Characterization of pathogenic germline mutations in human Protein Kinases

Background Protein Kinases are a superfamily of proteins involved in crucial cellular processes such as cell cycle regulation and signal transduction. Accordingly, they play an important role in cancer biology. To contribute to the study of the relation between kinases and disease we compared pathogenic mutations to neutral mutations as an extension to our previous analysis of cancer somatic mutations. First, we analyzed native and mutant proteins in terms of amino acid composition. Secondly, mutations were characterized according to their potential structural effects and finally, we assessed the location of the different classes of polymorphisms with respect to kinase-relevant positions in terms of subfamily specificity, conservation, accessibility and functional sites.<p></p> Results Pathogenic Protein Kinase mutations perturb essential aspects of protein function, including disruption of substrate binding and/or effector recognition at family-specific positions. Interestingly these mutations in Protein Kinases display a tendency to avoid structurally relevant positions, what represents a significant difference with respect to the average distribution of pathogenic mutations in other protein families.<p></p> Conclusions Disease-associated mutations display sound differences with respect to neutral mutations: several amino acids are specific of each mutation type, different structural properties characterize each class and the distribution of pathogenic mutations within the consensus structure of the Protein Kinase domain is substantially different to that for non-pathogenic mutations. This preferential distribution confirms previous observations about the functional and structural distribution of the controversial cancer driver and passenger somatic mutations and their use as a proxy for the study of the involvement of somatic mutations in cancer development.<p></p&gt

Electrocatalytic performance of SiO2-SWCNT nanocomposites prepared by electroassisted deposition

“The final publication is available at Springer via http://dx.doi.org/10.1007/s12678-013-0144-3”Composite materials made of porous SiO2 matrices filled with single-walled carbon nanotubes (SWCNTs) were deposited on electrodes by an electroassisted deposition method. The synthesized materials were characterized by several techniques, showing that porous silica prevents the aggregation of SWCNT on the electrodes, as could be observed by transmission electron microscopy and Raman spectroscopy. Different redox probes were employed to test their electrochemical sensing properties. The silica layer allows the permeation of the redox probes to the electrode surface and improves the electrochemical reversibility indicating an electrocatalytic effect by the incorporation of dispersed SWCNT into the silica films.This work was financed by the following research projects: MAT2010-15273 of the Spanish Ministerio de Economia y Competitividad and FEDER, PROMETEO/2013/038 of the GV, and CIVP16A1821 of the Fundacion Ramon Areces. Alonso Gamero-Quijano and David Salinas-Torres acknowledge Generalitat Valenciana (Santiago Grisolia Program) and Ministerio de Economia y Competitividad, respectively, for the funding of their research fellowships.Gamero-Quijano, A.; Huerta, F.; Salinas-Torres, D.; Morallón, E.; Montilla, F. (2013). Electrocatalytic performance of SiO2-SWCNT nanocomposites prepared by electroassisted deposition. Electrocatalysis. 4(4):259-266. https://doi.org/10.1007/s12678-013-0144-3S25926644P. Alivisatos, Nat. Biotechnol. 22, 47 (2004)S. Stankovich, D.A. Dikin, G.H. Dommett, K.M. Kohlhaas, E.J. Zimney, E.A. Stach, R.D. Piner, S.T. Nguyen, R.S. Ruoff, Nature 442, 282 (2006)D.W. Schaefer, R.S. Justice, Macromolecules 40, 8501 (2007)M. Endo, M.S. Strano, P.M. Ajayan, Carbon Nanotubes 111, 13 (2008)C.E. Banks, R.G. Compton, Analyst 131, 15 (2006)R.H. Baughman, A.A. Zakhidov, W.A. de Heer, Science 297, 787 (2002)Y.H. Lin, F. Lu, Y. Tu, Z.F. Ren, Nano Letters 4, 191 (2004)B.R. Azamian, J.J. Davis, K.S. Coleman, C.B. Bagshaw, M.L.H. Green, J. Am. Chem. Soc. 124, 12664 (2002)W. Yang, K. Ratinac, S. Ringer, P. Thordarson, J.G. Gooding, F. Braet, Angew. Chem. Int. Ed. 49, 2114 (2010)C.E. Banks, R.G. Compton, Analyst 130, 1232 (2005)L. Mazurenko, M. Etienne, O. Tananaiko, V. Zaitsev, A. Walcarius, Electrochim. Acta 83, 359 (2012)J.M.P. Paloma Yáñez-Sedeño, J. Riu, F.X. Rius, TrAC Trends in Analytical Chemistry 29, 939 (2010)Z.J. Wang, M. Etienne, S. Poller, W. Schuhmann, G.W. Kohring, V. Mamane, A. Walcarius, Electroanalysis 24, 376 (2012)R. Bandyopadhyaya, E. Nativ-Roth, O. Regev, R. Yerushalmi-Rozen, Nano Letters 2, 25 (2002)C. Park, Z. Ounaies, K.A. Watson, R.E. Crooks, J. Smith, S.E. Lowther, J.W. Connell, E.J. Siochi, J.S. Harrison, T.L.S. Clair, Chem. Phys. Lett. 364, 303 (2002)O. Matarredona, H. Rhoads, Z.R. Li, J.H. Harwell, L. Balzano, D.E. Resasco, Journal of Physical Chemistry B 107, 13357 (2003)L. Vaisman, H. Wagner, G. Marom, Advances in Colloid and Interface Science 128, 37 (2006)Y.C. Xing, Journal of Physical Chemistry B 108, 19255 (2004)J.J. Liang, Y. Huang, L. Zhang, Y. Wang, Y.F. Ma, T.Y. Guo, Y.S. Chen, Adv. Funct. Mater. 19, 2297 (2009)D. Salinas-Torres, F. Huerta, F. Montilla, E. Morallón, Electrochim. Acta 56, 2464 (2011)Z.F. Ren, Z.P. Huang, J.W. Xu, J.H. Wang, P. Bush, M.P. Siegal, P.N. Provencio, Science 282, 1105 (1998)W.Z. Li, S.S. Xie, L.X. Qian, B.H. Chang, B.S. Zou, W.Y. Zhou, R.A. Zhao, G. Wang, Science 274, 1701 (1996)M. Terrones, N. Grobert, J. Olivares, J.P. Zhang, H. Terrones, K. Kordatos, W.K. Hsu, J.P. Hare, P.D. Townsend, K. Prassides, A.K. Cheetham, H.W. Kroto, D.R.M. Walton, Nature 388, 52 (1997)R. Toledano, D. Mandler, Chem. Mater. 22, 3943 (2010)J.H. Rouse, Langmuir 21, 1055 (2005)X.B. Yan, B.K. Tay, Y. Yang, Journal of Physical Chemistry B 110, 25844 (2006)J. Lim, P. Malati, F. Bonet, B. Dunn, J. Electrochem. Soc. 154, A140 (2007)L.D. Zhu, C.Y. Tian, J.L. Zhai, R.L. Yang, Sensors and Actuators B-Chemical 125, 254 (2007)F. Montilla, M.A. Cotarelo, E. Morallón, J. Mater. Chem. 19, 305 (2009)D. Salinas-Torres, F. Montilla, F. Huerta, E. Morallón, Electrochim. Acta 56, 3620 (2011)T. Dobbins, R. Chevious, Y. Lvov, Polymers 3, 942 (2011)R. Esquembre, J.A. Poveda, C.R. Mateo, Journal of Physical Chemistry B 113, 7534 (2009)M.L. Ferrer, R. Esquembre, I. Ortega, C.R. Mateo, F. del Monte, Chem. Mater. 18, 554 (2006)M.J. O'Connell, S. Sivaram, S.K. Doorn, Physical Review B 69, 235415 (2004)C. Domingo, G. Santoro, Opt. Pura Apl 40, 175 (2007)M.S. Dresselhaus, G. Dresselhaus, R. Saito, A. Jorio, Physics Reports 409, 47 (2005)R.L. McCreery, Chem. Rev. 108, 2646 (2008)C.G. Zoski, in Handbook of Electrochemistry, 1st ed (Elsevier, Amsterdam, 2007

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

wKinMut: An integrated tool for the analysis and interpretation of mutations in human protein kinases

BACKGROUND: Protein kinases are involved in relevant physiological functions and a broad number of mutations in this superfamily have been reported in the literature to affect protein function and stability. Unfortunately, the exploration of the consequences on the phenotypes of each individual mutation remains a considerable challenge. RESULTS: The wKinMut web-server offers direct prediction of the potential pathogenicity of the mutations from a number of methods, including our recently developed prediction method based on the combination of information from a range of diverse sources, including physicochemical properties and functional annotations from FireDB and Swissprot and kinase-specific characteristics such as the membership to specific kinase groups, the annotation with disease-associated GO terms or the occurrence of the mutation in PFAM domains, and the relevance of the residues in determining kinase subfamily specificity from S3Det. This predictor yields interesting results that compare favourably with other methods in the field when applied to protein kinases. Together with the predictions, wKinMut offers a number of integrated services for the analysis of mutations. These include: the classification of the kinase, information about associations of the kinase with other proteins extracted from iHop, the mapping of the mutations onto PDB structures, pathogenicity records from a number of databases and the classification of mutations in large-scale cancer studies. Importantly, wKinMut is connected with the SNP2L system that extracts mentions of mutations directly from the literature, and therefore increases the possibilities of finding interesting functional information associated to the studied mutations. CONCLUSIONS: wKinMut facilitates the exploration of the information available about individual mutations by integrating prediction approaches with the automatic extraction of information from the literature (text mining) and several state-of-the-art databases. wKinMut has been used during the last year for the analysis of the consequences of mutations in the context of a number of cancer genome projects, including the recent analysis of Chronic Lymphocytic Leukemia cases and is publicly available at http://wkinmut.bioinfo.cnio.es

The Cysteine-Rich Protein Thimet Oligopeptidase as a Model of the Structural Requirements for S-glutathiolation and Oxidative Oligomerization

Thimet oligopeptidase (EP24.15) is a cysteine-rich metallopeptidase containing fifteen Cys residues and no intra-protein disulfide bonds. Previous work on this enzyme revealed that the oxidative oligomerization of EP24.15 is triggered by S-glutathiolation at physiological GSSG levels (10–50 µM) via a mechanism based on thiol-disulfide exchange. In the present work, our aim was to identify EP24.15 Cys residues that are prone to S-glutathiolation and to determine which structural features in the cysteinyl bulk are responsible for the formation of mixed disulfides through the reaction with GSSG and, in this particular case, the Cys residues within EP24.15 that favor either S-glutathiolation or inter-protein thiol-disulfide exchange. These studies were conducted by in silico structural analyses and simulations as well as site-specific mutation. S-glutathiolation was determined by mass spectrometric analyses and western blotting with anti-glutathione antibody. The results indicated that the stabilization of a thiolate sulfhydryl and the solvent accessibility of the cysteines are necessary for S-thiolation. The Solvent Access Surface analysis of the Cys residues prone to glutathione modification showed that the S-glutathiolated Cys residues are located inside pockets where the sulfur atom comes into contact with the solvent and that the positively charged amino acids are directed toward these Cys residues. The simulation of a covalent glutathione docking onto the same Cys residues allowed for perfect glutathione posing. A mutation of the Arg residue 263 that forms a saline bridge to the Cys residue 175 significantly decreased the overall S-glutathiolation and oligomerization of EP24.15. The present results show for the first time the structural requirements for protein S-glutathiolation by GSSG and are consistent with our previous hypothesis that EP24.15 oligomerization is dependent on the electron transfer from specific protonated Cys residues of one molecule to previously S-glutathionylated Cys residues of another one

Prediction of absolute risk of fragility fracture at 10 years in a Spanish population: validation of the WHO FRAX ™ tool in Spain

<p>Abstract</p> <p>Background</p> <p>Age-related bone loss is asymptomatic, and the morbidity of osteoporosis is secondary to the fractures that occur. Common sites of fracture include the spine, hip, forearm and proximal humerus. Fractures at the hip incur the greatest morbidity and mortality and give rise to the highest direct costs for health services. Their incidence increases exponentially with age.</p> <p>Independently changes in population demography, the age - and sex- specific incidence of osteoporotic fractures appears to be increasing in developing and developed countries. This could mean more than double the expected burden of osteoporotic fractures in the next 50 years.</p> <p>Methods/Design</p> <p>To assess the predictive power of the WHO FRAX™ tool to identify the subjects with the highest absolute risk of fragility fracture at 10 years in a Spanish population, a predictive validation study of the tool will be carried out. For this purpose, the participants recruited by 1999 will be assessed. These were referred to scan-DXA Department from primary healthcare centres, non hospital and hospital consultations. Study population: Patients attended in the national health services integrated into a FRIDEX cohort with at least one Dual-energy X-ray absorptiometry (DXA) measurement and one extensive questionnaire related to fracture risk factors. Measurements: At baseline bone mineral density measurement using DXA, clinical fracture risk factors questionnaire, dietary calcium intake assessment, history of previous fractures, and related drugs. Follow up by telephone interview to know fragility fractures in the 10 years with verification in electronic medical records and also to know the number of falls in the last year. The absolute risk of fracture will be estimated using the FRAX™ tool from the official web site.</p> <p>Discussion</p> <p>Since more than 10 years ago numerous publications have recognised the importance of other risk factors for new osteoporotic fractures in addition to low BMD. The extension of a method for calculating the risk (probability) of fractures using the FRAX™ tool is foreseeable in Spain and this would justify a study such as this to allow the necessary adjustments in calibration of the parameters included in the logarithmic formula constituted by FRAX™.</p

An exploration of the determinants for decision to migrate existing resources to cloud computing using an integrated TOE-DOI model

Migrating existing resources to cloud computing is a strategic organisational decision that can be difficult. It requires the consideration and evaluation of a wide range of technical and organisational aspects. Although a significant amount of attention has been paid by many industrialists and academics to aid migration decisions, the procedure remains difficult. This is mainly due to underestimation of the range of factors and characteristics affecting the decision for cloud migration. Further research is needed to investigate the level of effect these factors have on migration decisions and the overall complexity. This paper aims to explore the level of complexity of the decision to migrate the cloud. A research model based on the diffusion of innovation (DOI) theory and the technology-organization-environment (TOE) framework was developed. The model was tested using exploratory and confirmatory factor analysis. The quantitative analysis shows the level of impact of the identified variables on the decision to migrate. Seven determinants that contribute to the complexity of the decisions are identified. They need to be taken into account to ensure successful migration. This result has expanded the collective knowledge about the complexity of the issues that have to be considered when making decisions to migrate to the cloud. It contributes to the literature that addresses the complex and multidimensional nature of migrating to the cloud

Linking Self-Incompatibility, Dichogamy, and Flowering Synchrony in Two Euphorbia Species: Alternative Mechanisms for Avoiding Self-Fertilization?

Background: Plant species have several mechanisms to avoid selfing such as dichogamy or a self-incompatibility response. Dichogamy in a single flower may reduce autogamy but, to avoid geitonogamy, plants must show flowering synchronization among all their flowers (i.e. synchronous dichogamy). It is hypothesized that one species would not simultaneously show synchronous dichogamy and self-incompatibility because they are redundant mechanisms to reduce selfing; however, this has not been accurately assessed. Methodology/Principal Findings: This expectation was tested over two years in two natural populations of the closely related Mediterranean spurges Euphorbia boetica and E. nicaeensis, which completely avoid autogamy by protogyny at the cyathia level. Both spurges showed a high population synchrony (Z,79), and their inflorescences flower synchronously. In E. nicaeensis, there was no overlap among the cyathia in anthesis of successive inflorescence levels and the overlap between sexual phases of cyathia of the same inflorescence level was uncommon (4–16%). In contrast, E. boetica showed a high overlap among consecutive inflorescence levels (74–93%) and between sexual phases of cyathia of the same inflorescence level (48–80%). The flowering pattern of both spurges was consistent in the two populations and over the two successive years. A hand-pollination experiment demonstrated that E. nicaeensis was strictly self-compatible whereas E. boetica was partially self-incompatible. Conclusions/Significance: We propose that the complex pattern of synchronized protogyny in E. nicaeensis prevents geitonogamous crosses and, consequently, avoids selfing and inbreeding depression. In E. boetica, a high probability of geitonogamous crosses may occur but, alternatively, this plant escapes selfing through a self-incompatibility response. We posit that synchronous dichogamy and physiological self-incompatibility do not co-occur in the same species because each process is sufficiently effective in avoiding self-fertilization.España Ministerio de Ciencia y Tecnología PLO CGL2005-03731; CGL2008-02533-EEspaña Ministerio de Ciencia y Tecnología MA CGL2009-0825

Redox Modulation at Work: Natural Phytoprotective Polysulfanes From Alliums Based on Redox-Active Sulfur

Purpose of review: This article provides a brief overview of natural phytoprotective products of allium with a special focus on the therapeutic potential of diallyl polysulfanes from garlic, their molecular targets and their fate in the living organisms. A comprehensive overview of antimicrobial and anticancer properties of published literature is presented for the reader to understand the effective concentrations of polysulfanes and their sensitivity towards different human pathogenic microbes, fungi, and cancer cell lines. Recent findings: The article finds polysulfanes potentials as new generation novel antibiotics and chemo preventive agent. The effective dose rates of polysulfanes for antimicrobial properties are in the range of 0.5–40 mg/L and for anticancer 20–100 μM. The molecular targets for these redox modulators are mainly cellular thiols as well as inhibition and/or activation of certain cellular proteins in cancer cell lines. Summary: Antimicrobial and anticancer activities of polysulfanes published in the literature indicate that with further development, they could be promising candidates for cancer prevention due to their selectivity towards abnormal cells

First report on dung beetles in intra-Amazonian savannahs in Roraima, Brazil

This is the first study to address the dung beetle (Coleoptera: Scarabaeidae: Scarabaeinae) diversity in intra-Amazonian savannahs in the state of Roraima, Brazil. Our aim was to survey the dung beetle fauna associated with these savannahs (regionally called 'lavrado'), since little is known about the dung beetles from this environment. We conducted three field samples using pitfall traps baited with human dung in savannah areas near the city of Boa Vista during the rainy seasons of 1996, 1997, and 2008. We collected 383 individuals from ten species, wherein six have no previous record in intra-Amazonian savannahs. The most abundant species were Ontherus appendiculatus (Mannerheim, 1829), Canthidium aff. humerale (Germar, 1813), Dichotomius nisus (Olivier, 1789), and Pseudocanthon aff. xanthurus (Blanchard, 1846). We believe that knowing the dung beetles diversity associated with the intra-Amazonian savannahs is ideal for understanding the occurrence and distribution of these organisms in a highly threatened environment, it thus being the first step towards conservation strategy development