Since the outbreak of the HIV/AIDS pandemic in the 1980s, the disease has cost the lives of over 30 million people, and a further 33 million are currently living with the HIV infection. With the appropriate treatment, HIV/AIDS can today be regarded as a chronic but manageable disease. However, treatment is not available globally and UNAIDS still estimates that there are currently 5000 AIDS-related deaths worldwide per day. HIV protease inhibitors (PIs) constitute one of the fundaments of HIV treatment, and are commonly used in so-called highly active antiretroviral therapy (HAART), together with reverse transcriptase inhibitors. Although there are ten PIs on the market, there is still a need for novel structures. The rapid development of resistant strains, due to the high frequency of mutations, together with the commonly observed adverse effects of the drugs available, illustrate the need to develop new potent structures. Two novel scaffolds were investigated in this work. A tertiary alcohol-containing scaffold comprising a three-carbon tether, and a β-hydroxy γ-lactam-based scaffold were designed, synthesized and evaluated using enzyme- and cell-based assays. X-ray analyses of inhibitors from each class provided information on inhibitor–protease interactions. The inhibitors containing the tertiary alcohol provided at best an enzymatic inhibition (Ki) of 2.3 nM, and an inhibition in the cell-based assay (EC50) of 0.17 µM. The γ-lactam-based inhibitors exhibited better inhibition than the first series; the best values being Ki = 0.7 nM and EC50 = 0.04 µM. The second part of these studies involved the evaluation of a novel non-resonance continuous-flow microwave instrument. The instrument was validated regarding heating capacity, temperature stability and temperature homogeneity. A number of model reactions were performed with low- and high-microwave-absorbing solvents. It was found that the microwave heating source allowed rapid temperature adjustment, together with easily regulated, flow-dependent reaction times, providing an efficient tool for reaction optimisation.

Cyanide is a known toxic chemical, the production of plastics, electroplating, tanning, chemical syntheses, etc. At short-term exposure, cyanide causes rapid breathing, tremors, and long-term exposure to cyanide cause weight loss, thyroid effects, nerve damage and death. Although chemical and physical processes can be employed to degrade cyanide and its related compounds, they are often expensive and complex to operate. A proven alternative to these processes is biological treatment, which typically relies upon the acclimation and enhancement of indigenous microorganisms. Biological degradation of cyanide has often been offered as a potentially inexpensive and environmentally friendly alternative to conventional processes. The aims of first part of study were to evaluate the biodegradability of tetracyanonickelate (TCN) by Klebsiella oxytoca under anaerobic conditions. Results reveal that TCN can be biotransformed to methane by resting cells of K. oxytoca. Results also show that TCN biodegradation was inhibited by the addition of nitrate, nitrite, or ammonia at higher concentrations (5 and 10 mM). Moreover, it was found that the optimum pH for TCN conversion by K. oxytoca was about 7.1. Results from the fermenter experiment show that TCN can be completely degraded within 14 days. K. oxytoca is capable of using TCN as the nitrogen source under anaerobic conditions. TCN could be biotransformed to non-toxic end product (methane) by resting cells of K. oxytoca. Those studies provide us insight into the characteristics of TCN conversion by K. oxytoca under anaerobic conditions. In second part of this study, the technology of immobilized cells can be applied in biological treatment to enhance the efficiency and effectiveness of biodegradation. In this study, potassium cyanide (KCN) was used as the target compound and both alginate (AL) and cellulose triacetate (CT) gels were applied for the preparation of immobilized cells. The free suspension systems reveal that the cell viability was highly affected by initial KCN concentration and pH. Results show that immobilized cell systems could tolerate a higher level of KCN concentration and wider ranges of pH. In the batch experiments, the maximum KCN removal rates using alginate and cellulose triacetate immobilized beads were 0.108 and 0.101 mM h-1 at pH 7, respectively. Results also indicate that immobilized system can support a higher biomass concentration. Complete KCN degradation was observed after the operation of four consecutive degradation experiments with the same batch of immobilized cells. This suggests that the activity of immobilized cells can be maintained and KCN can be used as the nitrogen source throughout KCN degradation experiments. The maximum KCN removal rates using AL and CT immobilized beads in continuous-column system were 0.224 and 0.192 mM h-1 with initial KCN concentration of 3 mM, respectively. In third part of this study, a microbial process for the degradation of propionitrile by K. oxytoca was studied. The free and immobilized cells of K. oxytoca were then examined for their capabilities on degrading propionitrile under various conditions. The efficiency and produced metabolic intermediates and end-products of propionitrile degradation were monitored in bath and continuous bioreactor experiments. Results reveal that up to 100 mM and 150 mM of propionitrile could be removed completely by the free and immobilized cell systems, respectively. Furthermore, AL and CT immobilized cell systems show higher removal efficiencies in wider ranges of temperature (20-40¢XC) and pH (6-8) compared with the free cell system. Results also indicate that immobilized cell system could support a higher cell density to enhance the removal efficiency of propionitrile. Immobilized cells were reused in five consecutive degradation experiments, and up to 99% of propionitrile degradation was observed in each batch test. This suggests that the activity of immobilized cells can be maintained and reused throughout different propionitrile degradation processes. A two-step pathway was observed for the biodegradation of propionitrile. Propionamide was first produced followed by propionic acid and ammonia. Results suggest that nitrile hydratase and amidase were involved in the degradation pathways of K. oxytoca. In the continuous bioreactor, both immobilized cells were capable of removing 150 mM of propionitriles completely within 16 h, and the maximum propionitriles removal rates using AL and CT immobilized beads were 5.04 and 4.98 mM h-1, respectively. Comparing the removal rates obtained from batch experiments with immobilized cells (AL and CT were 1.57 and 2.18 mM h-1 at 150 mM of propionitrile, respectively), the continuous-flow bioreactor show higher potential for practical application. These findings would be helpful in designing a practical system inoculated with K. oxytoca for the treatment of cyanide-containing wastewater.

This thesis describes research efforts dedicated to the development of palladium(II)-catalyzed oxidative Heck and Heck/Suzuki domino reactions, and the applications of a new microwave heating technology, purpose-built for continuous flow in organic synthesis. Paper I describes the development of a ligand-modulated approach for attaching aryl groups to a chelating vinyl ether. By switching the ligand being used, selectivity for the arylation could be shifted to obtain three different outcomes: internal α- or terminal β-arylation, as well as a serendipitously discovered domino α,β-diarylation process. The latter was proposed to be an effect of para-benzoquinone, effectively acting as a stabilizing π-acidic ligand with the ability to suppress β-hydride elimination. Paper II explores the performance of a new microwave heating technology in combination with continuous flow. The novel nonresonant microwave applicator allowed rapid heating of common laboratory solvents and reaction mixtures above their boiling points with stable and reproducible temperature profiles. The technology was successfully applied to small-scale method development and subsequent scale-out of palladium-catalyzed reactions, heterocycle synthesis and classical organic transformations such as the Fischer indole synthesis. Paper III focuses on developing regioselective oxidative decarboxylative Heck reactions with electron-rich olefins. Successful internal α-arylations were achieved using various olefins and ortho-substituted aromatic acids. The mechanism was also studied by ESI-MS analysis. Key cationic organopalladium intermediates were identified, as well as an unexpected palladium(II)-complex which was isolated and characterized. Its experimentally deduced structure was in accordance with the lowest energy minimum found by DFT calculations. Preliminary findings suggested that the complex acts as a catalyst trap. Paper IV studies the mechanism of the reaction in Paper III by means of DFT calculations. Reductive elimination was identified as the rate-determining step when using a linear enamide as the olefin, due to its propensity to form low energy chelates. Its chelating properties also played a key role in the stability of the isolated palladium(II)-complex. The complex, which can act as a catalyst trap, was characterized by X-ray crystallography.

The research projects presented in this thesis are mainly focused toward green chemistry and engineering: developing innovative strategies to minimize waste, improve process efficiency and reduce energy consumption. Specifically, the work was centered on the design and applications of green solvents and processes for the sustainable production of pharmaceuticals. The first project was focused on the use of CO₂ to enhance Suzuki coupling reactions of substrates containing unprotected primary amines. This work established that exceptionally challenging substrates like halogenated amino pyridines (i.e. 4-amino-2-bromopyridine and 4-amino-2-chloropyridine) are suitable substrates for Suzuki coupling reactions under standard conditions using CO₂ pressures, without the need for protection/deprotection steps which are traditionally considered to be necessary for these reactions to proceed cleanly. The second project explored the use of water at elevated temperatures (WET) for the sustainable and selective removal of protecting groups. The favorable changes that occur in the physiochemical properties (i.e. density, dielectric constant and ionization constant) of water at elevated temperatures and pressures make it an attractive solvent for the development of sustainable, environmentally green processes for the removal of protecting groups. The water-mediated selective removal of protecting groups such as N-Boc, N-Acetyl and O-Acetyl from a range of organic model compounds was successfully achieved by tuning the temperature (125 to 275°C) or properties of water. The third project investigated the use of Organic-Aqueous Tunable Solvents (OATS) for the rhodium catalyzed hydroformylation of p-methylstyrene. This enables the reactions to be carried out efficiently under homogeneous conditions, followed by a carbon dioxide (CO₂) induced heterogeneous separation. Modest pressures of CO₂ induced the aqueous-rich phase (containing the catalyst) to separate from the organic-rich phase (containing the reactant), thus enabled an easy separation and recycling of catalyst. The use of Al(OtBu)₃ as a potent catalyst toward continuous Meerwein-Ponndorf-Verley (MPV) reductions was established in the fourth project. The MPV reduction of model compounds like benzaldehyde and acetophenone to their corresponding alcohols was investigated in continuous mode as a function of temperature and catalyst loading. These results established a roadmap for the pharmaceutical industry to document the implementation of continuous flow processes in their manufacturing operations.

Bioprocessing applications are gaining importance in the traditional chemical industries. With environmental, political, and economical concerns growing, research efforts have recently focused on the substitution of petroleum-derived transportation fuels and materials. As possible products and feedstocks are being investigated, it is important to ensure the new processes are also sustainable. There are several aspects to developing sustainable processes: minimize waste, use environmentally-benign chemicals, find renewable feedstocks, and limit the number of processing steps. This thesis examines ways to enhance the sustainability of bioprocesses. Novel, alternative solvent systems are studied and applied to a variety of bioprocesses. Downstream processing steps and waste can be minimized by designing systems that combine reactions and separations into one process unit. This is accomplished by designing new reactor systems and by replacing currently used solvents. Additional studies, involving analytical techniques that reduce the use of organic solvents, are tested and applied to industrial problems. Finally, new solvent systems are examined for potential processes using renewable carbohydrate feedstock.

FundaÃÃo Cearense de Apoio ao Desenvolvimento Cientifico e TecnolÃgico / Como o processo de gaseificaÃÃo do glicerol adquire um balanÃo energÃtico desfavorÃvel, à sugerida a operaÃÃo de um gaseificador como dispositivo de heat recovery. Nesse contexto, um reator de leito fixo à operado com gases de exaustÃo a uma temperatura de 820ÂC como fonte de energia e injeÃÃo eletrÃnica contÃnua de glicerol e Ãgua. O reator de leito fixo foi construÃdo com aÃo inox AISI 310 e com capacidade volumÃtrica de 3,73 litros e como material poroso do leito a alumina com 1,5 mm de diÃmetro. O experimento utilizou termopar do tipo K, sensor de pressÃo piezoresistivo e controle de vazÃo mÃssica com sensor de alta precisÃo do tipo Coriolis. A composiÃÃo dos gases do produto, a demanda energÃtica da gaseificaÃÃo e a eficiÃncia global do processo foram analisadas em funÃÃo da temperatura variando de 600 a 800 ÂC e a percentagem de glicerol na mistura variando de 30 a 90%. Para determinar a viabilidade do projeto foi realizado um estudo energÃtico do processo utilizando o software EES (Engineering Equation Solver). Apesar de o reator ter sido construÃdo com pequenas dimensÃes o objetivo do trabalho à obter resultados qualitativos para a gaseificaÃÃo do glicerol com praticidade, sem variÃveis de risco e dificuldades envolvidas em sistemas de grande porte. O experimento mostrou uma boa conversÃo dos produtos em hidrogÃnio com valores acima de 50% em 750ÂC e proporÃÃo de 70% de glicerol em Ãgua e um gasto energÃtico de 36 MJ/g com uma eficiÃncia do processo prÃxima a 100%. / As the gasification process of glycerol acquires an unfavorable energy balance, the operation of a gasifier in heat recovery mode is suggested. In this context, a fixed bed reactor was operated with exhaust gases at a temperature of 820ÂC as energy source and continuous electronic injection of glycerol and water. The fixed bed reactor was build with AISI 310 stainless steel and counted with a volumetric capacity of 3,713 liters and alumina with 1,5mm of diameter as the material of the porous bed. The experiments used K type thermocouples, piezoresistive pressure sensors and mass flow control based on a high precision Coriolis sensor. The exhaust gases composition, the energy demand for gasification and the overall efficiency of the process were analyzed in a temperature range from 600 to 800ÂC and a glycerol percentage at the mixture ranging from 30 to 90%. To determine the viability of the project, an energy study of the process was performed using the software EES (Engineering Equation Solver). Although the reactor was built using small dimensions, the objective of this work is to obtain qualitative results for the gasification of glycerol with practicality, without risk variables and difficulties involved in large systems. The experiment showed a good conversion of products in hydrogen, presenting a conversion above 50% at a temperature of 750ÂC and with a proportion of 70% of glycerol in water and an energy waste of 36MJ/g with gasification efficiency nearby 100%.

Orientador: Flavio Augusto Picchi / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Engenharia Civil, Arquitetura e Urbanismo / Made available in DSpace on 2018-08-13T21:18:03Z (GMT). No. of bitstreams: 1 Bulhoes_IamaraRossi_D.pdf: 3095643 bytes, checksum: f334cd2fe1eec7e0b2f48cca80f0b04b (MD5) Previous issue date: 2009 / Resumo: Os sistemas de produção na construção civil são caracterizados por muitas interrupções nos seus fluxos de trabalho, gerando desperdícios e a subutilização de recursos. Tais interrupções ocorrem principalmente devido à alta variabilidade nos processos de produção e à falta de sincronização entre os mesmos, resultando em elevadas percentagens de tempos improdutivos e de grandes estoques em processo. O presente trabalho tem como objetivo propor diretrizes para a implementação de fluxo contínuo na construção civil, com base nos conceitos e ferramentas da Mentalidade Enxuta. A estratégia de pesquisa adotada foi a pesquisa-ação, sendo realizados quatro estudos empíricos, dois em obras de edificações e dois em obras de montagem de estruturas pré-fabricadas de concreto. Duas principais contribuições desta pesquisa podem ser destacadas: (a) as diretrizes para implementar fluxo contínuo, vinculadas às etapas de diagnóstico, criação de condições iniciais, e planejamento e controle da produção; e (b) uma contribuição teórica no sentido de entender um conjunto de conceitos e princípios básicos de gestão da produção e a sua aplicação na indústria da construção. As diretrizes propostas para o contexto de obras de edificações são focadas no sistema de planejamento e controle da produção e na adaptação das ferramentas da Mentalidade Enxuta, tais como Mapa de Fluxo de Valor, Gráfico do Balanceamento do Operador e Tabela do Trabalho Padronizado Combinado, enquanto no contexto de obras de montagem de estrutura pré-fabricada as diretrizes enfatizam a realização do diagnóstico do processo de montagem, a introdução do planejamento integrado do projeto, fabricação e montagem, e a redução do tamanho do lote. Através destas diretrizes propõe-se o uso combinado das ferramentas tradicionais da Mentalidade Enxuta com ferramentas de Planejamento e Controle da Produção adequadas ao ambiente da construção civil. / Abstract: Production systems in the construction industry face many interruptions in work flows, causing waste and under-utilization of resources. Such interruptions are mostly due to high variability in production processes and also to the lack of synchronization between them, resulting in a large percentage of unproductive time and a high level of work in progress. The aim of this research work is to propose guidelines for the implementation of continuous flow in the construction industry, based on the Lean Thinking concepts and tools. Action research was the research strategy adopted in this study, involving four empirical studies, two in building projects and two in the fabrication and assembly of pre-fabricated concrete structures. Two main contributions of this research work are pointed out: (a) a set of guidelines for implementing continuous flow in production systems in the construction industry, which were related to the stages of diagnosis, establishment of the initial conditions, and planning and control; and (b) a theoretical contribution in terms of understanding a set of core production management concepts and principles and its application in the construction industry. The guidelines proposed for the context of building projects are focused on the production planning and control system and on the adaptation of Lean Thinking tools, such as Value Stream Mapping, Operator Balance Chart and Combined Standardized Work Chart, while in the context of prefabrication and assembly of concrete structures the guidelines emphasize the diagnosis of the assembly process, the introduction of an integrated planning and control process, including design prefabrication and assembly, and the reduction of lot size. Through those guidelines, the combined use of traditional Lean Thinking tools and planning and control tools that are suitable for the construction industry context. / Doutorado / Edificações / Doutor em Engenharia Civil

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The uptime of machinery in continuous flow process industries such as steel manufacturing plants puts pressure on the maintenance function. This in turn contributes to sustaining reliable physical assets. As absence of reliable physical assets highly affects the competitive advantage. Turnaround maintenance is a common practice in such production setups and requires top-of-the-line managerial attention to be planned,executed and assessed in an efficient manner. By applying an abductive approach and combining the qualitative and quantitative research approaches, this thesis aims to explore the managerial issue of coordinating turnaround maintenance within a continuous flow process industry. The research questions that guide this thesis consist of describing how turnaround maintenance can be coordinated and its associated challenges. By comparing publicly available literature and empirical evidence provided by performing a case study, it is confirmed that the main challenges for conducting efficient turnaround maintenance comes down to the management in all stages associated with the turnaround. To coordinate turnaround maintenance activities in the most efficient manner, several challenges must be overcome. Aligning organisational goals and generating management commitment is the first prerequisite before any improvements can be done. It is necessary to define a common scope that strives for creating reliable physical assets to enhance the competitive advantage. The defined challenges in coordination are related to before, during and after the turnaround execution. These relate to creating a cyclical process for the turnaround where previously acquired knowledge is used for improving future turnarounds. While detailed planning is necessary for each turnaround, a high level of contingency is also necessary. To achieve this and succeed, it is argued that a high level of visibility during the turnarounds and the use of standardised methods is required. / Drifttiden för maskiner i industrier med kontinuerligt flöde, såsom ståltillverkningsanläggningar, sätter press på underhållsverksamenheten. Detta för att i sin tur bidra till att upprätthålla tillförlitliga fysiska tillgångar. Eftersom avsaknad av tillförlitliga fysiska tillgångar påverkar konkurrensfördelen i hög grad. Storaunderhållstopp där den kontinuerliga produktionslinan stoppas, är en vanligt förekommande praxis i sådana produktionsanläggningar vilket kräver ledningens uppmärksamhet för att planera och utvärdera på ett effektivt sätt. Genom att tillämpa ett abduktivt tillvägagångssätt och kombinera kvalitativ och kvantitativ forskningsmetodik, syftar detta examensarbete till att utforska den ledarskapsrelaterade frågan om att koordinera underhållsaktiviteter för stora underhållstopp inom processindustrier med kontinuerligt flöde. Forskningsfrågorna som vägleder detta examensarbete består av att beskriva hur större underhållstopp kan koordineras och dess associerade utmaningar. Genom att jämföra offentligt tillgänglig litteratur och empiriska bevis från en fallstudie, bekräftas att de största utmaningarna för att genomföra ett effektivt underhållstopp beror på ledningen i alla steg som är förknippade med underhållstoppet. För att samordna underhållsaktiviteterna på ett så effektivt sätt som möjligt måste flera utmaningar övervinnas. Att anpassa organisationens mål och skapa engagemang hos ledningen är den första förutsättningen innan fler förbättringar kan utföras. Det är nödvändigt att definiera gemensamma mål som strävar efter att skapa tillförlitliga fysiska tillgångar för att i sin tur öka konkurrensfördelen. De definierademanagementutmaningarna sammankopplas till före, under och efter underhållsstoppet. Utmaningarnahandlar om att skapa en cyklisk process för underhållsstoppen där tidigare förvärvad kunskap nyttjas för att förbättra framtida stopp. Även om detaljerad planering är nödvändig för varje underhållstopp, är en hög nivå av beredskap också nödvändig. För att uppnå och lyckas med detta krävs en hög grad av visibilitet under underhållsstoppen och användning av standardiserade metoder.

(βα)8 TIM barrel proteins are one of the most common structural motifs found in biology. They have a complex folding free energy landscape that includes an initial off-pathway intermediate as well as two on-pathway intermediates. The formation of these intermediates is hypothesized to be driven by large clusters of the branched chain amino acids, isoleucine, leucine, and valine (ILV). All-atom MD simulations and circular dichroism experiments on polar mutants of the hydrophobic clusters of α-Trp synthase, a TIM barrel protein, revealed the importance of dehydrating the clusters on intermediate states. Custom, single-piece microfluidic chips were interfaced with small angle x-ray scattering and time resolved FRET experiments to monitor the role of a large ILV cluster on the microsecond timescale in a second TIM barrel protein, sIGPS. Dimensional analysis of the initial misfolded intermediate showed an ILV cluster was responsible for the initiation of structure in the intermediate. Early structure formation in the ILV cluster was confirmed by coarse grained simulations. Native state hydrogen exchange experiments were used to probe the higher energy species that are in equilibrium with the native state. Results from the NMR experiment complement the kinetic studies as the core of stability found by NMR mapped back to the same region of the ILV cluster that was found to initiate folding. When taken together, the results show the importance of hydrophobic clusters on the entire free energy surface of TIM barrel proteins.