MACiE: a database of enzyme reaction mechanisms.

SUMMARY: MACiE (mechanism, annotation and classification in enzymes) is a publicly available web-based database, held in CMLReact (an XML application), that aims to help our understanding of the evolution of enzyme catalytic mechanisms and also to create a classification system which reflects the actual chemical mechanism (catalytic steps) of an enzyme reaction, not only the overall reaction. AVAILABILITY: http://www-mitchell.ch.cam.ac.uk/macie/.EPSRC (G.L.H. and J.B.O.M.), the BBSRC (G.J.B. and J.M.T.—CASE studentship in association with Roche Products Ltd; N.M.O.B. and J.B.O.M.—grant BB/C51320X/1), the Chilean Government’s Ministerio de Planificacio´n y Cooperacio´n and Cambridge Overseas Trust (D.E.A.) for funding and Unilever for supporting the Centre for Molecular Science Informatics.application note restricted to 2 printed pages web site: http://www-mitchell.ch.cam.ac.uk/macie

Mathematically Gifted Adolescents Have Deficiencies in Social Valuation and Mentalization

Many mathematically gifted adolescents are characterized as being indolent, underachieving and unsuccessful despite their high cognitive ability. This is often due to difficulties with social and emotional development. However, research on social and emotional interactions in gifted adolescents has been limited. The purpose of this study was to observe differences in complex social strategic behaviors between gifted and average adolescents of the same age using the repeated Ultimatum Game. Twenty-two gifted adolescents and 24 average adolescents participated in the Ultimatum Game. Two adolescents participate in the game, one as a proposer and the other as a responder. Because of its simplicity, the Ultimatum Game is an apt tool for investigating complex human emotional and cognitive decision-making in an empirical setting. We observed strategic but socially impaired offers from gifted proposers and lower acceptance rates from gifted responders, resulting in lower total earnings in the Ultimatum Game. Thus, our results indicate that mathematically gifted adolescents have deficiencies in social valuation and mentalization

Confab - Systematic generation of diverse low-energy conformers

<p>Abstract</p> <p>Background</p> <p>Many computational chemistry analyses require the generation of conformers, either on-the-fly, or in advance. We present Confab, an open source command-line application for the systematic generation of low-energy conformers according to a diversity criterion.</p> <p>Results</p> <p>Confab generates conformations using the 'torsion driving approach' which involves iterating systematically through a set of allowed torsion angles for each rotatable bond. Energy is assessed using the MMFF94 forcefield. Diversity is measured using the heavy-atom root-mean-square deviation (RMSD) relative to conformers already stored. We investigated the recovery of crystal structures for a dataset of 1000 ligands from the Protein Data Bank with fewer than 1 million conformations. Confab can recover 97% of the molecules to within 1.5 Å at a diversity level of 1.5 Å and an energy cutoff of 50 kcal/mol.</p> <p>Conclusions</p> <p>Confab is available from <url>http://confab.googlecode.com</url>.</p

CheS-Mapper - Chemical Space Mapping and Visualization in 3D

Analyzing chemical datasets is a challenging task for scientific researchers in the field of chemoinformatics. It is important, yet difficult to understand the relationship between the structure of chemical compounds, their physico-chemical properties, and biological or toxic effects. To that respect, visualization tools can help to better comprehend the underlying correlations. Our recently developed 3D molecular viewer CheS-Mapper (Chemical Space Mapper) divides large datasets into clusters of similar compounds and consequently arranges them in 3D space, such that their spatial proximity reflects their similarity. The user can indirectly determine similarity, by selecting which features to employ in the process. The tool can use and calculate different kind of features, like structural fragments as well as quantitative chemical descriptors. These features can be highlighted within CheS-Mapper, which aids the chemist to better understand patterns and regularities and relate the observations to established scientific knowledge. As a final function, the tool can also be used to select and export specific subsets of a given dataset for further analysis

The validation of a new measure quantifying the social quality of life of ethnically diverse older women: two cross-sectional studies

<p>Abstract</p> <p>Background</p> <p>To our knowledge, the available psychometric literature does not include an instrument for the quantification of social quality of life among older women from diverse ethnic backgrounds. To address the need for a tool of this kind, we conducted two studies to assess the initial reliability and validity of a new instrument. The latter was created specifically to quantify the contribution of a) social networks and resources (e.g., family, friends, and community) as well as b) one's perceived power and respect within family and community to subjective well-being in non-clinical, ethnically diverse populations of older women.</p> <p>Methods</p> <p>In Study 1, we recruited a cross-sectional sample of primarily non-European-American older women (<it>N </it>= 220) at a variety of community locations. Participants were administered the following: a short screener for dementia; a demographic list; an initial pool of 50 items from which the final items of the new Older Women's Social Quality of Life Inventory (OWSQLI) were to be chosen (based on a statistical criterion to apply to the factor analysis findings); the Single Item Measure of Social Support (SIMSS); and the Medical Outcome Study 36-item Short-Form Health Survey (MOS SF-36). Study 2 was conducted on a second independent sample of ethnically diverse older women. The same recruitment strategies, procedures, and instruments as those of Study 1 were utilized in Study 2, whose sample was comprised of 241 older women with mostly non-European-American ethnic status.</p> <p>Results</p> <p>In Study 1, exploratory factor analysis of the OWSQLI obtained robust findings: the total variance explained by one single factor with the final selection of 22 items was over 44%. The OWSQLI demonstrated strong internal consistency (<it>α </it>= .92, <it>p </it>< .001), adequate criterion validity with the SIMSS (<it>r </it>= .33; <it>p </it>< .01), and (as expected) moderate concurrent validity with the MOS SF-36 for both physical (<it>r </it>= .21; <it>p </it>< .01) and mental (<it>r </it>= .26; <it>p </it>< .01) quality of life. In order to confirm the validity of the 22-item OWSQLI scale that emerged from Study 1 analyses, we replicated those analyses in Study 2, although using confirmatory factor analysis. The total variance accounted for by one factor was about 42%, again quite high and indicative of a strong single-factor solution. Study 2 data analyses yielded the same strong reliability findings (i.e., <it>α </it>= .92, <it>p </it>< .001). The 22-item OWSQLI was correlated with the SIMSS (<it>r </it>= .27, <it>p </it>< .001) in the expected direction. Finally, correlations with the MOS SF- 36 demonstrated moderate concurrent validity for physical (<it>r </it>= .14; <it>p </it>< .01) and mental (<it>r </it>= .18; <it>p </it>< .01) quality of life, as expected.</p> <p>Conclusions</p> <p>The findings of these two studies highlight the potential for our new tool to provide a valid measure of older women's social quality of life, yet they require duplication in longitudinal research. Interested clinicians should consider using the OWSQLI in their assessment battery to identify older women's areas of lower versus higher social quality of life, and should establish the maximization of patients' social quality of life as an important therapeutic goal, as this variable is significantly related to both physical and mental health.</p

Defective Leukocyte Adhesion and Chemotaxis Contributes to Combined Immunodeficiency in Humans with Autosomal Recessive MST1 Deficiency.

PURPOSE: To investigate the clinical and functional aspects of MST1 (STK4) deficiency in a profoundly CD4-lymphopenic kindred with a novel homozygous nonsense mutation in STK4. Although recent studies have described the cellular effects of murine Mst1 deficiency, the phenotype of MST1-deficient human lymphocytes has yet to be fully explored. Patient lymphocytes were therefore investigated in the context of current knowledge of murine Mst1 deficiency. METHODS: Genetic etiology was identified by whole exome sequencing of genomic DNA from two siblings, combined with linkage analysis in the wider family. MST1 protein expression was assessed by immunoblotting. The ability of patient lymphocytes to adhere to ICAM-1 under flow conditions was measured, and transwell assays were used to assess chemotaxis. Chemokine receptor expression was examined by flow cytometry and receptor signalling by immunoblotting. RESULTS: A homozygous nonsense mutation in STK4 (c.442C > T, p.Arg148Stop) was found in the patients, leading to a lack of MST1 protein expression. Patient leukocytes exhibited deficient chemotaxis after stimulation with CXCL11, despite preserved expression of CXCR3. Patient lymphocytes were also unable to bind effectively to immobilised ICAM-1 under flow conditions, in keeping with a failure to develop high affinity binding. CONCLUSION: The observed abnormalities of adhesion and migration imply a profound trafficking defect among human MST1-deficient lymphocytes. By analogy with murine Mst1 deficiency and other defects of leucocyte trafficking, this is likely to contribute to immunodeficiency by impairing key aspects of T-cell development and function such as positive selection in the thymus, thymic egress and immune synapse formation in the periphery.This is thepublished version. It first appeared at http://link.springer.com/article/10.1007%2Fs10875-016-0232-2

Open Babel: An open chemical toolbox

Background: A frequent problem in computational modeling is the interconversion of chemical structures between different formats. While standard interchange formats exist (for example, Chemical Markup Language) and de facto standards have arisen (for example, SMILES format), the need to interconvert formats is a continuing problem due to the multitude of different application areas for chemistry data, differences in the data stored by different formats (0D versus 3D, for example), and competition between software along with a lack of vendorneutral formats. Results: We discuss, for the first time, Open Babel, an open-source chemical toolbox that speaks the many languages of chemical data. Open Babel version 2.3 interconverts over 110 formats. The need to represent such a wide variety of chemical and molecular data requires a library that implements a wide range of cheminformatics algorithms, from partial charge assignment and aromaticity detection, to bond order perception and canonicalization. We detail the implementation of Open Babel, describe key advances in the 2.3 release, and outline a variety of uses both in terms of software products and scientific research, including applications far beyond simple format interconversion. Conclusions: Open Babel presents a solution to the proliferation of multiple chemical file formats. In addition, it provides a variety of useful utilities from conformer searching and 2D depiction, to filtering, batch conversion, and substructure and similarity searching. For developers, it can be used as a programming library to handle chemical data in areas such as organic chemistry, drug design, materials science, and computational chemistry. It is freely available under an open-source license fro

Is EC class predictable from reaction mechanism?

We thank the Scottish Universities Life Sciences Alliance (SULSA) and the Scottish Overseas Research Student Awards Scheme of the Scottish Funding Council (SFC) for financial support.Background: We investigate the relationships between the EC (Enzyme Commission) class, the associated chemical reaction, and the reaction mechanism by building predictive models using Support Vector Machine (SVM), Random Forest (RF) and k-Nearest Neighbours (kNN). We consider two ways of encoding the reaction mechanism in descriptors, and also three approaches that encode only the overall chemical reaction. Both cross-validation and also an external test set are used. Results: The three descriptor sets encoding overall chemical transformation perform better than the two descriptions of mechanism. SVM and RF models perform comparably well; kNN is less successful. Oxidoreductases and hydrolases are relatively well predicted by all types of descriptor; isomerases are well predicted by overall reaction descriptors but not by mechanistic ones. Conclusions: Our results suggest that pairs of similar enzyme reactions tend to proceed by different mechanisms. Oxidoreductases, hydrolases, and to some extent isomerases and ligases, have clear chemical signatures, making them easier to predict than transferases and lyases. We find evidence that isomerases as a class are notably mechanistically diverse and that their one shared property, of substrate and product being isomers, can arise in various unrelated ways. The performance of the different machine learning algorithms is in line with many cheminformatics applications, with SVM and RF being roughly equally effective. kNN is less successful, given the role that non-local information plays in successful classification. We note also that, despite a lack of clarity in the literature, EC number prediction is not a single problem; the challenge of predicting protein function from available sequence data is quite different from assigning an EC classification from a cheminformatics representation of a reaction.Publisher PDFPeer reviewe