Uncertainty in climate change impacts on basin-scale freshwater resources – preface to the special issue: the QUEST-GSI methodology and synthesis of results

This paper presents a preface to this Special Issue on the results of the QUEST-GSI (Global Scale Impacts) project on climate change impacts on catchment-scale water resources. A detailed description of the unified methodology, subsequently used in all studies in this issue, is provided. The project method involved running simulations of catchment-scale hydrology using a unified set of past and future climate scenarios, to enable a consistent analysis of the climate impacts around the globe. These scenarios include "policy-relevant" prescribed warming scenarios. This is followed by a synthesis of the key findings. Overall, the studies indicate that in most basins the models project substantial changes to river flow, beyond that observed in the historical record, but that in many cases there is considerable uncertainty in the magnitude and sign of the projected changes. The implications of this for adaptation activities are discussed

Revisiting protein aggregation as pathogenic in sporadic Parkinson and Alzheimer diseases.

The gold standard for a definitive diagnosis of Parkinson disease (PD) is the pathologic finding of aggregated α-synuclein into Lewy bodies and for Alzheimer disease (AD) aggregated amyloid into plaques and hyperphosphorylated tau into tangles. Implicit in this clinicopathologic-based nosology is the assumption that pathologic protein aggregation at autopsy reflects pathogenesis at disease onset. While these aggregates may in exceptional cases be on a causal pathway in humans (e.g., aggregated α-synuclein in SNCA gene multiplication or aggregated β-amyloid in APP mutations), their near universality at postmortem in sporadic PD and AD suggests they may alternatively represent common outcomes from upstream mechanisms or compensatory responses to cellular stress in order to delay cell death. These 3 conceptual frameworks of protein aggregation (pathogenic, epiphenomenon, protective) are difficult to resolve because of the inability to probe brain tissue in real time. Whereas animal models, in which neither PD nor AD occur in natural states, consistently support a pathogenic role of protein aggregation, indirect evidence from human studies does not. We hypothesize that (1) current biomarkers of protein aggregates may be relevant to common pathology but not to subgroup pathogenesis and (2) disease-modifying treatments targeting oligomers or fibrils might be futile or deleterious because these proteins are epiphenomena or protective in the human brain under molecular stress. Future precision medicine efforts for molecular targeting of neurodegenerative diseases may require analyses not anchored on current clinicopathologic criteria but instead on biological signals generated from large deeply phenotyped aging populations or from smaller but well-defined genetic-molecular cohorts

An investigation of minimisation criteria

Minimisation can be used within treatment trials to ensure that prognostic factors are evenly distributed between treatment groups. The technique is relatively straightforward to apply but does require running tallies of patient recruitments to be made and some simple calculations to be performed prior to each allocation. As computing facilities have become more widely available, minimisation has become a more feasible option for many. Although the technique has increased in popularity, the mode of application is often poorly reported and the choice of input parameters not justified in any logical way

Higher Derivative Corrections to R-charged Black Holes: Boundary Counterterms and the Mass-Charge Relation

We carry out the holographic renormalization of Einstein-Maxwell theory with curvature-squared corrections. In particular, we demonstrate how to construct the generalized Gibbons-Hawking surface term needed to ensure a perturbatively well-defined variational principle. This treatment ensures the absence of ghost degrees of freedom at the linearized perturbative order in the higher-derivative corrections. We use the holographically renormalized action to study the thermodynamics of R-charged black holes with higher derivatives and to investigate their mass to charge ratio in the extremal limit. In five dimensions, there seems to be a connection between the sign of the higher derivative couplings required to satisfy the weak gravity conjecture and that violating the shear viscosity to entropy bound. This is in turn related to possible constraints on the central charges of the dual CFT, in particular to the sign of c-a.Comment: 30 pages. v2: references added, some equations simplifie

Comparing the immune response to a novel intranasal nanoparticle PLGA vaccine and a commercial BPI3V vaccine in dairy calves

peer-reviewedBackground There is a need to improve vaccination against respiratory pathogens in calves by stimulation of local immunity at the site of pathogen entry at an early stage in life. Ideally such a vaccine preparation would not be inhibited by the maternally derived antibodies. Additionally, localized immune response at the site of infection is also crucial to control infection at the site of entry of virus. The present study investigated the response to an intranasal bovine parainfluenza 3 virus (BPI3V) antigen preparation encapsulated in PLGA (poly dl-lactic-co-glycolide) nanoparticles in the presence of pre-existing anti-BPI3V antibodies in young calves and comparing it to a commercially available BPI3V respiratory vaccine. Results There was a significant (P < 0.05) increase in BPI3V-specific IgA in the nasal mucus of the BPI3V nanoparticle vaccine group alone. Following administration of the nanoparticle vaccine an early immune response was induced that continued to grow until the end of study and was not observed in the other treatment groups. Virus specific serum IgG response to both the nanoparticle vaccine and commercial live attenuated vaccine showed a significant (P < 0.05) rise over the period of study. However, the cell mediated immune response observed didn’t show any significant rise in any of the treatment groups. Conclusion Calves administered the intranasal nanoparticle vaccine induced significantly greater mucosal IgA responses, compared to the other treatment groups. This suggests an enhanced, sustained mucosal-based immunological response to the BPI3V nanoparticle vaccine in the face of pre-existing antibodies to BPI3V, which are encouraging and potentially useful characteristics of a candidate vaccine. However, ability of nanoparticle vaccine in eliciting cell mediated immune response needs further investigation. More sustained local mucosal immunity induced by nanoparticle vaccine has obvious potential if it translates into enhanced protective immunity in the face of virus outbreak

Algorithmic Complexity for Short Binary Strings Applied to Psychology: A Primer

Since human randomness production has been studied and widely used to assess executive functions (especially inhibition), many measures have been suggested to assess the degree to which a sequence is random-like. However, each of them focuses on one feature of randomness, leading authors to have to use multiple measures. Here we describe and advocate for the use of the accepted universal measure for randomness based on algorithmic complexity, by means of a novel previously presented technique using the the definition of algorithmic probability. A re-analysis of the classical Radio Zenith data in the light of the proposed measure and methodology is provided as a study case of an application.Comment: To appear in Behavior Research Method

Game theory of mind

This paper introduces a model of ‘theory of mind’, namely, how we represent the intentions and goals of others to optimise our mutual interactions. We draw on ideas from optimum control and game theory to provide a ‘game theory of mind’. First, we consider the representations of goals in terms of value functions that are prescribed by utility or rewards. Critically, the joint value functions and ensuing behaviour are optimised recursively, under the assumption that I represent your value function, your representation of mine, your representation of my representation of yours, and so on ad infinitum. However, if we assume that the degree of recursion is bounded, then players need to estimate the opponent's degree of recursion (i.e., sophistication) to respond optimally. This induces a problem of inferring the opponent's sophistication, given behavioural exchanges. We show it is possible to deduce whether players make inferences about each other and quantify their sophistication on the basis of choices in sequential games. This rests on comparing generative models of choices with, and without, inference. Model comparison is demonstrated using simulated and real data from a ‘stag-hunt’. Finally, we note that exactly the same sophisticated behaviour can be achieved by optimising the utility function itself (through prosocial utility), producing unsophisticated but apparently altruistic agents. This may be relevant ethologically in hierarchal game theory and coevolution

IMPLEmenting a clinical practice guideline for acute low back pain evidence-based manageMENT in general practice (IMPLEMENT) : cluster randomised controlled trial study protocol

Background: Evidence generated from reliable research is not frequently implemented into clinical practice. Evidence-based clinical practice guidelines are a potential vehicle to achieve this. A recent systematic review of implementation strategies of guideline dissemination concluded that there was a lack of evidence regarding effective strategies to promote the uptake of guidelines. Recommendations from this review, and other studies, have suggested the use of interventions that are theoretically based because these may be more effective than those that are not. An evidencebased clinical practice guideline for the management of acute low back pain was recently developed in Australia. This provides an opportunity to develop and test a theory-based implementation intervention for a condition which is common, has a high burden, and for which there is an evidence-practice gap in the primary care setting. Aim: This study aims to test the effectiveness of a theory-based intervention for implementing a clinical practice guideline for acute low back pain in general practice in Victoria, Australia. Specifically, our primary objectives are to establish if the intervention is effective in reducing the percentage of patients who are referred for a plain x-ray, and improving mean level of disability for patients three months post-consultation. Methods/Design: This study protocol describes the details of a cluster randomised controlled trial. Ninety-two general practices (clusters), which include at least one consenting general practitioner, will be randomised to an intervention or control arm using restricted randomisation. Patients aged 18 years or older who visit a participating practitioner for acute non-specific low back pain of less than three months duration will be eligible for inclusion. An average of twenty-five patients per general practice will be recruited, providing a total of 2,300 patient participants. General practitioners in the control arm will receive access to the guideline using the existing dissemination strategy. Practitioners in the intervention arm will be invited to participate in facilitated face-to-face workshops that have been underpinned by behavioural theory. Investigators (not involved in the delivery of the intervention), patients, outcome assessors and the study statistician will be blinded to group allocation. Trial registration: Australian New Zealand Clinical Trials Registry ACTRN012606000098538 (date registered 14/03/2006).The trial is funded by the NHMRC by way of a Primary Health Care Project Grant (334060). JF has 50% of her time funded by the Chief Scientist Office3/2006). of the Scottish Government Health Directorate and 50% by the University of Aberdeen. PK is supported by a NHMRC Health Professional Fellowship (384366) and RB by a NHMRC Practitioner Fellowship (334010). JG holds a Canada Research Chair in Health Knowledge Transfer and Uptake. All other authors are funded by their own institutions

Effects of beta-alanine supplementation on brain homocarnosine/carnosine signal and cognitive function: an exploratory study

Objectives: Two independent studies were conducted to examine the effects of 28 d of beta-alanine supplementation at 6.4 g d-1 on brain homocarnosine/carnosine signal in omnivores and vegetarians (Study 1) and on cognitive function before and after exercise in trained cyclists (Study 2). Methods: In Study 1, seven healthy vegetarians (3 women and 4 men) and seven age- and sex-matched omnivores undertook a brain 1H-MRS exam at baseline and after beta-alanine supplementation. In study 2, nineteen trained male cyclists completed four 20-Km cycling time trials (two pre supplementation and two post supplementation), with a battery of cognitive function tests (Stroop test, Sternberg paradigm, Rapid Visual Information Processing task) being performed before and after exercise on each occasion. Results: In Study 1, there were no within-group effects of beta-alanine supplementation on brain homocarnosine/carnosine signal in either vegetarians (p = 0.99) or omnivores (p = 0.27); nor was there any effect when data from both groups were pooled (p = 0.19). Similarly, there was no group by time interaction for brain homocarnosine/carnosine signal (p = 0.27). In study 2, exercise improved cognitive function across all tests (P0.05) of beta-alanine supplementation on response times or accuracy for the Stroop test, Sternberg paradigm or RVIP task at rest or after exercise. Conclusion: 28 d of beta-alanine supplementation at 6.4g d-1 appeared not to influence brain homocarnosine/ carnosine signal in either omnivores or vegetarians; nor did it influence cognitive function before or after exercise in trained cyclists

Primary and malignant cholangiocytes undergo CD40 mediated Fas dependent Apoptosis, but are insensitive to direct activation with exogenous fas ligand

Introduction Cholangiocarcinoma is a rare malignancy of the biliary tract, the incidence of which is rising, but the pathogenesis of which remains uncertain. No common genetic defects have been described but it is accepted that chronic inflammation is an important contributing factor. We have shown that primary human cholangiocyte and hepatocyte survival is tightly regulated via co-operative interactions between two tumour necrosis family (TNF) receptor family members; CD40 and Fas (CD95). Functional deficiency of CD154, the ligand for CD40, leads to a failure of clearance of biliary tract infections and a predisposition to cholangiocarcinoma implying a direct link between TNF receptor-mediated apoptosis and the development of cholangiocarcinoma. Aims To determine whether malignant cholangiocytes display defects in CD40 mediated apoptosis. By comparing CD40 and Fas-mediated apoptosis and intracellular signalling in primary human cholangiocytes and three cholangiocyte cell lines. Results Primary cholangiocytes and cholangiocyte cell lines were relatively insensitive to direct Fas-mediated killing with exogenous FasL when compared with Jurkat cells, which readily underwent Fas-mediated apoptosis, but were extremely sensitive to CD154 stimulation. The sensitivity of cells to CD40 activation was similar in magnitude in both primary and malignant cells and was STAT-3 and AP-1 dependent in both. Conclusions 1) Both primary and malignant cholangiocytes are relatively resistant to Fas–mediated killing but show exquisite sensitivity to CD154, suggesting that the CD40 pathway is intact and fully functional in both primary and malignant cholangiocytes 2) The relative insensitivity of cholangiocytes to Fas activation demonstrates the importance of CD40 augmentation of Fas dependent death in these cells. Agonistic therapies which target CD40 and associated intracellular signalling pathways may be effective in promoting apoptosis of malignant cholangiocytes