Living the Life You Choose: The Introduction of the Vanguard Method into an Organisation Providing Support to People with Learning Disabilities

This article describes the work undertaken to apply the Vanguard Method (Seddon, Freedom from command and control: a better way to make the work work Vanguard Education Ltd., Buckingham, 2003) to a not-for-profit organisation that exists to provide support for adults with learning disabilities. As chief executive of the organisation, the author directly participated in the intervention. This article is therefore a personal reflection on the experience of a leader who has been a participant observer and has changed the way he thinks about the way services should be delivered. Along the way, the organisation uncovered and removed substantial waste whilst improving the way services were designed around the individual.     

Naturalization of plains cottonwood ( Populus deltoides subsp. monilifera ) along river drainages west of the Rocky Mountains

Historic botanical surveys documented that the natural distribution of the plains cottonwood ( Populus deltoides subsp. monilifera ) was limited to semiarid drainages east of the Rocky Mountains. Recently, a number of isolated populations of plains cottonwood have been found along the Kootenai, lower Snake, and Columbia Rivers and their tributaries. We used isozyme analysis to assess the genetic structure of these Pacific Northwest (PNW) populations in relation to native cottonwood populations east of the Rocky Mountains. These genetic data along with field surveys (dbh, age estimates) and cadastral field survey notes (mid-1800s) were used to understand the origin of these disjunct populations (i.e., relictual natives versus naturalized introductions). Genetic analyses revealed high levels of genetic diversity within and among PNW populations as well as hybridization with black cottonwood ( P. trichocarpa ). The observed range of genetic variation for PNW populations was similar to that of native cottonwood populations. Collectively, these data confirm that these scattered populations are plains cottonwood ( Populus deltoides subsp. monilifera ). Age estimates of the largest individuals found within study populations ranged from 27 to 51 years. Cadastral field surveys also noted the absence of woody vegetation along the lower Snake and Columbia Rivers. Considered together, the data suggest that these populations are of recent origin. The high levels of observed genetic variation are consistent with the reproductive biology of Populus spp. (i.e., obligate outcrossing and widespread dispersal of pollen and seed by wind and water) and a recurrent introduction of plains cottonwood throughout the study area.     

COT drives resistance to RAF inhibition through MAP kinase pathway reactivation

Oncogenic mutations in the serine/threonine kinase B-RAF (also known as BRAF) are found in 50-70% of malignant melanomas. Pre-clinical studies have demonstrated that the B-RAF(V600E) mutation predicts a dependency on the mitogen-activated protein kinase (MAPK) signalling cascade in melanoma-an observation that has been validated by the success of RAF and MEK inhibitors in clinical trials. However, clinical responses to targeted anticancer therapeutics are frequently confounded by de novo or acquired resistance. Identification of resistance mechanisms in a manner that elucidates alternative 'druggable' targets may inform effective long-term treatment strategies. Here we expressed ～600 kinase and kinase-related open reading frames (ORFs) in parallel to interrogate resistance to a selective RAF kinase inhibitor. We identified MAP3K8 (the gene encoding COT/Tpl2) as a MAPK pathway agonist that drives resistance to RAF inhibition in B-RAF(V600E) cell lines. COT activates ERK primarily through MEK-dependent mechanisms that do not require RAF signalling. Moreover, COT expression is associated with de novo resistance in B-RAF(V600E) cultured cell lines and acquired resistance in melanoma cells and tissue obtained from relapsing patients following treatment with MEK or RAF inhibitors. We further identify combinatorial MAPK pathway inhibition or targeting of COT kinase activity as possible therapeutic strategies for reducing MAPK pathway activation in this setting. Together, these results provide new insights into resistance mechanisms involving the MAPK pathway and articulate an integrative approach through which high-throughput functional screens may inform the development of novel therapeutic strategies.     

Generalized Lévy walks and the role of chemokines in migration of effector CD8+ T cells

Chemokines have a central role in regulating processes essential to the immune function of T cells, such as their migration within lymphoid tissues and targeting of pathogens in sites of inflammation. Here we track T cells using multi-photon microscopy to demonstrate that the chemokine CXCL10 enhances the ability of CD8+ T cells to control the pathogen Toxoplasma gondii in the brains of chronically infected mice. This chemokine boosts T-cell function in two different ways: it maintains the effector T-cell population in the brain and speeds up the average migration speed without changing the nature of the walk statistics. Notably, these statistics are not Brownian; rather, CD8+ T-cell motility in the brain is well described by a generalized Lévy walk. According to our model, this unexpected feature enables T cells to find rare targets with more than an order of magnitude more efficiency than Brownian random walkers. Thus, CD8+ T-cell behaviour is similar to Lévy strategies reported in organisms ranging from mussels to marine predators and monkeys, and CXCL10 aids T cells in shortening the average time taken to find rare targets.     

Signal clipping by the rod output synapse

The properties of synapses between retinal neurons make an essential contribution to early visual processing. Light produces a graded hyperpolarization in photoreceptors, up to 25 mV in amplitude, and it is conventionally assumed that all of this response range is available for coding visual information. We report here, however, that the rod output synapse rectifies strongly, so that only potential changes within 5 mV of the rod dark potential are transmitted effectively to postsynaptic horizontal cells. This finding is consistent with the voltage-dependence of the calcium current presumed to control neurotransmitter release from rods. It suggests functional roles for the strong electrical coupling of adjacent rods and the weak electrical coupling of adjacent rods and cones. The existence of photoreceptor coupling resolves the apparent paradox that rods have a 25 mV response range, while signals greater than 5 mV in amplitude are clipped during synaptic transmission. We predict that the strengths of rod-rod and rod-cone coupling are quantitatively linked to the relationship between the rod response range and the synapse operating range.