Aujourd’hui, l’usage des données lié aux services et contenus proposés sur Internet est en croissance continue et les opérateurs de télécommunications font face à une demande croissante en connectivité. Dans ce contexte, il est indispensable que la transition vers les réseaux très haut débit soit gérée de manière efficace afin de préserver, voire incrémenter, le niveau de concurrence sur le marché ainsi que maximiser l’investissement efficace au bénéfice des consommateurs à travers une combinaison appropriée de différentes formes de concurrence, de différentes technologies et d’investissement à la fois privé et public. Si accompagnée de manière efficace, cette transition peut représenter une grande opportunité pour les marchés des télécommunications européens, les transformant en marchés modernes et concurrentiels et permettant à la régulation ex ante de se retirer progressivement. Nous passons en revue les cadres institutionnels et réglementaires pour les réseaux d’accès fixes de nouvelle génération implémentés en France, Allemagne, Italie, Royaume-Uni et Espagne. A partir d’un modèle de concurrence calibré, nous simulons l’évolution des marchés à horizon 2050 et analysons dans quelle mesure ces cadres paraissent efficaces afin de restituer les meilleurs résultats pour le secteur et pour les consommateurs. Les résultats de notre modèle calibré suggèrent que, afin d’obtenir des meilleurs résultats en terme de bien-être total de long-terme, dans des proportions plus ou moins grandes, certains ajustements pourraient être introduits dans les cadres institutionnels et réglementaires considérés.Nous formulons ainsi, pour chacun des pays analysés, des recommandations visant à accélérer la couverture en très haut débit et à améliorer le niveau de concurrence. / Today, data usage driven by content and service providers over the Internet is constantly increasing and telecoms operators are expected to meet an increasing demand for connectivity. In this context, it is vital that the transition between legacy and ultrabroadband networks is properly managed in order both to preserve or improve the state of competition in the market and to maximize efficient investment to the benefit of consumers through an appropriate combination of different forms of competition, of different technologies and of private and public investment. If properly accompanied, the transition from legacy to next generation access networks can represent a major opportunity for the current European telecommunications markets, definitively transforming them into competitive and modern markets and allowing ex ante regulation to progressively step-back.We review the institutional and regulatory frameworks for fixed next generation access networks currently implemented in France, Germany, Italy, United Kingdom and Spain. Based on a calibrated competition model, we simulate market evolution up to 2050 and appraise to what extent these frameworks seem effective in order to achieve the best long-term results both for the industry and for consumers. The results of our calibrated model suggest that, to a greater or lesser extent, some adjustments might be introduced in the above-mentioned frameworks in order to achieve better outcomes in terms of total welfare in the long run. For each of the countries reviewed, we formulate policy recommendations aimed to accelerate NGA coverage and to improve the state of competition in ultrabroadband.

Introduction : Les dyschromies cutanées en mosaïque ont fait suspecter de longue date l’implication d’un mosaïcisme génétique sous-jacent. Ces évènements post-zygotiques sont cependant difficilement détectables par les techniques conventionnelles. Ainsi, les bases génétiques des dyschromies en mosaïque étaient restées mal connues. Matériel et méthodes : la cohorte M.U.S.T.A.R.D rassemble des échantillons d’ADN de biopsies cutanées de patients porteurs d’un mosaïcisme pigmentaire. Après une analyse phénotypique spécialisée, ces échantillons sont étudiés en séquençage à forte profondeur, d’exome (ES) en trio, ou ciblé. Les données sont analysées à l’aide d’un pipeline dédié, permettant la détection de variations ponctuelles en mosaïque (mSNV) mais également de diverses anomalies chromosomiques en mosaïque. Résultats : De 2013 à 2019, 101 patients ont été inclus. Un ES a été réalisé pour 56 patients, identifiant un mSNV chez 12 patients, dans 7 gènes dont 4 nouveaux (RHOA, DOCK1, GNA13, TFE3), et une anomalie chromosomique chez 17 patients. Une étude ciblée de ces gènes chez 40 autres patients était positive pour 17, soit un rendement diagnostique global à 55% (46/84). Conclusion : Ce travail illustre l’importance d’une approche bioinformatique polyvalente, combinée à une expertise clinique, pour la détermination des causes génétiques des dyschromies cutanées en mosaïque. Il a également mis en évidence le rôle de la voie de signalisation dépendant des Rho GTPases, faisant progresser notre compréhension de la physiopathologie des dyschromies en mosaïque, une étape nécessaire à l’amélioration de la prise en charge de ces patients porteurs de maladies rares et complexes. / Introduction: Mosaic cutaneous dyschromia is strongly evocative of an underlying genetic mosaicism. These post-zygotic events are challenging for conventional diagnostic tools. Thus, genetic basis of mosaic cutaneous dyschromia still remained poorly understood. Materials and Methods: The M.U.S.T.A.R.D. cohort gathers DNA from skin biopsies of patients with mosaic cutaneous dyschromia. After a specialised phenotype analysis, they are referred to either trio exome sequencing (ES) at 200X, or targeted ultra-deep sequencing (60,000X) of candidate genes. Data are analysed with a tailored pipeline, allowing detection of both low-rate nucleotidic variations or chromosomal events. Results: From 2013 to 2019, 101 patients were included. ES was performed for 56, with identification of mosaic SNV in 12 patients in 7 new genes, including 4 new genes (RHOA, DOCK1, GNA13, TFE3), and mosaic chromosomal anomalies in 17 patients. A targeted sequencing of these genes was performed for 40 more patients, with a confirmed mosaic SNV in 17, and a global diagnostic yield of 55% (46/84). Conclusion: This work highlights the importance of a versatile bioinformatic approach combined to a clinical expertise, to decipher the chromosomal and molecular aetiologies of developmental anomalies with mosaic cutaneous dyschromia. It also pinpoints the role of the Rho GTPase pathway, which will help enhancing our understanding of mosaic cutaneous dyschromia, and may ultimately result in better patients’ care.

Gut microbiota is considered an important factor in the development of various diseases including inflammatory bowel disease (IBD, n = 127), Ulcerative colitis, Crohn's disease, and colorectal cancer (CRC, n = 64). A part of this thtesis is to prepare clinical material of different sorts (stool, biopsy) for sequencing on Illumina Miseq platform. This is achieved trough DNA isolation, amplification of 16S and internal transcribed spacer (ITS), normalization and ligation of sequencing adaptors. The aim of this project is to describe the differences between microbiota in healthy and diseased subjects in case of IBD or unimpaired and tumorous tissue for CRC patients. This research is also being based on cultivation, where a fresh stool samples (n = 3) are cultivated in a broad range of conditions, which enables us to obtain ecophysiological and species diversity of these samples by traditional and molecular methods. The cultivable fungi are also assigned reliable taxonomy by amplification of relevant genes (ITS1, β tubulin, second largest subunit of RNA polymerase II, RPB2) followed by both-sided Sanger sequencing. Selected species of fungi are processed into lysates, which are used for stimulation of mice macrofage cell line (RAW). Therefore the impact on immunity response is studied in vitro and...

A geological repository for spent nuclear fuel (SNF) and an associated encapsulation facility will be built in Sweden.  The encapsulation facility is planned to be in operation in 2025 and it will be the last place where verifying safeguards measurements of SNF can be performed. It is not clear what types of measurements that will be performed, because such requirements are not yet posed by national and international authorities and inspecting organizations. This report describes the objective and most recent results of a master thesis project, whereby a few existing non-destructive assay techniques for verifying SNF are selected for a review. The study focuses on the verifying ability of different techniques, or system of techniques in relation to the requirement that may be put on the future encapsulation plant. In addition, possible needs for future simulations and measurements are discussed. The work is done as a collaboration between Uppsala University in Sweden and Los Alamos National Laboratory in the USA.

L’arrivée récente de l’immunothérapie a bouleversé la prise en charge des cancers broncho-pulmonaires non à petites cellules (CBNPC). Le nivolumab, anticorps inhibiteur du point de contrôle immunitaire PD-1, a montré des résultats remarquables en deuxième ligne métastatique après échec des chimiothérapies standards de première intention. Cependant, seul un quart des patients tire un bénéfice durable de la prise de ce traitement. `A ce jour, aucun biomarqueur prédictif de l'efficacité thérapeutique du nivolumab n'a pu être identifié de manière claire et consensuelle. La recherche de biomarqueurs prédictifs de bénéfice ou de résistance à ce traitement répresente donc un enjeu majeur.L’apparition du séquençage à haut débit au cours de la dernière décennie a eu un impact considérable sur la recherche clinique et fondamentale, permettant d’appréhender la génétique d’une tumeur dans son ensemble. Ces nouvelles techniques s’ajoutent à d’autres déjà éprouvées telles que l’immunophénotypage ou l’immunohistochimie à disposition des chercheurs pour une analyse extensive des caractéristiques de la tumeur et du patient.L’objectif de ce travail a été d’identifier des marqueurs prédictifs d’efficacité du nivolumab dans le traitement des CBNPC avancés au moyen de ces différentes technologies. Pour cela, notre étude s'est alors intéressée à une cohorte multicentrique de 115 patients atteints de CBNPC et traités par nivolumab en deuxième ou troisième ligne métastatique après échec d'un doublet cytotoxique. Dans les limites de disponibilité et de qualité des échantillons, les profils génétique, transcriptomique et immunohistochimique de la tumeur ainsi que les profils clinique et immunologique des patients ont été analysés.Nos résultats mettent en évidence des marqueurs prédictifs majeurs de réponse au nivolumab. Ainsi, une bonne réponse au doublet cytotoxique de première intention favorise une efficacité optimale du nivolumab en ligne ultérieure. Par ailleurs, un contrôle régulier de l'évolution des cellules myéloïdes immunosuppresives et des cellules cytotoxiques exprimant TIM-3 d'un patient permet de détecter une résistance primaire ou secondaire au traitement. D'autre part, l'estimation conjointe des expressions des protéines PD-L1 et CD8 par séquençage d'ARN constitue un marqueur prédictif majeur de réponse. Sa capacité prédictive surpasse celle de l'estimation de PD-L1 seule et celle d'autres signatures transcriptomiques précédemment établies et composées d'un nombre plus important de gènes. Enfin, l'étude des séquençages d'exome des tumeurs montre l'importance d'une analyse étendue de la génétique tumorale et la nécessité de ne pas se limiter à l'estimation de sa charge mutationnelle.Dans ce travail, nous avons pu mettre en évidence des marqueurs prédictifs d'efficacité du nivolumab dans le traitement des CBNPC avancés. Nos résultats soulignent l'importance de l'utilisation de plusieurs technologies pour la caractérisation de la biologie tumorale et de l'immunité du patient dans une démarche de découverte de biomarqueurs et de construction de modèles prédictifs d'efficacité des immunothérapies. / The recent introduction of immunotherapy has disrupted the management of non-small cell lung cancer (NSCLC). Nivolumab, an antibody targeting the immune checkpoint inhibitor PD-1, has shown remarkable results in seconde-line setting after failure of standard first-line chemotherapy. However, only a quarter of patients benefits from this therapy. To date, no predictive biomarker of the therapeutic efficacy of nivolumab has been identified in a clear and consensual manner. The research for predictive biomarkers of efficacy or resistance to this treatment is, therefore, a major challenge.The emergence of high-throughput sequencing over the past decade has had a significant impact on clinical and fundamental research, making possible to understand the genetics of a tumor as a whole. These new techniques are in addition to other already proven techniques such as immunophenotyping or immunohistochemistry available to researchers for extensive analysis of tumor and patient characteristics.The objective of this work was to identify predictors of the efficacy of nivolumab in the treatment of advanced NSCLC using these different technologies. To do this, our study focused on a multicentre cohort of 115 NSCLC patients treated with nivolumab in the second- or third-line after failure of a cytotoxic doublet. Within the limits of sample availability and quality, the genetic, transcriptomic and immunohistochemical profiles of the tumor as well as the clinical and immunological profiles of the patients were analysed.Our results highlight major predictive markers of response to nivolumab. Thus, a good response to the first-line cytotoxic doublet promotes optimal efficacy of subsequent online nivolumab. In addition, regular monitoring of the evolution of a patient's immunosuppressive myeloid cells and cytotoxic cells expressing TIM-3 can detect primary or secondary resistance to treatment. On the other hand, the joint estimation of PD-L1 and CD8 protein expressions by RNA sequencing is a major predictive marker of response. Its predictive capacity surpasses that of the PD-L1 estimate alone and that of other previously established transcriptomic signatures composed of a larger number of genes. Finally, the study of tumor exome sequencing shows the importance of extensive analysis of tumor genetics and the need not only to focus on the estimation its mutation burden.In this work, we were able to identify predictive markers of the efficacy of nivolumab in the treatment of advanced NSCLC. Our results highlight the importance of using several technologies for the characterization of tumor biology and patient immunity in a process of biomarker discovery and the construction of predictive models of the efficacy of immunotherapies.

As the field of next-generation sequencing (NGS) matures and the technology grows more advanced, it is becoming an increasingly strong tool for solving various biological problems. Harvesting and analysing the full genomic sequence of an individual and comparing it to a reference genome can unravel information about detrimental mutations, in particular ones that give rise to diseases such as cancer. At the Rudbeck Laboratory, Uppsala University, a fully automatic software pipeline for somatic mutational analysis of cancer patient sequence data is in development. This will increase the efficiency and accuracy of a process which today consists of several discrete computation steps. In turn, this will reduce the time to result and facilitate the process of making a diagnosis and delegate the optimal treatment for the patient. However, the genomic data of an individual is very sensitive and private, which demands that great security precautions are taken. Moreover, as more and more data are produced storage space is becoming increasingly valuable, which requires that data are handled and stored as efficiently as possible. In this project, I developed a Python pipeline for automatic compression and encryption of NGS alignment data, which aims to ensure full privacy protection of patient data while maintaining high computational and storage efficiency. The pipeline uses a state-of-the-art real-time compression algorithm combined with an Advanced Encryption Standard cipher. It offers security that meets rigorous modern standards, and performance which at least matches that of existing solutions. The system is made to be easily integrated in the somatic mutation analysis pipeline. This way, the data generated during the analysis, which are too large to be kept in operational memory, can safely be stored to disk.

A list of genes have been identified to carry mutations causing familial ALS such as SOD1, TARDBP, C9orf72. But for sporadic ALS, which is 90% of all ALS cases, the underlying genetic variants are still largely unknown. There are multiple genome-wide association study (GWAS) for sporadic ALS, but usually a large number nominated SNP can hardly be replicated in larger cohort analysis. Also majority of GWAS SNP lie within noncoding region of genome, imposing a huge challenge to study their biological role in ALS pathology. With the rapid development of next-generation sequencing technology, we are able to sequence exome and whole-genome of a large number of ALS patients to search for novel genetic variants and their potential biological function. Here by analyzing exam data, we discovered two novel or extremely rare missense mutations of DPP6 from a Mestizo Mexican ALS family. We showed the two mutations could exert loss-of-function effect by affecting electrophysiological properties of Potassium channels as well as the membrane localization of DPP6. To our knowledge this is the first report of DPP6 nonsynonymous mutations in familial ALS patients. In addition, by analyzing whole-genome data, we discovered strong linkage disequilibrium between SNP rs12608932, a repeatedly significant ALS GWAS signal, and one polymorphic TGGA tetra-nucleotide tandem repeat, which is further flanked by large TGGA repetitive sequences. We also demonstrated rs12608932 risk allele is associated with reduced UNC13A expression level in human cerebellum and UNC13A knockout could lead to shorter survival in SOD1-G93A ALS mice. Thus the TGGA repeat might be the real underlying genetic variation that confer risk to sporadic ALS.

Le secteur des télécommunications passe par une phase délicate en raison de profondes mutations technologiques, principalement motivées par le développement de l'Internet. Elles ont un impact majeur sur l'industrie des télécommunications dans son ensemble et, par conséquent, sur les futurs déploiements des nouveaux réseaux, plateformes et services. L'évolution de l'Internet a un impact particulièrement fort sur les opérateurs des télécommunications (Telcos). En fait, l'industrie des télécommunications est à la veille de changements majeurs en raison de nombreux facteurs, comme par exemple la banalisation progressive de la connectivité, la domination dans le domaine des services de sociétés du web (Webcos), l'importance croissante de solutions à base de logiciels et la flexibilité qu'elles introduisent (par rapport au système statique des opérateurs télécoms). Cette thèse élabore, propose et compare les scénarios possibles basés sur des solutions et des approches qui sont technologiquement viables. Les scénarios identifiés couvrent un large éventail de possibilités: 1) Telco traditionnel; 2) Telco transporteur de Bits; 3) Telco facilitateur de Plateforme; 4) Telco fournisseur de services; 5) Disparition des Telco. Pour chaque scénario, une plateforme viable (selon le point de vue des opérateurs télécoms) est décrite avec ses avantages potentiels et le portefeuille de services qui pourraient être fournis / The telecommunications industry is going through a difficult phase because of profound technological changes, mainly originated by the development of the Internet. They have a major impact on the telecommunications industry as a whole and, consequently, the future deployment of new networks, platforms and services. The evolution of the Internet has a particularly strong impact on telecommunications operators (Telcos). In fact, the telecommunications industry is on the verge of major changes due to many factors, such as the gradual commoditization of connectivity, the dominance of web services companies (Webcos), the growing importance of software based solutions that introduce flexibility (compared to static system of telecom operators). This thesis develops, proposes and compares plausible future scenarios based on future solutions and approaches that will be technologically feasible and viable. Identified scenarios cover a wide range of possibilities: 1) Traditional Telco; 2) Telco as Bit Carrier; 3) Telco as Platform Provider; 4) Telco as Service Provider; 5) Telco Disappearance. For each scenario, a viable platform (from the point of view of telecom operators) is described highlighting the enabled service portfolio and its potential benefits

The majority of Grade 5 students demonstrate limited science knowledge on state assessments. This trend has been documented since 2010 with no evidence of improvement. Because state accountability formulas include proficiency scores and carry sanctions against districts that fail to meet proficiency thresholds, improved student performance in science is an important issue to school districts. The purpose of this study was to explore elementary teachers' perceptions about their students' science knowledge, the strategies used to teach science, the barriers affecting science teaching, and the self-efficacy beliefs teachers maintain for teaching science. This study, guided by Vygotsky's social constructivist theory and Bandura's concept of self-efficacy, was a bounded instrumental case study in which 15 participants, required to be teaching K-5 elementary science in the county, were interviewed. An analytic technique was used to review the qualitative interview data through open coding, clustering, and analytical coding resulting in identified categorical themes that addressed the research questions. Key findings reflect students' limited content knowledge in earth and physical science. Teachers identified barriers including limited science instructional time, poor curricular resources, few professional learning opportunities, concern about new state standards, and a lack of teaching confidence. To improve student content knowledge, teachers identified the need for professional development. The project is a professional development series provided by a regional education service agency for K-5 teachers to experience science and engineering 3-dimensional learning. Area students will demonstrate deeper science content knowledge and benefit from improved science instructional practice and learning opportunities to become science problem solvers and innovative contributors to society.

Indiana University-Purdue University Indianapolis (IUPUI) / Triple-negative breast cancers (TNBCs) are pathologically defined by the absence of estrogen, progesterone, and HER2 receptors. Compared to other breast cancers, TNBC has a relatively high mortality. In addition, TNBC patients are more likely to relapse in the first few years after treatment, and experiencing a shorter median time from recurrence to death. Detecting the presence of tumor in patients who are technically “disease-free” after neoadjuvant chemotherapy and surgery as early as possible might be able to predict recurrence of patients, and then provide timely intervention for additional therapy. To this end, I applied the analysis of “liquid biopsies” for early detection of minimal residual disease (MRD) on early-stage TNBC patients using next-generation sequencing. For the first part of this study, I focused on detecting circulating tumor DNA (ctDNA) from TNBC patients after neoadjuvant chemotherapy and surgery. First, patient-specific somatic mutations were identified by sequencing primary tumors. From these data, 82% of the patients had at least one TP53 mutation, followed by 16% of the patients having at least one PIK3CA mutation. Next, I sequenced matched plasma samples collected after surgery to identify ctDNA with the same mutations. I observed that by detecting corresponding ctDNA I was able to predict rapid recurrence, but not distant recurrence. To increase the sensitivity of MRD detection, in the second part I developed a strategy to co-detect ctDNA along with circulating tumor RNA (ctRNA). An advantage of ctRNA is its active release into the circulation from living cancer cells. Preliminary data showed that more mutant molecules were identified after incorporating ctRNA with ctDNA detection in a metastatic breast cancer setting. A validation study in early-stage TNBC is in progress. In summary, my study suggests that co-detection of ctDNA and ctRNA could be a potential solution for the early detection of disease recurrence. / 2021-08-05