99 research outputs found
Genetic modulation of soluble Aβ rescues cognitive and synaptic impairment in a mouse model of Alzheimer\u27s disease
An unresolved debate in Alzheimer's disease (AD) is whether amyloid plaques are pathogenic, causing overt physical disruption of neural circuits, or protective, sequestering soluble forms of amyloid-β (Aβ) that initiate synaptic damage and cognitive decline. Few animal models of AD have been capable of isolating the relative contribution made by soluble and insoluble forms of Aβ to the behavioral symptoms and biochemical consequences of the disease. Here we use a controllable transgenic mouse model expressing a mutant form of amyloid precursor protein (APP) to distinguish the impact of soluble Aβ from that of deposited amyloid on cognitive function and synaptic structure. Rapid inhibition of transgenic APP modulated the production of Aβ without affecting pre-existing amyloid deposits and restored cognitive performance to the level of healthy controls in Morris water maze, radial arm water maze, and fear conditioning. Selective reduction of Aβ with a γ-secretase inhibitor provided similar improvement, suggesting that transgene suppression restored cognition, at least in part by lowering Aβ. Cognitive improvement coincided with reduced levels of synaptotoxic Aβ oligomers, greater synaptic density surrounding amyloid plaques, and increased expression of presynaptic and postsynaptic markers. Together these findings indicate that transient Aβ species underlie much of the cognitive and synaptic deficits observed in this model and demonstrate that significant functional and structural recovery can be attained without removing deposited amyloid
Sensitive detection of Cre-mediated recombination using droplet digital PCR reveals Tg(BGLAP-Cre) and Tg(DMP1-Cre) are active in multiple non-skeletal tissues
In humans, somatic activating mutations in PIK3CA are associated with skeletal overgrowth. In order to determine if activated PI3K signaling in bone cells causes overgrowth, we used Tg(BGLAP-Cre) and Tg(DMP1-Cre) mouse strains to somatically activate a disease-causing conditional Pik3ca allele (Pik3caH1047R) in osteoblasts and osteocytes. We observed Tg(BGLAP-Cre);Pik3caH1047R/+ offspring were born at the expected Mendelian frequency. However, these mice developed cutaneous lymphatic malformations and died before 7 weeks of age. In contrast, Tg(DMP1-Cre);Pik3caH1047R/+ offspring survived and had no cutaneous lymphatic malformations. Assuming that Cre-activity outside of the skeletal system accounted for the difference in phenotype between Tg(BGLAP-Cre);Pik3caH1047R/+ and Tg(DMP1-Cre);Pik3caH1047R/+ mice, we developed sensitive and specific droplet digital PCR (ddPCR) assays to search for and quantify rates of Tg(BGLAP-Cre)- and Tg(DMP1-Cre)-mediated recombination in non-skeletal tissues. We observed Tg(BGLAP-Cre)-mediated recombination in several tissues including skin, muscle, artery, and brain; two CNS locations, hippocampus and cerebellum, exhibited Cre-mediated recombination in >5% of cells. Tg(DMP1-Cre)-mediated recombination was also observed in muscle, artery, and brain. Although we cannot preclude that differences in phenotype between mice with Tg(BGLAP-Cre)- and Tg(DMP1-Cre)-mediated PIK3CA activation are due to Cre-recombination being induced at different stages of osteoblast differentiation, differences in recombination at non-skeletal sites are the more likely explanation. Since unanticipated sites of recombination can affect the interpretation of data from experiments involving conditional alleles, we recommend ddPCR as a good first step for assessing efficiency, leakiness, and off-targeting in experiments that employ Cre-mediated or Flp-mediated recombination
Attitudes of healthcare workers in U.S. hospitals regarding smallpox vaccination
BACKGROUND: The United States is implementing plans to immunize 500,000 hospital-based healthcare workers against smallpox. Vaccination is voluntary, and it is unknown what factors drive vaccine acceptance. This study's aims were to estimate the proportion of workers willing to accept vaccination and to identify factors likely to influence their decisions. METHODS: The survey was conducted among physicians, nurses, and others working primarily in emergency departments or intensive care units at 21 acute-care hospitals in 10 states during the two weeks before the U.S. national immunization program for healthcare workers was announced in December 2002. Of the questionnaires distributed, 1,165 were returned, for a response rate of 81%. The data were analyzed by logistic regression and were adjusted for clustering within hospital and for different number of responses per hospital, using generalized linear mixed models and SAS's NLMIXED procedure. RESULTS: Sixty-one percent of respondents said they would definitely or probably be vaccinated, while 39% were undecided or inclined against it. Fifty-three percent rated the risk of a bioterrorist attack using smallpox in the United States in the next two years as either intermediate or high. Forty-seven percent did not feel well-informed about the risks and benefits of vaccination. Principal concerns were adverse reactions and the risk of transmitting vaccinia. In multivariate analysis, four variables were associated with willingness to be vaccinated: perceived risk of an attack, self-assessed knowledge about smallpox vaccination, self-assessed previous smallpox vaccination status, and gender. CONCLUSIONS: The success of smallpox vaccination efforts will ultimately depend on the relative weight in people's minds of the risk of vaccine adverse events compared with the risk of being exposed to the disease. Although more than half of the respondents thought the likelihood of a bioterrorist smallpox attack was intermediate or high, less than 10% of the group slated for vaccination has actually accepted it at this time. Unless new information about the threat of a smallpox attack becomes available, healthcare workers' perceptions of the vaccine's risks will likely continue to drive their ongoing decisions about smallpox vaccination
The Atacama Cosmology Telescope: A Measurement of the Thermal Sunyaev-Zel'dovich Effect Using the Skewness of the CMB Temperature Distribution
We present a detection of the unnormalized skewness induced by the
thermal Sunyaev-Zel'dovich (tSZ) effect in filtered Atacama Cosmology Telescope
(ACT) 148 GHz cosmic microwave background temperature maps. Contamination due
to infrared and radio sources is minimized by template subtraction of resolved
sources and by constructing a mask using outlying values in the 218 GHz
(tSZ-null) ACT maps. We measure = -31 +- 6 \mu K^3 (measurement error
only) or +- 14 \mu K^3 (including cosmic variance error) in the filtered ACT
data, a 5-sigma detection. We show that the skewness is a sensitive probe of
sigma_8, and use analytic calculations and tSZ simulations to obtain
cosmological constraints from this measurement. From this signal alone we infer
a value of sigma_8= 0.79 +0.03 -0.03 (68 % C.L.) +0.06 -0.06 (95 % C.L.). Our
results demonstrate that measurements of non-Gaussianity can be a useful method
for characterizing the tSZ effect and extracting the underlying cosmological
information.Comment: 9 pages, 5 figures. Replaced with version accepted by Phys. Rev. D,
with improvements to the likelihood function and the IR source treatment;
only minor changes in the result
The Atacama Cosmology Telescope: Sunyaev-Zel'dovich Selected Galaxy Clusters at 148 GHz from Three Seasons of Data
[Abridged] We present a catalog of 68 galaxy clusters, of which 19 are new
discoveries, detected via the Sunyaev-Zel'dovich effect (SZ) at 148 GHz in the
Atacama Cosmology Telescope (ACT) survey of 504 square degrees on the celestial
equator. A subsample of 48 clusters within the 270 square degree region
overlapping SDSS Stripe 82 is estimated to be 90% complete for M_500c > 4.5e14
Msun and 0.15 < z < 0.8. While matched filters are used to detect the clusters,
the sample is studied further through a "Profile Based Amplitude Analysis"
using a single filter at a fixed \theta_500 = 5.9' angular scale. This new
approach takes advantage of the "Universal Pressure Profile" (UPP) to fix the
relationship between the cluster characteristic size (R_500) and the integrated
Compton parameter (Y_500). The UPP scalings are found to be nearly identical to
an adiabatic model, while a model incorporating non-thermal pressure better
matches dynamical mass measurements and masses from the South Pole Telescope. A
high signal to noise ratio subsample of 15 ACT clusters is used to obtain
cosmological constraints. We first confirm that constraints from SZ data are
limited by uncertainty in the scaling relation parameters rather than sample
size or measurement uncertainty. We next add in seven clusters from the ACT
Southern survey, including their dynamical mass measurements based on galaxy
velocity dispersions. In combination with WMAP7 these data simultaneously
constrain the scaling relation and cosmological parameters, yielding \sigma_8 =
0.829 \pm 0.024 and \Omega_m = 0.292 \pm 0.025. The results include
marginalization over a 15% bias in dynamical mass relative to the true halo
mass. In an extension to LCDM that incorporates non-zero neutrino mass density,
we combine our data with WMAP7+BAO+Hubble constant measurements to constrain
\Sigma m_\nu < 0.29 eV (95% C. L.).Comment: 32 pages, 21 figures To appear in J. Cosmology and Astroparticle
Physic
The Atacama Cosmology Telescope: Temperature and Gravitational Lensing Power Spectrum Measurements from Three Seasons of Data
We present the temperature power spectra of the cosmic microwave background
(CMB) derived from the three seasons of data from the Atacama Cosmology
Telescope (ACT) at 148 GHz and 218 GHz, as well as the cross-frequency spectrum
between the two channels. We detect and correct for contamination due to the
Galactic cirrus in our equatorial maps. We present the results of a number of
tests for possible systematic error and conclude that any effects are not
significant compared to the statistical errors we quote. Where they overlap, we
cross-correlate the ACT and the South Pole Telescope (SPT) maps and show they
are consistent. The measurements of higher-order peaks in the CMB power
spectrum provide an additional test of the Lambda CDM cosmological model, and
help constrain extensions beyond the standard model. The small angular scale
power spectrum also provides constraining power on the Sunyaev-Zel'dovich
effects and extragalactic foregrounds. We also present a measurement of the CMB
gravitational lensing convergence power spectrum at 4.6-sigma detection
significance.Comment: 21 pages; 20 figures, Submitted to JCAP, some typos correcte
The Atacama Cosmology Telescope: Dynamical Masses and Scaling Relations for a Sample of Massive Sunyaev-Zel'dovich Effect Selected Galaxy Clusters
We present the first dynamical mass estimates and scaling relations for a
sample of Sunyaev-Zel'dovich effect (SZE) selected galaxy clusters. The sample
consists of 16 massive clusters detected with the Atacama Cosmology Telescope
(ACT) over a 455 sq. deg. area of the southern sky. Deep multi-object
spectroscopic observations were taken to secure intermediate-resolution
(R~700-800) spectra and redshifts for ~60 member galaxies on average per
cluster. The dynamical masses M_200c of the clusters have been calculated using
simulation-based scaling relations between velocity dispersion and mass. The
sample has a median redshift z=0.50 and a median mass M_200c~12e14 Msun/h70
with a lower limit M_200c~6e14 Msun/h70, consistent with the expectations for
the ACT southern sky survey. These masses are compared to the ACT SZE
properties of the sample, specifically, the match-filtered central SZE
amplitude y, the central Compton parameter y0, and the integrated Compton
signal Y_200c, which we use to derive SZE-Mass scaling relations. All SZE
estimators correlate with dynamical mass with low intrinsic scatter (<~20%), in
agreement with numerical simulations. We explore the effects of various
systematic effects on these scaling relations, including the correlation
between observables and the influence of dynamically disturbed clusters. Using
the 3-dimensional information available, we divide the sample into relaxed and
disturbed clusters and find that ~50% of the clusters are disturbed. There are
hints that disturbed systems might bias the scaling relations but given the
current sample sizes these differences are not significant; further studies
including more clusters are required to assess the impact of these clusters on
the scaling relations.Comment: 15 pages, 4 figures. Accepted for publication in The Astrophysical
Journal; matches published version. Full Table 8 with complete spectroscopic
member sample available in machine-readable form in the journal site and upon
request to C. Sif\'o
The Atacama Cosmology Telescope: Data Characterization and Map Making
We present a description of the data reduction and mapmaking pipeline used
for the 2008 observing season of the Atacama Cosmology Telescope (ACT). The
data presented here at 148 GHz represent 12% of the 90 TB collected by ACT from
2007 to 2010. In 2008 we observed for 136 days, producing a total of 1423 hours
of data (11 TB for the 148 GHz band only), with a daily average of 10.5 hours
of observation. From these, 1085 hours were devoted to a 850 deg^2 stripe (11.2
hours by 9.1 deg) centered on a declination of -52.7 deg, while 175 hours were
devoted to a 280 deg^2 stripe (4.5 hours by 4.8 deg) centered at the celestial
equator. We discuss sources of statistical and systematic noise, calibration,
telescope pointing, and data selection. Out of 1260 survey hours and 1024
detectors per array, 816 hours and 593 effective detectors remain after data
selection for this frequency band, yielding a 38% survey efficiency. The total
sensitivity in 2008, determined from the noise level between 5 Hz and 20 Hz in
the time-ordered data stream (TOD), is 32 micro-Kelvin sqrt{s} in CMB units.
Atmospheric brightness fluctuations constitute the main contaminant in the data
and dominate the detector noise covariance at low frequencies in the TOD. The
maps were made by solving the least-squares problem using the Preconditioned
Conjugate Gradient method, incorporating the details of the detector and noise
correlations. Cross-correlation with WMAP sky maps, as well as analysis from
simulations, reveal that our maps are unbiased at multipoles ell > 300. This
paper accompanies the public release of the 148 GHz southern stripe maps from
2008. The techniques described here will be applied to future maps and data
releases.Comment: 20 pages, 18 figures, 6 tables, an ACT Collaboration pape
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