Continuation of homoclinic orbits in the suspension bridge equation: a computer-assisted proof

In this paper, we prove existence of symmetric homoclinic orbits for the suspension bridge equation $u""+\beta u" + e^u-1=0$ for all parameter values $\beta \in [0.5,1.9]$. For each $\beta$, a parameterization of the stable manifold is computed and the symmetric homoclinic orbits are obtained by solving a projected boundary value problem using Chebyshev series. The proof is computer-assisted and combines the uniform contraction theorem and the radii polynomial approach, which provides an efficient means of determining a set, centered at a numerical approximation of a solution, on which a Newton-like operator is a contraction.Comment: 37 pages, 6 figure

AN INTEGRATIVE SYSTEMS BIOINFORMATICS APPROACH OF THE ENVIRONMENTAL, GENETIC AND MOLECULAR FACTORS REGULATING SLEEP

Environmental changes and genetic variations are two important drivers of biological diversity. In complex traits, a multitude of genetic and environmental factors interact and combine in cryptic ways to direct the phenotypic variation. Sleep is a classic illustration of a complex trait that is vital and heritable but still poorly understood. Many aspects of sleep like the timing, duration and quality are regulated by the interaction of two processes: the circadian oscillations and the sleep homeostasis. In the context of a study that aimed at uncovering more clearly the molecular pathways regulating the sleep homeostat through the ambiguous relationship that exists between sleep- wake cycle and metabolism, we built, assembled, analyzed an extensive multi-scaled dataset using the systems genetics design. Machine learning algorithms and novel high-throughput sequencing technology permit to appraise more precisely and broadly the plethora of physiological and molecular phenotypes that contribute to sleep under disparate circumstances and genetic background, in order to build novel hypotheses based on data-driven discoveries. This dataset is composed of 33 recombinant inbred lines (RIL) from the BXD panel that were interrogated under sleep deprivation and undisturbed conditions for 341 sleep-wake related physiological phenotypes, 124 blood plasma metabolites, and cortical and liver transcriptomics. First analyses pointed out the pervasive effects of sleep deprivation and genetics both at the molecular and behavioral level and the complex interaction between genetic and environmental factors at all phenotypic layers. Then, two novel integrative methods were developed, the first to prioritize candidate genes within large associated genomic regions for physiological or metabolic phenotypes and the second to visualize the meta-dimensionality of the molecular network using the deterministic structure of hiveplots. Our findings led to the discovery of a bidirectional relationship between fatty acid turnover and sleep homeostasis but also between brain slow-waves activity and ionotropic glutamate receptor transport. Using markup language and cloud-based technologies, we aimed at transforming this resourceful, multidisciplinary dataset into an exploitable digital research object. The generation of dynamic analysis reports and workflow metadata promoted the reproducibility this data-object. In addition, tools were developed for the exploration and mining of integrated data. The resulting database and associated web interface ensures the reusability of this dataset and associated methodologies. -- La diversité biologique est dirigée par deux opérateurs importants, les changements environnementaux ainsi que les variations génétiques. Pour les traits dits complexe, leur variation est le fruit de nombreux facteurs génétiques et environnementaux qui vont interagir et se combiner, souvent de manière cryptique. Le sommeil est un exemple-type de trait complexe, il est vital et héritable mais fondamentalement méconnu. La régulation de nombreux aspects du sommeil comme sa durée, timing ou qualité fait intervenir deux processus : les oscillations circadiennes et l’homéostasie du sommeil. Afin de mieux cerner les voies qui régulent le mécanisme d’homéostasie du sommeil, en particulier celle mêlant le métabolisme, nous avons créé, assemblé et analysé un grand set de données en utilisant une approche dite de génétique des systèmes. Avec l’aide d’algorithmes d’apprentissage automatique et de nouvelles technologies de séquençage à haut-débit, nous avons pu mesurer dans des conditions et contextes génétiques différents de nombreux phénotypes moléculaires ou physiologiques qui contribuent à la régulation du sommeil. Notre approche étant ainsi principalement axée sur la construction d’hypothèse guidée par les données. Ce set est composé de 33 lignées de souris consanguines recombinantes (BXD) dont on a examiné, dans des conditions de privation de sommeil et de contrôle : 341 phénotypes physiologiques liés au sommeil et à l’éveil, 124 métabolites du plasma sanguin, ainsi que leur transcriptome du cortex et du foie. Les premières analyses ont pointé l’effet aigu de la privation de sommeil, de la génétique ainsi que leur interaction sur tous les niveaux de phénotypes. Ensuite, deux nouvelles méthodes d’intégration ont été développées, la première pour prioritiser les gènes opérateurs du sommeil et du métabolisme à l’intérieur de grande région génomique, la deuxième pour visualiser la méta-dimensionalité des données moléculaires via une structure de ‘hiveplot’. Nous avons mis en avant une relation bidirectionnelle entre les modifications d’acides gras et l’homéostasie du sommeil, ainsi que l’activité des ondes lentes du cerveau et le transport de récepteur au glutamate ionotropique. En utilisant le langage de balisage ainsi que des technologies basées sur le cloud, nous avons cherché à transformer ce jeu de données en un objet de recherche numérique. La reproductibilité de cet objet a été améliorée par la génération de rapports d'analyse dynamiques ainsi que de métadonnées. De plus, des outils ont été développés pour l'exploration et l'extraction de données via une interface web et assurent ainsi la réutilisation de ce set et de ces méthodologies associées

Expressiveness of SHACL Features

SHACL is a W3C-proposed schema language for expressing structural constraints on RDF graphs. Recent work on formalizing this language has revealed a striking relationship to description logics. SHACL expressions can use four fundamental features that are not so common in description logics. These features are zero-or-one path expressions; equality tests; disjointness tests; and closure constraints. Moreover, SHACL is peculiar in allowing only a restricted form of expressions (so-called targets) on the left-hand side of inclusion constraints. The goal of this paper is to obtain a clear picture of the impact and expressiveness of these features and restrictions. We show that each of the four features is primitive: using the feature, one can express boolean queries that are not expressible without using the feature. We also show that the restriction that SHACL imposes on allowed targets is inessential, as long as closure constraints are not used

Thymidine kinase and thymidylate synthase in advanced breast cancer: response to tamoxifen and chemotherapy

Thymidylate synthase (TS) is a crucial target for 5-fluorouracil (5-FU) in the de novo pathway of pyrimidine synthesis, which is necessary for DNA synthesis. Thymidine kinase (TK) plays a key role in the complementary or alternative salvage pathway of pyrimidine synthesis in acute or pathological tissue stress. In the present study, the activity levels of TS and TK were determined in 257 primary breast tumors of patients who received tamoxifen as first-line systemic therapy after diagnosis of advanced disease. In 155 (60%) responding patients, the median response duration was 23 months for tumors with low TK activity, 15 months for tumors with intermediate TK activity, and 13 months for tumors with high TK activity (P = 0.003). In Cox multivariate analysis corrected for classical predictive factors including estrogen receptor and progesterone receptor, patients with intermediate and high levels of TK activity in their tumors showed a rapid disease progression (P = 0.0002) and an early death (P = 0.002) after start of tamoxifen treatment. Tumor TS activity levels were not significantly associated with the efficacy of tamoxifen treatment. In 121 patients who became resistant to tamoxifen or additional endocrine treatments and who received 5-FU-containing polychemotherapy, tumor TK activity was not significantly related to the efficacy of chemotherapy. Of the 13 patients with low tumor TS activity, only 1 (8%) responded favorably, whereas 46% (43 of 93) of those with intermediate and 73% (11 of 15) of those with high TS activity responded (P = 0.001). In Cox multivariate regression analysis in which TS was the only significant variable, intermediate and high TS activities were associated with a slow disease progression (P = 0.005) and prolonged survival (P = 0.016) on chemotherapy. In conclusion, for patients with recurrent breast cancer, high tumor TK activity is a significant marker of poor clinical outcome on tamoxifen therapy. Elevated tumor TS activity predicts a favorable outcome for 5-FU-containing polychemotherapy when applied after tumor progression on endocrine therapy

Die Generation Y : Arbeitnehmer der Zukunft. Herausforderungen für das Personalmanagement

Die Generation der ab den 1980er Jahren Geborenen, genannt Generation Y, tritt seit einiger Zeit als Arbeitnehmer in die Arbeitsmärkte ein. Im Jahr 2020 wird diese Gruppe die Hälfte der Arbeitnehmer in der Bundesrepublik ausmachen. Lebensstil, Globalisierung, kulturelles und mediales Angebot führen bei dieser Generation auch in der Arbeitswelt zu anderen Erwartungen und Ansprüchen als dies bei vorherigen Generationen der Fall war. In Literatur und Studien wird diese Generation fast ausschließlich als selbstbewusst, ehrgeizig, aufstrebend, sozial engagiert und mobil beschrieben. Vor dem Hintergrund des zu erwartenden Fachkräftemangels widmet sich diese Arbeit unter anderem der Frage, mit welchen Instrumenten das Personalmanagement der Unternehmen auf diese Situation reagieren kann, um bei der Gewinnung und Bindung von Mitarbeitern erfolgreich zu sein