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In Drosophila melanogaster, the transcription factor Dorsal initiates dorsal-ventral (DV) patterning in the early embryo by activating or repressing genes, such as the transcription factors Twist and Snail, along the DV axis. Previous studies have shown that the microRNA gene miR-184 in the ventral portion of the embryos (the prospective mesoderm) at the early stages of Drosophila embryogenesis. In order to identify the tissue-specific enhancer that regulates miR-184 expression in the mesoderm, we generated transgenic fly lines and observed the expression of a reporter gene under the control of a potential cis-regulatory module (CRM). Our results show that this CRM is responsible for the regulation of miR-184 and furthermore, it is activated by Twist. / Biology

In Indian Classical Music (ICM), the Raga is a musical piece's melodic framework. It encompasses the characteristics of a scale, a mode, and a tune, with none of them fully describing it, rendering the Raga a unique concept in ICM. The Raga provides musicians with a melodic fabric, within which all compositions and improvisations must take place. Identifying and categorizing the Raga is challenging due to its dynamism and complex structure as well as the polyphonic nature of ICM. Hence, Raga recognition—identify the constituent Raga in an audio file—has become an important problem in music informatics with several known prior approaches. Advancing the state of the art in Raga recognition paves the way to improving other Music Information Retrieval tasks in ICM, including transcribing notes automatically, recommending music, and organizing large databases. This thesis presents a novel melodic pattern-based approach to recognizing Ragas by representing this task as a document classification problem, solved by applying a deep learning technique. A digital audio excerpt is hierarchically processed and split into subsequences and gamaka sequences to mimic a textual document structure, so our model can learn the resulting tonal and temporal sequence patterns using a Recurrent Neural Network. Although training and testing on these smaller sequences, we predict the Raga for the entire audio excerpt, with the accuracy of 90.3% for the Carnatic Music Dataset and 95.6% for the Hindustani Music Dataset, thus outperforming prior approaches in Raga recognition. / Master of Science / In Indian Classical Music (ICM), the Raga is a musical piece's melodic framework. The Raga is a unique concept in ICM, not fully described by any of the fundamental concepts of Western classical music. The Raga provides musicians with a melodic fabric, within which all compositions and improvisations must take place. Raga recognition refers to identifying the constituent Raga in an audio file, a challenging and important problem with several known prior approaches and applications in Music Information Retrieval. This thesis presents a novel approach to recognizing Ragas by representing this task as a document classification problem, solved by applying a deep learning technique. A digital audio excerpt is processed into a textual document structure, from which the constituent Raga is learned. Based on the evaluation with third-party datasets, our recognition approach achieves high accuracy, thus outperforming prior approaches.

Yes / Multiple factors and conditions can lead to impaired wound healing. Chronic non-healing wounds are a common problem among the elderly. To identify microRNAs negatively impacting the wound repair, global miRNA profiling of wounds collected from young and old mice was performed. A subset of miRNAs that exhibited an age-dependent expression pattern during wound closure was identified, including miR-31 and miR-200c. The expression of miR-200 family members was markedly downregulated upon wounding in both young and aged mice, with an exception of acute upregulation of miR-200c at the early phase of wound healing in aged skin. In unwounded aged skin (versus unwounded younger skin), the level of miR-200c was also found elevated in both human and mice. Overexpression of miR-200c in human ex vivo wounds delayed re-epithelialisation and inhibited cell proliferation in the wound epithelium. Modulation of miR-200c expression in both human and mouse keratinocytes in vitro revealed inhibitory effects of miR-200c on migration, but not proliferation. Accelerated wound closure in vitro induced by anti-miR-200c was associated with upregulation of genes controlling cell migration. Thus, our study identified miR-200c as a critical determinant that inhibits cell migration during skin repair after injury and may contribute to ageassociated alterations in wound repair. / Supported by a grant from Medical Research Council UK (MR/K011324/1)

Le carcinome rénal à cellules claires (cRCC) est le principal type histologique de carcinome rénal et l'une des tumeurs les plus résistantes à la chimio et à la radiothérapie. L'absence de biomarqueurs pour la détection précoce et pour le suivi des patients est responsable d'un mauvais pronostic. Il est nécessaire d'identifier de nouveaux biomarqueurs et des cibles thérapeutiques pour améliorer la prise en charge des patients. Les microARNs, des petits ARN non codants de 22 nucléotides, qui ont été précédemment montrés comme favorisant l'initiation et la progression tumoral, semblent être de bons candidats. Nous avons focalisé notre étude sur (i) miR-21 qui est le principal oncomiR surexprimé dans le cRCC et (ii) le récepteur nucléaire PPARα (Peroxisome Proliferator Activated Receptor), l'une des cibles de miR-21.D'une part, sur une cohorte de 99 échantillons de cRCC primaires, nous avons montré que l'expression de miR-21 était plus élevée dans les tissus cancéreux que dans les tissus non tumoraux adjacents. In vitro, miR-21 est également surexprimé dans les lignées cellulaires de carcinomes rénaux comparées à la lignée cellulaire épithéliale HK-2 provenant de tubes proximaux humains. De plus, nous avons également montré que la surexpression de miR-21 augmente les propriétés de migration et d'invasion des cellules cancéreuses rénales ainsi que les voies de signalisation prolifératives et anti-apoptotiques, alors que des résultats opposés ont été observés en utilisant une stratégie d'inhibition anti-miR-21. Enfin, nous avons évalué le rôle du miR-21 dans la chimiorésistance du cRCC et montré, en outre, que l'inhibition de miR-21 augmentait significativement la chimiosensibilité au paclitaxel, au 5-fluorouracile, à l'oxaliplatine et au dovitinib, diminuait l'expression des transporteurs à efflux MRP1-6/ABCC1-6 et augmentait l'expression des transporteurs à influx SLC22A1/OCT1, SLC22A2/OCT2 et SLC31A1/CTR1. Ces résultats ont permis la publication d'un article dans Tumor Biology se trouvant en annexe.D'autre part, dans les tissus de patients atteints de cRCC, nous avons montré pour la première fois que la surexpression de miR-21 est en corrélation avec une perte d'expression de PPARα. In vitro, nous avons montré que miR-21 cible le 3'-UTR de PPARα et diminue son expression protéique et que la surexpression de miR-21 diminue l'activité transcriptionnelle de PPARα. En outre, la surexpression et l'activation de PPARα diminuent l'expression de miR-21. En effet, PPARα interagit avec les facteurs de transcription AP-1 et NF-κB et empêche ainsi leur liaison au promoteur de miR-21 diminuant ainsi sa transcription.En conclusion, nous avons montré que (i) miR-21 est un acteur clé de la progression du cancer du rein et joue un rôle important dans la résistance aux chimiothérapies et (ii) qu'il existe une boucle de régulation négative entre miR-21 et PPARα dans le cRCC. / Renal clear cell carcinoma (cRCC) is the major histological type of renal carcinoma and one of the most chemo- and radio-resistant tumors. The absence of biomarkers for early detection and for monitoring patients is responsible of a poor prognosis. It is necessary to identify new biomarkers and therapeutic targets to improve patient care. MicroRNAs, small noncoding RNAs of 22 nucleotides, which have been previously shown to promote malignant initiation and progression, appear to be good candidates.We focused our study on (i) miR-21 which is the main overexpressed oncomirs in cRCC and (ii) the nuclear receptor PPARα (Peroxisome Proliferator Activated Receptor), one of miR-21 targets.In one hand, by using a cohort of 99 primary cRCC samples, we showed that miR-21 expression in cancer tissues was higher than in adjacent non-tumor tissues. In vitro, miR-21 was also overexpressed in renal carcinoma cell lines compared to HK-2 human proximal tubule epithelial cell line. Moreover, we also showed that miR-21 overexpression increased migratory, invasive, proliferative, and anti-apoptotic signaling pathways whereas opposite results were observed using an anti-miR-21-based silencing strategy. Finally, we assessed the role of miR-21 in mediating cRCC chemoresistance and further showed that miR-21 silencing significantly increased chemosensitivity of paclitaxel, 5-fluorouracil, oxaliplatin and dovitinib, decreased expression of multi-drug resistance genes and increased SLC22A1/OCT1, SLC22A2/OCT2 and SLC31A1/CTR1 platinum influx transporter expression. These results led to the publication of an article in Tumor Biology in annex.In other hand, in cRCC tissue patients, we showed for the first time that miR-21 overexpression correlates with a loss of expression of PPARα. In vitro, we showed that miR-21 targets PPARα 3'-UTR and decreases its protein expression and miR-21 overexpression decreases the transcriptional activity of PPARα. Furthermore, PPARα overexpression and activation decrease miR-21 expression. In fact, PPARα interacts with AP-1 and NF-kappaB transcription factors and thus prevents their binding to the miR-21 promoter thus decreasing its transcription.In conclusion, we have shown that (i) miR-21 is a key actor of renal cancer progression and plays an important role in the resistance to chemotherapeutic drugs and (ii) there is a negative regulatory loop between miR-21 and PPARα in cRCC.

Cette recherche propose d’étudier la transmission de l’attachement d’une génération à l’autre dans une population spécifique, ainsi que le rôle de la résilience dans cette transmission. Dans une approche psychodynamique et systémique, nous questionnons l’impact du passé de la première génération sur leur parentalité et sur leurs enfants. Nous nous appuyons sur deux postulats concernant la première génération. Le premier concerne le passé familial et le contexte du placement qui constituent une expérience traumatique. Selon le deuxième postulat, les personnes de notre corpus clinique sont inscrites dans un processus de résilience. La population est composée de 24 sujets de la première génération (G1) dont la particularité réside dans le fait que dans leur petite enfance, ils ont été séparés de leurs familles d’origine et placés. La recherche inclut également 20 sujets adultes (G2), qui sont des enfants des personnes placées (G1). Un entretien semi-directif et le test Ca-MIR de Pierrehumbert et al. (1996) représentent des outils principaux. Les données recueillies ont fait l’objet d’une analyse catégorielle, des traitements statistiques et d’une analyse avec le logiciel Alceste de Reinert (1993). Nos résultats confirment nos postulats et indiquent une nette amélioration de la qualité de l’attachement à la deuxième génération. Tandis que plus de 70% de la G1 sont insécures, 95% de la G2 utilisent la stratégie primaire sécure. Cependant, l’attachement des sujets ayant subi un trauma demeure invariable, malgré des relations ultérieures sécurisantes. La deuxième génération, bien que sécure, porte en elle la blessure faite au parent. Ces résultats nous amènent à reconsidérer la transmission intergénérationnelle de l’attachement et à ajuster le soutien à la parentalité proposé aux personnes ayant été séparées et placées durant leur petite enfance. / This study suggests studying the transmission of the attachment from one generation to another in a specific population, and the role of resilience in this transmission. In a psychodynamic and systemic approach, we observe the impact of the past of the first generation to their parenthood and to their children. Our research relies on two premises. The first is that the family history and the context of foster care is a traumatic experience. According to the second postulate, the people of our clinical corpus are founded in a process of resilience. Our population is composed of 24 subjects of the first generation (G1) whose peculiarity consists in the fact that in their infancy, they were separated from their families of origin and lived in a foster care. The research also includes 20 adult subjects (G2), who are children of the foster persons (G1).A semi-structured interview and the test of Ca-MIR Pierrehumbert et al. (1996) represent the main tools. The data collected were subject to a category-specific analysis, statistical processing and analysis software with Alceste Reinert (1993). Our results confirm our assumptions and indicate a marked improvement in the quality of attachment to the second generation. While over 70% of the G1 are insecure, 95% of the G2 use the secure primary strategy. However, the attachment of subjects who suffered trauma remains unchanged despite subsequent relations reassuring. The second generation, although secure, holds the injury done to the parent. These results lead us to reconsider the intergenerational transmission of attachment and to adjust the parenting support offered to the people who came from foster care.