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This comprehensive survey of the life and work of the Canadian artist David Milne (1882-1953) accompanies the first UK exhibition of Milne's work at Dulwich Picture Gallery and brings together one hundred and twenty of his most significant works in oil, watercolour and dry-point printmaking. Like the members of the Group of Seven, Milne primarily chose landscape as his subject matter. However, his true subject was the process of perception and representation, reducing his painting to its essentials and infusing it with his own distinctive modern sensibility. Through the use of photographs, archival material and Milne's own writings the book presents a moving account of one man's spiritual and emotional voyage into modernity - from his early life in small town Ontario, to the bustling sidewalks of New York, on to the war torn landscapes of northern France as an official war artist and back again to the woods, lakes and fields of upstate New York. Pivoting as it does on Milne's war art, which includes some of the most formally daring of his career, the publication will serve as a poignant locus of remembrance, underscoring the historic bond between Canada and Great Britain, and offering a unique perspective on history through the eyes of one of Canada's most sophisticated modern painters.

Subduction related to the ancient supercontinent cycle is poorly constrained by mantle samples. Sublithospheric diamond crystallization records the release of melts from subducting oceanic lithosphere at 300–700 km depths 1 , 2 and is especially suited to tracking the timing and effects of deep mantle processes on supercontinents. Here we show that four isotope systems (Rb–Sr, Sm–Nd, U–Pb and Re–Os) applied to Fe-sulfide and CaSiO 3 inclusions within 13 sublithospheric diamonds from Juína (Brazil) and Kankan (Guinea) give broadly overlapping crystallization ages from around 450 to 650 million years ago. The intracratonic location of the diamond deposits on Gondwana and the ages, initial isotopic ratios, and trace element content of the inclusions indicate formation from a peri-Gondwanan subduction system. Preservation of these Neoproterozoic–Palaeozoic sublithospheric diamonds beneath Gondwana until its Cretaceous breakup, coupled with majorite geobarometry 3 , 4 , suggests that they accreted to and were retained in the lithospheric keel for more than 300 Myr during supercontinent migration. We propose that this process of lithosphere growth—with diamonds attached to the supercontinent keel by the diapiric uprise of depleted buoyant material and pieces of slab crust—could have enhanced supercontinent stability. The ages and geochemical compositions of inclusions of sublithospheric diamonds indicate additions to the mantle keel of Gondwana by the underplating of buoyant subducted material, originating from 300–700-km depth, which may have contributed to supercontinent stability during long-distance migration.

Through a case-study of one significant courtyard house owned by the Drapers’ Company and known as ‘The Erber’, this article argues that mercantile livery companies supported London's growing centrality within an expanding network of trade through the use and development of corporate properties. The micro-history at the heart of this article reveals that the ‘everyday’ built environment of sixteenth- and seventeenth-century London was shaped not just by the city elite. Also relevant to that process were the different sorts of tenants of the Drapers’ Company, who benefited from the expansion at all levels of London's mercantile activity. The trickle-down effects of global mercantilism affected spaces small and large. The investigation of the Erber highlights the domestic implications of global commercial expansion.

Multiple sclerosis (MS) is an autoimmune demyelinating disease affecting the central nervous system (CNS). T helper (Th) 17 cells are involved in the pathogenesis of MS and its animal model of experimental autoimmune encephalomyelitis (EAE) by infiltrating the CNS and producing effector molecules that engage resident glial cells. Among these glial cells, astrocytes have a central role in coordinating inflammatory processes by responding to cytokines and chemokines released by Th17 cells. In this study, we examined the impact of pathogenic Th17 cells on astrocytes in vitro and in vivo. We identified that Th17 cells reprogram astrocytes by driving transcriptomic changes partly through a Janus Kinase (JAK)1-dependent mechanism, which included increased chemokines, interferon-inducible genes, and cytokine receptors. In vivo, we observed a region-specific heterogeneity in the expression of cell surface cytokine receptors on astrocytes, including those for IFN-γ, IL-1, TNF-α, IL-17, TGFβ, and IL-10. Additionally, these receptors were dynamically regulated during EAE induced by adoptive transfer of myelin-reactive Th17 cells. This study overall provides evidence of Th17 cell reprogramming of astrocytes, which may drive changes in the astrocytic responsiveness to cytokines during autoimmune neuroinflammation.

The 2015 United Nations Paris Agreement on Climate reinforces actions to conserve and enhance forests as carbon reservoirs. A decade after sub-national demonstration projects to reduce emissions from deforestation and forest degradation (REDD+) commenced, we examine why many REDD+ schemes appear to have fuelled social conflict while having limited success in addressing the drivers of forest loss and degradation. Our analysis is two-tiered: first we synthesise findings from a set of ethnographic case studies of REDD+ in Mainland Southeast Asia, conducted by the authors; second, we explore whether the insights from our regional synthesis apply globally, through a comparative review of published qualitative research on REDD+ field experiences. Our results reveal three major implementation dynamics that can undermine REDD+ in practice, which we conceptualise from science and technology studies and critical political ecology as follows: 1) problems with the enrolment of governments, civil society, and local forest users in REDD+ governance; 2) the prevalence of overly simplified codification systems for REDD+ implementation that mismatch targeted societies and landscapes; and 3) the consequent dissonance between REDD+ objectives and outcomes. Together, these problematic dynamics reveal how and why REDD+ so often misses its targets of reducing deforestation and delivering community benefits. In effect, it appears that REDD+ in the course of implementation maps onto local power structures and political economies, rendering it blunt as tool for change. The potential of REDD+ as a ‘solution’ in the global climate regime must therefore be scrutinized, along with other similar mechanisms espoused by the green economy.

Multiple sclerosis (MS) is one of the most common neurological disorders in young adults. The etiology of MS is not known but it is widely accepted that it is autoimmune in nature. Disease onset is believed to be initiated by the activation of CD4+ T cells that target autoantigens of the central nervous system (CNS) and their infiltration into the CNS, followed by the expansion of local and infiltrated peripheral effector myeloid cells that create an inflammatory milieu within the CNS, which ultimately lead to tissue damage and demyelination. Clinical studies have shown that progression of MS correlates with the abnormal expression of certain cytokines. The use of experimental autoimmune encephalomyelitis (EAE) model further delineates the role of these cytokines in neuroinflammation and the therapeutic potential of manipulating their biological activity in vivo. In this review, we will first present an overview on cytokines that may contribute to the pathogenesis of MS or EAE, and provide successful examples and roadblock of translating data obtained from EAE to MS. We will then focus in depth on recent findings that demonstrate the pathological role of granulocyte-macrophage colony-stimulating factor (GM-CSF) in MS and EAE, and briefly discuss the potential of targeting effector myeloid cells as a treatment strategy for MS.

The implementation of “reducing emissions from deforestation and forest degradation” (REDD+) will inevitably be affected by local social and political dynamics, with the potential for success depending significantly on cooperation from a range of stakeholders at the subnational level. Building on recent critical research on REDD+, we look at how global policy is interpreted locally by actors who are likely to be involved in REDD+ implementation. We do this by examining local stakeholder perceptions of REDD+ and forest management in two contrasting provinces of Indonesia, Riau and Papua, where deforestation rates are high and low, respectively. Using data collected from stakeholder workshops, we conduct a discourse analysis that reveals how subnational actors perceive and position themselves around REDD+ and forest governance. The results reveal six discourses common to both case-study provinces, which variously conflict and converge as they are employed by different actors. Seen together, these discourses provide critical insights into the subnational policy environment, which is largely a product of Indonesia’s underlying land and forest politics, and they indicate in turn how REDD+ in practice is likely to be interpreted and reconstituted at the local level. A key finding is that local discourses can be grouped around two divergent positions on REDD+: one that supports forest exploitation and sees limited prospects in forest carbon, and one that embraces sustainable forest management and expresses conditional support for REDD+ subject to benefit-sharing and property arrangements. REDD+ practitioners will therefore need to craft policies and project processes that account for these discursive dynamics.

Background Individuals with Friedreich ataxia (FRDA) can find it difficult to access specialized clinical care. To facilitate best practice in delivering healthcare for FRDA, clinical management guidelines (CMGs) were developed in 2014. However, the lack of high-certainty evidence and the inadequacy of accepted metrics to measure health status continues to present challenges in FRDA and other rare diseases. To overcome these challenges, the Grading of Recommendations Assessment and Evaluation (GRADE) framework for rare diseases developed by the RARE-Bestpractices Working Group was adopted to update the clinical guidelines for FRDA. This approach incorporates additional strategies to the GRADE framework to support the strength of recommendations, such as review of literature in similar conditions, the systematic collection of expert opinion and patient perceptions, and use of natural history data. Methods A panel representing international clinical experts, stakeholders and consumer groups provided oversight to guideline development within the GRADE framework. Invited expert authors generated the Patient, Intervention, Comparison, Outcome (PICO) questions to guide the literature search (2014 to June 2020). Evidence profiles in tandem with feedback from individuals living with FRDA, natural history registry data and expert clinical observations contributed to the final recommendations. Authors also developed best practice statements for clinical care points that were considered self-evident or were not amenable to the GRADE process. Results Seventy clinical experts contributed to fifteen topic-specific chapters with clinical recommendations and/or best practice statements. New topics since 2014 include emergency medicine, digital and assistive technologies and a stand-alone section on mental health. Evidence was evaluated according to GRADE criteria and 130 new recommendations and 95 best practice statements were generated. Discussion and conclusion Evidence-based CMGs are required to ensure the best clinical care for people with FRDA. Adopting the GRADE rare-disease framework enabled the development of higher quality CMGs for FRDA and allows individual topics to be updated as new evidence emerges. While the primary goal of these guidelines is better outcomes for people living with FRDA, the process of developing the guidelines may also help inform the development of clinical guidelines in other rare diseases.

To identify gait and balance measures that are responsive to change during the timeline of a clinical trial in Friedreich ataxia (FRDA), we administered a battery of potential measures three times over a 12-month period. Sixty-one ambulant individuals with FRDA underwent assessment of gait and balance at baseline, 6 months and 12 months. Outcomes included GAITRite® spatiotemporal gait parameters; Biodex Balance System Postural Stability Test (PST) and Limits of Stability; Berg Balance Scale (BBS); Timed 25-Foot Walk Test; Dynamic Gait Index (DGI); SenseWear MF Armband step and energy activity; and the Friedreich Ataxia Rating Scale Upright Stability Subscale (FARS USS). The standardised response mean (SRM) or correlation coefficients were reported as effect size indices for comparison of internal responsiveness. Internal responsiveness was also analysed in subgroups. SenseWear Armband daily step count had the largest effect size of all the variables over 6 months (SRM = −0.615), while the PST medial–lateral index had the largest effect size (SRM = 0.829) over 12 months. The FARS USS (SRM = 0.824) and BBS (SRM = −0.720) were the only outcomes able to detect change over 12 months in all subgroups. The DGI was the most responsive outcome in children, detecting a mean change of −2.59 (95% CI −3.52 to −1.66, p < 0.001, SRM = −1.429). In conclusion, the FARS USS and BBS are highly responsive and can detect change in a wide range of ambulant individuals with FRDA. However, therapeutic effects in children may be best measured by the DGI.

IntroductionEmerging evidence indicates that rehabilitation can improve ataxia, mobility and independence in everyday activities in individuals with hereditary cerebellar ataxia. However, with the rarity of the genetic ataxias and known recruitment challenges in rehabilitation trials, most studies have been underpowered, non-randomised or non-controlled. This study will be the first, appropriately powered randomised controlled trial to examine the efficacy of an outpatient and home-based rehabilitation programme on improving motor function for individuals with hereditary cerebellar ataxia.Methods and analysisThis randomised, single-blind, parallel group trial will compare a 30-week rehabilitation programme to standard care in individuals with hereditary cerebellar ataxia. Eighty individuals with a hereditary cerebellar ataxia, aged 15 years and above, will be recruited. The rehabilitation programme will include 6 weeks of outpatient land and aquatic physiotherapy followed immediately by a 24- week home exercise programme supported with fortnightly physiotherapy sessions. Participants in the standard care group will be asked to continue their usual physical activity. The primary outcome will be the motor domain of the Functional Independence Measure. Secondary outcomes will measure the motor impairment related to ataxia, balance, quality of life and cost-effectiveness. Outcomes will be administered at baseline, 7 weeks, 18 weeks and 30 weeks by a physiotherapist blinded to group allocation. A repeated measures mixed-effects linear regression model will be used to analyse the effect of the treatment group for each of the dependent continuous variables. The primary efficacy analysis will follow the intention-to-treat principle.Ethics and disseminationThe study has been approved by the Monash Health Human Research Ethics Committee (HREC/18/MonH/418) and the Human Research Ethics Committee of the Northern Territory Department of Health and Menzies School of Health Research (2019/3503). Results will be published in peer-reviewed journals, presented at national and/or international conferences and disseminated to Australian ataxia support groups.Trial registration numberACTRN12618000908235.