47,640 research outputs found
Tuning transcriptional regulation through signaling: A predictive theory of allosteric induction
Allosteric regulation is found across all domains of life, yet we still lack
simple, predictive theories that directly link the experimentally tunable
parameters of a system to its input-output response. To that end, we present a
general theory of allosteric transcriptional regulation using the
Monod-Wyman-Changeux model. We rigorously test this model using the ubiquitous
simple repression motif in bacteria by first predicting the behavior of strains
that span a large range of repressor copy numbers and DNA binding strengths and
then constructing and measuring their response. Our model not only accurately
captures the induction profiles of these strains but also enables us to derive
analytic expressions for key properties such as the dynamic range and
. Finally, we derive an expression for the free energy of allosteric
repressors which enables us to collapse our experimental data onto a single
master curve that captures the diverse phenomenology of the induction profiles.Comment: Substantial revisions for resubmission (3 new figures, significantly
elaborated discussion); added Professor Mitchell Lewis as another author for
his continuing contributions to the projec
Intrinsic limits to gene regulation by global crosstalk
Gene regulation relies on the specificity of transcription factor (TF) - DNA
interactions. In equilibrium, limited specificity may lead to crosstalk: a
regulatory state in which a gene is either incorrectly activated due to
noncognate TF-DNA interactions or remains erroneously inactive. We present a
tractable biophysical model of global crosstalk, where many genes are
simultaneously regulated by many TFs. We show that in the simplest regulatory
scenario, a lower bound on crosstalk severity can be analytically derived
solely from the number of (co)regulated genes and a suitable parameter that
describes binding site similarity. Estimates show that crosstalk could present
a significant challenge for organisms with low-specificity TFs, such as
metazoans, unless they use appropriate regulation schemes. Strong cooperativity
substantially decreases crosstalk, while joint regulation by activators and
repressors, surprisingly, does not; moreover, certain microscopic details about
promoter architecture emerge as globally important determinants of crosstalk
strength. Our results suggest that crosstalk imposes a new type of global
constraint on the functioning and evolution of regulatory networks, which is
qualitatively distinct from the known constraints acting at the level of
individual gene regulatory elements
Intermediate coherent-incoherent charge transport: DNA as a case study
We study an intermediate quantum coherent-incoherent charge transport
mechanism in metal-molecule-metal junctions using B\"uttiker's probe technique.
This tool allows us to include incoherent effects in a controlled manner, and
thus to study situations in which partial decoherence affects charge transfer
dynamics. Motivated by recent experiments on intermediate coherent-incoherent
charge conduction in DNA molecules [L. Xiang {\it et al.}, Nature Chem. 7,
221-226 (2015)], we focus on two representative structures: alternating
(GC) and stacked GC sequences; the latter structure is argued to
support charge delocalization within G segments, and thus an intermediate
coherent-incoherent conduction. We begin our analysis with a highly simplified
1-dimensional tight-binding model, while introducing environmental effects
through B\"uttiker's probes. This minimal model allows us to gain fundamental
understanding of transport mechanisms and derive analytic results for molecular
resistance in different limits. We then use a more detailed ladder-model
Hamiltonian to represent double-stranded DNA structures---with environmental
effects captured by B\"uttiker's probes. We find that hopping conduction
dominates in alternating sequences, while in stacked sequences charge
delocalization (visualized directly through the electronic density matrix)
supports significant resonant-ballistic charge dynamics reflected by an
even-odd effect and a weak distance dependence for resistance. Our analysis
illustrates that lessons learned from minimal models are helpful for
interpreting charge dynamics in DNA.Comment: 16 pages, 14 figure
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Can graph-cutting improve microarray gene expression reconstructions?
Microarrays produce high-resolution image data that are, unfortunately, permeated with a great deal of “noise” that must be removed for precision purposes. This paper presents a technique for such a removal process. On completion of this non-trivial task, a new surface (devoid of gene spots) is subtracted from the original to render more precise gene expressions. The graph-cutting technique as implemented has the benefits that only the most appropriate pixels are replaced and these replacements are replicates rather than estimates. This means the influence of outliers and other artifacts are handled more appropriately (than in previous methods) as well as the variability of the final gene expressions being considerably reduced. Experiments are carried out to test the technique against commercial and previously researched reconstruction methods. Final results show that the graph-cutting inspired identification mechanism has a positive significant impact on reconstruction accuracy
Phase diagram of solution of oppositely charged polyelectrolytes
We study a solution of long polyanions (PA) with shorter polycations (PC) and
focus on the role of Coulomb interaction. A good example is solutions of DNA
and PC which are widely studied for gene therapy. In the solution, each PA
attracts many PCs to form a complex. When the ratio of total charges of PA and
PC in the solution, , equals to 1, complexes are neutral and they condense
in a macroscopic drop. When is far away from 1, complexes are strongly
charged. The Coulomb repulsion is large and free complexes are stable. As
approaches to 1, PCs attached to PA disproportionate themselves in two
competing ways. One way is inter-complex disproportionation, in which PCs make
some complexes neutral and therefore condensed in a macroscopic drop while
other complexes become even stronger charged and stay free. The other way is
intra-complex disproportionation, in which PCs make one end of a complex
neutral and condensed in a small droplet while the rest of the complex forms a
strongly charged tail. Thus each complex becomes a "tadpole". These two ways
can also combine together to give even lower free energy. We get a phase
diagram of PA-PC solution in a plane of and inverse screening radius of the
monovalent salt, which includes phases or phase coexistence with both kinds of
disproportionation.Comment: 29 pages, 10 figures. Major change in results and tex
The influence of horizontal gene transfer on the mean fitness of unicellular populations in static environments
This paper develops a mathematical model describing the influence that
conjugation-mediated Horizontal Gene Transfer (HGT) has on the
mutation-selection balance in an asexually reproducing population of
unicellular, prokaryotic organisms. It is assumed that mutation-selection
balance is reached in the presence of a fixed background concentration of
antibiotic, to which the population must become resistant in order to survive.
We analyze the behavior of the model in the limit of low and high
antibiotic-induced first-order death rate constants, and find that the highest
mean fitness is obtained at low rates of bacterial conjugation. As the rate of
conjugation crosses a threshold, the mean fitness decreases to a minimum, and
then rises asymptotically to a limiting value as the rate of conjugation
becomes infinitely large. However, this limiting value is smaller than the mean
fitness obtained in the limit of low conjugation rate. This dependence of the
mean fitness on the conjugation rate is fairly small for the parameter ranges
we have considered, and disappears as the first-order death rate constant due
to the presence of antibiotic approaches zero. For large values of the
antibiotic death rate constant, we have obtained an analytical solution for the
behavior of the mean fitness that agrees well with the results of simulations.
The results of this paper suggest that conjugation-mediated HGT has a slightly
deleterious effect on the mean fitness of a population at mutation-selection
balance. Therefore, we argue that HGT confers a selective advantage by allowing
for faster adaptation to a new or changing environment. The results of this
paper are consistent with the observation that HGT can be promoted by
environmental stresses on a population.Comment: 27 pages, 4 figure
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