Using noncanonical amino acids in computational protein design

The structure of noncanonical amino acid (NCAA) side chains allows them to explore conformations inaccessible to canonical amino acids (CAAs). Peptides made of the D-enantiomers of amino acid backbones are resistant to proteolysis. The long term goal of this research is to adapt the current tools of computational protein design to create functional molecules be they proteins or not. In this thesis we have attempted the first steps toward this longer goal. The increased sequence and conformation space accessible to a protein during a design simulation when NCAAs are included, allows us to design tighter protein-protein interactions, with a higher degree of specificity. The computational protein design program Rosetta has been modified for compatibility with NCAAs. The use of knowledge-based potentials was the major hurdle as the potentials are based on statistics collected from known protein structures and few protein structures have been determined containing NCAAs. Using quantum mechanics (QM) calculations of the amino acids valine and isoleucine, with a helical conformation, we found an even distribution of rotamer preference. When that was used in rotamer recovery benchmarks, outperformed the knowledge-based potential that was biased because of long-range interactions imposed by the [alpha]-helical secondary structure. QM, although accurate and compatible with NCAAs was found to be too computationally expensive. We created a modified energy function that can evaluate the energy of both CAAs and NCAAs, where the knowledge-based energy potentials have been replaced with physically-based MM potentials that performs comparable to the stock energy function. We have developed methods to create rotamer libraries for both CAAs and NCAAs that are comparable to knowledge-based rotamer libraries. We have used these tools to create rotamer libraries for 88 different NCAAs that can now be used within Rosetta. The interface between calpain and the calpastatin peptide as well as the interface between HIV GP41 and the integration inhibitor, PIE12, developed by the Kay lab, has been redesigned using NCAAs to increase the binding affinity between the two pairs. The research has take protein design in a new direction and has enabled the development of novel protein interactions, and protein-like therapeutics

A História da Alimentação: balizas historiográficas

Os M. pretenderam traçar um quadro da História da Alimentação, não como um novo ramo epistemológico da disciplina, mas como um campo em desenvolvimento de práticas e atividades especializadas, incluindo pesquisa, formação, publicações, associações, encontros acadêmicos, etc. Um breve relato das condições em que tal campo se assentou faz-se preceder de um panorama dos estudos de alimentação e temas correia tos, em geral, segundo cinco abardagens Ia biológica, a econômica, a social, a cultural e a filosófica!, assim como da identificação das contribuições mais relevantes da Antropologia, Arqueologia, Sociologia e Geografia. A fim de comentar a multiforme e volumosa bibliografia histórica, foi ela organizada segundo critérios morfológicos. A seguir, alguns tópicos importantes mereceram tratamento à parte: a fome, o alimento e o domínio religioso, as descobertas européias e a difusão mundial de alimentos, gosto e gastronomia. O artigo se encerra com um rápido balanço crítico da historiografia brasileira sobre o tema

Does the Model for End-stage Liver Disease Accurately Predict the Occurrence of Ninety-Day Wait-List Mortality in Atlantic Canadian Liver Transplant Candidates? A Validation Study

Bibliography: p. 155-163Some pages are in colour.Includes copies of ethics approval and copyright permission. Original copies with original Partial Copyright Licence

Are there Geographical Disparities in Access to Liver Transplantation in Atlantic Canada?

OBJECTIVE: To characterize the patient population served by Atlantic Canada’s Multi-Organ Transplant Program liver transplant service over the first five years of activity in its current iteration

The Model for End-stage Liver Disease accurately predicts 90-day liver transplant wait-list mortality in Atlantic Canada

OBJECTIVE: To determine the generalizability of the predictions for 90-day mortality generated by Model for End-stage Liver Disease (MELD) and the serum sodium augmented MELD (MELDNa) to Atlantic Canadian adults with end-stage liver disease awaiting liver transplantation (LT)

The Model for End-Stage Liver Disease Accurately Predicts 90-Day Liver Transplant Wait-List Mortality in Atlantic Canada

OBJECTIVE: To determine the generalizability of the predictions for 90-day mortality generated by Model for End-stage Liver Disease (MELD) and the serum sodium augmented MELD (MELDNa) to Atlantic Canadian adults with end-stage liver disease awaiting liver transplantation (LT)