265 research outputs found
Dysregulation of Na+/K+ ATPase by amyloid in APP+PS1 transgenic mice
BACKGROUND: The pathology of Alzheimer's disease (AD) is comprised of extracellular amyloid plaques, intracellular tau tangles, dystrophic neurites and neurodegeneration. The mechanisms by which these various pathological features arise are under intense investigation. Here, expanding upon pilot gene expression studies, we have further analyzed the relationship between Na+/K+ ATPase and amyloid using APP+PS1 transgenic mice, a model that develops amyloid plaques and memory deficits in the absence of tangle formation and neuronal or synaptic loss. RESULTS: We report that in addition to decreased mRNA expression, there was decreased overall Na+/K+ ATPase enzyme activity in the amyloid-containing hippocampi of the APP+PS1 mice (although not in the amyloid-free cerebellum). In addition, dual immunolabeling revealed an absence of Na+/K+ ATPase staining in a zone surrounding congophilic plaques that was occupied by dystrophic neurites. We also demonstrate that cerebral Na+/K+ ATPase activity can be directly inhibited by high concentrations of soluble Aβ. CONCLUSIONS: The data suggest that the reductions in Na+/K+ ATPase activity in Alzheimer tissue may not be purely secondary to neuronal loss, but may results from direct effects of amyloid on this enzyme. This disruption of ion homeostasis and osmotic balance may interfere with normal electrotonic properties of dendrites, blocking intraneuronal signal processing, and contribute to neuritic dystrophia. These results suggest that therapies aimed at enhancing Na+/K+ ATPase activity in AD may improve symptoms and/or delay disease progression
Activation of matrix metalloproteinases following anti-Aβ immunotherapy; implications for microhemorrhage occurrence
<p>Abstract</p> <p>Background</p> <p>Anti-Aβ immunotherapy is a promising approach to the prevention and treatment of Alzheimer's disease (AD) currently in clinical trials. There is extensive evidence, both in mice and humans that a significant adverse event is the occurrence of microhemorrhages. Also, vasogenic edema was reported in phase 2 of a passive immunization clinical trial. In order to overcome these vascular adverse effects it is critical that we understand the mechanism(s) by which they occur.</p> <p>Methods</p> <p>We have examined the matrix metalloproteinase (MMP) protein degradation system in two previously published anti-Aβ immunotherapy studies. The first was a passive immunization study in which we examined 22 month old APPSw mice that had received anti-Aβ antibodies for 1, 2 or 3 months. The second is an active vaccination study in which we examined 16 month old APPSw/NOS2-/- mice treated with Aβ vaccination for 4 months.</p> <p>Results</p> <p>There is a significant activation of the MMP2 and MMP9 proteinase degradation systems by anti-Aβ immunotherapy, regardless of whether this is delivered through active vaccination or passive immunization. We have characterized this activation by gene expression, protein expression and zymography assessment of MMP activity.</p> <p>Conclusions</p> <p>Since the MMP2 and MMP9 systems are heavily implicated in the pathophysiology of intracerbral hemorrhage, these data may provide a potential mechanism of microhemorrhage due to immunotherapy. Increased activity of the MMP system, therefore, is likely to be a major factor in increased microhemorrhage occurrence.</p
An Inducible, Isogenic Cancer Cell Line System for Targeting the State of Mismatch Repair Deficiency
The DNA mismatch repair system (MMR) maintains genome stability through recognition and repair of single-base mismatches and small insertion-deletion loops. Inactivation of the MMR pathway causes microsatellite instability and the accumulation of genomic mutations that can cause or contribute to cancer. In fact, 10-20% of certain solid and hematologic cancers are MMR-deficient. MMR-deficient cancers do not respond to some standard of care chemotherapeutics because of presumed increased tolerance of DNA damage, highlighting the need for novel therapeutic drugs. Toward this goal, we generated isogenic cancer cell lines for direct comparison of MMR-proficient and MMR-deficient cells. We engineered NCI-H23 lung adenocarcinoma cells to contain a doxycycline-inducible shRNA designed to suppress the expression of the mismatch repair gene MLH1, and compared single cell subclones that were uninduced (MLH1-proficient) versus induced for the MLH1 shRNA (MLH1-deficient). Here we present the characterization of these MMR-inducible cell lines and validate a novel class of rhodium metalloinsertor compounds that differentially inhibit the proliferation of MMR-deficient cancer cells
Saturn's emitted power
Long-term (2004–2009) on-orbit observations by Cassini Composite Infrared Spectrometer are analyzed to precisely measure Saturn's emitted power and its meridional distribution. Our evaluations suggest that the average global emitted power is 4.952 ± 0.035 W m^(−2) during the period of 2004–2009. The corresponding effective temperature is 96.67 ± 0.17 K. The emitted power is 16.6% higher in the Southern Hemisphere than in the Northern Hemisphere. From 2005 to 2009, the global mean emitted power and effective temperature decreased by ~2% and ~0.5%, respectively. Our study further reveals the interannual variability of emitted power and effective temperature between the epoch of Voyager (~1 Saturn year ago) and the current epoch of Cassini, suggesting changes in the cloud opacity from year to year on Saturn. The seasonal and interannual variability of emitted power implies that the energy balance and internal heat are also varying
Forward Neutral Pion Transverse Single Spin Asymmetries in p+p Collisions at \sqrt{s}=200 GeV
We report precision measurements of the Feynman-x dependence, and first
measurements of the transverse momentum dependence, of transverse single spin
asymmetries for the production of \pi^0 mesons from polarized proton collisions
at \sqrt{s}=200 GeV. The x_F dependence of the results is in fair agreement
with perturbative QCD model calculations that identify orbital motion of quarks
and gluons within the proton as the origin of the spin effects. Results for the
p_T dependence at fixed x_F are not consistent with pQCD-based calculations.Comment: 6 pages, 4 figure
Reduction Algorithms for the Multiband Imaging Photometer for Spitzer
We describe the data reduction algorithms for the Multiband Imaging
Photometer for Spitzer (MIPS) instrument. These algorithms were based on
extensive preflight testing and modeling of the Si:As (24 micron) and Ge:Ga (70
and 160 micron) arrays in MIPS and have been refined based on initial flight
data. The behaviors we describe are typical of state-of-the-art infrared focal
planes operated in the low backgrounds of space. The Ge arrays are bulk
photoconductors and therefore show a variety of artifacts that must be removed
to calibrate the data. The Si array, while better behaved than the Ge arrays,
does show a handful of artifacts that also must be removed to calibrate the
data. The data reduction to remove these effects is divided into three parts.
The first part converts the non-destructively read data ramps into slopes while
removing artifacts with time constants of the order of the exposure time. The
second part calibrates the slope measurements while removing artifacts with
time constants longer than the exposure time. The third part uses the
redundancy inherit in the MIPS observing modes to improve the artifact removal
iteratively. For each of these steps, we illustrate the relevant laboratory
experiments or theoretical arguments along with the mathematical approaches
taken to calibrate the data. Finally, we describe how these preflight
algorithms have performed on actual flight data.Comment: 21 pages, 16 figures, PASP accepted (May 2005 issue), version of
paper with full resolution images is available at
http://dirty.as.arizona.edu/~kgordon/papers/PS_files/mips_dra.pd
Indications of Conical Emission of Charged Hadrons at the BNL Relativistic Heavy Ion Collider
Three-particle azimuthal correlation measurements with a high transverse
momentum trigger particle are reported for pp, d+Au, and Au+Au collisions at
200 GeV by the STAR experiment. Dijet structures are observed in pp, d+Au and
peripheral Au+Au collisions. An additional structure is observed in central
Au+Au data, signaling conical emission of correlated charged hadrons. The
conical emission angle is found to be 1.37 +- 0.02(stat) +0.06-0.07(syst),
independent of pt.Comment: 7 pages, 4 figures, 1 tabl
SDSS-III: Massive Spectroscopic Surveys of the Distant Universe, the Milky Way Galaxy, and Extra-Solar Planetary Systems
Building on the legacy of the Sloan Digital Sky Survey (SDSS-I and II),
SDSS-III is a program of four spectroscopic surveys on three scientific themes:
dark energy and cosmological parameters, the history and structure of the Milky
Way, and the population of giant planets around other stars. In keeping with
SDSS tradition, SDSS-III will provide regular public releases of all its data,
beginning with SDSS DR8 (which occurred in Jan 2011). This paper presents an
overview of the four SDSS-III surveys. BOSS will measure redshifts of 1.5
million massive galaxies and Lya forest spectra of 150,000 quasars, using the
BAO feature of large scale structure to obtain percent-level determinations of
the distance scale and Hubble expansion rate at z<0.7 and at z~2.5. SEGUE-2,
which is now completed, measured medium-resolution (R=1800) optical spectra of
118,000 stars in a variety of target categories, probing chemical evolution,
stellar kinematics and substructure, and the mass profile of the dark matter
halo from the solar neighborhood to distances of 100 kpc. APOGEE will obtain
high-resolution (R~30,000), high signal-to-noise (S/N>100 per resolution
element), H-band (1.51-1.70 micron) spectra of 10^5 evolved, late-type stars,
measuring separate abundances for ~15 elements per star and creating the first
high-precision spectroscopic survey of all Galactic stellar populations (bulge,
bar, disks, halo) with a uniform set of stellar tracers and spectral
diagnostics. MARVELS will monitor radial velocities of more than 8000 FGK stars
with the sensitivity and cadence (10-40 m/s, ~24 visits per star) needed to
detect giant planets with periods up to two years, providing an unprecedented
data set for understanding the formation and dynamical evolution of giant
planet systems. (Abridged)Comment: Revised to version published in The Astronomical Journa
The James Webb Space Telescope Mission
Twenty-six years ago a small committee report, building on earlier studies,
expounded a compelling and poetic vision for the future of astronomy, calling
for an infrared-optimized space telescope with an aperture of at least .
With the support of their governments in the US, Europe, and Canada, 20,000
people realized that vision as the James Webb Space Telescope. A
generation of astronomers will celebrate their accomplishments for the life of
the mission, potentially as long as 20 years, and beyond. This report and the
scientific discoveries that follow are extended thank-you notes to the 20,000
team members. The telescope is working perfectly, with much better image
quality than expected. In this and accompanying papers, we give a brief
history, describe the observatory, outline its objectives and current observing
program, and discuss the inventions and people who made it possible. We cite
detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space
Telescope Overview, 29 pages, 4 figure
- …