Planning under partial observability by classical replanning: theory and experiments

Planning with partial observability can be formulated as a non-deterministic search problem in belief space. The problem is harder than classical planning as keeping track of beliefs is harder than keeping track of states, and searching for action policies is harder than searching for action sequences. In this work, we develop a framework for partial observability that avoids these limitations and leads to a planner that scales up to larger problems. For this, the class of problems is restricted to those in which 1) the non-unary clauses representing the uncertainty about the initial situation are nvariant, and 2) variables that are hidden in the initial situation do not appear in the body of conditional effects, which are all assumed to be deterministic. We show that such problems can be translated in linear time into equivalent fully observable non-deterministic planning problems, and that an slight extension of this translation renders the problem solvable by means of classical planners. The whole approach is sound and complete provided that in addition, the state-space is connected. Experiments are also reported.

Formation of knots in partially replicated DNA molecules.

Bacterial plasmids with two origins of replication in convergent orientation are frequently knotted in vivo. The knots formed are localised within the newly replicated DNA regions. Here, we analyse DNA knots tied within replication bubbles of such plasmids, and observe that the knots formed show predominantly positive signs of crossings. We propose that helical winding of replication bubbles in vivo leads to topoisomerase-mediated formation of knots on partially replicated DNA molecules.

Designs and model effects definitions in the initial stage of a plant breeding program

The objective of this work was to compare the relative efficiency of initial selection and genetic parameter estimation, using augmented blocks design (ABD), augmented blocks twice replicated design (DABD) and group of randomised block design experiments with common treatments (ERBCT), by simulations, considering fixed effect model and mixed model with regular treatment effects as random. For the simulations, eight different conditions (scenarios) were considered. From the 600 simulations in each scenario, the mean percentage selection coincidence, the Pearsons´s correlation estimates between adjusted means for the fixed effects model, and the heritability estimates for the mixed model were evaluated. DABD and ERBCT were very similar in their comparisons and slightly superior to ABD. Considering the initial stages of selection in a plant breeding program, ABD is a good alternative for selecting superior genotypes, although none of the designs had been effective to estimate heritability in all the different scenarios evaluated.

Effect of neighborhood and plot size on experiments with multiple-harvest oleraceous crops

The objective of this work was to determine the efficiency of the Papadakis method on the quality evaluation of experiments with multiple-harvest oleraceous crops, and on the estimate of the covariate and the ideal plot size. Data from nine uniformity trials (five with bean pod, two with zucchini, and two with sweet pepper) and from one experiment with treatments (with sweet pepper) were used. Through the uniformity trials, the best way to calculate the covariate was defined and the optimal plot size was calculated. In the experiment with treatments, analyses of variance and covariance were performed, in which the covariate was calculated by the Papadakis method, and experimental precision was evaluated based on four statistics. The use of analysis of covariance with the covariate obtained by the Papadakis method increases the quality of experiments with multiple-harvest oleraceous crops and allows the use of smaller plot sizes. The best covariate is the one that considers a neighboring plot of each side of the reference plot.

A microarray-based system for the simultaneous analysis of single nucleotide polymorphisms in human genes involved in the metabolism of anti-malarial drugs

Background: In order to provide a cost-effective tool to analyse pharmacogenetic markers in malaria treatment, DNA microarray technology was compared with sequencing of polymerase chain reaction (PCR) fragments to detect single nucleotide polymorphisms (SNPs) in a larger number of samples. Methods: The microarray was developed to affordably generate SNP data of genes encoding the human cytochrome P450 enzyme family (CYP) and N-acetyltransferase-2 (NAT2) involved in antimalarial drug metabolisms and with known polymorphisms, i.e. CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5, and NAT2. Results: For some SNPs, i.e. CYP2A6*2, CYP2B6*5, CYP2C8*3, CYP2C9*3/*5, CYP2C19*3, CYP2D6*4 and NAT2*6/*7/*14, agreement between both techniques ranged from substantial to almost perfect (kappa index between 0.61 and 1.00), whilst for other SNPs a large variability from slight to substantial agreement (kappa index between 0.39 and 1.00) was found, e. g. CYP2D6*17 (2850C>T), CYP3A4*1B and CYP3A5*3. Conclusion: The major limit of the microarray technology for this purpose was lack of robustness and with a large number of missing data or with incorrect specificity.

Role of mutations in the phosphoprotein on RNA polymerase activity of canine distemper virus following cell culture adaptation

Abstract: The canine distemper virus A75/17 wild-type strain, which is unable to replicate in cell lines, was adapted to growth in Vero cells. Sequence comparison between the A75/17 and the Vero cell-adapted A75/17-V virus revealed 7 amino acid differences between the 2 viruses. Three of these were located in the matrix protein, three in the phosphoprotein also changing the V protein but not the C protein and one in the large protein. The phosphoprotein and the large protein constituted the viral RNA polymerase whose activity was studied by transfection experiments using a reverse genetic system with a plasmid encoding a minireplicon and expression plasmids encoding the nucleocapsid protein and the viral RNA polymerase subunits. Surprinsingly, the enzyme of A75/17 CDV was significantly more active in cell lines compared to the polymerase of A75/17-V CDV. The decrease in overall enzyme activity was found to be due to both decreased replication and transcription activity. This polymerase attenuation was confirmed in CHO cells infection stably expressing the dog SLAM receptor mainly found in dog's lymphoid organs and allowing both virus strains to enter these cells at the same efficiency. A75/17-V CDV replicated more slowly in CHODogSLAM cells than A75/17 CDV and syncytium formation was significantly decreased compared to A75/17 infected CHODogSLAM cells.. Cell culture adaptation lead to an attenuated virus strain both in vitro and in vivo with decreased polymerase activity and syncytium forming capability showing an important role of the polymerase in determining the phenoytpe of the virus. In addition, this reduced phenotype of A75/17-V CDV was shown to be due to the P mutations in the P protein only, showing an important function of the polycistronic P gene in the adaptation process. The role of the matrix protein was found not to have any effect on polymerase activity, however its participation in the adaptation process still needs to be elucidated. The accessory proteins V and C were shown to act on polymerase activity, but their functions in virus pathogenicity and in inhibiting the interferon system have not been studied in this thesis. The V proteins have an activating effect on the polymerase of both the A75/17 and the A75/17-V CDV strains. Although the C protein amino acid sequence was not changed during adaptation of wild-type canine distemper virus in Vero cells, the C protein was demonstrated to have opposite effects on polymerase activity of both virus strains suggesting a different interaction of the C protein with the proteins forming the polymerase complex, which could modulate polymeras activity. These effects were demonstrated by transfection experiments and studying recombinant viruses not expressing the C protein. Thus, the abrogation of the C protein decrease the activity of the wild-type polymerase. In contrast, the polymerase activity of the Vero cell- adapted virus is enhanced in the absence of the C protein and this has also been demonstrated with a recombinant virus, which grew faster in the first 48 hours of infection. Future studies will focus on the generation of recombinant wild-type viruses, which should be very helpful in understanding the molecular mechanisms underlying the adaptation process and the loss of pathogenicity.

MPRO-Spanish: development and experiments with a linguistic parser for Spanish texts

This paper describes the main features and present results of MPRO-Spanish, a parser for morphological and syntactic analysis of unrestricted Spanish text developed at the IAI1. This parser makes direct use of X-phrase structure rules to handle a variety of patterns from derivational morphology and syntactic structure. Both analyses, morphological and syntactic, are realised by two subsequent modules. One module analyses and disambiguates the source words at morphological level while the other consists of a series of programs and a deterministic, procedural and explicit grammar. The article explains the main features of MPRO and resumes some of the experiments on some of its applications, some of which still being implemented like the monolingual and bilingual term extraction while others need further work like indexing. The results and applications obtained so far with simple and relatively complex sentences give us grounds to believe in its reliability.

Relaxation and derelaxation of pure and hydrogenated amorphous silicon during thermal annealing experiments

The structural relaxation of pure amorphous silicon a-Si and hydrogenated amorphous silicon a-Si:H materials, that occurs during thermal annealing experiments, has been analyzed by Raman spectroscopy and differential scanning calorimetry. Unlike a-Si, the heat evolved from a-Si:H cannot be explained by relaxation of the Si-Si network strain but it reveals a derelaxation of the bond angle strain. Since the state of relaxation after annealing is very similar for pure and hydrogenated materials, our results give strong experimental support to the predicted configurational gap between a-Si and crystalline silicon.

Evolutionary Games in Networked Populations: Models and Experiments

Cooperation and coordination are desirable behaviors that are fundamental for the harmonious development of society. People need to rely on cooperation with other individuals in many aspects of everyday life, such as teamwork and economic exchange in anonymous markets. However, cooperation may easily fall prey to exploitation by selfish individuals who only care about short- term gain. For cooperation to evolve, specific conditions and mechanisms are required, such as kinship, direct and indirect reciprocity through repeated interactions, or external interventions such as punishment. In this dissertation we investigate the effect of the network structure of the population on the evolution of cooperation and coordination. We consider several kinds of static and dynamical network topologies, such as Baraba´si-Albert, social network models and spatial networks. We perform numerical simulations and laboratory experiments using the Prisoner's Dilemma and co- ordination games in order to contrast human behavior with theoretical results. We show by numerical simulations that even a moderate amount of random noise on the Baraba´si-Albert scale-free network links causes a significant loss of cooperation, to the point that cooperation almost vanishes altogether in the Prisoner's Dilemma when the noise rate is high enough. Moreover, when we consider fixed social-like networks we find that current models of social networks may allow cooperation to emerge and to be robust at least as much as in scale-free networks. In the framework of spatial networks, we investigate whether cooperation can evolve and be stable when agents move randomly or performing Le´vy flights in a continuous space. We also consider discrete space adopting purposeful mobility and binary birth-death process to dis- cover emergent cooperative patterns. The fundamental result is that cooperation may be enhanced when this migration is opportunistic or even when agents follow very simple heuristics. In the experimental laboratory, we investigate the issue of social coordination between indi- viduals located on networks of contacts. In contrast to simulations, we find that human players dynamics do not converge to the efficient outcome more often in a social-like network than in a random network. In another experiment, we study the behavior of people who play a pure co- ordination game in a spatial environment in which they can move around and when changing convention is costly. We find that each convention forms homogeneous clusters and is adopted by approximately half of the individuals. When we provide them with global information, i.e., the number of subjects currently adopting one of the conventions, global consensus is reached in most, but not all, cases. Our results allow us to extract the heuristics used by the participants and to build a numerical simulation model that agrees very well with the experiments. Our findings have important implications for policymakers intending to promote specific, desired behaviors in a mobile population. Furthermore, we carry out an experiment with human subjects playing the Prisoner's Dilemma game in a diluted grid where people are able to move around. In contrast to previous results on purposeful rewiring in relational networks, we find no noticeable effect of mobility in space on the level of cooperation. Clusters of cooperators form momentarily but in a few rounds they dissolve as cooperators at the boundaries stop tolerating being cheated upon. Our results highlight the difficulties that mobile agents have to establish a cooperative environment in a spatial setting without a device such as reputation or the possibility of retaliation. i.e. punishment. Finally, we test experimentally the evolution of cooperation in social networks taking into ac- count a setting where we allow people to make or break links at their will. In this work we give particular attention to whether information on an individual's actions is freely available to poten- tial partners or not. Studying the role of information is relevant as information on other people's actions is often not available for free: a recruiting firm may need to call a job candidate's refer- ences, a bank may need to find out about the credit history of a new client, etc. We find that people cooperate almost fully when information on their actions is freely available to their potential part- ners. Cooperation is less likely, however, if people have to pay about half of what they gain from cooperating with a cooperator. Cooperation declines even further if people have to pay a cost that is almost equivalent to the gain from cooperating with a cooperator. Thus, costly information on potential neighbors' actions can undermine the incentive to cooperate in dynamical networks.

A copula-based method for synthetic microarray data generation

In this work, we propose a copula-based method to generate synthetic gene expression data that account for marginal and joint probability distributions features captured from real data. Our method allows us to implant significant genes in the synthetic dataset in a controlled manner, giving the possibility of testing new detection algorithms under more realistic environments.

Connexin43 Inhibition Prevents Human Vein Grafts Intimal Hyperplasia.

Venous bypass grafts often fail following arterial implantation due to excessive smooth muscle cells (VSMC) proliferation and consequent intimal hyperplasia (IH). Intercellular communication mediated by Connexins (Cx) regulates differentiation, growth and proliferation in various cell types. Microarray analysis of vein grafts in a model of bilateral rabbit jugular vein graft revealed Cx43 as an early upregulated gene. Additional experiments conducted using an ex-vivo human saphenous veins perfusion system (EVPS) confirmed that Cx43 was rapidly increased in human veins subjected ex-vivo to arterial hemodynamics. Cx43 knock-down by RNA interference, or adenoviral-mediated overexpression, respectively inhibited or stimulated the proliferation of primary human VSMC in vitro. Furthermore, Cx blockade with carbenoxolone or the specific Cx43 inhibitory peptide 43gap26 prevented the burst in myointimal proliferation and IH formation in human saphenous veins. Our data demonstrated that Cx43 controls proliferation and the formation of IH after arterial engraftment.

Post-transcriptional regulation of circadian gene expression by miRNAs

La grande majorité des organismes vivants ont développé un système d'horloges biologiques internes, appelées aussi horloges circadiennes, contrôlant l'expression de gênes impliqués dans de nombreux processus moléculaires et comportementaux. Au cours de la dernière décennie, des analyses « microarray » et séquençages à haut débit sur divers tissus de mammifères, indiquent que jusqu'à 20% du transcriptome serait sous contrôle circadien. Il était jusqu'à présent admis que la majorité des ARNm ayant une accumulation rythmique était générée par une transcription qui était elle-même rythmique. Toutefois, de récentes études ont suggéré qu'une proportion considérable des ARNm cycliques serait en fait générée par des mécanismes post-transcriptionnelles, incluant une régulation par micro-ARN (miARN). Lorsque j'ai débuté mon travail de thèse, l'influence des miARN sur l'expression des gènes circadiens, au niveau pangénomique, était encore méconnue. Par l'utilisation d'un modèle murin, dont la biogenèse des miARN a été spécifiquement désactivée au niveau des cellules hépatiques (knockout conditionnel pour Dicer), je me suis donc intéressée au rôle que jouaient ces molécules régulatrices sur la rythmicité de l'expression génique dans le foie. Des séquençages sur l'ensemble du transcriptome révèlent que l'horloge interne du foie est étonnement résistante à la perte totale des miARN. Nous avons cependant trouvé que les miARN agissent de façon importante sur la régulation de l'expression des gènes contrôlés par l'horloge moléculaire. La corégulation par les miARN, affectant jusqu'à 30% des gènes transcrits de façon rythmiques, conduit ainsi à une modulation de phase et d'amplitude du rythme de l'abondance des ARNm. En revanche, seuls peu de transcrits dépendent uniquement des miARN pour la rythmicité de leur accumulation. Enfin, mon travail met en évidence plusieurs miARN spécifiques, qui semblent préférentiellement moduler l'expression des gènes cycliques et permet l'identification de voies hépatiques particulièrement sujettes à une double régulation par les miARN et l'horloge biologique interne. La première masse d'analyses a essentiellement porté sur le rôle que jouent les miARN au niveau de l'expression des gènes contrôlés par l'horloge interne. Dans deux études de suivi, je me suis penchée sur deux aspects supplémentaires et complémentaires de la manière dont les miARN et l'oscillation de l'expression des gènes interagissent. Dans les hépatocytes murins, spécifiquement privés de Dicer, je me suis demandée si un phénotype horloge avait pu être masqué, dû à un entraînement stable de l'horloge du foie par l'horloge maîtresse du cerveau. J'ai donc commencé une série d'expériences ambitieuses (impliquant la mesure de la rythmicité du foie in vivo, chez l'animal vivant) afin de déséquilibrer l'entrainement de l'horloge hépatique via l'utilisation d'un protocole nutritionnel spécifique. Les premiers résultats suggèrent que dans des conditions où l'animal subit une restriction alimentaire pendant la journée, les miARN sont importants dans la cinétique d'adaptation des organes périphériques à un nouvel horaire de sustentation. Dans une deuxième ligne de recherche, j'ai plus profondément étudié quels seraient les miARN responsables des rythmes post-transcriptionnels des ARNm, en utilisant le séquençage de « small » ARN sur 24h. L'analyse est en cours et se poursuivra après l'obtention de mon diplôme. De façon générale, mon travail révèle d'importants et nouveaux rôles des miARN dans la modulation de l'expression circadienne des gènes hépatiques. De plus, le set de données générées dans l'étude déjà publiée, peut dorénavant servir de ressource valable pour de prochaines investigations sur le rôle physiologique que les miARN jouent au niveau du foie. -- Most living organisms have developed internal timing systems, called circadian clocks, to drive the rhythmic expression of genes involved in many molecular and behavioral processes. Over the last decade, microarray analyses and high- throughput sequencing from various mammalian tissues have indicated that up to 20% of the transcriptome are under circadian control. It was generally assumed that the majority of rhythmic mRNA accumulation is generated by rhythmic transcription. However, recent studies have suggested that a considerable proportion of mRNA cycling may actually be generated by post-transcriptional mechanisms, including by microRNAs. When I started my thesis work, it was still unknown how miRNAs influence circadian gene expression in a genome-wide fashion. Using a mouse model in which miRNA biogenesis can be inactivated in hepatocytes (conditional Dicer knockout mouse), I have thus addressed the role that these regulatory molecules play in rhythmic gene expression in the liver. Whole transcriptome sequencing revealed that the hepatic core clock was surprisingly resilient to total miRNA loss. However, we found that miRNAs acted as important regulators of clock-controlled gene expression. Co- regulation by miRNAs, which affected up to 30% of rhythmically transcribed genes, thus led to the modulation of phases and amplitudes of mRNA abundance rhythms. By contrast, only very few transcripts were strictly dependent on miRNAs for their rhythmic accumulation. Finally, my work highlights several specific miRNAs that appear to preferentially modulate cyclic gene expression, and identifies pathways in the liver that are particularly prone to dual regulation through miRNAs and the clock. The first bulk of analyses mainly dealt with the role that miRNAs play at the level of rhythmic clock output gene expression. In two follow-up studies I further delved into two additional, complementary aspects of how miRNAs and gene expression oscillations interact. First, I addressed whether a core clock phenotype in the hepatocyte-specific Dicer knockout could have been masked due to the stable entrainment of the liver clock by the animals' master clock in the brain. I thus started a series of ambitious experiments (involving the in vivo recording of liver rhythms in live animals) to bring the stable entrainment of the liver clock out of equilibrium using specific feeding protocols. My first results suggest that under conditions when animals are challenged by food restriction to daytime, miRNAs are important for the kinetics of adapting to unusual mealtime in peripheral tissue. In a second line of research, I have more carefully investigated which miRNAs are responsible for post- transcriptional mRNA rhythms using small RNA sequencing around-the-clock. The analyses are ongoing and will be continued after my graduation. Overall, my work uncovered important and novel roles of miRNA activity in shaping hepatic circadian gene expression; moreover, the datasets collect in the published studies can serve as a valuable resource for further investigations into the physiological roles that miRNAs play in liver. -- L'alternance du jour et de la nuit dirige depuis longtemps la vie quotidienne des êtres humains et de la plupart des organismes sur terre. Ce cycle de 24 heures façonne beaucoup de changements comportementaux et physiologiques tels que la vigilance, la température corporelle et le sommeil. Les rythmes journaliers, appelés rythmes circadiens, sont dirigés par des horloges biologiques tournant dans presque chaque cellule du corps. Une structure dans le cerveau agit en tant qu'horloge maitresse pour synchroniser les horloges internes entre elles et en fonction des signaux de jour/nuit extérieurs. Dans les cellules "les gènes de l'horloge" sont activés et désactivés une fois par jour ce qui déclenche des cycles dans lesquels des protéines sont produites de manière circadienne. Ces rythmes protéiques sont spécialisés pour chaque tissu ou organe et peuvent les aider à réaliser leurs tâches quotidiennes. Les rythmes circadiens peuvent être générés d'autres manières n'impliquant pas directement les composants des gènes de l'horloge. Les ARN messagers (ARNm) sont des molécules intermédiaires dans la production de protéines à partir d'ADN. Dans le foie des souris jusqu'à 20% des molécules d'ARNm sont produites suivant des rythmes circadiens. Le foie réalise des tâches essentielles dans le contrôle du métabolisme incluant celui des hydrates de carbone, des graisses et du cholestérol. Un timing précis est important afin de traiter les substances nutritives correctement lors des repas il en résulte une variation des quantités de certains ARNm et protéines coïncidant avec les repas. Les microARNs constituent une autre classe de molécules ARN de très petite taille qui régulent l'efficacité de traduction des ARNm en protéines et la stabilité des ARNm. Lors de mon travail de thèse, j'ai exploré de manière approfondie l'influence de ces petits régulateurs sur les rythmes circadiens du foie de souris. Ces expériences qui impliquaient le "Knock-out" d'un gène essentiel à la production de microARNs montrent qu'au lieu de générer les rythmes des ARNm, les microARNs les ajustent pour répondre aux besoins spécifiques du foie comme assurer leur pic au bon moment de la journée. Le ciblage de microARNs spécifiques peut révéler de nouvelles stratégies pour rectifier ces rythmes lorsque par exemple les fonctions métaboliques ne fonctionnent plus normalement. -- The rising and setting of the sun have long driven the daily schedules of humans and most organisms on the earth. This 24-hr cycle shapes many behavioural and physiological changes, such as alertness, body temperature, and sleep. These daily rhythms, which are called circadian rhythms, are dictated by biological clocks that are ticking in almost every single cell of the body. A region in the brain acts as a master clock to synchronize the internal clocks with each other and with the outside light/dark cycles. In cells, "core clock genes" are turned on and off once per day, which triggers cycles that cause some proteins to be produced in a circadian manner. The protein rhythms are specialized to a particular tissue or organ, and may help them to carry out their designated daily tasks. However, circadian rhythms might also be produced by other ways that do not involve these core clock components. Messenger RNAs (mRNAs) are intermediate molecules in the production of proteins from DNA. In the mouse liver, up to 20% of mRNA molecules are produced in circadian cycles. The liver performs essential tasks that control metabolism-including that of carbohydrates, fats, and cholesterol. Precisely timing when certain mRNAs and proteins reach peaks and troughs in their activities to coincide with mealtimes is important for nutrients to be properly processed. Other RNA molecules called microRNAs, i.e. RNAs of very small size, regulate at which rate mRNA molecules are translated into proteins. In my thesis work, I have explored at the influence of these small regulators on circadian rhythms in the mouse liver in greater detail. These experiments, which involved "knocking out" a gene that is essential for the production of microRNAs, show that rather than generating the mRNA rhythms, the microRNAs appear to adjust them to meet the specific needs of the liver, such as ensuring that they peak at the right time-of-day. Targeting specific microRNA molecules may reveal new strategies to tweak these rhythms, which could help to improve conditions when metabolic functions go wrong.

The Influence of Chronic and Situational Social Status on Stereotype Susceptibility

We tested whether stereotypical situations would affect low-status group members' performance more strongly than high-status group members'. Experiment 1 and 2 tested this hypothesis using gender as a proxy of chronic social status and a gender-neutral task thathas been randomly presented to favor boys (men superiority condition), favor girls (women superiority condition), or show no gender preference (control condition). Both experiments found that women's (Experiment 1) and girls' performance (Experiment 2) suffered more from the evoked stereotypes than did men's and boys' ones. This result was replicated in Experiment 3, indicating that short men (low-status group) were more affected compared to tallmen (high-status group). Additionally, men were more affected compared to women when they perceived height as a threat. Hence, individuals are more or less vulnerable to identity threats as a function of the chronic social status at play; enjoying a high status provides protection and endorsing a low one weakens individual performance in stereotypical situations.