528 research outputs found
A Computational Model for Understanding Stem Cell, Trophectoderm and Endoderm Lineage Determination
Background: Recent studies have associated the transcription factors, Oct4, Sox2 and Nanog as parts of a self-regulating network which is responsible for maintaining embryonic stem cell properties: self renewal and pluripotency. In addition, mutual antagonism between two of these and other master regulators have been shown to regulate lineage determination. In particular, an excess of Cdx2 over Oct4 determines the trophectoderm lineage whereas an excess of Gata-6 over Nanog determines differentiation into the endoderm lineage. Also, under/over-expression studies of the master regulator Oct4 have revealed that some self-renewal/pluripotency as well as differentiation genes are expressed in a biphasic manner with respect to the concentration of Oct4.
Methodology/Principal Findings: We construct a dynamical model of a minimalistic network, extracted from ChIP-on-chip and microarray data as well as literature studies. The model is based upon differential equations and makes two plausible assumptions; activation of Gata-6 by Oct4 and repression of Nanog by an Oct4–Gata-6 heterodimer. With these assumptions, the results of simulations successfully describe the biphasic behavior as well as lineage commitment. The model also predicts that reprogramming the network from a differentiated state, in particular the endoderm state, into a stem cell state, is best achieved by over-expressing Nanog, rather than by suppression of differentiation genes such as Gata-6.
Conclusions: The computational model provides a mechanistic understanding of how different lineages arise from the dynamics of the underlying regulatory network. It provides a framework to explore strategies of reprogramming a cell from a differentiated state to a stem cell state through directed perturbations. Such an approach is highly relevant to regenerative medicine since it allows for a rapid search over the host of possibilities for reprogramming to a stem cell state
Evidence for Non-Random Hydrophobicity Structures in Protein Chains
The question of whether proteins originate from random sequences of amino
acids is addressed. A statistical analysis is performed in terms of blocked and
random walk values formed by binary hydrophobic assignments of the amino acids
along the protein chains. Theoretical expectations of these variables from
random distributions of hydrophobicities are compared with those obtained from
functional proteins. The results, which are based upon proteins in the
SWISS-PROT data base, convincingly show that the amino acid sequences in
proteins differ from what is expected from random sequences in a statistical
significant way. By performing Fourier transforms on the random walks one
obtains additional evidence for non-randomness of the distributions.
We have also analyzed results from a synthetic model containing only two
amino-acid types, hydrophobic and hydrophilic. With reasonable criteria on good
folding properties in terms of thermodynamical and kinetic behavior, sequences
that fold well are isolated. Performing the same statistical analysis on the
sequences that fold well indicates similar deviations from randomness as for
the functional proteins. The deviations from randomness can be interpreted as
originating from anticorrelations in terms of an Ising spin model for the
hydrophobicities.
Our results, which differ from previous investigations using other methods,
might have impact on how permissive with respect to sequence specificity the
protein folding process is -- only sequences with non-random hydrophobicity
distributions fold well. Other distributions give rise to energy landscapes
with poor folding properties and hence did not survive the evolution.Comment: 16 pages, 8 Postscript figures. Minor changes, references adde
Quantum ergodicity on the Bruhat-Tits building for in the Benjamini-Schramm limit
We study eigenfunctions of the spherical Hecke algebra acting on
where with a
non-archimedean local field of characteristic zero, with the ring of integers of , and
is a sequence of cocompact torsionfree lattices. We prove a form of
equidistribution on average for eigenfunctions whose spectral parameters lie in
the tempered spectrum when the associated sequence of quotients of the
Bruhat-Tits building Benjamini-Schramm converges to the building itself.Comment: 111 pages, 25 figures, 2 table
Local Interactions and Protein Folding: A 3D Off-Lattice Approach
The thermodynamic behavior of a three-dimensional off-lattice model for
protein folding is probed. The model has only two types of residues,
hydrophobic and hydrophilic. In absence of local interactions, native structure
formation does not occur for the temperatures considered. By including sequence
independent local interactions, which qualitatively reproduce local properties
of functional proteins, the dominance of a native state for many sequences is
observed. As in lattice model approaches, folding takes place by gradual
compactification, followed by a sequence dependent folding transition. Our
results differ from lattice approaches in that bimodal energy distributions are
not observed and that high folding temperatures are accompanied by relatively
low temperatures for the peak of the specific heat. Also, in contrast to
earlier studies using lattice models, our results convincingly demonstrate that
one does not need more than two types of residues to generate sequences with
good thermodynamic folding properties in three dimensions.Comment: 18 pages, 11 Postscript figure
Genetic networks with canalyzing Boolean rules are always stable
We determine stability and attractor properties of random Boolean genetic
network models with canalyzing rules for a variety of architectures. For all
power law, exponential, and flat in-degree distributions, we find that the
networks are dynamically stable. Furthermore, for architectures with few inputs
per node, the dynamics of the networks is close to critical. In addition, the
fraction of genes that are active decreases with the number of inputs per node.
These results are based upon investigating ensembles of networks using
analytical methods. Also, for different in-degree distributions, the numbers of
fixed points and cycles are calculated, with results intuitively consistent
with stability analysis; fewer inputs per node implies more cycles, and vice
versa. There are hints that genetic networks acquire broader degree
distributions with evolution, and hence our results indicate that for single
cells, the dynamics should become more stable with evolution. However, such an
effect is very likely compensated for by multicellular dynamics, because one
expects less stability when interactions among cells are included. We verify
this by simulations of a simple model for interactions among cells.Comment: Final version available through PNAS open access at
http://www.pnas.org/cgi/content/abstract/0407783101v
Airline Crew Scheduling with Potts Neurons
A Potts feedback neural network approach for finding good solutions to
resource allocation problems with a non-fixed topology is presented. As a
target application the airline crew scheduling problem is chosen. The
topological complication is handled by means of a propagator defined in terms
of Potts neurons. The approach is tested on artificial random problems tuned to
resemble real-world conditions. Very good results are obtained for a variety of
problem sizes. The computer time demand for the approach only grows like
\mbox{(number of flights)}^3. A realistic problem typically is solved within
minutes, partly due to a prior reduction of the problem size, based on an
analysis of the local arrival/departure structure at the single airportsComment: 9 pages LaTeX, 3 postscript figures, uufiles forma
Scaling and Scale Breaking in Polyelectrolyte
We consider the thermodynamics of a uniformly charged polyelectrolyte with
harmonic bonds. For such a system there is at high temperatures an approximate
scaling of global properties like the end-to-end distance and the interaction
energy with the chain-length divided by the temperature. This scaling is broken
at low temperatures by the ultraviolet divergence of the Coulomb potential. By
introducing a renormalization of the strength of the nearest- neighbour
interaction the scaling is restored, making possible an efficient blocking
method for emulating very large polyelectrolytes using small systems. The high
temperature behaviour is well reproduced by the analytical high- expansions
even for fairly low temperatures and system sizes. In addition, results from
low- expansions, where the coefficients have been computed numerically, are
presented. These results approximate well the corresponding Monte Carlo results
at realistic temperatures. A corresponding analysis of screened chains is
performed. The situation here is complicated by the appearance of an additional
parameter, the screening length. A window is found in parameter space, where
scaling holds for the end-to-end distance. This window corresponds to
situations where the range of the potential interpolates between the bond
length and the size of the chain. This scaling behaviour, which is verified by
Monte Carlo results, is consistent with Flory scaling. Also for the screened
chain a blocking approach can be devised, that performs well for low
temperatures, whereas the low- expansion is inaccurate at realistic
temperatures.Comment: 18 pages, latex, 6 figure
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