Computational Predictions of G Protein-Coupled Receptor Structures and Binding Sites

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.

Production of the chironomids of the Uchinsk Reservoir. [Translation of: Methods for the estimation of production of aquatic animals. (Handbook and papers) (ed. G. G. Vinberg) p226-239. Minsk, Vysheishaya Shkola, 1968]

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.

Free algebras in Von Neumann-Bernays-Gӧdel set theory and positive elementary inductions in reasonable structures

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.

Structural Characterization of Pro-inflammatory and Anti-inflammatory Immunoglobulin G Fc Proteins

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.

Action of ecdysterone on the moulting of amphipod females: Gammarus pulex (L.) and G.fossarum Koch. Early results. [Translation from: Crustaceana 28, 86-88, 1975.]

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.

Feeding of Gammarus lacustris Sars under different conditions of habitation [Translation from: [Trophic relations of freshwater invertebrates.] (ed. G. G. Vinberg) pp.94-98. Leningrad, Zool.Inst.AN SSSR, 1980]

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.

Erlazio afektiboa sexualak espetxe garaian, askatasun (g)une?

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.

Coincidence point theorems in quasi-metric spaces without assuming the mixed monotone property and consequences in G-metric spaces

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.

Estudio de la Calidad Experimentada (QoE) en el Servicio de Navegación Web: Contribución a la Validación de las Recomendaciones ITU-T P.1501 e ITU-T G.1031

Muchos de los servicios que hasta hace relativamente poco tiempo eran ofertados únicamente por los operadores de telecomunicaciones, han pasado en la actualidad a ser prestados por terceros gracias al modelo de servicios en la nube, impulsando el auge de este modelo frente al tradicional. Esto trae consigo un incremento en la complejidad en la implantación por parte del proveedor de políticas para la gestión de la QoS demandada por el cliente.En este nuevo escenario, el concepto de calidad de servicio ha venido evolucionando desde su definición clásica, entendida como el análisis objetivo de los indicadores intrínsecos de calidad que definen el rendimiento de un servicio, hacia una visión subjetiva centrada en el punto de vista del cliente respecto a dicho servicio. En este contexto, organismos de estandarización como la ITU, a través de sus grupos de trabajo, están fomentando el interesante planteamiento de abordar los servicios de telecomunicaciones ampliamente asentados y más que estudiados desde la vertiente clásica de la QoS, desde este nuevo prisma enfocado al cliente, en el que poder establecer una metodología de estudio de la QoE en dichos servicios. En particular, el trabajo presentado en este documento se asienta en la validación del draft de la recientemente aprobada recomendación ITU-T P.1501 (Metodología de test subjetiva para el servicio de navegación web), así como en la contribución a la recomendación G.1031 (Factores de QoE en el servicio de navegación web).

O laboratório analítico: a psicologia de C.G. Jung examinada pela teoria do ator-rede

O psiquiatra suíço Carl Gustav Jung (1875-1961) é um dos principais nomes da psicologia e da psicoterapia do século XX. Algumas de suas maiores contribuições teórico-metodológicas são as idéias de realidade psíquica, complexo, arquétipo (inconsciente coletivo), processo de individuação, método dialético, método construtivo e imaginação ativa. A psicologia analítica de Jung, ao longo de sua formação, foi influenciada por diversas disciplinas, dentre elas a etnologia (ciências sociais). Este trabalho buscou dar continuidade a este processo de construção epistêmica, mediante exame das concepções de Jung por intermédio da teoria do ator-rede (TAR), uma importante corrente da sociologia contemporânea. Pretendeu-se também saber se a psicologia analítica se mantém atual ou se já é uma teoria e prática clínica anacrônicas. O principal autor relacionado à TAR a quem se recorreu neste trabalho foi o sociólogo francês Bruno Latour. De sua perspectiva, o acordo moderno, disjuntor de Natureza e Cultura, é insuficiente para explicar a complicação inerente às entidades que compõem a realidade. Para escapar das armadilhas conceptuais da modernidade, Latour opera com constructos tais como coletivo (social), ator-rede, proposição, vínculo e plasma. Além do pensamento de Latour, este trabalho valeu-se das idéias sociológicas de Gabriel Tarde e da influenciologia etnopsicanalítica de Tobie Nathan, aproveitando-se da afinidade teórica que compartilham com Latour. Nathan, por desenvolver uma prática em psicoterapia, permitiu propor à psicologia clínica de Jung determinadas questões que o enfoque mais estritamente sociológico de Latour não possibilitava. Uma vez expostas as concepções de Latour, Tarde e Nathan, apresentaram-se os elementos da psicologia analítica com os quais se esperava que elas fossem compatíveis. Concluiu-se que, apesar das diferenças, muitas aproximações são plausíveis entre psicologia analítica e TAR. Constatou-se que a concepção de Jung de um psiquismo multifacetado, em devir, cujos componentes se relacionam de diferentes maneiras, é comparável à noção de ator-rede trabalhada por Latour e à monadologia de Tarde. Verificou-se também que a abordagem pragmática e construtiva identificada na psicoterapia junguiana é em muitos aspectos análoga à prática da etnopsicanálise. Assim, foi possível afirmar que a TAR e a psicologia analítica podem formar aliança.

Um estudo comparativo de escritas limítrofes em A paixão segundo G.H. de Clarice Lispector e em Malina de Ingebog Bachmann

Esta pesquisa analisa os romances A paixão segundo G.H. (1964), de Clarice Lispector e Malina (1971), de Ingeborg Bachmann, detendo-se nos conceitos de narração e identidade, procurando estabelecer um ponto de contato entre os dois, visto que é através da consciência do ato narrativo que as personagens-narradoras dos dois romances podem dispor de elementos que as ajude a construir sua identidade. Os romances serão analisados como sendo exemplos de romance de formação do século XX, assumindo então que o caminho percorrido pelas personagens G.H. e Eu seria uma trajetória formativa na qual conscientizam-se de si mesmas e amadurecem através do enfrentamento de conflitos existenciais. Os corpora desta dissertação foram escritas em um período limítrofe entre a literatura Modernista e Pós-Moderna, agregando em si características de ambas as épocas, destacados por um enredo denso e repleto de artifícios de linguagem que explicitam a consciência narrativa das personagens-narradoras do romance. O objetivo desta dissertação é, portanto, analisar a importância da consciência da narrativa de G.H. e Eu durante o seu processo formativo e porque a narração cede lugar ao silêncio nas obras de ambas as escritoras, ainda que de maneira distinta