226 research outputs found
Long-term efficacy and safety of migalastat treatment in Fabry disease: 30-month results from the open-label extension of the randomized, phase 3 ATTRACT study
Results from the 18-month randomized treatment period of the phase 3 ATTRACT study demonstrated the efficacy and safety of oral migalastat compared with enzyme replacement therapy (ERT) in patients with Fabry disease who previously received ERT. Here, we report data from the subsequent 12-month, migalastat-only, open-label extension (OLE) period. ATTRACT (Study AT1001–012; NCT01218659) was a randomized, open-label, active-controlled study in patients aged 16–74 years with Fabry disease, an amenable GLA variant, and an estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2. During the OLE, patients who received migalastat 150 mg every other day (QOD) during the randomized period continued receiving migalastat (Group 1 [MM]); patients who received ERT every other week discontinued ERT and started migalastat treatment (Group 2 [EM]). Outcome measures included eGFR, left ventricular mass index (LVMi), composite clinical outcome (renal, cardiac or cerebrovascular events), and safety. Forty-six patients who completed the randomized treatment period continued into the OLE (Group 1 [MM], n = 31; Group 2 [EM], n = 15). eGFR remained stable in both treatment groups. LVMi decreased from baseline at month 30 in Group 1 (MM) in patients with left ventricular hypertrophy at baseline. Only 10% of patients experienced a new composite clinical event with migalastat treatment during the OLE. No new safety concerns were reported. In conclusion, in patients with Fabry disease and amenable GLA variants, migalastat 150 mg QOD was well tolerated and demonstrated durable, long-term stability of renal function and reduction in LVMi
Resonant particle production with non-minimally coupled scalar fields in preheating after inflation
We investigate a resonant particle production of a scalar field
coupled non-minimally to a spacetime curvature () as well as
to an inflaton field (). In the case of , effect assists -resonance in certain parameter regimes.
However, for , -resonance is not enhanced by
effect because of suppression effect as well as a back reaction effect.
If , the maximal fluctuation of produced -particle is
GeV for , which is larger than the minimally coupled case with .Comment: 33pages, 12figures. to appear in Physical Review
Cosmological Perturbations with Multiple Fluids and Fields
We consider the evolution of perturbed cosmological spacetime with multiple
fluids and fields in Einstein gravity. Equations are presented in gauge-ready
forms, and are presented in various forms using the curvature (\Phi or
\phi_\chi) and isocurvature (S_{(ij)} or \delta \phi_{(ij)}) perturbation
variables in the general background with K and \Lambda. We clarify the
conditions for conserved curvature and isocurvature perturbations in the
large-scale limit. Evolutions of curvature perturbations in many different
gauge conditions are analysed extensively. In the multi-field system we present
a general solution to the linear order in slow-roll parameters.Comment: 19 pages, 6 figures, revised thoroughly; published version in Class.
Quant. Gra
Inertial mechanism: dynamical mass as a source of particle creation
A kinetic theory of vacuum particle creation under the action of an inertial
mechanism is constructed within a nonpertrubative dynamical approach. At the
semi-phenomenological level, the inertial mechanism corresponds to quantum
field theory with a time-dependent mass. At the microscopic level, such a
dependence may be caused by different reasons: The non-stationary Higgs
mechanism, the influence of a mean field or condensate, the presence of the
conformal multiplier in the scalar-tensor gravitation theory etc. In what
follows, a kinetic theory in the collisionless approximation is developed for
scalar, spinor and massive vector fields in the framework of the oscillator
representation, which is an effective tool for transition to the quasiparticle
description and for derivation of non-Markovian kinetic equations. Properties
of these equations and relevant observables (particle number and energy
densities, pressure) are studied. The developed theory is applied here to
describe the vacuum matter creation in conformal cosmological models and
discuss the problem of the observed number density of photons in the cosmic
microwave background radiation. As other example, the self-consistent evolution
of scalar fields with non-monotonic self-interaction potentials (the
W-potential and Witten - Di Vecchia - Veneziano model) is considered. In
particular, conditions for appearance of tachyonic modes and a problem of the
relevant definition of a vacuum state are considered.Comment: 51 pages, 18 figures, submitted to PEPAN (JINR, Dubna); v2: added
reference
Massless Metric Preheating
Can super-Hubble metric perturbations be amplified exponentially during
preheating ? Yes. An analytical existence proof is provided by exploiting the
conformal properties of massless inflationary models. The traditional conserved
quantity \zeta is non-conserved in many regions of parameter space. We include
backreaction through the homogeneous parts of the inflaton and preheating
fields and discuss the role of initial conditions on the post-preheating
power-spectrum. Maximum field variances are strongly underestimated if metric
perturbations are ignored. We illustrate this in the case of strong
self-interaction of the decay products. Without metric perturbations,
preheating in this case is very inefficient. However, metric perturbations
increase the maximum field variances and give alternative channels for the
resonance to proceed. This implies that metric perturbations can have a large
impact on calculations of relic abundances of particles produced during
preheating.Comment: 8 pages, 4 colour figures. Version to appear in Phys. Rev. D.
Contains substantial new analysis of the ranges of parameter space for which
large changes to the inflation-produced power spectrum are expecte
Turbulent Thermalization
We study, analytically and with lattice simulations, the decay of coherent
field oscillations and the subsequent thermalization of the resulting
stochastic classical wave-field. The problem of reheating of the Universe after
inflation constitutes our prime motivation and application of the results. We
identify three different stages of these processes. During the initial stage of
``parametric resonance'', only a small fraction of the initial inflaton energy
is transferred to fluctuations in the physically relevant case of sufficiently
large couplings. A major fraction is transfered in the prompt regime of driven
turbulence. The subsequent long stage of thermalization classifies as free
turbulence. During the turbulent stages, the evolution of particle distribution
functions is self-similar. We show that wave kinetic theory successfully
describes the late stages of our lattice calculation. Our analytical results
are general and give estimates of reheating time and temperature in terms of
coupling constants and initial inflaton amplitude.Comment: 27 pages, 13 figure
Vacuum decay in quantum field theory
We study the contribution to vacuum decay in field theory due to the
interaction between the long and short-wavelength modes of the field. The field
model considered consists of a scalar field of mass with a cubic term in
the potential. The dynamics of the long-wavelength modes becomes diffusive in
this interaction. The diffusive behaviour is described by the reduced Wigner
function that characterizes the state of the long-wavelength modes. This
function is obtained from the whole Wigner function by integration of the
degrees of freedom of the short-wavelength modes. The dynamical equation for
the reduced Wigner function becomes a kind of Fokker-Planck equation which is
solved with suitable boundary conditions enforcing an initial metastable vacuum
state trapped in the potential well. As a result a finite activation rate is
found, even at zero temperature, for the formation of true vacuum bubbles of
size . This effect makes a substantial contribution to the total decay
rate.Comment: 27 pages, RevTeX, 1 figure (uses epsf.sty
Vacuum decay in quantum field theory
We study the contribution to vacuum decay in field theory due to the
interaction between the long and short-wavelength modes of the field. The field
model considered consists of a scalar field of mass with a cubic term in
the potential. The dynamics of the long-wavelength modes becomes diffusive in
this interaction. The diffusive behaviour is described by the reduced Wigner
function that characterizes the state of the long-wavelength modes. This
function is obtained from the whole Wigner function by integration of the
degrees of freedom of the short-wavelength modes. The dynamical equation for
the reduced Wigner function becomes a kind of Fokker-Planck equation which is
solved with suitable boundary conditions enforcing an initial metastable vacuum
state trapped in the potential well. As a result a finite activation rate is
found, even at zero temperature, for the formation of true vacuum bubbles of
size . This effect makes a substantial contribution to the total decay
rate.Comment: 27 pages, RevTeX, 1 figure (uses epsf.sty
The degradation of p53 and its major E3 ligase Mdm2 is differentially dependent on the proteasomal ubiquitin receptor S5a.
p53 and its major E3 ligase Mdm2 are both ubiquitinated and targeted to the proteasome for degradation. Despite the importance of this in regulating the p53 pathway, little is known about the mechanisms of proteasomal recognition of ubiquitinated p53 and Mdm2. In this study, we show that knockdown of the proteasomal ubiquitin receptor S5a/PSMD4/Rpn10 inhibits p53 protein degradation and results in the accumulation of ubiquitinated p53. Overexpression of a dominant-negative deletion of S5a lacking its ubiquitin-interacting motifs (UIM)s, but which can be incorporated into the proteasome, also causes the stabilization of p53. Furthermore, small-interferring RNA (siRNA) rescue experiments confirm that the UIMs of S5a are required for the maintenance of low p53 levels. These observations indicate that S5a participates in the recognition of ubiquitinated p53 by the proteasome. In contrast, targeting S5a has no effect on the rate of degradation of Mdm2, indicating that proteasomal recognition of Mdm2 can be mediated by an S5a-independent pathway. S5a knockdown results in an increase in the transcriptional activity of p53. The selective stabilization of p53 and not Mdm2 provides a mechanism for p53 activation. Depletion of S5a causes a p53-dependent decrease in cell proliferation, demonstrating that p53 can have a dominant role in the response to targeting S5a. This study provides evidence for alternative pathways of proteasomal recognition of p53 and Mdm2. Differences in recognition by the proteasome could provide a means to modulate the relative stability of p53 and Mdm2 in response to cellular signals. In addition, they could be exploited for p53-activating therapies. This work shows that the degradation of proteins by the proteasome can be selectively dependent on S5a in human cells, and that this selectivity can extend to an E3 ubiquitin ligase and its substrate
The Suppressor of AAC2 Lethality SAL1 Modulates Sensitivity of Heterologously Expressed Artemia ADP/ATP Carrier to Bongkrekate in Yeast
The ADP/ATP carrier protein (AAC) expressed in Artemia franciscana is refractory to bongkrekate. We generated two strains of Saccharomyces cerevisiae where AAC1 and AAC3 were inactivated and the AAC2 isoform was replaced with Artemia AAC containing a hemagglutinin tag (ArAAC-HA). In one of the strains the suppressor of ΔAAC2 lethality, SAL1, was also inactivated but a plasmid coding for yeast AAC2 was included, because the ArAACΔsal1Δ strain was lethal. In both strains ArAAC-HA was expressed and correctly localized to the mitochondria. Peptide sequencing of ArAAC expressed in Artemia and that expressed in the modified yeasts revealed identical amino acid sequences. The isolated mitochondria from both modified strains developed 85% of the membrane potential attained by mitochondria of control strains, and addition of ADP yielded bongkrekate-sensitive depolarizations implying acquired sensitivity of ArAAC-mediated adenine nucleotide exchange to this poison, independent from SAL1. However, growth of ArAAC-expressing yeasts in glycerol-containing media was arrested by bongkrekate only in the presence of SAL1. We conclude that the mitochondrial environment of yeasts relying on respiratory growth conferred sensitivity of ArAAC to bongkrekate in a SAL1-dependent manner. © 2013 Wysocka-Kapcinska et al
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