Mechanistic Modelling of DNA Repair and Cellular Survival Following Radiation-Induced DNA Damage

Characterising and predicting the effects of ionising radiation on cells remains challenging, with the lack of robust models of the underlying mechanism of radiation responses providing a significant limitation to the development of personalised radiotherapy. In this paper we present a mechanistic model of cellular response to radiation that incorporates the kinetics of different DNA repair processes, the spatial distribution of double strand breaks and the resulting probability and severity of misrepair. This model enables predictions to be made of a range of key biological endpoints (DNA repair kinetics, chromosome aberration and mutation formation, survival) across a range of cell types based on a set of 11 mechanistic fitting parameters that are common across all cells. Applying this model to cellular survival showed its capacity to stratify the radiosensitivity of cells based on aspects of their phenotype and experimental conditions such as cell cycle phase and plating delay (correlation between modelled and observed Mean Inactivation Doses R(2) > 0.9). By explicitly incorporating underlying mechanistic factors, this model can integrate knowledge from a wide range of biological studies to provide robust predictions and may act as a foundation for future calculations of individualised radiosensitivity

Modelling radiobiology

Radiotherapy has played an essential role in cancer treatment for over a century, and remains one of the best-studied methods of cancer treatment. Because of its close links with the physical sciences, it has been the subject of extensive quantitative mathematical modelling, but a complete understanding of the mechanisms of radiotherapy has remained elusive. In part this is because of the complexity and range of scales involved in radiotherapy—from physical radiation interactions occurring over nanometres to evolution of patient responses over months and years. This review presents the current status and ongoing research in modelling radiotherapy responses across these scales, including basic physical mechanisms of DNA damage, the immediate biological responses this triggers, and genetic- and patient-level determinants of response. Finally, some of the major challenges in this field and potential avenues for future improvements are also discussed

Fundamental Behavior of Electric Field Enhancements in the Gaps Between Closely Spaced Nanostructures

We demonstrate that the electric field enhancement that occurs in a gap between two closely spaced nanostructures, such as metallic nanoparticles, is the result of a transverse electromagnetic waveguide mode. We derive an explicit semianalytic equation for the enhancement as a function of gap size, which we show has a universal qualitative behavior in that it applies irrespective of the material or geometry of the nanostructures and even in the presence of surface plasmons. Examples of perfect electrically conducting and Ag thin-wire antennas and a dimer of Ag spheres are presented and discussed.Comment: 9 pages and 4 figure

Mechanistic Modelling of Radiation Responses

Radiobiological modelling has been a key part of radiation biology and therapy for many decades, and many aspects of clinical practice are guided by tools such as the linear-quadratic model. However, most of the models in regular clinical use are abstract and empirical, and do not provide significant scope for mechanistic interpretation or making predictions in novel cell lines or therapies. In this review, we will discuss the key areas of ongoing mechanistic research in radiation biology, including physical, chemical, and biological steps, and review a range of mechanistic modelling approaches which are being applied in each area, highlighting the possible opportunities and challenges presented by these techniques

Control and efficiency analysis for a Lundell-alternator/active-rectifier system in automotive applications

This paper presents a control strategy for a conventional Lundell alternator and an active-rectifier. The control scheme focuses on the minimisation of the stator copper losses of the alternator in an effort to maximise its efficiency. The modulation scheme of the active-rectifier is being investigated with the introduction of three different modulation techniques in order to quantify the effect they have on the alternator’s efficiency. Steady-state results from experimental measurements of the alternator rectifier system are compared against a standard passive rectifier. The comparison indicates that the modulation scheme of the active-rectifier is significant to the alternator’s efficiency as well as to the overall system efficiency

Efficiency improvement and power loss breakdown for a Lundell-alternator/active-rectifier system in automotive applications

A control strategy for a conventional Lundell alternator and an active-rectifier using different modulation schemes was proposed in previous work. The modulation techniques examined indicated that the system could operate more efficiently than a passive rectifier over a certain speed and power range. This paper extends the modulation scheme analysis using a SVM scheme with six commutations per switching cycle, giving better electrical and overall efficiency. Furthermore, a power loss breakdown is performed for the active-rectifier with the assistance of experimental and simulation results of double pulse tests. Switching loss estimation curves are produced allowing the loss examination of the active-rectifier. Switching losses account only for a minor portion of the total rectifier losses in comparison to conduction losses. Finally, a higher dc-link voltage of 14.5 V was introduced using SVM scheme, giving better efficiency, in order to exploit further the rectifier loss distribution

Using an engineered glutamate-gated chloride channel to silence sensory neurons and treat neuropathic pain at the source

Peripheral neuropathic pain arises as a consequence of injury to sensory neurons; the development of ectopic activity in these neurons is thought to be critical for the induction and maintenance of such pain. Local anaesthetics and anti-epileptic drugs can suppress hyperexcitability; however, these drugs are complicated by unwanted effects on motor, central nervous system and cardiac function, and alternative more selective treatments to suppress hyperexcitability are therefore required. Here we show that a glutamate-gated chloride channel modified to be activated by low doses of ivermectin (but not glutamate) is highly effective in silencing sensory neurons and reversing neuropathic pain-related hypersensitivity. Activation of the glutamate-gated chloride channel expressed in either rodent or human induced pluripotent stem cell-derived sensory neurons in vitro potently inhibited their response to both electrical and algogenic stimuli. We have shown that silencing is achieved both at nerve terminals and the soma and is independent of membrane hyperpolarization and instead likely mediated by lowering of the membrane resistance. Using intrathecal adeno-associated virus serotype 9-based delivery, the glutamate-gated chloride channel was successfully targeted to mouse sensory neurons in vivo, resulting in high level and long-lasting expression of the channel selectively in sensory neurons. This enabled reproducible and reversible modulation of thermal and mechanical pain thresholds in vivo; analgesia was observed for 3 days after a single systemic dose of ivermectin. We did not observe any motor or proprioceptive deficits and noted no reduction in cutaneous afferent innervation or upregulation of the injury marker ATF3 following prolonged glutamate-gated chloride channel expression. Established mechanical and cold pain-related hypersensitivity generated by the spared nerve injury model of neuropathic pain was reversed by ivermectin treatment. The efficacy of ivermectin in ameliorating behavioural hypersensitivity was mirrored at the cellular level by a cessation of ectopic activity in sensory neurons. These findings demonstrate the importance of aberrant afferent input in the maintenance of neuropathic pain and the potential for targeted chemogenetic silencing as a new treatment modality in neuropathic pain