A generic model of execution for synthesizing domain-specific models

Software engineering researchers are challenged to provide increasingly more powerful levels of abstractions to address the rising complexity inherent in software solutions. One new development paradigm that places models as abstraction at the forefront of the development process is Model-Driven Software Development (MDSD). MDSD considers models as first class artifacts, extending the capability for engineers to use concepts from the problem domain of discourse to specify apropos solutions. A key component in MDSD is domain-specific modeling languages (DSMLs) which are languages with focused expressiveness, targeting a specific taxonomy of problems. The de facto approach used is to first transform DSML models to an intermediate artifact in a HLL e.g., Java or C++, then execute that resulting code.^ Our research group has developed a class of DSMLs, referred to as interpreted DSMLs (i-DSMLs), where models are directly interpreted by a specialized execution engine with semantics based on model changes at runtime. This execution engine uses a layered architecture and is referred to as a domain-specific virtual machine (DSVM). As the domain-specific model being executed descends the layers of the DSVM the semantic gap between the user-defined model and the services being provided by the underlying infrastructure is closed. The focus of this research is the synthesis engine, the layer in the DSVM which transforms i-DSML models into executable scripts for the next lower layer to process.^ The appeal of an i-DSML is constrained as it possesses unique semantics contained within the DSVM. Existing DSVMs for i-DSMLs exhibit tight coupling between the implicit model of execution and the semantics of the domain, making it difficult to develop DSVMs for new i-DSMLs without a significant investment in resources.^ At the onset of this research only one i-DSML had been created for the user- centric communication domain using the aforementioned approach. This i-DSML is the Communication Modeling Language (CML) and its DSVM is the Communication Virtual machine (CVM). A major problem with the CVM's synthesis engine is that the domain-specific knowledge (DSK) and the model of execution (MoE) are tightly interwoven consequently subsequent DSVMs would need to be developed from inception with no reuse of expertise.^ This dissertation investigates how to decouple the DSK from the MoE and subsequently producing a generic model of execution (GMoE) from the remaining application logic. This GMoE can be reused to instantiate synthesis engines for DSVMs in other domains. The generalized approach to developing the model synthesis component of i-DSML interpreters utilizes a reusable framework loosely coupled to DSK as swappable framework extensions.^ This approach involves first creating an i-DSML and its DSVM for a second do- main, demand-side smartgrid, or microgrid energy management, and designing the synthesis engine so that the DSK and MoE are easily decoupled. To validate the utility of the approach, the SEs are instantiated using the GMoE and DSKs of the two aforementioned domains and an empirical study to support our claim of reduced developmental effort is performed.^

The role of individualism and collectivism as predictors of attributions for unethical work behavior : an empirical examination across two culturally diverse groups

This dissertation addresses how the cultural dimensions of individualism and collectivism affect the attributions people make for unethical behavior at work. The moderating effect of ethnicity is also examined by considering two culturally diverse groups: Hispanics and Anglos. The sample for this study is a group of business graduate students from two universities in the Southeast. A 20-minute survey was distributed to master's degree students at their classroom and later on returned to the researcher. Individualism and collectivism were operationalized as by a set of attitude items, while unethical work behavior was introduced in the form of hypothetical descriptions or scenarios. Data analysis employed multiple group confirmatory factor analysis for both independent and dependent variables, and subsequently multiple group LISREL models, in order to test predictions. Results confirmed the expected link between cultural variables and attribution responses, although the role of independent variables shifted, due to the moderating effect of ethnicity, and to the nuances of each particular situation.

Variable Speed Limit Strategies to Reduce the Impacts of Traffic Flow Breakdown at Recurrent Freeway Bottlenecks

Variable Speed Limit (VSL) strategies identify and disseminate dynamic speed limits that are determined to be appropriate based on prevailing traffic conditions, road surface conditions, and weather conditions. This dissertation develops and evaluates a shockwave-based VSL system that uses a heuristic switching logic-based controller with specified thresholds of prevailing traffic flow conditions. The system aims to improve operations and mobility at critical bottlenecks. Before traffic breakdown occurrence, the proposed VSL’s goal is to prevent or postpone breakdown by decreasing the inflow and achieving uniform distribution in speed and flow. After breakdown occurrence, the VSL system aims to dampen traffic congestion by reducing the inflow traffic to the congested area and increasing the bottleneck capacity by deactivating the VSL at the head of the congested area. The shockwave-based VSL system pushes the VSL location upstream as the congested area propagates upstream. In addition to testing the system using infrastructure detector-based data, this dissertation investigates the use of Connected Vehicle trajectory data as input to the shockwave-based VSL system performance. Since the field Connected Vehicle data are not available, as part of this research, Vehicle-to-Infrastructure communication is modeled in the microscopic simulation to obtain individual vehicle trajectories. In this system, wavelet transform is used to analyze aggregated individual vehicles’ speed data to determine the locations of congestion. The currently recommended calibration procedures of simulation models are generally based on the capacity, volume and system-performance values and do not specifically examine traffic breakdown characteristics. However, since the proposed VSL strategies are countermeasures to the impacts of breakdown conditions, considering breakdown characteristics in the calibration procedure is important to have a reliable assessment. Several enhancements were proposed in this study to account for the breakdown characteristics at bottleneck locations in the calibration process. In this dissertation, performance of shockwave-based VSL is compared to VSL systems with different fixed VSL message sign locations utilizing the calibrated microscopic model. The results show that shockwave-based VSL outperforms fixed-location VSL systems, and it can considerably decrease the maximum back of queue and duration of breakdown while increasing the average speed during breakdown.

Surface Mean Flow and Turbulence Structure in Tropical Cyclone Winds

Hurricanes are one of the deadliest and costliest natural hazards affecting the Gulf coast and Atlantic coast areas of the United States. An effective way to minimize hurricane damage is to strengthen structures and buildings. The investigation of surface level hurricane wind behavior and the resultant wind loads on structures is aimed at providing structural engineers with information on hurricane wind characteristics required for the design of safe structures. Information on mean wind profiles, gust factors, turbulence intensity, integral scale, and turbulence spectra and co-spectra is essential for developing realistic models of wind pressure and wind loads on structures. The research performed for this study was motivated by the fact that considerably fewer data and validated models are available for tropical than for extratropical storms. Using the surface wind measurements collected by the Florida Coastal Monitoring Program (FCMP) during hurricane passages over coastal areas, this study presents comparisons of surface roughness length estimates obtained by using several estimation methods, and estimates of the mean wind and turbulence structure of hurricane winds over coastal areas under neutral stratification conditions. In addition, a program has been developed and tested to systematically analyze Wall of Wind (WoW) data, that will make it possible to perform analyses of baseline characteristics of flow obtained in the WoW. This program can be used in future research to compare WoW data with FCMP data, as gust and turbulence generator systems and other flow management devices will be used to create WoW flows that match as closely as possible real hurricane wind conditions. Hurricanes are defined as tropical cyclones for which the maximum 1-minute sustained surface wind speeds exceed 74 mph. FCMP data include data for tropical cyclones with lower sustained speeds. However, for the winds analyzed in this study the speeds were sufficiently high to assure that neutral stratification prevailed. This assures that the characteristics of those winds are similar to those prevailing in hurricanes. For this reason in this study the terms tropical cyclones and hurricanes are used interchangeably.

Lattice Boltzmann Modeling of Fluid Flow and Solute Transport in Karst Aquifers

A novel modeling approach is applied to karst hydrology. Long-standing problems in karst hydrology and solute transport are addressed using Lattice Boltzmann methods (LBMs). These methods contrast with other modeling approaches that have been applied to karst hydrology. The motivation of this dissertation is to develop new computational models for solving ground water hydraulics and transport problems in karst aquifers, which are widespread around the globe. This research tests the viability of the LBM as a robust alternative numerical technique for solving large-scale hydrological problems. The LB models applied in this research are briefly reviewed and there is a discussion of implementation issues. The dissertation focuses on testing the LB models. The LBM is tested for two different types of inlet boundary conditions for solute transport in finite and effectively semi-infinite domains. The LBM solutions are verified against analytical solutions. Zero-diffusion transport and Taylor dispersion in slits are also simulated and compared against analytical solutions. These results demonstrate the LBM’s flexibility as a solute transport solver. The LBM is applied to simulate solute transport and fluid flow in porous media traversed by larger conduits. A LBM-based macroscopic flow solver (Darcy’s law-based) is linked with an anisotropic dispersion solver. Spatial breakthrough curves in one and two dimensions are fitted against the available analytical solutions. This provides a steady flow model with capabilities routinely found in ground water flow and transport models (e.g., the combination of MODFLOW and MT3D). However the new LBM-based model retains the ability to solve inertial flows that are characteristic of karst aquifer conduits. Transient flows in a confined aquifer are solved using two different LBM approaches. The analogy between Fick’s second law (diffusion equation) and the transient ground water flow equation is used to solve the transient head distribution. An altered-velocity flow solver with source/sink term is applied to simulate a drawdown curve. Hydraulic parameters like transmissivity and storage coefficient are linked with LB parameters. These capabilities complete the LBM’s effective treatment of the types of processes that are simulated by standard ground water models. The LB model is verified against field data for drawdown in a confined aquifer.

Integrated Surface-Ground Water Modeling in Wetlands With Improved Methods to Simulate Vegetative Resistance to Flow

This dissertation focused on developing an integrated surface – subsurface hydrologic simulation numerical model by programming and testing the coupling of the USGS MODFLOW-2005 Groundwater Flow Process (GWF) package (USGS, 2005) with the 2D surface water routing model: FLO-2D (O’Brien et al., 1993). The coupling included the necessary procedures to numerically integrate and verify both models as a single computational software system that will heretofore be referred to as WHIMFLO-2D (Wetlands Hydrology Integrated Model). An improved physical formulation of flow resistance through vegetation in shallow waters based on the concept of drag force was also implemented for the simulations of floodplains, while the use of the classical methods (e.g., Manning, Chezy, Darcy-Weisbach) to calculate flow resistance has been maintained for the canals and deeper waters. A preliminary demonstration exercise WHIMFLO-2D in an existing field site was developed for the Loxahatchee Impoundment Landscape Assessment (LILA), an 80 acre area, located at the Arthur R. Marshall Loxahatchee National Wild Life Refuge in Boynton Beach, Florida. After applying a number of simplifying assumptions, results have illustrated the ability of the model to simulate the hydrology of a wetland. In this illustrative case, a comparison between measured and simulated stages level showed an average error of 0.31% with a maximum error of 2.8%. Comparison of measured and simulated groundwater head levels showed an average error of 0.18% with a maximum of 2.9%.

Eulerian-Lagrangian Two Phase Debris Flow Model

The main objective of this work is to develop a quasi three-dimensional numerical model to simulate stony debris flows, considering a continuum fluid phase, composed by water and fine sediments, and a non-continuum phase including large particles, such as pebbles and boulders. Large particles are treated in a Lagrangian frame of reference using the Discrete Element Method, the fluid phase is based on the Eulerian approach, using the Finite Element Method to solve the depth-averaged Navier–Stokes equations in two horizontal dimensions. The particle’s equations of motion are in three dimensions. The model simulates particle-particle collisions and wall-particle collisions, taking into account that particles are immersed in a fluid. Bingham and Cross rheological models are used for the continuum phase. Both formulations provide very stable results, even in the range of very low shear rates. Bingham formulation is better able to simulate the stopping stage of the fluid when applied shear stresses are low. Results of numerical simulations have been compared with data from laboratory experiments on a flume-fan prototype. Results show that the model is capable of simulating the motion of big particles moving in the fluid flow, handling dense particulate flows and avoiding overlap among particles. An application to simulate debris flow events that occurred in Northern Venezuela in 1999 shows that the model could replicate the main boulder accumulation areas that were surveyed by the USGS. Uniqueness of this research is the integration of mud flow and stony debris movement in a single modeling tool that can be used for planning and management of debris flow prone areas.

Numerical groundwater flow modeling in the Wakal River basin, India

Increasing dependence on groundwater in the Wakal River basin, India, jeopardizes water supply sustainability. A numerical groundwater model was developed to better understand the aquifer system and to evaluate its potential in terms of quantity and replenishment. Potential artificial recharge areas were delineated using landscape and hydrogeologic parameters, Geographic Information System (GIS), and remote sensing. Groundwater models are powerful tools for recharge estimation when transmissivity is known. Proper recharge must be applied to reproduce field-measured heads. The model showed that groundwater levels could decline significantly if there are two drought years in every four years that result in reduced recharge, and groundwater withdrawal is increased by 15%. The effect of such drought is currently uncertain however, because runoff from the basin is unknown. Remote sensing and GIS revealed areas with slopes less than 5%, forest cover, and Normalized Difference Vegetative Index greater than 0.5 that are suitable recharge sites.

Empirical likelihood based longitudinal studies

In longitudinal data analysis, our primary interest is in the regression parameters for the marginal expectations of the longitudinal responses; the longitudinal correlation parameters are of secondary interest. The joint likelihood function for longitudinal data is challenging, particularly for correlated discrete outcome data. Marginal modeling approaches such as generalized estimating equations (GEEs) have received much attention in the context of longitudinal regression. These methods are based on the estimates of the first two moments of the data and the working correlation structure. The confidence regions and hypothesis tests are based on the asymptotic normality. The methods are sensitive to misspecification of the variance function and the working correlation structure. Because of such misspecifications, the estimates can be inefficient and inconsistent, and inference may give incorrect results. To overcome this problem, we propose an empirical likelihood (EL) procedure based on a set of estimating equations for the parameter of interest and discuss its characteristics and asymptotic properties. We also provide an algorithm based on EL principles for the estimation of the regression parameters and the construction of a confidence region for the parameter of interest. We extend our approach to variable selection for highdimensional longitudinal data with many covariates. In this situation it is necessary to identify a submodel that adequately represents the data. Including redundant variables may impact the model’s accuracy and efficiency for inference. We propose a penalized empirical likelihood (PEL) variable selection based on GEEs; the variable selection and the estimation of the coefficients are carried out simultaneously. We discuss its characteristics and asymptotic properties, and present an algorithm for optimizing PEL. Simulation studies show that when the model assumptions are correct, our method performs as well as existing methods, and when the model is misspecified, it has clear advantages. We have applied the method to two case examples.

Mechanistic Models of Anti-HIV Microbicide Drug Delivery

A new modality for preventing HIV transmission is emerging in the form of topical microbicides. Some clinical trials have shown some promising results of these methods of protection while other trials have failed to show efficacy. Due to the relatively novel nature of microbicide drug transport, a rigorous, deterministic analysis of that transport can help improve the design of microbicide vehicles and understand results from clinical trials. This type of analysis can aid microbicide product design by helping understand and organize the determinants of drug transport and the potential efficacies of candidate microbicide products.

Microbicide drug transport is modeled as a diffusion process with convection and reaction effects in appropriate compartments. This is applied here to vaginal gels and rings and a rectal enema, all delivering the microbicide drug Tenofovir. Although the focus here is on Tenofovir, the methods established in this dissertation can readily be adapted to other drugs, given knowledge of their physical and chemical properties, such as the diffusion coefficient, partition coefficient, and reaction kinetics. Other dosage forms such as tablets and fiber meshes can also be modeled using the perspective and methods developed here.

The analyses here include convective details of intravaginal flows by both ambient fluid and spreading gels with different rheological properties and applied volumes. These are input to the overall conservation equations for drug mass transport in different compartments. The results are Tenofovir concentration distributions in time and space for a variety of microbicide products and conditions. The Tenofovir concentrations in the vaginal and rectal mucosal stroma are converted, via a coupled reaction equation, to concentrations of Tenofovir diphosphate, which is the active form of the drug that functions as a reverse transcriptase inhibitor against HIV. Key model outputs are related to concentrations measured in experimental pharmacokinetic (PK) studies, e.g. concentrations in biopsies and blood. A new measure of microbicide prophylactic functionality, the Percent Protected, is calculated. This is the time dependent volume of the entire stroma (and thus fraction of host cells therein) in which Tenofovir diphosphate concentrations equal or exceed a target prophylactic value, e.g. an EC50.

Results show the prophylactic potentials of the studied microbicide vehicles against HIV infections. Key design parameters for each are addressed in application of the models. For a vaginal gel, fast spreading at small volume is more effective than slower spreading at high volume. Vaginal rings are shown to be most effective if inserted and retained as close to the fornix as possible. Because of the long half-life of Tenofovir diphosphate, temporary removal of the vaginal ring (after achieving steady state) for up to 24h does not appreciably diminish Percent Protected. However, full steady state (for the entire stromal volume) is not achieved until several days after ring insertion. Delivery of Tenofovir to the rectal mucosa by an enema is dominated by surface area of coated mucosa and whether the interiors of rectal crypts are filled with the enema fluid. For the enema 100% Percent Protected is achieved much more rapidly than for vaginal products, primarily because of the much thinner epithelial layer of the mucosa. For example, 100% Percent Protected can be achieved with a one minute enema application, and 15 minute wait time.

Results of these models have good agreement with experimental pharmacokinetic data, in animals and clinical trials. They also improve upon traditional, empirical PK modeling, and this is illustrated here. Our deterministic approach can inform design of sampling in clinical trials by indicating time periods during which significant changes in drug concentrations occur in different compartments. More fundamentally, the work here helps delineate the determinants of microbicide drug delivery. This information can be the key to improved, rational design of microbicide products and their dosage regimens.

Elucidating the Space-Time Structure of Low Level Warm Season Precipitation Processes in the Southern Appalachian Mountains Using Models and Observations

Light rainfall is the baseline input to the annual water budget in mountainous landscapes through the tropics and at mid-latitudes. In the Southern Appalachians, the contribution from light rainfall ranges from 50-60% during wet years to 80-90% during dry years, with convective activity and tropical cyclone input providing most of the interannual variability. The Southern Appalachians is a region characterized by rich biodiversity that is vulnerable to land use/land cover changes due to its proximity to a rapidly growing population. Persistent near surface moisture and associated microclimates observed in this region has been well documented since the colonization of the area in terms of species health, fire frequency, and overall biodiversity. The overarching objective of this research is to elucidate the microphysics of light rainfall and the dynamics of low level moisture in the inner region of the Southern Appalachians during the warm season, with a focus on orographically mediated processes. The overarching research hypothesis is that physical processes leading to and governing the life cycle of orographic fog, low level clouds, and precipitation, and their interactions, are strongly tied to landform, land cover, and the diurnal cycles of flow patterns, radiative forcing, and surface fluxes at the ridge-valley scale. The following science questions will be addressed specifically: 1) How do orographic clouds and fog affect the hydrometeorological regime from event to annual scale and as a function of terrain characteristics and land cover?; 2) What are the source areas, governing processes, and relevant time-scales of near surface moisture convergence patterns in the region?; and 3) What are the four dimensional microphysical and dynamical characteristics, including variability and controlling factors and processes, of fog and light rainfall? The research was conducted with two major components: 1) ground-based high-quality observations using multi-sensor platforms and 2) interpretive numerical modeling guided by the analysis of the in situ data collection. Findings illuminate a high level of spatial – down to the ridge scale - and temporal – from event to annual scale - heterogeneity in observations, and a significant impact on the hydrological regime as a result of seeder-feeder interactions among fog, low level clouds, and stratiform rainfall that enhance coalescence efficiency and lead to significantly higher rainfall rates at the land surface. Specifically, results show that enhancement of an event up to one order of magnitude in short-term accumulation can occur as a result of concurrent fog presence. Results also show that events are modulated strongly by terrain characteristics including elevation, slope, geometry, and land cover. These factors produce interactions between highly localized flows and gradients of temperature and moisture with larger scale circulations. Resulting observations of DSD and rainfall patterns are stratified by region and altitude and exhibit clear diurnal and seasonal cycles.

Latent Space and Social Psychological Models of Diffusion

The problem of social diffusion has animated sociological thinking on topics ranging from the spread of an idea, an innovation or a disease, to the foundations of collective behavior and political polarization. While network diffusion has been a productive metaphor, the reality of diffusion processes is often muddier. Ideas and innovations diffuse differently from diseases, but, with a few exceptions, the diffusion of ideas and innovations has been modeled under the same assumptions as the diffusion of disease. In this dissertation, I develop two new diffusion models for "socially meaningful" contagions that address two of the most significant problems with current diffusion models: (1) that contagions can only spread along observed ties, and (2) that contagions do not change as they spread between people. I augment insights from these statistical and simulation models with an analysis of an empirical case of diffusion - the use of enterprise collaboration software in a large technology company. I focus the empirical study on when people abandon innovations, a crucial, and understudied aspect of the diffusion of innovations. Using timestamped posts, I analyze when people abandon software to a high degree of detail.

To address the first problem, I suggest a latent space diffusion model. Rather than treating ties as stable conduits for information, the latent space diffusion model treats ties as random draws from an underlying social space, and simulates diffusion over the social space. Theoretically, the social space model integrates both actor ties and attributes simultaneously in a single social plane, while incorporating schemas into diffusion processes gives an explicit form to the reciprocal influences that cognition and social environment have on each other. Practically, the latent space diffusion model produces statistically consistent diffusion estimates where using the network alone does not, and the diffusion with schemas model shows that introducing some cognitive processing into diffusion processes changes the rate and ultimate distribution of the spreading information. To address the second problem, I suggest a diffusion model with schemas. Rather than treating information as though it is spread without changes, the schema diffusion model allows people to modify information they receive to fit an underlying mental model of the information before they pass the information to others. Combining the latent space models with a schema notion for actors improves our models for social diffusion both theoretically and practically.

The empirical case study focuses on how the changing value of an innovation, introduced by the innovations' network externalities, influences when people abandon the innovation. In it, I find that people are least likely to abandon an innovation when other people in their neighborhood currently use the software as well. The effect is particularly pronounced for supervisors' current use and number of supervisory team members who currently use the software. This case study not only points to an important process in the diffusion of innovation, but also suggests a new approach -- computerized collaboration systems -- to collecting and analyzing data on organizational processes.

On the Advancement of Probabilistic Models of Decompression Sickness

The work presented in this dissertation is focused on applying engineering methods to develop and explore probabilistic survival models for the prediction of decompression sickness in US NAVY divers. Mathematical modeling, computational model development, and numerical optimization techniques were employed to formulate and evaluate the predictive quality of models fitted to empirical data. In Chapters 1 and 2 we present general background information relevant to the development of probabilistic models applied to predicting the incidence of decompression sickness. The remainder of the dissertation introduces techniques developed in an effort to improve the predictive quality of probabilistic decompression models and to reduce the difficulty of model parameter optimization.

The first project explored seventeen variations of the hazard function using a well-perfused parallel compartment model. Models were parametrically optimized using the maximum likelihood technique. Model performance was evaluated using both classical statistical methods and model selection techniques based on information theory. Optimized model parameters were overall similar to those of previously published Results indicated that a novel hazard function definition that included both ambient pressure scaling and individually fitted compartment exponent scaling terms.

We developed ten pharmacokinetic compartmental models that included explicit delay mechanics to determine if predictive quality could be improved through the inclusion of material transfer lags. A fitted discrete delay parameter augmented the inflow to the compartment systems from the environment. Based on the observation that symptoms are often reported after risk accumulation begins for many of our models, we hypothesized that the inclusion of delays might improve correlation between the model predictions and observed data. Model selection techniques identified two models as having the best overall performance, but comparison to the best performing model without delay and model selection using our best identified no delay pharmacokinetic model both indicated that the delay mechanism was not statistically justified and did not substantially improve model predictions.

Our final investigation explored parameter bounding techniques to identify parameter regions for which statistical model failure will not occur. When a model predicts a no probability of a diver experiencing decompression sickness for an exposure that is known to produce symptoms, statistical model failure occurs. Using a metric related to the instantaneous risk, we successfully identify regions where model failure will not occur and identify the boundaries of the region using a root bounding technique. Several models are used to demonstrate the techniques, which may be employed to reduce the difficulty of model optimization for future investigations.

Piezoelectric energy harvesting using blood-flow-like excitation for implantable devices

The goal of this research is to produce a system for powering medical implants to increase the lifetime of the implanted devices and reduce the battery size. The system consists of a number of elements – the piezoelectric material for generating power, the device design, the circuit for rectification and energy storage. The piezoelectric material is analysed and a process for producing a repeatable high quality piezoelectric material is described. A full width half maximum (FWHM) of the rocking curve X-Ray diffraction (XRD) scan of between ~1.5° to ~1.7° for test wafers was achieved. This is state of the art for AlN on silicon and means devices with good piezoelectric constants can be fabricated. Finite element modelling FEM) was used to design the structures for energy harvesting. The models developed in this work were established to have an accuracy better than 5% in terms of the difference between measured and modelled results. Devices made from this material were analysed for power harvesting ability as well as the effect that they have on the flow of liquid which is an important consideration for implantable devices. The FEM results are compared to experimental results from laser Doppler vibrometry (LDV), magnetic shaker and perfusion machine tests. The rectifying circuitry for the energy harvester was also investigated. The final solution uses multiple devices to provide the power to augment the battery and so this was a key feature to be considered. Many circuits were examined and a solution based on a fully autonomous circuit was advanced. This circuit was analysed for use with multiple low power inputs similar to the results from previous investigations into the energy harvesting devices. Polymer materials were also studied for use as a substitute for the piezoelectric material as well as the substrate because silicon is more brittle.

Bile acids destabilise HIF-1α and promote anti-tumour phenotypes in cancer cell models

BACKGROUND: The role of the microbiome has become synonymous with human health and disease. Bile acids, as essential components of the microbiome, have gained sustained credibility as potential modulators of cancer progression in several disease models. At physiological concentrations, bile acids appear to influence cancer phenotypes, although conflicting data surrounds their precise physiological mechanism of action. Previously, we demonstrated bile acids destabilised the HIF-1α subunit of the Hypoxic-Inducible Factor-1 (HIF-1) transcription factor. HIF-1 overexpression is an early biomarker of tumour metastasis and is associated with tumour resistance to conventional therapies, and poor prognosis in a range of different cancers. METHODS: Here we investigated the effects of bile acids on the cancer growth and migratory potential of cell lines where HIF-1α is known to be active under hypoxic conditions. HIF-1α status was investigated in A-549 lung, DU-145 prostate and MCF-7 breast cancer cell lines exposed to bile acids (CDCA and DCA). Cell adhesion, invasion, migration was assessed in DU-145 cells while clonogenic growth was assessed in all cell lines. RESULTS: Intracellular HIF-1α was destabilised in the presence of bile acids in all cell lines tested. Bile acids were not cytotoxic but exhibited greatly reduced clonogenic potential in two out of three cell lines. In the migratory prostate cancer cell line DU-145, bile acids impaired cell adhesion, migration and invasion. CDCA and DCA destabilised HIF-1α in all cells and significantly suppressed key cancer progression associated phenotypes; clonogenic growth, invasion and migration in DU-145 cells. CONCLUSIONS: These findings suggest previously unobserved roles for bile acids as physiologically relevant molecules targeting hypoxic tumour progression.