The Input Signal Step Function (ISSF), a Standard Method to Encode Input Signals in SBML Models with Software Support, Applied to Circadian Clock Models

LetterThis is the final version of the article. Available from SAGE Publications via the DOI in this record.Time-dependent light input is an important feature of computational models of the circadian clock. However, publicly available models encoded in standard representations such as the Systems Biology Markup Language (SBML) either do not encode this input or use different mechanisms to do so, which hinders reproducibility of published results as well as model reuse. The authors describe here a numerically continuous function suitable for use in SBML for models of circadian rhythms forced by periodic light-dark cycles. The Input Signal Step Function (ISSF) is broadly applicable to encoding experimental manipulations, such as drug treatments, temperature changes, or inducible transgene expression, which may be transient, periodic, or mixed. It is highly configurable and is able to reproduce a wide range of waveforms. The authors have implemented this function in SBML and demonstrated its ability to modify the behavior of publicly available models to accurately reproduce published results. The implementation of ISSF allows standard simulation software to reproduce specialized circadian protocols, such as the phase-response curve. To facilitate the reuse of this function in public models, the authors have developed software to configure its behavior without any specialist knowledge of SBML. A community-standard approach to represent the inputs that entrain circadian clock models could particularly facilitate research in chronobiology.K.S. was supported by the UK BBSRC grant BB/E015263/1. SynthSys Edinburgh is a Centre for Integrative Systems Biology (CISB) funded by BBSRC and EPSRC, reference BB/D019621/1

Bulk rheology and microrheology of active fluids

We simulate macroscopic shear experiments in active nematics and compare them with microrheology simulations where a spherical probe particle is dragged through an active fluid. In both cases we define an effective viscosity: in the case of bulk shear simulations this is the ratio between shear stress and shear rate, whereas in the microrheology case it involves the ratio between the friction coefficient and the particle size. We show that this effective viscosity, rather than being solely a property of the active fluid, is affected by the way chosen to measure it, and strongly depends on details such as the anchoring conditions at the probe surface and on both the system size and the size of the probe particle.Comment: 12 pages, 10 figure

Colloids in active fluids: Anomalous micro-rheology and negative drag

We simulate an experiment in which a colloidal probe is pulled through an active nematic fluid. We find that the drag on the particle is non-Stokesian (not proportional to its radius). Strikingly, a large enough particle in contractile fluid (such as an actomyosin gel) can show negative viscous drag in steady state: the particle moves in the opposite direction to the externally applied force. We explain this, and the qualitative trends seen in our simulations, in terms of the disruption of orientational order around the probe particle and the resulting modifications to the active stress.Comment: 5 pages, 3 figure

Optimising Structural Loading and Power Production for Floating Wave Energy Converters

This is the author accepted manuscript. The final version is available from EWTEC via the link in this record.This paper investigates the design trade-off between power production and structural loading for Wave Energy Converters (WECs), based on tank test results for the Albatern 12S floating wave energy array. This work feeds into the design development process, which is currently in the concept design and testing phase. The paper focuses on two methods for reducing structural loading: limiting the power take off (PTO) torque generation capacity (for operational loads), and controlling the PTO damping (for extreme loads). The torque that can be generated by the primary PTO mechanism affects the size (and cost) of the structural components within the device. Increased torque results in a potentially greater power capture, but also greater structural loading. It is therefore important to highlight the target torque limit early in the design process. The aim of this work is to identify the optimum torque limit to refine the design towards the lowest overall Levelised Cost of Energy (LCoE). In addition, a high-level investigation of the impact of PTO damping on extreme loading has been carried out, to help to identify appropriate “operational” and “survival” sea states for the device. The paper calculates an optimum torque limit for the device at the West Harris site and quantifies the trade-off between Annual Energy Production and structural cost, using the LCoE as an optimisation criteria. The approach is in principle applicable to other technologies, if the design drivers are adjusted to the technology’s working principle.Tank testing was funded by Wave Energy Scotland (WES) as part of the Novel Wave Energy Converter Stage 1 (NWEC1) programme. This work has been carried out as part of the IDCORE programme, funded by the Energy Technology Institute and RCUK Energy programme (grant no. EP/J500847/1

The effect of radiosensitizers on the pharmacokinetics of melphalan and cyclophosphamide in the mouse.

Misonidazole (MISO) has been shown to affect the pharmacokinetics of both cyclophosphamide (CY) and melphalan (MEL) in WHT mice resulting in increased plasma levels of the cytotoxic drugs. The effect is not solely due to the reduction in body temperature observed with large single doses of MISO, as a change in MEL pharmacokinetics was still observed when the mice were maintained at 37 degrees C. Inhibition of cytotoxic drug metabolism may also be a possible mechanism. Such a pharmacokinetic effect could account for part of the potentiation of MEL and CY action observed in tumours with large single doses of MISO. However, a chronic low dosing schedule of MISO did not affect the plasma half-life of either cytotoxic drug, although a significant potentiation of each drug in combination with a chronic MISO dose has been obtained in some tumours. These results suggest that potentiation of chemotherapeutic drug action by MISO in the clinical situation is unlikely to be due to changes in drug pharmacokinetics

Steel-concrete connections for floating wave energy converters

In order to make wave power technologies competitive within the overall energy market, there needs to be significant reductions in the levelised cost of energy (LCoE). One area for potential cost reduction is the use of cheaper materials that are suitable for use in the harsh marine environment, such as reinforced concrete, which gives good corrosion and fatigue properties while providing excellent strength and stiffness at low unit cost. Concrete has the potential to be used for a wide range of wave energy device configurations, however in general use has been limited to nearshore fixed bottom wave energy converters. To date, no dynamic floating wave energy devices have successfully utilised reinforced concrete as structural material, mainly due to the uncertainty surrounding the behaviour of critical dynamic connections between concrete sections and other materials. This paper explores the main issues surrounding steel-concrete connections for floating wave energy converters, providing a review of available design options and standards and assessing the applicability of these to WECs. A methodology is proposed for the evaluation of connection options, and a case study of the Squid 12S floating WEC (developed by Albatern) is presented.This work has been carried out as part of the IDCORE programme, funded by the Energy Technology Institute and RCUK Energy programme (grant no. EP/J500847/1

Using MathML to Represent Units of Measurement for Improved Ontology Alignment

Ontologies provide a formal description of concepts and their relationships in a knowledge domain. The goal of ontology alignment is to identify semantically matching concepts and relationships across independently developed ontologies that purport to describe the same knowledge. In order to handle the widest possible class of ontologies, many alignment algorithms rely on terminological and structural meth- ods, but the often fuzzy nature of concepts complicates the matching process. However, one area that should provide clear matching solutions due to its mathematical nature, is units of measurement. Several on- tologies for units of measurement are available, but there has been no attempt to align them, notwithstanding the obvious importance for tech- nical interoperability. We propose a general strategy to map these (and similar) ontologies by introducing MathML to accurately capture the semantic description of concepts specified therein. We provide mapping results for three ontologies, and show that our approach improves on lexical comparisons.Comment: Conferences on Intelligent Computer Mathematics (CICM 2013), Bath, Englan

Estimating the number needed to treat from continuous outcomes in randomised controlled trials: methodological challenges and worked example using data from the UK Back Pain Exercise and Manipulation (BEAM) trial

Background Reporting numbers needed to treat (NNT) improves interpretability of trial results. It is unusual that continuous outcomes are converted to numbers of individual responders to treatment (i.e., those who reach a particular threshold of change); and deteriorations prevented are only rarely considered. We consider how numbers needed to treat can be derived from continuous outcomes; illustrated with a worked example showing the methods and challenges. Methods We used data from the UK BEAM trial (n = 1, 334) of physical treatments for back pain; originally reported as showing, at best, small to moderate benefits. Participants were randomised to receive 'best care' in general practice, the comparator treatment, or one of three manual and/or exercise treatments: 'best care' plus manipulation, exercise, or manipulation followed by exercise. We used established consensus thresholds for improvement in Roland-Morris disability questionnaire scores at three and twelve months to derive NNTs for improvements and for benefits (improvements gained+deteriorations prevented). Results At three months, NNT estimates ranged from 5.1 (95% CI 3.4 to 10.7) to 9.0 (5.0 to 45.5) for exercise, 5.0 (3.4 to 9.8) to 5.4 (3.8 to 9.9) for manipulation, and 3.3 (2.5 to 4.9) to 4.8 (3.5 to 7.8) for manipulation followed by exercise. Corresponding between-group mean differences in the Roland-Morris disability questionnaire were 1.6 (0.8 to 2.3), 1.4 (0.6 to 2.1), and 1.9 (1.2 to 2.6) points. Conclusion In contrast to small mean differences originally reported, NNTs were small and could be attractive to clinicians, patients, and purchasers. NNTs can aid the interpretation of results of trials using continuous outcomes. Where possible, these should be reported alongside mean differences. Challenges remain in calculating NNTs for some continuous outcomes