Size effects on the magnetoelectric response on PVDF/Vitrovac 4040 laminate composites

Tri-layered and bi-layered magnetoelectric (ME) flexible composite structures of varying geometries and sizes consisting on magnetostrictive Vitrovac and piezoelectric poly(vinylidene fluoride) (PVDF) layers were fabricated by direct bonding. From the ME measurements it was determined that tri-layered composites structures (magnetostrictive-piezoelectric-magnetostrictive type), show a higher ME response (75 V.cm-1.Oe-1) than the bi-layer structure (66 V.cm 1.Oe-1). The ME voltage coefficient decreased with increasing longitudinal size aspect ratio between PVDF and Vitrovac layers (from 1.1 to 4.3), being observed a maximum ME voltage coefficient of 66 V.cm-1.Oe-1. It was also observed that the composite with the lowest transversal aspect ratio between PVDF and Vitrovac layers resulted in better ME performance than the structures with higher transversal size aspect ratios. It was further determined an intimate relation between the Vitrovac PVDF Area Area ratio and the ME response of the composites. When such ratio values approach 1, the ME response is the largest. Additionally the ME output value and magnetic field response was controlled by changing the number of Vitrovac layers, which allows the development of magnetic sensors and energy harvesting devices.

Study of grapevine solute transporters involved in berry quality. A biochemical and molecular approach

Tese de Doutoramento em Biologia de Plantas

Inactivation of PNKP by mutant ATXN3 triggers apoptosis by activating the DNA damage-response pathway in SCA3.

Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD), is an untreatable autosomal dominant neurodegenerative disease, and the most common such inherited ataxia worldwide. The mutation in SCA3 is the expansion of a polymorphic CAG tri-nucleotide repeat sequence in the C-terminal coding region of the ATXN3 gene at chromosomal locus 14q32.1. The mutant ATXN3 protein encoding expanded glutamine (polyQ) sequences interacts with multiple proteins in vivo, and is deposited as aggregates in the SCA3 brain. A large body of literature suggests that the loss of function of the native ATNX3-interacting proteins that are deposited in the polyQ aggregates contributes to cellular toxicity, systemic neurodegeneration and the pathogenic mechanism in SCA3. Nonetheless, a significant understanding of the disease etiology of SCA3, the molecular mechanism by which the polyQ expansions in the mutant ATXN3 induce neurodegeneration in SCA3 has remained elusive. In the present study, we show that the essential DNA strand break repair enzyme PNKP (polynucleotide kinase 3'-phosphatase) interacts with, and is inactivated by, the mutant ATXN3, resulting in inefficient DNA repair, persistent accumulation of DNA damage/strand breaks, and subsequent chronic activation of the DNA damage-response ataxia telangiectasia-mutated (ATM) signaling pathway in SCA3. We report that persistent accumulation of DNA damage/strand breaks and chronic activation of the serine/threonine kinase ATM and the downstream p53 and protein kinase C-d pro-apoptotic pathways trigger neuronal dysfunction and eventually neuronal death in SCA3. Either PNKP overexpression or pharmacological inhibition of ATM dramatically blocked mutant ATXN3-mediated cell death. Discovery of the mechanism by which mutant ATXN3 induces DNA damage and amplifies the pro-death signaling pathways provides a molecular basis for neurodegeneration due to PNKP inactivation in SCA3, and for the first time offers a possible approach to treatment.

HOXA9 as a key regulator in glioma initiation, aggressiveness and response to therapy

Tese de Doutoramento em Ciências da Saúde

Orientation of the snail Biomphalaria straminea (Dunker, 1848) in response to light in a situation of selection

The behavioral response of Biomphalaria straminea to light was evaluted in terms of location of the snail in a Y-shaped aquarium in a situation of selection and of the rate (cm/hour) and direction of locomotion under homogeneous 9vertical) or differential (horizontal) lighting upon only one arm of the aquarium. The light source consisted of daylight fluorescent lamps with a spectrum close to that of natural light, with illumination varying from 28 to 350 lux. Analysis of the data showed that all animals, whether in groups or isolated, were attracted to light, although the time needed to approach the light source was 50% shorter for the former than for the latter. The rate of locomotion of B. straminea was 35% higher than observed in B. glabrata and 51% higher than that observed in B. tenagophila studied under similar conditions. The results are discussed in terms of social factors and geographical distribution of the three species.

A computable general equilibrium analysis of the relative price sensitivity required to induce rebound effects in response to an improvement in energy efficiency in the UK economy

In recent years there has been extensive debate in the energy economics and policy literature on the likely impacts of improvements in energy efficiency. This debate has focussed on the notion of rebound effects. Rebound effects occur when improvements in energy efficiency actually stimulate the direct and indirect demand for energy in production and/or consumption. This phenomenon occurs through the impact of the increased efficiency on the effective, or implicit, price of energy. If demand is stimulated in this way, the anticipated reduction in energy use, and the consequent environmental benefits, will be partially or possibly even more than wholly (in the case of ‘backfire’ effects) offset. A recent report published by the UK House of Lords identifies rebound effects as a plausible explanation as to why recent improvements in energy efficiency in the UK have not translated to reductions in energy demand at the macroeconomic level, but calls for empirical investigation of the factors that govern the extent of such effects. Undoubtedly the single most important conclusion of recent analysis in the UK, led by the UK Energy Research Centre (UKERC) is that the extent of rebound and backfire effects is always and everywhere an empirical issue. It is simply not possible to determine the degree of rebound and backfire from theoretical considerations alone, notwithstanding the claims of some contributors to the debate. In particular, theoretical analysis cannot rule out backfire. Nor, strictly, can theoretical considerations alone rule out the other limiting case, of zero rebound, that a narrow engineering approach would imply. In this paper we use a computable general equilibrium (CGE) framework to investigate the conditions under which rebound effects may occur in the Scottish regional and UK national economies. Previous work has suggested that rebound effects will occur even where key elasticities of substitution in production are set close to zero. Here, we carry out a systematic sensitivity analysis, where we gradually introduce relative price sensitivity into the system, focusing in particular on elasticities of substitution in production and trade parameters, in order to determine conditions under which rebound effects become a likely outcome. We find that, while there is positive pressure for rebound effects even where (direct and indirect) demand for energy is very price inelastic, this may be partially or wholly offset by negative income and disinvestment effects, which also occur in response to falling energy prices.

Detecting epistasis with restricted response patterns in pairs of biallelic loci.

Well-established examples of genetic epistasis between a pair of loci typically show characteristic patterns of phenotypic distributions in joint genotype tables. However, inferring epistasis given such data is difficult due to the lack of power in commonly used approaches, which decompose the epistatic patterns into main plus interaction effects followed by testing the interaction term. Testing additive-only or all terms may have more power, but they are sensitive to nonepistatic patterns. Alternatively, the epistatic patterns of interest can be enumerated and the best matching one is found by searching through the possibilities. Although this approach requires multiple testing correction over possible patterns, each pattern can be fitted with a regression model with just one degree of freedom and thus the overall power can still be high, if the number of possible patterns is limited. Here we compare the power of the linear decomposition and pattern search methods, by applying them to simulated data generated under several patterns of joint genotype effects with simple biological interpretations. Interaction-only tests are the least powerful; while pattern search approach is the most powerful if the range of possibilities is restricted, but still includes the true pattern.

The Role of model uncertainty and learning in the U.S. postwar policy response to oil prices

This paper studies optimal monetary policy in a framework that explicitly accounts for policymakers' uncertainty about the channels of transmission of oil prices into the economy. More specfically, I examine the robust response to the real price of oil that US monetary authorities would have been recommended to implement in the period 1970 2009; had they used the approach proposed by Cogley and Sargent (2005b) to incorporate model uncertainty and learning into policy decisions. In this context, I investigate the extent to which regulator' changing beliefs over different models of the economy play a role in the policy selection process. The main conclusion of this work is that, in the specific environment under analysis, one of the underlying models dominates the optimal interest rate response to oil prices. This result persists even when alternative assumptions on the model's priors change the pattern of the relative posterior probabilities, and can thus be attributed to the presence of model uncertainty itself.

Probability of achieving optimal molecular response to imatinib in chronic myeloid leukemia (CML) patients: Pharmacokinetic/Pharmacodynamic (PK/PD) relationships observed under field-conditions

Objectives: Imatinib has been increasingly proposed for therapeutic drug monitoring (TDM), as trough concentrations (Cmin) correlate with response rates in CML patients. This analysis aimed to evaluate the impact of imatinib exposure on optimal molecular response rates in a large European cohort of patients followed by centralized TDM.¦Methods: Sequential PK/PD analysis was performed in NONMEM 7 on 2230 plasma (PK) samples obtained along with molecular response (PD) data from 1299 CML patients. Model-based individual Bayesian estimates of exposure, parameterized as to initial dose adjusted and log-normalized Cmin (log-Cmin) or clearance (CL), were investigated as potential predictors of optimal molecular response, while accounting for time under treatment (stratified at 3 years), gender, CML phase, age, potentially interacting comedication, and TDM frequency. PK/PD analysis used mixed-effect logistic regression (iterative two-stage method) to account for intra-patient correlation.¦Results: In univariate analyses, CL, log-Cmin, time under treatment, TDM frequency, gender (all p<0.01) and CML phase (p=0.02) were significant predictors of the outcome. In multivariate analyses, all but log-Cmin remained significant (p<0.05). Our model estimates a 54.1% probability of optimal molecular response in a female patient with a median CL of 14.4 L/h, increasing by 4.7% with a 35% decrease in CL (percentile 10 of CL distribution), and decreasing by 6% with a 45% increased CL (percentile 90), respectively. Male patients were less likely than female to be in optimal response (odds ratio: 0.62, p<0.001), with an estimated probability of 42.3%.¦Conclusions: Beyond CML phase and time on treatment, expectedly correlated to the outcome, an effect of initial imatinib exposure on the probability of achieving optimal molecular response was confirmed in field-conditions by this multivariate analysis. Interestingly, male patients had a higher risk of suboptimal response, which might not exclusively derive from their 18.5% higher CL, but also from reported lower adherence to the treatment. A prospective longitudinal study would be desirable to confirm the clinical importance of identified covariates and to exclude biases possibly affecting this observational survey.

Population pharmacokinetics and clinical response for artemether-lumefantrine in pregnant and nonpregnant women with uncomplicated Plasmodium falciparum malaria in Tanzania.

Artemether-lumefantrine (AL) is the first-line treatment for uncomplicated malaria in the second and third trimesters of pregnancy. Its efficacy during pregnancy has recently been challenged due to altered pharmacokinetic (PK) properties in this vulnerable group. The aim of this study was to determine the PK profile of AL in pregnant and nonpregnant women and assess their therapeutic outcome. Thirty-three pregnant women and 22 nonpregnant women with malaria were treated with AL (80/480 mg) twice daily for 3 days. All patients provided five venous plasma samples for drug quantification at random times over 7 days. Inter- and intraindividual variability was assessed, and the effects of covariates were quantified using a nonlinear mixed-effects modeling approach (NONMEM). A one-compartment model with first-order absorption and elimination with linear metabolism from drug to metabolite fitted the data best for both arthemether (AM) and lumefantrine (LF) and their metabolites. Pregnancy status and diarrhea showed a significant influence on LF PK. The relative bioavailability of lumefantrine and its metabolism rate into desmethyl-lumefantrine were, respectively, 34% lower and 78% higher in pregnant women than in nonpregnant patients. The overall PCR-uncorrected treatment failure rates were 18% in pregnant women and 5% in nonpregnant women (odds ratio [OR] = 4.04; P value of 0.22). A high median day 7 lumefantrine concentration was significantly associated with adequate clinical and parasitological response (P = 0.03). The observed reduction in the relative bioavailability of lumefantrine in pregnant women may explain the higher treatment failure in this group, mostly due to lower posttreatment prophylaxis. Hence, a modified treatment regimen of malaria in pregnancy should be considered.

IPH Submission to Department of the Environment, Heritage and Local Government Climate Change Response Bill 2010

The main purpose of the Clmate Change Bill is to provide for the adoption of a national policy for reducing greenhouse gas (GHG) emissions; to support this through the making of mitigation and adaptation action plans; and to make provision for emission reduction targets to support the objective of transition to a low carbon, climate resilient and environmentally sustainable economy.The remit of the Institute of Public Health in Ireland (IPH) is to promote cooperation for public health between Northern Ireland and the Republic of Ireland in the areas of research and information, capacity building and policy advice. Our approach is to support Departments of Health and their agencies in both jurisdictions, and maximise the benefits of all-island cooperation to achieve practical benefits for people in Northern Ireland and the Republic of Ireland.IPH has a keen interest in the effects of climate change on health. In September 2010 the IPH published a paper – Climate Change and Health: A platform for action - to inform policy-makers and the public about the health benefits in reducing greenhouse gas emissions. This paper followed a seminar with international speakers, opened by Minister Gormley, on the same topic in February 2010. 

IPH response to Department of the Environment, Heritage and Local Government and the Department for Regional Development Spatial Strategies

The remit of the Institute of Public Health in Ireland (IPH) is to promote cooperation for public health between Northern Ireland and the Republic of Ireland in the areas of research and information, capacity building and policy advice. Our approach is to support Departments of Health and their agencies in both jurisdictions, and maximise the benefits of all-island cooperation to achieve practical benefits for people in Northern Ireland and the Republic of Ireland. As an all-island body, the Institute of Public Health in Ireland particularly welcomes that the Framework for Collaboration has been co-produced by the Department for Regional Development and the Department of the Environment, Heritage and Local Government. In addition the Institute of Public Health welcomes a more holistic approach to spatial planning that takes into account the environment and sustainable economic development. A clean environment and a more equitable distribution of prosperity have associated health benefits, as outlined in the IPH’s Active travel – healthy lives (2011) and Health impacts of the built environment- a review (2006).

IPH response to the National Transport Authority on the Greater Dublin Area Draft Transport Strategy 2011-2030

The remit of the Institute of Public Health in Ireland (IPH) is to promote cooperation for public health between Northern Ireland and the Republic of Ireland in the areas of research and information, capacity building and policy advice. Our approach is to support Departments of Health and their agencies in both jurisdictions, and maximise the benefits of all-island cooperation to achieve practical benefits for people in Northern Ireland and the Republic of Ireland.IPH has a keen interest in the interactions between transport and health. IPH has produced two papers in the recent past on this topic, the most recent being Active travel – healthy lives published in January 2011 which built on the 2005 publication Health impacts of transport. The IPH welcomes the draft transport strategy in terms of addressing each of the key messages outlined in the Active travel – healthy lives paper.IPH is interested in this area not only in terms of increasing ‘active travel’ for healthier lives, but also in terms of the environmental and social impacts of inequitable access to forms of private and public transport.

IPH response to DSD Urban Regeneration and Community Development Policy Framework Consultation

The Urban Regeneration and Community Development Policy Framework for Northern Ireland sets out for DSD and its partners, clear priorities for urban regeneration and community development programmes, both before and after the operational responsibility for these is transferred to councils under the reform of local government. Four policy objectives have been developed, which will focus on the underlying structural problems in urban areas and also help strengthen community development throughout Northern Ireland. The policy objectives are as follows: Policy Objective 1 – To tackle area-based deprivation: Policy Objective 2 – To strengthen the competitiveness of our towns and cities: Policy Objective 3 – To improve linkages between areas of need and areas of opportunity: and Policy Objective 4 –To develop more cohesive and engaged communities. Key points from IPH response Urban regeneration and community development provide a basis for addressing the social determinants of health and reducing inequalities in health. This policy framework presents an opportunity for coherence and complementarity with ‘Fit and Well - Changing Lives’ as part of government’s overall approach to tackling health inequalities. It is now well established that a focus on early years’ interventions and family support services yields significant returns, so prioritising action in these areas is essential. Defined action plans on child poverty are essential if this policy framework is to make a real and lasting difference in deprived urban areas. Development of the environmental infrastructure to improve health in deprived areas should be supported by well-planned monitoring and evaluation. Linking the policy framework to economic development and local community plans will enhance effectiveness in the areas of education, job creation, commercial investment and access to services, which in turn are critical for the economic growth and stability of urban communities. Community profile data and health intelligence (as available through IPH Health Well) could usefully inform central and local government in terms of resource allocation and targeted service delivery.

IPH response to Department of Health (ROI) consultation on National Strategy on Dementia

The current prevalence of dementia and its associated economic and social burden presents a challenge for the configuration of dementia care services at present and it is clear that this challenge will become ever more urgent as a consequence of population ageing. IPH supports the development of a Dementia Strategy in Ireland that is comprehensive and holistic. We recommend that the strategy encompasses aspects of prevention as well as optimal management at all stages of the disease. IPH considers that a social determinants of health approach that focuses on the prevention of disease and disability could form an important strand of the strategy. Key points from IPH response IPH would emphasise the following key priorities for inclusion in the Dementia Strategy.   Adoption of a public health approach as set out by WHO (2011) and the development of an implementation plan and structures to support the Strategy A commitment to primary, secondary and tertiary prevention of dementia.  Resourcing of a programme of research to support primary, secondary and tertiary prevention of dementia to ensure a systematic approach to generate an evidence-base and disseminate pertinent findings in the Irish context. Emphasis should be placed on high quality research specifically to:enhance information systems on dementia at a national level A life course approach to tackle the social determinants of dementia and ill-health in later life. Supporting carers for people with dementia