338 research outputs found
Kinesin light chain-1 serine-460 phosphorylation is altered in Alzheimer's disease and regulates axonal transport and processing of the amyloid precursor protein
Damage to axonal transport is an early pathogenic event in Alzheimer's disease. The amyloid precursor protein (APP) is a key axonal transport cargo since disruption to APP transport promotes amyloidogenic processing of APP. Moreover, altered APP processing itself disrupts axonal transport. The mechanisms that regulate axonal transport of APP are therefore directly relevant to Alzheimer's disease pathogenesis. APP is transported anterogradely through axons on kinesin-1 motors and one route for this transport involves calsyntenin-1, a type-1 membrane spanning protein that acts as a direct ligand for kinesin-1 light chains (KLCs). Thus, loss of calsyntenin-1 disrupts APP axonal transport and promotes amyloidogenic processing of APP. Phosphorylation of KLC1 on serine-460 has been shown to reduce anterograde axonal transport of calsyntenin-1 by inhibiting the KLC1-calsyntenin-1 interaction. Here we demonstrate that in Alzheimer's disease frontal cortex, KLC1 levels are reduced and the relative levels of KLC1 serine-460 phosphorylation are increased; these changes occur relatively early in the disease process. We also show that a KLC1 serine-460 phosphomimetic mutant inhibits axonal transport of APP in both mammalian neurons in culture and in Drosophila neurons in vivo. Finally, we demonstrate that expression of the KLC1 serine-460 phosphomimetic mutant promotes amyloidogenic processing of APP. Together, these results suggest that increased KLC1 serine-460 phosphorylation contributes to Alzheimer's disease
Current Status of Simulations
As the title suggests, the purpose of this chapter is to review the current
status of numerical simulations of black hole accretion disks. This chapter
focuses exclusively on global simulations of the accretion process within a few
tens of gravitational radii of the black hole. Most of the simulations
discussed are performed using general relativistic magnetohydrodynamic (MHD)
schemes, although some mention is made of Newtonian radiation MHD simulations
and smoothed particle hydrodynamics. The goal is to convey some of the exciting
work that has been going on in the past few years and provide some speculation
on future directions.Comment: 15 pages, 14 figures, to appear in the proceedings of the ISSI-Bern
workshop on "The Physics of Accretion onto Black Holes" (8-12 October 2012
Modulational Instability in Equations of KdV Type
It is a matter of experience that nonlinear waves in dispersive media,
propagating primarily in one direction, may appear periodic in small space and
time scales, but their characteristics --- amplitude, phase, wave number, etc.
--- slowly vary in large space and time scales. In the 1970's, Whitham
developed an asymptotic (WKB) method to study the effects of small
"modulations" on nonlinear periodic wave trains. Since then, there has been a
great deal of work aiming at rigorously justifying the predictions from
Whitham's formal theory. We discuss recent advances in the mathematical
understanding of the dynamics, in particular, the instability of slowly
modulated wave trains for nonlinear dispersive equations of KdV type.Comment: 40 pages. To appear in upcoming title in Lecture Notes in Physic
The Role of Color Neutrality in Nuclear Physics--Modifications of Nucleonic Wave Functions
The influence of the nuclear medium upon the internal structure of a
composite nucleon is examined. The interaction with the medium is assumed to
depend on the relative distances between the quarks in the nucleon consistent
with the notion of color neutrality, and to be proportional to the nucleon
density. In the resulting description the nucleon in matter is a superposition
of the ground state (free nucleon) and radial excitations. The effects of the
nuclear medium on the electromagnetic and weak nucleon form factors, and the
nucleon structure function are computed using a light-front constituent quark
model. Further experimental consequences are examined by considering the
electromagnetic nuclear response functions. The effects of color neutrality
supply small but significant corrections to predictions of observables.Comment: 37 pages, postscript figures available on request to
[email protected]
Black Hole Spin via Continuum Fitting and the Role of Spin in Powering Transient Jets
The spins of ten stellar black holes have been measured using the
continuum-fitting method. These black holes are located in two distinct classes
of X-ray binary systems, one that is persistently X-ray bright and another that
is transient. Both the persistent and transient black holes remain for long
periods in a state where their spectra are dominated by a thermal accretion
disk component. The spin of a black hole of known mass and distance can be
measured by fitting this thermal continuum spectrum to the thin-disk model of
Novikov and Thorne; the key fit parameter is the radius of the inner edge of
the black hole's accretion disk. Strong observational and theoretical evidence
links the inner-disk radius to the radius of the innermost stable circular
orbit, which is trivially related to the dimensionless spin parameter a_* of
the black hole (|a_*| < 1). The ten spins that have so far been measured by
this continuum-fitting method range widely from a_* \approx 0 to a_* > 0.95.
The robustness of the method is demonstrated by the dozens or hundreds of
independent and consistent measurements of spin that have been obtained for
several black holes, and through careful consideration of many sources of
systematic error. Among the results discussed is a dichotomy between the
transient and persistent black holes; the latter have higher spins and larger
masses. Also discussed is recently discovered evidence in the transient sources
for a correlation between the power of ballistic jets and black hole spin.Comment: 30 pages. Accepted for publication in Space Science Reviews. Also to
appear in hard cover in the Space Sciences Series of ISSI "The Physics of
Accretion onto Black Holes" (Springer Publisher). Changes to Sections 5.2,
6.1 and 7.4. Section 7.4 responds to Russell et al. 2013 (MNRAS, 431, 405)
who find no evidence for a correlation between the power of ballistic jets
and black hole spi
Measurement of the scintillation time spectra and pulse-shape discrimination of low-energy beta and nuclear recoils in liquid argon with DEAP-1
The DEAP-1 low-background liquid argon detector was used to measure
scintillation pulse shapes of electron and nuclear recoil events and to
demonstrate the feasibility of pulse-shape discrimination (PSD) down to an
electron-equivalent energy of 20 keV.
In the surface dataset using a triple-coincidence tag we found the fraction
of beta events that are misidentified as nuclear recoils to be (90% C.L.) for energies between 43-86 keVee and for a nuclear recoil
acceptance of at least 90%, with 4% systematic uncertainty on the absolute
energy scale. The discrimination measurement on surface was limited by nuclear
recoils induced by cosmic-ray generated neutrons. This was improved by moving
the detector to the SNOLAB underground laboratory, where the reduced background
rate allowed the same measurement with only a double-coincidence tag.
The combined data set contains events. One of those, in the
underground data set, is in the nuclear-recoil region of interest. Taking into
account the expected background of 0.48 events coming from random pileup, the
resulting upper limit on the electronic recoil contamination is
(90% C.L.) between 44-89 keVee and for a nuclear recoil
acceptance of at least 90%, with 6% systematic uncertainty on the absolute
energy scale.
We developed a general mathematical framework to describe PSD parameter
distributions and used it to build an analytical model of the distributions
observed in DEAP-1. Using this model, we project a misidentification fraction
of approx. for an electron-equivalent energy threshold of 15 keV for
a detector with 8 PE/keVee light yield. This reduction enables a search for
spin-independent scattering of WIMPs from 1000 kg of liquid argon with a
WIMP-nucleon cross-section sensitivity of cm, assuming
negligible contribution from nuclear recoil backgrounds.Comment: Accepted for publication in Astroparticle Physic
Supermassive Black Hole Binaries: The Search Continues
Gravitationally bound supermassive black hole binaries (SBHBs) are thought to
be a natural product of galactic mergers and growth of the large scale
structure in the universe. They however remain observationally elusive, thus
raising a question about characteristic observational signatures associated
with these systems. In this conference proceeding I discuss current theoretical
understanding and latest advances and prospects in observational searches for
SBHBs.Comment: 17 pages, 4 figures. To appear in the Proceedings of 2014 Sant Cugat
Forum on Astrophysics. Astrophysics and Space Science Proceedings, ed.
C.Sopuerta (Berlin: Springer-Verlag
An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics
For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale. Analysis of clinicopathologic annotations for over 11,000 cancer patients in the TCGA program leads to the generation of TCGA Clinical Data Resource, which provides recommendations of clinical outcome endpoint usage for 33 cancer types
Macroalgal meadow habitats support fish and fisheries in diverse tropical seascapes
Canopy-forming macroalgae can construct extensive meadow habitats in tropical seascapes occupied by fishes that span a diversity of taxa, life-history stages and ecological roles. Our synthesis assessed whether these tropical macroalgal habitats have unique fish assemblages, provide fish nurseries and support local fisheries. We also applied a meta-analysis of independent surveys across 23 tropical reef locations in 11 countries to examine how macroalgal canopy condition is related to the abundance of macroalgal-associated fishes. Over 627 fish species were documented in tropical macroalgal meadows, with 218 of these taxa exhibiting higher local abundance within this habitat (cf. nearby coral reef) during at least one life-history stage. Major overlap (40%–43%) in local fish species richness among macroalgal and seagrass or coral reef habitats suggest macroalgal meadows may provide an important habitat refuge. Moreover, the prominence of juvenile fishes suggests macroalgal meadows facilitate the triphasic life cycle of many fishes occupying diverse tropical seascapes. Correlations between macroalgal canopy structure and juvenile abundance suggests macroalgal habitat condition can influence levels of replenishment in tropical fish populations, including the majority of macroalgal-associated fishes that are targeted by commercial, subsistence or recreational fisheries. While many macroalgal-associated fishery species are of minor commercial value, their local importance for food and livelihood security can be substantial (e.g. up to 60% of landings in Kenyan reef fisheries). Given that macroalgal canopy condition can vary substantially with sea temperature, there is a high likelihood that climate change will impact macroalgal-associated fish and fisheries
Whole genome analysis of a schistosomiasis-transmitting freshwater snail
Biomphalaria snails are instrumental in transmission of the human blood fluke Schistosoma mansoni. With the World Health Organization's goal to eliminate schistosomiasis as a global health problem by 2025, there is now renewed emphasis on snail control. Here, we characterize the genome of Biomphalaria glabrata, a lophotrochozoan protostome, and provide timely and important information on snail biology. We describe aspects of phero-perception, stress responses, immune function and regulation of gene expression that support the persistence of B. glabrata in the field and may define this species as a suitable snail host for S. mansoni. We identify several potential targets for developing novel control measures aimed at reducing snail-mediated transmission of schistosomiasis
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