A Study of Archiving Strategies in Multi-Objective PSO for Molecular Docking

Molecular docking is a complex optimization problem aimed at predicting the position of a ligand molecule in the active site of a receptor with the lowest binding energy. This problem can be formulated as a bi-objective optimization problem by minimizing the binding energy and the Root Mean Square Deviation (RMSD) difference in the coordinates of ligands. In this context, the SMPSO multi-objective swarm-intelligence algorithm has shown a remarkable performance. SMPSO is characterized by having an external archive used to store the non-dominated solutions and also as the basis of the leader selection strategy. In this paper, we analyze several SMPSO variants based on different archiving strategies in the scope of a benchmark of molecular docking instances. Our study reveals that the SMPSOhv, which uses an hypervolume contribution based archive, shows the overall best performance.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

MOLA: a bootable, self-configuring system for virtual screening using AutoDock4/Vina on computer clusters

<p>Abstract</p> <p>Background</p> <p>Virtual screening of small molecules using molecular docking has become an important tool in drug discovery. However, large scale virtual screening is time demanding and usually requires dedicated computer clusters. There are a number of software tools that perform virtual screening using AutoDock4 but they require access to dedicated Linux computer clusters. Also no software is available for performing virtual screening with Vina using computer clusters. In this paper we present MOLA, an easy-to-use graphical user interface tool that automates parallel virtual screening using AutoDock4 and/or Vina in bootable non-dedicated computer clusters.</p> <p>Implementation</p> <p>MOLA automates several tasks including: ligand preparation, parallel AutoDock4/Vina jobs distribution and result analysis. When the virtual screening project finishes, an open-office spreadsheet file opens with the ligands ranked by binding energy and distance to the active site. All results files can automatically be recorded on an USB-flash drive or on the hard-disk drive using VirtualBox. MOLA works inside a customized Live CD GNU/Linux operating system, developed by us, that bypass the original operating system installed on the computers used in the cluster. This operating system boots from a CD on the master node and then clusters other computers as slave nodes via ethernet connections.</p> <p>Conclusion</p> <p>MOLA is an ideal virtual screening tool for non-experienced users, with a limited number of multi-platform heterogeneous computers available and no access to dedicated Linux computer clusters. When a virtual screening project finishes, the computers can just be restarted to their original operating system. The originality of MOLA lies on the fact that, any platform-independent computer available can he added to the cluster, without ever using the computer hard-disk drive and without interfering with the installed operating system. With a cluster of 10 processors, and a potential maximum speed-up of 10x, the parallel algorithm of MOLA performed with a speed-up of 8,64× using AutoDock4 and 8,60× using Vina.</p

Zebrafish as a model for cardiac disease; Cryo-EM structure of native cardiac thin filaments from Danio Rerio.

Actin, tropomyosin and troponin, the proteins that comprise the contractile apparatus of the cardiac thin filament, are highly conserved across species. We have used cryo-EM to study the three-dimensional structure of the zebrafish cardiac thin and actin filaments. With 70% of human genes having an obvious zebrafish orthologue, and conservation of 85% of disease-causing genes, zebrafish are a good animal model for the study of human disease. Our structure of the zebrafish thin filament reveals the molecular interactions between the constituent proteins, showing that the fundamental organisation of the complex is the same as that reported in the human reconstituted thin filament. A reconstruction of zebrafish cardiac F-actin demonstrates no deviations from human cardiac actin over an extended length of 14 actin subunits. Modelling zebrafish homology models into our maps enabled us to compare, in detail, the similarity with human models. The structural similarities of troponin-T in particular, a region known to contain a hypertrophic cardiomyopathy 'hotspot', confirm the suitability of zebrafish to study these disease-causing mutations

Upper body movement analysis of multiple limb asymmetry in 367 clinically lame horses

Background Compensatory lameness is common in horses and evaluation can be challenging. Objectives To investigate patterns of compensatory movements in clinical cases with fore- or hindlimb lameness before and after diagnostic analgesia. Study design Retrospective clinical study. Methods Multiple limb lameness of 367 horses was characterised by type (push-off, impact or mixed), limb (fore- or hindlimb in predominant lameness) and side (ipsi- or contralateral in concurrent lameness) using a body-mounted inertial sensor (BMIS). Diagnostic analgesia was performed until the percentage improvement of the vector sum in forelimb lameness and the mean difference of the maximum or minimum pelvic height (PDmax or PDmin) in hindlimb lameness was >= 50%. Linear mixed model and post-estimation of effects were performed by contrast command with multiple comparisons adjusted by Bonferroni method. Correlation of pre- and post-analgesia of all head and pelvis asymmetry parameters was tested with Spearman's rank correlation. Results Improvement in vector sum per mm after diagnostic analgesia in forelimb impact lameness positively correlated with decrease in PDmax in contralateral mixed lameness (0.187 mm, r = .58, P < .05). Improvement in PDmin per mm after diagnostic analgesia in hindlimb mixed and PDmax in hindlimb push-off lameness decreased vector sum in ipsilateral forelimb impact lameness by 0.570 and 0.696 mm, respectively (P < .05), with no positive correlation. Main limitations A variety of cases with inhomogeneous distribution of lameness patterns was investigated retrospectively, therefore, it is impossible to distinguish between true multiple limb lameness and compensatory lameness in this clinical material. Conclusions Various asymmetry patterns of concurrent lameness were seen in horses with naturally occurring primary forelimb impact lameness with contralateral compensatory hindlimb lameness with a mixed component being the most common. In horses with hindlimb lameness, compensatory movements were seen in ipsilateral forelimbs, mostly as an ipsilateral impact lameness during straight line trot

Parameter Estimation and Quantitative Parametric Linkage Analysis with GENEHUNTER-QMOD

Objective: We present a parametric method for linkage analysis of quantitative phenotypes. The method provides a test for linkage as well as an estimate of different phenotype parameters. We have implemented our new method in the program GENEHUNTER-QMOD and evaluated its properties by performing simulations. Methods: The phenotype is modeled as a normally distributed variable, with a separate distribution for each genotype. Parameter estimates are obtained by maximizing the LOD score over the normal distribution parameters with a gradient-based optimization called PGRAD method. Results: The PGRAD method has lower power to detect linkage than the variance components analysis (VCA) in case of a normal distribution and small pedigrees. However, it outperforms the VCA and Haseman-Elston regression for extended pedigrees, nonrandomly ascertained data and non-normally distributed phenotypes. Here, the higher power even goes along with conservativeness, while the VCA has an inflated type I error. Parameter estimation tends to underestimate residual variances but performs better for expectation values of the phenotype distributions. Conclusion: With GENEHUNTER-QMOD, a powerful new tool is provided to explicitly model quantitative phenotypes in the context of linkage analysis. It is freely available at http://www.helmholtz-muenchen.de/genepi/downloads. Copyright (C) 2012 S. Karger AG, Base

Chromosomal disorders:estimating baseline birth prevalence and pregnancy outcomes worldwide

Chromosomal disorders, of which Down syndrome is the most common, can cause multi-domain disability. In addition, compared to the general population, there is a higher frequency of death before the age of five. In many settings, large gaps in data availability have hampered policy-making, programme priorities and resource allocation for these important conditions. We have developed methods, which overcome this lack of data and allow estimation of the burden of affected pregnancies and their outcomes in different settings worldwide. For example, the methods include a simple equation relating the percentage of mothers 35 and over to Down syndrome birth prevalence. The results obtained provide a starting point for consideration of services that can be implemented for the care and prevention of these disorders

Can being gay provide a boost in the hiring process? Maybe if the boss is female

Purpose – The purpose of this study was to investigate whether men and women differentially prefer hiring gay and lesbian job applicants relative to equally qualified heterosexual job applicants. Design/methodology/approach – Data were collected from two samples of non-student participants. Each participant evaluated the perceived hirability of an ostensibly real job applicant by reviewing the applicant’s resume. In reality, all participants were randomly assigned to evaluate the same fictitious resume that differed only in the gender and sexual orientation of the applicant. Findings – We find that men perceived gay and lesbian job applicants as less hirable, while women perceived gay and lesbian job applicants as more hirable than heterosexual job applicants. Additionally, we show perceptions of hirability are mediated by perceptions of gay and lesbian job applicants’ competence. Implications – These results show that bias against gays and lesbians is much more nuanced than previous work suggests. One implication is that placing more women in selection roles within organizations could be a catalyst for the inclusion of gay and lesbian employees. Additionally, these results could influence when and how gays and lesbians disclose their gay identities at work. Originality/value –These studies are the first to identify a positive bias in favor of gay and lesbian job applicants. As attitudes toward gays and lesbians become more positive, results like these are important to document as they signal a shift in intergroup relations. These results will also help managers and organizations design selection processes to minimize bias towards applicants. Keywords: gender, sexual orientation, selection, bia

Design, synthesis, molecular modelling and in vitro screening of monoamine oxidase inhibitory activities of novel quinazolyl hydrazine derivatives

Funding: Deanship of Scientific Research at Taibah University, Al-Madinah Al-Munawarah, Saudi Arabia (project # 7101).A new series of N'-substituted benzylidene-2-(4-oxo-2-phenyl-1,4-dihydroquinazolin-3(2H)-yl)acetohydrazide (5a-5h) has been synthesized, characterized by FT-IR, NMR spectroscopy and mass spectrometry and tested against human monoamine oxidase (MAO) A and B. Only (3-methoxy-4-hydroxy)benzoyl substituted compounds gave submicromolar inhibition of MAO-A and MAO-B. Changing the phenyl substituent to methyl on the unsaturated quinazoline ring (12a-12d) decreased inhibition but a less flexible linker (14a-14d) resulted in selective micromolar inhibition of hMAO B providing insight for ongoing design.Publisher PDFPeer reviewe