Toward a Dependability Case Language and Workflow for a Radiation Therapy System

We present a near-future research agenda for bringing a suite of modern programming-languages verification tools - specifically interactive theorem proving, solver-aided languages, and formally defined domain-specific languages - to the development of a specific safety-critical system, a radiotherapy medical device. We sketch how we believe recent programming-languages research advances can merge with existing best practices for safety-critical systems to increase system assurance and developer productivity. We motivate hypotheses central to our agenda: That we should start with a single specific system and that we need to integrate a variety of complementary verification and synthesis tools into system development

BioSimulators: a central registry of simulation engines and services for recommending specific tools

Computational models have great potential to accelerate bioscience, bioengineering, and medicine. However, it remains challenging to reproduce and reuse simulations, in part, because the numerous formats and methods for simulating various subsystems and scales remain siloed by different software tools. For example, each tool must be executed through a distinct interface. To help investigators find and use simulation tools, we developed BioSimulators (https://biosimulators.org), a central registry of the capabilities of simulation tools and consistent Python, command-line and containerized interfaces to each version of each tool. The foundation of BioSimulators is standards, such as CellML, SBML, SED-ML and the COMBINE archive format, and validation tools for simulation projects and simulation tools that ensure these standards are used consistently. To help modelers find tools for particular projects, we have also used the registry to develop recommendation services. We anticipate that BioSimulators will help modelers exchange, reproduce, and combine simulations

Changes in the rates of floodplain and in-channel bench accretion in response to catchment disturbance, central Queensland, Australia

Analysis of the changes in rates of catchment sediment storage can provide material evidence of the impact of landscape disturbance on catchment sediment flux. A number of studies have suggested increased sediment yields from the rivers draining to the Great Barrier Reef since European settlement in the mid-nineteenth century. Many of these predictions, which indicate increases between four to ten times the pre-disturbance estimates, are based on large-scale catchment modelling that make some critical assumptions about pre-disturbance erosion rates and/or sediment delivery ratios. In addition, the majority have not been validated by empirical data. This study uses single-grain OSL dating and 137Cs depth profiles to determine pre- and post-floodplain accretion rates in Theresa Creek, a subcatchment of the dry-tropical Fitzroy River basin. We demonstrate that floodplain accretion rates have increased by three to four times since European settlement (ca. A.D. 1850). Decreased rates of floodplain accretion since the mid-twentieth century at sites contributed to by gullied terrain suggest a decrease in the supply of sediment derived from gully networks. In contrast, floodplain accretion rates from areas dominated by cultivation remain high. Widespread in-channel benches deposited since European settlement are stable and appear to be important stores of large volumes of sediment. Low magnitude increases in post-disturbance floodplain sedimentation rates (3 to 4 times), in comparison to those reported from mainly temperate climates (10 to 100 times), are attributed to the naturally high sediment loads typical of dry-tropical catchments. Consequently, previous predictions of large post-disturbance increases in sediment yields from large dry-tropical catchments draining to the Great Barrier Reef are likely to be overestimates

Determining floodplain sedimentation rates using 137Cs in a low fallout environment dominated by channel- and cultivation-derived sediment inputs, central Queensland, Australia

Fallout (137)Cs has been widely used to determine floodplain sedimentation rates in temperate environments, particularly in the northern hemisphere. Its application in low fallout, tropical environments in the southern hemisphere has been limited. In this study we assess the utility of (137)Cs for determining rates of floodplain sedimentation in a dry-tropical catchment in central Queensland, Australia. Floodplain and reference site cores were analysed in two centimetre increments, depth profiles were produced and total (137)Cs inventories calculated from the detailed profile data. Information on the rates of (137)Cs migration through local soils was obtained from the reference site soil cores. This data was used in an advection-diffusion model to account of (137)Cs mobility in floodplain sediment cores. This allowed sedimentation rates to be determined without the first year of detection for (137)Cs being known and without having to assume that (137)Cs remains immobile following deposition. Caesium-137 depth profiles in this environment are demonstrated to be an effective way of determining floodplain sedimentation rates. The total (137)Cs inventory approach was found to be less successful, with only one of the three sites analysed being in unequivocal agreement with the depth profile results. The input of sediment from catchment sources that have little, or no, (137)Cs attached results in true depositional sites having total inventories that are not significantly different from those of undisturbed reference sites.</p

Sediment source changes over the last 250 years in a dry-tropical catchment, central Queensland, Australia

Rivers draining to the Great Barrier Reef are receiving increased attention with the realisation that European land use changes over the last ∼ 150 years may have increased river sediment yields, and that these may have adversely affected the reef environment. Mitigation of the effects associated with such changes is only possible if information on the spatial provenance and dominant types of erosion is known. To date, very few field-based studies have attempted to provide this information. This study uses fallout radionuclide (137Cs and 210Pbex) and geochemical tracing of river bed and floodplain sediments to examine sources over the last ∼ 250 years for Theresa Creek, a subcatchment of the Fitzroy River basin, central Queensland, Australia. A Monte Carlo style mixing model is used to predict the relative contribution of both the spatial (geological) sources and erosion types. The results indicate that sheetwash and rill erosion from cultivated basaltic land and channel erosion from non-basaltic parts of the catchment are currently contributing most sediment to the river system. Evidence indicates that the dominant form of channel erosion is gully headcut and sidewall erosion. Sheetwash and rill erosion from uncultivated land (i.e., grazed pasture/woodland) is a comparatively minor contributor of sediment to the river network. Analysis of the spatial provenance of floodplain core sediments, in conjunction with optical dating and 137Cs depth profile data, suggests that a phase of channel erosion was initiated in the late nineteenth century. With the development of land underlain by basalt in the mid-twentieth century the dominant source of erosion shifted to cultivated land, although improvements in land management practices have probably resulted in a decrease in sediment yield from cultivated areas in the later half of the twentieth century. On a basin-wide scale, because of the limited spatial extent of cultivation, channel sources are likely to be the largest contributor of sediment to the Fitzroy River. Accordingly, catchment management measures focused on reducing sediment delivery to the Great Barrier Reef should focus primarily on decreasing erosion from channel sources

Ralaniten Sensitizes Enzalutamide-Resistant Prostate Cancer to Ionizing Radiation in Prostate Cancer Cells that Express Androgen Receptor Splice Variants

Blocking androgen receptor (AR) transcriptional activity by androgen deprivation therapy (ADT) improves the response to radiotherapy for intermediate and high risk prostate cancer. Unfortunately, ADT, antiandrogens, and abiraterone increase expression of constitutively active splice variants of AR (AR-Vs) which regulate DNA damage repair leading to resistance to radiotherapy. Here we investigate whether blocking the transcriptional activities of full-length AR and AR-Vs with ralaniten leads to enhanced sensitivity to radiotherapy. Combination therapies using ralaniten with ionizing radiation were evaluated for effects on proliferation, colony formation, cell cycle, DNA damage, and Western blot analyses in human prostate cancer cells that express both full-length AR and AR-Vs. Ralaniten and a potent next-generation analog (EPI-7170) decreased expression of DNA repair genes whereas enzalutamide had no effect. FACS analysis revealed a dose-dependent decrease of BrdU incorporation with increased accumulation of γH2AX with a combination of ionizing radiation with ralaniten. An additive inhibitory effect on proliferation of enzalutamide-resistant cells was achieved with a combination of ralaniten compounds with ionizing radiation. Ralaniten and EPI-7170 sensitized prostate cancer cells that express full-length AR and AR-Vs to radiotherapy whereas enzalutamide had no added benefit.Medicine, Faculty ofScience, Faculty ofNon UBCChemistry, Department ofPathology and Laboratory Medicine, Department ofReviewedFacultyOthe