The (In)Stability of Planetary Systems

We present results of numerical simulations which examine the dynamical stability of known planetary systems, a star with two or more planets. First we vary the initial conditions of each system based on observational data. We then determine regions of phase space which produce stable planetary configurations. For each system we perform 1000 ~1 million year integrations. We examine upsilon And, HD83443, GJ876, HD82943, 47UMa, HD168443, and the solar system (SS). We find that the resonant systems, 2 planets in a first order mean motion resonance, (HD82943 and GJ876) have very narrow zones of stability. The interacting systems, not in first order resonance, but able to perturb each other (upsilon And, 47UMa, and SS) have broad regions of stability. The separated systems, 2 planets beyond 10:1 resonance, (we only examine HD83443 and HD168443) are fully stable. Furthermore we find that the best fits to the interacting and resonant systems place them very close to unstable regions. The boundary in phase space between stability and instability depends strongly on the eccentricities, and (if applicable) the proximity of the system to perfect resonance. In addition to million year integrations, we also examined stability on ~100 million year timescales. For each system we ran ~10 long term simulations, and find that the Keplerian fits to these systems all contain configurations which may be regular on this timescale.Comment: 37 pages, 49 figures, 13 tables, submitted to Ap

Accurate Mental Maps as an Aspect of Local Ecological Knowledge (LEK): A Case Study from Lough Neagh, Northern Ireland

A mental map of the substrate of Lough Neagh, Northern Ireland, compiled from interviews with local fishermen, is compared with maps produced by science-based techniques. The comparison reveals that the mental map is highly accurate. This finding contrasts with the spatial distortion characteristic of the classic mental map. The accuracy of the Lough Neagh map is attributed to the fact that it is a compendium of the knowledge of several generations, rather than an individual perception. Individual distortions are filtered out, and accuracy is promoted by economic self-interest. High accuracy may be characteristic of the mental maps held by artisanal exploiters of natural resources

N-Body Simulations of Growth from 1 km Planetesimals at 0.4 AU

We present N-body simulations of planetary accretion beginning with 1 km radius planetesimals in orbit about a 1 solar mass star at 0.4 AU. The initial disk of planetesimals contains too many bodies for any current N-body code to integrate; therefore, we model a sample patch of the disk. Although this greatly reduces the number of bodies, we still track in excess of 10^5 particles. We consider three initial velocity distributions and monitor the growth of the planetesimals. The masses of some particles increase by more than a factor of 100. Additionally, the escape speed of the largest particle grows considerably faster than the velocity dispersion of the particles, suggesting impending runaway growth, although no particle grows large enough to detach itself from the power law size-frequency distribution. These results are in general agreement with previous statistical and analytical results. We compute rotation rates by assuming conservation of angular momentum around the center of mass at impact and that merged planetesimals relax to spherical shapes. At the end of our simulations, the majority of bodies that have undergone at least one merger are rotating faster than the breakup frequency. This implies that the assumption of completely inelastic collisions (perfect accretion), which is made in most simulations of planetary growth at sizes 1 km and above, is inappropriate. Our simulations reveal that, subsequent to the number of particles in the patch having been decreased by mergers to half its initial value, the presence of larger bodies in neighboring regions of the disk may limit the validity of simulations employing the patch approximation.Comment: 19 pages, 32 figures, 5 tables, accepted to Icaru

A Statistical Examination of the Short Term Stability of the Upsilon Andromedae System

Because of the high eccentricities (~0.3) of two of the possible planets about the star Upsilon Andromeda, the stability of the system requires careful study. We present results of 1000 numerical simulations which explore the orbital parameter space as constrained by the observations. The orbital parameters of each planet are chosen from a Gaussian error distribution, and the resulting configuration is integrated for 1,000,000 years. We find that 84% of these integrations are stable. Configurations in which the eccentricity of the third planet is 0.45 the system is always unstable, typically producing a close encounter between the second and third planets. A similar exercise with the gas giants in our own Solar System sampled with the same error distribution was performed. Approximately 81% of these simulations were stable for 10^6 years.Comment: 12 pages, 1 figure, submitted to Ap

5-HT2A receptor signalling through phospholipase D1 associated with its C-terminal tail

The 5-HT2AR (5-hydroxytryptamine-2A receptor) is a GPCR (G-protein-coupled receptor) that is implicated in the actions of hallucinogens and represents a major target of atypical antipsychotic agents. In addition to its classical signalling though PLC (phospholipase C), the receptor can activate several other pathways, including ARF (ADP-ribosylation factor)-dependent activation of PLD (phospholipase D), which appears to be achieved through a mechanism independent of heterotrimeric G-proteins. In the present study we show that wild-type and inactive constructs of PLD1 (but not PLD2) respectively facilitate and inhibit ARF-dependent PLD signalling by the 5-HT2AR. Furthermore we demonstrate that PLD1 specifically co-immunoprecipitates with the receptor and binds to a distal site in GST (glutathione transferase) fusion protein constructs of its C-terminal tail which is distinct from the ARF-interaction site, thereby suggesting the existence of a functional ARF-PLD signalling complex directly associated with this receptor. This reveals the spatial co-ordination of an important GPCR, transducer and effector into a physical complex that is likely to reinforce the impact of receptor activation on a heterotrimeric G-protein-independent signalling pathway. Signalling of this receptor through such non-canonical pathways may be important to its role in particular disorders

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

Virological failure and development of new resistance mutations according to CD4 count at combination antiretroviral therapy initiation

Objectives: No randomized controlled trials have yet reported an individual patient benefit of initiating combination antiretroviral therapy (cART) at CD4 counts > 350 cells/μL. It is hypothesized that earlier initiation of cART in asymptomatic and otherwise healthy individuals may lead to poorer adherence and subsequently higher rates of resistance development. Methods: In a large cohort of HIV-positive individuals, we investigated the emergence of new resistance mutations upon virological treatment failure according to the CD4 count at the initiation of cART. Results: Of 7918 included individuals, 6514 (82.3%), 996 (12.6%) and 408 (5.2%) started cART with a CD4 count ≤ 350, 351-499 and ≥ 500 cells/μL, respectively. Virological rebound occurred while on cART in 488 (7.5%), 46 (4.6%) and 30 (7.4%) with a baseline CD4 count ≤ 350, 351-499 and ≥ 500 cells/μL, respectively. Only four (13.0%) individuals with a baseline CD4 count > 350 cells/μL in receipt of a resistance test at viral load rebound were found to have developed new resistance mutations. This compared to 107 (41.2%) of those with virological failure who had initiated cART with a CD4 count < 350 cells/μL. Conclusions: We found no evidence of increased rates of resistance development when cART was initiated at CD4 counts above 350 cells/μL. HIV Medicin

Quantifying HIV transmission flow between high-prevalence hotspots and surrounding communities: a population-based study in Rakai, Uganda

Background International and global organisations advocate targeting interventions to areas of high HIV prevalence (ie, hotspots). To better understand the potential benefits of geo-targeted control, we assessed the extent to which HIV hotspots along Lake Victoria sustain transmission in neighbouring populations in south-central Uganda. Methods We did a population-based survey in Rakai, Uganda, using data from the Rakai Community Cohort Study. The study surveyed all individuals aged 15–49 years in four high-prevalence Lake Victoria fishing communities and 36 neighbouring inland communities. Viral RNA was deep sequenced from participants infected with HIV who were antiretroviral therapy-naive during the observation period. Phylogenetic analysis was used to infer partial HIV transmission networks, including direction of transmission. Reconstructed networks were interpreted through data for current residence and migration history. HIV transmission flows within and between high-prevalence and low-prevalence areas were quantified adjusting for incomplete sampling of the population. Findings Between Aug 10, 2011, and Jan 30, 2015, data were collected for the Rakai Community Cohort Study. 25 882 individuals participated, including an estimated 75·7% of the lakeside population and 16·2% of the inland population in the Rakai region of Uganda. 5142 participants were HIV-positive (2703 [13·7%] in inland and 2439 [40·1%] in fishing communities). 3878 (75·4%) people who were HIV-positive did not report antiretroviral therapy use, of whom 2652 (68·4%) had virus deep-sequenced at sufficient quality for phylogenetic analysis. 446 transmission networks were reconstructed, including 293 linked pairs with inferred direction of transmission. Adjusting for incomplete sampling, an estimated 5·7% (95% credibility interval 4·4–7·3) of transmissions occurred within lakeside areas, 89·2% (86·0–91·8) within inland areas, 1·3% (0·6–2·6) from lakeside to inland areas, and 3·7% (2·3–5·8) from inland to lakeside areas. Interpretation Cross-community HIV transmissions between Lake Victoria hotspots and surrounding inland populations are infrequent and when they occur, virus more commonly flows into rather than out of hotspots. This result suggests that targeted interventions to these hotspots will not alone control the epidemic in inland populations, where most transmissions occur. Thus, geographical targeting of high prevalence areas might not be effective for broader epidemic control depending on underlying epidemic dynamics. Funding The Bill & Melinda Gates Foundation, the National Institute of Allergy and Infectious Diseases, the National Institute of Mental Health, the National Institute of Child Health and Development, the Division of Intramural Research of the National Institute for Allergy and Infectious Diseases, the World Bank, the Doris Duke Charitable Foundation, the Johns Hopkins University Center for AIDS Research, and the President's Emergency Plan for AIDS Relief through the Centers for Disease Control and Prevention

International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist