The process of end-joining during nonhomologous repair of DNA double-strand breaks (DSBs) after radiation damage is considered. Experimental evidence has revealed that the dynamics of DSB ends ...exhibit subdiffusive motion rather than simple diffusion with rare directional movement. Traditional models often overlook the rare long-range directed motion. To address this limitation, we present a heterogeneous anomalous diffusion model consisting of subdiffusive fractional Brownian motion interchanged with short periods of long-range movement. Our model sheds light on the underlying mechanisms of heterogeneous diffusion in DSB repair and could be used to quantify the DSB dynamics on a time scale inaccessible to single particle tracking analysis. The model predicts that the long-range movement of DSB ends is responsible for the misrepair of DSBs in the form of dicentric chromosome lesions.
Previous studies examining binocular coordination during reading have reported conflicting results in terms of the nature of disparity (e.g. Kliegl, Nuthmann, & Engbert (Journal of Experimental ...Psychology General 135:12-35,
2006
); Liversedge, White, Findlay, & Rayner (Vision Research 46:2363-2374,
2006
). One potential cause of this inconsistency is differences in acquisition devices and associated analysis technologies. We tested this by directly comparing binocular eye movement recordings made using SR Research EyeLink 1000 and the Fourward Technologies Inc. DPI binocular eye-tracking systems. Participants read sentences or scanned horizontal rows of dot strings; for each participant, half the data were recorded with the EyeLink, and the other half with the DPIs. The viewing conditions in both testing laboratories were set to be very similar. Monocular calibrations were used. The majority of fixations recorded using either system were aligned, although data from the EyeLink system showed greater disparity magnitudes. Critically, for unaligned fixations, the data from both systems showed a majority of uncrossed fixations. These results suggest that variability in previous reports of binocular fixation alignment is attributable to the specific viewing conditions associated with a particular experiment (variables such as luminance and viewing distance), rather than acquisition and analysis software and hardware.
In this paper, we provide a unified approach to simulate diffusion bridges. The proposed method covers a wide range of processes including univariate and multivariate diffusions, and the diffusions ...can be either time-homogeneous or time-inhomogeneous. We provide a theoretical framework for the proposed method. In particular, using the parametrix representations we show that the approximated probability transition density function converges to that of the true diffusion, which in turn implies the convergence of the approximation. Unlike most of the methods proposed in the literature, our approach does not involve acceptance-rejection mechanics. That is, it is acceptance-rejection free. Extensive numerical examples are provided for illustration and demonstrate the accuracy of the proposed method.
Evidence regarding exercise capacity and physical activity in children born extremely preterm (EP) is limited. Since survivors remain at high risk for developing bronchopulmonary dysplasia (BPD) and ...long-term pulmonary sequelae, reductions in exercise capacity and activity levels may be present.
To compare maximal exercise ventilation characteristics and physical activity levels at 11 years of age in children born EP (<25 completed weeks gestation) with those of full-term controls.
Participants performed spirometry, body plethysmography and gas transfer testing. A peak exercise test was performed on a cycle ergometer. Physical activity was monitored by accelerometry for 7 days.
Lung function and exercise results were obtained in 38 EP children (71% prior BPD) and 38 controls. Those born EP had significantly lower Z-scores (mean (95% CI) of difference) for forced expiratory volume in 1 s (FEV(1); -1.74 (-2.25 to -1.23) and gas transfer (-0.73 (-1.31 to -0.17), and significantly greater Z-scores for residual volume (RV; 0.58 (0.10 to 1.10)) and RV/total lung capacity (TLC; 0.74 (0.29 to 1.19)). EP birth was associated with a significant reduction in peak oxygen consumption. EP children employed greater breathing frequencies and lower tidal volumes during peak exercise. No differences were observed in physical activity between groups.
The reduction in peak oxygen consumption in children born EP, and alterations in ventilatory adaptations during peak exercise were not explained by differences in physical activity, but probably reflects the long-term pathophysiological impact of EP birth.
Preclinical radiotherapy studies using small animals are an indispensable step in the pathway from in vitro experiments to clinical implementation. As radiotherapy techniques advance in the clinic, ...it is important that preclinical models evolve to keep in line with these developments. The use of orthotopic tumour sites, the development of tissue-equivalent mice phantoms and the recent introduction of image-guided small animal radiation research platforms has enabled similar precision treatments to be delivered in the laboratory.These technological developments, however, are hindered by a lack of corresponding dosimetry standards and poor reporting of methodologies. Without robust and well documented preclinical radiotherapy quality assurance processes, it is not possible to ensure the accuracy and repeatability of dose measurements between laboratories. As a consequence current RT-based preclinical models are at risk of becoming irrelevant.In this review we explore current standardization initiatives, focusing in particular on recent developments in small animal irradiation equipment, 3D printing technology to create customisable tissue-equivalent dosimetry phantoms and combining these phantoms with commonly used detectors.
To investigate and benchmark the current clinical and dosimetric practices in stereotactic radiosurgery (SRS) in the UK.
A detailed questionnaire was sent to 70 radiotherapy centres in the UK. 97% ...(68/70) of centres replied between June and December 2014.
21 centres stated that they are practising SRS, and a further 12 centres plan to start SRS by the end of 2016. The most commonly treated indications are brain metastases and acoustic neuromas. A large range of prescription isodoses that range from 45% to 100% between different radiotherapy centres was seen. Ionization chambers and solid-water phantoms are used by the majority of centres for patient-specific quality assurance, and thermoplastic masks for patient immobilization are more commonly used than fixed stereotactic frames. The majority of centres perform orthogonal kilovoltage X-rays for localization before and during delivery. The acceptable setup accuracy reported ranges from 0.1 to 2 mm with a mean of 0.8 mm.
SRS has been increasing in use in the UK and will continue to increase in the next 2 years. There is no current consensus between SRS centres as a whole, or even between SRS centres with the same equipment, on the practices followed. This indicates the need for benchmarking and standardization in SRS practices within the UK.
This article outlines the current practices in SRS and provides a benchmark for reference and comparison with future research in this technique.
Cosmic Rays, Clouds, and Climate Carslaw, K. S.; Harrison, R. G.; Kirkby, J.
Science (American Association for the Advancement of Science),
11/2002, Letnik:
298, Številka:
5599
Journal Article
Recenzirano
It has been proposed that Earth's climate could be affected by changes in cloudiness caused by variations in the intensity of galactic cosmic rays in the atmosphere. This proposal stems from an ...observed correlation between cosmic ray intensity and Earth's average cloud cover over the course of one solar cycle. Some scientists question the reliability of the observations, whereas others, who accept them as reliable, suggest that the correlation may be caused by other physical phenomena with decadal periods or by a response to volcanic activity or El Niño. Nevertheless, the observation has raised the intriguing possibility that a cosmic ray-cloud interaction may help explain how a relatively small change in solar output can produce much larger changes in Earth's climate. Physical mechanisms have been proposed to explain how cosmic rays could affect clouds, but they need to be investigated further if the observation is to become more than just another correlation among geophysical variables.
An increased rate of cellular proliferation is a hallmark of cancer and may be accompanied by an increase in ribosome biogenesis and dysregulation in rRNA synthesis. In this regard, CX-5461 has been ...developed as a novel RNA polymerase I inhibitor and is currently in Phase I/II clinical trials for solid and hematological malignancies. In the present study, interactions between CX-5461 and single-dose X-ray exposure were assessed using isobologram analysis using MTS assay and drug-induced cell death was assessed using flow cytometric, confocal microscopy and Western blot analysis. Combination treatments involving CX-5461 and single-dose X-ray exposure highlighted increased effectiveness compared to individual treatment alone in the CaSki cervical cancer line, with marked synergistic interaction occurring within the low-drug (50 nM) and low-dose radiation range (2–6 Gy). Cell lines challenged with CX-5461 demonstrated the presence of DNA damage, induction of apoptosis, autophagy and senescence alongside high percentages of G2/M cell cycle arrest. In addition, we report preferential sensitivity of ovarian cancer cells with BRCA2 mutation to this novel agent. Taken together, CX-5461 displayed a broad spectrum of activity in a panel of solid cancer cell lines with IC50 values ranging from 35 nM to >1 µM. The work described herein identifies the synergistic effects of CX-5461 in combination with X-rays in solid cancers and may also aid in the design of clinical trials involving this novel agent.
Abstract
Immunofluorescent tagging of DNA double-strand break (DSB) markers, such as
γ
-H2AX and other DSB repair proteins, are powerful tools in understanding biological consequences following ...irradiation. However, whilst the technique is widespread, there are many uncertainties related to its ability to resolve and reliably deduce the number of foci when counting using microscopy. We present a new tool for simulating radiation-induced foci in order to evaluate microscope performance within in silico immunofluorescent images. Simulations of the DSB distributions were generated using Monte Carlo track-structure simulation. For each DSB distribution, a corresponding DNA repair process was modelled and the un-repaired DSBs were recorded at several time points. Corresponding microscopy images for both a DSB and (
γ
-H2AX) fluorescent marker were generated and compared for different microscopes, radiation types and doses. Statistically significant differences in miscounting were found across most of the tested scenarios. These inconsistencies were propagated through to repair kinetics where there was a perceived change between radiation-types. These changes did not reflect the underlying repair rate and were caused by inconsistencies in foci counting. We conclude that these underlying uncertainties must be considered when analysing images of DNA damage markers to ensure differences observed are real and are not caused by non-systematic miscounting.
PDF
