The effect of topology on the structure and free energy landscape of DNA kissing complexes

We use a recently developed coarse-grained model for DNA to study kissing complexes formed by hybridization of complementary hairpin loops. The binding of the loops is topologically constrained because their linking number must remain constant. By studying systems with linking numbers -1, 0 or 1 we show that the average number of interstrand base pairs is larger when the topology is more favourable for the right-handed wrapping of strands around each other. The thermodynamic stability of the kissing complex also decreases when the linking number changes from -1 to 0 to 1. The structures of the kissing complexes typically involve two intermolecular helices that coaxially stack with the hairpin stems at a parallel four-way junction

Strong-Segregation Theory of Bicontinuous Phases in Block Copolymers

We compute phase diagrams for $A_nB_m$ starblock copolymers in the strong-segregation regime as a function of volume fraction $\phi$, including bicontinuous phases related to minimal surfaces (G, D, and P surfaces) as candidate structures. We present the details of a general method to compute free energies in the strong segregation limit, and demonstrate that the gyroid G phase is the most nearly stable among the bicontinuous phases considered. We explore some effects of conformational asymmetry on the topology of the phase diagram.Comment: 14 pages, latex, 21 figures, to appear in Macromolecule

A simulation model of intraherd transmission of foot and mouth disease with reference to disease spread before and after clinical diagnosis

Abstract. Intraherd transmission of foot and mouth disease virus (FMDV) was examined using a simulation model for a hypothetical 1,000-cow dairy, assuming clinical diagnosis was made when at least 1% (10 cows) or 5% (50 cows) had clinical signs of FMD, 1 index case cow, and transition state distributions for the latent, subclinically infectious, and clinically infectious periods of FMD calculated from published data. Estimates assumed for the number of animal-to-animal contacts (k) adequate for transmission ranged from 0.6 to 9.0 per hour (13.7-216.0 per day). A total of 40,000 iterations (5,000 for each scenario, assessing 4 adequate contact rates and 2 detection criteria) were run. The model predicted that FMD would not be diagnosed in the herd until 10.0-13.5 days after the index case cow had become infected, at which time between 65% and 97% of the cows (646-967 cows) to nearly 100% (978-996 cows) would already have become infected with the virus, if the number of cows showing clinical signs of FMD at the time of diagnosis were 10 or 50, respectively. At the time of diagnosis, the simulated number of infectious cattle varied substantially from 82-472 to 476-537 cows, depending on adequate contact rate and whether the diagnosis was made when 10 or 50 animals were showing clinical signs, respectively. The simulated number of infectious cows increased rapidly during the first few days after diagnosis. In the scenario where at least 10 cows showing clinical signs was necessary before a clinical diagnosis was made, each day after diagnosis, the number of infectious animals increased by nearly 100 to more than 200 cases per day up to day 5, assuming 0.57-9.0 animal-to-animal contacts per hour, respectively. Results obtained when it was assumed that at least 50 clinical cases were present at the time of diagnosis showed smaller relative increases because nearly one-half of the herd was projected to be infected at the time of diagnosis. From these results, it is clear that once an individual in a herd becomes infected with FMDV, herd infectivity is not static, rather it accelerates as would be expected as long as there are sufficient susceptible animals to sustain the increasing transmission rate, after which time the rate at which new infections occurs will diminish. Results indicate that biosecurity strategies aimed at minimizing both intraherd and interherd contact will be critical in minimizing the spread of FMD before the initial diagnosis is made. In addition, simulations suggest that very early clinical diagnosis of FMD and effective isolation or depopulation and disposal will be critical in limiting the number of infectious animals capable of transmitting the virus to other herds and thus in timely control of an epidemic. Early diagnosis will rely on early virus detection from animals in the preclinical phase of infection, rather than waiting for clinical signs to manifest in sufficient numbers to be noticed and to warrant investigation. Foot and mouth disease (FMD) is one of the most economically important livestock diseases in the world. In recent years, large-scale epidemics have been observed in Taiwan in 1997, 11 the UK in 2001

Use of peptide antibodies to probe for the mitoxantrone resistance-associated protein MXR/BCRP/ABCP/ABCG2

AbstractRecent studies have characterized the ABC half-transporter associated with mitoxantrone resistance in human cancer cell lines. Encoded by the ABCG2 gene, overexpression confers resistance to camptothecins, as well as to mitoxantrone. We developed four polyclonal antibodies against peptides corresponding to four different epitopes on the mitoxantrone resistance-associated protein, ABCG2. Three epitopes localized on the cytoplasmic region of ABCG2 gave rise to high-affinity antibodies, which were demonstrated to be specific for ABCG2. Western blot analysis of cells with high levels of ABCG2 showed a single major band of the expected 72-kDa molecular size of ABCG2 under denaturing conditions. Immunoblot analysis performed under non-reducing conditions and after treatment with cross-linking reagents demonstrated a molecular weight shift from 72 kDa to several bands of 180 kDa and higher molecular weight, suggesting detection of dimerization products of ABCG2. Evidence of N-linked glycosylation was also obtained using tunicamycin and N-glycosidase F. Finally, both by light, fluorescence and electron microscopic immunohistochemical staining, we demonstrate cytoplasmic and predominantly plasma membrane localization of ABCG2 in cell lines with high levels of expression. Plasma membrane staining was observed on the surface of the chorionic villi in placenta. These results support the hypothesis that ABCG2 is an ABC half-transporter that forms dimers in the plasma membrane, functioning as an ATP-dependent outward pump for substrate transport

Recalculation of dose for each fraction of treatment on TomoTherapy.

OBJECTIVE: The VoxTox study, linking delivered dose to toxicity requires recalculation of typically 20-37 fractions per patient, for nearly 2000 patients. This requires a non-interactive interface permitting batch calculation with multiple computers. METHODS: Data are extracted from the TomoTherapy(®) archive and processed using the computational task-management system GANGA. Doses are calculated for each fraction of radiotherapy using the daily megavoltage (MV) CT images. The calculated dose cube is saved as a digital imaging and communications in medicine RTDOSE object, which can then be read by utilities that calculate dose-volume histograms or dose surface maps. The rectum is delineated on daily MV images using an implementation of the Chan-Vese algorithm. RESULTS: On a cluster of up to 117 central processing units, dose cubes for all fractions of 151 patients took 12 days to calculate. Outlining the rectum on all slices and fractions on 151 patients took 7 h. We also present results of the Hounsfield unit (HU) calibration of TomoTherapy MV images, measured over an 8-year period, showing that the HU calibration has become less variable over time, with no large changes observed after 2011. CONCLUSION: We have developed a system for automatic dose recalculation of TomoTherapy dose distributions. This does not tie up the clinically needed planning system but can be run on a cluster of independent machines, enabling recalculation of delivered dose without user intervention. ADVANCES IN KNOWLEDGE: The use of a task management system for automation of dose calculation and outlining enables work to be scaled up to the level required for large studies.JES is supported by Cancer Research UK through the Cambridge Cancer Centre. MR, AB and KH are supported by Cancer Research UK through the VoxTox Research Programme. NGB is supported by the NIHR Cambridge Biomedical Research Centre.This is the author accepted manuscript. The final version is available from British Institute of Radiology via http://dx.doi.org/10.1259/bjr.2015077

Systematic interaction network filtering identifies CRMP1 as a novel suppressor of huntingtin misfolding and neurotoxicity

Assemblies of huntingtin (HTT) fragments with expanded polyglutamine (polyQ) tracts are a pathological hallmark of Huntington's disease (HD). The molecular mechanisms by which these structures are formed and cause neuronal dysfunction and toxicity are poorly understood. Here, we utilized available gene expression data sets of selected brain regions of HD patients and controls for systematic interaction network filtering in order to predict disease-relevant, brain region-specific HTT interaction partners. Starting from a large protein-protein interaction (PPI) data set, a step-by-step computational filtering strategy facilitated the generation of a focused PPI network that directly or indirectly connects 13 proteins potentially dysregulated in HD with the disease protein HTT. This network enabled the discovery of the neuron-specific protein CRMP1 that targets aggregation-prone, N-terminal HTT fragments and suppresses their spontaneous self-assembly into proteotoxic structures in various models of HD. Experimental validation indicates that our network filtering procedure provides a simple but powerful strategy to identify disease-relevant proteins that influence misfolding and aggregation of polyQ disease proteins.DFG [SFB740, 740/2-11, SFB618, 618/3-09, SFB/TRR43 A7]; BMBF(NGFN-Plus) [01GS08169-73, 01GS08150, 01GS08108]; HDSA Coalition for the Cure; EU (EuroSpin) [Health-F2-2009-241498, HEALTH-F2-2009-242167]; Helmholtz Association (MSBN, HelMA) [HA-215]; FCT [IF/00881/2013]info:eu-repo/semantics/publishedVersio

Small and large polarons in nickelates, manganites, and cuprates

By comparing the optical conductivities of La_{1.67}Sr_{0.33}NiO_{4} (LSNO), Sr_{1.5}La_{0.5}MnO_4 (SLMO), Nd_2CuO_{4-y} (NCO), and Nd_{1.96}Ce_{0.04}CuO_{4} (NCCO), we have identified a peculiar behavior of polarons in this cuprate family. While in LSNO and SLMO small polarons localize into ordered structures below a transition temperature, in those cuprates the polarons appear to be large, and at low T their binding energy decreases. This reflects into an increase of the polaron radius, which may trigger coherent transport.Comment: File latex, 15 p. incl. 4 Figs. epsf, to appear on the Journal of Superconductivity - Proc. "Stripes 1996" - Roma Dec 199

Genome-wide screening for DNA variants associated with reading and language traits

This research was funded by: Max Planck Society, the University of St Andrews - Grant Number: 018696, US National Institutes of Health - Grant Number: P50 HD027802, Wellcome Trust - Grant Number: 090532/Z/09/Z, and Medical Research Council Hub Grant Grant Number: G0900747 91070Reading and language abilities are heritable traits that are likely to share some genetic influences with each other. To identify pleiotropic genetic variants affecting these traits, we first performed a genome‐wide association scan (GWAS) meta‐analysis using three richly characterized datasets comprising individuals with histories of reading or language problems, and their siblings. GWAS was performed in a total of 1862 participants using the first principal component computed from several quantitative measures of reading‐ and language‐related abilities, both before and after adjustment for performance IQ. We identified novel suggestive associations at the SNPs rs59197085 and rs5995177 (uncorrected P ≈ 10–7 for each SNP), located respectively at the CCDC136/FLNC and RBFOX2 genes. Each of these SNPs then showed evidence for effects across multiple reading and language traits in univariate association testing against the individual traits. FLNC encodes a structural protein involved in cytoskeleton remodelling, while RBFOX2 is an important regulator of alternative splicing in neurons. The CCDC136/FLNC locus showed association with a comparable reading/language measure in an independent sample of 6434 participants from the general population, although involving distinct alleles of the associated SNP. Our datasets will form an important part of on‐going international efforts to identify genes contributing to reading and language skills.Publisher PDFPeer reviewe

Accumulated dose to the rectum, measured using dose-volume histograms and dose-surface maps, is different from planned dose in all patients treated with radiotherapy for prostate cancer.

OBJECTIVE: We sought to calculate accumulated dose (DA) to the rectum in patients treated with radiotherapy for prostate cancer. We were particularly interested in whether dose-surface maps (DSMs) provide additional information to dose-volume histograms (DVHs). METHODS: Manual rectal contours were obtained for kilovoltage and daily megavoltage CT scans for 10 participants from the VoxTox study (380 scans). Daily delivered dose recalculation was performed using a ray-tracing algorithm. Delivered DVHs were summated to create accumulated DVHs. The rectum was considered as a cylinder, cut and unfolded to produce daily delivered DSMs; these were summated to produce accumulated DSMs. RESULTS: Accumulated dose-volumes were different from planned in all participants. For one participant, all DA levels were higher and all volumes were larger than planned. For four participants, all DA levels were lower and all volumes were smaller than planned. For each of these four participants, ≥1% of pixels on the accumulated DSM received ≥5 Gy more than had been planned. CONCLUSION: Differences between accumulated and planned dose-volumes were seen in all participants. DSMs were able to identify differences between DA and planned dose that could not be appreciated from the DVHs. Further work is needed to extract the dose data embedded in the DSMs. These will be correlated with toxicity as part of the VoxTox Programme. ADVANCES IN KNOWLEDGE: DSMs are able to identify differences between DA and planned dose that cannot be appreciated from DVHs alone and should be incorporated into future studies investigating links between DA and toxicity.JES is supported by Cancer Research UK through the Cambridge Cancer Centre. NGB is supported by the NIHR Cambridge Biomedical Research Centre. KH, MR and AMB are supported by the VoxTox Research Programme, which is funded by Cancer Research UK.This is the final version of the article. It first appeared from the British Institute of Radiology via http://dx.doi.org/10.1259/bjr.2015024

Fast and accurate modelling of longitudinal and repeated measures neuroimaging data

Despite the growing importance of longitudinal data in neuroimaging, the standard analysis methods make restrictive or unrealistic assumptions (e.g., assumption of Compound Symmetry—the state of all equal variances and equal correlations—or spatially homogeneous longitudinal correlations). While some new methods have been proposed to more accurately account for such data, these methods are based on iterative algorithms that are slow and failure-prone. In this article, we propose the use of the Sandwich Estimator (SwE) method which first estimates the parameters of interest with a simple Ordinary Least Square model and second estimates variances/covariances with the “so-called” SwE which accounts for the within-subject correlation existing in longitudinal data. Here, we introduce the SwE method in its classic form, and we review and propose several adjustments to improve its behaviour, specifically in small samples. We use intensive Monte Carlo simulations to compare all considered adjustments and isolate the best combination for neuroimaging data. We also compare the SwE method to other popular methods and demonstrate its strengths and weaknesses. Finally, we analyse a highly unbalanced longitudinal dataset from the Alzheimer's Disease Neuroimaging Initiative and demonstrate the flexibility of the SwE method to fit within- and between-subject effects in a single model. Software implementing this SwE method has been made freely available at http://warwick.ac.uk/tenichols/SwE