Discovery of TUG-770: a highly potent free fatty acid receptor 1 (FFA1/GPR40) agonist for treatment of type 2 diabetes

Free fatty acid receptor 1 (FFA1 or GPR40) enhances glucose-stimulated insulin secretion from pancreatic β-cells and currently attracts high interest as a new target for the treatment of type 2 diabetes. We here report the discovery of a highly potent FFA1 agonist with favorable physicochemical and pharmacokinetic properties. The compound efficiently normalizes glucose tolerance in diet-induced obese mice, an effect that is fully sustained after 29 days of chronic dosing

Linear response functions for a vibrational configuration interaction state

Linear response functions are implemented for a vibrational configuration interaction state allowing accurate analytical calculations of pure vibrational contributions to dynamical polarizabilities. Sample calculations are presented for the pure vibrational contributions to the polarizabilities of water and formaldehyde. We discuss the convergence of the results with respect to various details of the vibrational wave function description as well as the potential and property surfaces. We also analyze the frequency dependence of the linear response function and the effect of accounting phenomenologically for the finite lifetime of the excited vibrational states. Finally, we compare the analytical response approach to a sum-over-states approac

First Order Kaon Condensation in Neutron Stars: Finite Size Effects in the Mixed Phase

We study the role of Coulomb and surface effects on the phase transition from dense nuclear matter to a mixed phase of nuclear and kaon-condensed matter. We calculate corrections to the bulk calculation of the equation of state (EOS) and the critical density for the transition by solving explicitly for spherical, cylindrical, and planar structures. The importance of Debye screening in the determination of the charged particle profiles is studied in some detail. We find that the surface and Coulomb contributions to the energy density are small, but that they play an important role in the determination of the critical pressure for the transition, as well as affecting the size and geometry of favored structures. This changes the EOS over a wide range of pressure and consequently increases the maximum mass by about 0.1 solar masses. Implications for transport properties of the mixed phase are also discussed.Comment: 18 pages, 6 figure

Probabilistic Weyl laws for quantized tori

For the Toeplitz quantization of complex-valued functions on a $2n$-dimensional torus we prove that the expected number of eigenvalues of small random perturbations of a quantized observable satisfies a natural Weyl law. In numerical experiments the same Weyl law also holds for ``false'' eigenvalues created by pseudospectral effects.Comment: 33 pages, 3 figures, v2 corrected listed titl

Trematominae and Artedidraconinae: contrasted mitogenome evolution for two Antarctic radiations

Cellular respiration has been widely studied in Antarctic teleost fishes because of their peculiar adaptations to an extreme environment. In parallel mitochondrial sequence markers have become highly popular for molecular systematics. However, there are few whole mitochondrial genome sequences published, and none available for some of the subfamilies. Here, we present two large mitogenome datasets including most species and multiple sequences for many species of two subfamilies, Trematominae and Artedidraconinae (Duhamel et al. 2014). These include two highly diverse but very different adaptative radiations, with contrasting divergence dates, morphological polymorphism, and habitat dominance. The sampling is based on a well identified, extensive collection resulting from the 2008 CEAMARC survey and the subsequent REVOLTA surveys in Terre Adélie (IPEV), already DNA barcoded and sequenced in previous studies. The mitogenome sequences for these two subfamilies differ in composition, gene order, and relative divergence of mitochondrial markers, with strong, taxon-specific biases like very high C contents in some regions. The gene order change provides a synapomorphy for the subfamily Trematominae and an interesting development in teleost mitogenomes. The complete Artedidraconinae mitogenomes provide a much higher amount of variable sites (approx*30), while previous sequence datasets were plagued by low informativeness (Lecointre et al. 2011). As already established on single mitochondrial genes, intraspecific variability is lower than interspecific variability within each subfamily, however interspecific variability in Artedidraconinae is lower or similar to intraspecific variability in Trematominae. This expanded dataset confirms the unusual evolution of the mitochondrial coded sequences involved in the cellular respiration in Antarctic Nototheniidae, as well as the usefulness of complete mitochondrial genomes for their systematics. The two level multiplexing (Timmermans et al. 2010) and next generation sequencing of long PCR amplicons (following Hinsinger et al. 2015) is efficient to obtain large mitogenomic datasets representative of both inter- and intraspecific variability, key to the understanding of mitochondrial evolution and a step closer to resolving the relationships among these taxa.RECTO (Refugia and Ecosystem Tolerance in the Southern Ocean, BR/154/A1/RECTO

Gluon distributions in nucleons and pions at a low resolution scale

In this paper we study the gluon distribution functions in nucleons and pions at a low resolution $Q^2$ scale. This is an important issue since parton densities at low $Q^2$ have always been taken as an external input which is adjusted through DGLAP evolution to fit the experimental data at higher scales. Here, in the framework of a model recently developed, it is shown that the hypothetical cloud of {\it neutral} pions surrounding nucleons and pions appears to be responsible for the characteristic valence-like gluon distributions needed at the inital low scale. As an additional result, we get the remarkable prediction that neutral and charged pions have different intrinsic sea flavor contents.Comment: final version to appear in Phys. Rev. D. Discussion on several points enlarge

Angular dependence of the magnetic-field driven superconductor-insulator transition in thin films of amorphous indium-oxide

A significant anisotropy of the magnetic-field driven superconductor-insulator transition is observed in thin films of amorphous indium-oxide. The anisotropy is largest for more disordered films which have a lower transition field. At higher magnetic field the anisotropy reduces and even changes sign beyond a sample specific and temperature independent magnetic field value. The data are consistent with the existence of more that one mechanism affecting transport at high magnetic fields.Comment: 4 pages, 5 figure

The biological origin of linguistic diversity

In contrast with animal communication systems, diversity is characteristic of almost every aspect of human language. Languages variously employ tones, clicks, or manual signs to signal differences in meaning; some languages lack the noun-verb distinction (e.g., Straits Salish), whereas others have a proliferation of fine-grained syntactic categories (e.g., Tzeltal); and some languages do without morphology (e.g., Mandarin), while others pack a whole sentence into a single word (e.g., Cayuga). A challenge for evolutionary biology is to reconcile the diversity of languages with the high degree of biological uniformity of their speakers. Here, we model processes of language change and geographical dispersion and find a consistent pressure for flexible learning, irrespective of the language being spoken. This pressure arises because flexible learners can best cope with the observed high rates of linguistic change associated with divergent cultural evolution following human migration. Thus, rather than genetic adaptations for specific aspects of language, such as recursion, the coevolution of genes and fast-changing linguistic structure provides the biological basis for linguistic diversity. Only biological adaptations for flexible learning combined with cultural evolution can explain how each child has the potential to learn any human language