A peptide mimic of the chemotaxis inhibitory protein of Staphylococcus aureus: towards the development of novel anti-inflammatory compounds

Complement factor C5a is one of the most powerful pro-inflammatory agents involved in recruitment of leukocytes, activation of phagocytes and other inflammatory responses. C5a triggers inflammatory responses by binding to its G-protein-coupled C5a-receptor (C5aR). Excessive or erroneous activation of the C5aR has been implicated in numerous inflammatory diseases. The C5aR is therefore a key target in the development of specific anti-inflammatory compounds. A very potent natural inhibitor of the C5aR is the 121-residue chemotaxis inhibitory protein of Staphylococcus aureus (CHIPS). Although CHIPS effectively blocks C5aR activation by binding tightly to its extra-cellular N terminus, it is not suitable as a potential anti-inflammatory drug due to its immunogenic properties. As a first step in the development of an improved CHIPS mimic, we designed and synthesized a substantially shorter 50-residue adapted peptide, designated CHOPS. This peptide included all residues important for receptor binding as based on the recent structure of CHIPS in complex with the C5aR N terminus. Using isothermal titration calorimetry we demonstrate that CHOPS has micromolar affinity for a model peptide comprising residues 7–28 of the C5aR N terminus including two O-sulfated tyrosine residues at positions 11 and 14. CD and NMR spectroscopy showed that CHOPS is unstructured free in solution. Upon addition of the doubly sulfated model peptide, however, the NMR and CD spectra reveal the formation of structural elements in CHOPS reminiscent of native CHIPS

Percentile reference values for anthropometric body composition indices in European children from the IDEFICS study

INTRODUCTION: To characterise the nutritional status in children with obesity or wasting conditions, European anthropometric reference values for body composition measures beyond the body mass index (BMI) are needed. Differentiated assessment of body composition in children has long been hampered by the lack of appropriate references. OBJECTIVES: The aim of our study is to provide percentiles for body composition indices in normal weight European children, based on the IDEFICS cohort (Identification and prevention of Dietary-and lifestyle-induced health Effects in Children and infantS). METHODS: Overall 18 745 2.0-10.9-year-old children from eight countries participated in the study. Children classified as overweight/obese or underweight according to IOTF (N = 5915) were excluded from the analysis. Anthropometric measurements (BMI (N = 12 830); triceps, subscapular, fat mass and fat mass index (N = 11 845-11 901); biceps, suprailiac skinfolds, sum of skinfolds calculated from skinfold thicknesses (N = 8129-8205), neck circumference (N = 12 241); waist circumference and waist-to-height ratio (N = 12 381)) were analysed stratified by sex and smoothed 1st, 3rd, 10th, 25th, 50th, 75th, 90th, 97th and 99th percentile curves were calculated using GAMLSS. RESULTS: Percentile values of the most important anthropometric measures related to the degree of adiposity are depicted for European girls and boys. Age-and sex-specific differences were investigated for all measures. As an example, the 50th and 99th percentile values of waist circumference ranged from 50.7-59.2 cm and from 51.3-58.7 cm in 4.5-to < 5.0-year-old girls and boys, respectively, to 60.6-74.5 cm in girls and to 59.9-76.7 cm in boys at the age of 10.5-10.9 years. CONCLUSION: The presented percentile curves may aid a differentiated assessment of total and abdominal adiposity in European children

Inactivation of Staphylococcal Phenol Soluble Modulins by Serum Lipoprotein Particles

Staphylococcus aureus virulence has been associated with the production of phenol soluble modulins (PSM). PSM are known to activate, attract and lyse neutrophils. However, the functional characterizations were generally performed in the absence of human serum. Here, we demonstrate that human serum can inhibit all the previously-described activities of PSM. We observed that serum can fully block both the cell lysis and FPR2 activation of neutrophils. We show a direct interaction between PSM and serum lipoproteins in human serum and whole blood. Subsequent analysis using purified high, low, and very low density lipoproteins (HDL, LDL, and VLDL) revealed that they indeed neutralize PSM. The lipoprotein HDL showed highest binding and antagonizing capacity for PSM. Furthermore, we show potential intracellular production of PSM by S. aureus upon phagocytosis by neutrophils, which opens a new area for exploration of the intracellular lytic capacity of PSM. Collectively, our data show that in a serum environment the function of PSM as important extracellular toxins should be reconsidered

Interactive Actor Analysis for Rural Water Management in The Netherlands

Recent developments in the policy sciences emphasize the social environment in which decisions are made. The ‘network metaphor’ is often used to describe the key role of interactions between interdependent actors involved in decision making. These interactions take place in a policy arena drawn up by actors with an interest in and control over decisions on the issues addressed. Interdependencies, caused by the need for actors to increase their means of realizing objectives, are the driving force behind these interactions. Dependency relations are of special interest to water management and river basin management because of the fundamental asymmetrical interdependencies that exist in river basins between upstream and downstream stakeholders. Coleman’s linear system of action models decision making process involving dependencies between multiple stakeholders as exchange of control over issues, while interactions are required to negotiate exchanges of control. We developed an interactive method for actor analysis based on Coleman’s linear system of action and applied it to the national rural water management policy domain in The Netherlands. The method is firmly rooted in mathematical sociology and defies the criticism that methods for actor and stakeholder analysis do not specify a theoretical basis explaining the causal relations between the variables analyzed and policy change. With the application to the rural water management policy arena we intended to increase our insight into the practical applicability of this analyticmethod in an interactive workshop, the acceptability of the approach for the participating actors, its contribution to the process of decision making and our understanding of the rural water management policy arena in The Netherlands. We found that the Association of Water Authorities, the Ministry of Public Works and the Ministry of Agriculture are the most powerful actor in the policy domain, while governance and cost and benefits of rural water management are the most salient issues. Progress in policy development for rural water management is probably most promising for the issues governance, costs and benefits, safety and rural living conditions through improved interaction between the Association of Water Authorities, the Ministry of Agriculture and the Rural Credit Bank. Besides these analytic results the interactive approach implemented increased the participants understanding of their dependency on other actors in the rural water management policy domain and supported them in developing a sound perspective on their dependency position. We concluded that the method developed is acceptable to real-world policy decision makers, can successfully be applied in an interactive setting, potentially contributes to the process of decision making by increasing the participants understanding of their dependency position, has the potential to delivers valuable advice for future decision-making and increases our understanding of policy development for rural water management in general

Reproductive Isolation and Ecological Niche Partition among Larvae of the Morphologically Cryptic Sister Species Chironomus riparius and C. piger

Background One of the central issues in ecology is the question what allows sympatric occurrence of closely related species in the same general area? The non-biting midges Chironomus riparius and C. piger, interbreeding in the laboratory, have been shown to coexist frequently despite of their close relatedness, similar ecology and high morphological similarity. Methodology/Principal Findings In order to investigate factors shaping niche partitioning of these cryptic sister species, we explored the actual degree of reproductive isolation in the field. Congruent results from nuclear microsatellite and mitochondrial haplotype analyses indicated complete absence of interspecific gene-flow. Autocorrelation analysis showed a non-random spatial distribution of the two species. Though not dispersal limited at the scale of the study area, the sister species occurred less often than expected at the same site, indicating past or present competition. Correlation and multiple regression analyses suggested the repartition of the available habitat along water chemistry gradients (nitrite, conductivity, CaCO3), ultimately governed by differences in summer precipitation regime. Conclusions We show that these morphologically cryptic sister species partition their niches due to a certain degree of ecological distinctness and total reproductive isolation in the field. The coexistence of these species provides a suitable model system for the investigation of factors shaping the distribution of closely related, cryptic species

Exogenous 17-β estradiol administration blunts progression of established angiotensin II-induced abdominal aortic aneurysms in female ovariectomized mice

BACKGROUND: Abdominal aortic aneurysms (AAAs) occur predominately in males. However, AAAs in females have rapid growth rates and rupture at smaller sizes. Mechanisms contributing to AAA progression in females are undefined. We defined effects of ovariectomy, with and without 17-β estradiol (E2), on progression of established angiotensin II (AngII)-induced AAAs in female mice. METHODS: We used neonatal testosterone exposures at 1 day of age to promote susceptibility to AngII-induced AAAs in adult female Ldlr(−/−) mice. Females were infused with AngII for 28 days to induce AAAs, and then stratified into groups that were sham, ovariectomized (Ovx, vehicle), or Ovx with E2 administration for 2 months of continued AngII infusions. Aortic lumen diameters were quantified by ultrasound and analyzed by linear mixed model, and maximal AAA diameters were analyzed by one-way ANOVA. Atherosclerosis was quantified en face in the aortic arch. AAA tissue sections were analyzed for cellular composition. We quantified effects of E2 on abdominal aortic smooth muscle cell (SMC) growth, α-actin and transforming growth factor-beta (TGF-β) production, and wound healing. RESULTS: Serum E2 concentrations were increased significantly by E2. Aortic lumen diameters increased over time in sham-operated and Ovx (vehicle) females, but not in Ovx females administered E2. At day 70, E2 administration decreased significantly aortic lumen diameters compared to Ovx vehicle and sham-operated females. Compared to Ovx females (vehicle), maximal AAA diameters were reduced significantly by E2. AAA tissue sections from Ovx females administered E2 exhibited significant increases in α-actin and decreases in neutrophils compared to Ovx females administered vehicle. In abdominal aortic SMCs, E2 resulted in a concentration-dependent increase in α-actin, elevated TGF-β, and more rapid wound healing. E2 administration to Ovx females also significantly reduced atherosclerotic lesions compared to sham-operated females. This effect was accompanied by significant reductions in serum cholesterol concentrations. CONCLUSIONS: E2 administration to Ovx females abolished progressive growth and decreased severity of AngII-induced AAAs. These effects were accompanied by increased SMC α-actin, elevated TGF-β, and reduced neutrophils. Similarly, E2 administration reduced AngII-induced atherosclerosis. These results suggest that loss of E2 in post-menopausal females may contribute to progressive growth of AAAs. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13293-015-0030-1) contains supplementary material, which is available to authorized users

Fortnightly changes in water transport direction across the mouth of a narrow estuary

This research investigates the dynamics of the axial tidal flow and residual circulation at the lower Guadiana Estuary, south Portugal, a narrow mesotidal estuary with low freshwater inputs. Current data were collected near the deepest part of the channel for 21 months and across the channel during two (spring and neap) tidal cycles. Results indicate that at the deep channel, depth-averaged currents are stronger and longer during the ebb at spring and during the flood at neap, resulting in opposite water transport directions at a fortnightly time scale. The net water transport across the entire channel is up-estuary at spring and down-estuary at neap, i.e., opposite to the one at the deep channel. At spring tide, when the estuary is considered to be well mixed, the observed pattern of circulation (outflow in the deep channel, inflow over the shoals) results from the combination of the Stokes transport and compensating return flow, which varies laterally with the bathymetry. At neap tide (in particular for those of lowest amplitude each month), inflows at the deep channel are consistently associated with the development of gravitational circulation. Comparisons with previous studies suggest that the baroclinic pressure gradient (rather than internal tidal asymmetries) is the main driver of the residual water transport. Our observations also indicate that the flushing out of the water accumulated up-estuary (at spring) may also produce strong unidirectional barotropic outflow across the entire channel around neap tide.info:eu-repo/semantics/publishedVersio

Beauty photoproduction measured using decays into muons in dijet events in ep collisions at s\sqrt{s}=318 GeV

The photoproduction of beauty quarks in events with two jets and a muon has been measured with the ZEUS detector at HERA using an integrated luminosity of 110 pb$^{- 1}$. The fraction of jets containing b quarks was extracted from the transverse momentum distribution of the muon relative to the closest jet. Differential cross sections for beauty production as a function of the transverse momentum and pseudorapidity of the muon, of the associated jet and of $x_{\gamma}^{jets}$, the fraction of the photon's momentum participating in the hard process, are compared with MC models and QCD predictions made at next-to-leading order. The latter give a good description of the data.Comment: 32 pages, 6 tables, 7 figures Table 6 and Figure 7 revised September 200

Measurement of D-s(+) and D-s(*+) production in B meson decays and from continuum e(+)e(-) annihilation at √s=10.6 GeV

This is the pre-print version of the Article. The official published version can be accessed from the links below. Copyright @ 2002 APSNew measurements of Ds+ and Ds*+ meson production rates from B decays and from qq̅ continuum events near the Υ(4S) resonance are presented. Using 20.8 fb-1 of data on the Υ(4S) resonance and 2.6 fb-1 off-resonance, we find the inclusive branching fractions B(B⃗Ds+X)=(10.93±0.19±0.58±2.73)% and B(B⃗Ds*+X)=(7.9±0.8±0.7±2.0)%, where the first error is statistical, the second is systematic, and the third is due to the Ds+→φπ+ branching fraction uncertainty. The production cross sections σ(e+e-→Ds+X)×B(Ds+→φπ+)=7.55±0.20±0.34pb and σ(e+e-→Ds*±X)×B(Ds+→φπ+)=5.8±0.7±0.5pb are measured at center-of-mass energies about 40 MeV below the Υ(4S) mass. The branching fractions ΣB(B⃗Ds(*)+D(*))=(5.07±0.14±0.30±1.27)% and ΣB(B⃗Ds*+D(*))=(4.1±0.2±0.4±1.0)% are determined from the Ds(*)+ momentum spectra. The mass difference m(Ds+)-m(D+)=98.4±0.1±0.3MeV/c2 is also measured.This work was supported by DOE and NSF (USA), NSERC (Canada), IHEP (China), CEA and CNRS-IN2P3 (France), BMBF (Germany), INFN (Italy), NFR (Norway), MIST (Russia), and PPARC (United Kingdom). Individuals have received support from the Swiss NSF, A. P. Sloan Foundation, Research Corporation, and Alexander von Humboldt Foundation