Les fractures de l'os temporal constituent une pathologie fréquente insuffisamment étudiée sur le plan biomécanique, et mal prise en charge sur le plan thérapeutique. Leur complexité biomécanique et leur polymorphisme clinique ont donc été analysés dans cette étude. Ainsi une base de données prospectives de patients pris en charge pour fractures temporales a été initiée afin d'évaluer les séquelles et leur impact sur la qualité de vie. Une étude expérimentale de traumatismes temporaux a été réalisée afin d'apporter des données dans la caractérisation biomécanique de l'os temporal. En complément, un modèle éléments finis d'os temporal a été developpé, et un traumatisme temporal a été simulé. La régénération du nerf facial traumatisé a été étudiée, et un effet thérapeutique de la vitamine D3 a été recherché par une étude expérimentale animale. Nos résultats montrent qu'une amélioration de la prévention des fractures temporales est nécessaire surtout par adaptation et utilisation des casques dans le cadre de la pratique du vélo. Cette prévention doit se reposer sur la caractérisation biomécanique des traumatismes temporaux par une double approche, expérimentale et numérique. La vitamine D3 augmente significativement la récupération fonctionnelle et la myélinisation dans un modèle animal de traumatisme du nerf facial. Cette étude ouvre la perspective d'essais cliniques. La fréquence des séquelles cochléo-vestibulaires invalidantes après fractures temporales et leur impact sur la qualité de vie montrent la nécessité d'un suivi des patients dans un cadre multidisciplinaire. / Temporal bone fracture is a frequent pathology insufficiently studied on terms of biomechanical, and poorly managed on terms of therapeutic. The biomechanical complexity and the clinical polymorphism of temporal bone trauma were analysed in this study. Our dynamic was to zoom from patient with temporal bone trauma to lesional process of temporal bone fracture. A prospective database of patients with temporal bone fracture was initiated to analyse sequelae and their impact on quality of life. An experimental study of temporal bone trauma was conducted to bring data in biomechanical characterization of temporal bone. In addition, a finite element model of the temporal bone was designed, and a lateral impact was simulated. The regeneration of traumatized facial nerve was studied, and a therapeutic effect of vitamin D3 (cholécalciférol) was evaluated with animal experimental study. Our results showed that an improvement of temporal fracture prevention is necessary by promoting the use of helmets and improvements in helmet design as part of cycling practice. This prevention must base on biomechanical characterization of temporal bone trauma with experimental and numerical approach. Vitamin D3 increases significantly functional recovery and myelination in an animal model of facial nerve trauma. It paves further the way for clinical trials. The frequency of cochleovestibular sequelae after temporal bone fracture and their impact on quality of life demonstrate the importance of, and the need for, on-going follow up with a multidisciplinary management.

Le modèle induit par injectionunilatérale intrahippocampique d’acide kaïniquechez la souris présente de grandes analogiesavec l’épilepsie mésio-temporale (EMT) chezl’homme caractérisée par la périoded’épileptogénèse et par une sclérosehippocampique (SH) typique.De récents travaux ex vivo ont révélé l’existencede processus neuroinflammatoires au niveau dela SH chez des patients épileptiques et dans desmodèles animaux. La protéine translocatrice de18kDa (TSPO), la plus étudiée actuellement aumoyen de différents traceurs, est considéréecomme une cible de référence pour visualiser etquantifier la neuroinflammation.Ma thèse a donc eu pour objectif de déterminerl’évolution de l’expression de TSPO au cours dela constitution de la SH à l’aide de laTomographie par émission de positons (TEP) au18F-DPA-714 dans une étude longitudinale chezce modèle d’EMT, et à identifier son origine àpartir d’analyses d’immunohistofluorescence.Nous avons démontré la faisabilité de la TEPpour suivre in vivo le processus inflammatoiremême dans de petites structures cérébrales à lafois par la mesure locale du pourcentaged’activité injectée et par l’estimation du volumede distribution.Le signal maximum a été observé durantl’épileptogénèse et correspondait aux microgliesactivées puis il diminuait mais persistait lorsquela SH était bien établie, et était alorsprincipalement lié aux astrocytes activés.Nos principaux résultats ont permis d’identifierles phases pendant lesquelles de nouvellesstratégies thérapeutiques ciblant différentescomposants de la neuroinflammationmériteraient d’être étudiés. / The model induced by unilateralinjection of kainic acid is considered as the bestreliable model for the mesial temporal lobeepilepsy (MTLE) and reproduces theepileptogenesis and the typical hippocampalsclerosis (HS).Recent ex vivo studies have revealed theexistence of neuroinflammation in the HS ofepileptic patients and animal models. The18kDa translocator protein (TSPO), which iscurrently the most widely studied with variousradiotracers, is considered as a reference targetto visualize and quantify theneuroinflammation.In that context, my thesis focused ondetermining the evolution of TSPO during theconstitution of HS using 18F-DPA-714positrons emission tomography (PET) in alongitudinal study in this mouse model, and toidentify its origin fromimmunohistofluorescence analysis.We demonstrated the feasibility of PET tomonitor in vivo the inflammatory process evenin small cerebral structures both by the localmeasurement of the percent injected dose or bythe measurement of the volume of distribution.The peak signal was found during theepileptogenesis and corresponded to activatedmicroglia, and then this signal decreased butpersisted after the HS was well established, andmainly originated from activated astrocytesduring this period.Our main results allowed us to identifydifferent phases during which potential antiepileptictreatment targeting differentcomponents of neuroinflammation could beinvestigated.

Recently, verification and analysis of data words have gained a lot of interest. Metric temporal logic (MTL) and timed propositional temporal logic (TPTL) are two extensions of Linear time temporal logic (LTL). In MTL, the temporal operator are indexed by a constraint interval. TPTL is a more powerful logic that is equipped with a freeze formalism. It uses register variables, which can be set to the current data value and later these register variables can be compared with the current data value. For monotonic data words, Alur and Henzinger proved that MTL and TPTL are equally expressive and the satisfiability problem is decidable. We study the expressive power, satisfiability problems and path checking problems for MLT and TPTL over all data words. We introduce Ehrenfeucht-Fraisse games for MTL and TPTL. Using the EF-game for MTL, we show that TPTL is strictly more expressive than MTL. Furthermore, we show that the MTL definability problem that whether a TPTL-formula is definable in MTL is not decidable. When restricting the number of register variables, we are able to show that TPTL with two register variables is strictly more expressive than TPTL with one register variable. For the satisfiability problem, we show that for MTL, the unary fragment of MTL and the pure fragment of MTL, SAT is not decidable. We prove the undecidability by reductions from the recurrent state problem and halting problem of two-counter machines. For the positive fragments of MTL and TPTL, we show that a positive formula is satisfiable if and only it is satisfied by a finite data word. Finitary SAT and infinitary SAT coincide for positive MTL and positive TPTL. Both of them are r.e.-complete. For existential TPTL and existential MTL, we show that SAT is NP-complete. We also investigate the complexity of path checking problems for TPTL and MTL over data words. These data words can be either finite or infinite periodic. For periodic words without data values, the complexity of LTL model checking belongs to the class AC^1(LogDCFL). For finite monotonic data words, the same complexity bound has been shown for MTL by Bundala and Ouaknine. We show that path checking for TPTL is PSPACE-complete, and for MTL is P-complete. If the number of register variables allowed is restricted, we obtain path checking for TPTL with only one register variable is P-complete over both infinite and finite data words; for TPTL with two register variables is PSPACE-complete over infinite data words. If the encoding of constraint numbers of the input TPTL-formula is in unary notation, we show that path checking for TPTL with a constant number of variables is P-complete over infinite unary encoded data words. Since the infinite data word produced by a deterministic one-counter machine is periodic, we can transfer all complexity results for the infinite periodic case to model checking over deterministic one-counter machines.

Ontology-mediated query answering is a popular paradigm for enriching answers to user queries with background knowledge. For querying the absence of information, however, there exist only few ontology-based approaches. Moreover, these proposals conflate the closed-domain and closed-world assumption, and therefore are not suited to deal with the anonymous objects that are common in ontological reasoning. Many real-world applications, like processing electronic health records (EHRs), also contain a temporal dimension, and require efficient reasoning algorithms. Moreover, since medical data is not recorded on a regular basis, reasoners must deal with sparse data with potentially large temporal gaps. Our contribution consists of three main parts: Firstly, we introduce a new closed-world semantics for answering conjunctive queries with negation over ontologies formulated in the description logic ELH⊥, which is based on the minimal universal model. We propose a rewriting strategy for dealing with negated query atoms, which shows that query answering is possible in polynomial time in data complexity. Secondly, we introduce a new temporal variant of ELH⊥ that features a convexity operator. We extend this minimal-world semantics for answering metric temporal conjunctive queries with negation over the logic and obtain similar rewritability and complexity results. Thirdly, apart from the theoretical results, we evaluate minimal-world semantics in practice by selecting patients, based their EHRs, that match given criteria.

Constraint Satisfaction Problems (CSPs) are a class of decision problems where one usually fixes a structure A and seeks to decide whether or not a given conjunction of atomic formulas is satisfiable in A or not. It has been shown by Bodirsky and Grohe that every computational decision problem is equivalent to some CSP via a polynomial-time Turing reduction. For structures A with finite domain Zhuk and Bulatov both proved an algebraic criterion classifying in which cases the CSP of A is in P and when it is NP-hard. For some classes of structures with infinite domain, there are similar P vs NP-hard dichotomies. This thesis continues the latter line of research for CSPs of first-order theories. In this version of CSPs, a theory is fixed and one seeks to decide whether or not a given conjunction of atomic formulas is satisfiable in some model of T. Assuming that the CSPs of theories T1 and T2 are polynomial-time tractable, we prove necessary and sufficient conditions for polynomial-time tractability of the union of T1 and T2. For some classes of theories, P vs NP-hard dichotomies are proven. To achieve this, various 'combinations' of structures are examined, a technique called 'sampling' is generalized to theories and clones of polymorphisms of temporal structures are examined in detail.

La sclérose latérale amyotrophique (SLA) et la démence fronto-temporale (DFT) sont des maladies neurodégénératives fatales, actuellement sans traitement. Ces maladies entrainent la dégénérescence des neurones moteurs et corticaux, engendrant des troubles moteurs et cognitifs et ultimement menant à la mort des patients souvent par détresse respiratoire trois à cinq ans après l’apparition des premiers symptômes. À l’échelle d’une vie, le risque de développer ces pathologies est de 1 pour 300-400 pour la SLA et 1 pour 742 pour la DFT, faisant de ces pathologies un risque majeur. Avec le vieillissement de la population que nous connaissons actuellement, il est évident que l’incidence de ces maladies deviendra de plus en plus élevée. Ainsi il est essentiel de comprendre les mécanismes moléculaires sous-jacents à ces pathologies dans le but de développer des thérapies effectives et prévenir l’impact de ces pathologies dans notre société. À ce jour, l’étiologie de la SLA-DFT est encore débattue, cependant la communauté scientifique s’accorde sur le fait que l’interaction entre la génétique et l’environnement joue un rôle essentiel dans le développement de ces maladies. La caractéristique moléculaire principale de ces pathologies est la localisation cytoplasmique de la protéine, normalement, nucléaire TDP-43. TDP-43 est un régulateur clef de l’homéostasie des ARNs. Parmi ces nombreuses fonctions, TDP-43 régule la formation des granules de stress, en régulant leur protéine régulatrice G3BP1. Ces granules formés d’ARN et de protéines se forment pour protéger les cellules durant une période de stress. Récemment, ces granules ont fait l’objet de nombreuses études et leurs dysfonctions ont été associées à la SLA-DFT. Dans cette thèse, nous avons approfondi l’étude de la régulation de TDP-43 sur G3BP1. Nous avons défini que TDP-43 stabilise les transcrits de G3BP1 de par une liaison forte à une séquence conservée à travers l’évolution se situant dans le 3’UTR de G3BP1. La perte de localisation nucléaire, la présence de mutations ou de TDP-35, une isoforme pathologique de TDP-43, sont associées à une diminution des niveaux de G3BP1. Également, d’un point de vue histopathologique, dans le cortex orbitofrontal des patients atteints de SLA-DFT, les neurones présentant une localisation cytoplasmique de TDP-43 ont une perte des niveaux transcriptionnels de G3BP1, associant alors directement G3BP1 à la maladie. Par la suite, nous avons défini que la perte de fonction en tant que stabilisateur, permet la liaison de microARNs sur les transcrits de G3BP1, engendrant leur dégradation. Le blocage de la liaison de microARNs sur G3BP1 empêche la dégradation des transcrits et restaure les fonctions de la protéine. Ainsi, nous avons déterminé un moyen de contrer la perte de fonction de TDP-43 sur G3BP1. De façon intéressante, en plus de la formation des granules de stress, G3BP1 est essentielle pour l’homéostasie neuronale et la survie neuronale post-stress. Par conséquent, la restauration de la protéine est potentiellement une avenue thérapeutique multi-approche pour le traitement de ces maladies. / Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two fatal neurodegenerative diseases, currently without cure. These diseases lead to the degeneration of motor and cortical neurons, causing motor and cognitive disorders and ultimately leading to death, often from respiratory distress three to five years after the onset. Over a lifetime, the risk of developing these conditions is 1 in 300-400 for ALS and 1 in 742 for FTD, making these conditions a major risk. With the current aging of the population, it is evident that the incidence of these diseases will become increasingly high. It is therefore essential to understand the molecular mechanisms underlying these pathologies in order to develop effective therapies. To this day, the etiology of ALS-FTD is still debated. However, the scientific community agrees that the interaction between genetics and the environment play an essential role in the development of these diseases. The main molecular characteristic of these pathologies is the cytoplasmic localization of the normally nuclear protein TDP-43. TDP-43 is a key regulator of RNA homoeostasis. Among these many functions, TDP-43 regulates the formation of stress granules, by regulating their nucleator protein G3BP1. These granules of RNA and protein form to protect cells during times of stress. Recently these granules have been the subject of several studies and their dysfunction has been associated with ALS-FTD. In this thesis, we have deepened the study of the regulation of TDP-43 on G3BP1. We have defined that TDP-43 stabilizes G3BP1 transcripts by strong binding to a sequence conserved through evolution located in the 3'UTR of G3BP1. Loss of nuclear localization, the presence of mutations or of TDP-35, a pathological isoform of TDP-43, are associated with decreased levels of G3BP1. Also, histopathologically, in the orbitofrontal cortex of patients with ALS-DFT, neurons with cytoplasmic localization of TDP-43 have a loss of transcriptional levels of G3BP1, directly associating G3BP1 with the disease. Subsequently, we defined that TDP-43 loss of function as a stabilizer allows the binding of two microRNAs on the G3BP1 transcripts, causing their degradation. Blocking the binding of these microRNAs to G3BP1 prevents the degradation of the transcripts and restores the functions of the protein. Thus, we have determined a way to counter the loss of function of TDP-43 on G3BP1. Interestingly, in addition to the formation of stress granules, G3BP1 is essential for neuronal homoeostasis and post-stress neuronal survival. Therefore, the restoration of the protein is potentially a multi-approach therapeutic avenue for the treatment of these diseases.

We present some initial results on ontology-based query answering with description logic ontologies that may employ temporal and probabilistic operators on concepts and axioms. Speci_cally, we consider description logics extended with operators from linear temporal logic (LTL), as well as subjective probability operators, and an extended query language in which conjunctive queries can be combined using these operators. We first show some complexity results for the setting in which either only temporal operators or only probabilistic operators may be used, both in the ontology and in the query, and then show a 2ExpSpace lower bound for the setting in which both types of operators can be used together. / This is an extended version of an article accepted at Description Logics 2019.

Ontology-based data access augments classical query answering over fact bases by adopting the open-world assumption and by including domain knowledge provided by an ontology. We implemented temporal query answering w.r.t. ontologies formulated in the Description Logic DL-Lite. Focusing on temporal conjunctive queries (TCQs), which combine conjunctive queries via the operators of propositional linear temporal logic, we regard three approaches for answering them: an iterative algorithm that considers all data available; a window-based algorithm; and a rewriting approach, which translates the TCQs to be answered into SQL queries. Since the relevant ontological knowledge is already encoded into the latter queries, they can be answered by a standard database system. Our evaluation especially shows that implementations of both the iterative and the window-based algorithm answer TCQs within a few milliseconds, and that the former achieves a constant performance, even if data is growing over time.

Ontology-based query answering augments classical query answering in databases by adopting the open-world assumption and by including domain knowledge provided by an ontology. We investigate temporal query answering w.r.t. ontologies formulated in DL-Lite, a family of description logics that captures the conceptual features of relational databases and was tailored for efficient query answering. We consider a recently proposed temporal query language that combines conjunctive queries with the operators of propositional linear temporal logic (LTL). In particular, we consider negation in the ontology and query language, and study both data and combined complexity of query entailment.

Formulae of linear temporal logic (LTL) can be used to specify (wanted or unwanted) properties of a dynamical system. In model checking, the system’s behaviour is described by a transition system, and one needs to check whether all possible traces of this transition system satisfy the formula. In runtime verification, one observes the actual system behaviour, which at any point in time yields a finite prefix of a trace. The task is then to check whether all continuations of this prefix to a trace satisfy (violate) the formula. More precisely, one wants to construct a monitor, i.e., a finite automaton that receives the finite prefix as input and then gives the right answer based on the state currently reached. In this paper, we extend the known approaches to LTL runtime verification in two directions. First, instead of propositional LTL we use the more expressive temporal logic ALC-LTL, which can use axioms of the Description Logic (DL) ALC instead of propositional variables to describe properties of single states of the system. Second, instead of assuming that the observed system behaviour provides us with complete information about the states of the system, we assume that states are described in an incomplete way by ALC-knowledge bases. We show that also in this setting monitors can effectively be constructed. The (double-exponential) size of the constructed monitors is in fact optimal, and not higher than in the propositional case. As an auxiliary result, we show how to construct Büchi automata for ALC-LTL-formulae, which yields alternative proofs for the known upper bounds of deciding satisfiability in ALC-LTL.