1,424 research outputs found
Multilevel Deconstruction of the In Vivo Behavior of Looped DNA-Protein Complexes
Protein-DNA complexes with loops play a fundamental role in a wide variety of
cellular processes, ranging from the regulation of DNA transcription to
telomere maintenance. As ubiquitous as they are, their precise in vivo
properties and their integration into the cellular function still remain
largely unexplored. Here, we present a multilevel approach that efficiently
connects in both directions molecular properties with cell physiology and use
it to characterize the molecular properties of the looped DNA-lac repressor
complex while functioning in vivo. The properties we uncover include the
presence of two representative conformations of the complex, the stabilization
of one conformation by DNA architectural proteins, and precise values of the
underlying twisting elastic constants and bending free energies. Incorporation
of all this molecular information into gene-regulation models reveals an
unprecedented versatility of looped DNA-protein complexes at shaping the
properties of gene expression.Comment: Open Access article available at
http://www.plosone.org/article/fetchArticle.action?articleURI=info%3Adoi%2F10.1371%2Fjournal.pone.000035
Three combinations of clonidine in association with tiletamine-zolazepam for anaesthesia induction in rats: evaluation of reflexes and pain sensibility
The aim of this study was to assess the combination of tiletamine-zolazepam (Zoletil 20\uae) with three different doses of clonidine for general anaesthesia induction in rats submitted to vascular microsurgery.
The evaluation of anaesthetic and analgesic effects was performed in 30 Wistar rats randomly divided into three groups and induced with Zoletil 20 [90 mg/kg Intraperitoneal (IP)] associated with three different doses of clonidine (60\u201390\u2013120 \u3bcg/kg IP). Four clinical parameters were evaluated after induction: loss of righting reflex, voluntary movement, the pedal withdrawal response, and pain sensitivity tested by pinching the tail. The combination of Zoletil with 90 and 120 \u3bcg/kg of clonidine provided a surgical anaesthesia; however, 90 \u3bcg/kg of clonidine provided the most rapid anaesthesia induction, as confirmed by data obtained by clinical evaluation of the loss of the pedal withdrawal response and the absence of the tail pinch response. The increase in dose of clonidine did not lead to
a more rapid action of the \u3b12 agonist, probably due to achievement of a dose-dependent plateau
Minimal Synthesis of String To String Functions From Examples
We study the problem of synthesizing string to string transformations from a
set of input/output examples. The transformations we consider are expressed
using deterministic finite automata (DFA) that read pairs of letters, one
letter from the input and one from the output. The DFA corresponding to these
transformations have additional constraints, ensuring that each input string is
mapped to exactly one output string.
We suggest that, given a set of input/output examples, the smallest DFA
consistent with the examples is a good candidate for the transformation the
user was expecting. We therefore study the problem of, given a set of examples,
finding a minimal DFA consistent with the examples and satisfying the
functionality and totality constraints mentioned above.
We prove that, in general, this problem (the corresponding decision problem)
is NP-complete. This is unlike the standard DFA minimization problem which can
be solved in polynomial time. We provide several NP-hardness proofs that show
the hardness of multiple (independent) variants of the problem.
Finally, we propose an algorithm for finding the minimal DFA consistent with
input/output examples, that uses a reduction to SMT solvers. We implemented the
algorithm, and used it to evaluate the likelihood that the minimal DFA indeed
corresponds to the DFA expected by the user.Comment: SYNT 201
The transition between stochastic and deterministic behavior in an excitable gene circuit
We explore the connection between a stochastic simulation model and an
ordinary differential equations (ODEs) model of the dynamics of an excitable
gene circuit that exhibits noise-induced oscillations. Near a bifurcation point
in the ODE model, the stochastic simulation model yields behavior dramatically
different from that predicted by the ODE model. We analyze how that behavior
depends on the gene copy number and find very slow convergence to the large
number limit near the bifurcation point. The implications for understanding the
dynamics of gene circuits and other birth-death dynamical systems with small
numbers of constituents are discussed.Comment: PLoS ONE: Research Article, published 11 Apr 201
On the nonequilibrium entropy of large and small systems
Thermodynamics makes definite predictions about the thermal behavior of
macroscopic systems in and out of equilibrium. Statistical mechanics aims to
derive this behavior from the dynamics and statistics of the atoms and
molecules making up these systems. A key element in this derivation is the
large number of microscopic degrees of freedom of macroscopic systems.
Therefore, the extension of thermodynamic concepts, such as entropy, to small
(nano) systems raises many questions. Here we shall reexamine various
definitions of entropy for nonequilibrium systems, large and small. These
include thermodynamic (hydrodynamic), Boltzmann, and Gibbs-Shannon entropies.
We shall argue that, despite its common use, the last is not an appropriate
physical entropy for such systems, either isolated or in contact with thermal
reservoirs: physical entropies should depend on the microstate of the system,
not on a subjective probability distribution. To square this point of view with
experimental results of Bechhoefer we shall argue that the Gibbs-Shannon
entropy of a nano particle in a thermal fluid should be interpreted as the
Boltzmann entropy of a dilute gas of Brownian particles in the fluid
Acute systemic response to intraperitoneal implantation of polypropylene mesh/chitosan-based film composite in pigs
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
The Role of the Mucus Barrier in Digestion
Mucus forms a protective layer across a variety of epithelial surfaces. In the gastrointestinal (GI) tract, the barrier has to permit the uptake of nutrients, while excluding potential hazards, such as pathogenic bacteria. In this short review article, we look at recent literature on the structure, location, and properties of the mammalian intestinal secreted mucins and the mucus layer they form over a wide range of length scales. In particular, we look at the structure of the gel-forming glycoprotein MUC2, the primary intestinal secreted mucin, and the influence this has on the properties of the mucus layer. We show that, even at the level of the protein backbone, MUC2 is highly heterogeneous and that this is reflected in the networks it forms. It is evident that a combination of charge and pore size determines what can diffuse through the layer to the underlying gut epithelium. This information is important for the targeted delivery of bioactive molecules, including nutrients and pharmaceuticals, and for understanding how GI health is maintained
Plasma Levels of Middle Molecules to Estimate Residual Kidney Function in Haemodialysis without Urine Collection
© 2015 Vilar et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, (http://creativecommons.org/Licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.BACKGROUND: Residual Kidney Function (RKF) is associated with survival benefits in haemodialysis (HD) but is difficult to measure without urine collection. Middle molecules such as Cystatin C and β2-microglobulin accumulate in renal disease and plasma levels have been used to estimate kidney function early in this condition. We investigated their use to estimate RKF in patients on HD. DESIGN: Cystatin C, β2-microglobulin, urea and creatinine levels were studied in patients on incremental high-flux HD or hemodiafiltration(HDF). Over sequential HD sessions, blood was sampled pre- and post-session 1 and pre-session 2, for estimation of these parameters. Urine was collected during the whole interdialytic interval, for estimation of residual GFR (GFRResidual = mean of urea and creatinine clearance). The relationships of plasma Cystatin C and β2-microglobulin levels to GFRResidual and urea clearance were determined. RESULTS: Of the 341 patients studied, 64% had urine output>100 ml/day, 32.6% were on high-flux HD and 67.4% on HDF. Parameters most closely correlated with GFRResidual were 1/β2-micoglobulin (r2 0.67) and 1/Cystatin C (r2 0.50). Both these relationships were weaker at low GFRResidual. The best regression model for GFRResidual, explaining 67% of the variation, was: GFRResidual = 160.3 · (1/β2m) - 4.2. Where β2m is the pre-dialysis β2 microglobulin concentration (mg/L). This model was validated in a separate cohort of 50 patients using Bland-Altman analysis. Areas under the curve in Receiver Operating Characteristic analysis aimed at identifying subjects with urea clearance≥2 ml/min/1.73 m2 was 0.91 for β2-microglobulin and 0.86 for Cystatin C. A plasma β2-microglobulin cut-off of ≤19.2 mg/L allowed identification of patients with urea clearance ≥2 ml/min/1.73 m2 with 90% specificity and 65% sensitivity. CONCLUSION: Plasma pre-dialysis β2-microglobulin levels can provide estimates of RKF which may have clinical utility and appear superior to cystatin C. Use of cut-off levels to identify patients with RKF may provide a simple way to individualise dialysis dose based on RKF.Peer reviewe
Spatial and topological organization of DNA chains induced by gene co-localization
Transcriptional activity has been shown to relate to the organization of
chromosomes in the eukaryotic nucleus and in the bacterial nucleoid. In
particular, highly transcribed genes, RNA polymerases and transcription factors
gather into discrete spatial foci called transcription factories. However, the
mechanisms underlying the formation of these foci and the resulting topological
order of the chromosome remain to be elucidated. Here we consider a
thermodynamic framework based on a worm-like chain model of chromosomes where
sparse designated sites along the DNA are able to interact whenever they are
spatially close-by. This is motivated by recurrent evidence that there exists
physical interactions between genes that operate together. Three important
results come out of this simple framework. First, the resulting formation of
transcription foci can be viewed as a micro-phase separation of the interacting
sites from the rest of the DNA. In this respect, a thermodynamic analysis
suggests transcription factors to be appropriate candidates for mediating the
physical interactions between genes. Next, numerical simulations of the polymer
reveal a rich variety of phases that are associated with different topological
orderings, each providing a way to increase the local concentrations of the
interacting sites. Finally, the numerical results show that both
one-dimensional clustering and periodic location of the binding sites along the
DNA, which have been observed in several organisms, make the spatial
co-localization of multiple families of genes particularly efficient.Comment: Figures and Supplementary Material freely available on
http://dx.doi.org/10.1371/journal.pcbi.100067
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