Towards disease-modifying therapy of alpha-synucleinopathies: new molecules and new approaches came into the lime-light

The accumulation of the various products of alpha-synuclein aggregation has been associated with the etiology and pathogenesis of several neurodegenerative conditions, including both familial and sporadic forms of Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). It is now well established that the aggregation and spread of alpha-synuclein aggregation pathology activate numerous pathogenic mechanisms that contribute to neurodegeneration and, ultimately, to disease progression. Therefore, the development of a safe and effective disease-modifying therapy that limits or prevents the accumulation of the toxic intermediate products of alpha-synuclein aggregation and the spread of alpha-synuclein aggregation pathology could provide significant positive clinical outcomes in PD/DLB cohorts. It has been suggested that this goal can be achieved by reducing the intracellular and/or extracellular levels of monomeric and already aggregated alpha-synuclein. The principal aim of this review is to critically evaluate the potential of therapeutic strategies that target the post-transcriptional steps of alpha-synuclein production and immunotherapy-based approaches to alpha-synuclein degradation in PD/DLB patients. Strategies aimed at the downregulation of alpha-synuclein production are at an early preclinical stage of drug development and, although they have shown promise in animal models of alpha-synuclein aggregation, many limitations need to be resolved before in-human clinical trials can be seriously considered. In contrast, many strategies aimed at the degradation of alpha-synuclein using immunotherapeutic approaches are at a more advanced stage of development, with some in-human Phase II clinical trials currently in progress. Translational barriers for both strategies include the limitations of alpha-synuclein aggregation models, poor understanding of the therapeutic window for the alpha-synuclein knockdown, and variability in alpha-synuclein pathology across patient cohorts. Overcoming such barriers should be the main focus of further studies. However, it is already clear that these strategies do have the potential to achieve a disease-modifying effect in PD and DLB

A new approach to characterising and predicting crop rotations using national-scale annual crop maps

Cropping decisions affect the nature, timing and intensity of agricultural management strategies. Specific crop rotations are associated with different environmental impacts, which can be beneficial or detrimental. The ability to map, characterise and accurately predict rotations enables targeting of mitigation measures where most needed and forecasting of potential environmental risks. Using six years of the national UKCEH Land Cover® plus: Crops maps (2015–2020), we extracted crop sequences for every agricultural field parcel in Great Britain (GB). Our aims were to first characterise spatial patterns in rotation properties over a national scale based on their length, type and structural diversity values, second, to test an approach to predicting the next crop in a rotation, using transition probability matrices, and third, to test these predictions at a range of spatial scales. Strict cyclical rotations only occupy 16 % of all agricultural land, whereas long-term grassland and complex-rotational agriculture each occupy over 40 %. Our rotation classifications display a variety of distinctive spatial patterns among rotation lengths, types and diversity values. Rotations are mostly 5 years in length, short mixed crops are the most abundant rotation type, and high structural diversity is concentrated in east Scotland. Predictions were most accurate when using the most local spatial approach (spatial scaling), 5-year rotations, and including long-term grassland. The prediction framework we built demonstrates that our crop predictions have an accuracy of 36–89 %, equivalent to classification accuracy of national crop and land cover mapping using earth observation, and we suggest this could be improved with additional contextual data. Our results emphasise that rotation complexity is multi-faceted, yet it can be mapped in different ways and forms the basis for further exploration in and beyond agronomy, ecology, and other disciplines

Modelling Landscape-scale Species Response to Agri-Environment Schemes

Agri-environment schemes (AES) are the most significant environmental policy delivery mechanism in England, and include the conservation of biodiversity as a key objective. Provisional results from the ongoing Landscape-scale species monitoring of AES (LandSpAES) baseline field survey have shown some positive responses of mobile taxa to AES gradients at local (1km2) or landscape (3 × 3km) scales. However, it is not known whether these provisional results might be more broadly applicable outside the regions surveyed in the LandSpAES project, i.e. in other regions, or nationally. Here, we present the findings of an analytical project to explore the use of national Citizen Science (CitSci) scheme data, to investigate whether similar relationships with AES gradients would be found at a national scale in CitSci data to those shown with LandSpAES data, and whether integrated modelling was possible with combined CitSci and LandSpAES datasets. The design of LandSpAES has high power to detect AES effects, including the independent testing of the local and landscape AES gradients, but is restricted to six regions. The national CitSci are more representative of England as a whole, but have not been designed to detect AES effects. The aim of this project was to determine whether the provisional taxon responses to the AES gradients found in the LandSpAES project could be detected at a national scale using CitSci scheme data. To achieve this aim, three key questions were addressed through the analytical work: 1) Can addition of covariates account for environmental variation between survey squares in each dataset, to improve the comparability of AES gradient effects between LandSpAES and CitSci schemes? 2) Do the CitSci scheme datasets show similar relationships between taxa responses and the AES gradients, to those found with the LandSpAES data? 3) Can integrated approaches to combining datasets be used to jointly model CitSci and LandSpAES data, and does integrated modelling reduce uncertainty in quantifying the effects of AES gradients on taxa responses at a national scale across England

Practical methods for the control of tor-grass (Brachypodium pinnatum s.l.) and the restoration of calcareous grassland

Calcareous grasslands are sites of high conservation value across Western Europe; however, they are increasingly threatened by the dominance of a native competitive grass, Brachypodium pinnatum, which reduces the diversity of the grassland. Despite this, there is no clear consensus on the most effective method for controlling B. pinnatum and restoring the grassland community. We established two experiments at a calcareous grassland of high nature conservation value in the UK, i) a herbicide spraying experiment with seeding and ii) a seasonal cut-and-graze experiment, to investigate the potential for reducing dense B. pinnatum cover and preventing further expansion of sparse cover, respectively. We examined the effect of different herbicide and cut-and-graze treatments on B. pinnatum cover, and on the species richness and diversity of the grassland over three consecutive years. Herbicide spraying reduced the cover of B. pinnatum, though two spray applications led to a greater reduction longer-term. Species richness and diversity initially declined with the herbicide spray, however this recovered rapidly to levels higher than before spraying commenced. Seeding the spray plots was beneficial for the establishment of Bromopsis erecta and potentially reduced the likelihood of re-colonisation by B. pinnatum and undesirable arable species. The cut-and-graze experiment also showed promising potential in terms of controlling the spread of B. pinnatum. Compared with a single cut in the spring or autumn, cutting and grazing twice, in both spring and autumn was found to reduce the cover of B. pinnatum, whilst also increasing species richness and diversity. Further monitoring is needed to determine the long-term effectiveness of this management treatment

Citizen science monitoring reveals links between honeybee health, pesticide exposure and seasonal availability of floral resources

We use a national citizen science monitoring scheme to quantify how agricultural intensifcation afects honeybee diet breadth (number of plant species). To do this we used DNA metabarcoding to identify the plants present in 527 honey samples collected in 2019 across Great Britain. The species richness of forage plants was negatively correlated with arable cropping area, although this was only found early in the year when the abundance of fowering plants was more limited. Within intensively farmed areas, honeybee diets were dominated by Brassica crops (including oilseed rape). We demonstrate how the structure and complexity of honeybee foraging relationships with plants is negatively afected by the area of arable crops surrounding hives. Using information collected from the beekeepers on the incidence of an economically damaging bee disease (Deformed Wing Virus) we found that the occurrence of this disease increased where bees foraged in agricultural land where there was a high use of foliar insecticides. Understanding impacts of land use on resource availability is fundamental to assessing long-term viability of pollinator populations. These fndings highlight the importance of supporting temporally timed resources as mitigation strategies to support wider pollinator population viability

Landscape-scale species monitoring of agri-environment schemes (LandSpAES project). Final project report, 2022

In this project, we applied a novel, pseudo-experimental design in order to collect a baseline survey dataset of the responses of mobile taxa to local and landscape AES gradients over four years, from 54 survey squares across six regions (NCAs) in England. This is the first project to monitor the responses of multiple mobile taxa to generalised AES gradients across large spatial extents, which were applied to arable, grassland and upland agricultural systems, in order specifically to address impacts beyond AES option or agreement boundaries. This baseline dataset supported a spatial assessment of relationships between the AES gradients and taxon abundance (or activity), species richness and diversity. Strong evidence for relationships with local and / or landscape AES gradients were found for one or more response variable for butterflies, moths and bats. Little or no evidence of AES gradient relationships were found for either bees or hoverflies and weak evidence for associations with bird metrics. A future resurvey would allow analyses of the longer-term changes in target taxa in response to AES management, against this baseline. The identification of various spatial relationships is encouraging in terms of the likely power to detect AES effects on biodiversity change in the future

COVID‐19 Vaccine Response in People with Multiple Sclerosis

ObjectiveThe purpose of this study was to investigate the effect of disease modifying therapies on immune response to severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) vaccines in people with multiple sclerosis (MS).MethodsFour hundred seventy-three people with MS provided one or more dried blood spot samples. Information about coronavirus disease 2019 (COVID-19) and vaccine history, medical, and drug history were extracted from questionnaires and medical records. Dried blood spots were eluted and tested for antibodies to SARS-CoV-2. Antibody titers were partitioned into tertiles with people on no disease modifying therapy as a reference. We calculated the odds ratio of seroconversion (univariate logistic regression) and compared quantitative vaccine response (Kruskal Wallis) following the SARS-CoV-2 vaccine according to disease modifying therapy. We used regression modeling to explore the effect of vaccine timing, treatment duration, age, vaccine type, and lymphocyte count on vaccine response.ResultsCompared to no disease modifying therapy, the use of anti-CD20 monoclonal antibodies (odds ratio = 0.03, 95% confidence interval [CI] = 0.01–0.06, p [less than] 0.001) and fingolimod (odds ratio = 0.04; 95% CI = 0.01–0.12) were associated with lower seroconversion following the SARS-CoV-2 vaccine. All other drugs did not differ significantly from the untreated cohort. Both time since last anti-CD20 treatment and total time on treatment were significantly associated with the response to the vaccination. The vaccine type significantly predicted seroconversion, but not in those on anti-CD20 medications. Preliminary data on cellular T-cell immunity showed 40% of seronegative subjects had measurable anti-SARS-CoV-2 T cell responses.InterpretationSome disease modifying therapies convey risk of attenuated serological response to SARS-CoV-2 vaccination in people with MS. We provide recommendations for the practical management of this patient group. ANN NEUROL 202

Gothic Revival Architecture Before Horace Walpole's Strawberry Hill

The Gothic Revival is generally considered to have begun in eighteenth-century Britain with the construction of Horace Walpole’s villa, Strawberry Hill, Twickenham, in the late 1740s. As this chapter demonstrates, however, Strawberry Hill is in no way the first building, domestic or otherwise, to have recreated, even superficially, some aspect of the form and ornamental style of medieval architecture. Earlier architects who, albeit often combining it with Classicism, worked in the Gothic style include Sir Christopher Wren, Nicholas Hawksmoor, William Kent and Batty Langley, aspects of whose works are explored here. While not an exhaustive survey of pre-1750 Gothic Revival design, the examples considered in this chapter reveal how seventeenth- and eighteenth-century Gothic emerged and evolved over the course of different architects’ careers, and how, by the time that Walpole came to create his own Gothic ‘castle’, there was already in existence in Britain a sustained Gothic Revivalist tradition