5,310 research outputs found
Probing the Mechanisms of Fibril Formation Using Lattice Models
Using exhaustive Monte Carlo simulations we study the kinetics and mechanism
of fibril formation using lattice models as a function of temperature and the
number of chains. While these models are, at best, caricatures of peptides, we
show that a number of generic features thought to govern fibril assembly are
present in the toy model. The monomer, which contains eight beads made from
three letters (hydrophobic, polar, and charged), adopts a compact conformation
in the native state. The kinetics of fibril assembly occurs in three distinct
stages. In each stage there is a cascade of events that transforms the monomers
and oligomers to ordered structures. In the first "burst" stage highly mobile
oligomers of varying sizes form. The conversion to the aggregation-prone
conformation occurs within the oligomers during the second stage. As time
progresses, a dominant cluster emerges that contains a majority of the chains.
In the final stage, the aggregation-prone conformation particles serve as a
template onto which smaller oligomers or monomers can dock and undergo
conversion to fibril structures. The overall time for growth in the latter
stages is well described by the Lifshitz-Slyazov growth kinetics for
crystallization from super-saturated solutions.Comment: 27 pages, 6 figure
Hysteresis multicycles in nanomagnet arrays
We predict two new physical effects in arrays of single-domain nanomagnets by
performing simulations using a realistic model Hamiltonian and physical
parameters. First, we find hysteretic multicycles for such nanomagnets. The
simulation uses continuous spin dynamics through the Landau-Lifshitz-Gilbert
(LLG) equation. In some regions of parameter space, the probability of finding
a multicycle is as high as ~0.6. We find that systems with larger and more
anisotropic nanomagnets tend to display more multicycles. This result
demonstrates the importance of disorder and frustration for multicycle
behavior. We also show that there is a fundamental difference between the more
realistic vector LLG equation and scalar models of hysteresis, such as Ising
models. In the latter case, spin and external field inversion symmetry is
obeyed but in the former it is destroyed by the dynamics, with important
experimental implications.Comment: 7 pages, 2 figure
Free fatty acids link metabolism and regulation of the insulin-sensitizing fibroblast growth factor-21
OBJECTIVE—Fibroblast growth factor (FGF)-21 improves insulin
sensitivity and lipid metabolism in obese or diabetic animal
models, while human studies revealed increased FGF-21 levels in obesity and type 2 diabetes. Given that FGF-21 has been suggested to be a peroxisome proliferator–activator receptor (PPAR) –dependent regulator of fasting metabolism, we hypothesized that free fatty acids (FFAs), natural agonists of PPAR, might modify FGF-21 levels.
RESEARCH DESIGN AND METHODS—The effect of fatty
acids on FGF-21 was investigated in vitro in HepG2 cells. Within a randomized controlled trial, the effects of elevated FFAs were studied in 21 healthy subjects (13 women and 8 men). Within a clinical trial including 17 individuals, the effect of insulin was analyzed using an hyperinsulinemic-euglycemic clamp and the effect of PPAR activation was studied subsequently in a rosiglitazone
treatment trial over 8 weeks.
RESULTS—Oleate and linoleate increased FGF-21 expression
and secretion in a PPAR-dependent fashion, as demonstrated
by small-interfering RNA–induced PPAR knockdown, while
palmitate had no effect. In vivo, lipid infusion induced an
increase of circulating FGF-21 in humans, and a strong correlation between the change in FGF-21 levels and the change in FFAs was observed. An artificial hyperinsulinemia, which was induced to delineate the potential interaction between elevated FFAs and
hyperinsulinemia, revealed that hyperinsulinemia also increased FGF-21 levels in vivo, while rosiglitazone treatment had no effect.
CONCLUSIONS—The results presented here offer a mechanism
explaining the induction of the metabolic regulator FGF-21 in the fasting situation but also in type 2 diabetes and obesity
Disorder-induced microscopic magnetic memory
Using coherent x-ray speckle metrology, we have measured the influence of
disorder on major loop return point memory (RPM) and complementary point memory
(CPM) for a series of perpendicular anisotropy Co/Pt multilayer films. In the
low disorder limit, the domain structures show no memory with field cycling--no
RPM and no CPM. With increasing disorder, we observe the onset and the
saturation of both the RPM and the CPM. These results provide the first direct
ensemble-sensitive experimental study of the effects of varying disorder on
microscopic magnetic memory and are compared against the predictions of
existing theories.Comment: 4 pages, 4 figures. Accepted for publication in Physical Review
Letters in Nov. 200
Optimised accelerated solvent extraction of hexahydro‐1, 3, 5‐trinitro‐1, 3, 5 triazine (RDX) from polymer bonded explosives
An Accelerated Solvent Extraction (ASE) method was developed and optimised to extract hexahydro‐1,3,5‐trinitro‐1,3,5‐triazine (RDX) from a polyurethane matrix. The ASE method development was benchmarked against Soxhlet extraction with a view to improving extraction efficiency in terms of time and solvent volume. Key parameters for the ASE method development involved selecting the most appropriate solvent, optimising static time, ensuring a safe oven temperature for explosives, determination of a sufficient number of rinse cycles and effective sample preparation. To achieve optimal extraction, cutting the PBX samples to maximise solvent exposure was essential. The use of acetone with a static time of 10 minutes at 100 °C with three rinse cycles achieved 97 %±10 % extraction of RDX from PBX in 40 minutes using 72 mL solvent. Extraction time was reduced from 48 hours and solvent use by half compared to the standard Soxhlet extraction. To validate the developed ASE method, two other PBX samples containing different quantities of explosive were also fully extracted using the same parameters. Overall, ASE efficiency was comparable to Soxhlet, which places the ASE as a good alternative and shows potential for implementation as a standard method for other polymer based explosives
Release of 1,3,5-trinitroperhydro-1,3,5-triazine (RDX) from polymer-bonded explosives (PBXN 109) into water by artificial weathering
Polymer-bonded explosives (PBX) fulfil the need for insensitive munitions. However, the environmental impacts of PBX are unclear, even though it is likely that PBX residues from low-order detonations and unexploded ordnance are deposited on military training ranges. The release of high explosives from the polymer matrix into the environment has not been studied in detail, although as polymers degrade slowly in the environment we anticipate high explosives to be released into the environment. In this study, PBXN-109 (nominally 64% RDX) samples were exposed to variable UK climatic conditions reproduced in the laboratory to determine the effects of temperature, UV irradiation and rainfall on the release of RDX from the polymer binder. The most extreme conditions for spring, summer and winter in the UK were artificially reproduced. We found that up to 0.03% of RDX was consistently released from PBXN-109. The rate of RDX release was highest in samples exposed to the summer simulation, which had the lowest rainfall, but the highest temperatures and longest UV exposure. This was confirmed by additional experiments simulating an extreme summer month with consistently high temperatures and long periods of sunlight. These results probably reflect the combination of polymer swelling and degradation when samples are exposed to higher temperatures and prolonged UV irradiation
Molecular Electroporation and the Transduction of Oligoarginines
Certain short polycations, such as TAT and polyarginine, rapidly pass through
the plasma membranes of mammalian cells by an unknown mechanism called
transduction as well as by endocytosis and macropinocytosis. These
cell-penetrating peptides (CPPs) promise to be medically useful when fused to
biologically active peptides. I offer a simple model in which one or more CPPs
and the phosphatidylserines of the inner leaflet form a kind of capacitor with
a voltage in excess of 180 mV, high enough to create a molecular electropore.
The model is consistent with an empirical upper limit on the cargo peptide of
40--60 amino acids and with experimental data on how the transduction of a
polyarginine-fluorophore into mouse C2C12 myoblasts depends on the number of
arginines in the CPP and on the CPP concentration. The model makes three
testable predictions.Comment: 15 pages, 5 figure
Finite size effects on thermal denaturation of globular proteins
Finite size effects on the cooperative thermal denaturation of proteins are
considered. A dimensionless measure of cooperativity, Omega, scales as N^zeta,
where N is the number of amino acids. Surprisingly, we find that zeta is
universal with zeta = 1 + gamma, where the exponent gamma characterizes the
divergence of the susceptibility for a self-avoiding walk. Our lattice model
simulations and experimental data are consistent with the theory. Our finding
rationalizes the marginal stability of proteins and substantiates the earlier
predictions that the efficient folding of two-state proteins requires the
folding transition temperature to be close to the collapse temperature.Comment: 3 figures. Physical Review Letters (in press
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