Il presente lavoro si è concentrato sui meccanismi neurofisiologici e comportamentali legati all'invecchiamento sano e patologico. Il primo studio ha esplorato le dinamiche comportamentali ed elettrofisiologiche (N2pc e CDA) del processamento di oggetti multipli in pazienti con decadimento cognitivo lieve ed in pazienti con malattia di Alzheimer (AD), al fine di identificare marcatori neurofisiologici per distinguere l’invecchiamento normale da quello patologico. I dati suggeriscono che la CDA può essere un marcatore neurale utile sia per distinguere tra invecchiamento sano e patologico che per caratterizzare le diverse fasi lungo il continuum della malattia di Alzheimer, diventando un biomarcatore per la diagnosi precoce di AD. Il secondo studio ha valutato la possibilità di applicare un protocollo di neuroriabilitazione non invasiva, mediante stimolazione elettrica transcranica (tES), per migliorare le prestazioni cognitive aumentando il livello di eccitazione. Sia le prestazioni comportamentali ad un compito di memoria a breve termine che gli indici di attivazione fisiologica autonomica (dilatazione pupillare e conduttanza cutanea) sono stati studiati in un gruppo di soggetti giovani sani e in un gruppo di soggetti anziani sani. Nei giovani, entrambe le risposte comportamentali e fisiologiche non sono state modulate dall’applicazione della tES. Negli anziani, invece, la stimolazione reale ha indotto la rievocazione di una proporzione significativamente più bassa di stimoli ad alta salienza, rispetto alla condizione sham, suggerendo una riduzione della capacità di memoria. Gli indici fisiologici risultano inaffidabile nei partecipanti anziani e non possono essere utilizzati per trarre conclusioni definitive sulle modulazioni indotte dalla tES sul livello di eccitazione. Questi risultati hanno mostrato che l’applicazione della tES, durante un compito di memoria a breve termine, modulano diversamente le prestazioni comportamentali nei partecipanti giovani ed in quelli anziani. / The present work focused on neurophysiological and behavioral mechanisms related to healthy and pathological aging. The first study explored the behavioral and electrophysiological dynamics (N2pc and CDA) of multiple object processing in mild cognitive impairment and Alzheimer's disease (AD) patients to identify neurophysiological markers able to differentiate normal from pathological aging. Data suggested that CDA may be a useful neural signature to both distinguish between healthy and pathological aging and characterize the different stages along the AD continuum, possibly becoming a reliable candidate for an early diagnostic biomarker of AD pathology. The second study evaluated the possibility to apply a non-invasive neurorehabilitation protocol, by means of transcranial electrical stimulation (tES), to improve cognitive performance by increasing the level of arousal. Both the behavioral performance to a short term memory task and indexes of autonomic physiological activation (pupillary dilatation and skin conductance) were investigated in a group of healthy young subjects and in a group of healthy elderly subjects. In young, both behavioural and physiological responses were not modulated by tES application. In elderly, instead, real tES induced the report of a significant lower proportion of high salient stimuli, compared to the sham condition, suggesting a reduction of the memory span. The physiological indexes resulted unreliable in elderly participants and they could not be used to draw firm conclusions on the tES modulations of the level of arousal. These results showed that bursts of tES, applied during a short term memory task, differently modulated behavioural performance in young and elderly participants.

74 pages

Les industriels du secteur agro-alimentaire sont responsables de la qualité des produits mis sur le marché. Un moyen de vérifier cette qualité consiste à déterminer la distribution de la contamination. Dans cette thèse, nous avons utilisé des données portant sur L. monocytogenes durant le procédé de fabrication de lardons et du saumon fumé. Nous avons ensuite élaboré des modèles hiérarchiques pour décrire la concentration en prenant ou non en compte diverses variabilités, nous avons estimé les paramètres par inférence bayésienne, puis comparé leur capacité à simuler des données proches des observations. Nous avons également comparé l'estimation de paramètres par inférence fréquentiste sur deux modèles en utilisant les données brutes issues des analyses microbiologiques et ces mêmes données converties en concentration. Par ailleurs, nous avons amélioré un modèle décrivant le devenir de L. monocytogenes au cours de la fabrication des lardons. Le plan d'échantillonnage permettant d'estimer la qualité des produits, nous avons appliqué la théorie de la décision aux couples L. monocytogenes/lardons et L. monocytogenes/saumon fumé en sortie usine pour déterminer la taille optimale de l'échantillon à prélever par lot de manière à minimiser les coûts moyens supportés par le fabricant. Enfin, nous avons comparé plusieurs plans d'échantillonnage de mesure de la température d'un plat en sauce fabriqué dans une cuisine centrale et placé dans une cellule de refroidissement rapide. L'objectif était de sélectionner le meilleur plan d'échantillonnage en fonction du risque admissible pour le gestionnaire quant à la croissance de C. perfringens. / Food business operators are responsible for the quality of the products they sell. A way to assess the safety of food is to determine the contamination distribution. During my PhD thesis, we used data about L. monocytogenes during the process of diced bacon and of cold smoked salmon. Then, we constructed several hierarchical models to describe contamination taking or not into account several kinds of variability such as between batches variability. We compared the capacity of each model to simulate data close to the observed ones. We also compared the parameters assessment by frequentist inference using raw data (the results of the microbiological analyses) and concentration-like data. In addition to the models describing the contamination at one step of the process, we improved an existing model describing the fate of L. monocytogenes throughout the diced bacon process. A tool to assess the quality of a product is the sampling plan. We applied the Bayesian theory of decision to the pairs L. monocytogenes/diced bacon and L. monocytogenes/cold smoked salmon at the end of the process to determine the optimal size of a sample analysed per batch so that the average cost for the manufacturer is as los as possible. We also compared several sampling plans of temperature measurement of a meal cooked in an institutional food service facility and put in a blast-chiller just after cooking. The aim was to select the best sampling plan regarding the risk of C. perfringens growth that the manager is ready to take.

Cette thèse est principalement consacrée à l’étude de quelques caractéristiques d’une population à plusieurs types d’individus qui évolue selon un modèle de branchement multi-type au cours du temps. Autrement dit,chaque individu vit un certain temps et donne naissance, à la fin de sa vie, à un nombre aléatoire d’individus, suivant une loi de probabilité qui ne dépend que de son type, indépendamment des autres individus. Plus précisément, nous nous intéressons aux aspects statistiques des mutations et des individus ayant une progéniture donnée dans la population en question.Les problèmes d’énumération de forêts multi-types constituent également une motivation de ce travail de thèse. / This thesis is devoted to the study of some characteristics of a population consisting of individuals of several types which evolve according to a multitype branching model. In other words, each individual lives a certain time and gives birth to a random number of individuals at the end of its life, following a probability law which depends only on the individual’s type, independently of the others individuals. More precisely, we are interested in in the statistical aspects of mutations and the individuals having a given offspring in the population of interest. The problems of enumeration of multitype forests also form a motivation of this thesis’s work.

This thesis explores the part gambling plays in an urban setting in Highland Papua New Guinea. Gambling did not exist in (what is now) Goroka Town before European contact, nor Papua New Guinea more broadly, but when I conducted fieldwork in 2009-2010 it was an inescapable part of everyday life. One card game proliferated into a multitude of games for different situations and participants, and was supplemented with slot machines, sports betting, darts, and bingo and lottery games. One could well imagine gambling becoming popular in societies new to it, especially coming on the back of money, wage-work and towns. Yet the popularity of gambling in the region is surprising to social scientists because the peoples now so enamoured by gambling are famous for their love of competitively giving things away, not competing for them. Gambling spread while gifting remained a central part of the way people did transactions. This thesis resists juxtaposing gifting and selfish acquisition. It shows how their opposition is false; that gambling is instead a new analytic technique for manipulating the value of gifts and acquisitions alike, through the medium of money. Too often gambling takes a familiar form in analyses: as the sharp end of capitalism, or the benign, chance-led redistributor of wealth in egalitarian societies. The thesis builds an ethnographic understanding of gambling, and uses it to interrogate theories of gambling, money, and Melanesian anthropology. In so doing, the thesis speaks to a trend in Melanesian anthropology to debate whether monetisation and urbanisation has brought about a radical split in peoples' understandings of the world. Dealing with some of the most starkly ‘modern' material I find a process of inclusive indigenous materialism that consumes the old and the new alike, turning them into a model for action in a dynamic money-led world.

In this thesis, we address the problem of identifying and quantifying variants (alternative splicing and genomic polymorphism) in RNA-seq data when no reference genome is available, without assembling the full transcripts. Based on the idea that each variant corresponds to a recognizable pattern, a bubble, in a de Bruijn graph constructed from the RNA-seq reads, we propose a general model for all variants in such graphs. We then introduce an exact method, called KisSplice, to extract alternative splicing events and show that it outperforms general purpose transcriptome assemblers. We put an extra effort to make KisSplice as scalable as possible. In order to improve the running time, we propose a new polynomial delay algorithm to enumerate bubbles. We show that it is several orders of magnitude faster than previous approaches. In order to reduce its memory consumption, we propose a new compact way to build and represent a de Bruijn graph. We show that our approach uses 30% to 40% less memory than the state of the art, with an insignificant impact on the construction time. Additionally, we apply the techniques developed to list bubbles in two classical problems: cycle enumeration and the K-shortest paths problem. We give the first optimal algorithm to list cycles in undirected graphs, improving over Johnson's algorithm. This is the first improvement to this problem in almost 40 years. We then consider a different parameterization of the K-shortest (simple) paths problem: instead of bounding the number of st-paths, we bound the weight of the st-paths. We present new algorithms using exponentially less memory than previous approaches

Biological research and Clinical Diagnostics heavily rely on Optical Microscopy for analyzing properties of cells. The experimental protocol for con-ducting a microscopy based diagnostic test consists of several manual steps, like sample extraction, slide preparation and inspection. Recent advances in optical microscopy have predominantly focused on resolution enhancement. Whereas, the aspect of automating the manual steps and enhancing imaging throughput were relatively less explored. Cost-e ective automation of clinical microscopy would potentially enable the creation of diagnostic devices with a wide range of medical and biological applications. Further, automation plays an important role in enabling diagnostic testing in resource-limited settings. This thesis presents a novel optofluidics based approach for automation of clinical diagnostic microscopy. A system-level integrated optofluidic architecture, which enables the automation of overall diagnostic work- ow has been proposed. Based on the proposed architecture, three different prototypes, which can enable point-of-care (POC) imaging cytometry have been developed. The characterization of these prototypes has been performed. Following which, the applicability of the platform for usage in diagnostic testing has been validated. The prototypes were used to demonstrate applications like Cell Viability Assay, Red Blood Cell Counting, Diagnosis of Malaria and Spherocytosis. An important performance metric of the device is the throughput (number of cells imaged per second). A novel microfluidic channel design, capable of enabling imaging throughputs of about 2000 cells per second has been incorporated into the instrument. Further, material properties of the sample handling component (microfluidic device) determine several functional aspects of the instrument. Ultrafast-laser inscription (ULI) based glass microfluidic devices have been identi ed and tested as viable alternatives to Polydimethylsiloxane (PDMS) based microfluidic chips. Cellular imaging with POC platforms has thus far been limited to acquisition of 2D morphology. To potentially enable 3D cellular imaging with POC platforms, a novel slanted channel microfluidic chip design has been proposed. The proposed design has been experimentally validated by performing 3D imaging of fluorescent microspheres and cells. It is envisaged that the proposed innovation would aid to the current e orts towards implementing good quality health-care in rural scenarios. The thesis is organized in the following manner : The overall thesis can be divided into two parts. The first part (chapters 2, 3) of the thesis deals with the optical aspects of the proposed Optofluidic instrument (development, characterization and validations demonstrating its use in poc diagnostic applications). The second part (chapters 4,5,6) of the thesis details the microfluidic sample handling aspects implemented with the help of custom fabricated microfludic devices, the integration of the prototype, func-tional framework of the device. Chapter 2 introduces the proposed optofluidic architecture for implementing the POC tool. Further, it details the first implementation of the proposed platform, based on the philosophy of adapting ubiquitously available electronic imaging devices to perform cellular diagnostic testing. The characterization of the developed prototypes is also detailed. Chapter 3 details the development of a stand-alone prototype based on the proposed architecture using inexpensive o -the-shelf, low frame-rate image sensors. The characterization of the developed prototype and its performance evaluation for application in malaria diagnostic testing are also presented. The chapter concludes with a comparative evaluation of the developed prototypes, so far. Chapter 4 presents a novel microfludic channel design, which enables the enhancement of imaging throughput, even while employing an inexpensive low frame-rate imaging modules. The design takes advantage of radial arrangement of microfludic channels for enhancing the achievable imaging throughput. The fabrication of the device and characterization of achievable throughputs is presented. The stand-alone optofluidic imaging system was then integrated into a single functional unit, with the proposed microfluidic channel design, a viscoelastic effect based micro uidic mixer and a suction-based microfluidic pumping mechanism. Chapter 5 brings into picture the aspect of the material used to fabricate the sample handling unit, the robustness of which determines certain functional aspects of the device. An investigative study on the applicability of glass microfluidic devices, fabricated using ultra-fast laser inscription in the context of the microfluidics based imaging flow cytometry is presented. As detailed in the introduction, imaging in poc platforms, has thus far been limited to acquisition of 2D images. The design and implementation of a novel slanted channel microfluidic chip, which can potentially enable 3D imaging with simplistic optical imaging systems (such as the one reported in the earlier chapters of this thesis) is detailed. A example application of the proposed microfludic chip architecture for imaging 3D fluorescence imaging of cells in flow is presented. Chapter 6 introduces a diagnostic assessment framework for the use of the developed of m in an actual clinical diagnostic scenario. The chapter presents the use of computational signatures (extracted from cell images) to be employed for cell recognition, as part of the proposed framework. The experimental results obtained while employing the framework to identify cells from three different leukemia cell lines have been presented in this chapter. Chapter 7 summarizes the contributions reported in this thesis. Potential future scope of the work is also detailed.

Notre objectif dans cette thèse est de proposer des algorithmes efficaces pour résoudre des problèmes d’optimisation combinatoire difficiles. Dans un premier temps, nous établissons le principe de l’énumération ordonnée qui consiste à générer dans un ordre adéquat les solutions d’un problème relâché associé au problème principal jusqu’à l’obtention de la preuve d’optimalité d’une solution. Nous construisons une procédure générique dans le cadre général des problème d’optimisation combinatoire. Dans un second temps nous abordons les applications de notre algorithme sur des problèmes qui admettent le problème d’affectation comme relaxation. Le premier cas particulier que nous étudions est la recherche d’une solution de bon compromis pour le problème d’affectation multiobjectif. La seconde application se rapporte au problème du voyageur de commerce asymétrique qui présente la difficulté de comporter des contraintes qui interdisent les sous-tournées, en plus des contraintes du problème d’affectation. / Our aim in this thesis is to propose efficient algorithms for solving difficult combinatorial optimization problems. Our algorithms are based on a generic method of ordered enumeration. Initially, we describe the principle of ordered enumeration which consists in generating in a specific order solutions of a relaxed problem associated to the difficult main problem, until meeting a proof of the optimality of a feasible solution. We construct a generic procedure in the general context of combinatorial optimization problems. In a second step we discuss applications of our algorithm on some difficult problems which admit the assignment problem as relaxation. The first special case we study is the search for a compromise solution to the multiobjective assignment problem. The second application is the asymmetric travelling salesman problem, which contains sub-tour constraints in addition to the constraints of the assignment problem.

[pt] Esta dissertação estuda formulações, algoritmos e métodos exatos para resolver instâncias do Problema de Alocação Generalizada (PAG) com uma separação de desigualdades (3, 0.5)-SRC que viabilize a enumeração de colunas. Este trabalho é motivado pela perspectiva de alcançar o estado-da-arte com resultados competitivos comparáveis às melhores soluções encontradas na literatura por Avella (2010) e Michelon (2012). A pesquisa abrange métodos exatos e heurísticas, com ênfase no estudo que aborda a decomposição de Dantzig-Wolfe, o algoritmo de geração de colunas, a estabilização de colunas por meio da ponderação de duais proposto por Wentges (1997) e a enumeração de colunas habilitada pela minimização do gap decorrente do algoritmo de price-and-cut. O algoritmo de price-and-cut desenvolvido recorre à geração de colunas (pricing) aliada à separação de (3, 0.5)-SRCs para aumentar o lower bound gerado, assim minimizando o gap. A geração de colunas implementada é inspirada no algoritmo de Savelsbergh (1997); e a separação de (3, 0.5)-SRCs é motivada pelo trabalho de Jepsen (2008) e pelo algoritmo branch-cut-andprice proposto por Poggi e Uchoa (2016) para o CVRP. De acordo com os experimentos computacionais, as desigualdades adotadas são capazes de reduzir o gap suficientemente para viabilizar a enumeração de colunas em diversas instâncias do PAG com até 200 tarefas e 20 máquinas. O método utilizado obteve resultados compatíveis às melhores soluções conhecidas, enumerando todas as colunas necessárias para cobrir o gap determinado pelo price-and-cut. Esse resultado incentiva futuras pesquisas para estender a aplicação do algoritmo a instâncias maiores e mais difíceis. / [en] This dissertation deals with formulations, algorithms and exact methods for solving the well-known Generalized Assignment Problem (GAP) through a price-and-cut approach with the separation of (3, 0.5)-SRC inequalities in order to improve column enumeration feasibility and efficiency. This work is motivated by the perspective of reaching state-of-the-art performance, attaining competitive results which are comparable with the best known solutions found in the literature by Avella (2010) and Michelon (2012). This research was build on exact methods and some heuristics with emphasis on the Dantzig- Wolfe decomposition, the column generation algorithm, the stabilization through weighted Dantzig-Wolfe decomposition proposed byWentges (1997) and finally the column enumeration motivated by the gap minimization reached through the price-and-cut algorithm. The price-and-cut algorithm proposed here resort to column generation (pricing) combined with the separation of (3, 0.5)-SRC cuts in order to increase the generated lower bound, thus minimizing the attained gap. This column generation algorithm follows the work of Savelsbergh (1997); and the separation of (3, 0.5)-SRCs is formulated by Jepsen (2008) and motivated by the branch-cut-and-price algorithm proposed by Poggi and Uchoa (2016) for the CVRP. According to computational experiments, the adopted inequalities are capable of sufficiently reducing the gap, assuring the feasibility of column enumeration for several GAP instances with up to 200 tasks and 20 machines. This method achieved expressive results, compatible with the best known solutions, enumerating all the necessary columns to cover the gap found by the price-and-cut. Therefore, these results motivate future research towards the extension of the method s applicability to larger and more complex instances.

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