The potential to narrow uncertainty in regional climate predictions

Faced by the realities of a changing climate, decision makers in a wide variety of organisations are increasingly seeking quantitative predictions of regional and local climate. An important issue for these decision makers, and for organisations that fund climate research, is what is the potential for climate science to deliver improvements - especially reductions in uncertainty - in such predictions? Uncertainty in climate predictions arises from three distinct sources: internal variability, model uncertainty and scenario uncertainty. Using data from a suite of climate models we separate and quantify these sources. For predictions of changes in surface air temperature on decadal timescales and regional spatial scales, we show that uncertainty for the next few decades is dominated by sources (model uncertainty and internal variability) that are potentially reducible through progress in climate science. Furthermore, we find that model uncertainty is of greater importance than internal variability. Our findings have implications for managing adaptation to a changing climate. Because the costs of adaptation are very large, and greater uncertainty about future climate is likely to be associated with more expensive adaptation, reducing uncertainty in climate predictions is potentially of enormous economic value. We highlight the need for much more work to compare: a) the cost of various degrees of adaptation, given current levels of uncertainty; and b) the cost of new investments in climate science to reduce current levels of uncertainty. Our study also highlights the importance of targeting climate science investments on the most promising opportunities to reduce prediction uncertainty.

Vesicular systems for delivering conventional small organic molecules and larger macromolecules to and through human skin

The history of using vesicular systems for drug delivery to and through skin started nearly three decades ago with a study utilizing phospholipid liposomes to improve skin deposition and reduce systemic effects of triamcinolone acetonide. Subsequently, many researchers evaluated liposomes with respect to skin delivery, with the majority of them recording localized effects and relatively few studies showing transdermal delivery effects. Shortly after this, Transfersomes were developed with claims about their ability to deliver their payload into and through the skin with efficiencies similar to subcutaneous administration. Since these vesicles are ultradeformable, they were thought to penetrate intact skin deep enough to reach the systemic circulation. Their mechanisms of action remain controversial with diverse processes being reported. Parallel to this development, other classes of vesicles were produced with ethanol being included into the vesicles to provide flexibility (as in ethosomes) and vesicles were constructed from surfactants and cholesterol (as in niosomes). Thee ultradeformable vesicles showed variable efficiency in delivering low molecular weight and macromolecular drugs. This article will critically evaluate vesicular systems for dermal and transdermal delivery of drugs considering both their efficacy and potential mechanisms of action.

Building synergies in development research: The application of the mosaic model to animal health research

Development research has responded to a number of charges over the past few decades. For example, when traditional research was accused of being 'top-down', the response was participatory research, linking the 'receptors' to the generators of research. As participatory processes were recognised as producing limited outcomes, the demand-led agenda was born. In response to the alleged failure of research to deliver its products, the 'joined-up' model, which links research with the private sector, has become popular. However, using examples from animal-health research, this article demonstrates that all the aforementioned approaches are seriously limited in their attempts to generate outputs to address the multi-faceted problems facing the poor. The article outlines a new approach to research: the Mosaic Model. By combining different knowledge forms, and focusing on existing gaps, the model aims to bridge basic and applied findings to enhance the efficiency and value of research, past, present, and future.

A Gentle/S approach to robot assisted neuro-rehabilitation

Movement disorders (MD) include a group of neurological disorders that involve neuromotor systems. MD can result in several abnormalities ranging from an inability to move, to severe constant and excessive movements. Strokes are a leading cause of disability affecting largely the older people worldwide. Traditional treatments rely on the use of physiotherapy that is partially based on theories and also heavily reliant on the therapists training and past experience. The lack of evidence to prove that one treatment is more effective than any other makes the rehabilitation of stroke patients a difficult task. UL motor re-learning and recovery levels tend to improve with intensive physiotherapy delivery. The need for conclusive evidence supporting one method over the other and the need to stimulate the stroke patient clearly suggest that traditional methods lack high motivational content, as well as objective standardised analytical methods for evaluating a patient's performance and assessment of therapy effectiveness. Despite all the advances in machine mediated therapies, there is still a need to improve therapy tools. This chapter describes a new approach to robot assisted neuro-rehabilitation for upper limb rehabilitation. Gentle/S introduces a new approach on the integration of appropriate haptic technologies to high quality virtual environments, so as to deliver challenging and meaningful therapies to people with upper limb impairment in consequence of a stroke. The described approach can enhance traditional therapy tools, provide therapy "on demand" and can present accurate objective measurements of a patient's progression. Our recent studies suggest the use of tele-presence and VR-based systems can potentially motivate patients to exercise for longer periods of time. Two identical prototypes have undergone extended clinical trials in the UK and Ireland with a cohort of 30 stroke subjects. From the lessons learnt with the Gentle/S approach, it is clear also that high quality therapy devices of this nature have a role in future delivery of stroke rehabilitation, and machine mediated therapies should be available to patient and his/her clinical team from initial hospital admission, through to long term placement in the patient's home following hospital discharge.

Anticoagulant resistance in Norway rats (Rattus norvegicus Berk.) in Kent - a VKORC1 single nucleotide polymorphism, tyrosine139phenylalanine, new to the UK

A sample of 10 Norway rats (Rattus norvegicus) was taken for DNA resistance testing from an agricultural site in Kent where applications of the anticoagulant rodenticide bromadiolone had been unsuccessful. All animals tested were homozygous for the single nucleotide VKORC1 polymorphism tyrosine139phenylalanine, or Y139F. This is a common resistance mutation found extensively in France and Belgium but not previously in the UK. Y139F confers a significant level of resistance to first-generation anticoagulants, such as chlorophacinone, and to the second-generation compound bromadiolone. Another compound widely used in the UK, difenacoum, is also thought to be partially resisted by rats which carry Y139F. A silent VKORC1 mutation was also found in all rats tested. The presence of a third important VKORC1 mutation which confers resistance to anticoagulant rodenticides in widespread use in the UK, the others being Y139C and L120Q, further threatens the ability of pest control practitioners to deliver effective rodent control.

Predicting microbial pollution concentrations in UK rivers in response to land use change

The Water Framework Directive has caused a paradigm shift towards the integrated management of recreational water quality through the development of drainage basin-wide programmes of measures. This has increased the need for a cost-effective diagnostic tool capable of accurately predicting riverine faecal indicator organism (FIO) concentrations. This paper outlines the application of models developed to fulfil this need, which represent the first transferrable generic FIO models to be developed for the UK to incorporate direct measures of key FIO sources (namely human and livestock population data) as predictor variables. We apply a recently developed transfer methodology, which enables the quantification of geometric mean presumptive faecal coliforms and presumptive intestinal enterococci concentrations for base- and high-flow during the summer bathing season in unmonitored UK watercourses, to predict FIO concentrations in the Humber river basin district. Because the FIO models incorporate explanatory variables which allow the effects of policy measures which influence livestock stocking rates to be assessed, we carry out empirical analysis of the differential effects of seven land use management and policy instruments (fiscal constraint, production constraint, cost intervention, area intervention, demand-side constraint, input constraint, and micro-level land use management) all of which can be used to reduce riverine FIO concentrations. This research provides insights into FIO source apportionment, explores a selection of pollution remediation strategies and the spatial differentiation of land use policies which could be implemented to deliver river quality improvements. All of the policy tools we model reduce FIO concentrations in rivers but our research suggests that the installation of streamside fencing in intensive milk producing areas may be the single most effective land management strategy to reduce riverine microbial pollution.

Evidence-based psychological therapies: from bench to bedside

Patients with mental health difficulties do not always receive appropriate and recommended psychological treatment for their difficulties, and clinicians are not always appropriately trained to deliver them. This paper considers why this might be the case and provides an overview of the Charlie Waller Institute, a not-for-profit organisation funded by the NHS, University of Reading, and the Charlie Waller Memorial Trust. The Institute seeks to address this problem by training clinicians in wide variety of evidence-based therapies and assessing the impact of this training on clinician knowledge and skill.

A nipple shield delivery system for oral drug delivery to breastfeeding infants : Microbicide delivery to inactivate HIV

A new drug delivery method for infants is presented which incorporates an active pharmaceutical ingredient (API)-loaded insert into a nipple shield delivery system (NSDS). The API is released directly into milk during breastfeeding. This study investigates the feasibility of using the NSDS to deliver the microbicide sodium dodecyl sulfate (SDS), with the goal of preventing mother-to-child transmission (MTCT) of HIV during breastfeeding in low-resource settings, when there is no safer alternative for the infant but to breastfeed. SDS has been previously shown to effectively inactivate HIV in human milk. An apparatus was developed to simulate milk flow through and drug release from a NSDS. Using this apparatus milk was pulsed through a prototype device containing a non-woven fiber insert impregnated with SDS and the microbicide was rapidly released. The total SDS release from inserts ranged from 70 to 100% of the average 0.07 g load within 50 ml (the volume of a typical breastfeed). Human milk spiked with H9/HIVIIIB cells was also passed through the same set-up. Greater than 99% reduction of cell-associated HIV infectivity was achieved in the first 10 ml of milk. This proof of concept study demonstrates efficient drug delivery to breastfeeding infants is achievable using the NSDS.

A socio-technical network approach to the adoption of low and zero carbon technologies in new housing

Housing in the UK accounts for 30.5% of all energy consumed and is responsible for 25% of all carbon emissions. The UK Government’s Code for Sustainable Homes requires all new homes to be zero carbon by 2016. The development and widespread diffusion of low and zero carbon (LZC) technologies is recognised as being a key solution for housing developers to deliver against this zero-carbon agenda. The innovation challenge to design and incorporate these technologies into housing developers’ standard design and production templates will usher in significant technical and commercial risks. In this paper we report early results from an ongoing Engineering and Physical Sciences Research Council project looking at the innovation logic and trajectory of LZC technologies in new housing. The principal theoretical lens for the research is the socio-technical network approach which considers actors’ interests and interpretative flexibilities of technologies and how they negotiate and reproduce ‘acting spaces’ to shape, in this case, the selection and adoption of LZC technologies. The initial findings are revealing the form and operation of the technology networks around new housing developments as being very complex, involving a range of actors and viewpoints that vary for each housing development.

A niche-based framework to assess current monitoring of European forest birds and guide indicator species' selection

Concern that European forest biodiversity is depleted and declining has provoked widespread efforts to improve management practices. To gauge the success of these actions, appropriate monitoring of forest ecosystems is paramount. Multi-species indicators are frequently used to assess the state of biodiversity and its response to implemented management, but generally applicable and objective methodologies for species' selection are lacking. Here we use a niche-based approach, underpinned by coarse quantification of species' resource use, to objectively select species for inclusion in a pan-European forest bird indicator. We identify both the minimum number of species required to deliver full resource coverage and the most sensitive species' combination, and explore the trade-off between two key characteristics, sensitivity and redundancy, associated with indicators comprising different numbers of species. We compare our indicator to an existing forest bird indicator selected on the basis of expert opinion and show it is more representative of the wider community. We also present alternative indicators for regional and forest type specific monitoring and show that species' choice can have a significant impact on the indicator and consequent projections about the state of the biodiversity it represents. Furthermore, by comparing indicator sets drawn from currently monitored species and the full forest bird community, we identify gaps in the coverage of the current monitoring scheme. We believe that adopting this niche-based framework for species' selection supports the objective development of multi-species indicators and that it has good potential to be extended to a range of habitats and taxa.

Effects of targeted delivery of propionate to the human colon on appetite regulation, body weight maintenance and adiposity in overweight adults

Objective The colonic microbiota ferment dietary fibres, producing short chain fatty acids. Recent evidence suggests that the short chain fatty acid propionate may play an important role in appetite regulation. We hypothesised that colonic delivery of propionate would increase peptide YY (PYY) and glucagon like peptide-1 (GLP-1) secretion in humans, and reduce energy intake and weight gain in overweight adults. Design To investigate whether propionate promotes PYY and GLP-1 secretion, a primary cultured human colonic cell model was developed. To deliver propionate specifically to the colon, we developed a novel inulin-propionate ester. An acute randomised, controlled cross-over study was used to assess the effects of this inulin-propionate ester on energy intake and plasma PYY and GLP-1 concentrations. The long-term effects of inulin-propionate ester on weight gain were subsequently assessed in a randomised, controlled 24-week study involving 60 overweight adults. Results Propionate significantly stimulated the release of PYY and GLP-1 from human colonic cells. Acute ingestion of 10 g inulin-propionate ester significantly increased postprandial plasma PYY and GLP-1 and reduced energy intake. Over 24 weeks, 10 g/day inulin-propionate ester supplementation significantly reduced weight gain, intra-abdominal adipose tissue distribution, intrahepatocellular lipid content and prevented the deterioration in insulin sensitivity observed in the inulin-control group. Conclusions These data demonstrate for the first time that increasing colonic propionate prevents weight gain in overweight adult humans

Challenges in quantifying wind generation's contribution to securing peak demand

Wind generation's contribution to supporting peak electricity demand is one of the key questions in wind integration studies. Differently from conventional units, the available outputs of different wind farms cannot be approximated as being statistically independent, and hence near-zero wind output is possible across an entire power system. This paper will review the risk model structures currently used to assess wind's capacity value, along with discussion of the resulting data requirements. A central theme is the benefits from performing statistical estimation of the joint distribution for demand and available wind capacity, focusing attention on uncertainties due to limited histories of wind and demand data; examination of Great Britain data from the last 25 years shows that the data requirements are greater than generally thought. A discussion is therefore presented into how analysis of the types of weather system which have historically driven extreme electricity demands can help to deliver robust insights into wind's contribution to supporting demand, even in the face of such data limitations. The role of the form of the probability distribution for available conventional capacity in driving wind capacity credit results is also discussed.

Functionalization of dendrimers for improved gene delivery to mesenchymal stem cell

Disease, injury, and age problems compromise human quality of life and continuously motivate the search for new and more efficacious therapeutic approaches. The field of Tissue Regeneration and Engineering has greatly evolved over the last years, mainly due to the combination of the important advances verified in Biomaterials Science and Engineering with those of Cell and Molecular Biology. In particular, a new and promising area arose – Nanomedicine – that takes advantage of the extremely small size and especial chemical and physical properties of Nanomaterials, offering powerful tools for health improvement. Research on Stem Cells, the self-renewing progenitors of body tissues, is also challenging to the medical and scientific communities, being expectable the appearance of new and exciting stem cell-based therapies in the next years. The control of cell behavior (namely, of cell proliferation and differentiation) is of key importance in devising strategies for Tissue Regeneration and Engineering. Cytokines, growth factors, transcription factors and other signaling molecules, most of them proteins, have been identified and found to regulate and support tissue development and regeneration. However, the application of these molecules in long-term regenerative processes requires their continuous presence at high concentrations as they usually present short half-lives at physiological conditions and may be rapidly cleared from the body. Alternatively, genes encoding such proteins can be introduced inside cells and be expressed using cell’s machinery, allowing an extended and more sustained production of the protein of interest (gene therapy). Genetic engineering of stem cells is particularly attractive because of their self-renewal capability and differentiation potential. For Tissue Regeneration and Engineering purposes, the patient’s own stem cells can be genetically engineered in vitro and, after, introduced in the body (with or without a scaffold) where they will not only modulate the behavior of native cells (stem cell-mediated gene therapy), but also directly participate in tissue repair. Cells can be genetically engineered using viral and non-viral systems. Viruses, as a result of millions of years of evolution, are very effective for the delivery of genes in several types of cells, including cells from primary sources. However, the risks associated with their use (like infection and immunogenic reactions) are driving the search for non-viral systems that will efficiently deliver genetic material into cells. Among them, chemical methods that are promising and being investigated use cationic molecules as carriers for DNA. In this case, gene delivery and gene expression level remain relatively low when primary cells are used. The main goal of this thesis was to develop and assess the in vitro potential of polyamidoamine (PAMAM) dendrimers based carriers to deliver genes to mesenchymal stem cells (MSCs). PAMAM dendrimers are monodispersive, hyperbranched and nanospherical molecules presenting unique characteristics that make them very attractive vehicles for both drug and gene delivery. Although they have been explored for gene delivery in a wide range of cell lines, the interaction and the usefulness of these molecules in the delivery of genes to MSCs remains a field to be explored. Adult MSCs were chosen for the studies due to their potential biomedical applications (they are considered multipotent cells) and because they present several advantages over embryonic stem cells, such as easy accessibility and the inexistence of ethical restrictions to their use. This thesis is divided in 5 interconnected chapters. Chapter I provides an overview of the current literature concerning the various non-viral systems investigated for gene delivery in MSCs. Attention is devoted to physical methods, as well as to chemical methods that make use of polymers (natural and synthetic), liposomes, and inorganic nanoparticles as gene delivery vectors. Also, it summarizes the current applications of genetically engineered mesenchymal stem cells using non-viral systems in regenerative medicine, with special focus on bone tissue regeneration. In Chapter II, the potential of native PAMAM dendrimers with amine termini to transfect MSCs is evaluated. The level of transfection achieved with the dendrimers is, in a first step, studied using a plasmid DNA (pDNA) encoding for the β-galactosidase reporter gene. The effect of dendrimer’s generation, cell passage number, and N:P ratio (where N= number of primary amines in the dendrimer; P= number of phosphate groups in the pDNA backbone) on the level of transfection is evaluated, being the values always very low. In a second step, a pDNA encoding for bone morphogenetic protein-2, a protein that is known for its role in MSCs proliferation and differentiation, is used. The BMP-2 content produced by transfected cells is evaluated by an ELISA assay and its effect on the osteogenic markers is analyzed through several classical assays including alkaline phosphatase activity (an early marker of osteogenesis), osteocalcin production, calcium deposition and mineralized nodules formation (late osteogenesis markers). Results show that a low transfection level is enough to induce in vitro osteogenic differentiation in MSCs. Next, from Chapter III to Chapter V, studies are shown where several strategies are adopted to change the interaction of PAMAM dendrimers with MSCs cell membrane and, as a consequence, to enhance the levels of gene delivery. In Chapter III, generations 5 and 6 of PAMAM dendrimers are surface functionalized with arginine-glycine-aspartic acid (RGD) containing peptides – experiments with dendrimers conjugated to 4, 8 and 16 RGD units were performed. The underlying concept is that by including the RGD integrin-binding motif in the design of the vectors and by forming RGD clusters, the level of transfection will increase as MSCs highly express integrins at their surface. Results show that cellular uptake of functionalized dendrimers and gene expression is enhanced in comparison with the native dendrimers. Furthermore, gene expression is dependent on both the electrostatic interaction established between the dendrimer moiety and the cell surface and the nanocluster RGD density. In Chapter IV, a new family of gene delivery vectors is synthesized consisting of a PAMAM dendrimer (generation 5) core randomly linked at the periphery to alkyl hydrophobic chains that vary in length and number. Herein, the idea is to take advantage of both the cationic nature of the dendrimer and the capacity of lipids to interact with biological membranes. These new vectors show a remarkable capacity for internalizing pDNA, being this effect positively correlated with the –CH2– content present in the hydrophobic corona. Gene expression is also greatly enhanced using the new vectors but, in this case, the higher efficiency is shown by the vectors containing the smallest hydrophobic chains. Finally, chapter V reports the synthesis, characterization and evaluation of novel gene delivery vectors based on PAMAM dendrimers (generation 5) conjugated to peptides with high affinity for MSCs membrane binding - for comparison, experiments are also done with a peptide with low affinity binding properties. These systems present low cytotoxicity and transfection efficiencies superior to those of native dendrimers and partially degraded dendrimers (Superfect®, a commercial product). Furthermore, with this biomimetic approach, the process of gene delivery is shown to be cell surface receptor-mediated. Overall, results show the potential of PAMAM dendrimers to be used, as such or modified, in Tissue Regeneration and Engineering. To our knowledge, this is the first time that PAMAM dendrimers are studied as gene delivery vehicles in this context and using, as target, a cell type with clinical relevancy. It is shown that the cationic nature of PAMAM dendrimers with amine termini can be synergistically combined with surface engineering approaches, which will ultimately result in suitable interactions with the cytoplasmic membrane and enhanced pDNA cellular entry and gene expression. Nevertheless, the quantity of pDNA detected inside cell nucleus is always very small when compared with the bigger amount reaching cytoplasm (accumulation of pDNA is evident in the perinuclear region), suggesting that the main barrier to transfection is the nuclear membrane. Future work can then be envisaged based on the versatility of these systems as biomedical molecular materials, such as the conjugation of PAMAM dendrimers to molecules able to bind nuclear membrane receptors and to promote nuclear translocation.

Strategies to promote farm animal welfare in Latin America and their effects on carcass and meat quality traits

Several initiatives, including research and development, increasing stakeholders' awareness and application of legislation and recommendation, have been carried out in Latin America to promote animal welfare and meat quality. Most activities focused on the impact of pre-slaughter conditions (facilities, equipment and handling procedures) on animal welfare and meat quality. The results are encouraging; data from Brazil, Chile and Uruguay showed that the application of the improved pre-slaughter handling practices reduced aggressive handling and the incidence of bruised carcasses at slaughter in cattle and pigs. These outcomes stimulated some to apply animal welfare concepts in livestock handling within the meat production chain as shown by the increasing demand for personnel training on the best. To attend this demand is important to expand local studies on farm animal welfare and to set up (or maintain) an efficient system for knowledge transfer to all stakeholders in the Latin America meat production chains. However, it is clear that to promote the long-term progress in this field is important to deliver practical solutions, assuring that they match the technical and financial conditions of those who are the target of training programs. (C) 2012 Elsevier Ltd. All rights reserved.

Pathogenesis II: Fungal responses to host responses: interaction of host cells with fungi

Most of our knowledge concerning the virulence determinants of pathogenic fungi comes from the infected host, mainly from animal models and more recently from in vitro studies with cell cultures. The fungi usually present intra- and/or extracellular host-parasite interfaces, with the parasitism phenomenon dependent on complementary surface molecules. Among living organisms, this has been characterized as a cohabitation event, where the fungus is able to recognize specific host tissues acting as an attractant, creating stable conditions for its survival. Several fungi pathogenic for humans and animals have evolved special strategies to deliver elements to their cellular targets that may be relevant to their pathogenicity. Most of these pathogens express surface factors that mediate binding to host cells either directly or indirectly, in the latter case binding to host adhesion components such as extracellular matrix (ECM) proteins, which act as 'interlinking' molecules. The entry of the pathogen into the host cell is initiated by fungal adherence to the cell surface, which generates an uptake signal that may induce its cytoplasmic internalization. Once this is accomplished, some fungi are able to alter the host cytoskeletal architecture, as manifested by a rearrangement of microtubule and microfilament proteins, and this can also induce epithelial host cells to become apoptotic. It is possible that fungal pathogens induce modulation of different host cell pathways in order to evade host defences and to foster their own proliferation. For a number of pathogens, the ability to bind ECM glycoproteins, the capability of internalization and the induction of apoptosis are considered important factors in virulence. Furthermore, specific recognition between fungal parasites and their host cell targets may be mediated by the interaction of carbohydrate-binding proteins, e.g., lectins on the surface of one type of cell, probably a parasite, that combine with complementary sugars on the surface of host-cell. These interactions supply precise models to study putative adhesins and receptor-containing molecules in the context of the fungus-host interface. The recognition of the host molecules by fungi such as Aspergillus fumigatus, Paracoccidioides brasiliensis and Histoplasma capsulatum, and their molecular mechanisms of adhesion and invasion, are reviewed in this paper.