An analytical framework for quantifying aquifer response time scales associated with transient boundary conditions

A major challenge in studying coupled groundwater and surface-water interactions arises from the considerable difference in the response time scales of groundwater and surface-water systems affected by external forcings. Although coupled models representing the interaction of groundwater and surface-water systems have been studied for over a century, most have focused on groundwater quantity or quality issues rather than response time. In this study, we present an analytical framework, based on the concept of mean action time (MAT), to estimate the time scale required for groundwater systems to respond to changes in surface-water conditions. MAT can be used to estimate the transient response time scale by analyzing the governing mathematical model. This framework does not require any form of transient solution (either numerical or analytical) to the governing equation, yet it provides a closed form mathematical relationship for the response time as a function of the aquifer geometry, boundary conditions, and flow parameters. Our analysis indicates that aquifer systems have three fundamental time scales: (i) a time scale that depends on the intrinsic properties of the aquifer; (ii) a time scale that depends on the intrinsic properties of the boundary condition, and; (iii) a time scale that depends on the properties of the entire system. We discuss two practical scenarios where MAT estimates provide useful insights and we test the MAT predictions using new laboratory-scale experimental data sets.

BIM support for disaster response

The introduction of Building Information Modelling (BIM) to the design, construction and operation of buildings is changing the way that the building construction industry works. BIM involves the development of a full 3D virtual model of a building which not only contains the 3D information necessary to show the building as it will appear, but also contains significant additional data about each component in the building. BIM represents both physical and virtual objects in a building. This includes the rooms and spaces within and around the building. The additional data stored on each part of the building can support building maintenance opera- tions and, more importantly from the perspective of this paper, support the generation and running of simula- tions of the operation of the building and behaviour of people within it under both normal and emergency scenarios. The initial discussion is around the use of BIM to support the design of resilient buildings which references the various codes and standards that define current best practice. The remainder of the discussion uses various recent events as the basis for discussion on how BIM could have been used to support rapid recovery and re- building.

Glucocorticoid receptor haploinsufficiency causes hypertension and attenuates hypothalamic-pituitary-adrenal axis and blood pressure adaptions to high-fat diet

Glucocorticoid hormones are critical to respond and adapt to stress. Genetic variations in the glucocorticoid receptor (GR) gene alter hypothalamic-pituitary-adrenal (HPA) axis activity and associate with hypertension and susceptibility to metabolic disease. Here we test the hypothesis that reduced GR density alters blood pressure and glucose and lipid homeostasis and limits adaption to obesogenic diet. Heterozygous GR βgeo/+ mice were generated from embryonic stem (ES) cells with a gene trap integration of a β-galactosidase-neomycin phosphotransferase (βgeo) cassette into the GR gene creating a transcriptionally inactive GR fusion protein. Although GRβgeo/+ mice have 50% less functional GR, they have normal lipid and glucose homeostasis due to compensatory HPA axis activation but are hypertensive due to activation of the renin-angiotensin- aldosterone system (RAAS). When challenged with a high-fat diet, weight gain, adiposity, and glucose intolerance were similarly increased in control and GRβgeo/+ mice, suggesting preserved control of intermediary metabolism and energy balance. However, whereas a high-fat diet caused HPA activation and increased blood pressure in control mice, these adaptions were attenuated or abolished in GRβgeo/+ mice. Thus, reduced GR density balanced by HPA activation leaves glucocorticoid functions unaffected but mineralocorticoid functions increased, causing hypertension. Importantly, reduced GR limits HPA and blood pressure adaptions to obesogenic diet.

Demand Response for Residential Appliances in a Smart Electricity Distribution Network: Utility and Customer Perspectives

This thesis introduces advanced Demand Response algorithms for residential appliances to provide benefits for both utility and customers. The algorithms are engaged in scheduling appliances appropriately in a critical peak day to alleviate network peak, adverse voltage conditions and wholesale price spikes also reducing the cost of residential energy consumption. Initially, a demand response technique via customer reward is proposed, where the utility controls appliances to achieve network improvement. Then, an improved real-time pricing scheme is introduced and customers are supported by energy management schedulers to actively participate in it. Finally, the demand response algorithm is improved to provide frequency regulation services.

Transcriptional pathway signatures predict MEK addiction and response to selumetinib (AZD6244)

Selumetinib (AZD6244, ARRY-142886) is a selective, non-ATP-competitive inhibitor of mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK)-1/2. The range of antitumor activity seen preclinically and in patients highlights the importance of identifying determinants of response to this drug. In large tumor cell panels of diverse lineage, we show that MEK inhibitor response does not have an absolute correlation with mutational or phospho-protein markers of BRAF/MEK, RAS, or phosphoinositide 3-kinase (PI3K) activity. We aimed to enhance predictivity by measuring pathway output through coregulated gene networks displaying differential mRNA expression exclusive to resistant cell subsets and correlated to mutational or dynamic pathway activity. We discovered an 18-gene signature enabling measurement of MEK functional output independent of tumor genotype. Where the MEK pathway is activated but the cells remain resistant to selumetinib, we identified a 13-gene signature that implicates the existence of compensatory signaling from RAS effectors other than PI3K. The ability of these signatures to stratify samples according to functional activation of MEK and/or selumetinib sensitivity was shown in multiple independent melanoma, colon, breast, and lung tumor cell lines and in xenograft models. Furthermore, we were able to measure these signatures in fixed archival melanoma tumor samples using a single RT-qPCR-based test and found intergene correlations and associations with genetic markers of pathway activity to be preserved. These signatures offer useful tools for the study of MEK biology and clinical application of MEK inhibitors, and the novel approaches taken may benefit other targeted therapies.

Potentiation of the early visual response to learned danger signals in adults and adolescents

The reinforcing effects of aversive outcomes on avoidance behaviour are well established. However, their influence on perceptual processes is less well explored, especially during the transition from adolescence to adulthood. Using electroencephalography, we examined whether learning to actively or passively avoid harm can modulate early visual responses in adolescents and adults. The task included two avoidance conditions, active and passive, where two different warning stimuli predicted the imminent, but avoidable, presentation of an aversive tone. To avoid the aversive outcome, participants had to learn to emit an action (active avoidance) for one of the warning stimuli and omit an action for the other (passive avoidance). Both adults and adolescents performed the task with a high degree of accuracy. For both adolescents and adults, increased N170 event-related potential amplitudes were found for both the active and the passive warning stimuli compared with control conditions. Moreover, the potentiation of the N170 to the warning stimuli was stable and long lasting. Developmental differences were also observed; adolescents showed greater potentiation of the N170 component to danger signals. These findings demonstrate, for the first time, that learned danger signals in an instrumental avoidance task can influence early visual sensory processes in both adults and adolescents.

Kari Gislason's response to the Ottoman Motel by Christopher Currie [The Art of Vanishing Parents]

A review of The Ottoman Hotel by Christopher Currie (Text Publishing, 2011). There is more than one moment in life when parents disappear. Teenagers routinely wish them away. Young adults at university return to find they have been abandoned, their possessions boxed, labelled and stored, their bedrooms turned into guest accommodation sometimes featuring lavender. You call your parents and they're not home. Your mother doesn't accept your friend request...

Innate transcriptional networks activated in bladder in response to uropathogenic Escherichia coli drive diverse biological pathways and rapid synthesis of IL-10 for defense against bacterial urinary tract infection

Early transcriptional activation events that occur in bladder immediately following bacterial urinary tract infection (UTI) are not well defined. In this study, we describe the whole bladder transcriptome of uropathogenic Escherichia coli (UPEC) cystitis in mice using genome-wide expression profiling to define the transcriptome of innate immune activation stemming from UPEC colonization of the bladder. Bladder RNA from female C57BL/6 mice, analyzed using 1.0 ST-Affymetrix microarrays, revealed extensive activation of diverse sets of innate immune response genes, including those that encode multiple IL-family members, receptors, metabolic regulators, MAPK activators, and lymphocyte signaling molecules. These were among 1564 genes differentially regulated at 2 h postinfection, highlighting a rapid and broad innate immune response to bladder colonization. Integrative systems-level analyses using InnateDB (http://www.innatedb.com) bioinformatics and ingenuity pathway analysis identified multiple distinct biological pathways in the bladder transcriptome with extensive involvement of lymphocyte signaling, cell cycle alterations, cytoskeletal, and metabolic changes. A key regulator of IL activity identified in the transcriptome was IL-10, which was analyzed functionally to reveal marked exacerbation of cystitis in IL-10–deficient mice. Studies of clinical UTI revealed significantly elevated urinary IL-10 in patients with UPEC cystitis, indicating a role for IL-10 in the innate response to human UTI. The whole bladder transcriptome presented in this work provides new insight into the diversity of innate factors that determine UTI on a genome-wide scale and will be valuable for further data mining. Identification of protective roles for other elements in the transcriptome will provide critical new insight into the complex cascade of events that underpin UTI.