Role of G protein coupled inwardly rectifier K+ channels (GIRK) on the neurobiology depression

353 págs.

La práctica de actividad física y deportiva (PAFYD) de la población adulta de Gipuzkoa como hábito líquido

440 p.

Synthesis, structure, and photophysics of polypyridophenazine transition-metal complexes

The condensation of phenanthroline-5,6-dione (phendione) with polyamines is a versatile synthetic route to a wide variety of chelating ligands. Condensation with 2,3- napthalene diamine gives benzo[i]dipyrido[3,2-a:2',3'-c]phenazine (bdppz) a ligand containing weakly-coupled orbitals of benzophenazine (bpz) and 2,2' -bipyridinde(bpy) character. The bpy character gives Re and Ru complexes excited-state redox properties; intramolecular electron transfer (ET) takes place to the bpz portion of the ligand. The charge-separated state so produced has an extraordinarily-long 50 µs lifetime. The slow rate of charge recombination arises from a combination of extremely weak coupling between the metal center and the bpz acceptor orbital and Marcus "inverted region" behavior. Molecular orbital calculations show that only 3% the electron density in the lowest unoccupied molecular orbital lies on the bpy atoms of bdppz, effectively trapping the transferred electron on the bpz portion. The rate of charge recombination decreases with increasing driving force, showing that these rates lie in the inverted region. Comparison of forward and back ET rates shows that donor-acceptor coupling is four orders of magnitude greater for photoinduced electron transfer than it is for thermal charge recombination.

Condensation of phendione with itself or tetramines gives a series of binucleating tetrapyridophenazine ligands of incrementally-varying coordination-site separation. When a photoredox-active metal center is attached, excited-state energy and electron transfer to an acceptor metal center at the other coordination site can be studied as a function of distance. A variety of monometallic and homo- and heterodimetallic tetrapyridophenazine complexes has been synthesized. Electro- and magnetochemistry show that no ground-state interaction exists between the metals in bimetallic complexes. Excited-state energy and electron transfer, however, takes place at rates which are invariant with increasing donor-acceptor separation, indicating that a very efficient coupling mechanism is at work. Theory and experiment have suggested that such behavior might exist in extended π-systems like those presented by these ligands.

Condensation of three equivalents of 4,5-dimethyl-1,2-phenylenediamine with hexaketocyclohexane gives the trinucleating ligand hexaazahexamethyltrinapthalene (hhtn). Attaching two photredox-active metal centers and a third catalytic center to hhtn provides means by which multielectron photocatalyzed reactions might be carried out. The coordination properties of hhtn have been examined; X-ray crystallographic structure determination shows that the ligand's constricted coordination pocket leads to distorted geometries in its mono- and dimetallic derivatives.

Carbon-carbon bond forming reactions from bis(carbene)-platinum(II) complexes and olefin polymerization and oligomerization using group 4 post-metallocene complexes

A long-standing challenge in transition metal catalysis is selective C–C bond coupling of simple feedstocks, such as carbon monoxide, ethylene or propylene, to yield value-added products. This work describes efforts toward selective C–C bond formation using early- and late-transition metals, which may have important implications for the production of fuels and plastics, as well as many other commodity chemicals.

The industrial Fischer-Tropsch (F-T) process converts synthesis gas (syngas, a mixture of CO + H₂) into a complex mixture of hydrocarbons and oxygenates. Well-defined homogeneous catalysts for F-T may provide greater product selectivity for fuel-range liquid hydrocarbons compared to traditional heterogeneous catalysts. The first part of this work involved the preparation of late-transition metal complexes for use in syngas conversion. We investigated C–C bond forming reactions via carbene coupling using bis(carbene)platinum(II) compounds, which are models for putative metal–carbene intermediates in F-T chemistry. It was found that C–C bond formation could be induced by either (1) chemical reduction of or (2) exogenous phosphine coordination to the platinum(II) starting complexes. These two mild methods afforded different products, constitutional isomers, suggesting that at least two different mechanisms are possible for C–C bond formation from carbene intermediates. These results are encouraging for the development of a multicomponent homogeneous catalysis system for the generation of higher hydrocarbons.

A second avenue of research focused on the design and synthesis of post-metallocene catalysts for olefin polymerization. The polymerization chemistry of a new class of group 4 complexes supported by asymmetric anilide(pyridine)phenolate (NNO) pincer ligands was explored. Unlike typical early transition metal polymerization catalysts, NNO-ligated catalysts produce nearly regiorandom polypropylene, with as many as 30-40 mol % of insertions being 2,1-inserted (versus 1,2-inserted), compared to <1 mol % in most metallocene systems. A survey of model Ti polymerization catalysts suggests that catalyst modification pathways that could affect regioselectivity, such as C–H activation of the anilide ring, cleavage of the amine R-group, or monomer insertion into metal–ligand bonds are unlikely. A parallel investigation of a Ti–amido(pyridine)phenolate polymerization catalyst, which features a five- rather than a six-membered Ti–N chelate ring, but maintained a dianionic NNO motif, revealed that simply maintaining this motif was not enough to produce regioirregular polypropylene; in fact, these experiments seem to indicate that only an intact anilide(pyridine)phenolate ligated-complex will lead to regioirregular polypropylene. As yet, the underlying causes for the unique regioselectivity of anilide(pyridine)phenolate polymerization catalysts remains unknown. Further exploration of NNO-ligated polymerization catalysts could lead to the controlled synthesis of new types of polymer architectures.

Finally, we investigated the reactivity of a known Ti–phenoxy(imine) (Ti-FI) catalyst that has been shown to be very active for ethylene homotrimerization in an effort to upgrade simple feedstocks to liquid hydrocarbon fuels through co-oligomerization of heavy and light olefins. We demonstrated that the Ti-FI catalyst can homo-oligomerize 1-hexene to C₁₂ and C₁₈ alkenes through olefin dimerization and trimerization, respectively. Future work will include kinetic studies to determine monomer selectivity by investigating the relative rates of insertion of light olefins (e.g., ethylene) vs. higher α-olefins, as well as a more detailed mechanistic study of olefin trimerization. Our ultimate goal is to exploit this catalyst in a multi-catalyst system for conversion of simple alkenes into hydrocarbon fuels.

Studies directed toward the synthesis of palau'amine and axinellamines A-D

The use of spiro [2.4]hepta-4,6-diene-1-methanol 7 as a general precursor for the synthesis of highly functionalized cyclopentyl rings is described. Diene 7 was converted to its silyl protected 4-nitrile derivative 24 in 46% overall yield. The cyclopropyl ring of 24 reacted with soft carbanionic nucleophiles to give ring opened homo-conjugate addition products 25a-h in 76-97% yield without loss of optical purity. The addition products could be further manipulated by selective mono-hydrogenation to give 1,2 substituted cyclopentenes 26a-e in 85-96% yield.

Diene 7 was used as a starting material for studies directed toward the synthesis of the stereochemically dense chloro-cyclopentyl core of palau'amine 1. Two advanced intermediates 50 and 72 were synthesized. Attempts to effect intramolecular chlorine transfer with 50 were unsuccessful. Attempted intramolecular chlorine transfer with 72 led, instead, to an oxygenated species resulting from oxygen radical trapping.

The enantioselective synthesis of the stereochemically dense chloro-cyclopenty l core of axinellamines A-D 2-5 starting from 7 is also described. The core is synthesized in 4.6% yield over 24 steps. Nakamura's radical dehalogenative hydroxylation is applied for the first time to a cyclopropyl carbonyl iodide to give the ring-opened product in 86% yield. Bolm's meso-anhydride desymmetrization is used to introduce asymmetry in a norbornene intermediate. The final step is a diastereoselective intermolecular chlorination using Barton's methodology to achieve chlorine transfer in 76% yield.

Transition metal clusters supported by multinucleating ligand frameworks as models of biological active sites

This dissertation describes efforts to model biological active sites with small molecule clusters. The approach used took advantage of a multinucleating ligand to control the structure and nuclearity of the product complexes, allowing the study of many different homo- and heterometallic clusters. Chapter 2 describes the synthesis of the multinucleating hexapyridyl trialkoxy ligand used throughout this thesis and the synthesis of trinuclear first row transition metal complexes supported by this framework, with an emphasis on tricopper systems as models of biological multicopper oxidases. The magnetic susceptibility of these complexes were studied, and a linear relation was found between the Cu-O(alkoxide)-Cu angles and the antiferromagnetic coupling between copper centers. The triiron(II) and trizinc(II) complexes of the ligand were also isolated and structurally characterized.

Chapter 3 describes the synthesis of a series of heterometallic tetranuclear manganese dioxido complexes with various incorporated apical redox-inactive metal cations (M = Na⁺, Ca²⁺, Sr²⁺, Zn²⁺, Y³⁺). Chapter 4 presents the synthesis of heterometallic trimanganese(IV) tetraoxido complexes structurally related to the CaMn₃ subsite of the oxygen-evolving complex (OEC) of Photosystem II. The reduction potentials of these complexes were studied, and it was found that each isostructural series displays a linear correlation between the reduction potentials and the Lewis acidities of the incorporated redox-inactive metals. The slopes of the plotted lines for both the dioxido and tetraoxido clusters are the same, suggesting a more general relationship between the electrochemical potentials of heterometallic manganese oxido clusters and their “spectator” cations. Additionally, these studies suggest that Ca²⁺ plays a role in modulating the redox potential of the OEC for water oxidation.

Chapter 5 presents studies of the effects of the redox-inactive metals on the reactivities of the heterometallic manganese complexes discussed in Chapters 3 and 4. Oxygen atom transfer from the clusters to phosphines is studied; although the reactivity is kinetically controlled in the tetraoxido clusters, the dioxido clusters with more Lewis acidic metal ions (Y³⁺ vs. Ca²⁺) appear to be more reactive. Investigations of hydrogen atom transfer and electron transfer rates are also discussed.

Appendix A describes the synthesis, and metallation reactions of a new dinucleating bis(N-heterocyclic carbene)ligand framework. Dicopper(I) and dicobalt(II) complexes of this ligand were prepared and structurally characterized. A dinickel(I) dichloride complex was synthesized, reduced, and found to activate carbon dioxide. Appendix B describes preliminary efforts to desymmetrize the manganese oxido clusters via functionalization of the basal multinucleating ligand used in the preceding sections of this dissertation. Finally, Appendix C presents some partially characterized side products and unexpected structures that were isolated throughout the course of these studies.

Família homoafetiva: efeitos patrimonais

Constituição de 1988. Novo ordenamento jurídico tem início, novo arcabouço, com novos valores e princípios, especialmente o da dignidade da pessoa humana. Este novo sistema jurídico precisa ser aplicado, os valores e princípios que passam a reger o ordenamento devem impregnar todos os ramos do direito, orientar sua interpretação e aplicação. Nestes se inclui o direito civil, que tem suas raízes fincadas no sujeito de direito, no credor e proprietário, digno de proteção. Um novo direito civil começa a surgir, na esteira de valores outros, absolutamente distintos dos anteriormente encontrados. Essa necessidade de mudança se faz notar mormente no direito de família, que tem arraigada na sua cultura secular a família patriarcal, hierarquizada na pessoa do pai, destinada a assegurar o patrimônio deste grupo, destinada a assegurar uma moral que se diz aceita socialmente, e cujos valores pretende preservar. Essa família entre em choque com os valores trazidos pela nova Constituição; não será por meio de sua simples promulgação que tais valores superarão a moral socialmente aceita para passarem a tutelar a pessoa em primeiro lugar, para buscar a proteção do indivíduo, da sua dignidade, em detrimento da propriedade outrora dominante. O trabalho do intérprete do direito é, pois, fazer do direito instrumento não só de manutenção do status quo, mas de transformação da sociedade, para que a Constituição não seja mera folha de papel, e sim norma que obriga e modifica a sociedade para a qual foi elaborada. A família atual é multifacetada, plural, capaz de se estruturar dos mais variados modos, desde que o seja da maneira mais apta a desenvolver a personalidade de cada um de seus integrantes, a proporcionar a vida digna e a convivência harmônica destes integrantes. Moral socialmente aceita não é aquela preestabelecida por algum grupo como única possível, mas qualquer uma capaz de, respeitando cada individualidade, proporcionar à pessoa o desenvolvimento de sua personalidade segundo suas concepções de vida digna. Não há uma moral, mais várias sem preconceitos e pré-julgamentos, tendo por base os princípios e valores constitucionais de liberdade, igualdade, dignidade, de vedação à discriminação de qualquer tipo. O presente trabalho pretende trazer algum auxílio no difícil labor de transformar a realidade, de transformar o direito civil do século XVIII, hierarquizado e apto a tutelar adequadamente apenas o patrimônio, no direito civil da Constituição de 1988, que busca o desenvolvimento da pessoa, a concretização de seus anseios e a promoção da sua dignidade na procura de uma sociedade livre, justa e solidária. Busca-se oferecer alternativas para que os princípios constitucionais possam suplantar a moral patrimonialista de outrora, que não mais se justifica no ordenamento posto.

Structural and Biophysical Characterization of Variants of the Mechanosensitive Channel of Large Conductance (MSCL)

The ability to sense mechanical force is vital to all organisms to interact with and respond to stimuli in their environment. Mechanosensation is critical to many physiological functions such as the senses of hearing and touch in animals, gravitropism in plants and osmoregulation in bacteria. Of these processes, the best understood at the molecular level involve bacterial mechanosensitive channels. Under hypo-osmotic stress, bacteria are able to alleviate turgor pressure through mechanosensitive channels that gate directly in response to tension in the membrane lipid bilayer. A key participant in this response is the mechanosensitive channel of large conductance (MscL), a non-selective channel with a high conductance of ~3 nS that gates at tensions close to the membrane lytic tension.

It has been appreciated since the original discovery by C. Kung that the small subunit size (~130 to 160 residues) and the high conductance necessitate that MscL forms a homo-oligomeric channel. Over the past 20 years of study, the proposed oligomeric state of MscL has ranged from monomer to hexamer. Oligomeric state has been shown to vary between MscL homologues and is influenced by lipid/detergent environment. In this thesis, we report the creation of a chimera library to systematically survey the correlation between MscL sequence and oligomeric state to identify the sequence determinants of oligomeric state. Our results demonstrate that although there is no combination of sequences uniquely associated with a given oligomeric state (or mixture of oligomeric states), there are significant correlations. In the quest to characterize the oligomeric state of MscL, an exciting discovery was made about the dynamic nature of the MscL complex. We found that in detergent solution, under mild heating conditions (37 °C – 60 °C), subunits of MscL can exchange between complexes, and the dynamics of this process are sensitive to the protein sequence.

Extensive efforts were made to produce high diffraction quality crystals of MscL for the determination of a high resolution X-ray crystal structure of a full length channel. The surface entropy reduction strategy was applied to the design of S. aureus MscL variants and while the strategy appears to have improved the crystallizability of S. aureus MscL, unfortunately the diffraction qualities of these crystals were not significantly improved. MscL chimeras were also screened for crystallization in various solubilization detergents, but also failed to yield high quality crystals.

MscL is a fascinating protein and continues to serve as a model system for the study of the structural and functional properties of mechanosensitive channels. Further characterization of the MscL chimera library will offer more insight into the characteristics of the channel. Of particular interest are the functional characterization of the chimeras and the exploration of the physiological relevance of intercomplex subunit exchange.

Oxy anion-accelerated rearrangements

The alkali metal salts of 1,5-hexadien-3-ols undergo accelerated Cope rearrangements to the enolates of δ, ε-unsaturated carbonyl compounds. The generality of the rearrangement was investigated in numerous systems, particularly acyclic cases, and the effect of changes in substituents, counterions, solvents, and geometrical structures were noted and discussed. Applications of this methodology in synthesis included the synthesis of the insect pheromone frontalin, the preparation of selectively monoprotected 1,6-dicarbonyl compounds from 4-methoxy- and 4-phenylthio-1,5-hexadien-3-ols, and the construction of complex ring structures such as a D-homo-estratetraenone derivative.

Thermochemical estimates of the energetics of anionpromoted alkoxide fragmentations were made, and in all cases heterolytic cleavage was favored over hemolytic cleavage by 8.5-53 kcal/mol. The implication of these and other thermochemical estimates is that the anionic oxy-Cope rearrangement occurs via a concerted mechanism rather than a dissociation-recombination process. The concepts of anion-induced bond weakening were successfully applied to an accelerated [1,3]-shift of a dithiane fragment in a cyclohexenyl system. Trapping experiments demonstrated that > 85% of the [1,3]-shift occurred within a solvent cage. Attempts at promoting an intramolecular ene reaction using the potassium salts of 2,7-octadien-1-o1 and 2,8-nonadien-1-o1 were unsuccessful. A general review of anion-promoted bond reorganizations and anion substituent effects is also presented.

Charge and spin transport in graphene devices

170 p.

O lugar do silêncio na violência homofóbica: o dizível e o indizível nas narrativas de sofrimento

O presente estudo tem por objetivo analisar o lugar ocupado pelo silêncio na narrativa de pessoas que sofreram violência homofóbica e que são acompanhadas pelos dispositivos públicos de atenção e cuidado a lésbicas, gays, bissexuais, travestis e transexuais implantados no estado do Rio de Janeiro. Utiliza-se neste trabalho o conceito de homofobia como violência motivada pelo preconceito sexual, que se origina do processo histórico que produziu a separação entre homo e heterossexualidade e estabeleceu a última como norma. O trabalho de campo realizado em dois Centros de Referência e num dispositivo público de saúde incluiu entrevistas semiestruturadas com 11 usuários e 25 profissionais, no período de junho a novembro de 2011. A análise do material indica que o silêncio constitui-se como um discurso legítimo sobre a dor, servindo de proteção para a manutenção de determinadas relações, preenchendo, portanto, um espaço de fala. Reconhecer o lugar do silêncio, mesmo em dispositivos que se propõe a acolher denúncias de violência, pode facilitar o fortalecimento do encontro entre profissionais e usuários dos serviços voltados para pessoas LGBT.

Configurações do estado de exceção no romance Ensaio sobre a cegueira de José Saramago

O romance Ensaio sobre a cegueira, do escritor português José Saramago, publicado em 1995, revela profundas críticas à estrutura da sociedade hodierna, bem como sua política. Em vistas desse fato, a presente dissertação investiga as relações políticas e filosóficas presentes no romance, estabelecendo como arcabouço teórico as pesquisas do filósofi italiano Giorgio Agamben sobre o estado de exceção na série de volumes Homo Sacer, que segue a trilha deixada por Michel Foucault sobre os dispositivos de poder e saber na sociedade contemporânea. A pesquisa ora apresentada revela uma leitura do estado de exceção enquanto uma estrutura de exclusão da vida nuaatravés de uma via biopolítica que encontra no romance do escritor português um intenso questionamento sobre o homem moderno descolado de si mesmo

Escolha profissional na contemporaneidade: verso e reverso

Neste trabalho, problematizamos as práticas de escolha profissional dos jovens e suas articulações com o mundo do trabalho, a educação e os processos de produção de subjetividade na cena contemporânea. Adotamos o referencial teórico da Análise Institucional, as ferramentas conceituais de Foucault e a Filosofia da Diferença e, como ferramenta metodológica da Filosofia da Diferença, a Cartografia. Sendo esta puro processo, sem começo nem fim, cartografamos, de forma parcial e provisória, os caminhos em que vida e trabalho foram se constituindo nas práticas localizadas e cotidianas dos jovens. A Cartografia permitiu-nos acompanhar a invenção de um percurso de pesquisa ditado pelos deslocamentos e práticas de contágio com jovens, pesquisadora e pesquisa. A radicalidade da experiência foi tanta que afetou o próprio corpo da escrita, produzindo o reverso, um outro lado do texto. Com o conceito de prática de Foucault, seguimos a formação discursiva do conceito de vocação e as suas articulações com as transformações do capital e os efeitos da lógica do mercado na vida dos jovens na atualidade. Diante das intricadas articulações, passamos a questionar a escolha como uma possibilidade, já que esse tema adquire um lugar central nas investigações atuais, pois a máquina capitalista se reinventa na própria produção de desejo. Em outra vertente, analisamos as práticas educacionais que produzem o Homo Economicus e outras práticas inventivas que questionam e se reinventam na composição com um Homo Politicus, numa intervenção em que as escolhas seguem com o outro e não sobre o outro. Trabalhamos com as oficinas como dispositivos de pesquisa que nos permitiram seguir os múltiplos atravessamentos nos jovens e em seus processos de vida, primeiramente em um colégio de uma área semirrural do município de Petrópolis RJ, e depois em Lisboa, Portugal, numa escola secundária pública, numa organização de apoio a migrantes e numa ONG que trabalha com a cultura hip-hop. Esses caminhos nos levaram a um modo de orientação profissional como processo, ao deslocar de uma orientação responsiva, linear, que orienta para um lugar no mundo, para uma orientação intensiva, que acolhe as dúvidas e que se abre a multiplicidades de práticas inventivas com o outro. Uma aprendizagem que pede tempo e corpo e potencializa novos modos de fazer vida, quiçá mais dignos, interessantes e solidários.

Newtonen mugimenduaren legeen azterketa Lehen Hezkuntzan

[Eus] Lan honetan Lehen Hezkuntzako hirugarren zikloko ikasleek fisikaren barnean Newtonen mugimenduen legeei buruz zer dakitenaren azterketa kuantitatibo bat egitea izan da. Horretarako, Gernika-Lumoko Seber Altube ikastolako 94 ikasleri Lehen Hezkuntzako ikasleentzat moldatutako FCI (Force Concept Inventory) testa pasatu zitzaien, ondoren emaitzak aztertzeko. Egindako ikerketan aurkitutako emaitzek, aurretiaz gai honi buruz izan diren lanekin bat egiten dute, generoaren araberako ezberdintasunak baztertuz eta Newtonen legeen artean emaitzen arteko ezberdintasun esanguratsuak azalduz.

Comportamento eleitoral e a variável religiosa na decisão do voto: um estudo sobre eleitores neopentecostais

Apresentando como principal expoente a Igreja Universal do Reino de Deus, o segmento evangélico neopentecostal tem obtido sucesso em sua inserção político eleitoral, através da utilização de estratégias eleitorais características, como o cadastramento de fiéis, a adoção de campanhas oficiais distribuídas por região de acordo com o potencial do eleitorado e o uso da mídia própria e dos púlpitos para o marketing político. Inserida nos estudos de comportamento eleitoral, esta dissertação fará uma análise sobre os eleitores dos autodenominados políticos de Deus, com a utilização de surveys, dados eleitorais e pesquisa de campo. Através da aplicação da Teoria da Escolha Racional, será investigada a hipótese de que os eleitores neopentecostais não se distanciam da concepção de Homo politicus da teoria downsiana, agindo racionalmente quando atribuem seu voto a um irmão de fé.