1,042 research outputs found
David Sobel, From Valuing to Value: A Defense of Subjectivism (Oxford: Oxford University Press, 2016), pp. vii + 312.
Pharmacogenomic variants and drug interactions identified through the genetic analysis of clozapine metabolism
Objective: Clozapine is the only effective medication for treatment-resistant schizophrenia, but its worldwide use is still limited because of its complex titration protocols. While the discovery of pharmacogenomic variants of clozapine metabolism may improve clinical management, no robust findings have yet been reported. This study is the first to adopt the framework of genome-wide association studies (GWASs) to discover genetic markers of clozapine plasma concentrations in a large sample of patients with treatment-resistant schizophrenia. Methods: The authors used mixed-model regression to combine data from multiple assays of clozapine metabolite plasma concentrations from a clozapine monitoring service and carried out a genome-wide analysis of clozapine, norclozapine, and their ratio on 10,353 assays from 2,989 individuals. These analyses were adjusted for demographic factors known to influence clozapine metabolism, although it was not possible to adjust for all potential mediators given the available data. GWAS results were used to pinpoint specific enzymes and metabolic pathways and compounds that might interact with clozapine pharmacokinetics. Results: The authors identified four distinct genome-wide significant loci that harbor common variants affecting the metabolism of clozapine or its metabolites. Detailed examination pointed to coding and regulatory variants at several CYP* and UGT* genes as well as corroborative evidence for interactions between the metabolism of clozapine, coffee, and tobacco. Individual effects of single single-nucleotide polymorphisms (SNPs) fine-mapped from these loci were large, such as the minor allele of rs2472297, which was associated with a reduction in clozapine concentrations roughly equivalent to a decrease of 50 mg/day in clozapine dosage. On their own, these single SNPs explained from 1.15% to 9.48% of the variance in the plasma concentration data. Conclusions: Common genetic variants with large effects on clozapine metabolism exist and can be found via genome-wide approaches. Their identification opens the way for clinical studies assessing the use of pharmacogenomics in the clinical management of patients with treatment-resistant schizophrenia
Amyloid Beta and Tau Cooperate to Cause Reversible Behavioral and Transcriptional Deficits in a Model of Alzheimer's Disease
Upper limits on the strength of periodic gravitational waves from PSR J1939+2134
The first science run of the LIGO and GEO gravitational wave detectors
presented the opportunity to test methods of searching for gravitational waves
from known pulsars. Here we present new direct upper limits on the strength of
waves from the pulsar PSR J1939+2134 using two independent analysis methods,
one in the frequency domain using frequentist statistics and one in the time
domain using Bayesian inference. Both methods show that the strain amplitude at
Earth from this pulsar is less than a few times .Comment: 7 pages, 1 figure, to appear in the Proceedings of the 5th Edoardo
Amaldi Conference on Gravitational Waves, Tirrenia, Pisa, Italy, 6-11 July
200
Improving the sensitivity to gravitational-wave sources by modifying the input-output optics of advanced interferometers
We study frequency dependent (FD) input-output schemes for signal-recycling
interferometers, the baseline design of Advanced LIGO and the current
configuration of GEO 600. Complementary to a recent proposal by Harms et al. to
use FD input squeezing and ordinary homodyne detection, we explore a scheme
which uses ordinary squeezed vacuum, but FD readout. Both schemes, which are
sub-optimal among all possible input-output schemes, provide a global noise
suppression by the power squeeze factor, while being realizable by using
detuned Fabry-Perot cavities as input/output filters. At high frequencies, the
two schemes are shown to be equivalent, while at low frequencies our scheme
gives better performance than that of Harms et al., and is nearly fully
optimal. We then study the sensitivity improvement achievable by these schemes
in Advanced LIGO era (with 30-m filter cavities and current estimates of
filter-mirror losses and thermal noise), for neutron star binary inspirals, and
for narrowband GW sources such as low-mass X-ray binaries and known radio
pulsars. Optical losses are shown to be a major obstacle for the actual
implementation of these techniques in Advanced LIGO. On time scales of
third-generation interferometers, like EURO/LIGO-III (~2012), with
kilometer-scale filter cavities, a signal-recycling interferometer with the FD
readout scheme explored in this paper can have performances comparable to
existing proposals. [abridged]Comment: Figs. 9 and 12 corrected; Appendix added for narrowband data analysi
Search for gravitational wave bursts in LIGO's third science run
We report on a search for gravitational wave bursts in data from the three
LIGO interferometric detectors during their third science run. The search
targets subsecond bursts in the frequency range 100-1100 Hz for which no
waveform model is assumed, and has a sensitivity in terms of the
root-sum-square (rss) strain amplitude of hrss ~ 10^{-20} / sqrt(Hz). No
gravitational wave signals were detected in the 8 days of analyzed data.Comment: 12 pages, 6 figures. Amaldi-6 conference proceedings to be published
in Classical and Quantum Gravit
Quantum state preparation and macroscopic entanglement in gravitational-wave detectors
Long-baseline laser-interferometer gravitational-wave detectors are operating
at a factor of 10 (in amplitude) above the standard quantum limit (SQL) within
a broad frequency band. Such a low classical noise budget has already allowed
the creation of a controlled 2.7 kg macroscopic oscillator with an effective
eigenfrequency of 150 Hz and an occupation number of 200. This result, along
with the prospect for further improvements, heralds the new possibility of
experimentally probing macroscopic quantum mechanics (MQM) - quantum mechanical
behavior of objects in the realm of everyday experience - using
gravitational-wave detectors. In this paper, we provide the mathematical
foundation for the first step of a MQM experiment: the preparation of a
macroscopic test mass into a nearly minimum-Heisenberg-limited Gaussian quantum
state, which is possible if the interferometer's classical noise beats the SQL
in a broad frequency band. Our formalism, based on Wiener filtering, allows a
straightforward conversion from the classical noise budget of a laser
interferometer, in terms of noise spectra, into the strategy for quantum state
preparation, and the quality of the prepared state. Using this formalism, we
consider how Gaussian entanglement can be built among two macroscopic test
masses, and the performance of the planned Advanced LIGO interferometers in
quantum-state preparation
Searching for a Stochastic Background of Gravitational Waves with LIGO
The Laser Interferometer Gravitational-wave Observatory (LIGO) has performed
the fourth science run, S4, with significantly improved interferometer
sensitivities with respect to previous runs. Using data acquired during this
science run, we place a limit on the amplitude of a stochastic background of
gravitational waves. For a frequency independent spectrum, the new limit is
. This is currently the most sensitive
result in the frequency range 51-150 Hz, with a factor of 13 improvement over
the previous LIGO result. We discuss complementarity of the new result with
other constraints on a stochastic background of gravitational waves, and we
investigate implications of the new result for different models of this
background.Comment: 37 pages, 16 figure
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