Multiple Autism-Linked Genes Mediate Synapse Elimination via Proteasomal Degradation of a Synaptic Scaffold PSD-95

SummaryThe activity-dependent transcription factor myocyte enhancer factor 2 (MEF2) induces excitatory synapse elimination in mouse neurons, which requires fragile X mental retardation protein (FMRP), an RNA-binding protein implicated in human cognitive dysfunction and autism. We report here that protocadherin 10 (Pcdh10), an autism-spectrum disorders gene, is necessary for this process. MEF2 and FMRP cooperatively regulate the expression of Pcdh10. Upon MEF2 activation, PSD-95 is ubiquitinated by the ubiquitin E3 ligase murine double minute 2 (Mdm2) and then binds to Pcdh10, which links it to the proteasome for degradation. Blockade of the Pcdh10-proteasome interaction inhibits MEF2-induced PSD-95 degradation and synapse elimination. In FMRP-lacking neurons, elevated protein levels of eukaryotic translation elongation factor 1 α (EF1α), an Mdm2-interacting protein and FMRP target mRNA, sequester Mdm2 and prevent MEF2-induced PSD-95 ubiquitination and synapse elimination. Together, our findings reveal roles for multiple autism-linked genes in activity-dependent synapse elimination

Editor's Choice - Carotid Stenosis Treatment : Variation in International Practice Patterns

Objectives: The aim was to determine current practice for the treatment of carotid stenosis among 12 countries participating in the International Consortium of Vascular Registries (ICVR). Methods: Data from the United States Vascular Quality Initiative (VQI) and the Vascunet registry collaboration (including 10 registries in Europe and Australasia) were used. Variation in treatment modality of asymptomatic versus symptomatic patients was analysed between countries and among centres within each country. Results: Among 58,607 procedures, octogenarians represented 18% of all patients, ranging from 8% (Hungary) to 22% (New Zealand and Australia). Women represented 36%, ranging from 29% (Switzerland) to 40% (USA). The proportion of carotid artery stenting (CAS) among asymptomatic patients ranged from 0% (Finland) to 26% (Sweden) and among symptomatic patients from 0% (Denmark) to 19% (USA). Variation among centres within countries for CAS was highest in the United States and Australia (from 0% to 80%). The overall proportion of asymptomatic patients was 48%, but varied from 0% (Denmark) to 73% (Italy). There was also substantial centre level variation within each country in the proportion of asymptomatic patients, most pronounced in Australia (0-72%), Hungary (5-55%), and the United States (0-100%). Countries with fee for service reimbursement had higher rates of treatment in asymptomatic patients than countries with population based reimbursement (OR 5.8, 95% CI 4.4-7.7). Conclusions: Despite evidence about treatment options for carotid artery disease, the proportion of asymptomatic patients, treatment modality, and the proportion of women and octogenarians vary considerably among and within countries. There was a significant association of treating more asymptomatic patients in countries with fee for service reimbursement. The findings reflect the inconsistency of the existing guidelines and a need for cooperation among guideline committees all over the world. (C) 2017 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.Peer reviewe

Bright Metal-Poor Stars from the Hamburg/ESO Survey. I. Selection and Follow-up Observations from 329 Fields

We present a sample of 1777 bright (9<B<14) metal-poor candidates selected from the Hamburg/ESO Survey (HES). Despite saturation effects present in the red portion of the HES objective-prism spectra, the data were recoverable and quantitative selection criteria could be applied to select the sample. Analyses of medium-resolution (~2 A) follow-up spectroscopy of the entire sample, obtained with several 2 to 4 m class telescopes, yielded 145 new metal-poor stars with metallicity [Fe/H]<-2.0, of which 79 have [Fe/H]<-2.5, and 17 have [Fe/H]<-3.0. We also obtained C/Fe estimates for all these stars. From this, we find a frequency of C-enhanced ([C/Fe]>1.0) metal-poor ([Fe/H]<-2.0) giants of 9% +- 2%, which is lower than previously reported. However, the frequency raises to similar (>20%) and higher values with increasing distance from the Galactic plane. Although the numbers of stars at low metallicity are falling rapidly at the lowest metallicities, there is evidence that the fraction of carbon-enhanced metal-poor stars is increasing rapidly as a function of declining metallicity. For ~60 objects, high-resolution data have already been obtained; one of these, HE 1327-2326, is the new record holder for the most iron-deficient star known.Comment: 29 pages (emulateapj), accepted for publication in Ap

Outcomes of “Anterior Versus Posterior Divisional Branches of the Hypogastric Artery as Distal Landing Zone for Iliac Branch Devices”: The International Multicentric R3OYAL Registry

Objective: The aim of this multicentric registry was to assess the outcomes of “anteRior versus posteRior divisional bRanches Of the hYpogastric artery as distAl landing zone for iLiac branch devices (R3OYAL).” Methods: The main exposure of interest for the purpose of this study was the internal iliac artery (IIA) divisional branch (anterior vs posterior) that was used as distal landing zone. Early endpoints included technical success and adverse events. Late endpoints included survival, primary/secondary IIA patency, and IIA branch instability. Results: A total of 171 patients were included in the study, of which 50 received bilateral implantation of iliac branch devices (IBDs). This resulted in a total of 221 incorporated IIAs included in the final analysis, of which 40 were anterior divisional branches and 181 were posterior divisional branches. Technical success was high in both groups (anterior division: 98% vs posterior division: 100%, P =.18). Occurrence of any adverse event was noted in 14% of patients in both groups (P = 1.0). The overall rate of freedom from the composite IBD branch instability did not show significant differences between patients receiving distal landing in the anterior or posterior division of the IIA at 3 years (79% vs 87%, log-rank test =.215). The 3-year estimates of IBD patency were significantly lower in patients who received distal landing in the anterior divisional branch than those who received distal landing in the posterior divisional branch (primary patency: 81% vs 96%, log-rank test =.009; secondary patency: 81% vs 97%, log-rank test <.001). Conclusions: The use of the anterior or posterior divisional branches of the IIA as distal landing zone for IBD implantation shows comparable profiles in terms of immediate technical success, perioperative safety, and side-branch instability up to 3 years. However, IBD patency at 3 years was higher when the distal landing zone was achieved within the posterior divisional branch of the IIA. Clinical Impact: The results from this large multicentric registry confirm that use of the anterior or posterior divisional branches of the internal iliac artery (IIA) as distal landing zone for implantation of iliac branch devices (IBD) shows comparable profiles of safety and feasibility, thereby allowing to extend the indications for endovascular repair of aorto-iliac aneurysms to cases with unsuitable anatomy within the IIA main trunk. Although mid-term rates of device durability and branch instability seem to be similar, the rates of primary and secondary IBD patency at three years was favored when the distal landing zone was achieved in the posterior divisional branch of the IIA

The Transformation of Citizenship in Complex Societies

The main purpose of this paper is to propose a theoretical framework for understanding the transformation of citizenship in complex societies. To this end, the paper is divided into six sections. The first section elucidates the main reasons for the renaissance of the concept of citizenship in the contemporary social sciences. The second section argues that a comprehensive sociological theory of citizenship needs to account for the importance of four dimensions: the content, the type, the conditions, and the arrangements of citizenship. The third section suggests that in order to understand the sociological significance of T.H. Marshall’s account of legal, political, and social rights we need to explore the particular historical contexts in which citizenship rights became ideologically and institutionally relevant. The fourth section offers some critical reflections on the main shortcomings of the Marshallian approach to citizenship. The fifth section draws an analogy between the transformation of social movements and the transformation of citizenship. The sixth section sheds light on the fact that contemporary citizenship studies are confronted with a curious paradox: the differentiation of citizenship has led to both the relativistic impoverishment and the pluralistic enrichment of contemporary accounts of ‘the social’ and ‘the political’.The paper concludes by arguing that, under conditions of late modernity, the state’s capacity to gain political legitimacy increasingly depends on its ability to confront the normative challenges posed by the ubiquity of societal complexity

Barriers to women entrepreneurship. Different methods, different results?

Building on research by Akehurst et al. (Serv Ind J 32:2489-2505, 2012), this study analysed internal and external factors in women entrepreneurship and linked these factors to the barriers that women face when starting businesses. To do so, two contrasting statistical techniques were used: PLS and QCA. After analysing results from each of these techniques, we observed that family duties and difficulties in obtaining financing (both internal and external) were the main factors related to barriers faced by women entrepreneurs

KM3NeT broadcast optical data transport system

The optical data transport system of the KM3NeT neutrino telescope at the bottom of the Mediterranean Sea will provide more than 6000 optical modules in the detector arrays with a point-to-point optical connection to the control stations onshore. The ARCA and ORCA detectors of KM3NeT are being installed at a depth of about 3500 m and 2500 m, respectively and their distance to the control stations is about 100 kilometers and 40 kilometers. In particular, the two detectors are optimised for the detection of cosmic neutrinos with energies above about 1 TeV (ARCA) and for the detection of atmospheric neutrinos with energies in the range 1 GeV-1 TeV (ORCA). The expected maximum data rate is 200 Mbps per optical module. The implemented optical data transport system matches the layouts of the networks of electro-optical cables and junction boxes in the deep sea. For efficient use of the fibres in the system the technology of Dense Wavelength Division Multiplexing is applied. The performance of the optical system in terms of measured bit error rates, optical budget are presented. The next steps in the implementation of the system are also discussed