Yaku'amide A shows a unique inhibitory profile against a series of 39 human cancer cell lines (JFCR39). In our efforts to synthesize yaku'amide A, we have optimized our regioselective base-free aminohydroxylation method with a series of nitrogen sources, developed a chiral reagent-mediated aminohydroxylation strategy and chemoselective deprotections of the resulting aminohydroxylation product, and explored a stereospecific E2 dehydration and O-N acyl transfer sequence. In addition, we have prepared the right-hand tetrapeptide and the NTA subunit. For our bulky α,β-dehydroamino acids project, we have developed strategies to incorporate α,β-dehydroamino acids such as ΔVal and ΔEnv into small synthetic peptides via Solid Phase Peptide Synthesis (SPPS). We have also prepared two analogues of a monomeric helical peptide with 13 residues.

Made available in DSpace on 2015-03-26T13:55:15Z (GMT). No. of bitstreams: 1 texto completo.pdf: 793112 bytes, checksum: d869c3853a7619f4cc816a4c2ba6dcca (MD5) Previous issue date: 2008-07-30 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / The objective of this research was to assess the kinetics of gastrointestinal transit of bulky using different mathematical models and indicators in cattle. It was used four Flemish-Zebu steers, fistulated in the rumen, distributed in experimental design 4 x 4 Latin square, and kept in confinement in individual stalls receiving daily 1 kg of concentrate and forage freely. The experimental treatments consisted of four sources of fiber, which were: silage corn (Zea mays), sugar cane (Saccharum officinarum), hay of ramie (Boehmeria nivea) and hay from tifton (Cynodon spp). The concentrate diet consisted of ground corn, soybean meal, urea and mineral supplement. We used the models G1 → G1 → O, proposed by Grovum and Williams (1973), G1 (n) → The proposed by Dhanoa et al. (1985) and G2 → G1 → The proposed by Pond et al. (1988) to estimate the passage rate of particles and the models proposed by G1 → Colluci et al. (1990) and G2 → proposed by Ellis et al. (1994) to estimate the rate of movement of fluids. We used the chrome mordant and Ytterbium as indicators of solid phase and cobalt-EDTA as indicators of the liquid phase. Comparisons between models were made by means of waste analysis and standard deviation standardized asymptotic. Among the models and markers studied to assess the kinetics of particles, the model G1 (n) → O (multicompartmental, proposed by Dhanoa et al., 1985) and the indicator registered chrome best fit for the passage rate of particles from sources Fiber distinct. The model G2 → (time-independent, proposed by Ellis et al. 1994) obtained better results, showing that the dependence of time to have a mixture of fluids existing with being inserted into the compartment. / Objetivou-se com esta pesquisa avaliar a cinética de trânsito gastrintestinal de volumosos utilizando diferentes modelos matemáticos e indicadores em bovinos. Utilizou-se quatro novilhos Holandês-Zebu, fistulados no rúmen, distribuídos em delineamento experimental quadrado latino 4 x 4, e mantidos em confinamentos em baias individuais recebendo diariamente 1 kg de concentrado e volumoso à vontade. Os tratamentos experimentais foram constituídos de quatro fontes de fibra, sendo elas: silagem de milho (Zea mays), cana-de-açúcar (Saccharum officinarum), feno de rami (Boehmeria nívea) e feno de tífton (Cynodon spp). O concentrado das dietas foi constituído de milho triturado, farelo de soja, uréia e suplemento mineral. Foram utilizados os modelos G1→ G1→O, proposto por Grovum e Williams (1973), G1(n)→ O proposto por Dhanoa et al. (1985) e G2→ G1→O proposto por Pond et al. (1988) para estimativa de taxa de passagem de partículas e os modelos G1→ proposto por Colluci et al. (1990) e G2→proposto por Ellis et al. (1994), para estimativa de taxa de passagem de fluidos. Utilizou-se o cromo mordente e itérbio como indicadores de fase sólida e cobalto-EDTA como indicadores de fase líquida. As comparações entre modelos foram efetuadas por meio de análise dos resíduos padronizados e o desvio padrão assintótico. Dentre os modelos e marcadores estudados, para avaliar a cinética de partículas, o modelo G1(n)→ O (multicompartimental, proposto por DHANOA et al., 1985) e o indicador cromo registraram melhor ajuste, para a taxa de passagem de partículas de fontes de fibra distintas. O modelo G2→ (tempo-independente, proposto por Ellis et al. 1994) obteve melhores resultados, comprovando que existe a dependência do tempo para que haja uma mistura dos fluidos já existentes com os que estão sendo inseridos no compartimento.

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Les facteurs endogènes et exogènes induisent diverses modifications chimiques et structurales dans l’ADN cellulaire et sont à l’origine de nombreuses erreurs lors de la réplication et de la division cellulaire. Elles sont souvent à l’origine de cancers et de maladies chroniques liées à l’âge. Les agents alkylants induisent des lésions complexes de l’ADN. Ils sont utilisés comme des outils efficaces dans les traitements par chimiothérapies. Les deux caractéristiques majeures des lésions complexes de l’ADN sont d’une part l’encombrement et d’autre part la présence de plus d’une modification dans un tour d’hélice. Les données biochimiques et génétiques montrent que l’élimination des dommages complexes de l’ADN nécessitent plusieurs voies de réparation distinctes. Les caractéristiques cliniques des maladies héréditaires caractérisées par des désordres de réparation de l’ADN, comme l’anémie de Fanconi et le syndrome de Cockayne, visent la nature complexe des lésions oxydatives endogène incluant les adduits encombrants et les pontages interbrins (PIBs). D’autre part, les effets biologiques sévères des agents ionisants, des traitements de chimiothérapie et des cancérigènes environnementaux sont impliqués dans la formation de cassures double brins, des PIBs et des adduits encombrants. Bien que ces derniers représentent une faible proportion des dommages de l’ADN induit par stress oxydatif et les agents chimiques dans les cellules, ils sont extrêmement cytotoxiques s’ils ne sont pas réparés. Par exemple, les cellules cancéreuses sont très sensibles aux PIBs et aux cassures double brins. Alors que la consommation de produits contenant de l’acide aristolochique (AA), qui génère des adduits encombrants dans l’ADN cellulaire, peut être à l’origine de neuropathies et a été associé à une cancérogénèse plus élevée que la fumée de cigarette. L’objectif majeur de ce projet est l’étude de la réparation des lésions complexes de l’ADN et leur implication dans le développement des cancers et leur thérapie. Dans cette présente étude, nous nous sommes intéressés aux mécanismes moléculaires de la réparation des PIBs et des adduits encombrants de l’ADN et leurs possibles rôles dans la chimio- et radiorésistance acquise. De plus, nous avons étudié le mécanisme moléculaire impliqué dans la mutagénèse induite par la réparation aberrante des adduits encombrants initiée par des ADN glycosylases de la voie BER dans des cellules bactériennes et de mammifères. Durant les trois années de thèse, (i) j’ai construit et caractérisé différents substrats d’ADN contenant diverses bases oxydées, des PIBs induits par le psoralène, des adduits encombrants aristolactame et des photoproduits issus des UV, (ii) j’ai purifié divers ADN glycosylases recombinantes (TDG, MBD4, NEIL1 et NEIL3), (iii) j’ai reconstruit in vitro la réparation des lésions de l’ADN et (iv) j’ai également étudié les interactions protéine-protéine et les modifications post-traductionnelles des protéines impliquées dans la réparation des PIBs générés par le cisplatine initiée par les ADN glycosylases NEIL1 et NEIL3. En combinant les différentes approches développées dans notre laboratoire, nous avons identifié et caractérisé des voies de réparation alternatives impliquées dans l’élimination des dommages complexes de l’ADN. Les résultats obtenus dans ce travail permettraient de comprendre la mécanistique du développement de certains cancers et à identifier les facteurs associés à la chimio- radiorésistance des cellules cancéreuses et par conséquent contribuer au développement de nouvelles préventions de stratégies thérapeutiques. / Endogenous and exogenous mutagenic factors induce variety of chemical and structural modifications in cellular DNA that are at the origin of errors that occur during DNA replication and cell division and often give rise to cancer and other age-related chronic diseases. Importantly, alkylating agents which induce complex DNA lesions are used as a powerful tool for anti-cancer chemotherapy. Two most important features of complex DNA lesions are their bulky character and presence of more than one modification within one turn of DNA helix. Genetic and biochemical data indicate that the elimination of complex DNA lesions requires several distinct DNA repair pathways. The clinical features of inherited human DNA repair deficient disorders such as Fanconi anemia and Cockayne syndrome point to complex nature of endogenous oxidative DNA damage which include bulky adducts and inter-strand DNA crosslinks (ICLs). On the other hand, severe biological effects of ionizing radiation, anticancer drugs and environmental carcinogens are correlated with formation of dirty DNA strand breaks, ICLs and bulky adducts. Although complex lesions typically constitute relatively small fraction of the total DNA damage induced by oxidative stress and drugs in cells, they are extremely cytotoxic if not repaired. For example, cancer cells are primarily very sensitive to ICLs and dirty DNA strand breaks. While, consumption of products containing aristolochic acid (AA), which generates bulky adenine DNA adducts in cellular DNA, can cause neuropathy and has been associated with higher risk of cancer than cigarette smoking. The major objective of the present project is to study the repair of complex DNA lesions and their implications in cancer development and therapy. Here, we investigated molecular mechanisms of the repair of ICLs and bulky DNA lesions and their possible role in the acquired chemo-resistance of cancer cells. In addition, we studied the molecular mechanism of mutagenesis induced by the aberrant DNA glycosylase-mediated BER towards bulky adducts in bacterial and mammalian cells. During three years of the project, I have (i) constructed and characterized DNA substrates containing various oxidized bases, psoralen-derived ICLs, bulky aristolactam-adenine adducts and UV photoproducts; (ii) purified several recombinant human DNA glycosylases (TDG, MBD4. NEIL1 and NEIL3); (iii) reconstituted in vitro the repair of complex DNA lesions; and finally (iv) studied the protein-protein interactions and post-translational protein modifications involved in the DNA glycosylases NEIL1 and NEIL3 initiated repair of cis-platinum induced ICLs. By combining the approaches developed in our laboratories we have identified and characterized alternative DNA repair pathways involved in the cellular processing of complex DNA damage. The results obtained in present work can provide mechanistic understanding of the development of certain cancer and lead to identification of the factors associated with the acquired chemo- and radio-resistance of tumour cells and therefore would contribute to development of new prevention and therapeutic strategies.

Yaku’amide A (YA) is a linear anticancer peptide that is rich in bulky dehydroamino acids (ΔAAs) and β-hydroxyamino acids (β-OHAAs). In our recent total synthesis of YA, we featured a one-pot anti dehydration–azide reduction–O→N acyl transfer process for the stereospecific construction of Z- and E- ∆Ile residues. Despite previous total syntheses and our efforts, the synthesis of YA remains lengthy. Via computational studies, we identified two analogue peptides that closely resemble the conformation of YA. The use of simpler and symmetrical bulky ΔAAs such as dehydrovaline (ΔVal) and dehydroethylnorvaline (ΔEnv) as surrogates of ∆Ile, along with azlactone chemistry for their incorporation, significantly decreased the overall number of synthetic steps. Biological studies revealed that our analogues exhibited very similar activity to that of the natural product YA, demonstrating their suitability as mimics and consistency with our computational model. Despite its utility in the construction of YA analogues, azlactone chemistry is sluggish and moderate to low yielding. For this reason, we have explored strategies to streamline the synthesis of peptides containing Z-dehydroaminobutyric acid (∆Abu), ∆Val, and Z-dehydrophenylalanine (∆Phe). The key process is to form the alkene moiety via elimination of a β-sulfonium or β-OHAA embedded within a peptide, avoiding the need to form the alkene moiety via azlactone-dipeptide dehydration and bypassing sluggish amidation/ring opening steps. β-sheet disruption of Tau-model hexapeptides is a key type of inhibition for modulating Alzheimer’s disease progression. Previous studies replaced key residues with proline, due to its rigidity and lack of amide proton, to inhibit β-sheet formation. Similar to proline, ∆AAs are also known for their rigidity and ability to favor other conformations (e.g. β-hairpin, 310-helix) along with increasing peptide half-life. We have incorporated ∆Abu, ∆Val and dehydrocyclohexylglycine (∆Chg) in a highly aggregative hexapeptide sequence, using previously studied methods, to assess their capabilities as putative β-sheet breakers and to stabilize against proteolysis. Studies are continuing.

Studien fokuserar på att identifiera utmaningar och lösningar för hantering av hyresgästernas avfallhos fastighetsägaren, Rikshem. Arbetet att identifiera och undersöka Rikshems utmaningar medavfallshantering på nationell nivå baserades på intervjuer med olika medarbetare i bolaget samtundersökning av kostnader och andra interna dokument. Tre utmaningar identifierades: felsortering,översopor samt nedskräpning och dumpning av grovavfall. Orsakerna och konsekvenserna till dessautmaningar sammanställdes. Intervjuerna med andra fastighetsägare bekräftades utmaningarna somåterkommande hos fastighetsägare i vissa av deras områden. I syfte att lösa dessa problem identifierades olika lösningar från intervjuerna och delades upp ipraktiska och strategiska lösningar med hjälp av tematisk analys. Lösningarna undersöktes senareutifrån Rikshem hållbarhetskompass. De strategiska lösningarna som att ta fram mål och vision samtsammanställa kostnader rekommenderades att utföras på bolagsnivå. De praktiska lösningarnainkluderar bland annat olika former av miljöhus, tekniska lösningar i form av TV-skärmar, sensoreroch kärlpress, alternativ för grovsoprum, personlig service och nudging. Dessa lösningar måstedäremot undersökas vidare då de utförs utifrån varje områdes enskilda förutsättningar och behov. / The study focuses on identifying challenges and solutions for managing tenants' waste living inRikshem’s houses. The work to identify and investigate Rikshem's challenges with waste managementat the national level was based on interviews with various employees in the company as well as anexamination of other internal documents. Three challenges were identified: incorrect sorting,overloaded waste containers and dumping of bulky waste. The causes and consequences of thesechallenges were compiled. The interviews with other property owners confirmed that these challengesrecur with other property owners. In order to solve these problems, different solutions from the interviews were identified and dividedinto practical and strategic solutions using thematic analysis. The solutions were later examined basedon Rikshem's sustainability compass. The strategic solutions such as developing goals and vision andcompiling costs were recommended to be carried out at a company level. The practical solutionsinclude various forms of environmental houses, technical solutions in the form of TV screens, sensorsand container-press, alternatives for bulky waste rooms, personal service and nudging. Thesesolutions, on the other hand, must be further investigated as they would be carried out on the basis ofeach area's individual conditions and needs.Keyword

L'objectiu d'aquest tesi és avaluar els diferents passos en el camí que va des de l'exposició a contaminants atmosfèrics/PAHs fins a la malaltia, el càncer de bufeta urinària. Es van mesurar partícules ultrafines a Barcelona. S'ha avaluat l'exposició a contaminació atmosfèrica en un estudi cas-control, recollint informació sobre la història residencial incloent diversos indicadors de l'exposició a contaminació atmosfèrica i altres factors de risc potencials. Es va dur a terme una revisió sistemàtica de la literatura per avaluar si els nivells de metabòlits del pirè i els aductes d'ADN i de proteïnes es correlacionaven amb nivells baixos d'exposició a PAHs. Vam mesurar els nivells d'aductes d'ADN en un subgrup d'individus de l'estudi cas-control amb la tècnica del radioetiquetatge amb fòsfor-32, tractament de la nucleasa P1. Vam analitzar 22 SNPs en set gens de la via de reparació de l'ADN per excisió de nucleòtids. / The aim of this thesis is to evaluate the different steps in the pathway from exposure (air-contaminants/PAHs) to disease (bladder cancer). We measured ultrafine particles in Barcelona. We evaluated the exposure to air pollutants in a case-control study, collecting information on the residential history with proxies for exposure to air pollution and other potential risk factors. We did a systematic review of the literature to evaluate if pyrene metabolites and DNA and protein adducts are correlated with low level exposure to PAHs. We measured bulky DNA adducts in a subgroup of subjects of the case-control study using 32P-Postlabeling, nuclease P1 treatment. We analyzed 22 SNPs in 7 genes of the nucleotide excision repair pathway.

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The master’s thesis deals with the application of optimization models in the waste management. The analysis of the current state, the estimation of information about the flow of a specific waste, the estimation of the probable processing site and the method of processing is developed by a suitable approach based on sophisticated mathematical methods. The mathematical model, which was created by merging the two already existing models, brings results suitable also for forecasting the state of the waste management. The output is a comprehensive computational tool that was tested on data from the year 2015. The results for mixed municipal waste (catalogue number 20 03 01), bulky waste (catalogue number 20 03 07) and waste with catalogue number 19 08 05, i.e. residual sludge from sewage plants, were processed in MS Excel.