461 research outputs found
Time delay as a key to Apoptosis Induction in the p53 Network
A feedback mechanism that involves the proteins p53 and mdm2, induces cell
death as a controled response to severe DNA damage. A minimal model for this
mechanism demonstrates that the respone may be dynamic and connected with the
time needed to translate the mdm2 protein. The response takes place if the
dissociation constant k between p53 and mdm2 varies from its normal value.
Although it is widely believed that it is an increase in k that triggers the
response, we show that the experimental behaviour is better described by a
decrease in the dissociation constant. The response is quite robust upon
changes in the parameters of the system, as required by any control mechanism,
except for few weak points, which could be connected with the onset of cancer
Exploring Hybrid Learning: Enhancing Access to Health and Safety Education at WorkSafeHealth
WorkSafeHealth, a not-for-profit health and safety association in the province of Ontario, is mandated by the Ministry of Labour, Immigration, Training and Skills Development to provide training and consultation services to client firm trainees across the province. Despite the efforts of WorkSafeHealth personnel to provide timely access to health and safety education, the vast regional expanse in which WorkSafeHealth provides these services hinders consultant-trainers’ abilities to furnish training to Ontario workers who must be equipped with this critical information to work safely in their respective industries. Therefore, current operational service delivery methods must change to support WorkSafeHealth personnel’s fulfillment of the organization’s mandate. Currently, learners residing in remote areas are often required to travel hundreds of kilometres to reach a training venue when a required course is offered: these commutes are often undertaken on rough terrain and other roads with hazards that could result in motor vehicle incidents. WorkSafeHealth can capitalize on the organization’s existing learning technologies to facilitate courses simultaneously to face-to-face and virtual learners: a training model known as hybrid learning. After illuminating WorkSafeHealth’s organizational context, mandate, and organizational influences, throughout this organizational improvement plan, effective approaches to leadership through which this solution can be implemented, communicated, and monitored and evaluated is presented
Oscillations and temporal signalling in cells
The development of new techniques to quantitatively measure gene expression
in cells has shed light on a number of systems that display oscillations in
protein concentration. Here we review the different mechanisms which can
produce oscillations in gene expression or protein concentration, using a
framework of simple mathematical models. We focus on three eukaryotic genetic
regulatory networks which show "ultradian" oscillations, with time period of
the order of hours, and involve, respectively, proteins important for
development (Hes1), apoptosis (p53) and immune response (NFkB). We argue that
underlying all three is a common design consisting of a negative feedback loop
with time delay which is responsible for the oscillatory behaviour
Mapping of mutation-sensitive sites in protein-like chains
In this work we have studied, with the help of a simple on-lattice model, the
distribution pattern of sites sensitive to point mutations ('hot' sites) in
protein-like chains. It has been found that this pattern depends on the
regularity of the matrix that rules the interaction between different kinds of
residues. If the interaction matrix is dominated by the hydrophobic effect
(Miyazawa Jernigan like matrix), this distribution is very simple - all the
'hot' sites can be found at the positions with maximum number of closest
nearest neighbors (bulk).
If random or nonlinear corrections are added to such an interaction matrix
the distribution pattern changes. The rising of collective effects allows the
'hot' sites to be found in places with smaller number of nearest neighbors
(surface) while the general trend of the 'hot' sites to fall into a bulk part
of a conformation still holds.Comment: 15 pages, 6 figure
Thermodynamics of beta-amyloid fibril formation
Amyloid fibers are aggregates of proteins. They are built out of a peptide
called --amyloid (A) containing between 41 and 43 residues,
produced by the action of an enzyme which cleaves a much larger protein known
as the Amyloid Precursor Protein (APP). X-ray diffraction experiments have
shown that these fibrils are rich in --structures, whereas the shape of
the peptide displays an --helix structure within the APP in its
biologically active conformation. A realistic model of fibril formation is
developed based on the seventeen residues A12--28 amyloid peptide, which
has been shown to form fibrils structurally similar to those of the whole
A peptide. With the help of physical arguments and in keeping with
experimental findings, the A12--28 monomer is assumed to be in four
possible states (i.e., native helix conformation, --hairpin, globular
low--energy state and unfolded state). Making use of these monomeric states,
oligomers (dimers, tertramers and octamers) were constructed. With the help of
short, detailed Molecular Dynamics (MD) calculations of the three monomers and
of a variety of oligomers, energies for these structures were obtained. Making
use of these results within the framework of a simple yet realistic model to
describe the entropic terms associated with the variety of amyloid
conformations, a phase diagram can be calculated of the whole many--body
system, leading to a thermodynamical picture in overall agreement with the
experimental findings. In particular, the existence of micellar metastable
states seem to be a key issue to determine the thermodynamical properties of
the system
Understanding the determinants of stability and folding of small globular proteins from their energetics
The results of minimal model calculations suggest that the stability and the
kinetic accessibility of the native state of small globular proteins are
controlled by few "hot" sites. By mean of molecular dynamics simulations around
the native conformation, which simulate the protein and the surrounding solvent
at full--atom level, we generate an energetic map of the equilibrium state of
the protein and simplify it with an Eigenvalue decomposition. The components of
the Eigenvector associated with the lowest Eigenvalue indicate which are the
"hot" sites responsible for the stability and for the fast folding of the
protein. Comparison of these predictions with the results of mutatgenesis
experiments, performed for five small proteins, provide an excellent agreement
Key interaction patterns in proteins revealed by cluster expansion of the partition function
The native conformation of structured proteins is stabilized by a complex
network of interactions. We analyzed the elementary patterns that constitute
such network and ranked them according to their importance in shaping protein
sequence design. To achieve this goal, we employed a cluster expansion of the
partition function in the space of sequences and evaluated numerically the
statistical importance of each cluster. An important feature of this procedure
is that it is applied to a dense, finite system. We found that patterns that
contribute most to the partition function are cycles with even numbers of
nodes, while cliques are typically detrimental. Each cluster also gives a
contribute to the sequence entropy, which is a measure of the evolutionary
designability of a fold. We compared the entropies associated with different
interaction patterns to their abundances in the native structures of real
proteins
Native state of natural proteins optimizes local entropy
The differing ability of polypeptide conformations to act as the native state of proteins has long been rationalized in terms of differing kinetic accessibility or thermodynamic stability. Building on the successful applications of physical concepts and sampling algorithms recently introduced in the study of disordered systems, in particular artificial neural networks, we quantitatively explore how well a quantity known as the local entropy describes the native state of model proteins. In lattice models and all-atom representations of proteins, we are able to efficiently sample high local entropy states and to provide a proof of concept of enhanced stability and folding rate. Our methods are based on simple and general statistical-mechanics arguments, and thus we expect that they are of very general use
Evolution of frustrated and stabilising contacts in reconstructed ancient proteins
Energetic properties of a protein are a major determinant of its evolutionary fitness. Using a reconstruction algorithm, dating the reconstructed proteins and calculating the interaction network between their amino acids through a coevolutionary approach, we studied how the interactions that stabilise 890 proteins, belonging to five families, evolved for billions of years. In particular, we focused our attention on the network of most strongly attractive contacts and on that of poorly optimised, frustrated contacts. Our results support the idea that the cluster of most attractive interactions extends its size along evolutionary time, but from the data, we cannot conclude that protein stability or that the degree of frustration tends always to decrease
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