Understanding PK/PD

Pharmacology is the science underpinning dosing, mechanisms of action and effectiveness of drugs. Central to pharmacology, are the studies of pharmacokinetics (PK) and pharmacodynamics (PD). On one hand, PK defines the time-course of drug concentrations in the body and incorporates the broad concepts of drug absorption, distribution, metabolism and elimination. On the other hand, PD describes the relationship between drug concentrations and pharmacological effects. In practice, PK is often referred as “what the body does to the drug” whilst PD as “what the drug does to the body”. Thus, PK/PD describes the relationship between drug dose and pharmacological effects with changes in drug concentrations leading to different pharmacological effects.

Urban informatics beyond data: Media architecture, placemaking, and citizen action

Since 2006, we have been conducting urban informatics research that we define as “the study, design, and practice of urban experiences across different urban contexts that are created by new opportunities of real-time, ubiquitous technology and the augmentation that mediates the physical and digital layers of people networks and urban infrastructures” [1]. Various new research initiatives under the label “urban informatics” have been started since then by universities (e.g., NYU’s Center for Urban Science and Progress) and industry (e.g., Arup, McKinsey) worldwide. Yet, many of these new initiatives are limited to what Townsend calls, “data-driven approaches to urban improvement” [2]. One of the key challenges is that any quantity of aggregated data does not easily translate directly into quality insights to better understand cities. In this talk, I will raise questions about the purpose of urban informatics research beyond data, and show examples of media architecture, participatory city making, and citizen activism. I argue for (1) broadening the disciplinary foundations that urban science approaches draw on; (2) maintaining a hybrid perspective that considers both the bird’s eye view as well as the citizen’s view, and; (3) employing design research to not be limited to just understanding, but to bring about actionable knowledge that will drive change for good.

Co-benefits of addressing climate change can motivate action around the world

Personal and political action on climate change is traditionally thought to be motivated by people accepting its reality and importance. However, convincing the public that climate change is real faces powerful ideological obstacles1, 2, 3, 4, and climate change is slipping in public importance in many countries5, 6. Here we investigate a different approach, identifying whether potential co-benefits of addressing climate change7 could motivate pro-environmental behaviour around the world for both those convinced and unconvinced that climate change is real. We describe an integrated framework for assessing beliefs about co-benefits8, distinguishing social conditions (for example, economic development, reduced pollution or disease) and community character (for example, benevolence, competence). Data from all inhabited continents (24 countries; 6,196 participants) showed that two co-benefit types, Development (economic and scientific advancement) and Benevolence (a more moral and caring community), motivated public, private and financial actions to address climate change to a similar degree as believing climate change is important. Critically, relationships were similar for both convinced and unconvinced participants, showing that co-benefits can motivate action across ideological divides. These relationships were also independent of perceived climate change importance, and could not be explained by political ideology, age, or gender. Communicating co-benefits could motivate action on climate change where traditional approaches have stalled.

Final report of Working Group 2: Traffic psychology [A COST Action TU1101 / HOPE collaboration]

BACKGROUND The workgroup of Traffic Psychology is concerned with the social, behavioral, and perceptual aspects that are associated with use and non-use of bicycle helmets, in their various forms and under various cycling conditions. OBJECTIVES The objectives of WG2 are to (1) share current knowledge among the people already working in the field, (2) suggest new ideas for research on and evaluation of the design of bicycle helmets, and (3) discuss options for funding of such research within the individual frameworks of the participants. Areas for research include 3.1. The patterns of use of helmets among different users: children, adults, and sports enthusiasts. 3.2. The use of helmets in different environments: rural roads, urban streets, and bike trails. 3.3. Concerns bicyclists have relative to their safety and convenience and the perceived impact of using helmets on comfort and convenience. 3.4. The benefit of helmets for enhancing visibility, and how variations in helmet design and colors affect daytime, nighttime, and dusktime visibility. 3.5. The role of helmets in the acceptance of city-wide pickup-and-drop-off bicycles. 3.6. The impact of helmets on visual search behaviour of bicyclists.

A comparative study of two design charrettes: Implications for codesign and participatory action research

The purpose of this paper is to explore how participatory prototyping, through the use of design charrettes, can advance participatory action research (PAR) approaches and contribute to codesign practices in organisational settings. This will be achieved through the comparison of two varying design charrette experiences from a PAR initiative to redesign spaces in the Auraria Library in Denver, Colorado. Each design charrette followed a three-stage sequence of information sharing, idea generation and prototyping, and prioritisation with each stage building upon the former, both in terms of design concepts and in building up elements of ‘making’. While both charrette structures were similar, leadership and execution varied considerably. Lessons learned from the two design charrette experiences are presented, including the value of participatory prototyping within PAR to support ‘research through design’ activities. In addition, it highlights the value of authentic design participation of ‘designing with’ rather than ‘designing for’ to encourage optimal design outcomes.

Pathogens penetrating the central nervous system: Infection pathways and the cellular and molecular mechanisms of invasion

The brain is well protected against microbial invasion by cellular barriers, such as the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB). In addition, cells within the central nervous system (CNS) are capable of producing an immune response against invading pathogens. Nonetheless, a range of pathogenic microbes make their way to the CNS, and the resulting infections can cause significant morbidity and mortality. Bacteria, amoebae, fungi, and viruses are capable of CNS invasion, with the latter using axonal transport as a common route of infection. In this review, we compare the mechanisms by which bacterial pathogens reach the CNS and infect the brain. In particular, we focus on recent data regarding mechanisms of bacterial translocation from the nasal mucosa to the brain, which represents a little explored pathway of bacterial invasion but has been proposed as being particularly important in explaining how infection with Burkholderia pseudomallei can result in melioidosis encephalomyelitis.

Targeting drug-resistant prostate cancer with dual PI3K/mTOR inhibition

The phosphatidylinositol-3-kinase (PI3K)/Akt/mTOR pathway is one of the most frequently activated signaling pathways in prostate cancer cells, and loss of the tumor suppressor PTEN and amplification of PIK3CA are the two most commonly detected mechanisms for the activation of these pathways. Aberrant activation of PI3K/Akt/mTOR has been implicated not only in the survival and metastasis of prostate cancer cells but also in the development of drug resistance. As such, selective inactivation of this pathway may provide opportunities to attack prostate cancer from all fronts. However, while preclinical studies examining specific inhibitors of PI3K or mTOR have yielded promising results, the evidence from clinical trials is less convincing. Emerging evidence from the analyses of some solid tumors suggests that a class of dual PI3K/mTOR inhibitors, which bind to and inactivate both PI3K and mTOR, may achieve better anti-cancer outcomes. In this review, we will summarize the mechanisms of action of these inhibitors, their effectiveness when used alone or in combination with other chemotherapeutic compounds, and their potential to serve as the next generation therapies for prostate cancer patients, particularly those who are resistant to the frontline chemotherapeutic drugs.

Population of computational rabbit-specific ventricular action potential models for investigating sources of variability in cellular repolarisation

Variability is observed at all levels of cardiac electrophysiology. Yet, the underlying causes and importance of this variability are generally unknown, and difficult to investigate with current experimental techniques. The aim of the present study was to generate populations of computational ventricular action potential models that reproduce experimentally observed intercellular variability of repolarisation (represented by action potential duration) and to identify its potential causes. A systematic exploration of the effects of simultaneously varying the magnitude of six transmembrane current conductances (transient outward, rapid and slow delayed rectifier K(+), inward rectifying K(+), L-type Ca(2+), and Na(+)/K(+) pump currents) in two rabbit-specific ventricular action potential models (Shannon et al. and Mahajan et al.) at multiple cycle lengths (400, 600, 1,000 ms) was performed. This was accomplished with distributed computing software specialised for multi-dimensional parameter sweeps and grid execution. An initial population of 15,625 parameter sets was generated for both models at each cycle length. Action potential durations of these populations were compared to experimentally derived ranges for rabbit ventricular myocytes. 1,352 parameter sets for the Shannon model and 779 parameter sets for the Mahajan model yielded action potential duration within the experimental range, demonstrating that a wide array of ionic conductance values can be used to simulate a physiological rabbit ventricular action potential. Furthermore, by using clutter-based dimension reordering, a technique that allows visualisation of multi-dimensional spaces in two dimensions, the interaction of current conductances and their relative importance to the ventricular action potential at different cycle lengths were revealed. Overall, this work represents an important step towards a better understanding of the role that variability in current conductances may play in experimentally observed intercellular variability of rabbit ventricular action potential repolarisation.

The production mechanisms of OH radicals in a pulsed direct current plasma jet

The production mechanism of OH radicals in a pulsed DC plasma jet is studied by a two-dimensional (2-D) plasma jet model and a one-dimensional (1-D) discharge model. For the plasma jet in the open air, electron-impact dissociation of H2O, electron neutralization of H2O+, as well as dissociation of H2O by O(1D) are found to be the main reactions to generate the OH species. The contribution of the dissociation of H2O by electron is more than the others. The additions of N2, O2, air, and H2O into the working gas increase the OH density outside the tube slightly, which is attributed to more electrons produced by Penning ionization. On the other hand, the additions of O2 and H2O into the working gas increase the OH density inside the tube substantially, which is attributed to the increased O (1D) and H2O concentration, respectively. The gas flow will transport high density OH out of the tube during pulse off period. It is also shown that the plasma chemistry and reactivity can be effectively controlled by the pulse numbers. These results are supported by the laser induced fluorescence measurements and are relevant to several applications of atmospheric-pressure plasmas in health care, medicine, and materials processing.

Physical mechanisms underlying the strain-rate-dependent mechanical behavior of kangaroo shoulder cartilage

Due to anatomical and biomechanical similarities to human shoulder, kangaroo was chosen as a model to study shoulder cartilage. Comprehensive enzymatic degradation and indentation tests were applied on kangaroo shoulder cartilage to study mechanisms underlying its strain-rate-dependent mechanical behavior. We report that superficial collagen plays a more significant role than proteoglycans in facilitating strain-rate-dependent behavior of kangaroo shoulder cartilage. By comparing the mechanical properties of degraded and normal cartilages it was noted that proteoglycan and collagen degradation significantly compromised strain-rate-dependent mechanical behavior of the cartilage. Superficial collagen contributed equally to the tissue behavior at all strain-rates. This is different to studies reported on knee cartilage and confirms the importance of superficial collagen on shoulder cartilage mechanical behavior. A porohyperelastic numerical model also indicated that collagen disruption would lead to faster damage of the shoulder cartilage than when proteoglycans are depleted.

The function of the RNA-binding protein TEL1 in moss reveals ancient regulatory mechanisms of shoot development

The shoot represents the basic body plan in land plants. It consists of a repeated structure composed of stems and leaves. Whereas vascular plants generate a shoot in their diploid phase, non-vascular plants such as mosses form a shoot (called the gametophore) in their haploid generation. The evolution of regulatory mechanisms or genetic networks used in the development of these two kinds of shoots is unclear. TERMINAL EAR1-like genes have been involved in diploid shoot development in vascular plants. Here, we show that disruption of PpTEL1 from the moss Physcomitrella patens, causes reduced protonema growth and gametophore initiation, as well as defects in gametophore development. Leafy shoots formed on ΔTEL1 mutants exhibit shorter stems with more leaves per shoot, suggesting an accelerated leaf initiation (shortened plastochron), a phenotype shared with the Poaceae vascular plants TE1 and PLA2/LHD2 mutants. Moreover, the positive correlation between plastochron length and leaf size observed in ΔTEL1 mutants suggests a conserved compensatory mechanism correlating leaf growth and leaf initiation rate that would minimize overall changes in plant biomass. The RNA-binding protein encoded by PpTEL1 contains two N-terminus RNA-recognition motifs, and a third C-terminus non-canonical RRM, specific to TEL proteins. Removal of the PpTEL1 C-terminus (including this third RRM) or only 16–18 amino acids within it seriously impairs PpTEL1 function, suggesting a critical role for this third RRM. These results show a conserved function of the RNA-binding PpTEL1 protein in the regulation of shoot development, from early ancestors to vascular plants, that depends on the third TEL-specific RRM.

Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis. © 2011 Macmillan Publishers Limited. All rights reserved.

Understanding file access mechanisms for embedded ubicomp collaboration interfaces

This paper explores the nature of interfaces to support people in accessing their files at tabletop displays embedded in the environment. To do this, we designed a study comparing people's interaction with two very different classes of file system access interface: Focus, explicitly designed for tabletops, and the familiar hierarchical Windows Explorer. In our within-subjects double-crossover study, participants collaborated on 4 planning tasks. Based on video, logs, questionnaires and interviews, we conclude that both classes of interface have a place. Notably, Focus contributed to improved collaboration and more efficient use of the workspace than with Explorer. Our results inform a set of recommendations for future interfaces enabling this important class of interaction -- supporting access to files for collaboration at tabletop devices embedded in an ubicomp environment.

The bias and assumptions in the Aboriginal and Torres Strait Islander Education Action Plan

This presentation argues that “genuine” engagement and consultation is required where Indigenous voice is included within the policy development process for “true” progress to be achieved. With the ever increasing engagement of Aboriginal and Torres Strait Islander people in the decision making processes of Indigenous education, it is anticipated that there will be provision of opportunities for better outcomes and a greater acceptance of the policy within community (Department of Prime Minister and Cabinet, 2014). This presentation is derived from a larger project where the Aboriginal and Torres Strait Islander Education Action Plan (MCEECDYA, 2011) was critically analysed using Fairclough’s (2001) Critical Discourse Analysis framework and Rigney’s (1999) Indigenist Research Principles. Within this study, the underlying assumptions and bias identified within the policy and how it positions Aboriginal and Torres Strait Islander people were articulated. The major findings that emerged from the data included: - a) the homogenous grouping of Aboriginal and Torres Strait Islander people; - b) the maintenance of the prevalent dominant ideology within policy, and finally; - c) the expectation by the power elite of increased engagement and connections by Aboriginal and Torres Strait Islander peoples without consideration of the detrimental effects of past policies and reforms.