Bimodal regulation of axonal transport by the GDNF-RET signalling axis in healthy and diseased motor neurons

Deficits in axonal transport are one of the earliest pathological outcomes in several models of amyotrophic lateral sclerosis (ALS), including SOD1G93A mice. Evidence suggests that rescuing these deficits prevents disease progression, stops denervation, and extends survival. Kinase inhibitors have been previously identified as transport enhancers, and are being investigated as potential therapies for ALS. For example, inhibitors of p38 mitogen-activated protein kinase and insulin growth factor receptor 1 have been shown to rescue axonal transport deficits in vivo in symptomatic SOD1G93A mice. In this work, we investigated the impact of RET, the tyrosine kinase receptor for glial cell line-derived neurotrophic factor (GDNF), as a modifier of axonal transport. We identified the fundamental interplay between RET signalling and axonal transport in both wild-type and SOD1G93A motor neurons in vitro. We demonstrated that blockade of RET signalling using pharmacological inhibitors and genetic knockdown enhances signalling endosome transport in wild-type motor neurons and uncovered a divergence in the response of primary motor neurons to GDNF compared with cell lines. Finally, we showed that inhibition of the GDNF-RET signalling axis rescues in vivo transport deficits in early symptomatic SOD1G93A mice, promoting RET as a potential therapeutic target in the treatment of ALS

Assessing the effectiveness, practicality and cost effectiveness of mitigation measures to reduce greenhouse gas emissions from intensively cultivated peatlands

Peatlands drained for agriculture are among the most intensive sources of greenhouse gas (GHG) emissions from the land-use sector. Policy decisions on the most effective strategies to reduce GHG emissions in line with Paris Agreement goals, alongside strategies that can halt any ongoing soil and biodiversity losses, are hindered by a lack of understanding on how proposed mitigation measures are likely to be received by the farming sector. Research has identified effective GHG reduction measures, but successful on-farm adoption of these measures is contingent upon farmer perceptions of the relative practicality of implementing the measures, and the economic impact that adoption will have on the farm business. In this study, Best–Worst Scaling, a discrete choice survey method, was utilised to elicit expert (climate change, policy and biodiversity) and farmer opinion on the relative effectiveness, practicality and level of economic cost of mitigation measures that can reduce GHG emissions at the farm level. The method enabled individual mitigation measures to be ranked by effectiveness (expert opinion), practicality and economic cost (farmer opinions). There were no measures ranked as both effective and practical, or effective with low cost, but there were measures ranked by farmers as practical and low cost to implement. These included: more effective nutrient management, reduced or no tillage, the installation of buffer zones, increased fossil fuel efficiency and the optimisation of irrigation systems. The strong divergence of ‘effective’ measures on the one hand, and ‘practical’ and ‘economic’ measures on the other, highlights the major challenges involved in reducing high GHG emissions from agricultural organic soils. Resolving these challenges will require a combination of financial mechanisms to compensate farmers for higher costs and/or reduced yields, engagement and advice to support farmers in adopting changes in management practice, and agricultural innovation and adaptation to maintain overall food production and economic viability. If these challenges are overcome, more sustainable landscape management on agricultural lowland peat could make significant contributions to achieve national and international climate change targets

Status Update and Interim Results from the Asymptomatic Carotid Surgery Trial-2 (ACST-2)

Objectives: ACST-2 is currently the largest trial ever conducted to compare carotid artery stenting (CAS) with carotid endarterectomy (CEA) in patients with severe asymptomatic carotid stenosis requiring revascularization. Methods: Patients are entered into ACST-2 when revascularization is felt to be clearly indicated, when CEA and CAS are both possible, but where there is substantial uncertainty as to which is most appropriate. Trial surgeons and interventionalists are expected to use their usual techniques and CE-approved devices. We report baseline characteristics and blinded combined interim results for 30-day mortality and major morbidity for 986 patients in the ongoing trial up to September 2012. Results: A total of 986 patients (687 men, 299 women), mean age 68.7 years (SD ± 8.1) were randomized equally to CEA or CAS. Most (96%) had ipsilateral stenosis of 70-99% (median 80%) with contralateral stenoses of 50-99% in 30% and contralateral occlusion in 8%. Patients were on appropriate medical treatment. For 691 patients undergoing intervention with at least 1-month follow-up and Rankin scoring at 6 months for any stroke, the overall serious cardiovascular event rate of periprocedural (within 30 days) disabling stroke, fatal myocardial infarction, and death at 30 days was 1.0%. Conclusions: Early ACST-2 results suggest contemporary carotid intervention for asymptomatic stenosis has a low risk of serious morbidity and mortality, on par with other recent trials. The trial continues to recruit, to monitor periprocedural events and all types of stroke, aiming to randomize up to 5,000 patients to determine any differential outcomes between interventions. Clinical trial: ISRCTN21144362. © 2013 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved

Second asymptomatic carotid surgery trial (ACST-2): a randomised comparison of carotid artery stenting versus carotid endarterectomy

Background: Among asymptomatic patients with severe carotid artery stenosis but no recent stroke or transient cerebral ischaemia, either carotid artery stenting (CAS) or carotid endarterectomy (CEA) can restore patency and reduce long-term stroke risks. However, from recent national registry data, each option causes about 1% procedural risk of disabling stroke or death. Comparison of their long-term protective effects requires large-scale randomised evidence. Methods: ACST-2 is an international multicentre randomised trial of CAS versus CEA among asymptomatic patients with severe stenosis thought to require intervention, interpreted with all other relevant trials. Patients were eligible if they had severe unilateral or bilateral carotid artery stenosis and both doctor and patient agreed that a carotid procedure should be undertaken, but they were substantially uncertain which one to choose. Patients were randomly allocated to CAS or CEA and followed up at 1 month and then annually, for a mean 5 years. Procedural events were those within 30 days of the intervention. Intention-to-treat analyses are provided. Analyses including procedural hazards use tabular methods. Analyses and meta-analyses of non-procedural strokes use Kaplan-Meier and log-rank methods. The trial is registered with the ISRCTN registry, ISRCTN21144362. Findings: Between Jan 15, 2008, and Dec 31, 2020, 3625 patients in 130 centres were randomly allocated, 1811 to CAS and 1814 to CEA, with good compliance, good medical therapy and a mean 5 years of follow-up. Overall, 1% had disabling stroke or death procedurally (15 allocated to CAS and 18 to CEA) and 2% had non-disabling procedural stroke (48 allocated to CAS and 29 to CEA). Kaplan-Meier estimates of 5-year non-procedural stroke were 2·5% in each group for fatal or disabling stroke, and 5·3% with CAS versus 4·5% with CEA for any stroke (rate ratio [RR] 1·16, 95% CI 0·86–1·57; p=0·33). Combining RRs for any non-procedural stroke in all CAS versus CEA trials, the RR was similar in symptomatic and asymptomatic patients (overall RR 1·11, 95% CI 0·91–1·32; p=0·21). Interpretation: Serious complications are similarly uncommon after competent CAS and CEA, and the long-term effects of these two carotid artery procedures on fatal or disabling stroke are comparable. Funding: UK Medical Research Council and Health Technology Assessment Programme

Utilising Reflective Practice Groups as pedagogy in ordination training and theological development

This is an Accepted Manuscript of an article published by Taylor & Francis in Practical Theology on 3-5-19, available online: https://doi.org/10.1080/1756073X.2019.1609254With the Church of England's ([2014. Formation Criteria with Mapped Selection Criteria for Ordained Ministry in the Church of England. https://www.churchofengland.org/media/2139103/formationcriteriaforordainedministryapprovedhofbpsdec2014.docx]) recent formation criteria now requiring ordinands to have a greater degree of reflexive capability, this article considers the pedagogy of Reflective Practice Groups in ordination training and focuses on how reflexivity can be developed in a group context, towards fostering greater spiritual formation, theological reflection, self-awareness, relational practices for pastoral encounter, resilience and self-care practices for ministry. Some ‘foci for reflexivity’ are advocated for use within Reflective Practice Groups in ordination training

BDNF-regulation of in vivo axonal transport is selectively impaired in fast motor neurons in SOD1ᴳ⁹³ᴬ mice

Background: Axonal transport ensures long-range delivery of essential cargoes between proximal and distal compartments of neurons, and is needed for neuronal development, function and survival. ALS mice, including SOD1G93A and TDP- 43M337V mice, display in vivo deficits in axonal transport pre-symptomatically suggesting that impairment contributes to disease. The aim of this study is to determine the influence of brain-derived neurotrophic factor (BDNF) and α-motor neuron (MN) subtypes on axonal transport. / Methods: Signalling endosome axonal transport was visualised in vivo with intramuscular injections of a fluorescently-labelled atoxic fragment of tetanus neurotoxin (HcT). HcT was delivered into the tibialis anterior (TA) or soleus muscles of wild-type (WT) and SOD1G93A mice +/- 25ng of recombinant BDNF. 4+ hours later, sciatic nerves were exposed in live, anaesthetised animals, and imaged using time-lapse confocal-microscopy at 37°C. Retrogradely transported signalling endosomes within single axons were tracked using the TrackMate plugin (FIJI/ImageJ). BDNF, TrkB and p75NTR levels were assessed in muscles, neuromuscular junctions and sciatic nerves in WT/SOD1G93A mice. / Results: Basal axonal transport analysis reveals that signalling endosome dynamics are similar between MN/muscle subgroups. BDNF-stimulation significantly enhanced axonal transport dynamics in WT MNs innervating TA only, and this was significantly impaired in SOD1G93A mice. BDNF, TrkB and p75NTR levels were differentially affected in both muscles and sciatic nerve in SOD1G93A mice. / Discussion and Conclusions: These data indicate that different MN/muscle subgroups have distinct axonal transport features and are differentially afflicted in SOD1G93A mice, and may reveal novel clues about selective MN vulnerability in ALS

Evaluating the accuracy and usefulness of commercially-available proximal soil mapping services for grassland nutrient management planning and soil health monitoring

Grasslands play an important role in global food security. However, there are increasing pressures to improve the sustainability of ruminant farming. Precision nutrient management tools (e.g., proximal soil sensors for soil mapping) offer opportunities to improve nutrient use efficiency through spatially-variable nutrient application rate maps. Despite little research validating these technologies on grasslands, commercial companies promote these technologies to grassland farmers. In this study, the accuracy of commercial companies offering these services was evaluated by comparing soil pH, P, K, Mg and SOM measurements derived from conventional soil sampling and laboratory analyses to measurements derived from the commercial operators, across a range of soils that are typical found in UK grasslands. Results showed that soil mapping services utilising gamma-ray spectroscopy (GRS) were not sufficiently accurate to predict soil pH, P, K and Mg on grasslands, and subsequently inappropriate for nutrient management planning for variable rate lime and nutrient application. Conversely, both GRS and visible-near infrared spectroscopy (Vis–NIR) accurately predicted between-field SOM variations in grassland soils but not within-field variation. This study emphasises the need for further research to explore the limitations of, and opportunities for, the universal application of these technologies across different soil types and/or land uses before their commercial application. It is therefore highly recommended that commercially-available soil mapping services are subject to certification, similar to centralised soil testing laboratories, to ensure data are accurate for soil management interpretation. The lack of reliability of such systems risks farmers’ confidence in the value of soil mapping, which could severely hinder future adoption of potentially valuable technologies