On rigid analytic uniformizations of Jacobians of Shimura curves

The main goal of this article is to give an explicit rigid analytic uniformization of the maximal toric quotient of the Jacobian of a Shimura curve over Q at a prime dividing exactly the level. This result can be viewed as complementary to the classical theorem of Cerednik and Drinfeld which provides rigid analytic uniformizations at primes dividing the discriminant. As a corollary, we offer a proof of a conjecture formulated by M. Greenberg in hispaper on Stark-Heegner points and quaternionic Shimura curves, thus making Greenberg's construction of local points on elliptic curves over Q unconditional.

Generic Nekhoroshev theory without small divisors

In this article, we present a new approach of Nekhoroshev theory for a generic unperturbed Hamiltonian which completely avoids small divisors problems. The proof is an extension of a method introduced by P. Lochak which combines averaging along periodic orbits with simultaneous Diophantine approximation and uses geometric arguments designed by the second author to handle generic integrable Hamiltonians. This method allows to deal with generic non-analytic Hamiltonians and to obtain new results of generic stability around linearly stable tori.

Significant correction of disease after postnatal administration of recombinant ectodysplasin A in canine X-linked ectodermal dysplasia.

Patients with defective ectodysplasin A (EDA) are affected by X-linked hypohidrotic ectodermal dysplasia (XLHED), a condition characterized by sparse hair, inability to sweat, decreased lacrimation, frequent pulmonary infections, and missing and malformed teeth. The canine model of XLHED was used to study the developmental impact of EDA on secondary dentition, since dogs have an entirely brachyodont, diphyodont dentition similar to that in humans, as opposed to mice, which have only permanent teeth (monophyodont dentition), some of which are very different (aradicular hypsodont) than brachyodont human teeth. Also, clinical signs in humans and dogs with XLHED are virtually identical, whereas several are missing in the murine equivalent. In our model, the genetically missing EDA was compensated for by postnatal intravenous administration of soluble recombinant EDA. Untreated XLHED dogs have an incomplete set of conically shaped teeth similar to those seen in human patients with XLHED. After treatment with EDA, significant normalization of adult teeth was achieved in four of five XLHED dogs. Moreover, treatment restored normal lacrimation and resistance to eye and airway infections and improved sweating ability. These results not only provide proof of concept for a potential treatment of this orphan disease but also demonstrate an essential role of EDA in the development of secondary dentition.

The pollutant diethylhexyl phthalate regulates hepatic energy metabolism via species-specific PPARalpha-dependent mechanisms.

Background: The modulation of energetic homeostasis by pollutants has recently emerged as a potential contributor to the onset of metabolic disorders. Diethylhexyl phthalate (DEHP) is a widely used industrial plasticizer to which humans are widely exposed. Phthalates can activate the three peroxisome proliferatoractivated receptor (PPAR) isotypes on cellular models and induce peroxisome proliferation in rodents.Objectives: In this study, we aimed to evaluate the systemic and metabolic consequences of DEHP exposure that have remained so far unexplored and to characterize the underlying molecular mechanisms of action.Methods: As a proof of concept and mechanism, genetically engineered mouse models of PPARs were exposed to high doses of DEHP, followed by metabolic and molecular analyses.Results: DEHP-treated mice were protected from diet-induced obesity via PPARalpha-dependent activation of hepatic fatty acid catabolism, whereas the activity of neither PPARbeta nor PPARgamma was affected. However, the lean phenotype observed in response to DEHP in wild-type mice was surprisingly abolished in PPARalpha-humanized mice. These species differences are associated with a different pattern of coregulator recruitment.Conclusion: These results demonstrate that DEHP exerts species-specific metabolic actions that rely to a large extent on PPARalpha signaling and highlight the metabolic importance of the species-specific activation of PPARalpha by xenobiotic compounds. Editor's SummaryDiethylhexyl phthalate (DEHP) is an industrial plasticizer used in cosmetics, medical devices, food packaging, and other applications. Evidence that DEHP metabolites can activate peroxisome proliferatoractivated receptors (PPARs) involved in fatty acid oxidation (PPARalpha and PPARbeta) and adiposite function and insulin resistance (PPARgamma) has raised concerns about potential effects of DEHP on metabolic homeostasis. In rodents, PPARalpha activation also induces hepatic peroxisome proliferation, but this response to PPARalpha activation is not observed in humans. Feige et al. (p. 234) evaluated systemic and metabolic consequences of high-dose oral DEHP in combination with a high-fat diet in wild-type mice and genetically engineered mouse PPAR models. The authors report that mice exposed to DEHP gained less weight than controls, without modifying their feeding behavior; they also exhibited lower triglyceride levels, smaller adipocytes, and improved glucose tolerance compared with controls. These effects, which were observed in mice fed both high-fat and standard diets, appeared to be mediated by PPARalpha-dependent activation of hepatic fatty acid catabolism without apparent involvement of PPARbeta or PPARgamma. However, mouse models that expressed human (versus mouse) PPARalpha tended to gain more weight on a high-fat diet than their DHEP-unexposed counterparts. The authors conclude that findings support species-specific metabolic effects of DEHP mediated by PPARalpha activation.

Banning Obsolete Weapons or Reshaping Perceptions of Military Utility: Discursive Dynamics in Weapons Prohibitions

The paper focuses on the argumentative process through which new international norms prohibiting the use of weapons causing severe civilian harm emerge. It examines the debate surrounding the use and usefulness of landmines and cluster munitions and traces the process through which NGOs change conceptions of military utility and effectiveness of certain weapons by highlighting their humanitarian problems and questioning their military value. By challenging military thinking on these issues, NGOs redefine the terms of the debate – from a commonplace practice, the use of such weapons becomes controversial and military decisions need to be justified. The argument-counterargument dynamic shifts the burden of proof of the necessity and safety of the weapons to the users. The process witnesses the ability of NGOs to influence debates on military issues despite their disadvantaged position in hard security issue areas. It also challenges realist assumptions that only weapons that are obsolete or low-cost force equalizers for weak actors can be banned. To the contrary, the paper shows that in the case of landmines and cluster munitions, defining the military (in)effectiveness of the weapons is part and parcel of the struggle for their prohibition.

Estudi de la reformació amb vapor de biocombustibles per a l'obtenció d'hidrogen utilitzant suports estructurats ceràmics funcionalitzats

Donada una aplicació racional en una varietat complexa, Bellon i Viallet van definit l’entropia algebraica d’aquesta aplicació i van provar que aquest valor és un invariant biracional. Un invariant biracional equivalent és el grau asimptòtic, grau dinàmic o complexitat, definit per Boukraa i Maillard. Aquesta noció és propera a la complexitat definida per Arnold. Conjecturalment, el grau asimptòtic satisfà una recurrència lineal amb coeficients enters. Aquesta conjectura ha estat provada en el cas polinòmic en el pla afí complex per Favre i Jonsson i resta oberta en per al cas projectiu global i per al cas local. L’estudi de l’arbre valoratiu de Favre i Jonsson ha resultat clau per resoldre la conjectura en el cas polinòmic en el pla afí complex. El beneficiari ha estudiat l’arbre valoratiu global de Favre i Jonsson i ha reinterpretat algunes nocions i resultats des d’un punt de vista més geomètric. Així mateix, ha estudiat la demostració de la conjectura de Bellon – Viallet en el cas polinòmic en el pla afí complex com a primer pas per trobar una demostració en el cas local i projectiu global en estudis futurs. El projecte inclou un estudi detallat de l'arbre valoratiu global des d'un punt de vista geomètric i els primers passos de la demostració de la conjectura de Bellon - Viallet en el cas polinòmic en el pla afí complex que van efectuar Favre i Jonsson.

Aspectes geomètrics i dinàmics de transformacions racionals planes

Donada una aplicació racional en una varietat complexa, Bellon i Viallet van definit l’entropia algebraica d’aquesta aplicació i van provar que aquest valor és un invariant biracional. Un invariant biracional equivalent és el grau asimptòtic, grau dinàmic o complexitat, definit per Boukraa i Maillard. Aquesta noció és propera a la complexitat definida per Arnold. Conjecturalment, el grau asimptòtic satisfà una recurrència lineal amb coeficients enters. Aquesta conjectura ha estat provada en el cas polinòmic en el pla afí complex per Favre i Jonsson i resta oberta en per al cas projectiu global i per al cas local. L’estudi de l’arbre valoratiu de Favre i Jonsson ha resultat clau per resoldre la conjectura en el cas polinòmic en el pla afí complex. El beneficiari ha estudiat l’arbre valoratiu global de Favre i Jonsson i ha reinterpretat algunes nocions i resultats des d’un punt de vista més geomètric. Així mateix, ha estudiat la demostració de la conjectura de Bellon – Viallet en el cas polinòmic en el pla afí complex com a primer pas per trobar una demostració en el cas local i projectiu global en estudis futurs. El projecte inclou un estudi detallat de l'arbre valoratiu global des d'un punt de vista geomètric i els primers passos de la demostració de la conjectura de Bellon - Viallet en el cas polinòmic en el pla afí complex que van efectuar Favre i Jonsson.

Natural killer cell mediated missing-self recognition can protect mice from primary chronic myeloid leukemia in vivo.

Background: Natural Killer (NK) cells are thought to protect from residual leukemic cells in patients receiving stem cell transplantation. However, multiple retrospective analyses of patient data have yielded conflicting conclusions regarding a putative role of NK cells and the essential NK cell recognition events mediating a protective effect against leukemia. Further, a NK cell mediated protective effect against primary leukemia in vivo has not been shown directly.Methodology/Principal Findings: Here we addressed whether NK cells have the potential to control chronic myeloid leukemia (CML) arising based on the transplantation of BCR-ABL1 oncogene expressing primary bone marrow precursor cells into lethally irradiated recipient mice. These analyses identified missing-self recognition as the only NK cell-mediated recognition strategy, which is able to significantly protect from the development of CML disease in vivo.Conclusion: Our data provide a proof of principle that NK cells can control primary leukemic cells in vivo. Since the presence of NK cells reduced the abundance of leukemia propagating cancer stem cells, the data raise the possibility that NK cell recognition has the potential to cure CML, which may be difficult using small molecule BCR-ABL1 inhibitors. Finally, our findings validate approaches to treat leukemia using antibody-based blockade of self-specific inhibitory MHC class I receptors.

Head motion detection using FID navigators.

This work explores a concept for motion detection in brain MR examinations using high channel-count RF coil arrays. It applies ultrashort (<100 μsec) free induction decay signals, making use of the knowledge that motion induces variations in these signals when compared to a reference free induction decay signal. As a proof-of-concept, the method was implemented in a standard structural MRI sequence. The stability of the free induction decay-signal was verified in phantom experiments. Human experiments demonstrated that the observed variations in the navigator data provide a sensitive measure for detection of relevant and common subject motion patterns. The proposed methodology provides a means to monitor subject motion throughout a MRI scan while causing little or no impact on the sequence timing and image contrast. It could hence complement available motion detection and correction methods, thus further reducing motion sensitivity in MR applications.

Ultrasensitive reporter protein detection in genetically engineered bacteria.

We demonstrate the use of laser-induced fluorescence confocal spectroscopy to measure analyte-stimulated enhanced green fluorescent protein (egfp) synthesis by genetically modified Escherichia coli bioreporter cells. Induction is measured in cell lysates and, since the spectroscopic focal volume is approximately the size of one bioreporter cell, also in individual live bacteria. This is, to our knowledge, the first ever proof-of-concept work utilizing instrumentation with single-molecule detection capability to monitor bioreporter response. Although we use arsenic inducible bioreporters here, the method is extensible to gfp/egfp bioreporters that are responsive to other substances.

A geometric mechanism of diffusion: Rigorous verification in a priori unstable Hamiltonian systems

In this paper we consider a representative a priori unstable Hamiltonian system with 2+1/2 degrees of freedom, to which we apply the geometric mechanism for diffusion introduced in the paper Delshams et al., Mem.Amer.Math. Soc. 2006, and generalized in Delshams and Huguet, Nonlinearity 2009, and provide explicit, concrete and easily verifiable conditions for the existence of diffusing orbits. The simplification of the hypotheses allows us to perform explicitly the computations along the proof, which contribute to present in an easily understandable way the geometric mechanism of diffusion. In particular, we fully describe the construction of the scattering map and the combination of two types of dynamics on a normally hyperbolic invariant manifold.

Refined asymptotics for the subcritical Keller-Segel system and related functional inequalities

We analyze the rate of convergence towards self-similarity for the subcritical Keller-Segel system in the radially symmetric two-dimensional case and in the corresponding one-dimensional case for logarithmic interaction. We measure convergence in Wasserstein distance. The rate of convergence towards self-similarity does not degenerate as we approach the critical case. As a byproduct, we obtain a proof of the logarithmic Hardy-Littlewood-Sobolev inequality in the one dimensional and radially symmetric two dimensional case based on optimal transport arguments. In addition we prove that the onedimensional equation is a contraction with respect to Fourier distance in the subcritical case.

Existence and uniqueness of viscosity solution for Hamilton-Jacobi equation with discontinuous coefficients dependent on time

The main result is a proof of the existence of a unique viscosity solution for Hamilton-Jacobi equation, where the hamiltonian is discontinuous with respect to variable, usually interpreted as the spatial one. Obtained generalized solution is continuous, but not necessarily differentiable.

Sharpened lower bounds for cut elimination

We present sharpened lower bounds on the size of cut free proofs for first-order logic. Prior lower bounds for eliminating cuts from a proof established superexponential lower bounds as a stack of exponentials, with the height of the stack proportional to the maximum depth d of the formulas in the original proof. Our new lower bounds remove the constant of proportionality, giving an exponential stack of height equal to d − O(1). The proof method is based on more efficiently expressing the Gentzen-Solovay cut formulas as low depth formulas.

Treatment of gastrointestinal stromal tumor after imatinib and sunitinib.

Purpose of review Tyrosine kinase inhibitors (TKIs), such as imatinib and sunitinib, have changed the outcome of patients with gastrointestinal stromal tumor (GIST) and prolonged survival by many-fold. Unfortunately, treatment failure and tumor progression seem inevitable over time and constitute an unresolved clinical challenge. This article reviews current efforts to overcome drug resistance and progression. Recent findings The major mechanism of resistance toward imatinib and sunitinib is the development of secondary resistance mutations in the kinase domain of KIT. Recent efforts aim at inhibitors with increased activity against resistance mutations or a broader spectrum of activity. Other strategies include indirect KIT inhibition by modulating KIT chaperone proteins or inhibition of KIT-dependent and independent signaling pathways. Summary dThe rapid improvement of our understanding of GIST biology as well as resistance mechanisms towards imatinib and sunitinib will greatly facilitate the development of novel treatment strategies. This article summarizes the results of recently reported third and fourth-line clinical trials in patients with resistant GIST and reviews data of important proof-of-concept studies.