for D145E in isolated cTnC and the cTn complex, however in the regulated thin filament (RTF) with myosin subfragment-1 (S1) and rigor crossbridges the Ca2+ affinity values were similar to the fiber Ca2+ sensitivity. For A8V, the RTF significantly increased the Ca2+ affinity, and addition of S1 and rigor crossbridges caused the values to parallel the Ca2+ sensitivity values. In conclusion, direct and indirect protein-protein interactions contribute to the enhanced Ca2+ sensitivity of the HCM mutants. The cTnC mutant screen allowed selection of mutations that mimic the disease states: S37G (RCM) and, E40A (DCM); A8V (HCM) from the patient study for analysis in knock-in mice for futures studies to determine if these disease states can be recapitulated in vivo.