82,952 research outputs found
Hexose-6-phosphate dehydrogenase modulates the effect of inhibitors and alternative substrates of 11[beta]-hydroxysteroid dehydrogenase 1
Intracellular glucocorticoid reactivation is catalyzed by 11[beta]-hydroxysteroid dehydrogenase 1 (11[beta]-HSD1), which functions predominantly as a reductase in cells expressing hexose-6-phosphate dehydrogenase (H6PDH). We recently showed that the ratios of cortisone to cortisol and 7-keto- to 7-hydroxy-neurosteroids are regulated by 11[beta]-HSD1 and very much depend on co-expression with H6PDH, providing cosubstrate NADPH. Here, we investigated the impact of H6PDH on the modulation of 11[beta]-HSD1-dependent inter-conversion of cortisone and cortisol by inhibitors and alternative substrates. Using HEK-293 cells expressing 11[beta]-HSD1 or co-expressing 11[beta]-HSD1 and H6PDH, we observed significant differences of 11[beta]-HSD1 inhibition by natural and pharmaceutical compounds as well as endogenous hormone metabolites. Furthermore, we show potent and dose-dependent inhibition of 11[beta]-HSD1 by 7-keto-DHEA in differentiated human THP-1 macrophages and in HEK-293 cells over-expressing 11[beta]-HSD1 with or without H6PDH. In contrast, 7-ketocholesterol (7-KC) did not inhibit 11[beta]-HSD1 in HEK-293 cells, even in the presence of H6PDH, but inhibited 11[beta]-HSD1 reductase activity in differentiated THP-1 macrophages (IC~50~ = 8.1 +/- 0.9 [mu]M). 7-keto-DHEA but not 7-KC inhibited 11[beta]-HSD1 in HEK-293 cell lysates. In conclusion, cellular factors such as H6PDH can significantly modulate the effect of inhibitors and alternative 7-oxygenated substrates on intracellular glucocorticoid availability
Uniform random generation of large acyclic digraphs
Directed acyclic graphs are the basic representation of the structure
underlying Bayesian networks, which represent multivariate probability
distributions. In many practical applications, such as the reverse engineering
of gene regulatory networks, not only the estimation of model parameters but
the reconstruction of the structure itself is of great interest. As well as for
the assessment of different structure learning algorithms in simulation
studies, a uniform sample from the space of directed acyclic graphs is required
to evaluate the prevalence of certain structural features. Here we analyse how
to sample acyclic digraphs uniformly at random through recursive enumeration,
an approach previously thought too computationally involved. Based on
complexity considerations, we discuss in particular how the enumeration
directly provides an exact method, which avoids the convergence issues of the
alternative Markov chain methods and is actually computationally much faster.
The limiting behaviour of the distribution of acyclic digraphs then allows us
to sample arbitrarily large graphs. Building on the ideas of recursive
enumeration based sampling we also introduce a novel hybrid Markov chain with
much faster convergence than current alternatives while still being easy to
adapt to various restrictions. Finally we discuss how to include such
restrictions in the combinatorial enumeration and the new hybrid Markov chain
method for efficient uniform sampling of the corresponding graphs.Comment: 15 pages, 2 figures. To appear in Statistics and Computin
Comprehensive characterization of molecular interactions based on nanomechanics
Molecular interaction is a key concept in our understanding of the biological mechanisms of life. Two physical properties change when one molecular partner binds to another. Firstly, the masses combine and secondly, the structure of at least one binding partner is altered, mechanically transducing the binding into subsequent biological reactions. Here we present a nanomechanical micro-array technique for bio-medical research, which not only monitors the binding of effector molecules to their target but also the subsequent effect on a biological system in vitro. This label-free and real-time method directly and simultaneously tracks mass and nanomechanical changes at the sensor interface using micro-cantilever technology. To prove the concept we measured lipid vesicle (approximately 748*10(6) Da) adsorption on the sensor interface followed by subsequent binding of the bee venom peptide melittin (2840 Da) to the vesicles. The results show the high dynamic range of the instrument and that measuring the mass and structural changes simultaneously allow a comprehensive discussion of molecular interactions
Composite Majorana Fermion Wavefunctions in Nanowires
We consider Majorana fermions (MFs) in quasi-one-dimensional nanowire systems
containing normal and superconducting sections where the topological phase
based on Rashba spin orbit interaction can be tuned by magnetic fields. We
derive explicit analytic solutions of the MF wavefunction in the weak and
strong spin orbit interaction regimes. We find that the wavefunction for one
single MF is a composite object formed by superpositions of different MF
wavefunctions which have nearly disjoint supports in momentum space. These
contributions are coming from the extrema of the spectrum, one centered around
zero momentum and the other around the two Fermi points. As a result, the
various MF wavefunctions have different localization lengths in real space and
interference among them leads to pronounced oscillations of the MF probability
density. For a transparent normal-superconducting junction we find that in the
topological phase the MF leaks out from the superconducting into the normal
section of the wire and is delocalized over the entire normal section, in
agreement with recent numerical results by Chevallier et al. (arXiv:1203.2643)
\theta^PMNS_13 = \theta_C / \sqrt2 from GUTs
The recent observations of the leptonic mixing angle \theta^PMNS_13 are
consistent with \theta^PMNS_13 = \theta_C / \sqrt2 (with \theta_C being the
Cabibbo angle \theta^CKM_12). We discuss how this relation can emerge in Grand
Unified Theories (GUTs) via charged lepton corrections. The key ingredient is
that in GUTs the down-type quark Yukawa matrix and the charged lepton Yukawa
matrix are generated from the same set of GUT operators, which implies that the
resulting entries are linked and differ only by group theoretical Clebsch
factors. This allows a link \theta^e_12 = \theta_C to be established, which can
induce \theta^PMNS_13 = \theta_C / \sqrt2 provided that the 1-3 mixing in the
neutrino mass matrix is much smaller than \theta_C. We find simple conditions
under which \theta^PMNS_13 = \theta_C / \sqrt2 can arise via this link in SU(5)
GUTs and Pati-Salam models. We also discuss possible corrections to this
relation. Using lepton mixing sum rules different neutrino mixing patterns can
be distinguished by their predictions for the Dirac CP phase \delta^PMNS.Comment: v3: 18 pages, section on corrections to exact relation adde
Study of Non-Strange Baryon Resonances with Meson Photoproduction
Photoproduction of mesons is an excellent tool for the study of nucleon
resonances. Complementary to pion induced reactions, photoproduction on the
free proton contributes to the determination of the basic properties of nucleon
resonances like excitation energy, decay widths, spin, and the coupling to the
photon. Photoproduction from light nuclei, in particular from the deuteron,
reveals the isospin structure of the electromagnetic excitation of the nucleon.
During the last few years, progress in this field has been substantial. New
accelerator facilities combined with state-of-the-art detector technologies
have pushed the experiments to unprecedented sensitivity and precision. The
experimental progress has been accompanied by new developments for the reaction
models, necessary to extract the properties of the nucleon states, and for
modern hadron models which try to connect these properties to QCD. The emphasis
of this review lies on the experimental side and focuses on experiments aiming
at precise studies of the low-lying nucleon resonances.Comment: 87 pages, 67 figures, Prog. Part. Nucl. Phys., accepte
Use of dynamical coupling for improved quantum state transfer
We propose a method to improve quantum state transfer in transmission lines.
The idea is to localize the information on the last qubit of a transmission
line, by dynamically varying the coupling constants between the first and the
last pair of qubits. The fidelity of state transfer is higher then in a chain
with fixed coupling constants. The effect is stable against small fluctuations
in the system parameters.Comment: 5 pages, 7 figure
Astrophysical Reaction Rates From Statistical Model Calculations
Theoretical reaction rates in the temperature range 0.01*10^9<=T[K]<=10.*10^9
are calculated in the statistical model (Hauser-Feshbach formalism) for targets
with 10<=Z<=83 (Ne to Bi) and for a mass range reaching the neutron and proton
driplines. Reactions considered are (n,gamma), (n,p), (n,alpha), (p,gamma),
(p,alpha),(alpha,gamma), and their inverse reactions. Reaction rates as a
function of temperature for thermally populated targets are given by analytic
seven parameter fits. To facilitate comparison with experimental rates, the
stellar enhancement factors are also tabulated. Two complete sets of rates have
been calculated, one of which includes a phenomenological treatment of shell
quenching for neutron-rich nuclei. These extensive datasets are provided
on-line as electronic files, while a selected subset from one calculation is
given as printed tables. A summary of the theoretical inputs and advice on the
use of the provided tabulations is included.Comment: 22 pages of text and 1 table; accepted by Atomic Data Nuclear Data
Tables; a preprint is also available from
http://quasar.physik.unibas.ch/~tommy/adndt.htm
A Bell-Evans-Polanyi principle for molecular dynamics trajectories and its implications for global optimization
The Bell-Evans-Polanyi principle that is valid for a chemical reaction that
proceeds along the reaction coordinate over the transition state is extended to
molecular dynamics trajectories that in general do not cross the dividing
surface between the initial and the final local minima at the exact transition
state. Our molecular dynamics Bell-Evans-Polanyi principle states that low
energy molecular dynamics trajectories are more likely to lead into the basin
of attraction of a low energy local minimum than high energy trajectories. In
the context of global optimization schemes based on molecular dynamics our
molecular dynamics Bell-Evans-Polanyi principle implies that using low energy
trajectories one needs to visit a smaller number of distinguishable local
minima before finding the global minimum than when using high energy
trajectories
Free-induction decay and envelope modulations in a narrowed nuclear spin bath
We evaluate free-induction decay for the transverse components of a localized
electron spin coupled to a bath of nuclear spins via the Fermi contact
hyperfine interaction. Our perturbative treatment is valid for special
(narrowed) bath initial conditions and when the Zeeman energy of the electron
exceeds the total hyperfine coupling constant : . Using one unified
and systematic method, we recover previous results reported at short and long
times using different techniques. We find a new and unexpected modulation of
the free-induction-decay envelope, which is present even for a purely isotropic
hyperfine interaction without spin echoes and for a single nuclear species. We
give sub-leading corrections to the decoherence rate, and show that, in
general, the decoherence rate has a non-monotonic dependence on electron Zeeman
splitting, leading to a pronounced maximum. These results illustrate the
limitations of methods that make use of leading-order effective Hamiltonians
and re-exponentiation of short-time expansions for a strongly-interacting
system with non-Markovian (history-dependent) dynamics.Comment: 13 pages, 9 figure
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