Nucleation in a sheared Ising model: effects of external field

Simulations using the Forward Flux Sampling method have shown a nonmonotonic de- pendence of the homogeneous nucleation rate on the shear rate for a sheared two dimensional Ising model [R. J. Allen et al, arXiv cond-mat/0805.3029]. For quasi-equilibrium systems (i.e. in the absence of shear), Classical Nucleation Theory (CNT) predicts the dependence of the critical cluster size and the nucleation rate on the external magnetic field. We investigate the behaviour of the sheared Ising model as a function of the external field. At low exter- nal field strength, the same nonmonotonic behaviour holds and the peak in the nucleation rate is remarkably insensitive to the field strength. This suggests that the same external field-dependence holds for the enhancement of nucleation by shear at low shear rates and the suppression of shear at high shear rates. At high field strength, the nucleation behaviour is qualitatively different. We also analyse the size and shape of the largest cluster in the transition state configurations, as a function of the external field. In the sheared system, the transition state cluster becomes larger and more elongated as the field strength decreases. We compare our results for the sheared system to the predictions of the CNT for the quasi- equilibrium case, and find that the CNT cannot easily be used to describe nucleation in the system under shear

PedGenie: an analysis approach for genetic association testing in extended pedigrees and genealogies of arbitrary size

BACKGROUND: We present a general approach to perform association analyses in pedigrees of arbitrary size and structure, which also allows for a mixture of pedigree members and independent individuals to be analyzed together, to test genetic markers and qualitative or quantitative traits. Our software, PedGenie, uses Monte Carlo significance testing to provide a valid test for related individuals that can be applied to any test statistic, including transmission disequilibrium statistics. Single locus at a time, composite genotype tests, and haplotype analyses may all be performed. We illustrate the validity and functionality of PedGenie using simulated and real data sets. For the real data set, we evaluated the role of two tagging-single nucleotide polymorphisms (tSNPs) in the DNA repair gene, NBS1, and their association with female breast cancer in 462 cases and 572 controls selected to be BRCA1/2 mutation negative from 139 high-risk Utah breast cancer families. RESULTS: The results from PedGenie were shown to be valid both for accurate p-value calculations and consideration of pedigree structure in the simulated data set. A nominally significant association with breast cancer was observed with the NBS1 tSNP rs709816 for carriage of the rare allele (OR = 1.61, 95% CI = 1.10–2.35, p = 0.019). CONCLUSION: PedGenie is a flexible and valid statistical tool that is intuitively simple to understand, makes efficient use of all the data available from pedigrees without requiring trimming, and is flexible to the types of tests to which it can be applied. Further, our analyses of real data indicate NBS1 may play a role in the genetic etiology of heritable breast cancer

A cautionary note on the appropriateness of using a linkage resource for an association study

BACKGROUND: Utilizing a linkage resource for association analysis requires consideration both of the marker data used and correlations among relatives in pedigrees. We previously developed a method for association testing in pedigrees. We applied our method to 50 replicates of microsatellite data surrounding five genes involved in high-density lipoprotein (HDL) in the Genetic Analysis Workshop 13 (GAW13) simulated data and examined association with HDL as well as linkage disequilibrium (LD) between markers. RESULTS: Although no association was intentionally simulated, we found significant evidence of weak LD between microsatellite markers (flanking/~5 cM from the genes), in some but not all replicates. This level of LD compared well to that observed in the real GAW13 Framingham data. Only one region had sufficient replicates to assess power, and this was low (12.5–20.8%). More power was attained using all individuals and accounting for relationships, compared with one independent individual/pedigree, although this was not significant due to small sample sizes. Not accounting for relatedness inflated statistical significance (p < 0.0001). CONCLUSION: A correction for dependence is necessary in association studies to avoid an inflation of significance probabilities. Our results further illustrate that use of microsatellite marker data is not an effective approach for association testing

Reaction coordinates for the flipping of genetic switches

We present a detailed analysis, based on the Forward Flux Sampling (FFS) simulation method, of the switching dynamics and stability of two models of genetic toggle switches, consisting of two mutually-repressing genes encoding transcription factors (TFs); in one model (the exclusive switch), they mutually exclude each other's binding, while in the other model (general switch) the two transcription factors can bind simultaneously to the shared operator region. We assess the role of two pairs of reactions that influence the stability of these switches: TF-TF homodimerisation and TF-DNA association/dissociation. We factorise the flipping rate k into the product of the probability rho(q*) of finding the system at the dividing surface (separatrix) between the two stable states, and a kinetic prefactor R. In the case of the exclusive switch, the rate of TF-operator binding affects both rho(q*) and R, while the rate of TF dimerisation affects only R. In the case of the general switch both TF-operator binding and TF dimerisation affect k, R and rho(q*). To elucidate this, we analyse the transition state ensemble (TSE). For the exclusive switch, varying the rate of TF-operator binding can drastically change the pathway of switching, while changing the rate of dimerisation changes the switching rate without altering the mechanism. The switching pathways of the general switch are highly robust to changes in the rate constants of both TF-operator and TF-TF binding, even though these rate constants do affect the flipping rate; this feature is unique for non-equilibrium systems.Comment: 24 pages, 7 figure

Astrocyte-secreted chordin-like 1 regulates spine density after ischemic injury

Ischemic injury occurs when the brain is deprived of blood flow, preventing cells from receiving essential nutrients. The injury core is the brain region directly deprived and is surrounded by the peri-infarct area, the region with recovery potential. In the peri-infarct area neurons undergo acute loss of dendritic spines, which modifies synaptic plasticity and determines neuronal survival. Astrocytes can be protective or detrimental to the ischemic injury response depending on the specific stage, yet we lack clear understanding of the underlying mechanisms. Chordin-like 1 (Chrdl1) is an astrocyte-secreted protein that promotes synaptic maturation and limits experience-dependent plasticity in the mouse visual cortex. Given this plasticity-limiting function we asked if Chrdl1 regulates the response to ischemic injury, modelled using photothrombosis (PT). We find that Chrdl1 mRNA is upregulated in astrocytes in the peri-infarct area in both acute and sub-acute phases post-PT. To determine the impact of increased Chrdl1 on the response to PT we analyzed Chrdl1 knock-out mice. We find that absence of Chrdl1 prevents ischemia-induced spine loss in the peri-infarct area and reduces cell death in the core, without impacting gliosis. These findings highlight the important role of astrocyte-secreted proteins in regulating structural plasticity in response to brain ischemic injuries

Clonal amplification of Fasciola hepatica in Galba truncatula: within and between isolate variation of triclabendazole-susceptible and -resistant clones

Background: Fasciola hepatica is of worldwide significance, impacting on the health, welfare and productivity of livestock and regarded by WHO as a re-emerging zoonosis. Triclabendazole (TCBZ), the drug of choice for controlling acute fasciolosis in livestock, is also the drug used to treat human infections. However TCBZ-resistance is now considered a major threat to the effective control of F. hepatica. It has yet to be demonstrated whether F. hepatica undergoes a genetic clonal expansion in the snail intermediate host, Galba truncatula, and to what extent amplification of genotypes within the snail facilitates accumulation of drug resistant parasites. Little is known about genotypic and phenotypic variation within and between F. hepatica isolates. Results: Six clonal isolates of F. hepatica (3× triclabendazole-resistant, TCBZ-R and 3× triclabendazole-susceptible, TCBZ-S) were generated. Snails infected with one miracidium started to shed cercariae 42–56 days post-infection and shed repeatedly up to a maximum of 11 times. A maximum of 884 cercariae were shed by one clonally-infected snail (FhLivS1) at a single time point, with > 3000 clonal metacercariae shed over its lifetime. Following experimental infection all 12 sheep were FEC positive at the time of TCBZ treatment. Sheep infected with one of three putative TCBZ-S clones and treated with TCBZ had no parasites in the liver at post-mortem, whilst sheep each infected with putative TCBZ-R isolates had 35–165 adult fluke at post-mortem, despite TCBZ treatment. All six untreated control animals had between 15–127 parasites. A single multi-locus genotype was reported for every fluke from each of the six clonal isolates. Adult F. hepatica showed considerable variation in weight, ranging from 20–280 mg, with variation in weight evident within and amongst clonal isolates. Conclusions: A genetic clonal expansion occurs within G. truncatula, highlighting the potential for amplification of drug resistant genotypes of F. hepatica. Variation in the weight of parasites within and between clonal isolates and when comparing isolates that are either susceptible or resistant to TCBZ represent inherent variation in liver fluke and cannot be attributed to their resistance or susceptibility traits

Eliminating fast reactions in stochastic simulations of biochemical networks: a bistable genetic switch

In many stochastic simulations of biochemical reaction networks, it is desirable to ``coarse-grain'' the reaction set, removing fast reactions while retaining the correct system dynamics. Various coarse-graining methods have been proposed, but it remains unclear which methods are reliable and which reactions can safely be eliminated. We address these issues for a model gene regulatory network that is particularly sensitive to dynamical fluctuations: a bistable genetic switch. We remove protein-DNA and/or protein-protein association-dissociation reactions from the reaction set, using various coarse-graining strategies. We determine the effects on the steady-state probability distribution function and on the rate of fluctuation-driven switch flipping transitions. We find that protein-protein interactions may be safely eliminated from the reaction set, but protein-DNA interactions may not. We also find that it is important to use the chemical master equation rather than macroscopic rate equations to compute effective propensity functions for the coarse-grained reactions.Comment: 46 pages, 5 figure

Xe films on a decagonal Al-Ni-Co quasicrystal surface

The grand canonical Monte Carlo method is employed to study the adsorption of Xe on a quasicrystalline Al-Ni-Co surface. The calculation uses a semiempirical gas-surface interaction, based on conventional combining rules and the usual Lennard-Jones Xe-Xe interaction. The resulting adsorption isotherms and calculated structures are consistent with the results of LEED experimental data. In this paper we focus on five features not discussed earlier (Phys. Rev. Lett. 95, 136104 (2005)): the range of the average density of the adsorbate, the order of the transition, the orientational degeneracy of the ground state, the isosteric heat of adsorption of the system, and the effect of the vertical cell dimension.Comment: 6 pages, 5 pic