Analyse mathématique de modèles de trafic routier congestionné

This thesis is devoted to the mathematical analysis of some models of congested road traffic. The essential notion is the Wardrop equilibrium. It continues Carlier and Santambrogio's works with coauthors. With Baillon they studied the case of two-dimensional cartesian networks that become very dense in the framework of Γ-convergence theory. Finding Wardrop equilibria is equivalent to solve convex minimisation problems. In Chapter 2 we look at what happens in the case of general networks, increasingly dense. New difficulties appear with respect to the original case of cartesian networks. To deal with these difficulties we introduce the concept of generalized curves. Structural assumptions on these sequences of discrete networks are necessary to obtain convergence. Sorts of Finsler distance are used and keep track of anisotropy of the network. We then have similar results to those in the cartesian case. In Chapter 3 we study the continuous model and in particular the limit problems. Then we find optimality conditions through a duale formulation that can be interpreted in terms of continuous Wardrop equilibria. However we work with generalized curves and we cannot directly apply Prokhorov's theorem, as in [Baillon and Carlier]. To use it we consider a relaxed version of the limit problem with Young's measures. In Chapter 4 we focus on the long-term case, that is, we fix only the distributions of supply and demand. As shown in [Brasco] the problem of Wardrop equilibria can be reformulated in a problem à la Beckmann and reduced to solve an elliptic anisotropic and degenerated PDE. We use the augmented Lagrangian scheme presented in [Benamou] to show a few numerical simulation examples. Finally Chapter 5 is devoted to studying Monge problems with as cost a Finsler distance. It leads to minimal flow problems. Discretization of these problems is equivalent to a saddle-point problem. We then solve it numerically again by an augmented Lagrangian algorithm.Cette thèse est dédiée à l'étude mathématique de quelques modèles de trafic routier congestionné. La notion essentielle est l'équilibre de Wardrop. Elle poursuit des travaux de Carlier et Santambrogio avec des coauteurs. Baillon et Carlier ont étudié le cas de grilles cartésiennes dans ℝ² de plus en plus denses, dans le cadre de la théorie de Γ-convergence. Trouver l'équilibre de Wardrop revient à résoudre des problèmes de minimisation convexe. Dans le chapitre 2, nous regardons ce qui se passe dans le cas de réseaux généraux, de plus en plus denses, dans ℝ^d. Des difficultés nouvelles surgissent par rapport au cas initial de réseaux cartésiens et pour les contourner, nous introduisons la notion de courbes généralisées. Des hypothèses structurelles sur ces suites de réseaux discrets sont nécessaires pour s'assurer de la convergence. Cela fait alors apparaître des fonctions qui sont des sortes de distances de Finsler et qui rendent compte de l'anisotropie du réseau. Nous obtenons ainsi des résultats similaires à ceux du cas cartésien. Dans le chapitre 3, nous étudions le modèle continu et en particulier, les problèmes limites. Nous trouvons alors des conditions d'optimalité à travers une formulation duale qui peut être interprétée en termes d'équilibres continus de Wardrop. Cependant, nous travaillons avec des courbes généralisées et nous ne pouvons pas appliquer directement le théorème de Prokhorov, comme cela a été le cas dans [Baillon et Carlier]. Pour pouvoir néanmoins l'utiliser, nous considérons une version relaxée du problème limite, avec des mesures d'Young. Dans le chapitre 4, nous nous concentrons sur le cas de long terme, c'est-à-dire, nous fixons uniquement les distributions d'offre et de demande. Comme montré dans [Brasco], le problème de l'équilibre de Wardrop est équivalent à un problème à la Beckmann et il se réduit à résoudre une EDP elliptique, anisotropique et dégénérée. Nous utilisons la méthode de résolution numérique de Lagrangien augmenté présentée dans [Benamou] pour proposer des exemples de simulation. Enfin, le chapitre 5 a pour objet l'étude de problèmes de Monge avec comme coût une distance de Finsler. Cela se reformule en des problèmes de flux minimal et une discrétisation de ces problèmes mène à un problème de point-selle. Nous le résolvons alors numériquement, encore grâce à un algorithme de Lagrangien augmenté

BRCA1 Recruitment to Transcriptional Pause Sites Is Required for R-Loop-Driven DNA Damage Repair

The mechanisms contributing to transcription-associated genomic instability are both complex and incompletely understood. Although R-loops are normal transcriptional intermediates, they are also associated with genomic instability. Here, we show that BRCA1 is recruited to R-loops that form normally over a subset of transcription termination regions. There it mediates the recruitment of a specific, physiological binding partner, senataxin (SETX). Disruption of this complex led to R-loop-driven DNA damage at those loci as reflected by adjacent γ-H2AX accumulation and ssDNA breaks within the untranscribed strand of relevant R-loop structures. Genome-wide analysis revealed widespread BRCA1 binding enrichment at R-loop-rich termination regions (TRs) of actively transcribed genes. Strikingly, within some of these genes in BRCA1 null breast tumors, there are specific insertion/deletion mutations located close to R-loop-mediated BRCA1 binding sites within TRs. Thus, BRCA1/SETX complexes support a DNA repair mechanism that addresses R-loop-based DNA damage at transcriptional pause sites

Lineage-specific genes are prominent DNA damage hotspots during leukemic transformation of B cell precursors

In human leukemia, lineage-specific genes represent predominant targets of deletion, with lymphoid-specific genes frequently affected in lymphoid leukemia and myeloid-specific genes in myeloid leukemia. To investigate the basis of lineage-specific alterations, we analyzed global DNA damage in primary B cell precursors expressing leukemia-inducing oncogenes by ChIP-seq. We identified more than 1,000 sensitive regions, of which B lineage-specific genes constitute the most prominent targets. Identified hotspots at B lineage genes relate to DNA-DSBs, affect genes that harbor genomic lesions in human leukemia, and associate with ectopic deletion in successfully transformed cells. Furthermore, we show that most identified regions overlap with gene bodies of highly expressed genes and that induction of a myeloid lineage phenotype in transformed B cell precursors promotes de novo DNA damage at myeloid loci. Hence, we demonstrate that lineage-specific transcription predisposes lineage-specific genes in transformed B cell precursors to DNA damage, which is likely to promote the frequent alteration of lineage-specific genes in human leukemia

A numerical solution to Monge's problem with a Finsler distance as cost

International audienceMonge's problem with a Finsler cost is intimately related to an optimal flow problem. Discretization of this problem and its dual leads to a well-posed finite-dimensional saddle-point problem which can be solved numerically relatively easily by an augmented Lagrangian approach in the same spirit as the Benamou-Brenier method for the optimal transport problem with quadratic cost. Numerical results validate the method. We also emphasize that the algorithm only requires elementary operations and in particular never involves evaluation of the Finsler distance or of geodesics

Chromatin loop anchors are associated with genome instability in cancer and recombination hotspots in the germline

Abstract Background Chromatin loops form a basic unit of interphase nuclear organization, with chromatin loop anchor points providing contacts between regulatory regions and promoters. However, the mutational landscape at these anchor points remains under-studied. Here, we describe the unusual patterns of somatic mutations and germline variation associated with loop anchor points and explore the underlying features influencing these patterns. Results Analyses of whole genome sequencing datasets reveal that anchor points are strongly depleted for single nucleotide variants (SNVs) in tumours. Despite low SNV rates in their genomic neighbourhood, anchor points emerge as sites of evolutionary innovation, showing enrichment for structural variant (SV) breakpoints and a peak of SNVs at focal CTCF sites within the anchor points. Both CTCF-bound and non-CTCF anchor points harbour an excess of SV breakpoints in multiple tumour types and are prone to double-strand breaks in cell lines. Common fragile sites, which are hotspots for genome instability, also show elevated numbers of intersecting loop anchor points. Recurrently disrupted anchor points are enriched for genes with functions in cell cycle transitions and regions associated with predisposition to cancer. We also discover a novel class of CTCF-bound anchor points which overlap meiotic recombination hotspots and are enriched for the core PRDM9 binding motif, suggesting that the anchor points have been foci for diversity generated during recent human evolution. Conclusions We suggest that the unusual chromatin environment at loop anchor points underlies the elevated rates of variation observed, marking them as sites of regulatory importance but also genomic fragility

PENDEKATAN METAKOGNITIF DALAM PROSES PEMBELAJARAN BIOLOGI UNTUK MENINGKATKAN KEMAMPUAN HIGH ORDER THINKING SKILLS SISWA KELAS XI MAN 2 PADANGSIDIMPUAN

Penelitian pendekatan metakognitif untuk meningkatkan High Thinking Order Skills (HOTS) ini merupakan penelitian lapangan (field research) dengan jenis penelitian kualitatif. Penelitian ini bertujuan untuk mengetahui dinamika budaya sekolah MAN 2 Padangsidimpuan dan bagaimana penerapan pendekatan metakognitif untuk meningkatkan HOTS siswa dalam pembelajaran Biologi. Populasi dalam penelitian ini adalah seluruh siswa MAN 2 Padangsidimpuan dan sampelnya adalah siswa kelas XI MIA 2. Hasil penelitian menunjukkan bahwa siswa di MAN 2 Padangsidimpuan memiliki dua kompetensi budaya sikap yaitu budaya spiritual dan budaya sosial. Sementara itu, penerapan pendekatan metakognitif untuk meningkatkan HOTS sudah terlihat dari hasil proses pembelajaran siswa dalam pembelajaran Biologi. Penerapan metakognitif ini terlihat pada disain pembelajaran metakogntif yang tertuang dalam Rencana Pelaksanaan Pembelajaran (RPP), proses pembelajaran, penilaian pembelajaran dan bahan ajar yang digunakan dalam proses pembelajaran. RPP pendekatan metakognitif untuk meningkatkan HOTS yang digunakan sudah memenuhi ketentuan acuan pembuatan RPP sesuai dengan standar ketentuan kurikulum 2013, tetapi RPP ini lebih dkembangkan lagi dan disesuaikan dengan kebutuhan. Sehingga, dapat ditarik kesimpulan bahwa RPP yang telah didisain dianggap mampu membantu siswa untuk memulai menggunakan pendekatan metakognitif dalam proses pembelajaran Biologi untuk meningkatkan HOTS.     Kata kunci: Pendekatan Metakognitif, Proses Pembelajaran Biologi, High Thinking Order Skills (HOTS

Drosha drives the formation of DNA:RNA hybrids around DNA break sites to facilitate DNA repair

The error-free and efficient repair of DNA double-stranded breaks (DSBs) is extremely important for cell survival. RNA has been implicated in the resolution of DNA damage but the mechanism remains poorly understood. Here, we show that miRNA biogenesis enzymes, Drosha and Dicer, control the recruitment of repair factors from multiple pathways to sites of damage. Depletion of Drosha significantly reduces DNA repair by both homologous recombination (HR) and non-homologous end joining (NHEJ). Drosha is required within minutes of break induction, suggesting a central and early role for RNA processing in DNA repair. Sequencing of DNA:RNA hybrids reveals RNA invasion around DNA break sites in a Drosha-dependent manner. Removal of the RNA component of these structures results in impaired repair. These results show how RNA can be a direct and critical mediator of DNA damage repair in human cells

E4F1 deficiency results in oxidative stress–mediated cell death of leukemic cells

Deletion of E4F1 inflicts mitochondrial damage and oxidative stress on murine and human myeloid leukemia cells but not healthy macrophages