92 research outputs found
Numerical evidence for relevance of disorder in a Poland-Scheraga DNA denaturation model with self-avoidance: Scaling behavior of average quantities
We study numerically the effect of sequence heterogeneity on the
thermodynamic properties of a Poland-Scheraga model for DNA denaturation taking
into account self-avoidance, i.e. with exponent c_p=2.15 for the loop length
probability distribution. In complement to previous on-lattice Monte Carlo like
studies, we consider here off-lattice numerical calculations for large sequence
lengths, relying on efficient algorithmic methods. We investigate finite size
effects with the definition of an appropriate intrinsic length scale x,
depending on the parameters of the model. Based on the occurrence of large
enough rare regions, for a given sequence length N, this study provides a
qualitative picture for the finite size behavior, suggesting that the effect of
disorder could be sensed only with sequence lengths diverging exponentially
with x. We further look in detail at average quantities for the particular case
x=1.3, ensuring through this parameter choice the correspondence between the
off-lattice and the on-lattice studies. Taken together, the various results can
be cast in a coherent picture with a crossover between a nearly pure system
like behavior for small sizes N < 1000, as observed in the on-lattice
simulations, and the apparent asymptotic behavior indicative of disorder
relevance, with an (average) correlation length exponent \nu_r >= 2/d (=2).Comment: Latex, 33 pages with 15 postscript figure
Numerical study of the disordered Poland-Scheraga model of DNA denaturation
We numerically study the binary disordered Poland-Scheraga model of DNA
denaturation, in the regime where the pure model displays a first order
transition (loop exponent ). We use a Fixman-Freire scheme for the
entropy of loops and consider chain length up to , with
averages over samples. We present in parallel the results of various
observables for two boundary conditions, namely bound-bound (bb) and
bound-unbound (bu), because they present very different finite-size behaviors,
both in the pure case and in the disordered case. Our main conclusion is that
the transition remains first order in the disordered case: in the (bu) case,
the disorder averaged energy and contact densities present crossings for
different values of without rescaling. In addition, we obtain that these
disorder averaged observables do not satisfy finite size scaling, as a
consequence of strong sample to sample fluctuations of the pseudo-critical
temperature. For a given sample, we propose a procedure to identify its
pseudo-critical temperature, and show that this sample then obeys first order
transition finite size scaling behavior. Finally, we obtain that the disorder
averaged critical loop distribution is still governed by in
the regime , as in the pure case.Comment: 12 pages, 13 figures. Revised versio
A stitch in time: Efficient computation of genomic DNA melting bubbles
Background: It is of biological interest to make genome-wide predictions of
the locations of DNA melting bubbles using statistical mechanics models.
Computationally, this poses the challenge that a generic search through all
combinations of bubble starts and ends is quadratic.
Results: An efficient algorithm is described, which shows that the time
complexity of the task is O(NlogN) rather than quadratic. The algorithm
exploits that bubble lengths may be limited, but without a prior assumption of
a maximal bubble length. No approximations, such as windowing, have been
introduced to reduce the time complexity. More than just finding the bubbles,
the algorithm produces a stitch profile, which is a probabilistic graphical
model of bubbles and helical regions. The algorithm applies a probability peak
finding method based on a hierarchical analysis of the energy barriers in the
Poland-Scheraga model.
Conclusions: Exact and fast computation of genomic stitch profiles is thus
feasible. Sequences of several megabases have been computed, only limited by
computer memory. Possible applications are the genome-wide comparisons of
bubbles with promotors, TSS, viral integration sites, and other melting-related
regions.Comment: 16 pages, 10 figure
Probabilistic sequence alignments: realistic models with efficient algorithms
Alignment algorithms usually rely on simplified models of gaps for
computational efficiency. Based on an isomorphism between alignments and
physical helix-coil models, we show in statistical mechanics that alignments
with realistic laws for gaps can be computed with fast algorithms. Improved
performances of probabilistic alignments with realistic models of gaps are
illustrated. Probabilistic and optimization formulations are compared, with
potential implications in many fields and perspectives for computationally
efficient extensions to Markov models with realistic long-range interactions
Delocalization transition of the selective interface model: distribution of pseudo-critical temperatures
According to recent progress in the finite size scaling theory of critical
disordered systems, the nature of the phase transition is reflected in the
distribution of pseudo-critical temperatures over the ensemble of
samples of size . In this paper, we apply this analysis to the
delocalization transition of an heteropolymeric chain at a selective
fluid-fluid interface. The width and the shift
are found to decay with the same exponent
, where . The distribution of
pseudo-critical temperatures is clearly asymmetric, and is well
fitted by a generalized Gumbel distribution of parameter . We also
consider the free energy distribution, which can also be fitted by a
generalized Gumbel distribution with a temperature dependent parameter, of
order in the critical region. Finally, the disorder averaged
number of contacts with the interface scales at like with
.Comment: 9 pages,6 figure
The Mystery of Two Straight Lines in Bacterial Genome Statistics. Release 2007
In special coordinates (codon position--specific nucleotide frequencies)
bacterial genomes form two straight lines in 9-dimensional space: one line for
eubacterial genomes, another for archaeal genomes. All the 348 distinct
bacterial genomes available in Genbank in April 2007, belong to these lines
with high accuracy. The main challenge now is to explain the observed high
accuracy. The new phenomenon of complementary symmetry for codon
position--specific nucleotide frequencies is observed. The results of analysis
of several codon usage models are presented. We demonstrate that the
mean--field approximation, which is also known as context--free, or complete
independence model, or Segre variety, can serve as a reasonable approximation
to the real codon usage. The first two principal components of codon usage
correlate strongly with genomic G+C content and the optimal growth temperature
respectively. The variation of codon usage along the third component is related
to the curvature of the mean-field approximation. First three eigenvalues in
codon usage PCA explain 59.1%, 7.8% and 4.7% of variation. The eubacterial and
archaeal genomes codon usage is clearly distributed along two third order
curves with genomic G+C content as a parameter.Comment: Significantly extended version with new data for all the 348 distinct
bacterial genomes available in Genbank in April 200
Endometrial carcinoma: molecular alterations involved in tumor development and progression
In the western world, endometrial carcinoma (EC) is the most common cancer of the female genital tract. The annual incidence has been estimated at 10-20 per 100 000 women. Two clinicopathological variants are recognized: the estrogen related (type I, endometrioid) and the non-estrogen related (type II, non-endometrioid).The clinicopathological differences are paralleled by specific genetic alterations, with type I showing microsatellite instability and mutations in phosphatase and tensin homologue deleted on chromosome 70, PIK3CA, K-RAS and CTNNB1 (beta-catenin), and type II exhibiting TP53 mutations and chromosomal instability. Some non-endometrioid carcinomas probably arise from pre-existing endometrioid carcinomas as a result of tumor progression and, not surprisingly, some tumors exhibit combined or mixed features at the clinical, pathological and molecular levels. In EC, apoptosis resistance may have a role in tumor progression. Understanding pathogenesis at the molecular level is essential in identifying biomarkers for successful targeted therapies. In this review, the genetic changes of endometrial carcinogenesis are discussed in the light of the morphological features of the tumors and their precursors
Correctly validating results from single molecule data: the case of stretched exponential decay in the catalytic activity of single lipase B molecules
The question of how to validate and interpret correctly the waiting time
probability density functions (WT-PDFs) from single molecule data is addressed.
It is shown by simulation that when a stretched exponential WT-PDF, with a
stretched exponent alfa and a time scale parameter tau, generates the off
periods of a two-state trajectory, a reliable recovery of the input WT-PDF from
the trajectory is obtained even when the bin size used to define the
trajectory, dt, is much larger than the parameter tau. This holds true as long
as the first moment of the WT-PDF is much larger than dt. Our results validate
the results in an earlier study of the activity of single Lipase B molecules
and disprove recent related critique
Local Cooperativity Mechanism in the DNA Melting Transition
We propose a new statistical mechanics model for the melting transition of
DNA. Base pairing and stacking are treated as separate degrees of freedom, and
the interplay between pairing and stacking is described by a set of local rules
which mimic the geometrical constraints in the real molecule. This microscopic
mechanism intrinsically accounts for the cooperativity related to the free
energy penalty of bubble nucleation. The model describes both the unpairing and
unstacking parts of the spectroscopically determined experimental melting
curves. Furthermore, the model explains the observed temperature dependence of
the effective thermodynamic parameters used in models of the nearest neighbor
(NN) type. We compute the partition function for the model through the transfer
matrix formalism, which we also generalize to include non local chain entropy
terms. This part introduces a new parametrization of the Yeramian-like transfer
matrix approach to the Poland-Scheraga description of DNA melting. The model is
exactly solvable in the homogeneous thermodynamic limit, and we calculate all
observables without use of the grand partition function. As is well known,
models of this class have a first order or continuous phase transition at the
temperature of complete strand separation depending on the value of the
exponent of the bubble entropy.Comment: Extended version of Phys. Rev. E pape
Biological effects of sodium phenylbutyrate and taurursodiol in Alzheimer's disease
INTRODUCTION: Sodium phenylbutyrate and taurursodiol (PB and TURSO) is hypothesized to mitigate endoplasmic reticulum stress and mitochondrial dysfunction, two of many mechanisms implicated in Alzheimer's disease (AD) pathophysiology. METHODS: The firstâinâindication phase 2a PEGASUS trial was designed to gain insight into PB and TURSO effects on mechanistic targets of engagement and disease biology in AD. The primary clinical efficacy outcome was a global statistical test combining three endpoints relevant to disease trajectory (cognition [Mild/Moderate Alzheimer's Disease Composite Score], function [Functional Activities Questionnaire], and total hippocampal volume on magnetic resonance imaging). Secondary clinical outcomes included various cognitive, functional, and neuropsychiatric assessments. Cerebrospinal fluid (CSF) biomarkers spanning multiple pathophysiological pathways in AD were evaluated in participants with both baseline and Week 24 samples (exploratory outcome). RESULTS: PEGASUS enrolled 95 participants (intentâtoâtreat [ITT] cohort); cognitive assessments indicated significantly greater baseline cognitive impairment in the PB and TURSO (n = 51) versus placebo (n = 44) group. Clinical efficacy outcomes did not significantly differ between treatment groups in the ITT cohort. CSF interleukinâ15 increased from baseline to Week 24 within the placebo group (n = 34). In the PB and TURSO group (n = 33), reductions were observed in core AD biomarkers phosphorylated tauâ181 (pâtau181) and total tau; synaptic and neuronal degeneration biomarkers neurogranin and fatty acid binding proteinâ3 (FABP3); and gliosis biomarker chitinase 3âlike protein 1 (YKLâ40), while the oxidative stress marker 8âhydroxyâ2âdeoxyguanosine (8âOHdG) increased. Betweenâgroup differences were observed for the AÎČ42/40 ratio, pâtau181, total tau, neurogranin, FABP3, YKLâ40, interleukinâ15, and 8âOHdG. Additional neurodegeneration, inflammation, and metabolic biomarkers showed no differences between groups. DISCUSSION: While betweenâgroup differences in clinical outcomes were not observed, most likely due to the small sample size and relatively short treatment duration, exploratory biomarker analyses suggested that PB and TURSO engages multiple pathophysiologic pathways in AD. Highlights: Proteostasis and mitochondrial stress play key roles in Alzheimer's disease (AD). Sodium phenylbutyrate and taurursodiol (PB and TURSO) targets these mechanisms. The PEGASUS trial was designed to assess PB and TURSO effects on biologic AD targets. PB and TURSO reduced exploratory biomarkers of AD and neurodegeneration. Supports further clinical development of PB and TURSO in neurodegenerative diseases
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