EpiTOP—a proteochemometric tool for MHC class II binding prediction

Motivation: T-cell epitope identification is a critical immunoinformatic problem within vaccine design. To be an epitope, a peptide must bind an MHC protein. Results: Here, we present EpiTOP, the first server predicting MHC class II binding based on proteochemometrics, a QSAR approach for ligands binding to several related proteins. EpiTOP uses a quantitative matrix to predict binding to 12 HLA-DRB1 alleles. It identifies 89% of known epitopes within the top 20% of predicted binders, reducing laboratory labour, materials and time by 80%. EpiTOP is easy to use, gives comprehensive quantitative predictions and will be expanded and updated with new quantitative matrices over time.

Predicting class II MHC-Peptide binding:a kernel based approach using similarity scores

Background - Modelling the interaction between potentially antigenic peptides and Major Histocompatibility Complex (MHC) molecules is a key step in identifying potential T-cell epitopes. For Class II MHC alleles, the binding groove is open at both ends, causing ambiguity in the positional alignment between the groove and peptide, as well as creating uncertainty as to what parts of the peptide interact with the MHC. Moreover, the antigenic peptides have variable lengths, making naive modelling methods difficult to apply. This paper introduces a kernel method that can handle variable length peptides effectively by quantifying similarities between peptide sequences and integrating these into the kernel. Results - The kernel approach presented here shows increased prediction accuracy with a significantly higher number of true positives and negatives on multiple MHC class II alleles, when testing data sets from MHCPEP [1], MCHBN [2], and MHCBench [3]. Evaluation by cross validation, when segregating binders and non-binders, produced an average of 0.824 AROC for the MHCBench data sets (up from 0.756), and an average of 0.96 AROC for multiple alleles of the MHCPEP database. Conclusion - The method improves performance over existing state-of-the-art methods of MHC class II peptide binding predictions by using a custom, knowledge-based representation of peptides. Similarity scores, in contrast to a fixed-length, pocket-specific representation of amino acids, provide a flexible and powerful way of modelling MHC binding, and can easily be applied to other dynamic sequence problems.

Toward prediction of class II mouse major histocompatibility complex peptide binding affinity:in silico bioinformatic evaluation using partial least squares, a robust multivariate statistical technique

The accurate identification of T-cell epitopes remains a principal goal of bioinformatics within immunology. As the immunogenicity of peptide epitopes is dependent on their binding to major histocompatibility complex (MHC) molecules, the prediction of binding affinity is a prerequisite to the reliable prediction of epitopes. The iterative self-consistent (ISC) partial-least-squares (PLS)-based additive method is a recently developed bioinformatic approach for predicting class II peptide−MHC binding affinity. The ISC−PLS method overcomes many of the conceptual difficulties inherent in the prediction of class II peptide−MHC affinity, such as the binding of a mixed population of peptide lengths due to the open-ended class II binding site. The method has applications in both the accurate prediction of class II epitopes and the manipulation of affinity for heteroclitic and competitor peptides. The method is applied here to six class II mouse alleles (I-Ab, I-Ad, I-Ak, I-As, I-Ed, and I-Ek) and included peptides up to 25 amino acids in length. A series of regression equations highlighting the quantitative contributions of individual amino acids at each peptide position was established. The initial model for each allele exhibited only moderate predictivity. Once the set of selected peptide subsequences had converged, the final models exhibited a satisfactory predictive power. Convergence was reached between the 4th and 17th iterations, and the leave-one-out cross-validation statistical terms - q2, SEP, and NC - ranged between 0.732 and 0.925, 0.418 and 0.816, and 1 and 6, respectively. The non-cross-validated statistical terms r2 and SEE ranged between 0.98 and 0.995 and 0.089 and 0.180, respectively. The peptides used in this study are available from the AntiJen database (http://www.jenner.ac.uk/AntiJen). The PLS method is available commercially in the SYBYL molecular modeling software package. The resulting models, which can be used for accurate T-cell epitope prediction, will be made freely available online (http://www.jenner.ac.uk/MHCPred).

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

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).

Two years survival rate of Class II ART restorations in primary molars using two ways to avoid saliva contamination

AIM To compare the survival rates of Class II Atraumatic Restorative Treatment (ART) restorations placed in primary molars using cotton rolls or rubber dam as isolation methods. METHODS A total of 232 children, 6-7 years old, both genders, were selected having one primary molar with proximal dentine lesion. The children were randomly assigned into two groups: control group with Class II ART restoration made using cotton rolls and experimental group using rubber dam. The restorations were evaluated by eight calibrated evaluators (Kappa > 0.8) after 6, 12, 18 and 24 months. RESULTS A total of 48 (20.7%) children were considered dropout, after 24 months. The cumulative survival rate after 6, 12, 18 and 24 months was 61.4%, 39.0%, 29.1% and 18.0%, respectively for the control group, and 64.1%, 55.1%, 40.1% and 32.1%, respectively for the rubber dam group. The log rank test for censored data showed no statistical significant difference between the groups (P = 0.07). The univariate Cox Regression showed no statistical significant difference after adjusting for independent variables (P > 0.05). CONCLUSION Both groups had similar survival rates, and after 2 years, the use of rubber dam does not increase the success of Class II ART restorations significantly.

Impacto das etapas do tratamento orto-cirúrgico na qualidade de vida de pacientes portadores de deformidades dentofaciais

Pacientes portadores de deformidades dentofaciais podem relatar dificuldades de mastigação e fala, desordens temporomandibulares, preocupação com a imagem corporal e baixa autoestima. Frequentemente, buscam tratamento orto-cirúrgico pela motivação de obter melhora notável nos aspectos estético, funcional e psicossocial. A evidência atualmente disponível sobre os benefícios na qualidade de vida relacionada à saúde bucal desta modalidade terapêutica ainda não é conclusiva, devido à diversidade de metodologias adotadas entre os estudos existentes, majoritariamente realizados na América do Norte, Europa, Oriente Médio e Ásia. Logo, é essencial utilizar instrumentos específicos para avaliar os efeitos desta modalidade de tratamento também na vida diária dos pacientes brasileiros. O propósito do presente estudo transversal foi determinar o impacto que o tratamento orto-cirúrgico exerce sobre a percepção de qualidade de vida dos pacientes portadores de deformidades dentofaciais, bem como a influência exercida pelo gênero, idade, renda, escolaridade e características da má oclusão, nas quatro etapas inerentes a esta modalidade de tratamento: (1) Inicial; (2) Preparo ortodôntico para a cirurgia; (3) Pós-cirúrgico; e (4) Contenção (pós-tratamento). Duzentos e cinquenta e quatro pacientes foram entrevistados em três importantes centros de atendimento na cidade do Rio de Janeiro. A qualidade de vida foi avaliada pelos questionários OHIP-14 (Oral Health Impact Profile - Short Version) e pelo OQLQ (Orthognathic Quality of Life Questionnaire) em suas versões traduzidas e validadas para o português. A gravidade da má oclusão e autopercepção estética foram avaliadas com base no Índice de Necessidade de Tratamento Ortodôntico (IOTN) e pelo Índice de Estética Dental (DAI). A análise dos dados foi efetuada pelos testes qui-quadrado, Kruskal-Wallis e modelos de regressão binomial negativa múltipla. Os pacientes dos quatro grupos foram semelhantes em relação ao gênero (p = 0,463), escolaridade (p = 0,276) e renda familiar (p = 0,100). Entre os entrevistados houve o predomínio de mulheres, com ensino médio completo e renda familiar entre 2 e 3 salários mínimos, portadores de má oclusão de Classe III de Angle grave. No modelo de regressão binomial negativa ajustado para os fatores gênero, idade, renda familiar e escolaridade, a qualidade de vida aferida pelo OHIP-14 demonstrou que o grupo Inicial sofreu impactos mais negativos do que os grupos Pós-cirúrgico, Preparo e Contenção; o OQLQ indicou que o grupo Inicial sofreu impactos mais negativos do que os grupos Preparo, Pós-cirúrgico e Contenção, nesta sequência. Não foi detectada influência da idade, renda e escolaridade nestes resultados. Foi observado que o gênero feminino sofreu mais impacto negativo na qualidade de vida, principalmente nas dimensões relativas à função e a aspectos sociais. Concluiu-se que os pacientes que finalizaram o tratamento orto-cirúrgico apresentaram como benefícios menores impactos na qualidade de vida específica e relacionada à saúde bucal, melhor autopercepção estética e menor gravidade da má oclusão, em comparação aos pacientes nas etapas pré e pós-cirúrgica e aos pacientes portadores de deformidades dentofaciais em busca de tratamento.

Distalização dos molares superiores com aparelho Pendex: estudo cefalométrico prospectivo

A distalização dos molares superiores constitui um desafio na correção da má oclusão de Classe II em tratamentos sem extrações dentárias e sem avanço mandibular. Há uma procura por dispositivos que substituam a tração extrabucal (AEB) e que não exijam demasiada colaboração do paciente, o que estimula os ortodontistas a testarem métodos alternativos aos relatados na literatura. Dentre estes, destacam-se os aparelhos Pêndulo e Pendex de Hilgers. OBJETIVO: a realização desta pesquisa teve o intuito de avaliar, mediante a cefalometria, os efeitos do aparelho Pendex aplicado no final da dentadura mista e na dentadura permanente. METODOLOGIA: a amostra constou de 14 pacientes com má oclusão de Classe II bilateral, com média de idade de 11 anos e 3 meses. Foram tomadas duas telerradiografias em norma lateral, uma correspondente ao início do tratamento e outra aproximadamente 5 meses após sua finalização, quando a relação dos molares encontrava-se sobrecorrigida. RESULTADOS: após a determinação e mensuração das grandezas cefalométricas lineares e angulares e análise estatística (Teste t de Student), pode-se concluir que os efeitos do aparelho Pendex foram predominantemente ortodônticos: distalização da coroa dos primeiros molares permanentes numa velocidade média de 0,8 mm/mês e vestibularização dos incisivos superiores com aumento do trespasse horizontal. CONCLUSÃO: assim sendo, quando há indicação para distalização dos molares, cumpre-se fazer uma análise dos fatores envolvidos, a fim de eleger, com prudência, a solução terapêutica mais adequada às exigências individuais e profissionais.

Correlation between morphology and function of the upper lip: a longitudinal evaluation

In order to evaluate the relationship between the morphology of the upper lip and muscle activity in a sample of 38 subjects (17 males and 21 females) with Angle Class II division 1 malocclusions, cephalometric and electromyographic analyses were conducted. The sample was subdivided into either predominantly nose or mouth breathers. The individuals were evaluated at two different periods, with a 2 year interval. At the first observation, the subjects were 11 years to 14 years 11 months of age and at the second observation, 13 years 4 months to 16 years 6 months of age. Height and thickness of the upper lip were measured on lateral cephalograms with the aid of a digital pachymeter. For each individual, electromyographic records were obtained of the orbicularis oris superior muscle at rest and in a series of 12 movements. The electromyographic data were normalized as a function of amplitude, for achievement of the percentage value of each movement. Pearson and Spearman correlation tests were applied.The results showed some correlation between morphology and muscle function (at a confidence level of 95 per cent). However, as the values of the correlation coefficient (r) were too low to establish associations between variables, it was concluded that the dimensions of the upper lip are not correlated with muscle activity.

Effects of cervical headgear and edgewise appliances on growing patients

Maxillary basal bone, dentoalveolar, and dental changes in Class II Division 1 patients treated to normal occlusion by using cervical headgear and edgewise appliances were retrospectively evaluated. A sample of 45 treated patients was compared with a group of 30 untreated patients. Subjects were drawn from the Department of Orthodontics, Araraquara School of Dentistry, Brazil, and ranged in age from 7.5 to 13.5 years. The groups were matched based on age, gender, and malocclusion. Roughly 87% of the treated group had a mesocephalic or brachicephalic pattern, and 13% had a dolicocephalic pattern. Cervical headgear was used until a Class I dental relationship was achieved. Our results demonstrated that the malocclusions were probably corrected by maintaining the maxillary first molars in position during maxillary growth. Maxillary basal bone changes (excluding dentoalveolar changes) did not differ significantly between the treated and the untreated groups. Molar extrusion after the use of cervical headgear was not supported by our data, and this must be considered in the treatment plan of patients who present similar facial types. (Am J Orthod Dentofacial Orthop 2001;119:531-9).

Short-term treatment effects produced by the herbst appliance in the mixed dentition

This prospective clinical investigation evaluates the dentoalveolar and skeletal cephalometric changes produced by the Herbst appliance during treatment of mixed dentition patients with Class II division 1 malocclusion. Thirty individuals (15 male and 15 female individuals; initial mean age nine years 10 months) were treated with the Herbst appliance for a period of 12 months. For comparison, the records of 30 untreated Class II children (15 boys, 15 girls; initial mean age nine years eight months) were followed without treatment for a period of 12 months. The results indicated that the treatment effects produced in the mixed dentition patients were primarily dentoalveolar in nature. The mandibular incisors were tipped labially, and the maxillary incisors were retruded; a significant increase in mandibular posterior dentoalveolar height occurred, and there was a restriction in the vertical development of the maxillary molars. There was no difference in the forward growth of the maxilla between the two groups. In comparison with the controls, however, the Herbst treatment produced a modest but statistically significant increase in total mandibular length. This increase in total mandibular length, however, was less than that observed in adolescent Herbst patients in other studies. © 2005 by The EH Angle Education and Research Foundation, Inc.

Occurrence, extension, and severity of gingival margin alterations after orthodontic treatment.

To assess the occurrence, extension, and severity of gingival margin alterations in a sample of youth after orthodontic treatment. Records from 209 Caucasian adolescents (118 female and 91 male) before and after orthodontic treatment were selected. Patients presented a mean age at the beginning of orthodontic treatment of 11.20 ± 1.86 years and a final mean age of 14.72 ± 1.83 years. Class I and II patients with mandibular incisors and canines that were completely erupted and with spacing or crowding not exceeding 4 mm were evaluated. The presence of gingival recession on the labial surface of the mandibular anterior teeth was evaluated in intraoral photographs and casts made before and after treatment. The proportion of patients with gingival recession after treatment was statistically higher than at the beginning (P<.001). After orthodontic treatment, gingival recession was not present in any of the teeth for 63.6% of the patients; in 29.2% of the patients, recession was present in at least 1 tooth. In terms of severity, the majority of affected teeth (47%) presented gingival recession less than 2 mm and in 2% more than 4 mm. It may be concluded that alterations in the gingival margin, especially gingival recession, occur in patients after orthodontic therapy, but the extent and severity of this finding are low. COPYRIGHT © 2007 BY QUINTESSENCE PUBLISHING CO, INC.

Electromyographic evaluation of the upper lip according to the breathing mode: A longitudinal study

The present study aimed at analyzing and comparing longitudinally the EMG (electromyographic activity) of the superior orbicularis oris muscle according to the breathing mode. The sample, 38 adolescents with Angle Class II Division 1 malocclusion with predominantly nose (PNB) or mouth (PMB) breathing, was evaluated at two different periods, with a two-year interval between them. For that purpose, a 16-channel electromyography machine was employed, which was properly calibrated in a PC equipped with an analogue-digital converter, with utilization of surface, passive and bipolar electrodes. The RMS data (root mean square) were collected at rest and in 12 movements and normalized according to time and amplitude, by the peak value of EMG, in order to allow comparisons between subjects and between periods. Comparison of the muscle function of PNB and PMB subjects at period 1 (P1), period 2 (P2) and the variation between periods (Δ) did not reveal statistically significant differences between groups (p < 0.05). However, longitudinal evaluation of the muscle function in PNB and PMB subjects demonstrated different evolutions in the percentage of required EMG for accomplishment of the movements investigated. It was possible to conclude that there are differences in the percentage of electric activity of the upper lip with the growth of the subjects according to the breathing mode.