V s and density structure beneath the Colorado Plateau constrained by gravity anomalies and joint inversions of receiver function and phase velocity data

The Colorado Plateau is a physiographic province in the western US with an average elevation of ∼1.9 km where, in contrast to neighboring provinces, there is little evidence of large scale tectonic deformation or magmatism. Recent availability of Earthscope/USArray seismic data allow us to better examine the crust and upper mantle structure beneath the region and test proposed explanations for the plateau's uplift and relative stability. Using phase velocities for fundamental mode Rayleigh waves and P receiver functions, we perform over 800 joint inversions for 1-D shear wave velocity VS profiles sampling the plateau and surrounding regions down to 150 km depth. We image a sharp change in crustal thickness at the western edge of the Colorado Plateau with a more gradual increase eastward moving into the Rocky Mountains. A relatively thick (≳100 km) lithosphere beneath the plateau extends into the Rocky Mountains to the north. We use empirical scaling relations to estimate densities from our VS results, and predict the associated gravity anomalies, which are inconsistent with the observed distribution of the Bouguer gravity anomalies. We somewhat reconcile the prediction and observations by assuming that lateral density variations below 50 km can be ignored and the lithospheric root is therefore neutrally buoyant. While there is some evidence for small scale convection and lithospheric removal at its edges, the shape of the lithospheric mantle anomaly is consistent with a large scale uplift of the plateau by heating since removal of the Farallon slab. We conclude that the lithospheric root is key to the long term stability of the Colorado Plateau, leading to a colder, stronger crust

Co-seismic deformation of deep slabs based on summed CMT data

We assess the co-seismic deformation inferred from earthquake moment tensor solutions for subducting slabs at depths greater than 50 km globally. We rotate each moment tensor into a local slab reference frame, then sum tensors within 50 km depth bins to approximate long term deformation characteristics. This builds upon previous analyses by using the up-to-date global Centroid Moment Tensor catalog, incorporating a more complete slab geometry, and focusing on the 3-D aspects of slab deformation. Results show a general consistency with Isacks and Molnar (1969), who found that most slabs can be divided into intermediate-extensional, intermediate-extensional-deep-compressional, and intermediate to deep-compressional categories. Exceptions to these three categories can be related to slab bending in the top 100 km, plate convergence that is oblique to the trench normal direction, and regions of higher focal mechanism heterogeneity. The regions of higher focal mechanism heterogeneity appear where there are along-strike changes in slab geometry and/or evidence of double-seismic zones. We find that the sense of deformation in the intermediate strain axis direction is opposite to that of the down-dip direction, in agreement with Kuge and Kawakatsu (1993). By quantitative comparison to numerical models of global mantle flow, we show that these observations are consistent with deformation of viscous slabs responding to their own negative buoyancy and an upper to lower mantle viscosity increas

Linkage of national health and social care data: a cross-sectional study of multimorbidity and social care use in people aged over 65 years in Scotland

Background: Little is known about the relationship between multimorbidity and social care use (also known as long-term care). The aim of this study was to assess the relationship between receipt of formal social care services and multimorbidity. Methods: This retrospective data linkage, observational study included all individuals over the age of 65 in the population of Scotland in financial years 2014/15 and 2015/16 (n= 975,265). The main outcome was receipt of social care measured by presence in the Scottish Social Care Survey. Logistic regression models were used to assess the influence of multimorbidity, age, sex, and socioeconomic position on the outcome reporting Average Marginal Effects (AME). Findings: 93.3% of those receiving social care had multimorbidity. 16.2% of those with multimorbidity received social care compared to 3.7% of those without. The strongest magnitudes of AME for receiving social care were seen for age and multimorbidity (respectively 50% and 18% increased probability comparing oldest to youngest and most severe multimorbidity to none). A 5.5% increased probability of receiving social care was observed for the most-deprived compared to the least-deprived. Interpretation: Higher levels of social care receipt are observed in those with increasing age, severe multimorbidity and living in more deprived areas. Multimorbidity does not fully moderate the relationship between social care receipt and either age or deprivation

Seasonality and the effects of weather on Campylobacter infections

Background Campylobacteriosis is a major public health concern. The weather factors that influence spatial and seasonal distributions are not fully understood. Methods To investigate the impacts of temperature and rainfall on Campylobacter infections in England and Wales, cases of Campylobacter were linked to local temperature and rainfall at laboratory postcodes in the 30 days before the specimen date. Methods for investigation included a comparative conditional incidence, wavelet, clustering, and time series analyses. Results The increase of Campylobacter infections in the late spring was significantly linked to temperature two weeks before, with an increase in conditional incidence of 0.175 cases per 100,000 per week for weeks 17 to 24; the relationship to temperature was not linear. Generalized structural time series model revealed that changes in temperature accounted for 33.3% of the expected cases of Campylobacteriosis, with an indication of the direction and relevant temperature range. Wavelet analysis showed a strong annual cycle with additional harmonics at four and six months. Cluster analysis showed three clusters of seasonality with geographic similarities representing metropolitan, rural, and other areas. Conclusions The association of Campylobacteriosis with temperature is likely to be indirect. High-resolution spatial temporal linkage of weather parameters and cases is important in improving weather associations with infectious diseases. The primary driver of Campylobacter incidence remains to be determined; other avenues, such as insect contamination of chicken flocks through poor biosecurity should be explored

Characterisation of SEQ0694 (PrsA/PrtM) of Streptococcus equi as a functional peptidyl-prolyl isomerase affecting multiple secreted protein substrates

YesPeptidyl-prolyl isomerase (PPIase) lipoproteins have been shown to influence the virulence of a number of Gram-positive bacterial human and animal pathogens, most likely through facilitating the folding of cell envelope and secreted virulence factors. Here, we used a proteomic approach to demonstrate that the Streptococcus equi PPIase SEQ0694 alters the production of multiple secreted proteins, including at least two putative virulence factors (FNE and IdeE2). We demonstrate also that, despite some unusual sequence features, recombinant SEQ0694 and its central parvulin domain are functional PPIases. These data add to our knowledge of the mechanisms by which lipoprotein PPIases contribute to the virulence of streptococcal pathogens

Oral abstracts 3: RA Treatment and outcomesO13. Validation of jadas in all subtypes of juvenile idiopathic arthritis in a clinical setting

Background: Juvenile Arthritis Disease Activity Score (JADAS) is a 4 variable composite disease activity (DA) score for JIA (including active 10, 27 or 71 joint count (AJC), physician global (PGA), parent/child global (PGE) and ESR). The validity of JADAS for all ILAR subtypes in the routine clinical setting is unknown. We investigated the construct validity of JADAS in the clinical setting in all subtypes of JIA through application to a prospective inception cohort of UK children presenting with new onset inflammatory arthritis. Methods: JADAS 10, 27 and 71 were determined for all children in the Childhood Arthritis Prospective Study (CAPS) with complete data available at baseline. Correlation of JADAS 10, 27 and 71 with single DA markers was determined for all subtypes. All correlations were calculated using Spearman's rank statistic. Results: 262/1238 visits had sufficient data for calculation of JADAS (1028 (83%) AJC, 744 (60%) PGA, 843 (68%) PGE and 459 (37%) ESR). Median age at disease onset was 6.0 years (IQR 2.6-10.4) and 64% were female. Correlation between JADAS 10, 27 and 71 approached 1 for all subtypes. Median JADAS 71 was 5.3 (IQR 2.2-10.1) with a significant difference between median JADAS scores between subtypes (p < 0.01). Correlation of JADAS 71 with each single marker of DA was moderate to high in the total cohort (see Table 1). Overall, correlation with AJC, PGA and PGE was moderate to high and correlation with ESR, limited JC, parental pain and CHAQ was low to moderate in the individual subtypes. Correlation coefficients in the extended oligoarticular, rheumatoid factor negative and enthesitis related subtypes were interpreted with caution in view of low numbers. Conclusions: This study adds to the body of evidence supporting the construct validity of JADAS. JADAS correlates with other measures of DA in all ILAR subtypes in the routine clinical setting. Given the high frequency of missing ESR data, it would be useful to assess the validity of JADAS without inclusion of the ESR. Disclosure statement: All authors have declared no conflicts of interest. Table 1Spearman's correlation between JADAS 71 and single markers DA by ILAR subtype ILAR Subtype Systemic onset JIA Persistent oligo JIA Extended oligo JIA Rheumatoid factor neg JIA Rheumatoid factor pos JIA Enthesitis related JIA Psoriatic JIA Undifferentiated JIA Unknown subtype Total cohort Number of children 23 111 12 57 7 9 19 7 17 262 AJC 0.54 0.67 0.53 0.75 0.53 0.34 0.59 0.81 0.37 0.59 PGA 0.63 0.69 0.25 0.73 0.14 0.05 0.50 0.83 0.56 0.64 PGE 0.51 0.68 0.83 0.61 0.41 0.69 0.71 0.9 0.48 0.61 ESR 0.28 0.31 0.35 0.4 0.6 0.85 0.43 0.7 0.5 0.53 Limited 71 JC 0.29 0.51 0.23 0.37 0.14 -0.12 0.4 0.81 0.45 0.41 Parental pain 0.23 0.62 0.03 0.57 0.41 0.69 0.7 0.79 0.42 0.53 Childhood health assessment questionnaire 0.25 0.57 -0.07 0.36 -0.47 0.84 0.37 0.8 0.66 0.4

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

Mitochondrial physiology

As the knowledge base and importance of mitochondrial physiology to evolution, health and disease expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow the latest SI guidelines and those of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols with the nomenclature of classical bioenergetics. We endeavour to provide a balanced view of mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of data repositories of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery

Vision, challenges and opportunities for a Plant Cell Atlas

With growing populations and pressing environmental problems, future economies will be increasingly plant-based. Now is the time to reimagine plant science as a critical component of fundamental science, agriculture, environmental stewardship, energy, technology and healthcare. This effort requires a conceptual and technological framework to identify and map all cell types, and to comprehensively annotate the localization and organization of molecules at cellular and tissue levels. This framework, called the Plant Cell Atlas (PCA), will be critical for understanding and engineering plant development, physiology and environmental responses. A workshop was convened to discuss the purpose and utility of such an initiative, resulting in a roadmap that acknowledges the current knowledge gaps and technical challenges, and underscores how the PCA initiative can help to overcome them.</jats:p