20S human proteasomes bind with a specific orientation to lipid monolayers in vitro

Abstract20S Proteasomes are non-lysosomal, high molecular weight proteinases implicated in the degradation of misfolded proteins and several short-lived regulatory proteins. They have a well established role, as the core of the 26S proteasome complex, in the ubiquitin-dependent proteolytic pathway and in antigen processing. While correctly folded proteins are not degraded by the 20S proteasome, unfolding, for example by oxidation, may render them degradable. The 20S proteasome is a 700-kDa cylindrical particle, composed of 14 subunits of molecular masses 20–35 kDa. There is evidence that 20S proteasomes are in close proximity to or associate with the endoplasmic reticulum and nuclear and plasma membranes in vivo. To better understand the lipid association of 20S proteasomes in vitro, we used a lipid monolayer system as a simple model system for biological membranes. The structure and orientation of the monolayer lipid bound 20S proteasomes has been determined by electron microscopy. 20S proteasomes associated in an ‘end-on’ configuration specifically on PI lipid monolayers forming large arrays, with their channels opposite the lipid headgroups. On ER and Golgi lipid films 20S proteasones were oriented in the same way as on the PI lipid film but were monodisperse. Protein molecules were randomly oriented in the presence of PA, PG, PS, PC and mitochondrial lipid monolayers. We show that 20S proteasomes bind to phospholipids in vitro in a preferred orientation which places the proteasome channel perpendicular to the membrane

Attitudes towards clinical services among people who self-harm: systematic review.

BACKGROUND: Self-harm is increasingly common in many countries, is often repeated and may have other negative outcomes. AIMS: To systematically review people's attitudes towards clinical services following self-harm in order to inform service design and improvement. METHOD: A search of electronic databases was conducted and experts in the field were contacted in order to identify relevant worldwide qualitative or quantitative studies. Data were extracted independently by two reviewers with more weight given to studies of greater quality and relevance. RESULTS: Thirty-one studies met the inclusion criteria. Despite variations in healthcare systems and setting, participants' experiences were remarkably similar. Poor communication between patients and staff and a perceived lack of staff knowledge with regard to self-harm were common themes. Many participants suggested that psychosocial assessments and access to after-care needed to be improved. CONCLUSIONS: Specific aspects of care that might increase service user satisfaction and treatment adherence include staff knowledge, communication and better after-care arrangements. A standard protocol could aid regular audits of users' experiences of services

Proton Beam Therapy Versus Conformal Photon Radiation Therapy for Childhood Craniopharyngioma: Multi-institutional Analysis of Outcomes, Cyst Dynamics, and Toxicity

PurposeWe compared proton beam therapy (PBT) with intensity modulated radiation therapy (IMRT) for pediatric craniopharyngioma in terms of disease control, cyst dynamics, and toxicity.Methods and MaterialsWe reviewed records from 52 children treated with PBT (n=21) or IMRT (n=31) at 2 institutions from 1996-2012. Endpoints were overall survival (OS), disease control, cyst dynamics, and toxicity.ResultsAt 59.6 months' median follow-up (PBT 33 mo vs IMRT 106 mo; P<.001), the 3-year outcomes were 96% for OS, 95% for nodular failure-free survival and 76% for cystic failure-free survival. Neither OS nor disease control differed between treatment groups (OS P=.742; nodular failure-free survival P=.546; cystic failure-free survival P=.994). During therapy, 40% of patients had cyst growth (20% requiring intervention); immediately after therapy, 17 patients (33%) had cyst growth (transient in 14), more commonly in the IMRT group (42% vs 19% PBT; P=.082); and 27% experienced late cyst growth (32% IMRT, 19% PBT; P=.353), with intervention required in 40%. Toxicity did not differ between groups. On multivariate analysis, cyst growth was related to visual and hypothalamic toxicity (P=.009 and .04, respectively). Patients given radiation as salvage therapy (for recurrence) rather than adjuvant therapy had higher rates of visual and endocrine (P=.017 and .024, respectively) dysfunction.ConclusionsSurvival and disease-control outcomes were equivalent for PBT and IMRT. Cyst growth is common, unpredictable, and should be followed during and after therapy, because it contributes to late toxicity. Delaying radiation therapy until recurrence may result in worse visual and endocrine function

Are mice good models for human neuromuscular disease? Comparing muscle excursions in walking between mice and humans

The mouse is one of the most widely used animal models to study neuromuscular diseases and test new therapeutic strategies. However, findings from successful pre-clinical studies using mouse models frequently fail to translate to humans due to various factors. Differences in muscle function between the two species could be crucial but often have been overlooked. The purpose of this study was to evaluate and compare muscle excursions in walking between mice and humans

Should patients with abnormal liver function tests in primary care be tested for chronic viral hepatitis: cost minimisation analysis based on a comprehensively tested cohort

Background Liver function tests (LFTs) are ordered in large numbers in primary care, and the Birmingham and Lambeth Liver Evaluation Testing Strategies (BALLETS) study was set up to assess their usefulness in patients with no pre-existing or self-evident liver disease. All patients were tested for chronic viral hepatitis thereby providing an opportunity to compare various strategies for detection of this serious treatable disease. Methods This study uses data from the BALLETS cohort to compare various testing strategies for viral hepatitis in patients who had received an abnormal LFT result. The aim was to inform a strategy for identification of patients with chronic viral hepatitis. We used a cost-minimisation analysis to define a base case and then calculated the incremental cost per case detected to inform a strategy that could guide testing for chronic viral hepatitis. Results Of the 1,236 study patients with an abnormal LFT, 13 had chronic viral hepatitis (nine hepatitis B and four hepatitis C). The strategy advocated by the current guidelines (repeating the LFT with a view to testing for specific disease if it remained abnormal) was less efficient (more expensive per case detected) than a simple policy of testing all patients for viral hepatitis without repeating LFTs. A more selective strategy of viral testing all patients for viral hepatitis if they were born in countries where viral hepatitis was prevalent provided high efficiency with little loss of sensitivity. A notably high alanine aminotransferase (ALT) level (greater than twice the upper limit of normal) on the initial ALT test had high predictive value, but was insensitive, missing half the cases of viral infection. Conclusions Based on this analysis and on widely accepted clinical principles, a "fast and frugal" heuristic was produced to guide general practitioners with respect to diagnosing cases of viral hepatitis in asymptomatic patients with abnormal LFTs. It recommends testing all patients where a clear clinical indication of infection is present (e.g. evidence of intravenous drug use), followed by testing all patients who originated from countries where viral hepatitis is prevalent, and finally testing those who have a notably raised ALT level (more than twice the upper limit of normal). Patients not picked up by this efficient algorithm had a risk of chronic viral hepatitis that is lower than the general population

Simple Viscous Flows: from Boundary Layers to the Renormalization Group

The seemingly simple problem of determining the drag on a body moving through a very viscous fluid has, for over 150 years, been a source of theoretical confusion, mathematical paradoxes, and experimental artifacts, primarily arising from the complex boundary layer structure of the flow near the body and at infinity. We review the extensive experimental and theoretical literature on this problem, with special emphasis on the logical relationship between different approaches. The survey begins with the developments of matched asymptotic expansions, and concludes with a discussion of perturbative renormalization group techniques, adapted from quantum field theory to differential equations. The renormalization group calculations lead to a new prediction for the drag coefficient, one which can both reproduce and surpass the results of matched asymptotics

Feminist phenomenology and the woman in the running body

Modern phenomenology, with its roots in Husserlian philosophy, has been taken up and utilised in a myriad of ways within different disciplines, but until recently has remained relatively under-used within sports studies. A corpus of sociological-phenomenological work is now beginning to develop in this domain, alongside a longer standing literature in feminist phenomenology. These specific social-phenomenological forms explore the situatedness of lived-body experience within a particular social structure. After providing a brief overview of key strands of phenomenology, this article considers some of the ways in which sociological, and particularly feminist phenomenology, might be used to analyse female sporting embodiment. For illustrative purposes, data from an autophenomenographic project on female distance running are also included, in order briefly to demonstrate the application of phenomenology within sociology, as both theoretical framework and methodological approach

Can Machines Be Artists? A Deweyan Response in Theory and Practice

To speak comfortably of the machine artist (as outlined in the call for papers for this Special Issue) makes key assumptions about what it is to be an artist. It assumes, for instance, that the experience of living as an artist, which includes the socialisation, hard work, single-mindedness, and focused energy of creative activity, is incidental rather than essential since these aspects are not comfortably applicable to machines. Instead, it supposes that what is essential is the artistic product, and it is the similarity of human and machine products that makes it possible to speak of machine artists. This definition of art in terms of products is supported by modern psychological theories of creativity, defined as the generation of novel ideas which give rise to valuable products. These ideas take place in the mind or brain, regarded as a closed system within whose workings the secret of creativity will eventually be revealed. This is the framework of what is widely referred to as “cognitivism”. This definition in terms of novel ideas and valuable products has been widely assumed by artificial intelligence (AI) and computational creativity (CC), and this has been backed up through a particular version of the Turing Test. In this, a machine can be said to be a creative artist if its products cannot be distinguished from human art. However, there is another psychological view of creativity, that of John Dewey, in which a lived experience of inquiry and focus is essential to being creative. In this theory, creativity is a function of the whole person interacting with the world, rather than originating in the brain. This makes creativity a Process rather than a Cognitivist framework. Of course, the brain is crucial in a Process theory, but as part of an open system which includes both body and environment. Developments in “machine art” have been seen as spectacular and are widely publicised. But there may be a danger that these will distract from what we take to be the most exciting prospect of all. This is the contribution of computer technology to stimulate, challenge, and provoke artistic practice of all forms

Are current dynamic water quality models too complex? A comparison of a new parsimonious phosphorus model, SimplyP, and INCA-P

Catchment-scale water quality models are becoming increasingly popular tools for exploring the potential effects of land management, land use change and climate change on water quality. However, the dynamic, catchment-scale nutrient models in common usage are complex, with many uncertain parameters requiring calibration, limiting their usability and robustness. A key question is whether this complexity is justified. To explore this, we have developed a parsimonious P model, SimplyP, incorporating a coupled rainfall-runoff model and a biogeochemical model able to simulate streamflow, suspended sediment, particulate and dissolved P dynamics. The model’s complexity is compared in a small rural catchment in northeast Scotland. For three land use classes, less than six SimplyP model parameters must be determined through calibration alone, the rest may be based on measurements; INCA-P has around 40 unmeasurable parameters. Despite simpler process-representation, SimplyP produced a slightly better dissolved P simulation during both calibration and validation, and produced similar long-term projections in response to changes in land management. Results support the hypothesis that INCA-P is overly complex for the study catchment. We hope our findings will help prompt wider model comparison exercises, as well as debate amongst the water quality modelling community as to whether today's models are fit for purpose. Simpler models such as SimplyP have the potential to be useful management and research tools, building blocks for future model development (prototype code is freely available), or benchmarks against which more complex models could be evaluated

Transport and dynamics of the Panay Sill overflow in the Philippine Seas

Author Posting. © American Meteorological Society, 2010. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Journal of Physical Oceanography 40 (2010): 2679–2695, doi:10.1175/2010JPO4395.1.Observations of stratification and currents between June 2007 and March 2009 reveal a strong overflow between 400- and 570-m depth from the Panay Strait into the Sulu Sea. The overflow water is derived from approximately 400 m deep in the South China Sea. Temporal mean velocity is greater than 0.75 m s−1 at 50 m above the 570-m Panay Sill. Empirical orthogonal function analysis of a mooring time series shows that the flow is dominated by the bottom overflow current with little seasonal variance. The overflow does not descend below 1250 m in the Sulu Sea but rather settles above high-salinity deep water derived from the Sulawesi Sea. The mean observed overflow transport at the sill is 0.32 × 106 m3 s−1. The observed transport was used to calculate a bulk diapycnal diffusivity of 4.4 × 10−4 m2 s−1 within the Sulu Sea slab (575–1250 m) ventilated from Panay Strait. Analysis of Froude number variation across the sill shows that the flow is hydraulically controlled. A suitable hydraulic control model shows overflow transport equivalent to the observed overflow. Thorpe-scale estimates show turbulent dissipation rates up to 5 × 10−7 W kg−1 just downstream of the supercritical to subcritical flow transition, suggesting a hydraulic jump downstream of the sill.This work was supported by the Office of Naval Research Grant N00014-09-1-0582 to Lamont-Doherty Earth Observatory of Columbia University; Grants ONR-13759000 and N00014-09-1-0582 to the Woods Hole Oceanographic Institution; Grant ONR-N00014-06-1-0690 to Scripps Institute of Oceanography; and a National Defense Science and Engineering Graduate Fellowship