Retreating to nature : rethinking 'therapeutic landscapes'

There is a long history of removing oneself from ‘society’ in order to recuperate or repair. This paper considers a yoga and massage retreat in Southern Spain, and what opportunities this retreat experience might offer for recuperation and the creation of healthy bodies. The paper positions ‘nature’ as an active participant, and as ‘enrolled’ in the experiences of the retreat as a ‘therapeutic landscape’, and questions how and what particular aspects of yoga practice (in intimate relation with place) give rise to therapeutic experiences

Catechol-O-methyltransferase gene val158met polymorphism and depressive symptoms during early childhood

Catechol-O-Methyltransferase (COMT) is a critical regulator of catecholamine levels in the brain. A functional polymorphism of the COMT gene, val158met, has been linked to internalizing symptoms (i.e., depression and anxiety) in adolescents and adults. We extended this research by investigating whether the val158met polymorphism was associated with childhood symptoms of depression and anxiety in two independent samples of young children (Ns=476 and 409). In both samples, preschool-aged children were genotyped for the COMT val158met polymorphism. Symptoms of psychopathology were assessed via parent interviews and primary caregiver reports. In both samples, children homozygous for the val allele had higher levels of depressive symptoms compared to children with at least one copy of the met allele. Our findings extend previous research in older participants by showing links between the COMT val158met polymorphism and internalizing symptoms in early childhood. © 2013 Wiley Periodicals, Inc

Targeted adenovirus-mediated transduction of human T cells in vitro and in vivo

Clinical success in T cell therapy has stimulated widespread efforts to increase safety and potency and to extend this technology to solid tumors. Yet progress in cell therapy remains restricted by the limited payload capacity, specificity of target cell transduction, and transgenic gene expression efficiency of applied viral vectors. This renders complex reprogramming or direct in vivo applications difficult. Here, we developed a synergistic combination of trimeric adapter constructs enabling T cell-directed transduction by the human adenoviral vector serotype C5 in vitro and in vivo. Rationally chosen binding partners showed receptor-specific transduction of otherwise non-susceptible human T cells by exploiting activation stimuli. This platform remains compatible with high-capacity vectors for up to 37 kb DNA delivery, increasing payload capacity and safety because of the removal of all viral genes. Together, these findings provide a tool for targeted delivery of large payloads in T cells as a potential avenue to overcome current limitations of T cell therapy

Forage Systems to Optimize Agronomic and Economic Performance in Organic Dairy Systems

Organic dairy production in the USA is growing, but most forage systems research focuses on conventional production practices. As a result, organic dairy producers have limited science-based information to assist with farm and livestock management. The objective of this project was to use a multi-faceted approach to determine the ideal species mixtures for organic dairy production as well as document forage quality, forage yield, soil characteristics, milk production and milk quality during the grazing season. The forages studied ranged from a single species monoculture to a four species mixture of warm and cool season grasses and legumes. Nine distinct forage systems were seeded into small plots at the University of Tennessee and University of Kentucky research farms using organic practices. These plots were monitored for three years for yield, quality, species composition, and soil characteristics. The four best performing forage systems were planted in small paddocks on organic dairy farms in Tennessee and Kentucky to evaluate forage yield, forage quality, seasonality of production, and suitability for on-farm milk production. The superior forage system was established on a 4 ha paddock and compared the existing forage system used by each of the dairy farms. These larger paddocks allowed continued measurements of forage yield and quality, as well as measurements of milk production, milk quality, and grazing behaviour of the animals. The information from this project is currently being incorporated into a total farm management system for organic dairy producers in the Southeastern USA

Inhibition of Plasmepsin V activity demonstrates its essential role in protein export, PfEMP1 display, and survival of malaria parasites

The malaria parasite Plasmodium falciparum exports several hundred proteins into the infected erythrocyte that are involved in cellular remodeling and severe virulence. The export mechanism involves the Plasmodium export element (PEXEL), which is a cleavage site for the parasite protease, Plasmepsin V (PMV). The PMV gene is refractory to deletion, suggesting it is essential, but definitive proof is lacking. Here, we generated a PEXEL-mimetic inhibitor that potently blocks the activity of PMV isolated from P. falciparum and Plasmodium vivax. Assessment of PMV activity in P. falciparum revealed PEXEL cleavage occurs cotranslationaly, similar to signal peptidase. Treatment of P. falciparum-infected erythrocytes with the inhibitor caused dose-dependent inhibition of PEXEL processing as well as protein export, including impaired display of the major virulence adhesin, PfEMP1, on the erythrocyte surface, and cytoadherence. The inhibitor killed parasites at the trophozoite stage and knockdown of PMV enhanced sensitivity to the inhibitor, while overexpression of PMV increased resistance. This provides the first direct evidence that PMV activity is essential for protein export in Plasmodium spp. and for parasite survival in human erythrocytes and validates PMV as an antimalarial drug target

Anti-CD45RC antibody immunotherapy prevents and treats experimental autoimmune polyendocrinopathy-candidiasis- ectodermal dystrophy syndrome

Targeted monoclonal antibody (mAb) therapies show great promise for the treatment of transplant rejection and autoimmune diseases by inducing more specific immunomodulatory effects than broadly immunosuppressive drugs routinely used. We recently described the therapeutic advantage of targeting CD45RC, expressed at high levels by conventional T (Tconv) cells (CD45RC(hi)), their precursors, and terminally differentiated T (TEMRA) cells, but not by regulatory T cells (Tregs; CD45RC(lo/-)). We demonstrated efficacy of anti-CD45RC mAb treatment in transplantation, but its potential has not been examined in autoimmune diseases. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare genetic syndrome caused by loss-of-function mutations of autoimmune regulator (AIRE), a key central tolerance mediator, leading to abnormal autoreactive T cell responses and autoantibody production. Herein, we show that, in a rat model of APECED syndrome, anti-CD45RC mAb was effective for both prevention and treatment of autoimmune manifestations and inhibited autoantibody development. Anti-CD45RC mAb intervention depleted CD45RC(hi) T cells, inhibited CD45RC(hi) B cells, and restored the Treg/Tconv cell ratio and the altered Treg transcriptomic profile. In APECED patients, CD45RC was significantly increased in peripheral blood T cells, and lesioned organs from APECED patients were infiltrated by CD45RC(hi) cells. Our observations highlight the potential role for CD45RC(hi) cells in the pathogenesis of experimental and human APECED syndrome and the potential of anti-CD45RC antibody treatment.Peer reviewe

Sequence-based prediction for vaccine strain selection and identification of antigenic variability in foot-and-mouth disease virus

Identifying when past exposure to an infectious disease will protect against newly emerging strains is central to understanding the spread and the severity of epidemics, but the prediction of viral cross-protection remains an important unsolved problem. For foot-and-mouth disease virus (FMDV) research in particular, improved methods for predicting this cross-protection are critical for predicting the severity of outbreaks within endemic settings where multiple serotypes and subtypes commonly co-circulate, as well as for deciding whether appropriate vaccine(s) exist and how much they could mitigate the effects of any outbreak. To identify antigenic relationships and their predictors, we used linear mixed effects models to account for variation in pairwise cross-neutralization titres using only viral sequences and structural data. We identified those substitutions in surface-exposed structural proteins that are correlates of loss of cross-reactivity. These allowed prediction of both the best vaccine match for any single virus and the breadth of coverage of new vaccine candidates from their capsid sequences as effectively as or better than serology. Sub-sequences chosen by the model-building process all contained sites that are known epitopes on other serotypes. Furthermore, for the SAT1 serotype, for which epitopes have never previously been identified, we provide strong evidence - by controlling for phylogenetic structure - for the presence of three epitopes across a panel of viruses and quantify the relative significance of some individual residues in determining cross-neutralization. Identifying and quantifying the importance of sites that predict viral strain cross-reactivity not just for single viruses but across entire serotypes can help in the design of vaccines with better targeting and broader coverage. These techniques can be generalized to any infectious agents where cross-reactivity assays have been carried out. As the parameterization uses pre-existing datasets, this approach quickly and cheaply increases both our understanding of antigenic relationships and our power to control disease

Skillful long-range prediction of European and North American winters

This is the final version. Available from AGU via the DOI in this recordUntil recently, long-range forecast systems showed only modest levels of skill in predicting surface winter climate around the Atlantic Basin and associated fluctuations in the North Atlantic Oscillation at seasonal lead times. Here we use a new forecast system to assess seasonal predictability of winter North Atlantic climate. We demonstrate that key aspects of European and North American winter climate and the surface North Atlantic Oscillation are highly predictable months ahead. We demonstrate high levels of prediction skill in retrospective forecasts of the surface North Atlantic Oscillation, winter storminess, near-surface temperature, and wind speed, all of which have high value for planning and adaptation to extreme winter conditions. Analysis of forecast ensembles suggests that while useful levels of seasonal forecast skill have now been achieved, key sources of predictability are still only partially represented and there is further untapped predictability. Key Points The winter NAO can be skilfully predicted months ahead The signal-to-noise ratio of the predictable signal is anomalously low Predictions of the risk of regional winter extremes are possibleThis work was supported by the Joint DECC/Defra Met Office Hadley Centre Climate Programme (GA01101), the UK Public Weather Service research program, and the European Union Framework 7 SPECS project. Leon Hermanson was funded as part of his Research Fellowship by Willis as part of Willis Research Network (WRN)

Contributions of scale: What we stand to gain from Indigenous and local inclusion in climate-health monitoring and surveillance systems

Understanding how climate change will affect global health is a defining challenge this century. This is predicated, however, on our ability to combine climate and health data to investigate the ways in which variations in climate, weather, and health outcomes interact. There is growing evidence to support the value of place- and community-based monitoring and surveillance efforts, which can contribute to improving both the quality and equity of data collection needed to investigate and understand the impacts of climate change on health. The inclusion of multiple and diverse knowledge systems in climate-health surveillance presents many benefits, as well as challenges. We conducted a systematic review, synthesis, and confidence assessment of the published literature on integrated monitoring and surveillance systems for climate change and public health. We examined the inclusion of diverse knowledge systems in climate-health literature, focusing on: 1) analytical framing of integrated monitoring and surveillance system processes 2) key contributions of Indigenous knowledge and local knowledge systems to integrated monitoring and surveillance systems processes; and 3) patterns of inclusion within these processes. In total, 24 studies met the inclusion criteria and were included for data extraction, appraisal, and analysis. Our findings indicate that the inclusion of diverse knowledge systems contributes to integrated climate-health monitoring and surveillance systems across multiple processes of detection, attribution, and action. These contributions include: the definition of meaningful problems; the collection of more responsive data; the reduction of selection and source biases; the processing and interpretation of more comprehensive datasets; the reduction of scale dependent biases; the development of multi-scale policy; long-term future planning; immediate decision making and prioritization of key issues; as well as creating effective knowledge-information-action pathways. The value of our findings and this review is to demonstrate how neither scientific, Indigenous, nor local knowledge systems alone will be able to contribute the breadth and depth of information necessary to detect, attribute, and inform action along these pathways of climate-health impact. Rather, it is the divergence or discordance between the methodologies and evidences of different knowledge systems that can contribute uniquely to this understanding. We critically discuss the possibility of what we, mainly local communities and experts, stand to lose if these processes of inclusion are not equitable. We explore how to shift the existing patterns of inclusion into balance by ensuring the equity of contributions and justice of inclusion in these integrated monitoring and surveillance system processes