Classifying general nonlinear force laws in cell-based models via the continuum limit

though discrete cell-based frameworks are now commonly used to simulate a whole range of biological phenomena, it is typically not obvious how the numerous different types of model are related to one another, nor which one is most appropriate in a given context. Here we demonstrate how individual cell movement on the discrete scale modeled using nonlinear force laws can be described by nonlinear diffusion coefficients on the continuum scale. A general relationship between nonlinear force laws and their respective diffusion coefficients is derived in one spatial dimension and, subsequently, a range of particular examples is considered. For each case excellent agreement is observed between numerical solutions of the discrete and corresponding continuum models. Three case studies are considered in which we demonstrate how the derived nonlinear diffusion coefficients can be used to (a) relate different discrete models of cell behavior; (b) derive discrete, intercell force laws from previously posed diffusion coefficients, and (c) describe aggregative behavior in discrete simulations.

Molecular modelling studies of binding of DACD derivatives into G-Quadruplex DNA: comparison of force field and quantum polarized ligand docking methods

The DNA G-qadruplexes are one of the targets being actively explored for anti-cancer therapy by inhibiting them through small molecules. This computational study was conducted to predict the binding strengths and orientations of a set of novel dimethyl-amino-ethyl-acridine (DACA) analogues that are designed and synthesized in our laboratory, but did not diffract in Synchrotron light.Thecrystal structure of DNA G-Quadruplex(TGGGGT)4(PDB: 1O0K) was used as target for their binding properties in our studies.We used both the force field (FF) and QM/MM derived atomic charge schemes simultaneously for comparing the predictions of drug binding modes and their energetics. This study evaluates the comparative performance of fixed point charge based Glide XP docking and the quantum polarized ligand docking schemes. These results will provide insights on the effects of including or ignoring the drug-receptor interfacial polarization events in molecular docking simulations, which in turn, will aid the rational selection of computational methods at different levels of theory in future drug design programs. Plenty of molecular modelling tools and methods currently exist for modelling drug-receptor or protein-protein, or DNA-protein interactionssat different levels of complexities.Yet, the capasity of such tools to describevarious physico-chemical propertiesmore accuratelyis the next step ahead in currentresearch.Especially, the usage of most accurate methods in quantum mechanics(QM) is severely restricted by theirtedious nature. Though the usage of massively parallel super computing environments resulted in a tremendous improvement in molecular mechanics (MM) calculations like molecular dynamics,they are still capable of dealing with only a couple of tens to hundreds of atoms for QM methods. One such efficient strategy that utilizes thepowers of both MM and QM are the QM/MM hybrid methods. Lately, attempts have been directed towards the goal of deploying several different QM methods for betterment of force field based simulations, but with practical restrictions in place. One of such methods utilizes the inclusion of charge polarization events at the drug-receptor interface, that is not explicitly present in the MM FF.

Extracting and validating force fields for disordered polymeric materials from neutron scattering data

We present a new approach that allows the determination and refinement of force field parameters for the description of disordered macromolecular systems from experimental neutron diffraction data obtained over a large Q range. The procedure is based on tight coupling between experimentally derived structure factors and computer modelling. By separating the potential into terms representing respectively bond stretching, angle bending and torsional rotation and by treating each of them separately, the various potential parameters are extracted directly from experiment. The procedure is illustrated on molten polytetrafluoroethylene.

Extracting force fields for disordered polymeric materials from neutron scattering data

We present a new approach that allows the determination of force-field parameters for the description of disordered macromolecular systems from experimental neutron diffraction data obtained over a large Q range. The procedure is based on a tight coupling between experimentally derived structure factors and computer modelling. We separate the molecular potential into non-interacting terms representing respectively bond stretching, angle bending and torsional rotation. The parameters for each of the potentials are extracted directly from experimental data through comparison of the experimental structure factor and those derived from atomistic level molecular models. The viability of these force fields is assessed by comparison of predicted large-scale features such as the characteristic ratio. The procedure is illustrated on molten poly(ethylene) and poly(tetrafluoroethylene).

Joint servoing for robust manipulator force control

An experimental and theoretical comparison is made of force control performance with different types of innerloop joint servoing techniques. The problem of disturbance rejection and sensitivity to plant dynamics variations (robustness) is addressed. Position, velocity, strain gauge derived joint torque, and current servos are designed and implemented on a specially instrumented industrial robot, and the end-effector force feedback performances achieved are compared. Joint strain derived torque servoing is found to provide the best overall robust force control performance. Experimental results of the robust hard-on-hard contact achieved with the novel force controller implementation based on joint torque sensing are provided. Conclusions are drawn on the force control performance achievable on a geared robot given the joint servoing technique.

Measurement of intrinsic properties of amyloid fibrils by the peak force QNM method

We report the investigation of the mechanical properties of different types of amyloid fibrils by the peak force quantitative nanomechanical (PF-QNM) technique. We demonstrate that this technique correctly measures the Young’s modulus independent of the polymorphic state and the cross-sectional structural details of the fibrils, and we show that values for amyloid fibrils assembled from heptapeptides, a-synuclein, Ab(1–42), insulin, b-lactoglobulin,lysozyme, ovalbumin, Tau protein and bovine serum albumin all fall in the range of 2–4 GPa.

Molecular and phenotypic characterization of a mouse model of oculopharyngeal muscular dystrophy reveals severe muscular atrophy restricted to fast glycolytic fibres

Oculopharyngeal muscular dystrophy (OPMD) is an adult-onset disorder characterized by ptosis, dysphagia and proximal limb weakness. Autosomal-dominant OPMD is caused by a short (GCG)8–13 expansions within the first exon of the poly(A)-binding protein nuclear 1 gene (PABPN1), leading to an expanded polyalanine tract in the mutated protein. Expanded PABPN1 forms insoluble aggregates in the nuclei of skeletal muscle fibres. In order to gain insight into the different physiological processes affected in OPMD muscles, we have used a transgenic mouse model of OPMD (A17.1) and performed transcriptomic studies combined with a detailed phenotypic characterization of this model at three time points. The transcriptomic analysis revealed a massive gene deregulation in the A17.1 mice, among which we identified a significant deregulation of pathways associated with muscle atrophy. Using a mathematical model for progression, we have identified that one-third of the progressive genes were also associated with muscle atrophy. Functional and histological analysis of the skeletal muscle of this mouse model confirmed a severe and progressive muscular atrophy associated with a reduction in muscle strength. Moreover, muscle atrophy in the A17.1 mice was restricted to fast glycolytic fibres, containing a large number of intranuclear inclusions (INIs). The soleus muscle and, in particular, oxidative fibres were spared, even though they contained INIs albeit to a lesser degree. These results demonstrate a fibre-type specificity of muscle atrophy in this OPMD model. This study improves our understanding of the biological pathways modified in OPMD to identify potential biomarkers and new therapeutic targets.

Codon and mRNA sequence optimization of microdystrophin transgenes improves expression and physiological outcome in dystrophic mdx mice following AAV2/8 gene transfer

Duchenne muscular dystrophy is a fatal muscle-wasting disorder. Lack of dystrophin compromises the integrity of the sarcolemma and results in myofibers that are highly prone to contraction-induced injury. Recombinant adenoassociated virus (rAAV)-mediated dystrophin gene transfer strategies to muscle for the treatment of Duchenne muscular dystrophy (DMD) have been limited by the small cloning capacity of rAAV vectors and high titers necessary to achieve efficient systemic gene transfer. In this study, we assess the impact of codon optimization on microdystrophin (ΔAB/R3-R18/ΔCT) expression and function in the mdx mouse and compare the function of two different configurations of codon-optimized microdystrophin genes (ΔAB/R3-R18/ΔCT and ΔR4-R23/ΔCT) under the control of a muscle-restrictive promoter (Spc5-12). Codon optimization of microdystrophin significantly increases levels of microdystrophin mRNA and protein after intramuscular and systemic administration of plasmid DNA or rAAV2/8. Physiological assessment demonstrates that codon optimization of ΔAB/R3-R18/ΔCT results in significant improvement in specific force, but does not improve resistance to eccentric contractions compared with noncodon-optimized ΔAB/ R3-R18/ΔCT. However, codon-optimized microdystrophin ΔR4-R23/ΔCT completely restored specific force generation and provided substantial protection from contraction-induced injury. These results demonstrate that codon optimization of microdystrophin under the control of a muscle-specific promoter can significantly improve expression levels such that reduced titers of rAAV vectors will be required for efficient systemic administration.

Are informed citizens more trusting? Transparency of performance data and trust towards a British police force

In Britain, substantial cuts in police budgets alongside controversial handling of incidents such as politically sensitive enquiries, public disorder and relations with the media have recently triggered much debate about public knowledge and trust in the police. To date, however, little academic research has investigated how knowledge of police performance impacts citizens’ trust. We address this long-standing lacuna by exploring citizens’ trust before and after exposure to real performance data in the context of a British police force. The results reveal that being informed of performance data affects citizens’ trust significantly. Furthermore, direction and degree of change in trust are related to variations across the different elements of the reported performance criteria. Interestingly, the volatility of citizens’ trust is related to initial performance perceptions (such that citizens with low initial perceptions of police performance react more significantly to evidence of both good and bad performance than citizens with high initial perceptions), and citizens’ intentions to support the police do not always correlate with their cognitive and affective trust towards the police. In discussing our findings, we explore the implications of how being transparent with performance data can both hinder and be helpful in developing citizens’ trust towards a public organisation such as the police. From our study, we pose a number of ethical challenges that practitioners face when deciding what data to highlight, to whom, and for what purpose.

Role of the Skyrme tensor force in heavy-ion fusion

We make use of the Skyrme effective nuclear interaction within the time-dependent Hartree-Fock framework to assess the effect of inclusion of the tensor terms of the Skyrme interaction on the fusion window of the 16O–16O reaction. We find that the lower fusion threshold, around the barrier, is quite insensitive to these details of the force, but the higher threshold, above which the nuclei pass through each other, changes by several MeV between different tensor parametrisations. The results suggest that eventually fusion properties may become part of the evaluation or fitting process for effective nuclear interactions.

The effect of the tensor force on the predicted stability of superheavy nuclei

The effect of the tensor component of the Skyrme effective nucleon-nucleon interaction on the single-particle structure in superheavy elements is studied. A selection of the available Skyrme forces has been chosen and their predictions for the proton and neutron shell closures investigated. The inclusion of the tensor term with realistic coupling strength parameters leads to a small increase in the spin-orbit splitting between the proton 2f7/2 and 2f5/2 partners, opening the Z=114 shell gap over a wide range of nuclei. The Z=126 shell gap, predicted by these models in the absence of the tensor term, is found to be stongly dependent on neutron number with a Z=138 gap opening for large neutron numbers, having a consequent implication for the synthesis of neutron-rich superheavy elements. The predicted neutron shell structures remain largely unchanged by inclusion of the tensor component.

FORCe: fully online and automated artifact removal for brain-computer interfacing

A fully automated and online artifact removal method for the electroencephalogram (EEG) is developed for use in brain-computer interfacing. The method (FORCe) is based upon a novel combination of wavelet decomposition, independent component analysis, and thresholding. FORCe is able to operate on a small channel set during online EEG acquisition and does not require additional signals (e.g. electrooculogram signals). Evaluation of FORCe is performed offline on EEG recorded from 13 BCI particpants with cerebral palsy (CP) and online with three healthy participants. The method outperforms the state-of the-art automated artifact removal methods Lagged auto-mutual information clustering (LAMIC) and Fully automated statistical thresholding (FASTER), and is able to remove a wide range of artifact types including blink, electromyogram (EMG), and electrooculogram (EOG) artifacts.