A "partitioned leaping" approach for multiscale modeling of chemical reaction dynamics

We present a novel multiscale simulation approach for modeling stochasticity in chemical reaction networks. The approach seamlessly integrates exact-stochastic and "leaping" methodologies into a single "partitioned leaping" algorithmic framework. The technique correctly accounts for stochastic noise at significantly reduced computational cost, requires the definition of only three model-independent parameters and is particularly well-suited for simulating systems containing widely disparate species populations. We present the theoretical foundations of partitioned leaping, discuss various options for its practical implementation and demonstrate the utility of the method via illustrative examples.Comment: v4: 12 pages, 5 figures, final accepted version. Error found and fixed in Appendi

Accurate implementation of leaping in space: The spatial partitioned-leaping algorithm

There is a great need for accurate and efficient computational approaches that can account for both the discrete and stochastic nature of chemical interactions as well as spatial inhomogeneities and diffusion. This is particularly true in biology and nanoscale materials science, where the common assumptions of deterministic dynamics and well-mixed reaction volumes often break down. In this article, we present a spatial version of the partitioned-leaping algorithm (PLA), a multiscale accelerated-stochastic simulation approach built upon the tau-leaping framework of Gillespie. We pay special attention to the details of the implementation, particularly as it pertains to the time step calculation procedure. We point out conceptual errors that have been made in this regard in prior implementations of spatial tau-leaping and illustrate the manifestation of these errors through practical examples. Finally, we discuss the fundamental difficulties associated with incorporating efficient exact-stochastic techniques, such as the next-subvolume method, into a spatial-leaping framework and suggest possible solutions.Comment: 15 pages, 9 figures, 2 table

BioNetGen 2.2: Advances in Rule-Based Modeling

BioNetGen is an open-source software package for rule-based modeling of complex biochemical systems. Version 2.2 of the software introduces numerous new features for both model specification and simulation. Here, we report on these additions, discussing how they facilitate the construction, simulation, and analysis of larger and more complex models than previously possible.Comment: 3 pages, 1 figure, 1 supplementary text file. Supplementary text includes a brief discussion of the RK-PLA along with a performance analysis, two tables listing all new actions/arguments added in BioNetGen 2.2, and the "BioNetGen Quick Reference Guide". Accepted for publication in Bioinformatic

Effects of Youth Tobacco Access and Possession Policy Interventions on Heavy Adolescent Smokers

This study evaluated the effects of tobacco PUP (Purchase, Use and Possession) laws on tobacco use patterns among students in twenty-four towns, which were randomly assigned into an experimental and a control group. The experimental group involved both PUP law enforcement and reducing minors’ access to commercial sources of tobacco, and the condition for the control group involved only efforts to reduce minors’ access to commercial sources of tobacco. The present study found that adolescents in the control group had a significantly greater increase in the percentage of youth who smoked 20 or more cigarettes per day when compared to the experimental group

Optical properties of a two-dimensional electron gas at even-denominator filling fractions

The optical properties of an electron gas in a magnetic field at filling fractions \nu = {1\over 2m} (m=1,2,3...) are investigated using the composite fermion picture. The response of the system to the presence of valence-band holes is calculated. The shapes of the emission spectra are found to differ qualitatively from the well-known electron-hole results at zero magnetic field. In particular, the asymmetry of the emission lineshape is found to be sensitive to the hole-composite fermion plane separation.Comment: 17 pages, LaTeX, 7 figures. This revised version is to appear in Physical Review

Human Papillomavirus E6 Triggers Upregulation of the Antiviral and Cancer Genomic DNA Deaminase APOBEC3B

ABSTRACT Several recent studies have converged upon the innate immune DNA cytosine deaminase APOBEC3B (A3B) as a significant source of genomic uracil lesions and mutagenesis in multiple human cancers, including those of the breast, head/neck, cervix, bladder, lung, ovary, and other tissues. A3B is upregulated in these tumor types relative to normal tissues, but the mechanism is unclear. Because A3B also has antiviral activity in multiple systems and is a member of the broader innate immune response, we tested the hypothesis that human papillomavirus (HPV) infection causes A3B upregulation. We found that A3B mRNA expression and enzymatic activity were upregulated following transfection of a high-risk HPV genome and that this effect was abrogated by inactivation of E6. Transduction experiments showed that the E6 oncoprotein alone was sufficient to cause A3B upregulation, and a panel of high-risk E6 proteins triggered higher A3B levels than did a panel of low-risk or noncancer E6 proteins. Knockdown experiments in HPV-positive cell lines showed that endogenous E6 is required for A3B upregulation. Analyses of publicly available head/neck cancer data further support this relationship, as A3B levels are higher in HPV-positive cancers than in HPV-negative cancers. Taken together with the established role for high-risk E6 in functional inactivation of TP53 and published positive correlations in breast cancer between A3B upregulation and genetic inactivation of TP53, our studies suggest a model in which high-risk HPV E6, possibly through functional inactivation of TP53, causes derepression of A3B gene transcription. This would lead to a mutator phenotype that explains the observed cytosine mutation biases in HPV-positive head/neck and cervical cancers

Functional annotation of the human brain methylome identifies tissue-specific epigenetic variation across brain and blood

notes: PMCID: PMC3446315© 2012 Davies et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Dynamic changes to the epigenome play a critical role in establishing and maintaining cellular phenotype during differentiation, but little is known about the normal methylomic differences that occur between functionally distinct areas of the brain. We characterized intra- and inter-individual methylomic variation across whole blood and multiple regions of the brain from multiple donors

Constraints on Type Ia Supernova Progenitor Companions from Early Ultraviolet Observations with Swift

We compare early ultraviolet (UV) observations of Type Ia Supernovae (SNe Ia) with theoretical predictions for the brightness of the shock associated with the collision between SN ejecta and a companion star. Our simple method is independent of the intrinsic flux from the SN and treats the flux observed with the Swift/Ultra-Violet Optical Telescope (UVOT) as conservative upper limits on the shock brightness. Comparing this limit with the predicted flux for various shock models, we constrain the geometry of the SN progenitor-companion system. We find the model of a 1 M_sun red supergiant companion in Roche lobe overflow to be excluded at a 95% confidence level for most individual SNe for all but the most unfavorable viewing angles. For the sample of 12 SNe taken together, the upper limits on the viewing angle are inconsistent with the expected distribution of viewing angles for RG stars as the majority of companions with high confidence. The separation distance constraints do allow MS companions. A better understanding of the UV flux arising from the SN itself as well as continued UV observations of young SNe Ia will further constrain the possible progenitors of SNe Ia.Comment: accepted versio