On the degeneracy phenomenon for nonlinear optimal control problems with higher index state constraints

Relatório Técnico do Núcleo de Investigação Officina Mathematica.Necessary conditions of optimality (NCO) play an important role in optimization problems. They are the major tool to select a set of candidates to minimizers. In optimal control theory, the NCO appear in the form of a Maximum Principle (MP). For certain optimal control problems with state constraints, it might happen that the MP are unable to provide useful information --- the set of all admissible solutions coincides with the set of candidates that satisfy the MP. When this happens, the MP is said to degenerate. In the recent years, there has been some literature on fortified forms of the MP in such way that avoid degeneracy. These fortified forms involve additional hypotheses --- Constraint Qualifications. Whenever the state constraints have higher index (i.e. their first derivative with respect to time does not depend on control), the current constraint qualifications are not adequate. So, the main purpose here is fortify the maximum principle for optimal control problems with higher index constraints, for which there is a need to develop new constraint qualifications. The results presented here are a generalization to nonlinear problems of a previous work.The financial support from Projecto FCT POSC/EEA-SRI/61831/2004 is gratefully acknowledged

Comparison of two self-etching primers and effect of saliva contamination on shear bond strength of orthodontic brackets

Introduction: Saliva contamination during the bonding procedure is a common cause of bracket bond failure. By combining acid and primer in one component, self-etching primers (SEP) reduce the working time and the risk of contamination. Objectives: The purpose of this study was to investigate the effect of saliva contamination of the enamel surface on the shear bond strength of orthodontic brackets cemented with two self-etching primers. Materials and Methods: One hundred orthodontic brackets were bonded to human premolars with Transbond Plus Self-etching Primer (TPSEP, 3M Unitek, Monrovia, CA) or First Step (FS, Reliance Orthodontic Products, Itasca, IL) under the following enamel surface conditions: 1) dry enamel; 2) saliva contamination/ primer; 3) saliva contamination/ air drying/ primer; 4) primer/ saliva contamination; 5) primer/ saliva contamination/ air drying/ reapplication of the primer. Samples were stored for 7 days in water at 37ºC and submitted to 500 cycles of thermal stress. Bond failure sites were classified by an Adhesive Remnant Index score system. Results:Mean shear bond strengths were significantly higher in the TPSEP groups compared to the FS groups (p < .001). For the same adhesive, no significant differences were found between the enamel surface conditions. More adhesive failures were observed in the FS groups. Conclusions: Brackets bonded with TPSEP had the highest shear bond strength values, under the different enamel surface conditions. For both SEPs, bond strengths were not significantly affected by the enamel surface conditions. The FS groups failed more frequently at the enamel / resin interface.Introdução: A contaminação salivar é uma das principais causas de insucesso na cimentação de brackets. Os selfetching primers, recentemente introduzidos em ortodontia, reduzem o tempo de execução da técnica e a probabilidade de contaminação. Objectivos: Determinar o efeito da contaminação salivar na resistência adesiva a forças de corte de brackets ortodônticos, cimentados com dois self-etching primers. Materiais e Métodos: Foram cimentados 100 brackets em premolares humanos (10 amostras por grupo), utilizando 2 adesivos (Transbond Plus e First Step) e 5 condições de superfície: 1) Condição ideal, esmalte seco; 2) Contaminação salivar antes do primer; 3) Contaminação salivar e secagem antes do primer; 4) Contaminação salivar depois do primer; 5) Contaminação salivar depois do primer, secagem e reaplicação do primer. As amostras foram armazenadas 7 dias em água a 37ºC e sujeitas a 500 ciclos de termociclagem. A área de adesão foi observada ao microscópio óptico para determinar o tipo de falha adesiva. Resultados: A análise de variância demonstrou diferenças significativas entre as forças de resistência adesiva, sendo o Transbond Plus superior ao First Step. A contaminação não influenciou significativamente a resistência adesiva. Conclusões: 1) A resistência adesiva foi mais elevada com o Transbond Plus em comparação com o First Step, independentemente da condição. 2) Para ambos os selfetching primers, a adesão não foi significativamente afectada pela presença de saliva ou pelos procedimentos de descontaminação. 3) No grupo do First Step foi encontrado um maior número de falhas adesivas na interface dente / resina composta.info:eu-repo/semantics/publishedVersio

Sustained gene expression in the retina by improved episomal vectors

Gene and cellular therapies are nowadays part of therapeutic strategies for the treatment of diverse pathologies. The drawbacks associated with gene therapy-low levels of transgene expression, vector loss during mitosis, and gene silencing-need to be addressed. The pEPI-1 and pEPito family of vectors was developed to overcome these limitations. It contains a scaffold/matrix attachment region, which anchors its replication to cell division in eukaryotic cells while in an extrachromosomal state and is less prone to silencing, due to a lower number of CpG motifs. Recent success showed that ocular gene therapy is an important tool for the treatment of several diseases, pending the overcome of the aforementioned limitations. To achieve sustained gene delivery in the retina, we evaluated several vectors based on pEPito and pEPI-1 for their ability to sustain transgene expression in retinal cells. These vectors stably transfected and replicated in retinal pigment epithelial (RPE) cells. Expression levels were promoter dependent with constitutive promoters cytomegalovirus immediate early promoter (CMV) and human CMV enhancer/human elongation factor 1 alpha promoter yielding the highest levels of transgene expression compared with the retina-specific RPE65 promoter. When injected in C57Bl6 mice, transgene expression was sustained for at least 32 days. Furthermore, the retina-specific RPE65 promoter showed higher efficiency in vivo compared to in vitro. In this study, we demonstrate that by combining tissue-specific promoters with a mitotic stable system, less susceptible to epigenetic silencing such as pEPito-based plasmids, we can achieve prolonged gene expression and a sustained therapeutic effect.Fundacao para a Ciencia e Tecnologia, Portugal [PEst/OE/EQB-LA 0023/2013, SFRH/BD/76873/2011, SFRH/BD/70318/2010, PTDC/SAU/BEB/098475/2008]; European Union [PIRG-GA-2009-249314

Identification and validation of novel microtubule suppressors with an imidazopyridine scaffold through structure-based virtual screening and docking

Targeting the colchicine binding site of α/β tubulin microtubules can lead to suppression of microtubule dynamics, cell cycle arrest and apoptosis. Therefore, the development of microtubule (MT) inhibitors is considered a promising route to anticancer agents. Our approach to identify novel scaffolds as MT inhibitors depends on a 3D-structure-based pharmacophore approach and docking using three programs MOE, Autodock and BUDE (Bristol University Docking Engine) to screen a library of virtual compounds. From this work we identified the compound 7-(3-Hydroxy-4-methoxy-phenyl)-3-(3-trifluoromethyl-phenyl)-6,7-dihydro-3H-imidazo[4,5-b]pyridin-5-ol (6) as a novel inhibitor scaffold. This compound inhibited several types of cancer cell proliferation at low micromolar concentrations with low toxicity. Compound 6 caused cell cycle arrest in the G2/M phase and blocked tubulin polymerization at low micromolar concentration (IC50 = 6.1 ±0.1 µM), inducing apoptosis via activation of caspase 9, increasing the level of the pro-apoptotic protein Bax and decreasing the level of the anti-apoptotic protein Bcl2. In summary, our approach identified a lead compound with potential antimitotic and antiproliferative activity

Dynamical nonequilibrium molecular dynamics reveals the structural basis for allostery and signal propagation in biomolecular systems

A dynamical approach to nonequilibrium molecular dynamics (D-NEMD), proposed in the 1970s by Ciccotti et al., is undergoing a renaissance and is having increasing impact in the study of biological macromolecules. This D-NEMD approach, combining MD simulations in stationary (in particular, equilibrium) and nonequilibrium conditions, allows for the determination of the time-dependent structural response of a system using the Kubo–Onsager relation. Besides providing a detailed picture of the system’s dynamic structural response to an external perturbation, this approach also has the advantage that the statistical significance of the response can be assessed. The D-NEMD approach has been used recently to identify a general mechanism of inter-domain signal propagation in nicotinic acetylcholine receptors, and allosteric effects in \upbeta -lactamase enzymes, for example. It complements equilibrium MD and is a very promising approach to identifying and analysing allosteric effects. Here, we review the D-NEMD approach and its application to biomolecular systems, including transporters, receptors, and enzymes

Development of a metric of aquatic invertebrates for volunteers (MAIV): a simple and friendly biotic metric to assess ecological quality of streams

Citizen science activities, involving local people in volunteer-supported and sustainable monitoring programs, are common. In this context, the objective of the present work was to develop a simple Metric of Aquatic Invertebrates for Volunteers (MAIV), including a user-friendly tool that can be easily accessed by volunteers, and to evaluate the e ciency of a volunteer monitoring program following an audit procedure. To obtain MAIV values, macroinvertebrate communities were reduced to 18 surrogate taxa, which represented an acceptable compromise between simplicity, e ciency, and reproducibility of the data, compared to the regular Water Framework Directive monitoring. When compared to results obtained with the National Classification System of Portugal, MAIV accurately detected moderate, poor, and bad ecological status. Thus, MAIV can be used by volunteers as a complement to the o cial monitoring program, as well as a prospective early warning tool for local problems related to ecological quality. Volunteers were students supervised by their teachers. Results obtained by volunteers were compared to results obtained by experts on macroinvertebrate identification to measure the e ciency of the procedure, by counting gains and losses on sorting, and identification. Characteristics of groups of volunteers (age and school level) did not influence significantly the e ciency of the procedure, and generally results of volunteers and experts matched.info:eu-repo/semantics/publishedVersio

Development of new analytical tools for monitoring of cardiovascular disease markers – towards the detection of homocysteine-thiolactone

Poster presented at the 4th International Conference on Bio-Sensing Technology, 10-13 May 2015, Lisbon, Portuga

New PON1-based biosensor for the detection of homocysteine-thiolactone in human plasma

Poster presented at the XXIII International Symposium on Bioelectrochemistry and Bioenergetics, 14-18 June 2015, Malmo, Sweden

An integral-type constraint qualification for optimal control problems with state constraints

Relatório Técnico do Núcleo de Investigação Officina Mathematica.Standard necessary conditions of optimality (NCO) for constrained optimal control problems -- Maximum Principle type onditions -- may fail to provide useful information to select candidates to minimizers among the overall set of admissible solutions. This phenomenon is known as the degeneracy phenomenon and there has been continuing interest in the literature in proposing stronger forms of NCO that can be informative in such cases: the so-called nondegenerate NCO. The nondegenerate NCO proposed here are validunder a different set of hypothesis and under a constraint qualification of an integral-type that, in relation to some previous literature, can be verified for more problems.Fundação para a Ciência e a Tecnologia (FCT) Projecto FCT POSC/EEA-SRI/61831/200