The ciliary machinery is repurposed for T cell immune synapse trafficking of LCK

Upon engagement of the T cell receptor with an antigen-presenting cell, LCK initiates TCR signaling by phosphorylating its activation motifs. However, the mechanism of LCK activation specifically at the immune synapse is a major question. We show that phosphorylation of the LCK activating Y394, despite modestly increasing its catalytic rate, dramatically focuses LCK localization to the immune synapse. We describe a trafficking mechanism whereby UNC119A extracts membrane-bound LCK by sequestering the hydrophobic myristoyl group, followed by release at the target membrane under the control of the ciliary ARL3/ARL13B. The UNC119A N terminus acts as a “regulatory arm” by binding the LCK kinase domain, an interaction inhibited by LCK Y394 phosphorylation, thus together with the ARL3/ARL13B machinery ensuring immune synapse focusing of active LCK. We propose that the ciliary machinery has been repurposed by T cells to generate and maintain polarized segregation of signals such as activated LCK at the immune synapse

Health economic burden that wounds impose on the National Health Service in the UK

OBJECTIVE: To estimate the prevalence of wounds managed by the UK's National Health Service (NHS) in 2012/2013 and the annual levels of healthcare resource use attributable to their management and corresponding costs. METHODS: This was a retrospective cohort analysis of the records of patients in The Health Improvement Network (THIN) Database. Records of 1000 adult patients who had a wound in 2012/2013 (cases) were randomly selected and matched with 1000 patients with no history of a wound (controls). Patients' characteristics, wound-related health outcomes and all healthcare resource use were quantified and the total NHS cost of patient management was estimated at 2013/2014 prices. RESULTS: Patients' mean age was 69.0 years and 45% were male. 76% of patients presented with a new wound in the study year and 61% of wounds healed during the study year. Nutritional deficiency (OR 0.53; p<0.001) and diabetes (OR 0.65; p<0.001) were independent risk factors for non-healing. There were an estimated 2.2 million wounds managed by the NHS in 2012/2013. Annual levels of resource use attributable to managing these wounds and associated comorbidities included 18.6 million practice nurse visits, 10.9 million community nurse visits, 7.7 million GP visits and 3.4 million hospital outpatient visits. The annual NHS cost of managing these wounds and associated comorbidities was pound5.3 billion. This was reduced to between pound5.1 and pound4.5 billion after adjusting for comorbidities. CONCLUSIONS: Real world evidence highlights wound management is predominantly a nurse-led discipline. Approximately 30% of wounds lacked a differential diagnosis, indicative of practical difficulties experienced by non-specialist clinicians. Wounds impose a substantial health economic burden on the UK's NHS, comparable to that of managing obesity ( pound5.0 billion). Clinical and economic benefits could accrue from improved systems of care and an increased awareness of the impact that wounds impose on patients and the NHS.Ye

Collagen fiber arrangement in normal and diseased cartilage studied by polarization sensitive nonlinear microscopy

Jessica C. Mansfield ; C. Peter Winlove ; Julian Moger and Steve J. Matcher "Collagen fiber arrangement in normal and diseased cartilage studied by polarization sensitive nonlinear microscopy", J. Biomed. Opt. 13(4), 044020 (July 15, 2008). Copyright © 2008 Society of Photo-Optical Instrumentation EngineersSecond harmonic generation (SHG) and two-photon fluorescence (TPF) microscopy is used to image the intercellular and pericellular matrix in normal and degenerate equine articular cartilage. The polarization sensitivity of SHG can be used directly to determine fiber orientation in the superficial 10 to 20 microm of tissue, and images of the ratio of intensities taken with two orthogonal polarization states reveal small scale variations in the collagen fiber organization that have not previously been reported. The signal from greater depths is influenced by the birefringence and biattenuance of the overlying tissue. An assessment of these effects is developed, based on the analysis of changes in TPF polarization with depth, and the approach is validated in tendon where composition is independent of depth. The analysis places an upper bound on the biattenuance of tendon of 2.65 x 10(-4). Normal cartilage reveals a consistent pattern of variation in fibril orientation with depth. In lesions, the pattern is severely disrupted and there are changes in the pericellular matrix, even at the periphery where the tissue appears microscopically normal. Quantification of polarization sensitivity changes with depth in cartilage will require detailed numerical models, but in the meantime, multiphoton microscopy provides sensitive indications of matrix changes in cartilage degeneration

Attention bias for negative semantic stimuli in late life depression and clinical research portfolio

Background: Recent studies indicate that depressed individuals may have difficulties disengaging visual-spatial attention from negative information. Preliminary studies in depressed older adults provide evidence for the existence of biased attention to negative stimuli. However, the specific components of attention driving the detected bias effects in this population are not known. Aims: This study examined the mechanisms underlying attention biases in Late Life Depression (LLD). It was predicted that depressed older adults, like their younger counterparts, would demonstrate an impaired ability to disengage attention from negative stimuli relative to neutral and positive stimuli, as compared to non-depressed older adult controls. Methods: 16 clinically depressed older adults and 22 older adult controls matched for age, gender and pre-morbid verbal IQ performed an emotional spatial cueing task that required classifying a target stimulus. The location of the target was correctly or incorrectly cued by a neutral, positive or negative word. Results: Planned comparisons did not support the primary hypotheses. However, participants in the depressed group, in general, were slower to respond than participants in the control group. Conclusions: Results suggest that the ability to disengage attention from negative words is not impaired in LLD; however methodological limitations prevent firm conclusions being drawn. Possible explanations for the results are discussed along with directions for future research

'Pictures of Every Posture in the Mind': Judging Sidney's Characters

Throughout the long history of its reception, Sidney's Arcadia has been consistently distinguished from other examples of Renaissance prose fiction by claims on behalf of its lifelikeness or proto-novelistic "realism." Presenting a legal analysis of the Old Arcadia, this article suggests that Sidney's representational methods, however, do not so much anticipate the novelistic mode, as draw heavily on the classical resources of forensic rhetoric and probable argument. Reading both in the trial scene of Book V and beyond, this article shows how forensic status theory informs the plotting even of non-legal scenes, and explores the implications of Sidney's preoccupation with motive and intention for readerly engagement with his fiction. Neoclassical debates concerning poetic unity and representational verisimilitude are also discussed, alongside Arcadia's sources in Roman New Comedy and Greek romance