977 resultados para Clarke, Frank G., 1850-1901.
Resumo:
G-protein coupled receptors (GPCRs) form a large family of proteins and are very important drug targets. They are membrane proteins, which makes computational prediction of their structure challenging. Homology modeling is further complicated by low sequence similarly of the GPCR superfamily.
In this dissertation, we analyze the conserved inter-helical contacts of recently solved crystal structures, and we develop a unified sequence-structural alignment of the GPCR superfamily. We use this method to align 817 human GPCRs, 399 of which are nonolfactory. This alignment can be used to generate high quality homology models for the 817 GPCRs.
To refine the provided GPCR homology models we developed the Trihelix sampling method. We use a multi-scale approach to simplify the problem by treating the transmembrane helices as rigid bodies. In contrast to Monte Carlo structure prediction methods, the Trihelix method does a complete local sampling using discretized coordinates for the transmembrane helices. We validate the method on existing structures and apply it to predict the structure of the lactate receptor, HCAR1. For this receptor, we also build extracellular loops by taking into account constraints from three disulfide bonds. Docking of lactate and 3,5-dihydroxybenzoic acid shows likely involvement of three Arg residues on different transmembrane helices in binding a single ligand molecule.
Protein structure prediction relies on accurate force fields. We next present an effort to improve the quality of charge assignment for large atomic models. In particular, we introduce the formalism of the polarizable charge equilibration scheme (PQEQ) and we describe its implementation in the molecular simulation package Lammps. PQEQ allows fast on the fly charge assignment even for reactive force fields.
Resumo:
G protein-coupled receptors (GPCRs) are the largest family of proteins within the human genome. They consist of seven transmembrane (TM) helices, with a N-terminal region of varying length and structure on the extracellular side, and a C-terminus on the intracellular side. GPCRs are involved in transmitting extracellular signals to cells, and as such are crucial drug targets. Designing pharmaceuticals to target GPCRs is greatly aided by full-atom structural information of the proteins. In particular, the TM region of GPCRs is where small molecule ligands (much more bioavailable than peptide ligands) typically bind to the receptors. In recent years nearly thirty distinct GPCR TM regions have been crystallized. However, there are more than 1,000 GPCRs, leaving the vast majority of GPCRs with limited structural information. Additionally, GPCRs are known to exist in a myriad of conformational states in the body, rendering the static x-ray crystal structures an incomplete reflection of GPCR structures. In order to obtain an ensemble of GPCR structures, we have developed the GEnSeMBLE procedure to rapidly sample a large number of variations of GPCR helix rotations and tilts. The lowest energy GEnSeMBLE structures are then docked to small molecule ligands and optimized. The GPCR family consists of five subfamilies with little to no sequence homology between them: class A, B1, B2, C, and Frizzled/Taste2. Almost all of the GPCR crystal structures have been of class A GPCRs, and much is known about their conserved interactions and binding sites. In this work we particularly focus on class B1 GPCRs, and aim to understand that family’s interactions and binding sites both to small molecules and their native peptide ligands. Specifically, we predict the full atom structure and peptide binding site of the glucagon-like peptide receptor and the TM region and small molecule binding sites for eight other class B1 GPCRs: CALRL, CRFR1, GIPR, GLR, PACR, PTH1R, VIPR1, and VIPR2. Our class B1 work reveals multiple conserved interactions across the B1 subfamily as well as a consistent small molecule binding site centrally located in the TM bundle. Both the interactions and the binding sites are distinct from those seen in the more well-characterized class A GPCRs, and as such our work provides a strong starting point for drug design targeting class B1 proteins. We also predict the full structure of CXCR4 bound to a small molecule, a class A GPCR that was not closely related to any of the class A GPCRs at the time of the work.
Resumo:
The method of E.V. Borutski was used for determining the production of chironomids, that is, the dynamics of the number and biomass of the larvae were analysed, their death, a calculation of emergence and the number of deposited egg layings was carried out. In addition to the method of Borutski, the authors also calculated the seasonal dynamics of the number of larvae of the younger age stages in the microbenthos.
Resumo:
This thesis consists of two independent chapters. The first chapter deals with universal algebra. It is shown, in von Neumann-Bernays-Gӧdel set theory, that free images of partial algebras exist in arbitrary varieties. It follows from this, as set-complete Boolean algebras form a variety, that there exist free set-complete Boolean algebras on any class of generators. This appears to contradict a well-known result of A. Hales and H. Gaifman, stating that there is no complete Boolean algebra on any infinite set of generators. However, it does not, as the algebras constructed in this chapter are allowed to be proper classes. The second chapter deals with positive elementary inductions. It is shown that, in any reasonable structure ᶆ, the inductive closure ordinal of ᶆ is admissible, by showing it is equal to an ordinal measuring the saturation of ᶆ. This is also used to show that non-recursively saturated models of the theories ACF, RCF, and DCF have inductive closure ordinals greater than ω.
Resumo:
Immunoglobulin G (IgG) is central in mediating host defense due to its ability to target and eliminate invading pathogens. The fragment antigen binding (Fab) regions are responsible for antigen recognition; however the effector responses are encoded on the Fc region of IgG. IgG Fc displays considerable glycan heterogeneity, accounting for its complex effector functions of inflammation, modulation and immune suppression. Intravenous immunoglobulin G (IVIG) is pooled serum IgG from multiple donors and is used to treat individuals with autoimmune and inflammatory disorders such as rheumatoid arthritis and Kawasaki’s disease, respectively. It contains all the subtypes of IgG (IgG1-4) and over 120 glycovariants due to variation of an Asparagine 297-linked glycan on the Fc. The species identified as the activating component of IVIG is sialylated IgG Fc. Comparisons of wild type Fc and sialylated Fc X-ray crystal structures suggests that sialylation causes an increase in conformational flexibility, which may be important for its anti-inflammatory properties.
Although glycan modifications can promote the anti-inflammatory properties of the Fc, there are amino acid substitutions that cause Fcs to initiate an enhanced immune response. Mutations in the Fc can cause up to a 100-fold increase in binding affinity to activating Fc gamma receptors located on immune cells, and have been shown to enhance antibody dependent cell-mediated cytotoxicity. This is important in developing therapeutic antibodies against cancer and infectious diseases. Structural studies of mutant Fcs in complex with activating receptors gave insight into new protein-protein interactions that lead to an enhanced binding affinity.
Together these studies show how dynamic and diverse the Fc region is and how both protein and carbohydrate modifications can alter structure, leading to IgG Fc’s switch from a pro-inflammatory to an anti-inflammatory protein.
Resumo:
In studying sexual attraction in gammarids of the group pulex, it has seemed necessary to dissociate the processes of moulting and ovogenesis in order to recognize their respective effects on this phenomenon. For this purpose a synthetic hormone, ecdysterone, was utilized. In the first instance the author followed the action of the hormone on isolated females in vitellogenesis. It was proved that the behaviour of Gammarus pulex and Gammarus fossarum vis-a-vis the ecdysterone used proves to be very close to that of isopods that was observed in Orchestia gammarellus in earlier research. Although they were in vitellogenesis, the females saw their intermoult cycle shortened.
Resumo:
The amphipod Gammarus lacustris, a regular representative of lacustrine communities, often plays a significant role in the transformation of matter and energy. The object of the present work was to clarify the quantitative side of the feeding of the amphipod under different conditions of habitation. Experimental works on determination of the rate of consumption of food and its dependence on body-weight were carried out in the summer periods 1975-1978 on three water-bodies of the Krasnoyarsk region, of different conditions of habitation for the amphipods.
Resumo:
Este trabalho se propõe analisar a construção da obra de Alexandre Herculano como historiador, que teve início com a publicação de inúmeros artigos no jornal O Panorama e na Revista Universal Lisbonense. Nesses textos, procuramos perceber as reflexões iniciais que levaram a um projeto de maior fôlego intelectual, a História de Portugal, publicada em um momento de emergência das nacionalidades e da formação das consciências nacionais. Nesse sentido, procuramos perceber como Herculano concebeu a sua história analisando sua trajetória como historiador/político em meio às graduais transformações sociais que ocorriam em Portugal à sua época. Assim, propusemo-nos pensar o Alexandre Herculano político em constante diálogo com a conjuntura daquele período, tendo como referência a sua atuação social e a sua intervenção textual no processo então em curso.
Resumo:
O objetivo da presente pesquisa é o de discutir a reescrita da história da Irlanda, mais especificamente aspectos relacionados à construção da identidade nacional e de marcas da tradição, a partir da leitura do romance Tipperary, de Frank Delaney. Publicada em 2007, essa obra aborda de forma singular as querelas sobre identidade nacional, nacionalismo, passado, memória, e seus personagens principais e a trama estão significativamente ligados ao contexto político-social da história da Irlanda. Nessa reconstrução da história, o passado é revisitado através de diferentes pontos de vista. Nossa atenção estará voltada para a seleção de elementos/momentos da história do país que ganham foco na narrativa, e as possíveis repercussões deste processo. Além disso, nos concentraremos na questão das tênues fronteiras entre história e ficção, ou seja, as fronteiras pouco delimitadas entre o discurso histórico e o discurso ficcional. Na escrita da história em Tipperary, Delaney aborda questões relativas a mitos, lendas e tradições como importantes fatores de identidade nacional em uma Irlanda que emerge como uma nação independente. No romance em questão, podemos observar como história e memória se unem na jornada do protagonista, em sua empreitada de narrar a história de sua vida e de seu país
Resumo:
Este trabalho contemplou a análise das relações entre imigração, negócios e poder a partir da inserção do imigrante português no comércio da cidade do Rio de Janeiro entre 1850 e 1875. Nesse período, as relações internacionais entre Brasil e Portugal caracterizaram-se essencialmente por duas forças sociais: o fluxo migratório e o comércio. Através do intercruzamento de fontes documentais, identificou-se o perfil dos membros da elite mercantil portuguesa instalada na capital do Império brasileiro, bem como suas estratégias de ascensão econômica e projeção política junto à sociedade e aos Estados de Portugal e Brasil. Avaliou-se, ainda, o estímulo causado pelas trajetórias de sucesso na realimentação do movimento de emigração portuguesa. Concluiu-se que os imigrantes lusos, através do comércio, tornaram-se agentes dinâmicos das relações bilaterais Brasil-Portugal.
Resumo:
Espetxearen iruditegia erabat maskulinoa den garai hauetan, emakumeak erdigunean jartzen dituen analisi feminista da ondorengoa. Espetxearen egunerokoan hain garrantzitsuak, baina aldi berean hain ikusezinak diren harreman afektibo sexualak aztertzea da helburu nagusia, emakume preso edo haien bikotekideak preso dituzten emakumeen testigantzak jasoz. Euskal preso politikoen kolektiboaren baitan egindako ikerketa honetan, jende gaztearen maitasun ereduez eta hauek espetxean duten eragin eta egoerez aritu gara.
Resumo:
In this paper, we present some coincidence point theorems in the setting of quasi-metric spaces that can be applied to operators which not necessarily have the mixed monotone property. As a consequence, we particularize our results to the field of metric spaces, partially ordered metric spaces and G-metric spaces, obtaining some very recent results. Finally, we show how to use our main theorems to obtain coupled, tripled, quadrupled and multidimensional coincidence point results.
Resumo:
O estudo da correspondência possibilita uma análise de detalhes que, de outra maneira, escapariam à compreensão da historiografia. A proposta deste trabalho é fazer uma análise do comportamento de um cafeicultor do Vale do Paraíba Fluminense, Manoel Antônio Esteves que, de 1845 a 1879, manteve correspondência com diversos elementos e soube preservar este material. Entre cartas recebidas e enviadas, através da microanálise, podemos compreender um pouco da realidade do oitocentos brasileiro, com destaque especial para as questões familiares, a criação e manutenção de redes de sociabilidade, a cultura política de um período que marcou a região em foco. Cartas são documentos ainda pouco explorados pela historiografia, mas guardam informações capazes de produzir novas interpretações de uma época. Elas podem, aqui, revelar muito ainda sobre o longo século XIX no Brasil.