An Interdisciplinary Approach To The Target Elucidation of Novel Antibiotic 31G12

Staphylococcus aureus is a Gram-positive bacterial pathogen responsible for nosocomial and community-acquired infections that can quickly acquire antibiotic resistance. We have identified a novel triazole antimicrobial 31G12 based on the natural product core of nonactin isolated from the fermentation of Streptomyces griseus, that is active against many Gram-positive bacteria as well as antibiotic resistant methicillin-resistant S. aureus and vancomycin-resistant Enterococcus. The synthesis and characterization indicate that 31G12 exists as a mixture of two rotamers at room temperature and displays bacteriostatic activity against S. aureus with moderate mammalian cell toxicity. We have currently identified potential protein targets of 31G12 in S. aureus via an interdisciplinary approach to the target elucidation. First, a chemical proteomic strategy using photoaffinity labeling revealed a potential target protein at approximately 110 kDa when visualized via western blot and in-gel scans. Second, whole-genome sequencing and a bioinformatics approach revealed two potential proteins, thioredoxin-fold protein and L11 methyltransferase to be good candidates based on dose-response curves. Although the mode of action has not been established, this work provides a rational framework to expand the efficacy of this novel class of antimicrobials through structure-based drug design to improve potency against Gram-positive bacteria and reduce mammalian cell toxicity

The social justice issues of smoke im/mobilities

In 2014, the Hazelwood mine fire burned for 45 days. Local communities were impacted by smoke and ash, and there were reports of raised carbon monoxide levels. Local news and social media reported residents experiencing numerous physical symptoms of smoke inhalation, including bleeding noses, coughing, wheezing and chest tightness. Paper masks to filter particulate matter were made available to residents to wear outside. The dust and ash constantly seeped into homes and offices, which required cleaning daily and sometimes multiple times during the day. Smoke was free to move across physical and bodily boundaries while those most vulnerable were hampered by lack of movement: pregnant women, the elderly and children were advised to leave the area. However, this suggestion to ‘simply’ move ignored the context of a community disproportionately impacted through years of economic decline and societal change. This paper explores the unequal mobilities of smoke and people that arose as a result of this event and draws on concepts of mobility justice (Sheller 2018) and emergency mobilities (Adey 2016) to reflect on the political dimensions of uneven mobility in times of crisi

Transforming Knowledge Orders: Museums, Collections and Exhibitions

The history of museums is closely connected not only with the history of collecting and collections, but also with the history of science and humanities. Collections and exhibitions reflect scientific theory and scholarly practice, and in turn shape them. Hence, museums transmit and disseminate, yet also produce knowledge. On the one hand, they visualise and stabilise orders of knowledge through assembling, classifying and fixing objects in exhibitions; on the other hand, new academic paradigms and political changes lead to rearrangements of facts and artefacts in museum storerooms and displays. This volume brings together case studies from various historical and cultural contexts that illuminate such dynamics. Its point of departure is transcultural collections and exhibitions such as cabinets of curiosities and ethnographic collections, whose attempts to inventorise and display the world testify to the desire for, but also the difficulties in establishing and maintaining orders of knowledge. A particular focus is on transformative moments in the history of museums, in particular on the early 1900s, when science and technology museums were established, and on more recent times, which have seen the refurbishment of numerous art and ethnographic museums

Physician-Perceived Barriers to Treating Opioid Use Disorder in the Emergency Department

Objective We aimed to assess physicians\u27 perceptions of barriers to starting medication-assisted treatment (MAT) in the Emergency Department (ED), views of the utility of MAT, and abilities to link patients with opioid use disorder (OUD) to MAT programs in their respective communities. Methods This was a cross-sectional survey study of American emergency medicine (EM) physicians with a self-administered online survey via SurveyMonkey (Survey Monkey, San Mateo, California). The survey was emailed to the Council of Residency Directors in Emergency Medicine (CORD) listserv and HCA Healthcare affiliated EM residency programs\u27 listservs. Attendings and residents of all post-graduate years participated. Questions assessed perceptions of barriers to starting OUD patients on MAT, knowledge of the X-waiver, and knowledge of MAT details. Statistics were performed with JMP software (SAS Institute Inc., Cary, NC) using the two-tailed Z-test for proportions. Results There were 98 responses, with 33% female, 55% resident physicians, and an overall 17% response rate. Residents were more eager to start OUD patients on MAT (71% vs 52%, p=0.04) than attendings but were less familiar with the X-waiver (38% vs 73%, p=0.001) or where community outpatient MAT facilities were (21% vs 43%, p=0.02). Conclusion Barriers in the ED were identified as a shortage of qualified prescribers, the lengthy X-waiver process, and the poor availability of outpatient MAT resources. EM residents showed more willingness to prescribe MAT but lacked a core understanding of the process. This shows an area of improvement for residency training as well as advocacy among attendings

Evidence for Color Dichotomy in the Primordial Neptunian Trojan Population

In the current model of early Solar System evolution, the stable members of the Jovian and Neptunian Trojan populations were captured into resonance from the leftover reservoir of planetesimals during the outward migration of the giant planets. As a result, both Jovian and Neptunian Trojans share a common origin with the primordial disk population, whose other surviving members constitute today's trans-Neptunian object (TNO) populations. The cold classical TNOs are ultra-red, while the dynamically excited "hot" population of TNOs contains a mixture of ultra-red and blue objects. In contrast, Jovian and Neptunian Trojans are observed to be blue. While the absence of ultra-red Jovian Trojans can be readily explained by the sublimation of volatile material from their surfaces due to the high flux of solar radiation at 5AU, the lack of ultra-red Neptunian Trojans presents both a puzzle and a challenge to formation models. In this work we report the discovery by the Dark Energy Survey (DES) of two new dynamically stable L4 Neptunian Trojans,2013 VX30 and 2014 UU240, both with inclinations i >30 degrees, making them the highest-inclination known stable Neptunian Trojans. We have measured the colors of these and three other dynamically stable Neptunian Trojans previously observed by DES, and find that 2013 VX30 is ultra-red, the first such Neptunian Trojan in its class. As such, 2013 VX30 may be a "missing link" between the Trojan and TNO populations. Using a simulation of the DES TNO detection efficiency, we find that there are 162 +/- 73 Trojans with Hr < 10 at the L4 Lagrange point of Neptune. Moreover, the blue-to-red Neptunian Trojan population ratio should be higher than 17:1. Based on this result, we discuss the possible origin of the ultra-red Neptunian Trojan population and its implications for the formation history of Neptunian Trojans

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London