Stimulation of the Na+/H+ exchanger in human endothelial cells activated by granulocyte- and granulocyte-macrophage-colony-stimulating factor. Evidence for a role in proliferation and migration.

It has been shown that human endothelial cells (HEC) are stimulated to migrate and proliferate by granulocyte (G)- and granulocyte-macrophage (GM)-colony-stimulating factor (CSF) (Bussolino, F., Wang, J. M., Defilipii, P. Turrini, F., Sanavio, F., Edgell, C.-J. S., Aglietta, M., Arese, P., and Mantovani, A. (1989) Nature 337, 471-473). The rapid intracellular events initiated by these cytokines on binding to their receptors on HEC are not defined. Addition of G- or GM-CSF to HEC produced a rapid activation of Na+/H+ exchanger resulting in an increase in intracellular pH (pHi). Both cytokines induced an alkaline displacement in the pHi dependence of the exchanger without affecting the affinity for external Na+ (Nao) and the rate of exchanger. Ethylisopropylamiloride, a selective inhibitor of the Na+/H+ exchanger, inhibited the intracellular alkalinization, the migration, and proliferation induced by G- and GM-CSF. The data indicate that G- and GM-CSF initiate a rapid exchange of Na+ and H+ by means of the Na+/H+ exchanger and that this ethylisopropylamiloride-sensitive ions flux is important to the biological effects of these cytokines on HEC

From Correlators to Wilson Loops in Chern-Simons Matter Theories

We study n-point correlation functions for chiral primary operators in three dimensional supersymmetric Chern-Simons matter theories. Our analysis is carried on in N=2 superspace and covers N=2,3 supersymmetric CFT's, the N=6 ABJM and the N=8 BLG models. In the limit where the positions of adjacent operators become light-like, we find that the one-loop n-point correlator divided by its tree level expression coincides with a light-like n-polygon Wilson loop. Remarkably, the result can be simply expressed as a linear combination of five dimensional two-mass easy boxes. We manage to evaluate the integrals analytically and find a vanishing result, in agreement with previous findings for Wilson loops.Comment: 32 pages, 6 figures, JHEP

New families of interpolating type IIB backgrounds

We construct new families of interpolating two-parameter solutions of type IIB supergravity. These correspond to D3-D5 systems on non-compact six-dimensional manifolds which are T^2 fibrations over Eguchi-Hanson and multi-center Taub-NUT spaces, respectively. One end of the interpolation corresponds to a solution with only D5 branes and vanishing NS three-form flux. A topology changing transition occurs at the other end, where the internal space becomes a direct product of the four-dimensional surface and the two-torus and the complexified NS-RR three-form flux becomes imaginary self-dual. Depending on the choice of the connections on the torus fibre, the interpolating family has either N=2 or N=1 supersymmetry. In the N=2 case it can be shown that the solutions are regular.Comment: 20 page

Ab initio and homology based prediction of protein domains by recursive neural networks

Background: Proteins, especially larger ones, are often composed of individual evolutionary units, domains, which have their own function and structural fold. Predicting domains is an important intermediate step in protein analyses, including the prediction of protein structures. Results: We describe novel systems for the prediction of protein domain boundaries powered by Recursive Neural Networks. The systems rely on a combination of primary sequence and evolutionary information, predictions of structural features such as secondary structure, solvent accessibility and residue contact maps, and structural templates, both annotated for domains (from the SCOP dataset) and unannotated (from the PDB). We gauge the contribution of contact maps, and PDB and SCOP templates independently and for different ranges of template quality. We find that accurately predicted contact maps are informative for the prediction of domain boundaries, while the same is not true for contact maps predicted ab initio. We also find that gap information from PDB templates is informative, but, not surprisingly, less than SCOP annotations. We test both systems trained on templates of all qualities, and systems trained only on templates of marginal similarity to the query (less than 25% sequence identity). While the first batch of systems produces near perfect predictions in the presence of fair to good templates, the second batch outperforms or match ab initio predictors down to essentially any level of template quality. We test all systems in 5-fold cross-validation on a large non-redundant set of multi-domain and single domain proteins. The final predictors are state-of-the-art, with a template-less prediction boundary recall of 50.8% (precision 38.7%) within ± 20 residues and a single domain recall of 80.3% (precision 78.1%). The SCOP-based predictors achieve a boundary recall of 74% (precision 77.1%) again within ± 20 residues, and classify single domain proteins as such in over 85% of cases, when we allow a mix of bad and good quality templates. If we only allow marginal templates (max 25% sequence identity to the query) the scores remain high, with boundary recall and precision of 59% and 66.3%, and 80% of all single domain proteins predicted correctly. Conclusion: The systems presented here may prove useful in large-scale annotation of protein domains in proteins of unknown structure. The methods are available as public web servers at the address: http://distill.ucd.ie/shandy/ and we plan on running them on a multi-genomic scale and make the results public in the near future.Science Foundation IrelandHealth Research BoardUCD President's Award 2004au, da, sp, ke, ab - kpw2/12/1

Distill: a suite of web servers for the prediction of one-, two- and three-dimensional structural features of proteins

BACKGROUND: We describe Distill, a suite of servers for the prediction of protein structural features: secondary structure; relative solvent accessibility; contact density; backbone structural motifs; residue contact maps at 6, 8 and 12 Angstrom; coarse protein topology. The servers are based on large-scale ensembles of recursive neural networks and trained on large, up-to-date, non-redundant subsets of the Protein Data Bank. Together with structural feature predictions, Distill includes a server for prediction of C(α )traces for short proteins (up to 200 amino acids). RESULTS: The servers are state-of-the-art, with secondary structure predicted correctly for nearly 80% of residues (currently the top performance on EVA), 2-class solvent accessibility nearly 80% correct, and contact maps exceeding 50% precision on the top non-diagonal contacts. A preliminary implementation of the predictor of protein C(α )traces featured among the top 20 Novel Fold predictors at the last CASP6 experiment as group Distill (ID 0348). The majority of the servers, including the C(α )trace predictor, now take into account homology information from the PDB, when available, resulting in greatly improved reliability. CONCLUSION: All predictions are freely available through a simple joint web interface and the results are returned by email. In a single submission the user can send protein sequences for a total of up to 32k residues to all or a selection of the servers. Distill is accessible at the address:

Ab initio and template-based prediction of multi-class distance maps by two-dimensional recursive neural networks

Background: Prediction of protein structures from their sequences is still one of the open grand challenges of computational biology. Some approaches to protein structure prediction, especially ab initio ones, rely to some extent on the prediction of residue contact maps. Residue contact map predictions have been assessed at the CASP competition for several years now. Although it has been shown that exact contact maps generally yield correct three-dimensional structures, this is true only at a relatively low resolution (3–4 Å from the native structure). Another known weakness of contact maps is that they are generally predicted ab initio, that is not exploiting information about potential homologues of known structure. Results: We introduce a new class of distance restraints for protein structures: multi-class distance maps. We show that C trace reconstructions based on 4-class native maps are significantly better than those from residue contact maps. We then build two predictors of 4-class maps based on recursive neural networks: one ab initio, or relying on the sequence and on evolutionary information; one template-based, or in which homology information to known structures is provided as a further input. We show that virtually any level of sequence similarity to structural templates (down to less than 10%) yields more accurate 4-class maps than the ab initio predictor. We show that template-based predictions by recursive neural networks are consistently better than the best template and than a number of combinations of the best available templates. We also extract binary residue contact maps at an 8 Å threshold (as per CASP assessment) from the 4-class predictors and show that the template-based version is also more accurate than the best template and consistently better than the ab initio one, down to very low levels of sequence identity to structural templates. Furthermore, we test both ab-initio and template-based 8 Å predictions on the CASP7 targets using a pre-CASP7 PDB, and find that both predictors are state-of-the-art, with the template-based one far outperforming the best CASP7 systems if templates with sequence identity to the query of 10% or better are available. Although this is not the main focus of this paper we also report on reconstructions of C traces based on both ab initio and template-based 4-class map predictions, showing that the latter are generally more accurate even when homology is dubious. Conclusion: Accurate predictions of multi-class maps may provide valuable constraints for improved ab initio and template-based prediction of protein structures, naturally incorporate multiple templates, and yield state-of-the- art binary maps. Predictions of protein structures and 8 Å contact maps based on the multi-class distance map predictors described in this paper are freely available to academic users at the url http://distill.ucd.ie/.Science Foundation IrelandHealth Research BoardUCD President's Award 2004au, ti, sp, ke, ab - kpw16/12/1

Air Pollution, Smoking, and Plasma Homocysteine

BACKGROUND: Mild hyperhomocysteinemia is independently associated with an increased risk of cardiovascular disease. Air pollution exposure induces short-term inflammatory changes that may determine hyperhomocysteinemia, particularly in the presence of a preexisting proinflammatory status such as that found in cigarette smokers. OBJECTIVE: We examined the relation of air pollution levels with fasting and postmethionine-load total homocysteine (tHcy) in 1,213 normal subjects from Lombardia, Italy. METHODS: We obtained hourly concentrations of particulate matter < 10 μm in aerodynamic diameter (PM(10)) and gaseous pollutants (carbon monoxide, nitrogen dioxide, sulfur dioxide(,) ozone) from 53 monitoring sites covering the study area. We applied generalized additive models to compute standardized regression coefficients controlled for age, sex, body mass index, smoking, alcohol, hormone use, temperature, day of the year, and long-term trends. RESULTS: The estimated difference in tHcy associated with an interquartile increase in average PM(10) concentrations in the 24 hr before the study was nonsignificant [0.4%; 95% confidence interval (CI), −2.4 to 3.3 for fasting; and 1.1%, 95% CI, −1.5 to 3.7 for postmethionine-load tHcy]. In smokers, 24-hr PM(10) levels were associated with 6.3% (95% CI, 1.3 to 11.6; p < 0.05) and 4.9% (95% CI, 0.5 to 9.6; p < 0.05) increases in fasting and postmethionine-load tHcy, respectively, but no association was seen in nonsmokers (p-interaction = 0.005 for fasting and 0.039 for postmethionine-load tHcy). Average 24-hr O(3) concentrations were associated with significant differences in fasting tHcy (6.7%; 95% CI, 0.9 to 12.8; p < 0.05), but no consistent associations were found when postmethionine-load tHcy and/or 7-day average O(3) concentrations were considered. CONCLUSIONS: Air particles may interact with cigarette smoking and increase plasma homocysteine in healthy subjects

Alkylphenols and polycyclic aromatic hydrocarbons in eastern Mediterranean Spanish coastal marine bivalves

This paper reports the first results on alkylphenol pollution in edible bivalves from the Spanish coast. Two sampling campaigns (July 2006 and July 2007) were carried out to determine the concentration of nonylphenol (NP), octylphenol (OP), and eight polycyclic aromatic hydrocarbons (PAHs) in wild mussels (Mytilus galloprovincialys) and clams (Donax trunculus) at 14 sampling sites along the eastern Mediterranean Spanish coast. The results show that NP is the predominant alkylphenol, being the port of Valencia the most polluted area (up to 147 mu g/kg wet weight in clams). Moving away from the ports the concentration of NP in bivalves decreased. OP concentration was below its detection limit in most of the studied areas and its maximum concentration (6 mu g/kg w/w) was measured in clams from the port of Sagunto. The presence of low levels of PAHs was observed in most of the studied areas. The total PAHs concentration (i.e., sum of the eight measured PAHs) achieved a maximum value of 10.09 mu g/kg w/w in the north coast of Valencia city. The distribution pattern of the individual PAHs showed that both pollution sources petrogenic and pyrolytic were present in the sampled areas. Fluoranthene was the most abundant PAH in mussels while benzo(b)fluoranthene in clams. The maximum concentration of 10 mu g/kg w/w for benzo(a)pyrene established by the European Commission was never reached, indeed sampled bivalves showed concentrations 10 times lower than this reference value. Thus, they can be considered safe for human consumption. Despite the low contamination levels, the results show an overall pollution of bivalves by alkylphenol and PAHs as well as an increment in the number of polluted areas from 2006 to 2007. Thus, periodical sampling campaigns should be carried out to monitor the long-term tendency of these toxic and persistent pollutants. © 2010 Springer Science+Business Media B.V.Financial support from Conselleria de Medio Ambiente, Agua, Urbanismo y Vivienda de la Generalitat Valenciana (Application of Water Framework Directive 2000/60/EC on endocrine disruptors and priority substances in coastal areas in the Comunidad Valenciana) is gratefully acknowledged.Bouzas Blanco, A.; Aguado García, D.; Martí Ortega, N.; Pastor, J.; Herraez, R.; Campins, P.; Seco Torrecillas, A. (2011). Alkylphenols and polycyclic aromatic hydrocarbons in eastern Mediterranean Spanish coastal marine bivalves. Environmental Monitoring and Assessment. 176(1-4):169-181. doi:10.1007/s10661-010-1574-5S1691811761-4Antizar-Ladislao, B. (2009). Polycyclic aromatic hydrocarbons, polycholirnated biphenyls, phthalates and organotins in northern Atlantic Spain’s coastal marine sediments. 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Elective Open Suprarenal Aneurysm Repair in England from 2000 to 2010 an Observational Study of Hospital Episode Statistics

Background: Open surgery is widely used as a benchmark for the results of fenestrated endovascular repair of complex abdominal aortic aneurysms (AAA). However, the existing evidence stems from single-centre experiences, and may not be reproducible in wider practice. National outcomes provide valuable information regarding the safety of suprarenal aneurysm repair. Methods: Demographic and clinical data were extracted from English Hospital Episodes Statistics for patients undergoing elective suprarenal aneurysm repair from 1 April 2000 to 31 March 2010. Thirty-day mortality and five-year survival were analysed by logistic regression and Cox proportional hazards modeling. Results: 793 patients underwent surgery with 14% overall 30-day mortality, which did not improve over the study period. Independent predictors of 30-day mortality included age, renal disease and previous myocardial infarction. 5-year survival was independently reduced by age, renal disease, liver disease, chronic pulmonary disease, and known metastatic solid tumour. There was significant regional variation in both 30-day mortality and 5-year survival after risk-adjustment. Regional differences in outcome were eliminated in a sensitivity analysis for perioperative outcome, conducted by restricting analysis to survivors of the first 30 days after surgery. Conclusions: Elective suprarenal aneurysm repair was associated with considerable mortality and significant regional variation across England. These data provide a benchmark to assess the efficacy of complex endovascular repair of supra-renal aneurysms, though cautious interpretation is required due to the lack of information regarding aneurysm morphology. More detailed study is required, ideally through the mandatory submission of data to a national registry of suprarenal aneurysm repair