Subtractive CRISPR screen identifies the ATG16L1/vacuolar ATPase axis as required for non-canonical LC3 lipidation

Although commonly associated with autophagosomes, LC3 can also be recruited to membranes by covalent lipidation in a variety of non-canonical contexts. These include responses to ionophores such as the M2 proton channel of influenza A virus. We report a subtractive CRISPR screen that identifies factors required for non-canonical LC3 lipidation. As well as the enzyme complexes directly responsible for LC3 lipidation in all contexts, we show the RALGAP complex is important for M2-induced, but not ionophore drug-induced, LC3 lipidation. In contrast, ATG4D is responsible for LC3 recycling in M2-induced and basal LC3 lipidation. Identification of a vacuolar ATPase subunit in the screen suggests a common mechanism for non-canonical LC3 recruitment. Influenza-induced and ionophore drug-induced LC3 lipidation lead to association of the vacuolar ATPase and ATG16L1 and can be antagonized by Salmonella SopF. LC3 recruitment to erroneously neutral compartments may therefore represent a response to damage caused by diverse invasive pathogens

Elementary processes governing the evolution of road networks

Urbanisation is a fundamental phenomenon whose quantitative characterisation is still inadequate. We report here the empirical analysis of a unique data set regarding almost 200 years of evolution of the road network in a large area located north of Milan (Italy). We find that urbanisation is characterised by the homogenisation of cell shapes, and by the stability throughout time of high-centrality roads which constitute the backbone of the urban structure, confirming the importance of historical paths. We show quantitatively that the growth of the network is governed by two elementary processes: (i) `densification', corresponding to an increase in the local density of roads around existing urban centres and (ii) `exploration', whereby new roads trigger the spatial evolution of the urbanisation front. The empirical identification of such simple elementary mechanisms suggests the existence of general, simple properties of urbanisation and opens new directions for its modelling and quantitative description.Comment: 10 pages, 6 figure

Latent cluster analysis of ALS phenotypes identifies prognostically differing groups

BACKGROUND Amyotrophic lateral sclerosis (ALS) is a degenerative disease predominantly affecting motor neurons and manifesting as several different phenotypes. Whether these phenotypes correspond to different underlying disease processes is unknown. We used latent cluster analysis to identify groupings of clinical variables in an objective and unbiased way to improve phenotyping for clinical and research purposes. METHODS Latent class cluster analysis was applied to a large database consisting of 1467 records of people with ALS, using discrete variables which can be readily determined at the first clinic appointment. The model was tested for clinical relevance by survival analysis of the phenotypic groupings using the Kaplan-Meier method. RESULTS The best model generated five distinct phenotypic classes that strongly predicted survival (p<0.0001). Eight variables were used for the latent class analysis, but a good estimate of the classification could be obtained using just two variables: site of first symptoms (bulbar or limb) and time from symptom onset to diagnosis (p<0.00001). CONCLUSION The five phenotypic classes identified using latent cluster analysis can predict prognosis. They could be used to stratify patients recruited into clinical trials and generating more homogeneous disease groups for genetic, proteomic and risk factor research

X-ray Absorption and Reflection in Active Galactic Nuclei

X-ray spectroscopy offers an opportunity to study the complex mixture of emitting and absorbing components in the circumnuclear regions of active galactic nuclei, and to learn about the accretion process that fuels AGN and the feedback of material to their host galaxies. We describe the spectral signatures that may be studied and review the X-ray spectra and spectral variability of active galaxies, concentrating on progress from recent Chandra, XMM-Newton and Suzaku data for local type 1 AGN. We describe the evidence for absorption covering a wide range of column densities, ionization and dynamics, and discuss the growing evidence for partial-covering absorption from data at energies > 10 keV. Such absorption can also explain the observed X-ray spectral curvature and variability in AGN at lower energies and is likely an important factor in shaping the observed properties of this class of source. Consideration of self-consistent models for local AGN indicates that X-ray spectra likely comprise a combination of absorption and reflection effects from material originating within a few light days of the black hole as well as on larger scales. It is likely that AGN X-ray spectra may be strongly affected by the presence of disk-wind outflows that are expected in systems with high accretion rates, and we describe models that attempt to predict the effects of radiative transfer through such winds, and discuss the prospects for new data to test and address these ideas.Comment: Accepted for publication in the Astronomy and Astrophysics Review. 58 pages, 9 figures. V2 has fixed an error in footnote

Using liminality to understand mothers’ experiences of long-term breastfeeding: ‘Betwixt and between’, and ‘matter out of place’

© 2015, © The Author(s) 2015. Breastmilk is widely considered as the optimum nutrition source for babies and an important factor in both improving public health and reducing health inequalities. Current international/national policy supports long-term breastfeeding. UK breastfeeding initiation rates are high but rapidly decline, and the numbers breastfeeding in the second year and beyond are unknown. This study used the concept of liminality to explore the experiences of a group of women breastfeeding long-term in the United Kingdom, building on Mahon-Daly and Andrews. Over 80 breastfeeding women were included within the study, which used micro-ethnographic methods (participant observation in breastfeeding support groups, face-to-face interviews and online asynchronous interviews via email). Findings about women’s experiences are congruent with the existing literature, although it is mostly dated and from outside the United Kingdom. Liminality was found to be useful in providing insight into women’s experiences of long-term breastfeeding in relation to both time and place. Understanding women’s experience of breastfeeding beyond current usual norms can be used to inform work with breastfeeding mothers and to encourage more women to breastfeed for longer

Second trimester inflammatory and metabolic markers in women delivering preterm with and without preeclampsia.

ObjectiveInflammatory and metabolic pathways are implicated in preterm birth and preeclampsia. However, studies rarely compare second trimester inflammatory and metabolic markers between women who deliver preterm with and without preeclampsia.Study designA sample of 129 women (43 with preeclampsia) with preterm delivery was obtained from an existing population-based birth cohort. Banked second trimester serum samples were assayed for 267 inflammatory and metabolic markers. Backwards-stepwise logistic regression models were used to calculate odds ratios.ResultsHigher 5-α-pregnan-3β,20α-diol disulfate, and lower 1-linoleoylglycerophosphoethanolamine and octadecanedioate, predicted increased odds of preeclampsia.ConclusionsAmong women with preterm births, those who developed preeclampsia differed with respect metabolic markers. These findings point to potential etiologic underpinnings for preeclampsia as a precursor to preterm birth

Prospects for progress on health inequalities in England in the post-primary care trust era : professional views on challenges, risks and opportunities

Background - Addressing health inequalities remains a prominent policy objective of the current UK government, but current NHS reforms involve a significant shift in roles and responsibilities. Clinicians are now placed at the heart of healthcare commissioning through which significant inequalities in access, uptake and impact of healthcare services must be addressed. Questions arise as to whether these new arrangements will help or hinder progress on health inequalities. This paper explores the perspectives of experienced healthcare professionals working within the commissioning arena; many of whom are likely to remain key actors in this unfolding scenario. Methods - Semi-structured interviews were conducted with 42 professionals involved with health and social care commissioning at national and local levels. These included representatives from the Department of Health, Primary Care Trusts, Strategic Health Authorities, Local Authorities, and third sector organisations. Results - In general, respondents lamented the lack of progress on health inequalities during the PCT commissioning era, where strong policy had not resulted in measurable improvements. However, there was concern that GP-led commissioning will fare little better, particularly in a time of reduced spending. Specific concerns centred on: reduced commitment to a health inequalities agenda; inadequate skills and loss of expertise; and weakened partnership working and engagement. There were more mixed opinions as to whether GP commissioners would be better able than their predecessors to challenge large provider trusts and shift spend towards prevention and early intervention, and whether GPs’ clinical experience would support commissioning action on inequalities. Though largely pessimistic, respondents highlighted some opportunities, including the potential for greater accountability of healthcare commissioners to the public and more influential needs assessments via emergent Health & Wellbeing Boards. Conclusions - There is doubt about the ability of GP commissioners to take clearer action on health inequalities than PCTs have historically achieved. Key actors expect the contribution from commissioning to address health inequalities to become even more piecemeal in the new arrangements, as it will be dependent upon the interest and agency of particular individuals within the new commissioning groups to engage and influence a wider range of stakeholders.</p

Having a lot of a good thing: multiple important group memberships as a source of self-esteem.

Copyright: © 2015 Jetten et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are creditedMembership in important social groups can promote a positive identity. We propose and test an identity resource model in which personal self-esteem is boosted by membership in additional important social groups. Belonging to multiple important group memberships predicts personal self-esteem in children (Study 1a), older adults (Study 1b), and former residents of a homeless shelter (Study 1c). Study 2 shows that the effects of multiple important group memberships on personal self-esteem are not reducible to number of interpersonal ties. Studies 3a and 3b provide longitudinal evidence that multiple important group memberships predict personal self-esteem over time. Studies 4 and 5 show that collective self-esteem mediates this effect, suggesting that membership in multiple important groups boosts personal self-esteem because people take pride in, and derive meaning from, important group memberships. Discussion focuses on when and why important group memberships act as a social resource that fuels personal self-esteem.This study was supported by 1. Australian Research Council Future Fellowship (FT110100238) awarded to Jolanda Jetten (see http://www.arc.gov.au) 2. Australian Research Council Linkage Grant (LP110200437) to Jolanda Jetten and Genevieve Dingle (see http://www.arc.gov.au) 3. support from the Canadian Institute for Advanced Research Social Interactions, Identity and Well-Being Program to Nyla Branscombe, S. Alexander Haslam, and Catherine Haslam (see http://www.cifar.ca)