Endocytic Sorting and Downregulation of the M2 Acetylcholine Receptor is Regulated by Ubiquitin and the ESCRT Complex

Acknowledgements The authors would like to thank Professor Mark von Zastrow from the University of California, San Francisco for sharing critical constructs. We would like to thank Kevin MacKenzie and the University of Aberdeen Microscopy core and the Iain Fraser Flow cytometry core for their assistance in the acquisition of data, and Professor Lynda Erskine for critical reading of the manuscript. This work was supported by a PhD studentship from the University of Aberdeen (DZ) and by funding from the Royal Society and Tenovus Scotland (JNH)Peer reviewedPostprin

Bridging the Binding Sites : Dualsteric Ligands for the Cannabinoid 2 Receptor (CB2R)

Acknowledgements This project was financially supported by the German Research Foundation (Deutsche Forschungsgemeinschaft under DFG DE1546/10-1). Gratitude is expressed to the International Doctorate Program “Receptor Dynamics” of the Elite Network of Bavaria (ENB) for financial support of A.T. and S.A.M.S. (grant No. K-BM-2013-247). Y.A.R. was granted a scholarship by the German Academic Exchange Service (Deutscher Akademischer Austauschdienst, DAAD) program “Research stays for university academics and scientists.” D.A.R.-S. was awarded a Ph.D. scholarship by the DAAD. J.N.H. was financially supported by NHS Grampian. Furthermore, the authors thank Professor Dr. Kristina Lorenz (Institute of Pharmacology and Toxicology, University of Würzburg) for enabling them to conduct in vitro experiments in her laboratory. Open access funding enabled and organized by Projekt DEAL.Peer reviewedPublisher PD

Dysbindin Promotes the Post-Endocytic Sorting of G Protein-Coupled Receptors to Lysosomes

BackgroundDysbindin, a cytoplasmic protein long known to function in the biogenesis of specialized lysosome-related organelles (LROs), has been reported to reduce surface expression of D2 dopamine receptors in neurons. Dysbindin is broadly expressed, and dopamine receptors are members of the large family of G protein-coupled receptors (GPCRs) that function in diverse cell types. Thus we asked if dysbindin regulates receptor number in non-neural cells, and further investigated the cellular basis of this regulation.Methodology/principal findingsWe used RNA interference to deplete endogenous dysbindin in HEK293 and HeLa cells, then used immunochemical and biochemical methods to assess expression and endocytic trafficking of epitope-tagged GPCRs. Dysbindin knockdown up-regulated surface expression of D2 receptors compared to D1 receptors, as reported previously in neurons. This regulation was not mediated by a change in D2 receptor endocytosis. Instead, dysbindin knockdown specifically reduced the subsequent trafficking of internalized D2 receptors to lysosomes. This distinct post-endocytic sorting function explained the minimal effect of dysbindin depletion on D1 receptors, which recycle efficiently and traverse the lysosomal pathway to only a small degree. Moreover, dysbindin regulated the delta opioid receptor, a more distantly related GPCR that is also sorted to lysosomes after endocytosis. Dysbindin was not required for lysosomal trafficking of all signaling receptors, however, as its depletion did not detectably affect down-regulation of the EGF receptor tyrosine kinase. Dysbindin co-immunoprecipitated with GASP-1 (or GPRASP-1), a cytoplasmic protein shown previously to modulate lysosomal trafficking of D2 dopamine and delta opioid receptors by direct interaction, and with HRS that is a core component of the conserved ESCRT machinery mediating lysosome biogenesis and sorting.Conclusions/significanceThese results identify a distinct, and potentially widespread function of dysbindin in promoting the sorting of specific GPCRs to lysosomes after endocytosis

Making subaltern shikaris: histories of the hunted in colonial central India

Academic histories of hunting or shikar in India have almost entirely focused on the sports hunting of British colonists and Indian royalty. This article attempts to balance this elite bias by focusing on the meaning of shikar in the construction of the Gond ‘tribal’ identity in late nineteenth and early twentieth-century colonial central India. Coining the term ‘subaltern shikaris’ to refer to the class of poor, rural hunters, typically ignored in this historiography, the article explores how the British managed to use hunting as a means of state penetration into central India’s forest interior, where they came to regard their Gond forest-dwelling subjects as essentially and eternally primitive hunting tribes. Subaltern shikaris were employed by elite sportsmen and were also paid to hunt in the colonial regime’s vermin eradication programme, which targeted tigers, wolves, bears and other species identified by the state as ‘dangerous beasts’. When offered economic incentives, forest dwellers usually willingly participated in new modes of hunting, even as impact on wildlife rapidly accelerated and became unsustainable. Yet as non-indigenous approaches to nature became normative, there was sometimes also resistance from Gond communities. As overkill accelerated, this led to exclusion of local peoples from natural resources, to their increasing incorporation into dominant political and economic systems, and to the eventual collapse of hunting as a livelihood. All of this raises the question: To what extent were subaltern subjects, like wildlife, ‘the hunted’ in colonial India

Global wealth disparities drive adherence to COVID-safe pathways in head and neck cancer surgery

Peer reviewe

BHPR research: qualitative1. Complex reasoning determines patients' perception of outcome following foot surgery in rheumatoid arhtritis

Background: Foot surgery is common in patients with RA but research into surgical outcomes is limited and conceptually flawed as current outcome measures lack face validity: to date no one has asked patients what is important to them. This study aimed to determine which factors are important to patients when evaluating the success of foot surgery in RA Methods: Semi structured interviews of RA patients who had undergone foot surgery were conducted and transcribed verbatim. Thematic analysis of interviews was conducted to explore issues that were important to patients. Results: 11 RA patients (9 ♂, mean age 59, dis dur = 22yrs, mean of 3 yrs post op) with mixed experiences of foot surgery were interviewed. Patients interpreted outcome in respect to a multitude of factors, frequently positive change in one aspect contrasted with negative opinions about another. Overall, four major themes emerged. Function: Functional ability & participation in valued activities were very important to patients. Walking ability was a key concern but patients interpreted levels of activity in light of other aspects of their disease, reflecting on change in functional ability more than overall level. Positive feelings of improved mobility were often moderated by negative self perception ("I mean, I still walk like a waddling duck”). Appearance: Appearance was important to almost all patients but perhaps the most complex theme of all. Physical appearance, foot shape, and footwear were closely interlinked, yet patients saw these as distinct separate concepts. Patients need to legitimize these feelings was clear and they frequently entered into a defensive repertoire ("it's not cosmetic surgery; it's something that's more important than that, you know?”). Clinician opinion: Surgeons' post operative evaluation of the procedure was very influential. The impact of this appraisal continued to affect patients' lasting impression irrespective of how the outcome compared to their initial goals ("when he'd done it ... he said that hasn't worked as good as he'd wanted to ... but the pain has gone”). Pain: Whilst pain was important to almost all patients, it appeared to be less important than the other themes. Pain was predominately raised when it influenced other themes, such as function; many still felt the need to legitimize their foot pain in order for health professionals to take it seriously ("in the end I went to my GP because it had happened a few times and I went to an orthopaedic surgeon who was quite dismissive of it, it was like what are you complaining about”). Conclusions: Patients interpret the outcome of foot surgery using a multitude of interrelated factors, particularly functional ability, appearance and surgeons' appraisal of the procedure. While pain was often noted, this appeared less important than other factors in the overall outcome of the surgery. Future research into foot surgery should incorporate the complexity of how patients determine their outcome Disclosure statement: All authors have declared no conflicts of interes

Internalised Values and Fairness Perception: Ethics in Knowledge Management

This chapter argues for ethical consideration in knowledge management (KM). It explores the effect that internalised values and fairness perception have on individuals’ participation in KM practices. Knowledge is power, and organisations seek to manage knowledge through KM practices. For knowledge to be processed, individual employees—the source of all knowledge—need to be willing to participate in KM practices. As knowledge is power and a key constituent part of knowledge is ethics, individuals’ internalised values and fairness perception affect knowledge-processing. Where an organisation claims ownership over knowledge, an individual may perceive being treated unfairly, which may obstruct knowledge-processing. Through adopting ethical KM practices, individual needs are respected, enabling knowledge-processing. Implications point towards an ethical agenda in KM theory and practice

The Dark Energy Survey Data Release 1

We describe the first public data release of the Dark Energy Survey, DES DR1, consisting of reduced single epoch images, coadded images, coadded source catalogs, and associated products and services assembled over the first three years of DES science operations. DES DR1 is based on optical/near-infrared imaging from 345 distinct nights (August 2013 to February 2016) by the Dark Energy Camera mounted on the 4-m Blanco telescope at Cerro Tololo Inter-American Observatory in Chile. We release data from the DES wide-area survey covering ~5,000 sq. deg. of the southern Galactic cap in five broad photometric bands, grizY. DES DR1 has a median delivered point-spread function of g = 1.12, r = 0.96, i = 0.88, z = 0.84, and Y = 0.90 arcsec FWHM, a photometric precision of < 1% in all bands, and an astrometric precision of 151 mas. The median coadded catalog depth for a 1.95" diameter aperture at S/N = 10 is g = 24.33, r = 24.08, i = 23.44, z = 22.69, and Y = 21.44 mag. DES DR1 includes nearly 400M distinct astronomical objects detected in ~10,000 coadd tiles of size 0.534 sq. deg. produced from ~39,000 individual exposures. Benchmark galaxy and stellar samples contain ~310M and ~ 80M objects, respectively, following a basic object quality selection. These data are accessible through a range of interfaces, including query web clients, image cutout servers, jupyter notebooks, and an interactive coadd image visualization tool. DES DR1 constitutes the largest photometric data set to date at the achieved depth and photometric precision.Comment: 30 pages, 20 Figures. Release page found at this url https://des.ncsa.illinois.edu/releases/dr