A cnidarian homologue of an insect gustatory receptor functions in developmental body patterning.

Insect gustatory and odorant receptors (GRs and ORs) form a superfamily of novel transmembrane proteins, which are expressed in chemosensory neurons that detect environmental stimuli. Here we identify homologues of GRs (Gustatory receptor-like (Grl) genes) in genomes across Protostomia, Deuterostomia and non-Bilateria. Surprisingly, two Grls in the cnidarian Nematostella vectensis, NvecGrl1 and NvecGrl2, are expressed early in development, in the blastula and gastrula, but not at later stages when a putative chemosensory organ forms. NvecGrl1 transcripts are detected around the aboral pole, considered the equivalent to the head-forming region of Bilateria. Morpholino-mediated knockdown of NvecGrl1 causes developmental patterning defects of this region, leading to animals lacking the apical sensory organ. A deuterostome Grl from the sea urchin Strongylocentrotus purpuratus displays similar patterns of developmental expression. These results reveal an early evolutionary origin of the insect chemosensory receptor family and raise the possibility that their ancestral role was in embryonic development

Phase 1 dose escalation study of the allosteric AKT inhibitor BAY 1125976 in advanced solid cancer-Lack of association between activating AKT mutation and AKT inhibition-derived efficacy

This open-label, phase I first-in-human study (NCT01915576) of BAY 1125976, a highly specific and potent allosteric inhibitor of AKT1/2, aimed to evaluate the safety, pharmacokinetics, and maximum tolerated dose of BAY 1125976 in patients with advanced solid tumors. Oral dose escalation was investigated with a continuous once daily (QD) treatment (21 days/cycle) and a twice daily (BID) schedule. A dose expansion in 28 patients with hormone receptor-positive metastatic breast cancer, including nine patients harboring th

Localization length and impurity dielectric susceptibility in the critical regime of the metal-insulator transition in homogeneously doped p-type Ge

We have determined the localization length \xi and the impurity dielectric susceptibility \chi_{\rm imp} as a function of Ga acceptor concentrations (N) in nominally uncompensated ^{70}Ge:Ga just below the critical concentration (N_c) for the metal-insulator transition. Both \xi and \chi_{\rm imp} diverge at N_c according to the functions \xi\propto(1-N/N_c)^{-\nu} and \chi_{\rm imp}\propto(N_c/N-1)^{-\zeta}, respectively, with \nu=1.2\pm0.3 and \zeta=2.3\pm0.6 for 0.99N_c< N< N_c. Outside of this region (N<0.99N_c), the values of the exponents drop to \nu=0.33\pm0.03 and \zeta=0.62\pm0.05. The effect of the small amount of compensating dopants that are present in our nominally uncompensated samples, may be responsible for the change of the critical exponents at N\approx0.99N_c.Comment: RevTeX, 4 pages with 5 embedded figures, final version (minor changes

Chemical composition of A and F dwarf members of the Coma Berenices open cluster

Abundances of 18 chemical elements have been derived for 11 A (normal and Am) and 11 F dwarfs members of the Coma Berenices open cluster in order to set constraints on evolutionary models including transport processes (radiative and turbulent diffusion)calculated with the Montreal code. A spectral synthesis iterative procedure has been applied to derive the abundances from selected high quality lines in high resolution high signal-to-noise echelle spectra obtained with ELODIE at the Observatoire de Haute Provence. The chemical pattern found for the A and F dwarfs in Coma Berenices is reminiscent of that found in the Hyades and the UMa moving group. In graphs representing the abundances [X/H] versus the effective temperature, the A stars often display abundances much more scattered around their mean values than the F stars do. Large star-to-star variations are detected for A stars in their abundances which we interpret as evidence of transport processes competing with radiative diffusion. The F stars have solar abundances for almost all elements except for Mg, Si, V and Ba. The derived abundances patterns, [X/H] versus atomic number, for the slow rotator HD108642 (A2m) and the moderately fast rotator HD106887 (A4m) were compared to the predictions of self consistent evolutionary model codes including radiative and different amounts of turbulent diffusion. None of the models reproduces entirely the overall shape of the abundance pattern. While part of the discrepancies between derived and predicted abundances may be accounted for by non-LTE effects, the inclusion of competing processes such as rotational mixing in the radiative zones of these stars seems necessary to improve the agreement between observed and predicted abundance patterns.Comment: 25 pages, 20 figure

Sub-electron Charge Relaxation via 2D Hopping Conductors

We have extended Monte Carlo simulations of hopping transport in completely disordered 2D conductors to the process of external charge relaxation. In this situation, a conductor of area $L \times W$ shunts an external capacitor $C$ with initial charge $Q_i$. At low temperatures, the charge relaxation process stops at some "residual" charge value corresponding to the effective threshold of the Coulomb blockade of hopping. We have calculated the r.m.s$.$ value $Q_R$ of the residual charge for a statistical ensemble of capacitor-shunting conductors with random distribution of localized sites in space and energy and random $Q_i$, as a function of macroscopic parameters of the system. Rather unexpectedly, $Q_{R}$ has turned out to depend only on some parameter combination: $X_0 \equiv L W \nu_0 e^2/C$ for negligible Coulomb interaction and $X_{\chi} \equiv LW \kappa^2/C^{2}$ for substantial interaction. (Here $\nu_0$ is the seed density of localized states, while $\kappa$ is the dielectric constant.) For sufficiently large conductors, both functions $Q_{R}/e =F(X)$ follow the power law $F(X)=DX^{-\beta}$, but with different exponents: $\beta = 0.41 \pm 0.01$ for negligible and $\beta = 0.28 \pm 0.01$ for significant Coulomb interaction. We have been able to derive this law analytically for the former (most practical) case, and also explain the scaling (but not the exact value of the exponent) for the latter case. In conclusion, we discuss possible applications of the sub-electron charge transfer for "grounding" random background charge in single-electron devices.Comment: 12 pages, 5 figures. In addition to fixing minor typos and updating references, the discussion has been changed and expande

A Numerical Study of Coulomb Interaction Effects on 2D Hopping Transport

We have extended our supercomputer-enabled Monte Carlo simulations of hopping transport in completely disordered 2D conductors to the case of substantial electron-electron Coulomb interaction. Such interaction may not only suppress the average value of hopping current, but also affect its fluctuations rather substantially. In particular, the spectral density $S_I (f)$ of current fluctuations exhibits, at sufficiently low frequencies, a $1/f$-like increase which approximately follows the Hooge scaling, even at vanishing temperature. At higher $f$, there is a crossover to a broad range of frequencies in which $S_I (f)$ is nearly constant, hence allowing characterization of the current noise by the effective Fano factor F\equiv S_I(f)/2e \left. For sufficiently large conductor samples and low temperatures, the Fano factor is suppressed below the Schottky value (F=1), scaling with the length $L$ of the conductor as $F = (L_c / L)^{\alpha}$. The exponent $\alpha$ is significantly affected by the Coulomb interaction effects, changing from $\alpha = 0.76 \pm 0.08$ when such effects are negligible to virtually unity when they are substantial. The scaling parameter $L_c$, interpreted as the average percolation cluster length along the electric field direction, scales as $L_c \propto E^{-(0.98 \pm 0.08)}$ when Coulomb interaction effects are negligible and $L_c \propto E^{-(1.26 \pm 0.15)}$ when such effects are substantial, in good agreement with estimates based on the theory of directed percolation.Comment: 19 pages, 7 figures. Fixed minor typos and updated reference

Electronic correlation effects and the Coulomb gap at finite temperature

We have investigated the effect of the long-range Coulomb interaction on the one-particle excitation spectrum of n-type Germanium, using tunneling spectroscopy on mechanically controllable break junctions. The tunnel conductance was measured as a function of energy and temperature. At low temperatures, the spectra reveal a minimum at zero bias voltage due to the Coulomb gap. In the temperature range above 1 K the Coulomb gap is filled by thermal excitations. This behavior is reflected in the temperature dependence of the variable-range hopping resitivity measured on the same samples: Up to a few degrees Kelvin the Efros-Shkovskii ln$R \propto T^{-1/2}$ law is obeyed, whereas at higher temperatures deviations from this law are observed, indicating a cross-over to Mott's ln$R \propto T^{-1/4}$ law. The mechanism of this cross-over is different from that considered previously in the literature.Comment: 3 pages, 3 figure

The analysis of heterotaxy patients reveals new loss-of-function variants of GRK5

G protein-coupled receptor kinase 5 (GRK5) is a regulator of cardiac performance and a potential therapeutic target in heart failure in the adult. Additionally, we have previously classified GRK5 as a determinant of left-right asymmetry and proper heart development using zebrafish. We thus aimed to identify GRK5 variants of functional significance by analysing 187 individuals with laterality defects (heterotaxy) that were associated with a congenital heart defect (CHD). Using Sanger sequencing we identified two moderately frequent variants in GRK5 with minor allele frequencies <10%, and seven very rare polymorphisms with minor allele frequencies <1%, two of which are novel variants. Given their evolutionarily conserved position in zebrafish, in-depth functional characterisation of four variants (p.Q41L, p.G298S, p.R304C and p.T425M) was performed. We tested the effects of these variants on normal subcellular localisation and the ability to desensitise receptor signalling as well as their ability to correct the left-right asymmetry defect upon Grk5l knockdown in zebrafish. While p.Q41L, p.R304C and p.T425M responded normally in the first two aspects, neither p.Q41L nor p.R304C were capable of rescuing the lateralisation phenotype. The fourth variant, p.G298S was identified as a complete loss-of-function variant in all assays and provides insight into the functions of GRK5

A Numerical Study of Transport and Shot Noise at 2D Hopping

We have used modern supercomputer facilities to carry out extensive Monte Carlo simulations of 2D hopping (at negligible Coulomb interaction) in conductors with the completely random distribution of localized sites in both space and energy, within a broad range of the applied electric field $E$ and temperature $T$, both within and beyond the variable-range hopping region. The calculated properties include not only dc current and statistics of localized site occupation and hop lengths, but also the current fluctuation spectrum. Within the calculation accuracy, the model does not exhibit $1/f$ noise, so that the low-frequency noise at low temperatures may be characterized by the Fano factor $F$. For sufficiently large samples, $F$ scales with conductor length $L$ as $(L_c/L)^{\alpha}$, where $\alpha=0.76\pm 0.08 < 1$, and parameter $L_c$ is interpreted as the average percolation cluster length. At relatively low $E$, the electric field dependence of parameter $L_c$ is compatible with the law $L_c\propto E^{-0.911}$ which follows from directed percolation theory arguments.Comment: 17 pages, 8 figures; Fixed minor typos and updated reference