428 research outputs found
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 shunts an external capacitor
with initial charge . 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
of the residual charge for a statistical ensemble of capacitor-shunting
conductors with random distribution of localized sites in space and energy and
random , as a function of macroscopic parameters of the system. Rather
unexpectedly, has turned out to depend only on some parameter
combination: for negligible Coulomb interaction
and for substantial interaction. (Here
is the seed density of localized states, while is the
dielectric constant.) For sufficiently large conductors, both functions
follow the power law , but with different
exponents: for negligible and
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 of current
fluctuations exhibits, at sufficiently low frequencies, a -like increase
which approximately follows the Hooge scaling, even at vanishing temperature.
At higher , there is a crossover to a broad range of frequencies in which
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 of the
conductor as . The exponent is significantly
affected by the Coulomb interaction effects, changing from when such effects are negligible to virtually unity when they are
substantial. The scaling parameter , interpreted as the average
percolation cluster length along the electric field direction, scales as when Coulomb interaction effects are negligible
and 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 law is obeyed,
whereas at higher temperatures deviations from this law are observed,
indicating a cross-over to Mott's ln 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 and
temperature , 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 noise, so
that the low-frequency noise at low temperatures may be characterized by the
Fano factor . For sufficiently large samples, scales with conductor
length as , where , and
parameter is interpreted as the average percolation cluster length. At
relatively low , the electric field dependence of parameter is
compatible with the law which follows from directed
percolation theory arguments.Comment: 17 pages, 8 figures; Fixed minor typos and updated reference
- …