1,813 research outputs found
Amyloid-β acts as a regulator of neurotransmitter release disrupting the interaction between synaptophysin and VAMP2.
BACKGROUND: It is becoming increasingly evident that deficits in the cortex and hippocampus at early stages of dementia in Alzheimer's disease (AD) are associated with synaptic damage caused by oligomers of the toxic amyloid-β peptide (Aβ42). However, the underlying molecular and cellular mechanisms behind these deficits are not fully understood. Here we provide evidence of a mechanism by which Aβ42 affects synaptic transmission regulating neurotransmitter release.
METHODOLOGY/FINDINGS: We first showed that application of 50 nM Aβ42 in cultured neurones is followed by its internalisation and translocation to synaptic contacts. Interestingly, our results demonstrate that with time, Aβ42 can be detected at the presynaptic terminals where it interacts with Synaptophysin. Furthermore, data from dissociated hippocampal neurons as well as biochemical data provide evidence that Aβ42 disrupts the complex formed between Synaptophysin and VAMP2 increasing the amount of primed vesicles and exocytosis. Finally, electrophysiology recordings in brain slices confirmed that Aβ42 affects baseline transmission.
CONCLUSIONS/SIGNIFICANCE: Our observations provide a necessary and timely insight into cellular mechanisms that underlie the initial pathological events that lead to synaptic dysfunction in Alzheimer's disease. Our results demonstrate a new mechanism by which Aβ42 affects synaptic activity
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Amyloid-ß Acts as a regulator of neurotransmitter release disrupting the interaction between synaptophysin and VAMP2
Magnetism, FeS colloids, and Origins of Life
A number of features of living systems: reversible interactions and weak
bonds underlying motor-dynamics; gel-sol transitions; cellular connected
fractal organization; asymmetry in interactions and organization; quantum
coherent phenomena; to name some, can have a natural accounting via
interactions, which we therefore seek to incorporate by expanding the horizons
of `chemistry-only' approaches to the origins of life. It is suggested that the
magnetic 'face' of the minerals from the inorganic world, recognized to have
played a pivotal role in initiating Life, may throw light on some of these
issues. A magnetic environment in the form of rocks in the Hadean Ocean could
have enabled the accretion and therefore an ordered confinement of
super-paramagnetic colloids within a structured phase. A moderate H-field can
help magnetic nano-particles to not only overcome thermal fluctuations but also
harness them. Such controlled dynamics brings in the possibility of accessing
quantum effects, which together with frustrations in magnetic ordering and
hysteresis (a natural mechanism for a primitive memory) could throw light on
the birth of biological information which, as Abel argues, requires a
combination of order and complexity. This scenario gains strength from
observations of scale-free framboidal forms of the greigite mineral, with a
magnetic basis of assembly. And greigite's metabolic potential plays a key role
in the mound scenario of Russell and coworkers-an expansion of which is
suggested for including magnetism.Comment: 42 pages, 5 figures, to be published in A.R. Memorial volume, Ed
Krishnaswami Alladi, Springer 201
Broken symmetry and the variation of critical properties in the phase behaviour of supramolecular rhombus tilings
The degree of randomness, or partial order, present in two-dimensional
supramolecular arrays of isophthalate tetracarboxylic acids is shown to vary
due to subtle chemical changes such as the choice of solvent or small
differences in molecular dimensions. This variation may be quantified using an
order parameter and reveals a novel phase behaviour including random tiling
with varying critical properties as well as ordered phases dominated by either
parallel or non-parallel alignment of neighbouring molecules, consistent with
long-standing theoretical studies. The balance between order and randomness is
driven by small differences in the intermolecular interaction energies, which
we show, using numerical simulations, can be related to the measured order
parameter. Significant variations occur even when the energy difference is much
less than the thermal energy highlighting the delicate balance between entropic
and energetic effects in complex self-assembly processes
On the experimental verification of quantum complexity in linear optics
The first quantum technologies to solve computational problems that are
beyond the capabilities of classical computers are likely to be devices that
exploit characteristics inherent to a particular physical system, to tackle a
bespoke problem suited to those characteristics. Evidence implies that the
detection of ensembles of photons, which have propagated through a linear
optical circuit, is equivalent to sampling from a probability distribution that
is intractable to classical simulation. However, it is probable that the
complexity of this type of sampling problem means that its solution is
classically unverifiable within a feasible number of trials, and the task of
establishing correct operation becomes one of gathering sufficiently convincing
circumstantial evidence. Here, we develop scalable methods to experimentally
establish correct operation for this class of sampling algorithm, which we
implement with two different types of optical circuits for 3, 4, and 5 photons,
on Hilbert spaces of up to 50,000 dimensions. With only a small number of
trials, we establish a confidence >99% that we are not sampling from a uniform
distribution or a classical distribution, and we demonstrate a unitary specific
witness that functions robustly for small amounts of data. Like the algorithmic
operations they endorse, our methods exploit the characteristics native to the
quantum system in question. Here we observe and make an application of a
"bosonic clouding" phenomenon, interesting in its own right, where photons are
found in local groups of modes superposed across two locations. Our broad
approach is likely to be practical for all architectures for quantum
technologies where formal verification methods for quantum algorithms are
either intractable or unknown.Comment: Comments welcom
No imminent quantum supremacy by boson sampling
It is predicted that quantum computers will dramatically outperform their
conventional counterparts. However, large-scale universal quantum computers are
yet to be built. Boson sampling is a rudimentary quantum algorithm tailored to
the platform of photons in linear optics, which has sparked interest as a rapid
way to demonstrate this quantum supremacy. Photon statistics are governed by
intractable matrix functions known as permanents, which suggests that sampling
from the distribution obtained by injecting photons into a linear-optical
network could be solved more quickly by a photonic experiment than by a
classical computer. The contrast between the apparently awesome challenge faced
by any classical sampling algorithm and the apparently near-term experimental
resources required for a large boson sampling experiment has raised
expectations that quantum supremacy by boson sampling is on the horizon. Here
we present classical boson sampling algorithms and theoretical analyses of
prospects for scaling boson sampling experiments, showing that near-term
quantum supremacy via boson sampling is unlikely. While the largest boson
sampling experiments reported so far are with 5 photons, our classical
algorithm, based on Metropolised independence sampling (MIS), allowed the boson
sampling problem to be solved for 30 photons with standard computing hardware.
We argue that the impact of experimental photon losses means that demonstrating
quantum supremacy by boson sampling would require a step change in technology.Comment: 25 pages, 9 figures. Comments welcom
Increased Matrix Metalloproteinase (MMPs) Levels Do Not Predict Disease Severity or Progression in Emphysema
Rationale: Though matrix metalloproteinases (MMPs) are critical in the pathogenesis of COPD, their utility as a disease biomarker remains uncertain. This study aimed to determine whether bronchoalveolar lavage (BALF) or plasma MMP measurements correlated with disease severity or functional decline in emphysema. Methods: Enzyme-linked immunosorbent assay and luminex assays measured MMP-1, -9, -12 and tissue inhibitor of matrix metalloproteinase-1 in the BALF and plasma of non-smokers, smokers with normal lung function and moderate-to-severe emphysema subjects. In the cohort of 101 emphysema subjects correlative analyses were done to determine if MMP or TIMP-1 levels were associated with key disease parameters or change in lung function over an 18-month time period. Main Results: Compared to non-smoking controls, MMP and TIMP-1 BALF levels were significantly elevated in the emphysema cohort. Though MMP-1 was elevated in both the normal smoker and emphysema groups, collagenase activity was only increased in the emphysema subjects. In contrast to BALF, plasma MMP-9 and TIMP-1 levels were actually decreased in the emphysema cohort compared to the control groups. Both in the BALF and plasma, MMP and TIMP-1 measurements in the emphysema subjects did not correlate with important disease parameters and were not predictive of subsequent functional decline. Conclusions: MMPs are altered in the BALF and plasma of emphysema; however, the changes in MMPs correlate poorly with parameters of disease intensity or progression. Though MMPs are pivotal in the pathogenesis of COPD, these findings suggest that measuring MMPs will have limited utility as a prognostic marker in this disease. © 2013 D'Armiento et al
Attenuation of muscle atrophy in a murine model of cachexia by inhibition of the dsRNA-dependent protein kinase
Atrophy of skeletal muscle is due to a depression in protein synthesis and an increase in degradation. Studies in vitro have suggested that activation of the dsRNA-dependent protein kinase (PKR) may be responsible for these changes in protein synthesis and degradation. In order to evaluate whether this is also applicable to cancer cachexia the action of a PKR inhibitor on the development of cachexia has been studied in mice bearing the MAC16 tumour. Treatment of animals with the PKR inhibitor (5 mg kg−1) significantly reduced levels of phospho-PKR in muscle down to that found in non-tumour-bearing mice, and effectively attenuated the depression of body weight, with increased muscle mass, and also inhibited tumour growth. There was an increase in protein synthesis in skeletal muscle, which paralleled a decrease in eukaryotic initiation factor 2α phosphorylation. Protein degradation rates in skeletal muscle were also significantly decreased, as was proteasome activity levels and expression. Myosin levels were increased up to values found in non-tumour-bearing animals. Proteasome expression correlated with a decreased nuclear accumulation of nuclear factor-κB (NF-κB). The PKR inhibitor also significantly inhibited tumour growth, although this appeared to be a separate event from the effect on muscle wasting. These results suggest that inhibition of the autophosphorylation of PKR may represent an appropriate target for the attenuation of muscle atrophy in cancer cachexia
30 days wild: development and evaluation of a large-scale nature engagement campaign to improve well-being
There is a need to increase people’s engagement with and connection to nature, both for human well-being and the conservation of nature itself. In order to suggest ways for people to engage with nature and create a wider social context to normalise nature engagement, The Wildlife Trusts developed a mass engagement campaign, 30 Days Wild. The campaign asked people to engage with nature every day for a month. 12,400 people signed up for 30 Days Wild via an online sign-up with an estimated 18,500 taking part overall, resulting in an estimated 300,000 engagements with nature by participants. Samples of those taking part were found to have sustained increases in happiness, health, connection to nature and pro-nature behaviours. With the improvement in health being predicted by the improvement in happiness, this relationship was mediated by the change in connection to nature
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