1,888 research outputs found
Effect of promoter architecture on the cell-to-cell variability in gene expression
According to recent experimental evidence, the architecture of a promoter,
defined as the number, strength and regulatory role of the operators that
control the promoter, plays a major role in determining the level of
cell-to-cell variability in gene expression. These quantitative experiments
call for a corresponding modeling effort that addresses the question of how
changes in promoter architecture affect noise in gene expression in a
systematic rather than case-by-case fashion. In this article, we make such a
systematic investigation, based on a simple microscopic model of gene
regulation that incorporates stochastic effects. In particular, we show how
operator strength and operator multiplicity affect this variability. We examine
different modes of transcription factor binding to complex promoters
(cooperative, independent, simultaneous) and how each of these affects the
level of variability in transcription product from cell-to-cell. We propose
that direct comparison between in vivo single-cell experiments and theoretical
predictions for the moments of the probability distribution of mRNA number per
cell can discriminate between different kinetic models of gene regulation.Comment: 35 pages, 6 figures, Submitte
Regulatory control and the costs and benefits of biochemical noise
Experiments in recent years have vividly demonstrated that gene expression
can be highly stochastic. How protein concentration fluctuations affect the
growth rate of a population of cells, is, however, a wide open question. We
present a mathematical model that makes it possible to quantify the effect of
protein concentration fluctuations on the growth rate of a population of
genetically identical cells. The model predicts that the population's growth
rate depends on how the growth rate of a single cell varies with protein
concentration, the variance of the protein concentration fluctuations, and the
correlation time of these fluctuations. The model also predicts that when the
average concentration of a protein is close to the value that maximizes the
growth rate, fluctuations in its concentration always reduce the growth rate.
However, when the average protein concentration deviates sufficiently from the
optimal level, fluctuations can enhance the growth rate of the population, even
when the growth rate of a cell depends linearly on the protein concentration.
The model also shows that the ensemble or population average of a quantity,
such as the average protein expression level or its variance, is in general not
equal to its time average as obtained from tracing a single cell and its
descendants. We apply our model to perform a cost-benefit analysis of gene
regulatory control. Our analysis predicts that the optimal expression level of
a gene regulatory protein is determined by the trade-off between the cost of
synthesizing the regulatory protein and the benefit of minimizing the
fluctuations in the expression of its target gene. We discuss possible
experiments that could test our predictions.Comment: Revised manuscript;35 pages, 4 figures, REVTeX4; to appear in PLoS
Computational Biolog
The role of input noise in transcriptional regulation
Even under constant external conditions, the expression levels of genes
fluctuate. Much emphasis has been placed on the components of this noise that
are due to randomness in transcription and translation; here we analyze the
role of noise associated with the inputs to transcriptional regulation, the
random arrival and binding of transcription factors to their target sites along
the genome. This noise sets a fundamental physical limit to the reliability of
genetic control, and has clear signatures, but we show that these are easily
obscured by experimental limitations and even by conventional methods for
plotting the variance vs. mean expression level. We argue that simple, global
models of noise dominated by transcription and translation are inconsistent
with the embedding of gene expression in a network of regulatory interactions.
Analysis of recent experiments on transcriptional control in the early
Drosophila embryo shows that these results are quantitatively consistent with
the predicted signatures of input noise, and we discuss the experiments needed
to test the importance of input noise more generally.Comment: 11 pages, 5 figures minor correction
Comparative overwiew of brain perfusion imaging techniques
Background and Purpose - Numerous imaging techniques have been developed and applied to evaluate brain hemodynamics. Among these are positron emission tomography, single photon emission computed tomography, Xenon-enhanced computed tomography, dynamic perfusion computed tomography, MRI dynamic susceptibility contrast, arterial spin labeling, and Doppler ultrasound. These techniques give similar information about brain hemodynamics in the form of parameters such as cerebral blood flow or cerebral blood volume. All of them are used to characterize the same types of pathological conditions. However, each technique has its own advantages and drawbacks.
Summary of Review - This article addresses the main imaging techniques dedicated to brain hemodynamics. It represents a comparative overview established by consensus among specialists of the various techniques.
Conclusions - For clinicians, this article should offer a clearer picture of the pros and cons of currently available brain perfusion imaging techniques and assist them in choosing the proper method for every specific clinical setting
Comparative overview of brain perfusion imaging techniques Epub
Background and Purpose - Numerous imaging techniques have been developed and applied to evaluate brain hemodynamics. Among these are positron emission tomography, single photon emission computed tomography, Xenon-enhanced computed tomography, dynamic perfusion computed tomography, MRI dynamic susceptibility contrast, arterial spin labeling, and Doppler ultrasound. These techniques give similar information about brain hemodynamics in the form of parameters such as cerebral blood flow or cerebral blood volume. All of them are used to characterize the same types of pathological conditions. However, each technique has its own advantages and drawbacks.
Summary of Review - This article addresses the main imaging techniques dedicated to brain hemodynamics. It represents a comparative overview established by consensus among specialists of the various techniques.
Conclusions - For clinicians, this article should offer a clearer picture of the pros and cons of currently available brain perfusion imaging techniques and assist them in choosing the proper method for every specific clinical setting
Garlic's ability to prevent in vitro Cu(2+)-induced lipoprotein oxidation in human serum is preserved in heated garlic: effect unrelated to Cu(2+)-chelation
BACKGROUND: It has been shown that several extracts and compounds derived from garlic are able to inhibit Cu(2+)-induced low density lipoprotein oxidation. In this work we explored if the ability of aqueous garlic extract to prevent in vitro Cu(2+)-induced lipoprotein oxidation in human serum is affected by heating (a) aqueous garlic extracts or (b) garlic cloves. In the first case, aqueous extract of raw garlic and garlic powder were studied. In the second case, aqueous extract of boiled garlic cloves, microwave-treated garlic cloves, and pickled garlic were studied. It was also studied if the above mentioned preparations were able to chelate Cu(2+). METHODS: Cu(2+)-induced lipoprotein oxidation in human serum was followed by the formation of conjugated dienes at 234 nm and 37°C by 240 min in a phosphate buffer 20 mM, pH 7.4. Blood serum and CuSO(4 )were added to a final concentration of 0.67% and 0.0125 mM, respectively. The lag time and the area under the curve from the oxidation curves were obtained. The Cu(2+)-chelating properties of garlic extracts were assessed using an approach based upon restoring the activity of xanthine oxidase inhibited in the presence of 0.050 mM Cu(2+). The activity of xanthine oxidase was assessed by monitoring the production of superoxide anion at 560 nm and the formation of uric acid at 295 nm. Data were compared by parametric or non-parametric analysis of variance followed by a post hoc test. RESULTS: Extracts from garlic powder and raw garlic inhibited in a dose-dependent way Cu(2+)-induced lipoprotein oxidation. The heating of garlic extracts or garlic cloves was unable to alter significantly the increase in lag time and the decrease in the area under the curve observed with the unheated garlic extracts or raw garlic. In addition, it was found that the garlic extracts were unable to chelate Cu(2+). CONCLUSIONS: (a) the heating of aqueous extracts of raw garlic or garlic powder or the heating of garlic cloves by boiling, microwave or pickling do not affect garlic's ability to inhibit Cu(2+)-induced lipoprotein oxidation in human serum, and (b) this ability is not secondary to Cu(2+)-chelation
Holographic Brownian Motion in Magnetic Environments
Using the gauge/gravity correspondence, we study the dynamics of a heavy
quark in two strongly-coupled systems at finite temperature: Super-Yang-Mills
in the presence of a magnetic field and non-commutative Super-Yang-Mills. In
the former, our results agree qualitatively with the expected behavior from
weakly-coupled theories. In the latter, we propose a Langevin equation that
accounts for the effects of non-commutativity and we find new interesting
features. The equation resembles the structure of Brownian motion in the
presence of a magnetic field and implies that the fluctuations along
non-commutative directions are correlated. Moreover, our results show that the
viscosity is smaller than the commutative case and that the diffusion
properties of the quark are unaffected by non-commutativity. Finally, we
compute the random force autocorrelator and verify that the
fluctuation-dissipation theorem holds in the presence of non-commutativity.Comment: 34 pages. v2: typos corrected. v3: title and abstract slightly
modified in order to better reflect the contents of the paper; footnote 3 and
one reference were also added; version accepted for publication in JHE
Quantum Fluctuations and the Unruh Effect in Strongly-Coupled Conformal Field Theories
Through the AdS/CFT correspondence, we study a uniformly accelerated quark in
the vacuum of strongly-coupled conformal field theories in various dimensions,
and determine the resulting stochastic fluctuations of the quark trajectory.
From the perspective of an inertial observer, these are quantum fluctuations
induced by the gluonic radiation emitted by the accelerated quark. From the
point of view of the quark itself, they originate from the thermal medium
predicted by the Unruh effect. We scrutinize the relation between these two
descriptions in the gravity side of the correspondence, and show in particular
that upon transforming the conformal field theory from Rindler space to the
open Einstein universe, the acceleration horizon disappears from the boundary
theory but is preserved in the bulk. This transformation allows us to directly
connect our calculation of radiation-induced fluctuations in vacuum with the
analysis by de Boer et al. of the Brownian motion of a quark that is on average
static within a thermal medium. Combining this same bulk transformation with
previous results of Emparan, we are also able to compute the stress-energy
tensor of the Unruh thermal medium.Comment: 1+31 pages; v2: reference adde
The Gluonic Field of a Heavy Quark in Conformal Field Theories at Strong Coupling
We determine the gluonic field configuration sourced by a heavy quark
undergoing arbitrary motion in N=4 super-Yang-Mills at strong coupling and
large number of colors. More specifically, we compute the expectation value of
the operator tr[F^2+...] in the presence of such a quark, by means of the
AdS/CFT correspondence. Our results for this observable show that signals
propagate without temporal broadening, just as was found for the expectation
value of the energy density in recent work by Hatta et al. We attempt to shed
some additional light on the origin of this feature, and propose a different
interpretation for its physical significance. As an application of our general
results, we examine when the quark undergoes oscillatory motion,
uniform circular motion, and uniform acceleration. Via the AdS/CFT
correspondence, all of our results are pertinent to any conformal field theory
in 3+1 dimensions with a dual gravity formulation.Comment: 1+38 pages, 16 eps figures; v2: completed affiliation; v3: corrected
typo, version to appear in JHE
Master equation simulation analysis of immunostained Bicoid morphogen gradient
<p>Abstract</p> <p>Background</p> <p>The concentration gradient of Bicoid protein which determines the developmental pathways in early <it>Drosophila </it>embryo is the best characterized morphogen gradient at the molecular level. Because different developmental fates can be elicited by different concentrations of Bicoid, it is important to probe the limits of this specification by analyzing intrinsic fluctuations of the Bicoid gradient arising from small molecular number. Stochastic simulations can be applied to further the understanding of the dynamics of Bicoid morphogen gradient formation at the molecular number level, and determine the source of the nucleus-to-nucleus expression variation (noise) observed in the Bicoid gradient.</p> <p>Results</p> <p>We compared quantitative observations of Bicoid levels in immunostained <it>Drosophila </it>embryos with a spatially extended Master Equation model which represents diffusion, decay, and anterior synthesis. We show that the intrinsic noise of an autonomous reaction-diffusion gradient is Poisson distributed. We demonstrate how experimental noise can be identified in the logarithm domain from single embryo analysis, and then separated from intrinsic noise in the normalized variance domain of an ensemble statistical analysis. We show how measurement sensitivity affects our observations, and how small amounts of rescaling noise can perturb the noise strength (Fano factor) observed. We demonstrate that the biological noise level in data can serve as a physical constraint for restricting the model's parameter space, and for predicting the Bicoid molecular number and variation range. An estimate based on a low variance ensemble of embryos suggests that the steady-state Bicoid molecular number in a nucleus should be larger than 300 in the middle of the embryo, and hence the gradient should extend to the posterior end of the embryo, beyond the previously assumed background limit. We exhibit the predicted molecular number gradient together with measurement effects, and make a comparison between conditions of higher and lower variance respectively.</p> <p>Conclusion</p> <p>Quantitative comparison of Master Equation simulations with immunostained data enabled us to determine narrow ranges for key biophysical parameters, which for this system can be independently validated. Intrinsic noise is clearly detectable as well, although the staining process introduces certain limits in resolution.</p
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