Static energy analysis of MHC class I and class II peptide-binding affinity

Antigenic peptide is presented to a T-cell receptor (TCR) through the formation of a stable complex with a major histocompatibility complex (MHC) molecule. Various predictive algorithms have been developed to estimate a peptide's capacity to form a stable complex with a given MHC class II allele, a technique integral to the strategy of vaccine design. These have previously incorporated such computational techniques as quantitative matrices and neural networks. A novel predictive technique is described, which uses molecular modeling of predetermined crystal structures to estimate the stability of an MHC class II-peptide complex. The structures are remodeled, energy minimized, and annealed before the energetic interaction is calculated.

Towards the in silico identification of class II restricted T-cell epitopes:a partial least squares iterative self-consistent algorithm for affinity prediction

Motivation: The immunogenicity of peptides depends on their ability to bind to MHC molecules. MHC binding affinity prediction methods can save significant amounts of experimental work. The class II MHC binding site is open at both ends, making epitope prediction difficult because of the multiple binding ability of long peptides. Results: An iterative self-consistent partial least squares (PLS)-based additive method was applied to a set of 66 pep- tides no longer than 16 amino acids, binding to DRB1*0401. A regression equation containing the quantitative contributions of the amino acids at each of the nine positions was generated. Its predictability was tested using two external test sets which gave r pred =0.593 and r pred=0.655, respectively. Furthermore, it was benchmarked using 25 known T-cell epitopes restricted by DRB1*0401 and we compared our results with four other online predictive methods. The additive method showed the best result finding 24 of the 25 T-cell epitopes. Availability: Peptides used in the study are available from http://www.jenner.ac.uk/JenPep. The PLS method is available commercially in the SYBYL molecular modelling software package. The final model for affinity prediction of peptides binding to DRB1*0401 molecule is available at http://www.jenner.ac.uk/MHCPred. Models developed for DRB1*0101 and DRB1*0701 also are available in MHC- Pred

Compactness in the First Baire Class and Baire-1 Operators

For a polish space M and a Banach space E let B1 (M, E) be the space of first Baire class functions from M to E, endowed with the pointwise weak topology. We study the compact subsets of B1 (M, E) and show that the fundamental results proved by Rosenthal, Bourgain, Fremlin, Talagrand and Godefroy, in case E = R, also hold true in the general case. For instance: a subset of B1 (M, E) is compact iff it is sequentially (resp. countably) compact, the convex hull of a compact bounded subset of B1 (M, E) is relatively compact, etc. We also show that our class includes Gulko compact. In the second part of the paper we examine under which conditions a bounded linear operator T : X ∗ → Y so that T |BX ∗ : (BX ∗ , w∗ ) → Y is a Baire-1 function, is a pointwise limit of a sequence (Tn ) of operators with T |BX ∗ : (BX ∗ , w∗ ) → (Y, · ) continuous for all n ∈ N. Our results in this case are connected with classical results of Choquet, Odell and Rosenthal.

EpiDOCK:a molecular docking-based tool for MHC class II binding prediction

Cellular peptide vaccines contain T-cell epitopes. The main prerequisite for a peptide to act as a T-cell epitope is that it binds to a major histocompatibility complex (MHC) protein. Peptide MHC binder identification is an extremely costly experimental challenge since human MHCs, named human leukocyte antigen, are highly polymorphic and polygenic. Here we present EpiDOCK, the first structure-based server for MHC class II binding prediction. EpiDOCK predicts binding to the 23 most frequent human, MHC class II proteins. It identifies 90% of true binders and 76% of true non-binders, with an overall accuracy of 83%. EpiDOCK is freely accessible at http://epidock.ddg-pharmfac. net. © The Author 2013. Published by Oxford University Press. All rights reserved.

MHC class II binding prediction by molecular docking

Proteins of the Major Histocompatibility Complex (MHC) bind self and nonself peptide antigens or epitopes within the cell and present them at the cell surface for recognition by T cells. All T-cell epitopes are MHC binders but not all MCH binders are T-cell epitopes. The MHC class II proteins are extremely polymorphic. Polymorphic residues cluster in the peptide-binding region and largely determine the MHC's peptide selectivity. The peptide binding site on MHC class II proteins consist of five binding pockets. Using molecular docking, we have modelled the interactions between peptide and MHC class II proteins from locus DRB1. A combinatorial peptide library was generated by mutation of residues at peptide positions which correspond to binding pockets (so called anchor positions). The binding affinities were assessed using different scoring functions. The normalized scoring functions for each amino acid at each anchor position were used to construct quantitative matrices (QM) for MHC class II binding prediction. Models were validated by external test sets comprising 4540 known binders. Eighty percent of the known binders are identified in the best predicted 15% of all overlapping peptides, originating from one protein. © 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Major Histocompatibility Complex (MHC) Class II sequence polymorphism in long-finned pilot whale (Globicephala melas) from the North Atlantic

Funding Silvia S. Monteiro and Marisa Ferreira were supported by a Ph.D. grant from Fundação para a Ciência e Tecnologia (ref SFRH/BD/38735/2007 and SFRH/BD/30240/2006, respectively). Alfredo López was supported by a postdoctoral grant from Fundação para a Ciência e Tecnologia (ref SFRH/BPD/82407/2011). Catarina Eira is supported by CESAM (UID/AMB/50017), from FCT/MEC through national funds and FEDER (PT2020, Compete 2020). The work related with strandings and tissue collection in Portugal was partially supported by the SafeSea Project EEAGrants PT 0039 (supported by Iceland, Liechtenstein and Norway through the EEA Financial Mechanism), by the Project MarPro–Life09 NAT/PT/000038 (funded by the European Union–Program Life+) and by the project CetSenti FCT RECI/AAG-GLO/0470/2012; FCOMP-01-0124-FEDER-027472 (Funded by the Program COMPETE and Fundação para a Ciência e Tecnologia).

Drugs for cardiac arrhythmmias, antithrombotic drugs and lipid modulating drugs

13.1 Drugs for cardiac arrhythmias 13.1.1 Introduction to cardiac arrhythmias 13.1.2 Cardiac action potentials 13.1.3 Mechanisms of cardiac arrhythmias 13.1.3 Class I 13.1.4 Class II 13.1.5 Class III 12.1.6 Class IV 13.1.7 Amiodarone 13.1.8 Adenosine 13.2 Antithrombotic drugs 13.2.1 Thrombus formation 13.2.2 Platelet aggregation and anti-platelet drugs 13.2.3 Coagulation 13.2.4 Anticoagulants 13.2.5 Fibrinolysis and fibrinolytics 13.3. Lipid modulating drugs 13.3.1 Cholesterol 13.3.2 Statins 13.3.3 Fibric acid derivatives 13.3.4 Ezetimibe

Molecular interactions of arbuscular mycorrhizal fungi with mycotoxin-producing fungi and their role in plant defense responses

Les trichothécènes de Fusarium appartiennent au groupe des sesquiterpènes qui sont des inhibiteurs la synthèse des protéines des eucaryotes. Les trichothécènes causent d’une part de sérieux problèmes de santé aux humains et aux animaux qui ont consommé des aliments infectés par le champignon et de l’autre part, elles sont des facteurs importants de la virulence chez plantes. Dans cette étude, nous avons isolé et caractérisé seize isolats de Fusarium de la pomme de terre infectée naturellement dans un champs. Les tests de pathogénicité ont été réalisés pour évaluer la virulence des isolats sur la pomme de terre ainsi que leur capacité à produire des trichothécènes. Nous avons choisi F. sambucinum souche T5 comme un modèle pour cette étude parce qu’il était le plus agressif sur la pomme de terre en serre en induisant un flétrissement rapide, un jaunissement suivi de la mort des plantes. Cette souche produit le 4,15-diacétoxyscirpénol (4,15-DAS) lorsqu’elle est cultivée en milieu liquide. Nous avons amplifié et caractérisé cinq gènes de biosynthèse trichothécènes (TRI5, TRI4, TRI3, TRI11, et TRI101) impliqués dans la production du 4,15-DAS. La comparaison des séquences avec les bases de données a montré 98% et 97% d'identité de séquence avec les gènes de la biosynthèse des trichothécènes chez F. sporotrichioides et Gibberella zeae, respectivement. Nous avons confrenté F. sambucinum avec le champignon mycorhizien à arbuscule Glomus irregulare en culture in vitro. Les racines de carotte et F. sambucinum seul, ont été utilisés comme témoins. Nous avons observé que la croissance de F. sambucinum a été significativement réduite avec la présence de G. irregulare par rapport aux témoins. Nous avons remarqué que l'inhibition de la croissance F. sambucinum a été associée avec des changements morphologiques, qui ont été observés lorsque les hyphes de G. irregulare ont atteint le mycélium de F. sambucinum. Ceci suggère que G. irregulare pourrait produire des composés qui inhibent la croissance de F. sambucinum. Nous avons étudié les patrons d’expression des gènes de biosynthèse de trichothécènes de F. sambucinum en présence ou non de G. irregulare, en utilisant le PCR en temps-réel. Nous avons observé que TRI5 et TRI6 étaient sur-exprimés, tandis que TRI4, TRI13 et TRI101 étaient en sous-exprimés en présence de G. irregulare. Des analyses par chromatographie en phase-gazeuse (GC-MS) montrent clairement que la présence de G. irregulare réduit significativement la production des trichothécènes par F. sambucinum. Le dosage du 4,15-DAS a été réduit à 39 μg/ml milieu GYEP par G. irregulare, comparativement à 144 μg/ml milieu GYEP quand F. sambucinum est cultivé sans G. irregulare. Nous avons testé la capacité de G. irregulare à induire la défense des plants de pomme de terre contre l'infection de F. sambucinum. Des essais en chambre de croissance montrent que G. irregulare réduit significativement l’incidence de la maladie causée par F. sambucinum. Nous avons aussi observé que G. irregulare augmente la biomasse des racines, des feuilles et des tubercules. En utilisant le PCR en temps-réel, nous avons étudié les niveaux d’expression des gènes impliqué dans la défense des plants de pommes de terre tels que : chitinase class II (ChtA3), 1,3-β-glucanase (Glub), peroxidase (CEVI16), osmotin-like protéin (OSM-8e) et pathogenèses-related protein (PR-1). Nous avons observé que G. irregulare a induit une sur-expression de tous ces gènes dans les racines après 72 heures de l'infection avec F. sambucinum. Nous avons également trové que la baisse provoquée par F. sambucinum des gènes Glub et CEVI16 dans les feuilles pourrait etre bloquée par le traitement AMF. Ceci montre que l’inoculation avec G. irregulare constitut un bio-inducteur systémique même dans les parties non infectées par F. sambucinum. En conclusion, cette étude apporte de nouvelles connaissances importantes sur les interactions entre les plants et les microbes, d’une part sur les effets directs des champignons mycorhiziens sur l’inhibition de la croissance et la diminution de la production des mycotoxines chez Fusarium et d’autre part, l’atténuation de la sévérité de la maladie dans des plantes par stimulation leur défense. Les données présentées ouvrent de nouvelles perspectives de bio-contrôle contre les pathogènes mycotoxinogènes des plantes.

Distalização dos molares superiores com aparelho Pendex unilateral: estudo piloto com radiografia panorâmica

OBJETIVO: o presente ensaio científico põe em pauta o efeito imediato da distalização unilateral de molares superiores, lançando mão do distalizador intrabucal Pendex de ação unilateral. METODOLOGIA: o estudo prospectivo foi conduzido em três pacientes na dentadura permanente madura, no estágio de adolescência, que apresentavam uma má oclusão Classe II, subdivisão. O aparelho Pendex foi instalado com a mola distalizadora de TMA, construída apenas no lado direito. A metodologia baseou-se nas radiografias panorâmicas inicial e pós-distalização para quantificar a inclinação axial mesiodistal dos molares superiores. RESULTADOS E CONCLUSÕES: os resultados mostraram que os molares do lado esquerdo mantiveram sua inclinação mesiodistal inicial, sugerindo ancoragem, enquanto os molares do lado direito foram inclinados para distal, à semelhança do que ocorre com a distalização simétrica dos molares superiores, obtida com o aparelho Pendex convencional. Os primeiros molares foram inclinados 11,5º, enquanto os segundos molares foram inclinados 21º para distal.

A discrepância de tamanho dentário, de Bolton, na oclusão normal e nos diferentes tipos de más oclusões, bem como sua relação com a forma de arco e o posicionamento dentário

Esta pesquisa teve como objetivo geral avaliar a discrepância de tamanho dentário, na oclusão normal e nos diferentes tipos de más oclusões e a sua relação com as medidas que determinam a forma de arco e o posicionamento dentário na região anterior. Para tanto, foram estudados 185 pares de modelos de gesso, divididos em 4 grupos: Grupo 1 (composto por 41 pares com Oclusão Normal, sendo 20 do gênero masculino e 21 do gênero feminino); Grupo 2 (composto por 44 pares com má oclusão de Classe I, divisão 1, sendo 22 do gênero masculino e 22 do gênero feminino); Grupo 3 (composto por 54 pares com má oclusão de Classe II, sendo 28 do gênero masculino e 26 do gênero feminino) e Grupo 4 (composto por 46 pares com Classe III, sendo 23 do gênero masculino e 23 do gênero feminino). Observou-se que não ocorreu dimorfismo sexual entre as discrepâncias de tamanho dentário e os diferentes tipos de oclusão dentária; as proporções estabelecidas por Bolton não se aplicaram ao grupo com Oclusão Normal; na Oclusão Normal, Classe I, Classe II e Classe III, houve um predomínio de excesso dentário total (RAZ12) no arco inferior; na Classe I houve uma igualdade na distribuição de excesso dentário anterior (RAZ6) nos arcos superior e inferior; na Oclusão Normal, Classe II e Classe III, ocorreu um predomínio de excesso dentário anterior (RAZ6) no arco inferior, em relação ao arco superior; os excessos dentários não contribuíram na ocorrência das más oclusões e as discrepâncias total e anterior (RAZ12 e RAZ6) não interferiram diretamente nas larguras e comprimentos dos arcos, bem como no posicionamento dos dentes anteriores.

A discrepância de tamanho dentário, de Bolton, na oclusão normal e nos diferentes tipos de más oclusões, de Angle, bem como sua relação com a forma de arco e o posicionamento dentário

Pós-graduação em Odontologia - FOAR

Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A

The major histocompatibility complex (MHC) on chromosome 6 is associated with susceptibility to more common diseases than any other region of the human genome, including almost all disorders classified as autoimmune. In type 1 diabetes the major genetic susceptibility determinants have been mapped to the MHC class II genes HLA-DQB1 and HLA-DRB1 (refs 1–3), but these genes cannot completely explain the association between type 1 diabetes and the MHC region4, 5, 6, 7, 8, 9, 10, 11. Owing to the region's extreme gene density, the multiplicity of disease-associated alleles, strong associations between alleles, limited genotyping capability, and inadequate statistical approaches and sample sizes, which, and how many, loci within the MHC determine susceptibility remains unclear. Here, in several large type 1 diabetes data sets, we analyse a combined total of 1,729 polymorphisms, and apply statistical methods—recursive partitioning and regression...

The TCP4 transcription factor of Arabidopsis blocks cell division in yeast at G1 -> S transition

The TCP transcription factors control important aspects of plant development. Members of class I TCP proteins promote cell cycle by regulating genes directly involved in cell proliferation. In contrast, members of class II TCP proteins repress cell division. While it has been postulated that class II proteins induce differentiation signal, their exact role on cell cycle has not been studied. Here, we report that TCP4, a class II TCP protein from Arabidopsis that repress cell proliferation in developing leaves, inhibits cell division by blocking G1 -> S transition in budding yeast. Cells expressing TCP4 protein with increased transcriptional activity fail to progress beyond G1 phase. By analyzing global transcriptional status of these cells, we show that expression of a number of cell cycle genes is altered. The possible mechanism of G1 -> S arrest is discussed. (C) 2011 Elsevier Inc. All rights reserved.