The unsteady flow of a weakly compressible fluid in a thin porous layer. I: Two-dimensional theory

We consider the problem of determining the pressure and velocity fields for a weakly compressible fluid flowing in a two-dimensional reservoir in an inhomogeneous, anisotropic porous medium, with vertical side walls and variable upper and lower boundaries, in the presence of vertical wells injecting or extracting fluid. Numerical solution of this problem may be expensive, particularly in the case that the depth scale of the layer h is small compared to the horizontal length scale l. This is a situation which occurs frequently in the application to oil reservoir recovery. Under the assumption that epsilon=h/l<<1, we show that the pressure field varies only in the horizontal direction away from the wells (the outer region). We construct two-term asymptotic expansions in epsilon in both the inner (near the wells) and outer regions and use the asymptotic matching principle to derive analytical expressions for all significant process quantities. This approach, via the method of matched asymptotic expansions, takes advantage of the small aspect ratio of the reservoir, epsilon, at precisely the stage where full numerical computations become stiff, and also reveals the detailed structure of the dynamics of the flow, both in the neighborhood of wells and away from wells

Designing a more inclusive world

This paper summarises the what, why and how of inclusive design, and presents key contributions of the 2006–2010 i~design research consortium, the third successive research consortium funded by the Engineering and Physical Sciences Research Council as part of the Extending Quality of Life initiative. Throughout 10 years of i~design research, the overarching goals have been to provide industrial decision makers with mechanisms for understanding the significance of age- and capability-related factors, and to provide the design community with the techniques and guidance required to deliver better products and services for people of all ages and abilities. In this latest period of research, the specific emphasis has been on quantifying design exclusion and enabling designers to work with users

Contemporary Guarani Shamanisms: “Traditional Medicine” and Discourses of Native Identity in Brazil

The psychoactive substance known as ayahuasca has long been identified with Amazonian shamanism and traditional medicine. Over the last two decades its use has spread outside this region to urban populations in different parts of the world. This paper examines the adoption of the ritual use of the beverage by the Guarani Indians along the southern coast of Brazil. We argue that this process is related to the growing politics of identity of Brazilian indigenous peoples as well as to public policies that promote cultural diversity. In the case analyzed here, the adoption of ayahuasca is articulated with an ongoing cultural revitalization in activities related to shamanism, health and education and with the specific desires and actions of the leading family in one Guarani village

Quantitative analysis of NRF2 pathway reveals key elements of the regulatory circuits underlying antioxidant response and proliferation of ovarian cancer cells

Cells are constantly exposed to Reactive Oxygen Species (ROS) produced both endogenously to meet physiological requirements and from exogenous sources. While endogenous ROS are considered as important signalling molecules, high uncontrollable ROS are detrimental. It is unclear how cells can achieve a balance between maintaining physiological redox homeostasis and robustly activate the antioxidant system to remove exogenous ROS. We have utilised a Systems Biology approach to understand how this robust adaptive system fulfils homeostatic requirements of maintaining steady-state ROS and growth rate, while undergoing rapid readjustment under challenged conditions. Using a panel of human ovarian and normal cell lines, we experimentally quantified and established interrelationships between key elements of ROS homeostasis. The basal levels of NRF2 and KEAP1 were cell line specific and maintained in tight correlation with their growth rates and ROS. Furthermore, perturbation of this balance triggered cell specific kinetics of NRF2 nuclear–cytoplasmic relocalisation and sequestration of exogenous ROS. Our experimental data were employed to parameterise a mathematical model of the NRF2 pathway that elucidated key response mechanisms of redox regulation and showed that the dynamics of NRF2-H2O2 regulation defines a relationship between half-life, total and nuclear NRF2 level and endogenous H2O2 that is cell line specific

A Galerkin boundary element method for high frequency scattering by convex polygons

In this paper we consider the problem of time-harmonic acoustic scattering in two dimensions by convex polygons. Standard boundary or finite element methods for acoustic scattering problems have a computational cost that grows at least linearly as a function of the frequency of the incident wave. Here we present a novel Galerkin boundary element method, which uses an approximation space consisting of the products of plane waves with piecewise polynomials supported on a graded mesh, with smaller elements closer to the corners of the polygon. We prove that the best approximation from the approximation space requires a number of degrees of freedom to achieve a prescribed level of accuracy that grows only logarithmically as a function of the frequency. Numerical results demonstrate the same logarithmic dependence on the frequency for the Galerkin method solution. Our boundary element method is a discretization of a well-known second kind combined-layer-potential integral equation. We provide a proof that this equation and its adjoint are well-posed and equivalent to the boundary value problem in a Sobolev space setting for general Lipschitz domains

Finite difference time domain modeling of steady state scattering from jet engines with moving turbine blades

The approach chosen to model steady state scattering from jet engines with moving turbine blades is based upon the Finite Difference Time Domain (FDTD) method. The FDTD method is a numerical electromagnetic program based upon the direct solution in the time domain of Maxwell's time dependent curl equations throughout a volume. One of the strengths of this method is the ability to model objects with complicated shape and/or material composition. General time domain functions may be used as source excitations. For example, a plane wave excitation may be specified as a pulse containing many frequencies and at any incidence angle to the scatterer. A best fit to the scatterer is accomplished using cubical cells in the standard cartesian implementation of the FDTD method. The material composition of the scatterer is determined by specifying its electrical properties at each cell on the scatterer. Thus, the FDTD method is a suitable choice for problems with complex geometries evaluated at multiple frequencies. It is assumed that the reader is familiar with the FDTD method

A novel mechanism of action of HER2 targeted immunotherapy is explained by inhibition of NRF2 function in ovarian cancer cells

Nuclear erythroid related factor-2 (NRF2) is known to promote cancer therapeutic detoxification and crosstalk with growth promoting pathways. HER2 receptor tyrosine kinase is frequently overexpressed in cancers leading to uncontrolled receptor activation and signaling. A combination of HER2 targeting monoclonal antibodies shows greater anticancer efficacy than the single targeting antibodies, however, its mechanism of action is largely unclear. Here we report novel actions of anti-HER2 drugs, Trastuzumab and Pertuzumab, involving NRF2. HER2 targeting by antibodies inhibited growth in association with persistent generation of reactive oxygen species (ROS), glutathione (GSH) depletion, reduction in NRF2 levels and inhibition of NRF2 function in ovarian cancer cell lines. The combination of antibodies produced more potent effects than single alone; downregulated NRF2 substrates by repressing the Antioxidant Response (AR) pathway with concomitant transcriptional inhibition of NRF2. We showed the antibody combination produced increased methylation at the NRF2 promoter consistent with repression of NRF2 antioxidant function, as HDAC and methylation inhibitors reversed such produced transcriptional effects. These findings demonstrate a novel mechanism and role for NRF2 in mediating the response of cancer cells to the combination of Trastuzumab and Pertuzumab and reinforce the importance of NRF2 in drug resistance and as a key anticancer target

Genetic Improvement of Software: a Comprehensive Survey

Genetic improvement (GI) uses automated search to find improved versions of existing software. We present a comprehensive survey of this nascent field of research with a focus on the core papers in the area published between 1995 and 2015. We identified core publications including empirical studies, 96% of which use evolutionary algorithms (genetic programming in particular). Although we can trace the foundations of GI back to the origins of computer science itself, our analysis reveals a significant upsurge in activity since 2012. GI has resulted in dramatic performance improvements for a diverse set of properties such as execution time, energy and memory consumption, as well as results for fixing and extending existing system functionality. Moreover, we present examples of research work that lies on the boundary between GI and other areas, such as program transformation, approximate computing, and software repair, with the intention of encouraging further exchange of ideas between researchers in these fields

Systems analysis of drug-induced receptor tyrosine kinase reprogramming following targeted mono- and combination anti-cancer therapy

The receptor tyrosine kinases (RTKs) are key drivers of cancer progression and targets for drug therapy. A major challenge in anti-RTK treatment is the dependence of drug effectiveness on co-expression of multiple RTKs which defines resistance to single drug therapy. Reprogramming of the RTK network leading to alteration in RTK co-expression in response to drug intervention is a dynamic mechanism of acquired resistance to single drug therapy in many cancers. One route to overcome this resistance is combination therapy. We describe the results of a joint in silico, in vitro, and in vivo investigations on the efficacy of trastuzumab, pertuzumab and their combination to target the HER2 receptors. Computational modelling revealed that these two drugs alone and in combination differentially suppressed RTK network activation depending on RTK co-expression. Analyses of mRNA expression in SKOV3 ovarian tumour xenograft showed up-regulation of HER3 following treatment. Considering this in a computational model revealed that HER3 up-regulation reprograms RTK kinetics from HER2 homodimerisation to HER3/HER2 heterodimerisation. The results showed synergy of the trastuzumab and pertuzumab combination treatment of the HER2 overexpressing tumour can be due to an independence of the combination effect on HER3/HER2 composition when it changes due to drug-induced RTK reprogramming

Assessment of the ergogenic effect of caffeine supplementation on mood, anticipation timing, and muscular strength in older adults

The effect of caffeine to promote improvements in mood, cognition, and exercise performance has been well established in young and athletic adults. However, little is known about whether such nutritional ergogenic aids are effective in enhancing psychological well-being, physiological or cognitive performance in older adults. This study assesses the ergogenic effect of caffeine on mood, perceptual-motor coupling, and muscular strength in an older human population. Following a familiarization session, 12 apparently healthy volunteers (nine females and three males; 69 ± 6 years) completed two laboratory visits. "Pre ingestion" trials of mood state Brunel Mood State Inventory (BRUMS) and coincidence anticipation performance (Bassin anticipation timer) at slow (3 mph) and fast (8 mph) stimulus speeds were completed on both visits. Using a randomized, double-blind, cross-over design, participants consumed either caffeine (3 mg/kg body mass) or a placebo. Sixty minutes postingestion participants repeated the trials before completing a set of 10 consecutive repetitions of maximal knee extension using isokinetic dynamometry. Rating of perceived exertion (RPE) was assessed following the fifth and final repetition. Caffeine ingestion significantly improved mood state scores for vigor by 17% (P = 0.009) and reduced absolute error by 35% (P = 0.045) during coincidence anticipation assessment at 8 mph compared to placebo. There were no other significant effects. Caffeine ingestion failed to augment maximal voluntary contraction of the knee extensors and RPE did not prove to be significantly different to from placebo (P > 0.33 in each case). Acute caffeine ingestion may not be an effective ergogenic aid for improving muscular strength in older adults but could possibly be used as a nutrition supplement for enhancing mood and improving cognitive performance in daily living tasks where interceptive timing skills are required