Multi-Objective Optimization of Mixed-Variable, Stochastic Systems Using Single-Objective Formulations

Many problems exist where one desires to optimize systems with multiple, often competing, objectives. Further, these problems may not have a closed form representation, and may also have stochastic responses. Recently, a method expanded mixed variable generalized pattern search/ranking and selection (MVPS-RS) and Mesh Adaptive Direct Search (MADS) developed for single-objective, stochastic problems to the multi-objective case by using aspiration and reservation levels. However, the success of this method in approximating the true Pareto solution set can be dependent upon several factors. These factors include the experimental design and ranges of the aspiration and reservation levels, and the approximation quality of the nadir point. Additionally, a termination criterion for this method does not yet exist. In this thesis, these aspects are explored. Furthermore, there may be alternatives or additions to this method that can save both computational time and function evaluations. These include the use of surrogates as approximating functions and the expansion of proven singleobjective formulations. In this thesis, two new approaches are developed that make use of all of these previous existing methods in combination

Intégration de signaux au niveau de la chromatine et perturbations de la ribogénèse pour une suppression tumorale efficace

Environ 30% des cancers humains ont une mutation gain de fonction dans l’oncogène RAS, menant à une prolifération cellulaire accrue et une expansion clonale. Cependant, il est bien établi qu’une hyperactivation soutenue de cette voie mène au phénotype inverse, soit la sénescence cellulaire, définie par un arrêt stable de la prolifération. Ce destin cellulaire caractérise les lésions bénignes et la progression vers une tumeur maligne est associée à son contournement. Toutefois, les mécanismes moléculaires permettant aux cellules de distinguer entre une signalisation normale et oncogénique par RAS afin de les engager vers la sénescence plutôt que la prolifération demeurent inconnus. Ainsi, l’hypothèse à la base de ces travaux est que la décision d’engagement vers la sénescence implique une reprogrammation transcriptionnelle qui précède l’établissement des phénotypes caractéristiques de la sénescence, tel le phénotype sécrétoire (SASP) (Article 1). Nous avons ainsi identifié un point de restriction (SeRP) critique pour l’engagement des cellules vers la sénescence en réponse à l’oncogène HRASG12V. Ce SeRP intègre l'intensité et la durée du stress oncogénique, tout en gardant une mémoire des stress antérieurs, en modulant l’accessibilité à la chromatine via l’induction d’un réseau auto-régulé de facteurs de transcription comprenant notamment ETV4 et RUNX1 (Article 2). Notre modèle actuel nous porte à croire que cette augmentation d’accessibilité à la chromatine impliquerait principalement une décondensation de l’hétérochromatine périnucléolaire. Ceci mènerait à l’induction du SASP et aux défauts de ribogénèse observés dans la sénescence. Nous montrons d’ailleurs via la génération d’un modèle murin transgénique que l’induction de tels défauts de ribogénèse à l’échelle systémique mène à un phénotype de vieillissement prématuré suggérant une sénescence des cellules souches (Article 3). Les cellules souches ayant des niveaux particulièrement élevés de ribogénèse et étant très sensibles à des altérations de leur niche tels que l’inflammation chronique, nous pensons que, de manière fortuite, ce modèle reproduit en quelque sorte les conséquences du SeRP. En somme, l’ensemble des travaux présentés dans cette thèse permettent une meilleure compréhension des mécanismes moléculaires régulant l’engagement vers la sénescence. À termes, ces nouvelles notions permettraient de concevoir des stratégies thérapeutiques permettant de faire pencher la balance vers la sénescence dans un contexte de cancers mutés en RAS.Around 30% of human cancers have a gain-of-function mutation in the RAS oncogene, resulting in increased cell proliferation and clonal expansion. However, it is well established that a sustained hyperactivation of this same pathway leads instead to the opposite phenotype, namely cellular senescence, which is defined by a stable proliferation arrest. This cell fate characterizes benign lesions and progression to malignancy is associated with its bypass. However, the molecular mechanisms allowing cells to distinguish between normal and oncogenic RAS signaling in order to commit them to senescence rather than proliferation remain unknown. Thus, the hypothesis underlying the present work is that this decision to commit to senescence involves a transcriptional reprogramming that precedes the establishment of the senescence-characteristic phenotypes such as the secretory phenotype (Article 1). We have thus identified a restriction point (SeRP) critical for the commitment of cells towards senescence in response to HRASG12V oncogene. This SeRP integrates both the intensity and duration of oncogenic stress while keeping a memory of previous stresses. This integration is achieved by modulating chromatin accessibility via the induction of a self-regulated network of transcription factors including among others ETV4 and RUNX1 (Article 2). Our current model leads us to believe that this increase in chromatin accessibility during the SeRP would mainly involve decondensation of perinucleolar heterochromatin. This would lead to the induction of the pro-inflammatory secretome of senescent cells (SASP) and the ribogenesis defects observed in senescence. Besides, we show via the generation of a transgenic mouse model that the induction of such ribogenesis defects at the systemic scale leads to a premature aging phenotype suggesting stem cells senescence (Article 3). Stem cells having particularly high levels of ribogenesis and being very sensitive to alterations of their niche such as chronic inflammation, we believe that serendipitously, this model somehow reproduces the consequences of the SeRP. In short, all the work presented in this thesis allows for a better understanding of the molecular mechanisms regulating the commitment to senescence. Ultimately, these new notions would allow to design therapeutic strategies to tip the balance towards senescence in the context of RAS-mutated cancers

Chave De Identificação Para Licófitas E Samambaias Dos Núcleos Picinguaba E Santa Virgínia, Parque Estadual Da Serra Do Mar, Ubatuba, Sp, Brasil

This work contributes to the knowledge of the fern and lycophytes diversity in the Picinguaba and Santa Virginia Nuclei, Parque Estadual da Serra do Mar (PESM), Ubatuba, São Paulo, Brazil, as well as to provide subsidies to identification of the found taxa in these areas. In total, 30 collecting expeditions were conducted and the vouchers were deposited at UEC Herbarium. We have identified 135 species distributed in 53 genera and 19 families for both areas. The most representative families were Polypodiaceae (28 species) and Dryopteridaceae (19 species), whereas Asplenium (12 species), Blechnum and Elaphoglossum (8 species each) were the most important genera. Epiphytic species predominated (62 overall), probably due to the presence of favorable habitats. Among the taxa, 41 are considered endemic from Brazil, 35 of them endemic to the Brazilian Atlantic Forest. Five species are classified as vulnerable according to the “Official list of endangered species in the State of São Paulo”: Elaphoglossum macahense (Fée) Rosenst., Anetium citrifolium (L.) Splitg., Asplenium muellerianum Rosenst., Cyathea glaziovii (Fée) Domin, and Thelypteris angustifolia (Willd.) Proctor, which emphasizes the importance of preservation areas such as the Parque Estadual da Serra do Mar. An identification key has been elaborated to help with the recognition of these groups in Picinguaba and Santa Virgínia Nuclei. © 2016, Universidade Estadual de Campinas UNICAMP. All rights reserved.16

Improved N-dimensional Data Visualization from Hyper-radial Values

Higher-dimensional data, which is becoming common in many disciplines due to big data problems, are inherently difficult to visualize in a meaningful way. While many visualization methods exist, they are often difficult to interpret, involve multiple plots and overlaid points, or require simultaneous interpretations. This research adapts and extends hyper-radial visualization, a technique used to visualize Pareto fronts in multi-objective optimizations, to become an n-dimensional visualization tool. Hyper-radial visualization is seen to offer many advantages by presenting a low-dimensionality representation of data through easily understood calculations. First, hyper-radial visualization is extended for use with general multivariate data. Second, a method is developed by which to optimally determine groupings of the data for use in hyper-radial visualization to create a meaningful visualization based on class separation and geometric properties. Finally, this optimal visualization is expanded from two to three dimensions in order to support even higher-dimensional data. The utility of this work is illustrated by examples using seven datasets of varying sizes, ranging in dimensionality from Fisher Iris with 150 observations, 4 features, and 3 classes to the Mixed National Institute of Standards and Technology data with 60,000 observations, 717 non-zero features, and 10 classes

Musical Intertextuality in Kurt Vonnegut's Cat's Cradle. A Razor Song that Cuts Clean through

Kurt Vonnegut's Cat's Cradle has received great scholarship, yet the representation of music in the novel has often been missed. I will study the music intertextuality and point out the fact that Vonnegut's milestone is highly indebted to the ballad tradition. The paper examines the leitmotifs Vonnegut used to write such a social satire, which are the same used in balladry. Secondly, the representation of music is analyzed by dividing the study into two main approaches, music in the text and music off the text. The former deals with the actual lyrics found in the novel and the Calypso. Music off the text though, focuses on the narrative, both its structure and its content.La novel·la de ficció Cat's Cradle escrita per Kurt Vonnegut ha rebut molta atenció per part dels crítics acadèmics. No obstant, la representació de la música en aquesta, ha estat obviada, tot i la seva clarivident existència. És per això que aquest treball estudia el tractament que se li ha donat a la música, defenent que aquesta té un paper clau que val la pena descobrir. A través d'exemples referents als temes centrals de la novel·la, així com també, exemples extrets de la pròpia narrativa i de les cançons que presenta el llibre, Cat's Cradle es pot considerar una novel·la de ficció post modernista formada a partir dels cànons de la literatura oral, és a dir, les balades

Perspectiva médico legal del mobbing en el ejercicio de la medicina y la enfermería en el ámbito hospitalario

El mobbing, también llamado ¿la nueva plaga laboral del siglo XXI¿, es un factor de riesgo psicosocial en el lugar de trabajo, que se nos oculta a la hora de identificarlo. Sería responsable, como consecuencia de sus conductas de hostigamiento, de un tercio de los accidentes y enfermedades relacionadas con el trabajo. Leymann, ya en los años ochenta, estimaba que un 3.5% de los trabajadores de una empresa experimentaban mobbing en sus puestos de trabajo. Por lo tanto, necesita ser prevenido investigando sus causas, conociendo sus manifestaciones, sus fases y sus consecuencias, y reconociendo su rápido crecimiento, para poder frenar la grave incidencia que dicho fenómeno está teniendo en la actualidad.El mobbing o acoso laboral, causa enormes sufrimientos en las personas que lo padecen y merma la competitividad potencial de las empresas. El 7.9% de las personas en activo, dicen estar de acuerdo con que el acoso laboral disminuye la eficacia en el lugar de trabajo (Primera Encuesta sobre Violencia en el Entorno Laboral ¿ Universidad Alcalá de Henares 2001). Con la investigación de esta tesis doctoral se pretende reunir información para evidenciar de forma objetiva, y por medio del análisis de resoluciones judiciales con un método observacional descriptivo, los conflictos médico legales que se derivan del mobbing en el ejercicio de la medicina y la enfermería en el ámbito hospitalario, a nivel nacional. También se quiere aportar a la comunidad científica, una base para futuras investigaciones comparadas que relacionen el Derecho Laboral, el Mobbing y la Medicina Legal..

Checklist of ferns and lycophytes from the Parque Estadual Turístico do Alto Ribeira, Iporanga, São Paulo, Brazil

We present the floristic survey of ferns and lycophytes from the “Parque Estadual Turístico do Alto Ribeira” (PETAR), a remnant of Atlantic Rain Forest of Southeastern Brazil, in São Paulo state. Besides a complete list of species, we also provide information on habit, geographic distribution, and conservation status. Among the 237 taxa, there are 235 species, one variety and one hybrid, distributed in 29 families and 74 genera. Ferns are represented by 223 taxa, whereas the lycophytes were represented by 14. The most representative families are Polypodiaceae (31 spp.), Pteridaceae (29 spp.) and Dryopteridaceae (28 spp.). The most diverse genera are Thelypteris (23 spp.), Asplenium (19 spp.), Elaphoglossum and Blechnum (10 spp. each). Noteworthy is the presence of Ctenitis anniesii, Dicksonia sellowiana, Elaphoglossum iguapense, E. prestonii, E. strictum, Thelypteris concinna, T. araucariensis and T. hatschbachii, all of them considered as endangered species in São Paulo state

Sleep duration and blood pressure: a longitudinal analysis from early to late adolescence

The aim of this study was to evaluate the association between sleep duration and blood pressure using a cross-sectional and longitudinal approach. As part of a population-based cohort, 1403 adolescents were evaluated at 13 and 17 years old. Sleep duration was estimated by the difference between self-reported usual bedtime and wake-up time. Blood pressure was measured using the auscultatory method. Regression coefficients (β) and respective 95% confidence intervals were computed to evaluate the association between sleep duration and blood pressure, using linear regression models adjusted for practice of sports and body mass index at 17 years old. The mean (standard deviation) sleep duration at 13 years old was 9.0 (0.76) h per day, and on average it decreased by 46 min up to 17 years old. The median (25th-75th) systolic blood pressure at 17 years old was 110.0 (103.5-119.0) mmHg in females and 114.0 (106.0-122.0)mmHg in males (P < 0.001); for diastolic blood pressure the values were 66.0 (60.0-71.0) and 69.0 (62.0-75.0) mmHg, respectively (P < 0.001). In cross-sectional analysis, at 17 years old, after adjustment, a positive association was found between sleep duration and blood pressure, significant only for systolic blood pressure among females [β = 0.730 (0.005; 1.455)]. In girls, no significant association was found between sleep duration at 13 years old and blood pressure at 17 years old, but in males an inverse association was found between sleep duration at 13 years old and blood pressure at 17 years old significant only for systolic blood pressure [β = -1.938 (-3.229; -0.647)]. This study found no association between sleep duration at 13 years old and blood pressure at 17 years old in girls, but among males an inverse association was found

Cyber-Physical Security with RF Fingerprint Classification through Distance Measure Extensions of Generalized Relevance Learning Vector Quantization

Radio frequency (RF) fingerprinting extracts fingerprint features from RF signals to protect against masquerade attacks by enabling reliable authentication of communication devices at the “serial number” level. Facilitating the reliable authentication of communication devices are machine learning (ML) algorithms which find meaningful statistical differences between measured data. The Generalized Relevance Learning Vector Quantization-Improved (GRLVQI) classifier is one ML algorithm which has shown efficacy for RF fingerprinting device discrimination. GRLVQI extends the Learning Vector Quantization (LVQ) family of “winner take all” classifiers that develop prototype vectors (PVs) which represent data. In LVQ algorithms, distances are computed between exemplars and PVs, and PVs are iteratively moved to accurately represent the data. GRLVQI extends LVQ with a sigmoidal cost function, relevance learning, and PV update logic improvements. However, both LVQ and GRLVQI are limited due to a reliance on squared Euclidean distance measures and a seemingly complex algorithm structure if changes are made to the underlying distance measure. Herein, the authors (1) develop GRLVQI-D (distance), an extension of GRLVQI to consider alternative distance measures and (2) present the Cosine GRLVQI classifier using this framework. To evaluate this framework, the authors consider experimentally collected Z -wave RF signals and develop RF fingerprints to identify devices. Z -wave devices are low-cost, low-power communication technologies seen increasingly in critical infrastructure. Both classification and verification, claimed identity, and performance comparisons are made with the new Cosine GRLVQI algorithm. The results show more robust performance when using the Cosine GRLVQI algorithm when compared with four algorithms in the literature. Additionally, the methodology used to create Cosine GRLVQI is generalizable to alternative measures