Antimicrobial activity of prodigiosin is attributable to plasma-membrane damage

The bacterial pigment prodigiosin has various biological activities; it is, for instance, an effective antimicrobial. Here, we investigate the primary site targeted by prodigiosin, using the cells of microbial pathogens of humans as model systems: Candida albicans, Escherichia coli, Staphylococcus aureus. Inhibitory concentrations of prodigiosin; leakage of intracellular K+ ions, amino acids, proteins and sugars; impacts on activities of proteases, catalases and oxidases; and changes in surface appearance of pathogen cells were determined. Prodigiosin was highly inhibitory (30% growth rate reduction of C. albicans, E. coli, S. aureus at 0.3, 100 and 0.18 μg ml−1, respectively); caused leakage of intracellular substances (most severe in S. aureus); was highly inhibitory to each enzyme; and caused changes to S. aureus indicative of cell-surface damage. Collectively, these findings suggest that prodigiosin, log Poctanol–water 5.16, is not a toxin but is a hydrophobic stressor able to disrupt the plasma membrane via a chaotropicity-mediated mode-of-action.

Systematic Review Protocol to Evaluate the Effectiveness and Cost Effectiveness of Personalised Surveillance after Colorectal Adenomatous Polypectomy

Lifetime risk of developing colorectal cancer (CRC) is 5% and five-year survival at early-stage is 92%. CRC risk following index colonoscopy should establish post-screening surveillance benefit, which may be greater in high-risk patients. This review evaluated published cost-effectiveness estimates of post-polypectomy surveillance to assess the potential for personalised recommendations by risk sub-group. Current data suggested colonoscopy identifies those at low-risk of CRC, who may not benefit from intensive surveillance, which risks unnecessary harms and inefficient use of colonoscopy resources. Meta-analyses of incidence of advanced-neoplasia post-polypectomy for low-risk was comparable to those without adenoma; both rates were under the lifetime risk of 5%. Therefore, greater personalisation through de-intensified strategies for low-risk individuals could be beneficial and could employ non-invasive testing such as faecal immunochemical tests (FIT) combined with primary prevention or chemoprevention, thereby reserving colonoscopy for targeted use in personalised risk-stratified surveillance.
This systematic review aims to:
1. Assess if there is evidence supporting a program of personalised surveillance in patients with colorectal adenoma according to risk sub-group.
2. Compare the effectiveness of surveillance colonoscopy with alternative prevention strategies.
3. Assess trade-off between costs, benefits and adverse effects which must be considered in a decision to adopt or reject personalised surveillance.

Non-pharmacological interventions for cognitive impairment due to systemic cancer treatment (Review)

Background

It is estimated that up to 75% of cancer survivors may experience cognitive impairment as a result of cancer treatment and given the increasing size of the cancer survivor population, the number of affected people is set to rise considerably in coming years. There is a need, therefore, to identify effective, non-pharmacological interventions for maintaining cognitive function or ameliorating cognitive impairment among people with a previous cancer diagnosis.
Objectives

To evaluate the cognitive effects, non-cognitive effects, duration and safety of non-pharmacological interventions among cancer patients targeted at maintaining cognitive function or ameliorating cognitive impairment as a result of cancer or receipt of systemic cancer treatment (i.e. chemotherapy or hormonal therapies in isolation or combination with other treatments).
Search methods

We searched the Cochrane Centre Register of Controlled Trials (CENTRAL), MEDLINE, Embase, PUBMED, Cumulative Index of Nursing and Allied Health Literature (CINAHL) and PsycINFO databases. We also searched registries of ongoing trials and grey literature including theses, dissertations and conference proceedings. Searches were conducted for articles published from 1980 to 29 September 2015.
Selection criteria

Randomised controlled trials (RCTs) of non-pharmacological interventions to improve cognitive impairment or to maintain cognitive functioning among survivors of adult-onset cancers who have completed systemic cancer therapy (in isolation or combination with other treatments) were eligible. Studies among individuals continuing to receive hormonal therapy were included. We excluded interventions targeted at cancer survivors with central nervous system (CNS) tumours or metastases, non-melanoma skin cancer or those who had received cranial radiation or, were from nursing or care home settings. Language restrictions were not applied.
Data collection and analysis

Author pairs independently screened, selected, extracted data and rated the risk of bias of studies. We were unable to conduct planned meta-analyses due to heterogeneity in the type of interventions and outcomes, with the exception of compensatory strategy training interventions for which we pooled data for mental and physical well-being outcomes. We report a narrative synthesis of intervention effectiveness for other outcomes.
Main results

Five RCTs describing six interventions (comprising a total of 235 participants) met the eligibility criteria for the review. Two trials of computer-assisted cognitive training interventions (n = 100), two of compensatory strategy training interventions (n = 95), one of meditation (n = 47) and one of physical activity intervention (n = 19) were identified. Each study focused on breast cancer survivors. All five studies were rated as having a high risk of bias. Data for our primary outcome of interest, cognitive function were not amenable to being pooled statistically. Cognitive training demonstrated beneficial effects on objectively assessed cognitive function (including processing speed, executive functions, cognitive flexibility, language, delayed- and immediate- memory), subjectively reported cognitive function and mental well-being. Compensatory strategy training demonstrated improvements on objectively assessed delayed-, immediate- and verbal-memory, self-reported cognitive function and spiritual quality of life (QoL). The meta-analyses of two RCTs (95 participants) did not show a beneficial effect from compensatory strategy training on physical well-being immediately (standardised mean difference (SMD) 0.12, 95% confidence interval (CI) -0.59 to 0.83; I2= 67%) or two months post-intervention (SMD - 0.21, 95% CI -0.89 to 0.47; I2 = 63%) or on mental well-being two months post-intervention (SMD -0.38, 95% CI -1.10 to 0.34; I2 = 67%). Lower mental well-being immediately post-intervention appeared to be observed in patients who received compensatory strategy training compared to wait-list controls (SMD -0.57, 95% CI -0.98 to -0.16; I2 = 0%). We assessed the assembled studies using GRADE for physical and mental health outcomes and this evidence was rated to be low quality and, therefore findings should be interpreted with caution. Evidence for physical activity and meditation interventions on cognitive outcomes is unclear.
Authors' conclusions

Overall, the, albeit low-quality evidence may be interpreted to suggest that non-pharmacological interventions may have the potential to reduce the risk of, or ameliorate, cognitive impairment following systemic cancer treatment. Larger, multi-site studies including an appropriate, active attentional control group, as well as consideration of functional outcomes (e.g. activities of daily living) are required in order to come to firmer conclusions about the benefits or otherwise of this intervention approach. There is also a need to conduct research into cognitive impairment among cancer patient groups other than women with breast cancer.

Extending Automated Testing To High-level Software Requirements : A study on the feasibility of automated acceptance-testing

Automated acceptance testing is the testing of software done in higher level to test whether the system abides by the requirements desired by the business clients by the use of piece of script other than the software itself. This project is a study of the feasibility of acceptance tests written in Behavior Driven Development principle. The project includes an implementation part where automated accep- tance testing is written for Touch-point web application developed by Dewire (a software consultant company) for Telia (a telecom company) from the require- ments received from the customer (Telia). The automated acceptance testing is in Cucumber-Selenium framework which enforces Behavior Driven Development principles. The purpose of the implementation is to verify the practicability of this style of acceptance testing. From the completion of implementation, it was concluded that all the requirements from customer in real world can be converted into executable specifications and the process was not at all time-consuming or difficult for a low-experienced programmer like the author itself. The project also includes survey to measure the learnability and understandability of Gherkin- the language that Cucumber understands. The survey consist of some Gherkin exam- ples followed with questions that include making changes to the Gherkin exam- ples. Survey had 3 parts: first being easy, second medium and third most difficult. Survey also had a linear scale from 1 to 5 to rate the difficulty level for each part of the survey. 1 stood for very easy and 5 for very difficult. Time when the partic- ipants began the survey was also taken in order to calculate the total time taken by the participants to learn and answer the questions. Survey was taken by 18 of the employers of Dewire who had primary working role as one of the programmer, tester and project manager. In the result, tester and project manager were grouped as non-programmer. The survey concluded that it is very easy and quick to learn Gherkin. While the participants rated Gherkin as very easy.

Implications de l’hétérogénéité comportementale et biologique pour la vaccination contre les virus du papillome humain au niveau de la population : modélisation mathématique, revue systématique et méta-analyse

Objectifs : Dans plusieurs pays la couverture vaccinale contre les virus du papillome humain (VPH) est associée aux déterminants sociaux des comportements sexuels et la participation au dépistage du cancer du col utérin. Ces vaccins protègent uniquement contre certains types de VPH, donc leur impact futur sur les VPH nonvaccinaux demeure incertain. L’hétérogénéité comportementale entre individus et biologique entre types de VPH affectera l’efficacité populationnelle de la vaccination contre les VPH. Les objectifs spécifiques de cette thèse étaient 1) de modéliser comment une couverture vaccinale inégale entre filles préadolescentes qui différeront selon leur activité sexuelle et leur participation au dépistage du cancer du col affectera l’efficacité populationnelle de la vaccination, 2) faire une synthèse et comparer les estimés d’efficacité croisée des vaccins contre les VPH dans des populations ADN-négatives aux VPH et 3) d’identifier, avec la modélisation, les devis d’étude épidémiologique qui réduisent les biais dans l’estimation des interactions biologiques entre types de VPH. Méthode : Nous avons utilisé des modèles de transmission dynamique et une revue systématique de la littérature pour répondre aux objectifs. 1) Nous avons modélisé une couverture vaccinale inégale entre filles qui différeront selon leur activité sexuelle et leur participation au dépistage, et examiné les changements postvaccination dans l’inégalité dans la prévalence des VPH et l’incidence des carcinomes malpighien (SCC) du col de l’utérus entre femmes ayant différents comportements. 2) Nous avons effectué une revue systématique et méta-analyse des efficacités croisées des vaccins contre les VPH estimées dans des populations ADNnégatives aux VPH. 3) Nous avons développé des modèles de transmission dynamique et d’interaction de deux types de VPH pour simuler les études épidémiologiques d’interactions entre les VPH. Résultats : Pour l’objectif 1), notre modèle de transmission prédit que l’efficacité populationnelle du vaccin dépendra de la distribution du vaccin dans la population. Après la vaccination, les inégalités absolues dans l’incidence de l’infection et des SCC entre groupes de femmes qui diffèrent selon leur activité sexuelle et leur participation au dépistage devraient diminuer. Inversement, les inégalités relatives pourraient augmenter si les femmes plus sexuellement actives et celles qui ne se font jamais dépister ont une couverture vaccinale moins élevée que les autres. Le taux d’incidence des SCC demeurera élevé chez les femmes qui ne sont jamais dépistées après la vaccination. L’efficacité croisée vaccinale et les interactions biologiques entre VPH ne sont pas encore assez bien caractérisées pour pouvoir prédire l’impact du vaccin sur les types de VPH nonvaccinaux. Pour l’objectif 2), notre méta-analyse des essais cliniques des vaccins suggère que le vaccin bivalent a une efficacité croisée significativement plus élevée que le quadrivalent contre les infections persistantes et lésions précancéreuses avec les VPH-31, 33 et 45. Les essais cliniques plus longs estiment une efficacité croisée plus faible. La modélisation des études épidémiologiques d’interactions pour l’objectif 3) montre que l’estimation des interactions biologiques entre types de VPH dans les études épidémiologiques est systématiquement biaisée par la corrélation entre le temps à risque d’infection avec un type de VPH et le temps à risque d’infection avec d’autres types de VPH. L’ajustement pour des marqueurs d’activité sexuelle ne réussit pas à contrôler ce biais. Une mesure valide des interactions biologiques entre types de VPH peut être obtenue uniquement avec des études épidémiologiques prospectives qui restreignent les analyses à des individus susceptibles ayant des partenaires sexuels infectés. Conclusion : L’hétérogénéité comportementale entre individus et l’hétérogénéité biologique entre VPH affecteront l’efficacité populationnelle du vaccin contre les VPH. Dans les contextes où les déterminants sociaux des comportements sexuels et la participation au dépistage sont aussi associés à la couverture vaccinale chez les préadolescentes, l’inégalité relative dans l’incidence des SCC risque d’augmenter. Ces comportements demeureront des facteurs de risque importants du cancer du col à l’avenir. L’effet à long terme du vaccin sur les types de VPH non-vaccinaux demeure incertain. Quoique nos résultats suggèrent que les vaccins offrent une efficacité croisée contre certains types de VPH, celle-ci pourrait diminuer après quelques années. Des interactions compétitives entre VPH pourraient exister malgré les associations observées entre les incidences des infections VPH, donc une augmentation post-vaccination de la prévalence des VPH non-vaccinaux demeure possible. Des devis d’analyse plus complexes sont nécessaires pour mesurer de façon valide les interactions biologiques entre les VPH dans les études épidémiologiques.

Real-time analytics on large dynamic graphs

In today's fast-paced and interconnected digital world, the data generated by an increasing number of applications is being modeled as dynamic graphs. The graph structure encodes relationships among data items, while the structural changes to the graphs as well as the continuous stream of information produced by the entities in these graphs make them dynamic in nature. Examples include social networks where users post status updates, images, videos, etc.; phone call networks where nodes may send text messages or place phone calls; road traffic networks where the traffic behavior of the road segments changes constantly, and so on. There is a tremendous value in storing, managing, and analyzing such dynamic graphs and deriving meaningful insights in real-time. However, a majority of the work in graph analytics assumes a static setting, and there is a lack of systematic study of the various dynamic scenarios, the complexity they impose on the analysis tasks, and the challenges in building efficient systems that can support such tasks at a large scale. In this dissertation, I design a unified streaming graph data management framework, and develop prototype systems to support increasingly complex tasks on dynamic graphs. In the first part, I focus on the management and querying of distributed graph data. I develop a hybrid replication policy that monitors the read-write frequencies of the nodes to decide dynamically what data to replicate, and whether to do eager or lazy replication in order to minimize network communication and support low-latency querying. In the second part, I study parallel execution of continuous neighborhood-driven aggregates, where each node aggregates the information generated in its neighborhoods. I build my system around the notion of an aggregation overlay graph, a pre-compiled data structure that enables sharing of partial aggregates across different queries, and also allows partial pre-computation of the aggregates to minimize the query latencies and increase throughput. Finally, I extend the framework to support continuous detection and analysis of activity-based subgraphs, where subgraphs could be specified using both graph structure as well as activity conditions on the nodes. The query specification tasks in my system are expressed using a set of active structural primitives, which allows the query evaluator to use a set of novel optimization techniques, thereby achieving high throughput. Overall, in this dissertation, I define and investigate a set of novel tasks on dynamic graphs, design scalable optimization techniques, build prototype systems, and show the effectiveness of the proposed techniques through extensive evaluation using large-scale real and synthetic datasets.

Changes in the perceived color of very bright stimuli

When very intense stimuli in the long-wavelength region of the visual spectrum are viewed continuously, they change in hue from red, through yellow, to green. The relation of the time course of these changes to the intensity of the stimulus is reported.

DESIGN, FABRICATION, AND PERFORMANCE CHARACTERIZATION OF MULTIFUNCTIONAL STRUCTURES TO HARVEST SOLAR ENERGY FOR FLAPPING WING AERIAL VEHICLES

Flapping Wing Aerial Vehicles (FWAVs) have the capability to combine the benefits of both fixed wing vehicles and rotary vehicles. However, flight time is limited due to limited on-board energy storage capacity. For most Unmanned Aerial Vehicle (UAV) operators, frequent recharging of the batteries is not ideal due to lack of nearby electrical outlets. This imposes serious limitations on FWAV flights. The approach taken to extend the flight time of UAVs was to integrate photovoltaic solar cells onto different structures of the vehicle to harvest and use energy from the sun. Integration of the solar cells can greatly improve the energy capacity of an UAV; however, this integration does effect the performance of the UAV and especially FWAVs. The integration of solar cells affects the ability of the vehicle to produce the aerodynamic forces necessary to maintain flight. This PhD dissertation characterizes the effects of solar cell integration on the performance of a FWAV. Robo Raven, a recently developed FWAV, is used as the platform for this work. An additive manufacturing technique was developed to integrate photovoltaic solar cells into the wing and tail structures of the vehicle. An approach to characterizing the effects of solar cell integration to the wings, tail, and body of the UAV is also described. This approach includes measurement of aerodynamic forces generated by the vehicle and measurements of the wing shape during the flapping cycle using Digital Image Correlation. Various changes to wing, body, and tail design are investigated and changes in performance for each design are measured. The electrical performance from the solar cells is also characterized. A new multifunctional performance model was formulated that describes how integration of solar cells influences the flight performance. Aerodynamic models were developed to describe effects of solar cell integration force production and performance of the FWAV. Thus, performance changes can be predicted depending on changes in design. Sensing capabilities of the solar cells were also discovered and correlated to the deformation of the wing. This demonstrated that the solar cells were capable of: (1) Lightweight and flexible structure to generate aerodynamic forces, (2) Energy harvesting to extend operational time and autonomy, (3) Sensing of an aerodynamic force associated with wing deformation. Finally, different flexible photovoltaic materials with higher efficiencies are investigated, which enable the multifunctional wings to provide enough solar power to keep the FWAV aloft without batteries as long as there is enough sunlight to power the vehicle.

The leaderless resistance: George Lincoln Rockwell and the White Separatist Movement

The scope of the thesis encapsulates the wider post-war White Separatist Movement from the origins of American Nazism under George Lincoln Rockwell to the later developments of leaderless resistance and the political and cultural changes to the movement. The specific focus will be upon the relationship between George Lincoln Rockwell and the leaderless resistance concepts, in particular through its development and utilisation. Due to the complexity of the issues and the variety of influencing factors it is necessary in the first instance to assess it in terms of a historiography to allow themes to develop. As a result of this historical analysis themes have become evident to allow a conceptual analysis. In particular the thesis will utilise the following thematic contexts for assessing the various developments within White Separatism: including, state building; political marketing; the role of the media; and the propensity for terror and hate activities. In assessing the basis upon which the conceptual analysis is developed the research has utilised extensive use of texts, radio broadcasts, and pamphlets from the movement. The study has also been able to consider, government reports, law enforcement updates and communications from Civil Rights groups and other agencies. In the conceptual analysis of this information and themes, the thesis utilises new concepts as a means of creating an understanding of a rapidly changing area of politics; including ‘organic politic’ and ‘political firms’, when assessing political marketing trends; and assessing terrorist motivation.

Use of business analysis in beef businesses to direct management practice change for climate adaptation outcomes

Beef businesses in northern Australia are facing increased pressure to be productive and profitable with challenges such as climate variability and poor financial performance over the past decade. Declining terms of trade, limited recent gains in on-farm productivity, low profit margins under current management systems and current climatic conditions will leave little capacity for businesses to absorb climate change-induced losses. In order to generate a whole-of-business focus towards management change, the Climate Clever Beef project in the Maranoa-Balonne region of Queensland trialled the use of business analysis with beef producers to improve financial literacy, provide a greater understanding of current business performance and initiate changes to current management practices. Demonstration properties were engaged and a systematic approach was used to assess current business performance, evaluate impacts of management changes on the business and to trial practices and promote successful outcomes to the wider industry. Focus was concentrated on improving financial literacy skills, understanding the business’ key performance indicators and modifying practices to improve both business productivity and profitability. To best achieve the desired outcomes, several extension models were employed: the ‘group facilitation/empowerment model’, the ‘individual consultant/mentor model’ and the ‘technology development model’. Providing producers with a whole-of-business approach and using business analysis in conjunction with on-farm trials and various extension methods proved to be a successful way to encourage producers in the region to adopt new practices into their business, in the areas of greatest impact. The areas targeted for development within businesses generally led to improvements in animal performance and grazing land management further improving the prospects for climate resilience.

A study of the electrical basis for the inhibition and excitation in autonomically innervated smooth muscle

The aim of this thesis was to investigate the electrical and mechanical responses to inhibitory non-adrenergic noncholinergic (NANC) nerve stimulation in the bovine retractor penis muscle (BRP) and compare them with those to an inhibitory extract made from this muscle. The extract may contain the NANC inhibitory transmitter of the BRP and possibly of other smooth muscles. Because of species differences in the electrical response to NANC nerves in the rat and rabbit anococcygeus the effects of the extract on these tissues was also investigated. Prior to the investigation of the extract, both the excitatory and inhibitory responses to field stimulation in the BRP, and the effects of passive membrane potential displacement were studied using conventional intra- or extracellular (sucrose gap) recording techniques. The majority of cells in the BRP were electrically quiescent independent of the resting tone. The most frequent (in approximately 25% of preparations) form of spontaneous activity, oscillations in membrane potential and tone, may represent a pacemaker activity. The BRP had cable properties; the time constant and space constant indicated a high membrane resistance. In the absence of tone, field stimulation of the BRP evoked excitatory junction potentials (ejps) in every cell impaled and contractions, graded with the strength, frequency and number of pulses; spikes were not observed. Guanethidine (1-3 x 10-5M) abolished the ejps and contractions, confirming their adrenergic origin. Noradrenaline added exogenously depolarised and contracted the muscle. These effects were blocked by the a-adrenoceptor antagonists, phentolamine and prazosin. However, phentolamine (2.5x 10-6M) inhibited the contraction without reducing the ejp significantly. These effects may be independent of adrenoceptor blockade or the ejp may be mediated by a substance other than noradrenaline (e.g. ATP) released from adrenergic nerves. Prazosin (1.4 x lO-6M) failed to block either the ejp or contraction, indicating the possible existence of two types of adrenoceptor in the BRP; one activated by neuronally-released and the other by exogenously-added noradrenaline. ATP, a contaminant in the extract, also depolarised and contracted the BRP. Physostigmine reduced whilst atropine enhanced the ejps and contractions without similarly affecting the response to exogenous noradrenaline. This confirmed the presence of a cholinergic inhibitory innervation acting on the excitatory adrenergic fibres (Klinge and Sjostrand, 1977). TEA (1 x lO-4M) enhanced the ejp and contraction. Higher concentrations (0.5 to 10 x 10-3M) depolarised, increased the tone and evoked electrical and mechanical oscillations but no spikes. The depolarisation and contraction to exogenous noradrenaline were not enhanced, indicating that TEA acts on the adrenergic nerves. Some post-synaptic effect to block K+ channels also seems likely. The relationship between ejp amplitude and membrane potential in the double sucrose gap was linear and indicated a reversal potential more positive than -30mV. Electrotonic pulse amplitude decreased during the ejp, indicating an increased membrane conductance. Ejps and contractions were reduced following the replacement of the NaCl of the Krebs solution with sodium glutamate. This may be due to the effects of glutamate itself (e.g. Ca2+ chelation) rather than reduction in the membrane Cl- gradient. Tone usually developed spontaneously and was accompanied by membrane depolarisation (from -53 to -45mV) which may open voltage-dependent channels, causing Ca2+ entry and/or its release from intracellular binding sites. Field stimulation produced inhibitory potentials (ijps) and relaxations graded with the strength and number of pulses but showing little frequency dependence. Rebound depolarisation and contraction often followed the ijp and relaxation. Tetrodotoxin (3 x IO-6M), but not adrenergic or cholinergic antagonists, abolished the ijp and relaxation, confirming their non-adrenergic non-cholinergic neurogenic nature. The extract, prepared and acid-activated as described by Gillespie, Hunter and Martin (1981), hyperpolarised and relaxed the BRP, as did sodium nitroprusside and adenosine triphosphate (ATP). Unlike the activated extract or sodium nitroprusside, desensitisation to ATP occurred rapidly and without any change in the inhibitory electrical or mechanical responses to field stimulation. The ijp and relaxation in the BRP were insensitive to apamin but abolished by oxyhaemoglobin (4-8 x 10-6M), as were the responses to extract and sodium nitroprusside. In TEA (10-2M), field stimulation evoked relaxations with no accompanying electrical change. The ijp may be unconnected with or additional to another mechanism producing relaxation. The relationship between membrane potential and ijp in the BRP was non-linear. Ijp amplitude was initially increased during membrane potential displacement from -45mV to approximately -60mV. Thereafter (-60 to -l03mV) the ijp was reduced. Ijps were abolished at -27 and -103mV; reversal was not observed. The hyperpolarisation to extract was also enhanced during passive displacement of the membrane potential to more negative values (-57mV). Membrane resistance increased during the ijp. The extract produced inconsistent changes in membrane resistance, possibly because of the presence of more than one active component. K+ withdrawal failed to enhance the ijp or hyperpolarisation to extract and 20mM K+ did not abolish the the ijp at membrane potentials exceeding EK (-49mV). Thus, the ijp or hyperpolarisation to extract are unlikely to be mediated by an increased K+ conductance. Reducing the Cl- abolished the hyperpolarisation to field stimulation and extract. This occurred more quickly than the anticipated reduction in the Cl- gradient and may be due to Ca2+ chelation by the anion substitute (glutamate or benzenesulphonate) or blockade of the resting conductance which is normally inactivated by the transmitter. Ouabain (1-5x 10-5M), which reduces both the Na+ and Cl- gradients, abolished the ijp, implicating either of these ions as the ionic species involved. In the rat and rabbit anococcygeus, field stimulation and extract each reduced guanethidine-induced tone. This was unaccompanied in the majority of cells in the rat by any significant electrical response. In the remaining cells, inhibition of the membrane potential oscillations occurred. The rabbit anococcygeus differed in that inhibition of the electrical oscillations was observed in every cell exhibiting this behaviour. However, the majority of cells in the rabbit were electrically quiescent and showed only small hyperpolarisations to field stimulation and no electrical response to extract. Apamin (1 x 10-7M) failed to block the electrical and mechanical response to field stimulation in the rabbit but did inhibit transiently that to extract. The latter effect may be due to the initial excitatory effects of apamin. The similarities between the electrical effects of the extract and those of inhibitory nerve stimulation in the BRP, rat and rabbit anococcygeus muscles are generally consistent with their being mediated by the same active component. Moreover, the ijp in the BRP shows properties which have not been reported in other non-adrenergic noncholinergically innervated smooth muscles.

Comparing fixed and flexible stocking as adaptations to inter-annual rainfall variability in the extensive beef industry of northern Australia

Many beef producers within the extensive cattle industry of northern Australia attempt to maintain a constant herd size from year-to-year (fixed stocking), whereas others adjust stock numbers to varying degrees annually in response to changes in forage supply. The effects of these strategies on pasture condition and cattle productivity cannot easily be assessed by grazing trials. Simulation studies, which include feedbacks of changes to pasture condition on cattle liveweight gain, can extend the results of grazing trials both spatially and temporally. They can compare a large number of strategies, over long periods of time, for a range of climate periods, at locations which differ markedly in climate. This simulation study compared the pasture condition and cattle productivity achieved by fixed stocking at the long-term carrying capacity with that of 55 flexible stocking strategies at 28 locations across Queensland and the Northern Territory. Flexible stocking strategies differed markedly in the degree they increased or decreased cattle stocking rates after good and poor pasture growing seasons, respectively. The 28 locations covered the full range in average annual rainfall and inter-annual rainfall variability experienced across northern Australia. Constrained flexibility, which limited increases in stocking rates after good growing seasons to 10% but decreased them by up to 20% after poor growing seasons, provides sustainable productivity gains for cattle producers in northern Australia. This strategy can improve pasture condition and increase cattle productivity relative to fixed stocking at the long-term carrying capacity, and its capacity to do this was greatest in the semiarid rangeland regions that contain the majority of beef cattle in northern Australia. More flexible stocking strategies, which also increased stocking rates after good growing seasons by only half as much as they decreased them after poor growing seasons, were equally sustainable and more productive than constrained flexibility, but are often impractical at property and industry scales. Strategies with the highest limits (e.g. 70%) for both annual increases and decreases in stocking rates could achieve higher cattle productivity, but this was at the expense of pasture condition and was not sustainable. Constrained flexible stocking, with a 10% limit for increases and a 20% limit for decreases in stocking rates annually, is a risk-averse adaptation to high and unpredictable rainfall variability for the extensive beef industry of northern Australia. © Australian Rangeland Society 2016.

Improving the use of G-CSF during chemotherapy using physiological mathematical modelling : a quantitative systems pharmacology approach

La diminution des doses administrées ou même la cessation complète d'un traitement chimiothérapeutique est souvent la conséquence de la réduction du nombre de neutrophiles, qui sont les globules blancs les plus fréquents dans le sang. Cette réduction dans le nombre absolu des neutrophiles, aussi connue sous le nom de myélosuppression, est précipitée par les effets létaux non spécifiques des médicaments anti-cancéreux, qui, parallèlement à leur effet thérapeutique, produisent aussi des effets toxiques sur les cellules saines. Dans le but d'atténuer cet impact myélosuppresseur, on administre aux patients un facteur de stimulation des colonies de granulocytes recombinant humain (rhG-CSF), une forme exogène du G-CSF, l'hormone responsable de la stimulation de la production des neutrophiles et de leurs libération dans la circulation sanguine. Bien que les bienfaits d'un traitement prophylactique avec le G-CSF pendant la chimiothérapie soient bien établis, les protocoles d'administration demeurent mal définis et sont fréquemment déterminés ad libitum par les cliniciens. Avec l'optique d'améliorer le dosage thérapeutique et rationaliser l'utilisation du rhG-CSF pendant le traitement chimiothérapeutique, nous avons développé un modèle physiologique du processus de granulopoïèse, qui incorpore les connaissances actuelles de pointe relatives à la production des neutrophiles des cellules souches hématopoïétiques dans la moelle osseuse. À ce modèle physiologique, nous avons intégré des modèles pharmacocinétiques/pharmacodynamiques (PK/PD) de deux médicaments: le PM00104 (Zalypsis®), un médicament anti-cancéreux, et le rhG-CSF (filgrastim). En se servant des principes fondamentaux sous-jacents à la physiologie, nous avons estimé les paramètres de manière exhaustive sans devoir recourir à l'ajustement des données, ce qui nous a permis de prédire des données cliniques provenant de 172 patients soumis au protocol CHOP14 (6 cycles de chimiothérapie avec une période de 14 jours où l'administration du rhG-CSF se fait du jour 4 au jour 13 post-chimiothérapie). En utilisant ce modèle physio-PK/PD, nous avons démontré que le nombre d'administrations du rhG-CSF pourrait être réduit de dix (pratique actuelle) à quatre ou même trois administrations, à condition de retarder le début du traitement prophylactique par le rhG-CSF. Dans un souci d'applicabilité clinique de notre approche de modélisation, nous avons investigué l'impact de la variabilité PK présente dans une population de patients, sur les prédictions du modèle, en intégrant des modèles PK de population (Pop-PK) des deux médicaments. En considérant des cohortes de 500 patients in silico pour chacun des cinq scénarios de variabilité plausibles et en utilisant trois marqueurs cliniques, soient le temps au nadir des neutrophiles, la valeur du nadir, ainsi que l'aire sous la courbe concentration-effet, nous avons établi qu'il n'y avait aucune différence significative dans les prédictions du modèle entre le patient-type et la population. Ceci démontre la robustesse de l'approche que nous avons développée et qui s'apparente à une approche de pharmacologie quantitative des systèmes (QSP). Motivés par l'utilisation du rhG-CSF dans le traitement d'autres maladies, comme des pathologies périodiques telles que la neutropénie cyclique, nous avons ensuite soumis l'étude du modèle au contexte des maladies dynamiques. En mettant en évidence la non validité du paradigme de la rétroaction des cytokines pour l'administration exogène des mimétiques du G-CSF, nous avons développé un modèle physiologique PK/PD novateur comprenant les concentrations libres et liées du G-CSF. Ce nouveau modèle PK a aussi nécessité des changements dans le modèle PD puisqu’il nous a permis de retracer les concentrations du G-CSF lié aux neutrophiles. Nous avons démontré que l'hypothèse sous-jacente de l'équilibre entre la concentration libre et liée, selon la loi d'action de masse, n'est plus valide pour le G-CSF aux concentrations endogènes et mènerait en fait à la surestimation de la clairance rénale du médicament. En procédant ainsi, nous avons réussi à reproduire des données cliniques obtenues dans diverses conditions (l'administration exogène du G-CSF, l'administration du PM00104, CHOP14). Nous avons aussi fourni une explication logique des mécanismes responsables de la réponse physiologique aux deux médicaments. Finalement, afin de mettre en exergue l’approche intégrative en pharmacologie adoptée dans cette thèse, nous avons démontré sa valeur inestimable pour la mise en lumière et la reconstruction des systèmes vivants complexes, en faisant le parallèle avec d’autres disciplines scientifiques telles que la paléontologie et la forensique, où une approche semblable a largement fait ses preuves. Nous avons aussi discuté du potentiel de la pharmacologie quantitative des systèmes appliquées au développement du médicament et à la médecine translationnelle, en se servant du modèle physio-PK/PD que nous avons mis au point.

Regulatory governance of ‘training markets’, ‘market failure’, and ‘quasi’ markets: historical dimensions of the post-initial training market in the Netherlands

This article examines regulatory governance of the post-initial training market in The Netherlands. From an historical perspective on policy formation processes, it examines market formation in terms of social, economic, and cultural factors in the development of provision and demand for post-initial training; the roles of stakeholders in the longterm construction of regulatory governance of the market; regulation of and public providers; policy responses to market failure; and tripartite division of responsibilities between the state, social partners, commercial and publicly-funded providers. Historical description and analysis examine policy narratives of key stakeholders with reference to: a) influence of societal stakeholders on regulatory decision-making; b) state regulation of the post-initial training market; c) public intervention regulating the market to prevent market failure; d) market deregulation, competition, employability and individual responsibility; and, e) regulatory governance to prevent ‘allocative failure’ by the market in non-delivery of post-initial training to specific target groups, particularly the low-qualified. Dominant policy narratives have resulted in limited state regulation of the supply-side, a tripartite system of regulatory governance by the state, social partners and commercial providers as regulatory actors. Current policy discourses address interventions on the demand-side to redistribute structures of opportunity throughout the life courses of individuals. Further empirical research from a comparative historical perspective is required to deepen contemporary understandings of regulatory governance of markets and the commodification of adult learning in knowledge societies and information economies. (DIPF/Orig.)

The Influence of Place Attachment, Aspirations, and Rapidly Changing Environments on Resettlement Decisions

Resettlement associated with development projects results in a variety of negative impacts. This dissertation uses the resettlement context to frame the dynamic relationships formed between peoples and places experiencing development. Two case studies contribute: (a) the border zone of Mozambique’s Limpopo National Park where residents contend with changes to land access and use; and (b) Bairro Chipanga in Moatize, Mozambique where a resettled population struggles to form place attachment and transform the post-resettlement site into a “good” place. Through analysis of data collected at these sites between 2009 and 2015, this dissertation investigates how changing environments impact person-place relationships before and after resettlement occurs. Changing environments create conditions leading to disemplacement—feeling like one no longer belongs—that reduces the environment’s ability to foster place attachment. Research findings indicate that responses taken by individuals living in the changing environment depend heavily upon whether resettlement has already occurred. In a pre-resettlement context, residents adjust their daily lives to diminish the effects of a changing environment and re-create the conditions to which they initially formed an attachment. They accept impoverishing conditions, including a narrowing of the spaces in which they live their daily lives, because it is preferred to the anxiety that accompanies being forced to resettle. In a post-resettlement context, resettlement disrupts the formation of place attachment and resettled peoples become a placeless population. When the resettlement has not resulted in anticipated outcomes, the aspiration for social justice—seeking conditions residents had reason to expect—negatively influences residents’ perspectives about the place. The post-resettlement site becomes a bad place with a future unchanged from the present. At best, this results in a population in which more members are willing to move away from the post-resettlement site, and, at worse, complete disengagement of other members from trying to improve the community. Resettlement thus has the potential to launch a cycle of movement- displacement-movement that prevents an entire generation from establishing place attachment and realizing its benefits. At the very least, resettlement impedes the formation of place attachment to new places. Thus, this dissertation draws attention to the unseen and uncompensated losses of resettlement.