494 research outputs found
An anticancer drug suppresses the primary nucleation reaction that initiates the production of the toxic Aβ42 aggregates linked with Alzheimer's disease.
The conversion of the β-amyloid (Aβ) peptide into pathogenic aggregates is linked to the onset and progression of Alzheimer's disease. Although this observation has prompted an extensive search for therapeutic agents to modulate the concentration of Aβ or inhibit its aggregation, all clinical trials with these objectives have so far failed, at least in part because of a lack of understanding of the molecular mechanisms underlying the process of aggregation and its inhibition. To address this problem, we describe a chemical kinetics approach for rational drug discovery, in which the effects of small molecules on the rates of specific microscopic steps in the self-assembly of Aβ42, the most aggregation-prone variant of Aβ, are analyzed quantitatively. By applying this approach, we report that bexarotene, an anticancer drug approved by the U.S. Food and Drug Administration, selectively targets the primary nucleation step in Aβ42 aggregation, delays the formation of toxic species in neuroblastoma cells, and completely suppresses Aβ42 deposition and its consequences in a Caenorhabditis elegans model of Aβ42-mediated toxicity. These results suggest that the prevention of the primary nucleation of Aβ42 by compounds such as bexarotene could potentially reduce the risk of onset of Alzheimer's disease and, more generally, that our strategy provides a general framework for the rational identification of a range of candidate drugs directed against neurodegenerative disorders.This work was supported by the Centre for Misfolding Diseases, University
of Cambridge.This is the final published version. It first appeared at http://advances.sciencemag.org/content/2/2/e1501244
Fast Fluorescence Lifetime Imaging Reveals the Aggregation Processes of α-Synuclein and Polyglutamine in Aging Caenorhabditis elegans.
The nematode worm Caenorhabditis elegans has emerged as an important model organism in the study of the molecular mechanisms of protein misfolding diseases associated with amyloid formation because of its small size, ease of genetic manipulation, and optical transparency. Obtaining a reliable and quantitative read-out of protein aggregation in this system, however, remains a challenge. To address this problem, we here present a fast time-gated fluorescence lifetime imaging (TG-FLIM) method and show that it provides functional insights into the process of protein aggregation in living animals by enabling the rapid characterization of different types of aggregates. Specifically, in longitudinal studies of C. elegans models of Parkinson's and Huntington's diseases, we observed marked differences in the aggregation kinetics and the nature of the protein inclusions formed by α-synuclein and polyglutamine. In particular, we found that α-synuclein inclusions do not display amyloid-like features until late in the life of the worms, whereas polyglutamine forms amyloid characteristics rapidly in early adulthood. Furthermore, we show that the TG-FLIM method is capable of imaging live and non-anaesthetized worms moving in specially designed agarose microchambers. Taken together, our results show that the TG-FLIM method enables high-throughput functional imaging of living C. elegans that can be used to study in vivo mechanisms of protein aggregation and that has the potential to aid the search for therapeutic modifiers of protein aggregation and toxicity
Simple, Fast and Accurate Implementation of the Diffusion Approximation Algorithm for Stochastic Ion Channels with Multiple States
The phenomena that emerge from the interaction of the stochastic opening and
closing of ion channels (channel noise) with the non-linear neural dynamics are
essential to our understanding of the operation of the nervous system. The
effects that channel noise can have on neural dynamics are generally studied
using numerical simulations of stochastic models. Algorithms based on discrete
Markov Chains (MC) seem to be the most reliable and trustworthy, but even
optimized algorithms come with a non-negligible computational cost. Diffusion
Approximation (DA) methods use Stochastic Differential Equations (SDE) to
approximate the behavior of a number of MCs, considerably speeding up
simulation times. However, model comparisons have suggested that DA methods did
not lead to the same results as in MC modeling in terms of channel noise
statistics and effects on excitability. Recently, it was shown that the
difference arose because MCs were modeled with coupled activation subunits,
while the DA was modeled using uncoupled activation subunits. Implementations
of DA with coupled subunits, in the context of a specific kinetic scheme,
yielded similar results to MC. However, it remained unclear how to generalize
these implementations to different kinetic schemes, or whether they were faster
than MC algorithms. Additionally, a steady state approximation was used for the
stochastic terms, which, as we show here, can introduce significant
inaccuracies. We derived the SDE explicitly for any given ion channel kinetic
scheme. The resulting generic equations were surprisingly simple and
interpretable - allowing an easy and efficient DA implementation. The algorithm
was tested in a voltage clamp simulation and in two different current clamp
simulations, yielding the same results as MC modeling. Also, the simulation
efficiency of this DA method demonstrated considerable superiority over MC
methods.Comment: 32 text pages, 10 figures, 1 supplementary text + figur
A systematic variation of the stellar initial mass function in early-type galaxies
Much of our knowledge of galaxies comes from analysing the radiation emitted
by their stars. It depends on the stellar initial mass function (IMF)
describing the distribution of stellar masses when the population formed.
Consequently knowledge of the IMF is critical to virtually every aspect of
galaxy evolution. More than half a century after the first IMF determination,
no consensus has emerged on whether it is universal in different galaxies.
Previous studies indicated that the IMF and the dark matter fraction in galaxy
centres cannot be both universal, but they could not break the degeneracy
between the two effects. Only recently indications were found that massive
elliptical galaxies may not have the same IMF as our Milky Way. Here we report
unambiguous evidence for a strong systematic variation of the IMF in early-type
galaxies as a function of their stellar mass-to-light ratio, producing
differences up to a factor of three in mass. This was inferred from detailed
dynamical models of the two-dimensional stellar kinematics for the large
Atlas3D representative sample of nearby early-type galaxies spanning two orders
of magnitude in stellar mass. Our finding indicates that the IMF depends
intimately on a galaxy's formation history.Comment: 4 pages, 2 figures, LaTeX. Accepted for publication as a Nature
Letter. More information about our Atlas3D project is available at
http://purl.org/atlas3
Massively parallel C. elegans tracking provides multi-dimensional fingerprints for phenotypic discovery.
BACKGROUND: The nematode worm C. elegans is a model organism widely used for studies of genetics and of human disease. The health and fitness of the worms can be quantified in different ways, such as by measuring their bending frequency, speed or lifespan. Manual assays, however, are time consuming and limited in their scope providing a strong motivation for automation. NEW METHOD: We describe the development and application of an advanced machine vision system for characterising the behaviour of C. elegans, the Wide Field-of-View Nematode Tracking Platform (WF-NTP), which enables massively parallel data acquisition and automated multi-parameter behavioural profiling of thousands of worms simultaneously. RESULTS: We screened more than a million worms from several established models of neurodegenerative disorders and characterised the effects of potential therapeutic molecules for Alzheimer's and Parkinson's diseases. By using very large numbers of animals we show that the sensitivity and reproducibility of behavioural assays is very greatly increased. The results reveal the ability of this platform to detect even subtle phenotypes. COMPARISON WITH EXISTING METHODS: The WF-NTP method has substantially greater capacity compared to current automated platforms that typically either focus on characterising single worms at high resolution or tracking the properties of populations of less than 50 animals. CONCLUSIONS: The WF-NTP extends significantly the power of existing automated platforms by combining enhanced optical imaging techniques with an advanced software platform. We anticipate that this approach will further extend the scope and utility of C. elegans as a model organism
Recommended from our members
Observation of an α-synuclein liquid droplet state and its maturation into Lewy body-like assemblies.
Misfolded α-synuclein is a major component of Lewy bodies, which are a hallmark of Parkinson's disease (PD). A large body of evidence shows that α-synuclein can aggregate into amyloid fibrils, but the relationship between α-synuclein self-assembly and Lewy body formation remains unclear. Here, we show, both in vitro and in a Caenorhabditis elegans model of PD, that α-synuclein undergoes liquid‒liquid phase separation by forming a liquid droplet state, which converts into an amyloid-rich hydrogel with Lewy-body-like properties. This maturation process towards the amyloid state is delayed in the presence of model synaptic vesicles in vitro. Taken together, these results suggest that the formation of Lewy bodies may be linked to the arrested maturation of α-synuclein condensates in the presence of lipids and other cellular components.Wellcome Trust (065807/Z/01/Z) (203249/Z/16/Z).
Also, the UK Medical Research Council (MRC) (MR/K02292X/1), Alzheimer Research UK (ARUK) (ARUK-PG013-14), Michael J Fox Foundation (16238) and from Infinitus China Ltd
Low Scale Flavor Gauge Symmetries
We study the possibility of gauging the Standard Model flavor group. Anomaly
cancellation leads to the addition of fermions whose mass is inversely
proportional to the known fermion masses. In this case all flavor violating
effects turn out to be controlled roughly by the Standard Model Yukawa,
suppressing transitions for the light generations. Due to the inverted
hierarchy the scale of new gauge flavor bosons could be as low as the
electroweak scale without violating any existing bound but accessible at the
Tevatron and the LHC. The mechanism of flavor protection potentially provides
an alternative to Minimal Flavor Violation, with flavor violating effects
suppressed by hierarchy of scales rather than couplings.Comment: 24 pages + appendices; v2) Refs. added and numerical examples
improved. Results unchanged; v3) small typos in appendix B correcte
Observation of an α-synuclein liquid droplet state and its maturation into Lewy body-like assemblies.
Misfolded α-synuclein is a major component of Lewy bodies, which are a hallmark of Parkinson's disease (PD). A large body of evidence shows that α-synuclein can aggregate into amyloid fibrils, but the relationship between α-synuclein self-assembly and Lewy body formation remains unclear. Here, we show, both in vitro and in a Caenorhabditis elegans model of PD, that α-synuclein undergoes liquid‒liquid phase separation by forming a liquid droplet state, which converts into an amyloid-rich hydrogel with Lewy-body-like properties. This maturation process towards the amyloid state is delayed in the presence of model synaptic vesicles in vitro. Taken together, these results suggest that the formation of Lewy bodies may be linked to the arrested maturation of α-synuclein condensates in the presence of lipids and other cellular components.Wellcome Trust (065807/Z/01/Z) (203249/Z/16/Z).
Also, the UK Medical Research Council (MRC) (MR/K02292X/1), Alzheimer Research UK (ARUK) (ARUK-PG013-14), Michael J Fox Foundation (16238) and from Infinitus China Ltd
Searches for Long Lived Neutral Particles
An intriguing possibility for TeV scale physics is the existence of neutral
long lived particles (LOLIPs) that subsequently decay into SM states. Such
particles are many cases indistinguishable from missing transverse energy (MET)
at colliders. We propose new methods to search for these particles using
neutrino telescopes. We study their detection prospects, assuming production
either at the LHC or through dark matter (DM) annihilations in the Sun and the
Earth. We find that the sensitivity for LOLIPs produced at the LHC is limited
by luminosity and detection energy thresholds. On the other hand, in the case
of DM annihilation into LOLIPs, the sensitivity of neutrino telescopes is
promising and may extend beyond the reach of upcoming direct detection
experiments. In the context of low scale hidden sectors weakly coupled to the
SM, such indirect searches allow to probe couplings as small as 10^-15.Comment: 22 pages, 6 figure
- …