854 research outputs found
Extreme value statistics of mutation accumulation in renewing cell populations
The emergence of a predominant phenotype within a cell population is often triggered by the chance accumulation of a sequence of rare genomic DNA mutations within a single cell. For example, tumors may be initiated by a single cell in which multiple mutations cooperate to bypass their natural
defense mechanism. The risk of such an event is thus determined by the extremal accumulation of mutations across tissue cells. To address this risk, here we study the statistics of the maximum mutation numbers in a generic, but tested, model of a renewing cell population. By drawing an analogy between the genealogy of a cell population and the theory of branching random walks, we obtain analytical estimates for the probability of exceeding a threshold number of mutations to trigger a proliferative advantage of a cell over its neighbors, and determine how the statistical distribution of maximum mutation numbers scales with age and cell population size.EPSR
Mixed population of competing TASEPs with a shared reservoir of particles
We introduce a mean-field theoretical framework to describe multiple totally
asymmetric simple exclusion processes (TASEPs) with different lattice lengths,
entry and exit rates, competing for a finite reservoir of particles. We present
relations for the partitioning of particles between the reservoir and the
lattices: these relations allow us to show that competition for particles can
have non-trivial effects on the phase behavior of individual lattices. For a
system with non-identical lattices, we find that when a subset of lattices
undergoes a phase transition from low to high density, the entire set of
lattice currents becomes independent of total particle number. We generalize
our approach to systems with a continuous distribution of lattice parameters,
for which we demonstrate that measurements of the current carried by a single
lattice type can be used to extract the entire distribution of lattice
parameters. Our approach applies to populations of TASEPs with any distribution
of lattice parameters, and could easily be extended beyond the mean-field case.Comment: 12 pages, 8 figure
Single-Bottleneck Approximation for Driven Lattice Gases with Disorder and Open Boundary Conditions
We investigate the effects of disorder on driven lattice gases with open
boundaries using the totally asymmetric simple exclusion process as a
paradigmatic example. Disorder is realized by randomly distributed defect sites
with reduced hopping rate. In contrast to equilibrium, even macroscopic
quantities in disordered non-equilibrium systems depend sensitively on the
defect sample. We study the current as function of the entry and exit rates and
the realization of disorder and find that it is, in leading order, determined
by the longest stretch of consecutive defect sites (single-bottleneck
approximation, SBA). Using results from extreme value statistics the SBA allows
to study ensembles with fixed defect density which gives accurate results, e.g.
for the expectation value of the current. Corrections to SBA come from
effective interactions of bottlenecks close to the longest one. Defects close
to the boundaries can be described by effective boundary rates and lead to
shifts of the phase transitions. Finally it is shown that the SBA also works
for more complex models. As an example we discuss a model with internal states
that has been proposed to describe transport of the kinesin KIF1A.Comment: submitted to J. Stat. Mec
Particle interactions and lattice dynamics: Scenarios for efficient bidirectional stochastic transport?
Intracellular transport processes driven by molecular motors can be described
by stochastic lattice models of self-driven particles. Here we focus on
bidirectional transport models excluding the exchange of particles on the same
track. We explore the possibility to have efficient transport in these systems.
One possibility would be to have appropriate interactions between the various
motors' species, so as to form lanes. However, we show that the lane formation
mechanism based on modified attachment/detachment rates as it was proposed
previously is not necessarily connected to an efficient transport state and is
suppressed when the diffusivity of unbound particles is finite. We propose
another interaction mechanism based on obstacle avoidance that allows to have
lane formation for limited diffusion. Besides, we had shown in a separate paper
that the dynamics of the lattice itself could be a key ingredient for the
efficiency of bidirectional transport. Here we show that lattice dynamics and
interactions can both contribute in a cooperative way to the efficiency of
transport. In particular, lattice dynamics can decrease the interaction
threshold beyond which lanes form. Lattice dynamics may also enhance the
transport capacity of the system even when lane formation is suppressed.Comment: 25 pages, 17 figures, 2 table
Asymmetric Exclusion Processes with Disorder: Effect of Correlations
Multi-particle dynamics in one-dimensional asymmetric exclusion processes
with disorder is investigated theoretically by computational and analytical
methods. It is argued that the general phase diagram consists of three
non-equilibrium phases that are determined by the dynamic behavior at the
entrance, at the exit and at the slowest defect bond in the bulk of the system.
Specifically, we consider dynamics of asymmetric exclusion process with two
identical defect bonds as a function of distance between them. Two approximate
theoretical methods, that treat the system as a sequence of segments with exact
description of dynamics inside the segments and neglect correlations between
them, are presented. In addition, a numerical iterative procedure for
calculating dynamic properties of asymmetric exclusion systems is developed.
Our theoretical predictions are compared with extensive Monte Carlo computer
simulations. It is shown that correlations play an important role in the
particle dynamics. When two defect bonds are far away from each other the
strongest correlations are found at these bonds. However, bringing defect bonds
closer leads to the shift of correlations to the region between them.Comment: 11 pages, 15 eps figures, RevtexI
Suitability versus fidelity for rating single-photon guns
The creation of specified quantum states is important for most, if not all,
applications in quantum computation and communication. The quality of the state
preparation is therefore an essential ingredient in any assessment of a
quantum-state gun. We show that the fidelity, under the standard definitions is
not sufficient to assess quantum sources, and we propose a new measure of
suitability that necessarily depends on the application for the source. We
consider the performance of single-photon guns in the context of quantum key
distribution (QKD) and linear optical quantum computation. Single-photon
sources for QKD need radically different properties than sources for quantum
computing. Furthermore, the suitability for single-photon guns is discussed
explicitly in terms of experimentally accessible criteria.Comment: 4 pages, 2 figures Revised per referee suggestion
Validation of DNA probes for molecular cytogenetics by mapping onto immobilized circular DNA
<p>Abstract</p> <p>Background</p> <p>Fluorescence <it>in situ </it>hybridization (FISH) is a sensitive and rapid procedure to detect gene rearrangements in tumor cells using non-isotopically labeled DNA probes. Large insert recombinant DNA clones such as bacterial artificial chromosome (BAC) or P1/PAC clones have established themselves in recent years as preferred starting material for probe preparations due to their low rates of chimerism and ease of use. However, when developing probes for the quantitative analysis of rearrangements involving genomic intervals of less than 100 kb, careful probe selection and characterization are of paramount importance.</p> <p>Results</p> <p>We describe a sensitive approach to quality control probe clones suspected of carrying deletions or for measuring clone overlap with near kilobase resolution. The method takes advantage of the fact that P1/PAC/BAC's can be isolated as circular DNA molecules, stretched out on glass slides and fine-mapped by multicolor hybridization with smaller probe molecules. Two examples demonstrate the application of this technique: mapping of a gene-specific ~6 kb plasmid onto an unusually small, ~55 kb circular P1 molecule and the determination of the extent of overlap between P1 molecules homologous to the human NF-κB2 locus.</p> <p>Conclusion</p> <p>The relatively simple method presented here does not require specialized equipment and may thus find widespread applications in DNA probe preparation and characterization, the assembly of physical maps for model organisms or in studies on gene rearrangements.</p
Extra c-myc oncogene copies in high risk cutaneous malignant melanoma and melanoma metastases
Amplification and overexpression of the c-myc gene have been associated with neoplastic transformation in a plethora of malignant tumours. We applied interphase fluorescence in situ hybridization (FISH) with a locus-specific probe for the c-myc gene (8q24) in combination with a corresponding chromosome 8 α-satellite probe to evaluate genetic alterations in 8 primary melanomas and 33 advanced melanomas and compared it to 12 melanocytic nevi, 7 safety margins and 2 cases of normal skin. Additionally, in metaphase spreads of 7 melanoma cell lines a whole chromosome 8 paint probe was used. We investigated the functionality of the c-myc gene by detecting c-myc RNA expression with RT-PCR and c-myc protein by immunohistochemistry. 4/8 primary melanomas and 11/33 melanoma metastases showed additional c-myc signals relative to the centromere of chromosome 8 copy number. None of the nevi, safety margins or normal skin samples demonstrated this gain. In 2/7 melanoma cell lines (C32 and WM 266–4) isochromosome 8q formation with a relative gain of c-myc copies and a loss of 8p was observed. The highest c-myc gene expression compared to GAPDH was found in melanoma metastases (17.5%). Nevi (6.6%) and primary melanomas (5.0%) expressed the c-myc gene on a lower level. 72.7% of the patients with c-myc extra copies had visceral melanoma metastases (UICC IV), patients without c-myc gain in 35.0% only. The collective with additional c-myc copies also expressed the gene on a significantly higher level. These results indicate that a c-myc gain in relation to the centromere 8 copy number might be associated with advanced cutaneous melanoma. © 2001 Cancer Research Campaign http://www.bjcancer.co
Toll-like receptor 4 signaling activates ERG function in prostate cancer and provides a therapeutic target
The TMPRSS2-ERG gene fusion and subsequent overexpression of the ERG transcription factor occurs in ∼50% of prostate tumors, making it the most common abnormality of the prostate cancer genome. While ERG has been shown to drive tumor progression and cancer-related phenotypes, as a transcription factor it is difficult to target therapeutically. Using a genetic screen, we identified the toll-like receptor 4 (TLR4) signaling pathway as important for ERG function in prostate cells. Our data confirm previous reports that ERG can transcriptionally activate TLR4 gene expression; however, using a constitutively active ERG mutant, we demonstrate that the critical function of TLR4 signaling is upstream, promoting ERG phosphorylation at serine 96 and ERG transcriptional activation. The TLR4 inhibitor, TAK-242, attenuated ERG-mediated migration, clonogenic survival, target gene activation and tumor growth. Together these data indicate a mechanistic basis for inhibition of TLR4 signaling as a treatment for ERG-positive prostate cancer
Mean field treatment of exclusion processes with random-force disorder
The asymmetric simple exclusion process with random-force disorder is studied
within the mean field approximation. The stationary current through a domain
with reversed bias is analyzed and the results are found to be in accordance
with earlier intuitive assumptions. On the grounds of these results, a
phenomenological random barrier model is applied in order to describe
quantitatively the coarsening phenomena. Predictions of the theory are compared
with numerical results obtained by integrating the mean field evolution
equations.Comment: 21 pages, 14 figure
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