Influence of peptidylarginine deiminase type 4 genotype and shared epitope on clinical characteristics and autoantibody profile of rheumatoid arthritis.

Background: Recent evidence suggests that distinction of subsets of rheumatoid arthritis (RA) depending on anticyclic citrullinated peptide antibody (anti-CCP) status may be helpful in distinguishing distinct aetiopathologies and in predicting the course of disease. HLA-DRB1 shared epitope (SE) and peptidylarginine deiminase type 4 (PADI4) genotype, both of which have been implicated in anti-CCP generation, are assumed to be associated with RA. Objectives: To elucidate whether PADI4 affects the clinical characteristics of RA, and whether it would modulate the effect of anti-CCPs on clinical course. The combined effect of SE and PADI4 on autoantibody profile was also analysed. Methods: 373 patients with RA were studied. SE, padi4_94C.T, rheumatoid factor, anti-CCPs and antinuclear antibodies (ANAs) were determined. Disease severity was characterised by cumulative therapy intensity classified into ordinal categories (CTI-1 to CTI-3) and by Steinbrocker score. Results: CTI was significantly associated with disease duration, erosive disease, disease activity score (DAS) 28 and anti-CCPs. The association of anti-CCPs with CTI was considerably influenced by padi4_94C.T genotype (C/C: ORadj=0.93, padj=0.92; C/T: ORadj=2.92, padj=0.093; T/T: ORadj=15.3, padj=0.002). Carriage of padi4_94T exhibited a significant trend towards higher Steinbrocker scores in univariate and multivariate analyses. An association of padi4_94C.T with ANAs was observed, with noteworthy differences depending on SE status (SE2: ORadj=6.20, padj,0.04; SE+: ORadj=0.36, padj=0.02) and significant heterogeneity between the two SE strata (p=0.006). Conclusions: PADI4 genotype in combination with anti- CCPs and SE modulates clinical and serological characteristics of RA

Vegetation complexity and nesting resource availability predict bee diversity and functional traits in community gardens

Urban gardens can support diverse bee communities through resource provision in resource poor environments. Yet the effects of local habitat and landscape factors on wild bee communities in cities is still insufficiently understood, nor is how this information could be applied to urban wildlife conservation. Here we investigate how taxonomic and functional diversity of wild bees and their traits in urban community gardens are related to garden factors and surrounding landscape factors (e.g., plant diversity, amount of bare ground, amount of nesting resources, amount of landscape imperviousness). Using active and passive methods in 18 community gardens in Berlin, Germany, we documented 26 genera and 102 species of bees. We found that higher plant species richness and plant diversity as well as higher amounts of deadwood in gardens leads to higher numbers of wild bee species and bee (functional) diversity. Furthermore, higher landscape imperviousness surrounding gardens correlates with more cavity nesting bees, whereas a higher amount of bare ground correlates with more ground‐nesting bees. Pollen specialization was positively associated with plant diversity, but no factors strongly predicted the proportion of endangered bees. Our results suggest that, aside from foraging resources, nesting resources should be implemented in management for more pollinator‐friendly gardens. If designed and managed using such evidence‐based strategies, urban gardens can create valuable foraging and nesting habitats for taxonomically and functionally diverse bee communities in cities

Functional dissection of Rab GTPases involved in primary cilium formation

Primary cilia are sensory structures involved in morphogen signalling during development, liquid flow in the kidney, mechanosensation, sight, and smell (Badano, J.L., N. Mitsuma, P.L. Beales, and N. Katsanis. 2006. Annu. Rev. Genomics Hum. Genet. 7:125–148; Singla, V., and J.F. Reiter. 2006. Science. 313:629–633.). Mutations that affect primary cilia are responsible for several diseases, including neural tube defects, polycystic kidney disease, retinal degeneration, and cancers (Badano et al., 2006; Singla and Reiter, 2006). Primary cilia formation and function requires tight integration of the microtubule cytoskeleton with membrane trafficking (Singla and Reiter, 2006), and this is poorly understood. We show that the Rab GTPase membrane trafficking regulators Rab8a, -17, and -23, and their cognate GTPase-activating proteins (GAPs), XM_037557, TBC1D7, and EVI5like, are involved in primary cilia formation. However, other human Rabs and GAPs are not. Additionally, Rab8a specifically interacts with cenexin/ODF2, a basal body and microtubule binding protein required for cilium biogenesis (Ishikawa, H., A. Kubo, S. Tsukita, and S. Tsukita. 2005. Nat. Cell Biol. 7:517–524), and is the sole Rab enriched at primary cilia. These findings provide a basis for understanding how specific membrane trafficking pathways cooperate with the microtubule cytoskeleton to give rise to the primary cilia

Complementarity of experimental and lattice QCD data on pion parton distributions

We extract pion parton distribution functions (PDFs) in a Monte Carlo global QCD analysis of experimental data together with reduced Ioffe time pseudo-distributions and matrix elements of current-current correlators generated from lattice QCD. By including both experimental and lattice QCD data, our analysis rigorously quantifies both the uncertainties of the pion PDFs and systematic effects intrinsic to the lattice QCD observables. The reduced Ioffe time pseudo-distributions significantly decrease the uncertainties on the PDFs, while the current-current correlators are limited by the systematic effects associated with the lattice. Consistent with recent phenomenological determinations, the behavior of the valence quark distribution of the pion at large momentum fraction is found to be $\sim (1-x)^{ \beta_{\rm eff}}$ with $\beta_{\rm eff} \approx 1.0-1.2$.Comment: 46 pages, 15 figure

Inositol Hexakisphosphate-Induced Autoprocessing of Large Bacterial Protein Toxins

Large bacterial protein toxins autotranslocate functional effector domains to the eukaryotic cell cytosol, resulting in alterations to cellular functions that ultimately benefit the infecting pathogen. Among these toxins, the clostridial glucosylating toxins (CGTs) produced by Gram-positive bacteria and the multifunctional-autoprocessing RTX (MARTX) toxins of Gram-negative bacteria have distinct mechanisms for effector translocation, but a shared mechanism of post-translocation autoprocessing that releases these functional domains from the large holotoxins. These toxins carry an embedded cysteine protease domain (CPD) that is activated for autoprocessing by binding inositol hexakisphosphate (InsP6), a molecule found exclusively in eukaryotic cells. Thus, InsP6-induced autoprocessing represents a unique mechanism for toxin effector delivery specifically within the target cell. This review summarizes recent studies of the structural and molecular events for activation of autoprocessing for both CGT and MARTX toxins, demonstrating both similar and potentially distinct aspects of autoprocessing among the toxins that utilize this method of activation and effector delivery

City-size bias in knowledge on the effects of urban nature on people and biodiversity

The evidence base for the benefits of urban nature for people and biodiversity is strong. However, cities are diverse and the social and environmental contexts of cities are likely to influence the observed effects of urban nature, and the application of evidence to differing contexts. To explore biases in the evidence base for the effects of urban nature, we text-matched city names in the abstracts and affiliations of 14 786 journal articles, from separate searches for articles on urban biodiversity, the health and wellbeing impacts of urban nature, and on urban ecosystem services. City names were found in 51% of article abstracts and 92% of affiliations. Most large cities were studied many times over, while only a small proportion of small cities were studied once or twice. Almost half the cities studied also had an author with an affiliation from that city. Most studies were from large developed cities, with relatively few studies from Africa and South America in particular. These biases mean the evidence base for the effects of urban nature on people and on biodiversity does not adequately represent the lived experience of the 41% of the world’s urban population who live in small cities, nor the residents of the many rapidly urbanising areas of the developing world. Care should be taken when extrapolating research findings from large global cities to smaller cities and cities in the developing world. Future research should encourage research design focussed on answering research questions rather than city selection by convenience, disentangle the role of city size from measures of urban intensity (such as population density or impervious surface cover), avoid gross urban-rural dualisms, and better contextualise existing research across social and environmental contexts

SPR imaging biosensor for the 20S proteasome: sensor development and application to measurement of proteasomes in human blood plasma

The 20S proteasome is a multicatalytic enzyme complex responsible for intracellular protein degradation in mammalian cells. Its antigen level or enzymatic activity in blood plasma are potentially useful markers for various malignant and nonmalignant diseases. We have developed a method for highly selective determination of the 20S proteasome using a Surface Plasmon Resonance Imaging (SPRI) technique. It is based on the highly selective interaction between the proteasome’s catalytic β5 subunit and immobilized inhibitors (the synthetic peptide PSI and epoxomicin). Inhibitor concentration and pH were optimized. Analytical responses, linear ranges, accuracy, precision and interferences were investigated. Biosensors based on either PSI and epoxomicin were found to be suitable for quantitative determination of the proteasome, with a precision of ±10% for each, and recoveries of 102% and 113%, respectively, and with little interference by albumin, trypsin, chymotrypsin, cathepsin B and papain. The proteasome also was determined in plasma of healthy subjects and of patients suffering from acute leukemia. Both biosensors gave comparable results (2860 ng·mL-1 on average for control, and 42300 ng·mL-1 on average for leukemia patients)