Modeling of enzyme–substrate complexes for the metalloproteases MMP-3, ADAM-9 and ADAM-10

The matrix metalloproteases (MMPs) and the ADAMs (A Disintegrin And Metalloprotease domain) are proteolytic enzyme families containing a catalytic zinc ion, that are implicated in a variety of normal and pathological processes involving tissue remodeling and cancer. Synthetic MMP inhibitors have been designed for applications in pathological situations. However, a greater understanding of substrate binding and the catalytic mechanism is required so that more effective and selective inhibitors may be developed for both experimental and clinical purposes. By modeling a natural substrate spanning P4-P4‘ in complex with the catalytic domains, we aim to compare substrate-specificities between Stromelysin-1 (MMP-3), ADAM-9 and ADAM–10, with the aid of molecular dynamics simulations. Our results show that the substrate retains a favourable antiparallel beta-sheet conformation on the P-side in addition to the well-known orientation of the P'-region of the scissile bond, and that the primary substrate selectivity is dominated by the sidechains in the S1' pocket and the S2/S3 region. ADAM-9 has a hydrophobic residue as the central determinant in the S1' pocket, while ADAM-10 has an amphiphilic residue, which suggests a different primary specificity. The S2/S3 pocket is largely hydrophobic in all three enzymes. Inspired by our molecular dynamics calculations and supported by a large body of literature, we propose a novel, hypothetical, catalytic mechanism where the Zn-ion polarizes the oxygens from the catalytic glutamate to form a nucleophile, leading to a tetrahedral oxyanion anhydride transition state.

Expression of the disintegrin metalloprotease ADAM-10 in prostate cancer and its regulation by dihydrotestosterone, insulin like growth factor -1 and epidermal growth factor in the prostate cell model LNCaP

Purpose: The disintegrin metalloprotease ADAM-10 is a multidomain metalloprotease that is potentially significant in tumor progression due to its extracellular matrix-degrading properties. Previously, ADAM-10 mRNA was detected in prostate cancer (PCa) cell lines; however, the presence of ADAM-10 protein and its cellular localization, regulation, and role have yet to be described. We hypothesized that ADAM-10 mRNA and protein may be regulated by growth factors such as 5α-dihydrotestosterone, insulin-like growth factor I, and epidermal growth factor, known modulators of PCa cell growth and invasion.

Experimental Design: ADAM-10 expression was analyzed by in situ hybridization and immunohistochemistry in prostate tissues obtained from 23 patients with prostate disease. ADAM-10 regulation was assessed using quantitative reverse transcription-PCR and Western blot analysis in the PCa cell line LNCaP.

Results: ADAM-10 expression was localized to the secretory cells of prostate glands, with additional basal cell expression in benign glands. ADAM-10 protein was predominantly membrane bound in benign glands but showed marked nuclear localization in cancer glands. By Western blot, the 100-kDa proform and the 60-kDa active form of ADAM-10 were synergistically up-regulated in LNCaP cells treated with insulin-like growth factor I plus 5α-dihydrotestosterone. Epidermal growth factor also up-regulated both ADAM-10 mRNA and protein.

Conclusions: This study describes for the first time the expression, regulation, and cellular localization of ADAM-10 protein in PCa. The regulation and membrane localization of ADAM-10 support our hypothesis that ADAM-10 has a role in extracellular matrix maintenance and cell invasion, although the potential role of nuclear ADAM-10 is not yet known.

AdaM : adaptive-maximum imputation for neighborhood-based collaborative filtering

In the context of collaborative filtering, the well known data sparsity issue makes two like-minded users have little similarity, and consequently renders the k nearest neighbour rule inapplicable. In this paper, we address the data sparsity problem in the neighbourhood-based CF methods by proposing an Adaptive-Maximum imputation method (AdaM). The basic idea is to identify an imputation area that can maximize the imputation benefit for recommendation purposes, while minimizing the imputation error brought in. To achieve the maximum imputation benefit, the imputation area is determined from both the user and the item perspectives; to minimize the imputation error, there is at least one real rating preserved for each item in the identified imputation area. A theoretical analysis is provided to prove that the proposed imputation method outperforms the conventional neighbourhood-based CF methods through more accurate neighbour identification. Experiment results on benchmark datasets show that the proposed method significantly outperforms the other related state-of-the-art imputation-based methods in terms of accuracy.

Adam Richards: diverse comedy with some mishits

Review of Adam Richard's Gayapocalypse for the 2014 Maelbourne Comedy Festival.

Adam Smith visto por Roberto Campos: a (re)criação do mito e as necessidades do capitalismo

This work aims at analyzing how Adam Smith, one of the founders of the liberal regime was seen by Roberto Campos, one of the patriarchs of Brazilian liberalism. In this sense, it will be shown how and why the legacy of Scotland was used to legitimize the new pattern of accumulation necessary to capitalism from the second half of the twentieth century on. So, it is the intention to make explicit that the changes in Campos discursive form are consistent with the requirements of capitalism in crisis and were fundamental in the creation of another common sense. To achieve these goals it will be assessed in what way the liberal rhetoric of the Brazilian, harmonized with foreign authors with the same vision, has become an important weapon to transform Smith into a myth in contrast to the political and economic criteria advocated by the same, but valuable to what Roberto Campos intended

A leitura do fantástico nos contos Ligeia de Edgard Allan Poe, e Véra, de Villiers de L'Isle-Adam

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

A tradução poética: Contes cruels de Villiers de L'Isle-Adam

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

L'Amour dácadent em dramas de Villiers de L'Isle-Adam e Maurice Maeterlinck

Pós-graduação em Estudos Literários - FCLAR

A voz baudelairiana em Fleurs de Ténèbres de Villiers de L’Isle-Adam

Este estudo tem o objetivo de apresentar uma análise do conto “Fleurs de Ténèbres” publicado na obra Contes cruels (1883) de Villiers de l’Isle-Adam (1838-1889). O trabalho visa, ainda, de forma particular, destacar elementos que permitem apontar relações de aproximação entre o conto villieriano e os poemas em prosa “La corde” e “Le tir et le cimetière” de Charles Baudelaire. Com efeito, a influência baudelairiana na escritura de Villiers de l’Isle-Adam diz respeito tanto aos procedimentos estilísticos quanto ao idealismo filosófico.

Souvenirs occultes de Villiers de L'Isle-Adam: um conto poético

Apoiando-se na análise do conto “Souvenirs occultes” recolhido na obra Contes cruels (1883) de Villiers de l’Isle-Adam (1839-1888), este trabalho tem a intenção de abordar alguns aspectos gerais da prosa poética do autor, tais como a estrutura formal circular característica da poesia, algumas imagens construídas pela sugestão e jogo de palavras, a questão do ponto de vista e algumas características do tempo, do espaço e do herói que revelam a presença de alguns mitos na obra. O conto “Souvenirs occultes” ilustra bem a osmose que se operou entre os gêneros no século XIX; com efeito, o poema em prosa com o título nervaliano “El Desdichado”, de Villiers, representa um esquemada versão defi nitiva do conto “Souvenirs occultes”, no qual cada uma das três estrofes do poema será retomada e desenvolvida. A análise vertical do texto, isto é, aquela em que procuramos depreender os sinais presentes nas palavras e símbolos por ele empregados, mostra, de fato, um autor brilhante que consegue, por meio da elaboração da linguagem, conduzir, o tempo todo, o leitor pela ambigüidade e dele demanda árduo trabalho para que desvende a segunda narrativa construída sob seu discurso simbólico. Palavras-chave: Villiers de l’Isle-Adam. “Souvenirs occultes”. Contes cruels. Literatura francesa. Simbolismo. Prosa poética.

Véra de Villiers de L'Isle-Adam: máscara de uma crítica social

A proposta deste trabalho é apresentar uma análise do discurso simbólico de “Véra” de Villiers de l’Isle-Adam, conto publicado, em sua versão definitiva, na obra Contes Cruels, em 1883. Villiers é considerado, por muitos teóricos, precursor do movimento simbolista na França e um dos maiores autores do gênero fantástico da segunda metade do século XIX. Assim, a maior parte das análises do conto insistem no elemento fantástico. Contudo, a prosa poética e o discurso fantástico – de natureza onírica, metafórica e ambígua – dos quais o autor faz uso, revelam uma crítica feroz à sociedade de seu tempo. Herói, narrador e autor se fundem para apresentar uma busca por um mundo ideal e, ao mesmo tempo, exprimir subtilmente uma crítica aos valores da sociedade burguesa. Com um discurso concentrado em sua composição, no qual cada palavra é escolhida de acordo com sua intenção e cujo principal objetivo é sugerir, Villiers caminha em direção a uma forma de expressão literária cheia de sensações e emoções individuais. Inquietudes existenciais e anseios de uma produção literária criadora contribuirão para o desenvolvimento de uma nova estética literária que se desenvolve na França a partir da segunda metade do século XIX: o Simbolismo. Palavras-chave: Villiers de L’Isle-Adam; Simbolismo; Véra; fantástico; crítica social; Idealismo.

Efeito do nível de atividade física nas concentrações da ADAM 10 em sujeitos com doença de Alzheimer e saudáveis

Pós-graduação em Ciências da Motricidade - IBRC