Dynamic transport and localization of alpha-synuclein in primary hippocampal neurons.

BACKGROUND: Alpha-synuclein is a presynaptic protein with a proposed role in neurotransmission and dopamine homeostasis. Abnormal accumulation of alpha-synuclein aggregates in dopaminergic neurons of the substantia nigra is diagnostic of sporadic Parkinson's disease, and mutations in the protein are linked to early onset forms of the disease. The folded conformation of the protein varies depending upon its environment and other factors that are poorly understood. When bound to phospholipid membranes, alpha-synuclein adopts a helical conformation that mediates specific interactions with other proteins. RESULTS: To investigate the role of the helical domain in transport and localization of alpha-synuclein, eGFP-tagged constructs were transfected into rat primary hippocampal neurons at 7 DIV. A series of constructs were analyzed in which each individual exon was deleted, for comparison to previous studies of lipid affinity and alpha-helix content. A53T and A30P substitutions, representing Parkinson's disease-associated variants, were analyzed as well. Single exon deletions within the lipid-binding N-terminal domain of alpha-synuclein (exons 2, 3, and 4) partially disrupted its presynaptic localization at 17-21 DIV, resulting in increased diffuse labeling of axons. Similar results were obtained for A30P, which exhibits decreased lipid binding, but not A53T. To examine whether differences in presynaptic enrichment were related to deficiencies in transport velocity, transport was visualized via live cell microscopy. Tagged alpha-synuclein migrated at a rate of 1.85 +/- 0.09 mum/s, consistent with previous reports, and single exon deletion mutants migrated at similar rates, as did A30P. Deletion of the entire N-terminal lipid-binding domain (Delta234GFP) did not significantly alter rates of particle movement, but decreased the number of moving particles. Only the A53TGFP mutant exhibited a significant decrease in transport velocity as compared to ASGFP. CONCLUSIONS: These results support the hypothesis that presynaptic localization involves a mechanism that requires helical conformation and lipid binding. Conversely, the rate of axonal transport is not determined by lipid affinity and is not sufficient to account for differences in presynaptic localization of alpha-synuclein-eGFP variants.This study was funded by the Branfman Family Foundation, including salary support for MLY, LH, and WSW

Collaborative Computation in Self-Organizing Particle Systems

Many forms of programmable matter have been proposed for various tasks. We use an abstract model of self-organizing particle systems for programmable matter which could be used for a variety of applications, including smart paint and coating materials for engineering or programmable cells for medical uses. Previous research using this model has focused on shape formation and other spatial configuration problems (e.g., coating and compression). In this work we study foundational computational tasks that exceed the capabilities of the individual constant size memory of a particle, such as implementing a counter and matrix-vector multiplication. These tasks represent new ways to use these self-organizing systems, which, in conjunction with previous shape and configuration work, make the systems useful for a wider variety of tasks. They can also leverage the distributed and dynamic nature of the self-organizing system to be more efficient and adaptable than on traditional linear computing hardware. Finally, we demonstrate applications of similar types of computations with self-organizing systems to image processing, with implementations of image color transformation and edge detection algorithms

Delayed gastric emptying and reduced postprandial small bowel water content of equicaloric whole meal bread versus rice meals in healthy subjects: novel MRI insights

BACKGROUND/OBJECTIVES: Postprandial bloating is a common symptom in patients with functional gastrointestinal (GI) diseases. Whole meal bread (WMB) often aggravates such symptoms though the mechanisms are unclear. We used magnetic resonance imaging (MRI) to monitor the intragastric fate of a WMB meal (11% bran) compared to a rice pudding (RP) meal. SUBJECTS/METHODS: 12 healthy volunteers completed this randomised crossover study. They fasted overnight and after an initial MRI scan consumed a glass of orange juice with a 2267 kJ WMB or an equicaloric RP meal. Subjects underwent serial MRI scans every 45 min up to 270 min to assess gastric volumes and small bowel water content and completed a GI symptom questionnaire. RESULTS: The MRI intragastric appearance of the two meals was markedly different. The WMB meal formed a homogeneous dark bolus with brighter liquid signal surrounding it. The RP meal separated into an upper, liquid layer and a lower particulate layer allowing more rapid emptying of the liquid compared to solid phase (sieving). The WMB meal had longer gastric half emptying times (132±8 min) compared to the RP meal (104±7 min), P<0.008. The WMB meal was associated with markedly reduced MRI-visible small bowel free mobile water content compared to the RP meal, P<0.0001. CONCLUSIONS: WMB bread forms a homogeneous bolus in the stomach which inhibits gastric sieving and hence empties slower than the equicaloric rice meal. These properties may explain why wheat causes postprandial bloating and could be exploited to design foods which prolong satiation

Subtle changes in the flavour and texture of a drink enhance expectations of satiety

Background: The consumption of liquid calories has been implicated in the development of obesity and weight gain. Energy-containing drinks are often reported to have a weak satiety value: one explanation for this is that because of their fluid texture they are not expected to have much nutritional value. It is important to consider what features of these drinks can be manipulated to enhance their expected satiety value. Two studies investigated the perception of subtle changes in a drink’s viscosity, and the extent to which thick texture and creamy flavour contribute to the generation of satiety expectations. Participants in the first study rated the sensory characteristics of 16 fruit yogurt drinks of increasing viscosity. In study two, a new set of participants evaluated eight versions of the fruit yogurt drink, which varied in thick texture, creamy flavour and energy content, for sensory and hedonic characteristics and satiety expectations. Results: In study one, participants were able to perceive small changes in drink viscosity that were strongly related to the actual viscosity of the drinks. In study two, the thick versions of the drink were expected to be more filling and have a greater expected satiety value, independent of the drink’s actual energy content. A creamy flavour enhanced the extent to which the drink was expected to be filling, but did not affect its expected satiety. Conclusions: These results indicate that subtle manipulations of texture and creamy flavour can increase expectations that a fruit yogurt drink will be filling and suppress hunger, irrespective of the drink’s energy content. A thicker texture enhanced expectations of satiety to a greater extent than a creamier flavour, and may be one way to improve the anticipated satiating value of energy-containing beverages

Large-scale synchrony of gap dynamics and the distribution of understory tree species in maple-beech forests

Large-scale synchronous variations in community dynamics are well documented for a vast array of organisms, but are considerably less understood for forest trees. Because of temporal variations in canopy gap dynamics, forest communities—even old-growth ones—are never at equilibrium at the stand scale. This paucity of equilibrium may also be true at the regional scale. Our objectives were to determine (1) if nonequilibrium dynamics caused by temporal variations in the formation of canopy gaps are regionally synchronized, and (2) if spatiotemporal variations in canopy gap formation aVect the relative abundance of tree species in the understory. We examined these questions by analyzing variations in the suppression and release history of Acer saccharum Marsh. and Fagus grandifolia Ehrh. from 481 growth series of understory saplings taken from 34 mature stands. We observed that (1) the proportion of stems in release as a function of time exhibited a U-shaped pattern over the last 35 years, with the lowest levels occurring during 1975–1985, and that (2) the response to this in terms of species composition was that A. saccharum became more abundant at sites that had the highest proportion of stems in release during 1975–1985. We concluded that the understory dynamics, typically thought of as a stand-scale process, may be regionally synchronized

Large tunable valley splitting in edge-free graphene quantum dots on boron nitride

Coherent manipulation of binary degrees of freedom is at the heart of modern quantum technologies. Graphene offers two binary degrees: the electron spin and the valley. Efficient spin control has been demonstrated in many solid state systems, while exploitation of the valley has only recently been started, yet without control on the single electron level. Here, we show that van-der Waals stacking of graphene onto hexagonal boron nitride offers a natural platform for valley control. We use a graphene quantum dot induced by the tip of a scanning tunneling microscope and demonstrate valley splitting that is tunable from -5 to +10 meV (including valley inversion) by sub-10-nm displacements of the quantum dot position. This boosts the range of controlled valley splitting by about one order of magnitude. The tunable inversion of spin and valley states should enable coherent superposition of these degrees of freedom as a first step towards graphene-based qubits

What is the 'problem' that outreach work seeks to address and how might it be tackled? Seeking theory in a primary health prevention programme

&lt;b&gt;Background&lt;/b&gt; Preventive approaches to health are disproportionately accessed by the more affluent and recent health improvement policy advocates the use of targeted preventive primary care to reduce risk factors in poorer individuals and communities. Outreach has become part of the health service response. Outreach has a long history of engaging those who do not otherwise access services. It has, however, been described as eclectic in its purpose, clientele and mode of practice; its effectiveness is unproven. Using a primary prevention programme in the UK as a case, this paper addresses two research questions: what are the perceived problems of non-engagement that outreach aims to address; and, what specific mechanisms of outreach are hypothesised to tackle these.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Methods&lt;/b&gt; Drawing on a wider programme evaluation, the study undertook qualitative interviews with strategically selected health-care professionals. The analysis was thematically guided by the concept of 'candidacy' which theorises the dynamic process through which services and individuals negotiate appropriate service use.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Results&lt;/b&gt; The study identified seven types of engagement 'problem' and corresponding solutions. These 'problems' lie on a continuum of complexity in terms of the challenges they present to primary care. Reasons for non-engagement are congruent with the concept of 'candidacy' but point to ways in which it can be expanded.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Conclusions&lt;/b&gt; The paper draws conclusions about the role of outreach in contributing to the implementation of inequalities focused primary prevention and identifies further research needed in the theoretical development of both outreach as an approach and candidacy as a conceptual framework

Translating clinicians' beliefs into implementation interventions (TRACII) : a protocol for an intervention modeling experiment to change clinicians' intentions to implement evidence-based practice

Background: Biomedical research constantly produces new findings, but these are not routinely incorporated into health care practice. Currently, a range of interventions to promote the uptake of emerging evidence are available. While their effectiveness has been tested in pragmatic trials, these do not form a basis from which to generalise to routine care settings. Implementation research is the scientific study of methods to promote the uptake of research findings, and hence to reduce inappropriate care. As clinical practice is a form of human behaviour, theories of human behaviour that have proved to be useful in other settings offer a basis for developing a scientific rationale for the choice of interventions. Aims: The aims of this protocol are 1) to develop interventions to change beliefs that have already been identified as antecedents to antibiotic prescribing for sore throats, and 2) to experimentally evaluate these interventions to identify those that have the largest impact on behavioural intention and behavioural simulation. Design: The clinical focus for this work will be the management of uncomplicated sore throat in general practice. Symptoms of upper respiratory tract infections are common presenting features in primary care. They are frequently treated with antibiotics, and research evidence is clear that antibiotic treatment offers little or no benefit to otherwise healthy adult patients. Reducing antibiotic prescribing in the community by the "prudent" use of antibiotics is seen as one way to slow the rise in antibiotic resistance, and appears safe, at least in children. However, our understanding of how to do this is limited. Participants will be general medical practitioners. Two theory-based interventions will be designed to address the discriminant beliefs in the prescribing of antibiotics for sore throat, using empirically derived resources. The interventions will be evaluated in a 2 × 2 factorial randomised controlled trial delivered in a postal questionnaire survey. Two outcome measures will be assessed: behavioural intention and behavioural simulation.This study is funded by the European Commission Research Directorate as part of a multi-partner program: Research Based Education and Quality Improvement (ReBEQI): A Framework and tools to develop effective quality improvement programs in European healthcare. (Proposal No: QLRT-2001-00657)

Amblyopia and quality of life: a systematic review

Background/Aims Amblyopia is a common condition which can affect up to 5% of the general population. The health-related quality of life (HRQoL) implications of amblyopia and/or its treatment have been explored in the literature. Methods A systematic literature search was undertaken (16th-30th January 2007) to identify the HRQoL implications of amblyopia and/or its treatment. Results A total of 25 papers were included in the literature review. The HRQoL implications of amblyopia related specifically to amblyopia treatment, rather than the condition itself. These included the impact upon family life; social interactions; difficulties undertaking daily activities; and feelings and behaviour. The identified studies adopted a number of methodologies. The study populations included; children with the condition; parents of children with amblyopia; and adults who had undertaken amblyopia treatment as a child. Some studies developed their own measures of HRQoL, and others determined HRQoL through proxy measures. Conclusions The reported findings of the HRQoL implications are of importance when considering the management of cases of amblyopia. Further research is required to assess the immediate and long-term effects of amblyopia and/or its treatment upon HRQoL using a more standardised approach

Healing Right Way: study protocol for a stepped wedge cluster randomised controlled trial to enhance rehabilitation services and improve quality of life in Aboriginal Australians after brain injury.

IntroductionDespite higher incidence of brain injury among Aboriginal compared with non-Aboriginal Australians, suboptimal engagement exists between rehabilitation services and Aboriginal brain injury survivors. Aboriginal patients often feel culturally insecure in hospital and navigation of services post discharge is complex. Health professionals report feeling ill-equipped working with Aboriginal patients. This study will test the impact of a research-informed culturally secure intervention model for Aboriginal people with brain injury. METHODS AND ANALYSIS: Design: Stepped wedge cluster randomised control trial design; intervention sequentially introduced at four pairs of healthcare sites across Western Australia at 26-week intervals.Recruitment: Aboriginal participants aged ≥18 years within 4 weeks of an acute stroke or traumatic brain injury.Intervention: (1) Cultural security training for hospital staff and (2) local, trial-specific, Aboriginal Brain Injury Coordinators supporting participants.Primary outcome: Quality-of-life using EuroQOL-5D-3L (European Quality of Life scale, five dimensions, three severity levels) Visual Analogue Scale score at 26 weeks post injury. Recruitment of 312 participants is estimated to detect a difference of 15 points with 80% power at the 5% significance level. A linear mixed model will be used to assess the between-condition difference.Secondary outcome measures: Modified Rankin Scale, Functional Independence Measure, Modified Caregiver Strain Index, Hospital Anxiety and Depression Scale at 12 and 26 weeks post injury, rehabilitation occasions of service received, hospital compliance with minimum care processes by 26 weeks post injury, acceptability of Intervention Package, feasibility of Aboriginal Brain Injury Coordinator role.Evaluations: An economic evaluation will determine the potential cost-effectiveness of the intervention. Process evaluation will document fidelity to study processes and capture changing contexts including barriers to intervention implementation and acceptability/feasibility of the intervention through participant questionnaires at 12 and 26 weeks.Ethics and disseminationThe study has approvals from Aboriginal, university and health services human research ethics committees. Findings will be disseminated through stakeholder reports, participant workshops, peer-reviewed journal articles and conference papers.Trial registration numberACTRN12618000139279