Quantum probability ranking principle for ligand-based virtual screening

Science.gov (United States)

Al-Dabbagh, Mohammed Mumtaz; Salim, Naomie; Himmat, Mubarak; Ahmed, Ali; Saeed, Faisal

2017-04-01

Chemical libraries contain thousands of compounds that need screening, which increases the need for computational methods that can rank or prioritize compounds. The tools of virtual screening are widely exploited to enhance the cost effectiveness of lead drug discovery programs by ranking chemical compounds databases in decreasing probability of biological activity based upon probability ranking principle (PRP). In this paper, we developed a novel ranking approach for molecular compounds inspired by quantum mechanics, called quantum probability ranking principle (QPRP). The QPRP ranking criteria would make an attempt to draw an analogy between the physical experiment and molecular structure ranking process for 2D fingerprints in ligand based virtual screening (LBVS). The development of QPRP criteria in LBVS has employed the concepts of quantum at three different levels, firstly at representation level, this model makes an effort to develop a new framework of molecular representation by connecting the molecular compounds with mathematical quantum space. Secondly, estimate the similarity between chemical libraries and references based on quantum-based similarity searching method. Finally, rank the molecules using QPRP approach. Simulated virtual screening experiments with MDL drug data report (MDDR) data sets showed that QPRP outperformed the classical ranking principle (PRP) for molecular chemical compounds.

Quantum probability ranking principle for ligand-based virtual screening.

Science.gov (United States)

Al-Dabbagh, Mohammed Mumtaz; Salim, Naomie; Himmat, Mubarak; Ahmed, Ali; Saeed, Faisal

2017-04-01

Chemical libraries contain thousands of compounds that need screening, which increases the need for computational methods that can rank or prioritize compounds. The tools of virtual screening are widely exploited to enhance the cost effectiveness of lead drug discovery programs by ranking chemical compounds databases in decreasing probability of biological activity based upon probability ranking principle (PRP). In this paper, we developed a novel ranking approach for molecular compounds inspired by quantum mechanics, called quantum probability ranking principle (QPRP). The QPRP ranking criteria would make an attempt to draw an analogy between the physical experiment and molecular structure ranking process for 2D fingerprints in ligand based virtual screening (LBVS). The development of QPRP criteria in LBVS has employed the concepts of quantum at three different levels, firstly at representation level, this model makes an effort to develop a new framework of molecular representation by connecting the molecular compounds with mathematical quantum space. Secondly, estimate the similarity between chemical libraries and references based on quantum-based similarity searching method. Finally, rank the molecules using QPRP approach. Simulated virtual screening experiments with MDL drug data report (MDDR) data sets showed that QPRP outperformed the classical ranking principle (PRP) for molecular chemical compounds.

Congestion game scheduling for virtual drug screening optimization

Science.gov (United States)

Nikitina, Natalia; Ivashko, Evgeny; Tchernykh, Andrei

2018-02-01

In virtual drug screening, the chemical diversity of hits is an important factor, along with their predicted activity. Moreover, interim results are of interest for directing the further research, and their diversity is also desirable. In this paper, we consider a problem of obtaining a diverse set of virtual screening hits in a short time. To this end, we propose a mathematical model of task scheduling for virtual drug screening in high-performance computational systems as a congestion game between computational nodes to find the equilibrium solutions for best balancing the number of interim hits with their chemical diversity. The model considers the heterogeneous environment with workload uncertainty, processing time uncertainty, and limited knowledge about the input dataset structure. We perform computational experiments and evaluate the performance of the developed approach considering organic molecules database GDB-9. The used set of molecules is rich enough to demonstrate the feasibility and practicability of proposed solutions. We compare the algorithm with two known heuristics used in practice and observe that game-based scheduling outperforms them by the hit discovery rate and chemical diversity at earlier steps. Based on these results, we use a social utility metric for assessing the efficiency of our equilibrium solutions and show that they reach greatest values.

Virtual colonoscopy: a new alternative for colorectal neoplasm screening?; Colonoscopia virtual: una nueva alternativa en el screening del cancer colorrectal?

Energy Technology Data Exchange (ETDEWEB)

Carrascosa, P; Castiglioni, R; Sanchez, F; Capunay, C; Mazzuco, J; Carrascosa, J [Diagnostico Maipu, Vicente Lopez, Buenos Aires (Argentina)

2000-07-01

The authors presents 46 patients-series with virtual colonoscopy. The findings obtained through virtual colonoscopy were divided into 7 groups: 1) Single polypoid lesion (9 patients); 2) Associated polypoid lesions (11 patients); 3) Tumoral stenosis without synchronic lesion (3 patients); 4) Tumoral stenosis with synchronic lesion (6 patients); 5) Non-tumoral stenosis (4 patients); 6) Normal studies (2 patients); 7) Patients excluded due to wrong preparation (11 patients). We concluded that the virtual colonoscopy is a valid alternative in the screening of the colorectal pathology, showing some advantages when compared to the usual studies, since it is non-invasive, does not require sedation, and allows the staging of the neoplasm. (author)

Prospective Assessment of Virtual Screening Heuristics Derived Using a Novel Fusion Score.

Science.gov (United States)

Pertusi, Dante A; O'Donnell, Gregory; Homsher, Michelle F; Solly, Kelli; Patel, Amita; Stahler, Shannon L; Riley, Daniel; Finley, Michael F; Finger, Eleftheria N; Adam, Gregory C; Meng, Juncai; Bell, David J; Zuck, Paul D; Hudak, Edward M; Weber, Michael J; Nothstein, Jennifer E; Locco, Louis; Quinn, Carissa; Amoss, Adam; Squadroni, Brian; Hartnett, Michelle; Heo, Mee Ra; White, Tara; May, S Alex; Boots, Evelyn; Roberts, Kenneth; Cocchiarella, Patrick; Wolicki, Alex; Kreamer, Anthony; Kutchukian, Peter S; Wassermann, Anne Mai; Uebele, Victor N; Glick, Meir; Rusinko, Andrew; Culberson, J Christopher

2017-09-01

High-throughput screening (HTS) is a widespread method in early drug discovery for identifying promising chemical matter that modulates a target or phenotype of interest. Because HTS campaigns involve screening millions of compounds, it is often desirable to initiate screening with a subset of the full collection. Subsequently, virtual screening methods prioritize likely active compounds in the remaining collection in an iterative process. With this approach, orthogonal virtual screening methods are often applied, necessitating the prioritization of hits from different approaches. Here, we introduce a novel method of fusing these prioritizations and benchmark it prospectively on 17 screening campaigns using virtual screening methods in three descriptor spaces. We found that the fusion approach retrieves 15% to 65% more active chemical series than any single machine-learning method and that appropriately weighting contributions of similarity and machine-learning scoring techniques can increase enrichment by 1% to 19%. We also use fusion scoring to evaluate the tradeoff between screening more chemical matter initially in lieu of replicate samples to prevent false-positives and find that the former option leads to the retrieval of more active chemical series. These results represent guidelines that can increase the rate of identification of promising active compounds in future iterative screens.

Virtual Screening of Receptor Sites for Molecularly Imprinted Polymers.

Science.gov (United States)

Bates, Ferdia; Cela-Pérez, María Concepción; Karim, Kal; Piletsky, Sergey; López-Vilariño, José Manuel

2016-08-01

Molecularly Imprinted Polymers (MIPs) are highly advantageous in the field of analytical chemistry. However, interference from secondary molecules can also impede capture of a target by a MIP receptor. This greatly complicates the design process and often requires extensive laboratory screening which is time consuming, costly, and creates substantial waste products. Herein, is presented a new technique for screening of "virtually imprinted receptors" for rebinding of the molecular template as well as secondary structures, correlating the virtual predictions with experimentally acquired data in three case studies. This novel technique is particularly applicable to the evaluation and prediction of MIP receptor specificity and efficiency in complex aqueous systems. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

DOVIS: A Tool for High-throughput Virtual Screening

National Research Council Canada - National Science Library

Jiang, Xiaohui; Kumar, Kamal; Wallqvist, Anders; Reifman, Jaques

2007-01-01

We developed a DOcking-based Virtual Screening (DO DOVIS) pipeline to predict how small molecules may interact with a given protein, so that we can rank a large database of molecules based on their predicted affinities to the protein...

Virtual screening methods as tools for drug lead discovery from large chemical libraries.

Science.gov (United States)

Ma, X H; Zhu, F; Liu, X; Shi, Z; Zhang, J X; Yang, S Y; Wei, Y Q; Chen, Y Z

2012-01-01

Virtual screening methods have been developed and explored as useful tools for searching drug lead compounds from chemical libraries, including large libraries that have become publically available. In this review, we discussed the new developments in exploring virtual screening methods for enhanced performance in searching large chemical libraries, their applications in screening libraries of ~ 1 million or more compounds in the last five years, the difficulties in their applications, and the strategies for further improving these methods.

A multi-infrastructure gateway for virtual drug screening

NARCIS (Netherlands)

Jaghoori, Mohammad Mahdi; van Altena, Allard J.; Bleijlevens, Boris; Ramezani, Sara; Font, Juan Luis; Olabarriaga, Silvia D.

2015-01-01

In computer-aided drug design, software tools are used to narrow down possible drug candidates, thereby reducing the amount of expensive in vitro research, by a process called virtual screening. This process includes large computations that require advanced computing infrastructure; however, using

GeauxDock: Accelerating Structure-Based Virtual Screening with Heterogeneous Computing

Science.gov (United States)

Fang, Ye; Ding, Yun; Feinstein, Wei P.; Koppelman, David M.; Moreno, Juana; Jarrell, Mark; Ramanujam, J.; Brylinski, Michal

2016-01-01

Computational modeling of drug binding to proteins is an integral component of direct drug design. Particularly, structure-based virtual screening is often used to perform large-scale modeling of putative associations between small organic molecules and their pharmacologically relevant protein targets. Because of a large number of drug candidates to be evaluated, an accurate and fast docking engine is a critical element of virtual screening. Consequently, highly optimized docking codes are of paramount importance for the effectiveness of virtual screening methods. In this communication, we describe the implementation, tuning and performance characteristics of GeauxDock, a recently developed molecular docking program. GeauxDock is built upon the Monte Carlo algorithm and features a novel scoring function combining physics-based energy terms with statistical and knowledge-based potentials. Developed specifically for heterogeneous computing platforms, the current version of GeauxDock can be deployed on modern, multi-core Central Processing Units (CPUs) as well as massively parallel accelerators, Intel Xeon Phi and NVIDIA Graphics Processing Unit (GPU). First, we carried out a thorough performance tuning of the high-level framework and the docking kernel to produce a fast serial code, which was then ported to shared-memory multi-core CPUs yielding a near-ideal scaling. Further, using Xeon Phi gives 1.9× performance improvement over a dual 10-core Xeon CPU, whereas the best GPU accelerator, GeForce GTX 980, achieves a speedup as high as 3.5×. On that account, GeauxDock can take advantage of modern heterogeneous architectures to considerably accelerate structure-based virtual screening applications. GeauxDock is open-sourced and publicly available at www.brylinski.org/geauxdock and https://figshare.com/articles/geauxdock_tar_gz/3205249. PMID:27420300

GeauxDock: Accelerating Structure-Based Virtual Screening with Heterogeneous Computing.

Directory of Open Access Journals (Sweden)

Ye Fang

Full Text Available Computational modeling of drug binding to proteins is an integral component of direct drug design. Particularly, structure-based virtual screening is often used to perform large-scale modeling of putative associations between small organic molecules and their pharmacologically relevant protein targets. Because of a large number of drug candidates to be evaluated, an accurate and fast docking engine is a critical element of virtual screening. Consequently, highly optimized docking codes are of paramount importance for the effectiveness of virtual screening methods. In this communication, we describe the implementation, tuning and performance characteristics of GeauxDock, a recently developed molecular docking program. GeauxDock is built upon the Monte Carlo algorithm and features a novel scoring function combining physics-based energy terms with statistical and knowledge-based potentials. Developed specifically for heterogeneous computing platforms, the current version of GeauxDock can be deployed on modern, multi-core Central Processing Units (CPUs as well as massively parallel accelerators, Intel Xeon Phi and NVIDIA Graphics Processing Unit (GPU. First, we carried out a thorough performance tuning of the high-level framework and the docking kernel to produce a fast serial code, which was then ported to shared-memory multi-core CPUs yielding a near-ideal scaling. Further, using Xeon Phi gives 1.9× performance improvement over a dual 10-core Xeon CPU, whereas the best GPU accelerator, GeForce GTX 980, achieves a speedup as high as 3.5×. On that account, GeauxDock can take advantage of modern heterogeneous architectures to considerably accelerate structure-based virtual screening applications. GeauxDock is open-sourced and publicly available at www.brylinski.org/geauxdock and https://figshare.com/articles/geauxdock_tar_gz/3205249.

The influence of the negative-positive ratio and screening database size on the performance of machine learning-based virtual screening.

Science.gov (United States)

Kurczab, Rafał; Bojarski, Andrzej J

2017-01-01

The machine learning-based virtual screening of molecular databases is a commonly used approach to identify hits. However, many aspects associated with training predictive models can influence the final performance and, consequently, the number of hits found. Thus, we performed a systematic study of the simultaneous influence of the proportion of negatives to positives in the testing set, the size of screening databases and the type of molecular representations on the effectiveness of classification. The results obtained for eight protein targets, five machine learning algorithms (SMO, Naïve Bayes, Ibk, J48 and Random Forest), two types of molecular fingerprints (MACCS and CDK FP) and eight screening databases with different numbers of molecules confirmed our previous findings that increases in the ratio of negative to positive training instances greatly influenced most of the investigated parameters of the ML methods in simulated virtual screening experiments. However, the performance of screening was shown to also be highly dependent on the molecular library dimension. Generally, with the increasing size of the screened database, the optimal training ratio also increased, and this ratio can be rationalized using the proposed cost-effectiveness threshold approach. To increase the performance of machine learning-based virtual screening, the training set should be constructed in a way that considers the size of the screening database.

Virtual Screening Approaches towards the Discovery of Toll-Like Receptor Modulators

Directory of Open Access Journals (Sweden)

Lucía Pérez-Regidor

2016-09-01

Full Text Available This review aims to summarize the latest efforts performed in the search for novel chemical entities such as Toll-like receptor (TLR modulators by means of virtual screening techniques. This is an emergent research field with only very recent (and successful contributions. Identification of drug-like molecules with potential therapeutic applications for the treatment of a variety of TLR-regulated diseases has attracted considerable interest due to the clinical potential. Additionally, the virtual screening databases and computational tools employed have been overviewed in a descriptive way, widening the scope for researchers interested in the field.

Machine learning in virtual screening.

Science.gov (United States)

Melville, James L; Burke, Edmund K; Hirst, Jonathan D

2009-05-01

In this review, we highlight recent applications of machine learning to virtual screening, focusing on the use of supervised techniques to train statistical learning algorithms to prioritize databases of molecules as active against a particular protein target. Both ligand-based similarity searching and structure-based docking have benefited from machine learning algorithms, including naïve Bayesian classifiers, support vector machines, neural networks, and decision trees, as well as more traditional regression techniques. Effective application of these methodologies requires an appreciation of data preparation, validation, optimization, and search methodologies, and we also survey developments in these areas.

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

Directory of Open Access Journals (Sweden)

Abreu Rui MV

2010-10-01

Full Text Available Abstract Background 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. Implementation 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. Conclusion 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

Comparative analysis of machine learning methods in ligand-based virtual screening of large compound libraries.

Science.gov (United States)

Ma, Xiao H; Jia, Jia; Zhu, Feng; Xue, Ying; Li, Ze R; Chen, Yu Z

2009-05-01

Machine learning methods have been explored as ligand-based virtual screening tools for facilitating drug lead discovery. These methods predict compounds of specific pharmacodynamic, pharmacokinetic or toxicological properties based on their structure-derived structural and physicochemical properties. Increasing attention has been directed at these methods because of their capability in predicting compounds of diverse structures and complex structure-activity relationships without requiring the knowledge of target 3D structure. This article reviews current progresses in using machine learning methods for virtual screening of pharmacodynamically active compounds from large compound libraries, and analyzes and compares the reported performances of machine learning tools with those of structure-based and other ligand-based (such as pharmacophore and clustering) virtual screening methods. The feasibility to improve the performance of machine learning methods in screening large libraries is discussed.

Protein-Ligand Empirical Interaction Components for Virtual Screening.

Science.gov (United States)

Yan, Yuna; Wang, Weijun; Sun, Zhaoxi; Zhang, John Z H; Ji, Changge

2017-08-28

A major shortcoming of empirical scoring functions is that they often fail to predict binding affinity properly. Removing false positives of docking results is one of the most challenging works in structure-based virtual screening. Postdocking filters, making use of all kinds of experimental structure and activity information, may help in solving the issue. We describe a new method based on detailed protein-ligand interaction decomposition and machine learning. Protein-ligand empirical interaction components (PLEIC) are used as descriptors for support vector machine learning to develop a classification model (PLEIC-SVM) to discriminate false positives from true positives. Experimentally derived activity information is used for model training. An extensive benchmark study on 36 diverse data sets from the DUD-E database has been performed to evaluate the performance of the new method. The results show that the new method performs much better than standard empirical scoring functions in structure-based virtual screening. The trained PLEIC-SVM model is able to capture important interaction patterns between ligand and protein residues for one specific target, which is helpful in discarding false positives in postdocking filtering.

Identification of VDR Antagonists among Nuclear Receptor Ligands Using Virtual Screening

Directory of Open Access Journals (Sweden)

Kelly Teske

2014-04-01

Full Text Available Herein, we described the development of two virtual screens to identify new vitamin D receptor (VDR antagonists among nuclear receptor (NR ligands. Therefore, a database of 14330 nuclear receptor ligands and their NR affinities was assembled using the online available “Binding Database.” Two different virtual screens were carried out in conjunction with a reported VDR crystal structure applying a stringent and less stringent pharmacophore model to filter docked NR ligand conformations. The pharmacophore models were based on the spatial orientation of the hydroxyl functionalities of VDR's natural ligands 1,25(OH2D3 and 25(OH2D3. The first virtual screen identified 32 NR ligands with a calculated free energy of VDR binding of more than -6.0 kJ/mol. All but nordihydroguaiaretic acid (NDGA are VDR ligands, which inhibited the interaction between VDR and coactivator peptide SRC2-3 with an IC50 value of 15.8 μM. The second screen identified 162 NR ligands with a calculated free energy of VDR binding of more than -6.0 kJ/mol. More than half of these ligands were developed to bind VDR followed by ERα/β ligands (26%, TRα/β ligands (7%, and LxRα/β ligands (7%. The binding between VDR and ERα ligand H6036 as well as TRα/β ligand triiodothyronine and a homoserine analog thereof was confirmed by fluorescence polarization.

Performance of machine learning methods for ligand-based virtual screening.

Science.gov (United States)

Plewczynski, Dariusz; Spieser, Stéphane A H; Koch, Uwe

2009-05-01

Computational screening of compound databases has become increasingly popular in pharmaceutical research. This review focuses on the evaluation of ligand-based virtual screening using active compounds as templates in the context of drug discovery. Ligand-based screening techniques are based on comparative molecular similarity analysis of compounds with known and unknown activity. We provide an overview of publications that have evaluated different machine learning methods, such as support vector machines, decision trees, ensemble methods such as boosting, bagging and random forests, clustering methods, neuronal networks, naïve Bayesian, data fusion methods and others.

Fragment virtual screening based on Bayesian categorization for discovering novel VEGFR-2 scaffolds.

Science.gov (United States)

Zhang, Yanmin; Jiao, Yu; Xiong, Xiao; Liu, Haichun; Ran, Ting; Xu, Jinxing; Lu, Shuai; Xu, Anyang; Pan, Jing; Qiao, Xin; Shi, Zhihao; Lu, Tao; Chen, Yadong

2015-11-01

The discovery of novel scaffolds against a specific target has long been one of the most significant but challengeable goals in discovering lead compounds. A scaffold that binds in important regions of the active pocket is more favorable as a starting point because scaffolds generally possess greater optimization possibilities. However, due to the lack of sufficient chemical space diversity of the databases and the ineffectiveness of the screening methods, it still remains a great challenge to discover novel active scaffolds. Since the strengths and weaknesses of both fragment-based drug design and traditional virtual screening (VS), we proposed a fragment VS concept based on Bayesian categorization for the discovery of novel scaffolds. This work investigated the proposal through an application on VEGFR-2 target. Firstly, scaffold and structural diversity of chemical space for 10 compound databases were explicitly evaluated. Simultaneously, a robust Bayesian classification model was constructed for screening not only compound databases but also their corresponding fragment databases. Although analysis of the scaffold diversity demonstrated a very unevenly distribution of scaffolds over molecules, results showed that our Bayesian model behaved better in screening fragments than molecules. Through a literature retrospective research, several generated fragments with relatively high Bayesian scores indeed exhibit VEGFR-2 biological activity, which strongly proved the effectiveness of fragment VS based on Bayesian categorization models. This investigation of Bayesian-based fragment VS can further emphasize the necessity for enrichment of compound databases employed in lead discovery by amplifying the diversity of databases with novel structures.

An Efficient Implementation of the Nwat-MMGBSA Method to Rescore Docking Results in Medium-Throughput Virtual Screenings

Directory of Open Access Journals (Sweden)

Irene Maffucci

2018-03-01

Full Text Available Nwat-MMGBSA is a variant of MM-PB/GBSA based on the inclusion of a number of explicit water molecules that are the closest to the ligand in each frame of a molecular dynamics trajectory. This method demonstrated improved correlations between calculated and experimental binding energies in both protein-protein interactions and ligand-receptor complexes, in comparison to the standard MM-GBSA. A protocol optimization, aimed to maximize efficacy and efficiency, is discussed here considering penicillopepsin, HIV1-protease, and BCL-XL as test cases. Calculations were performed in triplicates on both classic HPC environments and on standard workstations equipped by a GPU card, evidencing no statistical differences in the results. No relevant differences in correlation to experiments were also observed when performing Nwat-MMGBSA calculations on 4 or 1 ns long trajectories. A fully automatic workflow for structure-based virtual screening, performing from library set-up to docking and Nwat-MMGBSA rescoring, has then been developed. The protocol has been tested against no rescoring or standard MM-GBSA rescoring within a retrospective virtual screening of inhibitors of AmpC β-lactamase and of the Rac1-Tiam1 protein-protein interaction. In both cases, Nwat-MMGBSA rescoring provided a statistically significant increase in the ROC AUCs of between 20 and 30%, compared to docking scoring or to standard MM-GBSA rescoring.

An Efficient Implementation of the Nwat-MMGBSA Method to Rescore Docking Results in Medium-Throughput Virtual Screenings

Science.gov (United States)

Maffucci, Irene; Hu, Xiao; Fumagalli, Valentina; Contini, Alessandro

2018-03-01

Nwat-MMGBSA is a variant of MM-PB/GBSA based on the inclusion of a number of explicit water molecules that are the closest to the ligand in each frame of a molecular dynamics trajectory. This method demonstrated improved correlations between calculated and experimental binding energies in both protein-protein interactions and ligand-receptor complexes, in comparison to the standard MM-GBSA. A protocol optimization, aimed to maximize efficacy and efficiency, is discussed here considering penicillopepsin, HIV1-protease, and BCL-XL as test cases. Calculations were performed in triplicates on both classic HPC environments and on standard workstations equipped by a GPU card, evidencing no statistical differences in the results. No relevant differences in correlation to experiments were also observed when performing Nwat-MMGBSA calculations on 4 ns or 1 ns long trajectories. A fully automatic workflow for structure-based virtual screening, performing from library set-up to docking and Nwat-MMGBSA rescoring, has then been developed. The protocol has been tested against no rescoring or standard MM-GBSA rescoring within a retrospective virtual screening of inhibitors of AmpC β-lactamase and of the Rac1-Tiam1 protein-protein interaction. In both cases, Nwat-MMGBSA rescoring provided a statistically significant increase in the ROC AUCs of between 20% and 30%, compared to docking scoring or to standard MM-GBSA rescoring.

Computed Tomographic Virtual Colonoscopy to Screen for Colorectal Neoplasia in asymptomatic adults

International Nuclear Information System (INIS)

Pickhardt, Perry J.; Choi, J Richard; Hwang, Inku and others

2004-01-01

We evaluated the performance characteristics of computed tomographic (CT) virtual colonospy for the detection of colorectal neoplasia in an average-risk screening population. A total of 1233 symptomatic adults (mean age, 57.8 years) underwent same-day virtual and optical colonoscopy. Radiologists used the three-dimensional endoluminal display for the initial detection of polyps on CT virtual colonoscopy. For the initial examination of each colonic segment, the colonoscopists were unaware of the findings on virtual colonoscopy, which were revealed to them before any subsequent reexamination. The sensitivity and specificity of virtual colonoscopy and the sensitivity of optical colonoscopy were calculated with the use of the findings of the final, unblinded optical colonoscopy as the reference standard. The sensitivity of virtual colonoscopy for adenomatous polyps was 93.8 percent for polyps at least 10 mm in diameter, 93.9 percent for polyps at least 8 mm in diameter, and 88.7 percent for polyps at least 6 mm in diameter. The sensitivity of optical colonoscopy for adenomatous polyps was 87.5 percent, 91.5 percent, and 92.3 percent for the three sizes of polyps, respectively. The specificity of virtual colonoscopy for adenomatous polyps was 96.0 percent for polyps at least 10 mm in diameter, 92.2 percent for polyps at least 8 mm in diameter, and 79.6 percent for polyps at least 6 mm in diameter.Two polyps were malignant; both were detected on virtual colonoscopy, and one of them was missed on optical colonoscopy before the results on virtual colonoscopy were revealed. CT virtual colonoscopy with the use of a three-dimensional approach is an accurate screening method for the detection of colorectal neoplasia in symptomatic average-risk adults and compares favorably with optical colonoscopy in terms of the detection of clinically relevant lesions

1001 Ways to run AutoDock Vina for virtual screening

NARCIS (Netherlands)

Jaghoori, Mohammad Mahdi; Bleijlevens, Boris; Olabarriaga, Silvia D.

2016-01-01

Large-scale computing technologies have enabled high-throughput virtual screening involving thousands to millions of drug candidates. It is not trivial, however, for biochemical scientists to evaluate the technical alternatives and their implications for running such large experiments. Besides

Combining pharmacophore fingerprints and PLS-discriminant analysis for virtual screening and SAR elucidation

DEFF Research Database (Denmark)

Askjær, Sune; Langgård, Morten

2008-01-01

The criterion of success for the initial stages of a ligand-based drug-discovery project is dual. First, a set of suitable lead compounds has to be identified. Second, a level of a preliminary structure-activity relationship (SAR) of the identified ligands has to be established in order to guide ...... by the protein-binding site known from X-ray complexes. The result of this analysis assists in explaining the efficiency of 2D pharmacophore fingerprints as descriptors in virtual screening....... the lead optimization toward a final drug candidate. This paper presents a combined approach to solving these two problems of ligand-based virtual screening and elucidation of SAR based on interplay between pharmacophore fingerprints and interpretation of PLS-discriminant analysis (PLS-DA) models....... The virtual screening capability of the PLS-DA method is compared to group fusion maximum similarity searching in a test using four graph-based pharmacophore fingerprints over a range of 10 diverse targets. The PLS-DA method was generally found to do better than the Smax method. The GpiDAPH3 and PCH...

Role of Chemical Reactivity and Transition State Modeling for Virtual Screening.

Science.gov (United States)

Karthikeyan, Muthukumarasamy; Vyas, Renu; Tambe, Sanjeev S; Radhamohan, Deepthi; Kulkarni, Bhaskar D

2015-01-01

Every drug discovery research program involves synthesis of a novel and potential drug molecule utilizing atom efficient, economical and environment friendly synthetic strategies. The current work focuses on the role of the reactivity based fingerprints of compounds as filters for virtual screening using a tool ChemScore. A reactant-like (RLS) and a product- like (PLS) score can be predicted for a given compound using the binary fingerprints derived from the numerous known organic reactions which capture the molecule-molecule interactions in the form of addition, substitution, rearrangement, elimination and isomerization reactions. The reaction fingerprints were applied to large databases in biology and chemistry, namely ChEMBL, KEGG, HMDB, DSSTox, and the Drug Bank database. A large network of 1113 synthetic reactions was constructed to visualize and ascertain the reactant product mappings in the chemical reaction space. The cumulative reaction fingerprints were computed for 4000 molecules belonging to 29 therapeutic classes of compounds, and these were found capable of discriminating between the cognition disorder related and anti-allergy compounds with reasonable accuracy of 75% and AUC 0.8. In this study, the transition state based fingerprints were also developed and used effectively for virtual screening in drug related databases. The methodology presented here provides an efficient handle for the rapid scoring of molecular libraries for virtual screening.

Virtual screening of electron acceptor materials for organic photovoltaic applications

International Nuclear Information System (INIS)

D Halls, Mathew; Giesen, David J; Goldberg, Alexander; Djurovich, Peter J; Sommer, Jonathan; McAnally, Eric; Thompson, Mark E

2013-01-01

Virtual screening involves the generation of structure libraries, automated analysis to predict properties related to application performance and subsequent screening to identify lead systems and estimate critical structure–property limits across a targeted chemical design space. This approach holds great promise for informing experimental discovery and development efforts for next-generation materials, such as organic semiconductors. In this work, the virtual screening approach is illustrated for nitrogen-substituted pentacene molecules to identify systems for development as electron acceptor materials for use in organic photovoltaic (OPV) devices. A structure library of tetra-azapentacenes (TAPs) was generated by substituting four nitrogens for CH at 12 sites on the pentacene molecular framework. Molecular properties (e.g. E LUMO , E g and μ) were computed for each candidate structure using hybrid DFT at the B3LYP/6-311G** level of theory. The resulting TAPs library was then analyzed with respect to intrinsic properties associated with OPV acceptor performance. Marcus reorganization energies for charge transport for the most favorable TAP candidates were then calculated to further determine suitability as OPV electron acceptors. The synthesis, characterization and OPV device testing of TAP materials is underway, guided by these results. (paper)

Virtual drug screen schema based on multiview similarity integration and ranking aggregation.

Science.gov (United States)

Kang, Hong; Sheng, Zhen; Zhu, Ruixin; Huang, Qi; Liu, Qi; Cao, Zhiwei

2012-03-26

The current drug virtual screen (VS) methods mainly include two categories. i.e., ligand/target structure-based virtual screen and that, utilizing protein-ligand interaction fingerprint information based on the large number of complex structures. Since the former one focuses on the one-side information while the later one focuses on the whole complex structure, they are thus complementary and can be boosted by each other. However, a common problem faced here is how to present a comprehensive understanding and evaluation of the various virtual screen results derived from various VS methods. Furthermore, there is still an urgent need for developing an efficient approach to fully integrate various VS methods from a comprehensive multiview perspective. In this study, our virtual screen schema based on multiview similarity integration and ranking aggregation was tested comprehensively with statistical evaluations, providing several novel and useful clues on how to perform drug VS from multiple heterogeneous data sources. (1) 18 complex structures of HIV-1 protease with ligands from the PDB were curated as a test data set and the VS was performed with five different drug representations. Ritonavir ( 1HXW ) was selected as the query in VS and the weighted ranks of the query results were aggregated from multiple views through four similarity integration approaches. (2) Further, one of the ranking aggregation methods was used to integrate the similarity ranks calculated by gene ontology (GO) fingerprint and structural fingerprint on the data set from connectivity map, and two typical HDAC and HSP90 inhibitors were chosen as the queries. The results show that rank aggregation can enhance the result of similarity searching in VS when two or more descriptions are involved and provide a more reasonable similarity rank result. Our study shows that integrated VS based on multiple data fusion can achieve a remarkable better performance compared to that from individual ones and

Screening and dotting virtual slides: A new challenge for cytotechnologists

Directory of Open Access Journals (Sweden)

Walid E Khalbuss

2013-01-01

Full Text Available Digital images are increasingly being used in cytopathology. Whole-slide imaging (WSI is a digital imaging modality that uses computerized technology to scan and convert entire cytology glass slides into digital images that can be viewed on a digital display using the image viewer software. Digital image acquisition of cytology glass slides has improved significantly over the years due to the use of liquid-based preparations and advances in WSI scanning technology such as automatic multipoint pre-scan focus technology or z-stack scanning technology. Screening cytotechnologists are responsible for every cell that is present on an imaged slide. One of the challenges users have to overcome is to establish a technique to review systematically the entire imaged slide and to dot selected abnormal or significant findings. The scope of this article is to review the current user interface technology available for virtual slide navigation when screening digital slides in cytology. WSI scanner vendors provide tools, built into the image viewer software that allow for a more systematic navigation of the virtual slides, such as auto-panning, keyboard-controlled slide navigation and track map. Annotation tools can improve communication between the screener and the final reviewer or can be used for education. The tracking functionality allows recording of the WSI navigation process and provides a mechanism for confirmation of slide coverage by the screening cytotechnologist as well as a useful tool for quality assurance. As the WSI technology matures, additional features and tools to support navigation of a cytology virtual slide are anticipated.

Virtual high screening throughput and design of 14α-lanosterol ...

African Journals Online (AJOL)

STORAGESEVER

2009-07-06

Jul 6, 2009 ... Virtual high screening throughput and design of. 14α-lanosterol demethylase inhibitors against. Mycobacterium tuberculosis. Hildebert B. Maurice1*, Esther Tuarira1 and Kennedy Mwambete2. 1School of Pharmaceutical Sciences, Institute of Allied Health Sciences, Muhimbili University of Health and.

Structure-Based Virtual Screening of Commercially Available Compound Libraries.

Science.gov (United States)

Kireev, Dmitri

2016-01-01

Virtual screening (VS) is an efficient hit-finding tool. Its distinctive strength is that it allows one to screen compound libraries that are not available in the lab. Moreover, structure-based (SB) VS also enables an understanding of how the hit compounds bind the protein target, thus laying ground work for the rational hit-to-lead progression. SBVS requires a very limited experimental effort and is particularly well suited for academic labs and small biotech companies that, unlike pharmaceutical companies, do not have physical access to quality small-molecule libraries. Here, we describe SBVS of commercial compound libraries for Mer kinase inhibitors. The screening protocol relies on the docking algorithm Glide complemented by a post-docking filter based on structural protein-ligand interaction fingerprints (SPLIF).

Interactive screen experiments-innovative virtual laboratories for distance learners

International Nuclear Information System (INIS)

Hatherly, P A; Jordan, S E; Cayless, A

2009-01-01

The desirability and value of laboratory work for physics students is a well-established principle and issues arise where students are inherently remote from their host institution, as is the case for the UK's Open University. In this paper, we present developments from the Physics Innovations Centre for Excellence in Teaching and Learning (piCETL) in the production and technology of the virtual laboratory resources, interactive screen experiments, and the benefits and drawbacks of such resources. We also explore the motivations behind current implementation of interactive screen experiments and examine evaluation strategies and outcomes through a series of case studies

Computational fragment-based screening using RosettaLigand: the SAMPL3 challenge

Science.gov (United States)

Kumar, Ashutosh; Zhang, Kam Y. J.

2012-05-01

SAMPL3 fragment based virtual screening challenge provides a valuable opportunity for researchers to test their programs, methods and screening protocols in a blind testing environment. We participated in SAMPL3 challenge and evaluated our virtual fragment screening protocol, which involves RosettaLigand as the core component by screening a 500 fragments Maybridge library against bovine pancreatic trypsin. Our study reaffirmed that the real test for any virtual screening approach would be in a blind testing environment. The analyses presented in this paper also showed that virtual screening performance can be improved, if a set of known active compounds is available and parameters and methods that yield better enrichment are selected. Our study also highlighted that to achieve accurate orientation and conformation of ligands within a binding site, selecting an appropriate method to calculate partial charges is important. Another finding is that using multiple receptor ensembles in docking does not always yield better enrichment than individual receptors. On the basis of our results and retrospective analyses from SAMPL3 fragment screening challenge we anticipate that chances of success in a fragment screening process could be increased significantly with careful selection of receptor structures, protein flexibility, sufficient conformational sampling within binding pocket and accurate assignment of ligand and protein partial charges.

A cross docking pipeline for improving pose prediction and virtual screening performance

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Kumar, Ashutosh; Zhang, Kam Y. J.

2018-01-01

Pose prediction and virtual screening performance of a molecular docking method depend on the choice of protein structures used for docking. Multiple structures for a target protein are often used to take into account the receptor flexibility and problems associated with a single receptor structure. However, the use of multiple receptor structures is computationally expensive when docking a large library of small molecules. Here, we propose a new cross-docking pipeline suitable to dock a large library of molecules while taking advantage of multiple target protein structures. Our method involves the selection of a suitable receptor for each ligand in a screening library utilizing ligand 3D shape similarity with crystallographic ligands. We have prospectively evaluated our method in D3R Grand Challenge 2 and demonstrated that our cross-docking pipeline can achieve similar or better performance than using either single or multiple-receptor structures. Moreover, our method displayed not only decent pose prediction performance but also better virtual screening performance over several other methods.

How to benchmark methods for structure-based virtual screening of large compound libraries.

Science.gov (United States)

Christofferson, Andrew J; Huang, Niu

2012-01-01

Structure-based virtual screening is a useful computational technique for ligand discovery. To systematically evaluate different docking approaches, it is important to have a consistent benchmarking protocol that is both relevant and unbiased. Here, we describe the designing of a benchmarking data set for docking screen assessment, a standard docking screening process, and the analysis and presentation of the enrichment of annotated ligands among a background decoy database.

Application of Shape Similarity in Pose Selection and Virtual Screening in CSARdock2014 Exercise.

Science.gov (United States)

Kumar, Ashutosh; Zhang, Kam Y J

2016-06-27

To evaluate the applicability of shape similarity in docking-based pose selection and virtual screening, we participated in the CSARdock2014 benchmark exercise for identifying the correct docking pose of inhibitors targeting factor XA, spleen tyrosine kinase, and tRNA methyltransferase. This exercise provides a valuable opportunity for researchers to test their docking programs, methods, and protocols in a blind testing environment. In the CSARdock2014 benchmark exercise, we have implemented an approach that uses ligand 3D shape similarity to facilitate docking-based pose selection and virtual screening. We showed here that ligand 3D shape similarity between bound poses could be used to identify the native-like pose from an ensemble of docking-generated poses. Our method correctly identified the native pose as the top-ranking pose for 73% of test cases in a blind testing environment. Moreover, the pose selection results also revealed an excellent correlation between ligand 3D shape similarity scores and RMSD to X-ray crystal structure ligand. In the virtual screening exercise, the average RMSD for our pose prediction was found to be 1.02 Å, and it was one of the top performances achieved in CSARdock2014 benchmark exercise. Furthermore, the inclusion of shape similarity improved virtual screening performance of docking-based scoring and ranking. The coefficient of determination (r(2)) between experimental activities and docking scores for 276 spleen tyrosine kinase inhibitors was found to be 0.365 but reached 0.614 when the ligand 3D shape similarity was included.

Virtual screening approach to identifying influenza virus neuraminidase inhibitors using molecular docking combined with machine-learning-based scoring function.

Science.gov (United States)

Zhang, Li; Ai, Hai-Xin; Li, Shi-Meng; Qi, Meng-Yuan; Zhao, Jian; Zhao, Qi; Liu, Hong-Sheng

2017-10-10

In recent years, an epidemic of the highly pathogenic avian influenza H7N9 virus has persisted in China, with a high mortality rate. To develop novel anti-influenza therapies, we have constructed a machine-learning-based scoring function (RF-NA-Score) for the effective virtual screening of lead compounds targeting the viral neuraminidase (NA) protein. RF-NA-Score is more accurate than RF-Score, with a root-mean-square error of 1.46, Pearson's correlation coefficient of 0.707, and Spearman's rank correlation coefficient of 0.707 in a 5-fold cross-validation study. The performance of RF-NA-Score in a docking-based virtual screening of NA inhibitors was evaluated with a dataset containing 281 NA inhibitors and 322 noninhibitors. Compared with other docking-rescoring virtual screening strategies, rescoring with RF-NA-Score significantly improved the efficiency of virtual screening, and a strategy that averaged the scores given by RF-NA-Score, based on the binding conformations predicted with AutoDock, AutoDock Vina, and LeDock, was shown to be the best strategy. This strategy was then applied to the virtual screening of NA inhibitors in the SPECS database. The 100 selected compounds were tested in an in vitro H7N9 NA inhibition assay, and two compounds with novel scaffolds showed moderate inhibitory activities. These results indicate that RF-NA-Score improves the efficiency of virtual screening for NA inhibitors, and can be used successfully to identify new NA inhibitor scaffolds. Scoring functions specific for other drug targets could also be established with the same method.

A Multi-Projector Calibration Method for Virtual Reality Simulators with Analytically Defined Screens

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Cristina Portalés

2017-06-01

Full Text Available The geometric calibration of projectors is a demanding task, particularly for the industry of virtual reality simulators. Different methods have been developed during the last decades to retrieve the intrinsic and extrinsic parameters of projectors, most of them being based on planar homographies and some requiring an extended calibration process. The aim of our research work is to design a fast and user-friendly method to provide multi-projector calibration on analytically defined screens, where a sample is shown for a virtual reality Formula 1 simulator that has a cylindrical screen. The proposed method results from the combination of surveying, photogrammetry and image processing approaches, and has been designed by considering the spatial restrictions of virtual reality simulators. The method has been validated from a mathematical point of view, and the complete system—which is currently installed in a shopping mall in Spain—has been tested by different users.

Open challenges in structure-based virtual screening: Receptor modeling, target flexibility consideration and active site water molecules description.

Science.gov (United States)

Spyrakis, Francesca; Cavasotto, Claudio N

2015-10-01

Structure-based virtual screening is currently an established tool in drug lead discovery projects. Although in the last years the field saw an impressive progress in terms of algorithm development, computational performance, and retrospective and prospective applications in ligand identification, there are still long-standing challenges where further improvement is needed. In this review, we consider the conceptual frame, state-of-the-art and recent developments of three critical "structural" issues in structure-based drug lead discovery: the use of homology modeling to accurately model the binding site when no experimental structures are available, the necessity of accounting for the dynamics of intrinsically flexible systems as proteins, and the importance of considering active site water molecules in lead identification and optimization campaigns. Copyright © 2015 Elsevier Inc. All rights reserved.

Teaching Basic Field Skills Using Screen-Based Virtual Reality Landscapes

Science.gov (United States)

Houghton, J.; Robinson, A.; Gordon, C.; Lloyd, G. E. E.; Morgan, D. J.

2016-12-01

We are using screen-based virtual reality landscapes, created using the Unity 3D game engine, to augment the training geoscience students receive in preparing for fieldwork. Students explore these landscapes as they would real ones, interacting with virtual outcrops to collect data, determine location, and map the geology. Skills for conducting field geological surveys - collecting, plotting and interpreting data; time management and decision making - are introduced interactively and intuitively. As with real landscapes, the virtual landscapes are open-ended terrains with embedded data. This means the game does not structure student interaction with the information as it is through experience the student learns the best methods to work successfully and efficiently. These virtual landscapes are not replacements for geological fieldwork rather virtual spaces between classroom and field in which to train and reinforcement essential skills. Importantly, these virtual landscapes offer accessible parallel provision for students unable to visit, or fully partake in visiting, the field. The project has received positive feedback from both staff and students. Results show students find it easier to focus on learning these basic field skills in a classroom, rather than field setting, and make the same mistakes as when learning in the field, validating the realistic nature of the virtual experience and providing opportunity to learn from these mistakes. The approach also saves time, and therefore resources, in the field as basic skills are already embedded. 70% of students report increased confidence with how to map boundaries and 80% have found the virtual training a useful experience. We are also developing landscapes based on real places with 3D photogrammetric outcrops, and a virtual urban landscape in which Engineering Geology students can conduct a site investigation. This project is a collaboration between the University of Leeds and Leeds College of Art, UK, and all

Novel Data Mining Methods for Virtual Screening of Biological Active Chemical Compounds

KAUST Repository

Soufan, Othman

2016-01-01

compounds as candidate drugs for the treatment. Computational resources have been playing a significant role in this part through a step known as virtual screening. From a data mining perspective, availability of rich data resources is key in training

Library fingerprints: a novel approach to the screening of virtual libraries.

Science.gov (United States)

Klon, Anthony E; Diller, David J

2007-01-01

We propose a novel method to prioritize libraries for combinatorial synthesis and high-throughput screening that assesses the viability of a particular library on the basis of the aggregate physical-chemical properties of the compounds using a naïve Bayesian classifier. This approach prioritizes collections of related compounds according to the aggregate values of their physical-chemical parameters in contrast to single-compound screening. The method is also shown to be useful in screening existing noncombinatorial libraries when the compounds in these libraries have been previously clustered according to their molecular graphs. We show that the method used here is comparable or superior to the single-compound virtual screening of combinatorial libraries and noncombinatorial libraries and is superior to the pairwise Tanimoto similarity searching of a collection of combinatorial libraries.

Role of Open Source Tools and Resources in Virtual Screening for Drug Discovery.

Science.gov (United States)

Karthikeyan, Muthukumarasamy; Vyas, Renu

2015-01-01

Advancement in chemoinformatics research in parallel with availability of high performance computing platform has made handling of large scale multi-dimensional scientific data for high throughput drug discovery easier. In this study we have explored publicly available molecular databases with the help of open-source based integrated in-house molecular informatics tools for virtual screening. The virtual screening literature for past decade has been extensively investigated and thoroughly analyzed to reveal interesting patterns with respect to the drug, target, scaffold and disease space. The review also focuses on the integrated chemoinformatics tools that are capable of harvesting chemical data from textual literature information and transform them into truly computable chemical structures, identification of unique fragments and scaffolds from a class of compounds, automatic generation of focused virtual libraries, computation of molecular descriptors for structure-activity relationship studies, application of conventional filters used in lead discovery along with in-house developed exhaustive PTC (Pharmacophore, Toxicophores and Chemophores) filters and machine learning tools for the design of potential disease specific inhibitors. A case study on kinase inhibitors is provided as an example.

Statistical Analysis of EGFR Structures’ Performance in Virtual Screening

Science.gov (United States)

Li, Yan; Li, Xiang; Dong, Zigang

2015-01-01

In this work the ability of EGFR structures to distinguish true inhibitors from decoys in docking and MM-PBSA is assessed by statistical procedures. The docking performance depends critically on the receptor conformation and bound state. The enrichment of known inhibitors is well correlated with the difference between EGFR structures rather than the bound-ligand property. The optimal structures for virtual screening can be selected based purely on the complex information. And the mixed combination of distinct EGFR conformations is recommended for ensemble docking. In MM-PBSA, a variety of EGFR structures have identically good performance in the scoring and ranking of known inhibitors, indicating that the choice of the receptor structure has little effect on the screening. PMID:26476847

Assessing the utility and limitations of high throughput virtual screening

Directory of Open Access Journals (Sweden)

Paul Daniel Phillips

2016-05-01

Full Text Available Due to low cost, speed, and unmatched ability to explore large numbers of compounds, high throughput virtual screening and molecular docking engines have become widely utilized by computational scientists. It is generally accepted that docking engines, such as AutoDock, produce reliable qualitative results for ligand-macromolecular receptor binding, and molecular docking results are commonly reported in literature in the absence of complementary wet lab experimental data. In this investigation, three variants of the sixteen amino acid peptide, α-conotoxin MII, were docked to a homology model of the a3β2-nicotinic acetylcholine receptor. DockoMatic version 2.0 was used to perform a virtual screen of each peptide ligand to the receptor for ten docking trials consisting of 100 AutoDock cycles per trial. The results were analyzed for both variation in the calculated binding energy obtained from AutoDock, and the orientation of bound peptide within the receptor. The results show that, while no clear correlation exists between consistent ligand binding pose and the calculated binding energy, AutoDock is able to determine a consistent positioning of bound peptide in the majority of trials when at least ten trials were evaluated.

Design and Development of ChemInfoCloud: An Integrated Cloud Enabled Platform for Virtual Screening.

Science.gov (United States)

Karthikeyan, Muthukumarasamy; Pandit, Deepak; Bhavasar, Arvind; Vyas, Renu

2015-01-01

The power of cloud computing and distributed computing has been harnessed to handle vast and heterogeneous data required to be processed in any virtual screening protocol. A cloud computing platorm ChemInfoCloud was built and integrated with several chemoinformatics and bioinformatics tools. The robust engine performs the core chemoinformatics tasks of lead generation, lead optimisation and property prediction in a fast and efficient manner. It has also been provided with some of the bioinformatics functionalities including sequence alignment, active site pose prediction and protein ligand docking. Text mining, NMR chemical shift (1H, 13C) prediction and reaction fingerprint generation modules for efficient lead discovery are also implemented in this platform. We have developed an integrated problem solving cloud environment for virtual screening studies that also provides workflow management, better usability and interaction with end users using container based virtualization, OpenVz.

Identification by shape-based virtual screening and evaluation of new tyrosinase inhibitors

Directory of Open Access Journals (Sweden)

Qi Li

2018-01-01

Full Text Available Targeting tyrosinase is considered to be an effective way to control the production of melanin. Tyrosinase inhibitor is anticipated to provide new therapy to prevent skin pigmentation, melanoma and neurodegenerative diseases. Herein, we report our results in identifying new tyrosinase inhibitors. The shape-based virtual screening was performed to discover new tyrosinase inhibitors. Thirteen potential hits derived from virtual screening were tested by biological determinations. Compound 5186-0429 exhibited the most potent inhibitory activity. It dose-dependently inhibited the activity of tyrosinase, with the IC50 values 6.2 ± 2.0 µM and 10.3 ± 5.4 µM on tyrosine and L-Dopa formation, respectively. The kinetic study of 5186-0429 demonstrated that this compound acted as a competitive inhibitor. We believe the discoveries here could serve as a good starting point for further design of potent tyrosinase inhibitor.

Virtual reality skills training for health care professionals in alcohol screening and brief intervention.

Science.gov (United States)

Fleming, Michael; Olsen, Dale; Stathes, Hilary; Boteler, Laura; Grossberg, Paul; Pfeifer, Judie; Schiro, Stephanie; Banning, Jane; Skochelak, Susan

2009-01-01

Educating physicians and other health care professionals about the identification and treatment of patients who drink more than recommended limits is an ongoing challenge. An educational randomized controlled trial was conducted to test the ability of a stand-alone training simulation to improve the clinical skills of health care professionals in alcohol screening and intervention. The "virtual reality simulation" combined video, voice recognition, and nonbranching logic to create an interactive environment that allowed trainees to encounter complex social cues and realistic interpersonal exchanges. The simulation included 707 questions and statements and 1207 simulated patient responses. A sample of 102 health care professionals (10 physicians; 30 physician assistants or nurse practitioners; 36 medical students; 26 pharmacy, physican assistant, or nurse practitioner students) were randomly assigned to a no training group (n = 51) or a computer-based virtual reality intervention (n = 51). Professionals in both groups had similar pretest standardized patient alcohol screening skill scores: 53.2 (experimental) vs 54.4 (controls), 52.2 vs 53.7 alcohol brief intervention skills, and 42.9 vs 43.5 alcohol referral skills. After repeated practice with the simulation there were significant increases in the scores of the experimental group at 6 months after randomization compared with the control group for the screening (67.7 vs 58.1; P virtual reality simulation to demonstrate an increase in the alcohol screening and brief intervention skills of health care professionals.

A retrospective audit of the first screening round of the Maltese breast screening programme

International Nuclear Information System (INIS)

Mizzi, D.; Zarb, F.; Dennis, A.

2017-01-01

Purpose: To analyse whether the screening performance parameters of the Maltese National Breast Screening Programme first screening round met requirements set by European standards. The association between screening age and results of screening performance parameters was also investigated. Method: Quantitative methodology was used to review examinations of women who were recalled for a technical recall or further assessment rates. All accessible members of the population recalled during the first round were retrospectively reviewed resulting in a sample of 2300 recalled examinations. Results: Malta's first screening round met the European Guidelines recommendations for technical repeat rate (0.26%), early recall rate (0.45%), breast cancer detection rate (13.77 per 1000 women) and Positive Predictive Value of screening test (7.58%). However, local recall rate (18.53%) and further assessment rate (18.27%) were higher than recommended. The Chi square test showed a statistically significant difference (p ≤ 0.05) in recall rates between the compared age groups, as younger women (51–55 years) were more likely to have a negative diagnosis after the initial mammogram whereas older women (56–60 years) were more likely to be recalled. There was no age discrepancy (p ≥ 0.05) in local breast cancer detection rate and positive predictive value of screening test. Conclusion: Although the Maltese first screening round performed well, this study found deficiencies in recall and further assessment rates, which according to literature may result in psychological morbidity and inefficient use of screening resources. This study also concluded that when a cohort is analysed, age is not as significant as the screening round itself (first/subsequent). - Highlights: • The Maltese technical and early recall rates complied with European guidelines. • Breast cancer detection rate and positive predictive value conformed to guidelines. • The recall and further

Comparison of confirmed inactive and randomly selected compounds as negative training examples in support vector machine-based virtual screening.

Science.gov (United States)

Heikamp, Kathrin; Bajorath, Jürgen

2013-07-22

The choice of negative training data for machine learning is a little explored issue in chemoinformatics. In this study, the influence of alternative sets of negative training data and different background databases on support vector machine (SVM) modeling and virtual screening has been investigated. Target-directed SVM models have been derived on the basis of differently composed training sets containing confirmed inactive molecules or randomly selected database compounds as negative training instances. These models were then applied to search background databases consisting of biological screening data or randomly assembled compounds for available hits. Negative training data were found to systematically influence compound recall in virtual screening. In addition, different background databases had a strong influence on the search results. Our findings also indicated that typical benchmark settings lead to an overestimation of SVM-based virtual screening performance compared to search conditions that are more relevant for practical applications.

Virtual Ligand Screening Using PL-PatchSurfer2, a Molecular Surface-Based Protein-Ligand Docking Method.

Science.gov (United States)

Shin, Woong-Hee; Kihara, Daisuke

2018-01-01

Virtual screening is a computational technique for predicting a potent binding compound for a receptor protein from a ligand library. It has been a widely used in the drug discovery field to reduce the efforts of medicinal chemists to find hit compounds by experiments.Here, we introduce our novel structure-based virtual screening program, PL-PatchSurfer, which uses molecular surface representation with the three-dimensional Zernike descriptors, which is an effective mathematical representation for identifying physicochemical complementarities between local surfaces of a target protein and a ligand. The advantage of the surface-patch description is its tolerance on a receptor and compound structure variation. PL-PatchSurfer2 achieves higher accuracy on apo form and computationally modeled receptor structures than conventional structure-based virtual screening programs. Thus, PL-PatchSurfer2 opens up an opportunity for targets that do not have their crystal structures. The program is provided as a stand-alone program at http://kiharalab.org/plps2 . We also provide files for two ligand libraries, ChEMBL and ZINC Drug-like.

Automated tool for virtual screening and pharmacology-based pathway prediction and analysis

Directory of Open Access Journals (Sweden)

Sugandh Kumar

2017-10-01

Full Text Available The virtual screening is an effective tool for the lead identification in drug discovery. However, there are limited numbers of crystal structures available as compared to the number of biological sequences which makes (Structure Based Drug Discovery SBDD a difficult choice. The current tool is an attempt to automate the protein structure modelling and automatic virtual screening followed by pharmacology-based prediction and analysis. Starting from sequence(s, this tool automates protein structure modelling, binding site identification, automated docking, ligand preparation, post docking analysis and identification of hits in the biological pathways that can be modulated by a group of ligands. This automation helps in the characterization of ligands selectivity and action of ligands on a complex biological molecular network as well as on individual receptor. The judicial combination of the ligands binding different receptors can be used to inhibit selective biological pathways in a disease. This tool also allows the user to systemically investigate network-dependent effects of a drug or drug candidate.

Hit Identification and Optimization in Virtual Screening: Practical Recommendations Based Upon a Critical Literature Analysis

Science.gov (United States)

Zhu, Tian; Cao, Shuyi; Su, Pin-Chih; Patel, Ram; Shah, Darshan; Chokshi, Heta B.; Szukala, Richard; Johnson, Michael E.; Hevener, Kirk E.

2013-01-01

A critical analysis of virtual screening results published between 2007 and 2011 was performed. The activity of reported hit compounds from over 400 studies was compared to their hit identification criteria. Hit rates and ligand efficiencies were calculated to assist in these analyses and the results were compared with factors such as the size of the virtual library and the number of compounds tested. A series of promiscuity, drug-like, and ADMET filters were applied to the reported hits to assess the quality of compounds reported and a careful analysis of a subset of the studies which presented hit optimization was performed. This data allowed us to make several practical recommendations with respect to selection of compounds for experimental testing, defining hit identification criteria, and general virtual screening hit criteria to allow for realistic hit optimization. A key recommendation is the use of size-targeted ligand efficiency values as hit identification criteria. PMID:23688234

Hit identification and optimization in virtual screening: practical recommendations based on a critical literature analysis.

Science.gov (United States)

Zhu, Tian; Cao, Shuyi; Su, Pin-Chih; Patel, Ram; Shah, Darshan; Chokshi, Heta B; Szukala, Richard; Johnson, Michael E; Hevener, Kirk E

2013-09-12

A critical analysis of virtual screening results published between 2007 and 2011 was performed. The activity of reported hit compounds from over 400 studies was compared to their hit identification criteria. Hit rates and ligand efficiencies were calculated to assist in these analyses, and the results were compared with factors such as the size of the virtual library and the number of compounds tested. A series of promiscuity, druglike, and ADMET filters were applied to the reported hits to assess the quality of compounds reported, and a careful analysis of a subset of the studies that presented hit optimization was performed. These data allowed us to make several practical recommendations with respect to selection of compounds for experimental testing, definition of hit identification criteria, and general virtual screening hit criteria to allow for realistic hit optimization. A key recommendation is the use of size-targeted ligand efficiency values as hit identification criteria.

An effective docking strategy for virtual screening based on multi-objective optimization algorithm

Directory of Open Access Journals (Sweden)

Kang Ling

2009-02-01

Full Text Available Abstract Background Development of a fast and accurate scoring function in virtual screening remains a hot issue in current computer-aided drug research. Different scoring functions focus on diverse aspects of ligand binding, and no single scoring can satisfy the peculiarities of each target system. Therefore, the idea of a consensus score strategy was put forward. Integrating several scoring functions, consensus score re-assesses the docked conformations using a primary scoring function. However, it is not really robust and efficient from the perspective of optimization. Furthermore, to date, the majority of available methods are still based on single objective optimization design. Results In this paper, two multi-objective optimization methods, called MOSFOM, were developed for virtual screening, which simultaneously consider both the energy score and the contact score. Results suggest that MOSFOM can effectively enhance enrichment and performance compared with a single score. For three different kinds of binding sites, MOSFOM displays an excellent ability to differentiate active compounds through energy and shape complementarity. EFMOGA performed particularly well in the top 2% of database for all three cases, whereas MOEA_Nrg and MOEA_Cnt performed better than the corresponding individual scoring functions if the appropriate type of binding site was selected. Conclusion The multi-objective optimization method was successfully applied in virtual screening with two different scoring functions that can yield reasonable binding poses and can furthermore, be ranked with the potentially compromised conformations of each compound, abandoning those conformations that can not satisfy overall objective functions.

Structure-based virtual screening of molecular libraries as cdk2 inhibitors

International Nuclear Information System (INIS)

Riaz, U.; Khaleeq, M.

2011-01-01

CDK2 inhibitor is an important target in multiple processes associated with tumor growth and development, including proliferation, neovascularization, and metastasis. In this study, hit identification was performed by virtual screening of commercial and in-house compound libraries. Docking studies for the hits were performed, and scoring functions were used to evaluate the docking results and to rank ligand-binding affinities. Subsequently, hit optimization for potent and selective candidate CDK2 inhibitors was performed through focused library design and docking analyses. Consequently, we report that a novel compound with an IC50 value of 89 nM, representing 2-Amino-4,6-di-(4',6'-dibromophenyl)pyrimidine 1, is highly selective for CDK2 inhibitors. The docking structure of compound 1 with CDK2 inhibitor disclosed that the NH moiety and pyrimidine ring appeared to fit tightly into the hydrophobic pocket of CDK2 inhibitor. Additionally, the pyrimidine NH forms a hydrogen bond with the carboxyl group of Asp348. These results confirm the successful application of virtual screening studies in the lead discovery process, and suggest that our novel compound can be an effective CDK2 inhibitor candidate for further lead optimization. (author)

Discovery of novel PPAR ligands by a virtual screening approach based on pharmacophore modeling, 3D shape, and electrostatic similarity screening

DEFF Research Database (Denmark)

Markt, Patrick; Petersen, Rasmus K; Flindt, Esben N

2008-01-01

Peroxisome proliferator-activated receptors (PPARs) are important targets for drugs used in the treatment of atherosclerosis, dyslipidaemia, obesity, type 2 diabetes, and other diseases caused by abnormal regulation of the glucose and lipid metabolism. We applied a virtual screening workflow base...

FieldChopper, a new tool for automatic model generation and virtual screening based on molecular fields.

Science.gov (United States)

Kalliokoski, Tuomo; Ronkko, Toni; Poso, Antti

2008-06-01

Algorithms were developed for ligand-based virtual screening of molecular databases. FieldChopper (FC) is based on the discretization of the electrostatic and van der Waals field into three classes. A model is built from a set of superimposed active molecules. The similarity of the compounds in the database to the model is then calculated using matrices that define scores for comparing field values of different categories. The method was validated using 12 publicly available data sets by comparing the method to the electrostatic similarity comparison program EON. The results suggest that FC is competitive with more complex descriptors and could be used as a molecular sieve in virtual screening experiments when multiple active ligands are known.

Estimation of the applicability domain of kernel-based machine learning models for virtual screening

Directory of Open Access Journals (Sweden)

Fechner Nikolas

2010-03-01

Full Text Available Abstract Background The virtual screening of large compound databases is an important application of structural-activity relationship models. Due to the high structural diversity of these data sets, it is impossible for machine learning based QSAR models, which rely on a specific training set, to give reliable results for all compounds. Thus, it is important to consider the subset of the chemical space in which the model is applicable. The approaches to this problem that have been published so far mostly use vectorial descriptor representations to define this domain of applicability of the model. Unfortunately, these cannot be extended easily to structured kernel-based machine learning models. For this reason, we propose three approaches to estimate the domain of applicability of a kernel-based QSAR model. Results We evaluated three kernel-based applicability domain estimations using three different structured kernels on three virtual screening tasks. Each experiment consisted of the training of a kernel-based QSAR model using support vector regression and the ranking of a disjoint screening data set according to the predicted activity. For each prediction, the applicability of the model for the respective compound is quantitatively described using a score obtained by an applicability domain formulation. The suitability of the applicability domain estimation is evaluated by comparing the model performance on the subsets of the screening data sets obtained by different thresholds for the applicability scores. This comparison indicates that it is possible to separate the part of the chemspace, in which the model gives reliable predictions, from the part consisting of structures too dissimilar to the training set to apply the model successfully. A closer inspection reveals that the virtual screening performance of the model is considerably improved if half of the molecules, those with the lowest applicability scores, are omitted from the screening

Estimation of the applicability domain of kernel-based machine learning models for virtual screening.

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Fechner, Nikolas; Jahn, Andreas; Hinselmann, Georg; Zell, Andreas

2010-03-11

The virtual screening of large compound databases is an important application of structural-activity relationship models. Due to the high structural diversity of these data sets, it is impossible for machine learning based QSAR models, which rely on a specific training set, to give reliable results for all compounds. Thus, it is important to consider the subset of the chemical space in which the model is applicable. The approaches to this problem that have been published so far mostly use vectorial descriptor representations to define this domain of applicability of the model. Unfortunately, these cannot be extended easily to structured kernel-based machine learning models. For this reason, we propose three approaches to estimate the domain of applicability of a kernel-based QSAR model. We evaluated three kernel-based applicability domain estimations using three different structured kernels on three virtual screening tasks. Each experiment consisted of the training of a kernel-based QSAR model using support vector regression and the ranking of a disjoint screening data set according to the predicted activity. For each prediction, the applicability of the model for the respective compound is quantitatively described using a score obtained by an applicability domain formulation. The suitability of the applicability domain estimation is evaluated by comparing the model performance on the subsets of the screening data sets obtained by different thresholds for the applicability scores. This comparison indicates that it is possible to separate the part of the chemspace, in which the model gives reliable predictions, from the part consisting of structures too dissimilar to the training set to apply the model successfully. A closer inspection reveals that the virtual screening performance of the model is considerably improved if half of the molecules, those with the lowest applicability scores, are omitted from the screening. The proposed applicability domain formulations

Free Energy-Based Virtual Screening and Optimization of RNase H Inhibitors of HIV-1 Reverse Transcriptase.

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Zhang, Baofeng; D'Erasmo, Michael P; Murelli, Ryan P; Gallicchio, Emilio

2016-09-30

We report the results of a binding free energy-based virtual screening campaign of a library of 77 α-hydroxytropolone derivatives against the challenging RNase H active site of the reverse transcriptase (RT) enzyme of human immunodeficiency virus-1. Multiple protonation states, rotamer states, and binding modalities of each compound were individually evaluated. The work involved more than 300 individual absolute alchemical binding free energy parallel molecular dynamics calculations and over 1 million CPU hours on national computing clusters and a local campus computational grid. The thermodynamic and structural measures obtained in this work rationalize a series of characteristics of this system useful for guiding future synthetic and biochemical efforts. The free energy model identified key ligand-dependent entropic and conformational reorganization processes difficult to capture using standard docking and scoring approaches. Binding free energy-based optimization of the lead compounds emerging from the virtual screen has yielded four compounds with very favorable binding properties, which will be the subject of further experimental investigations. This work is one of the few reported applications of advanced-binding free energy models to large-scale virtual screening and optimization projects. It further demonstrates that, with suitable algorithms and automation, advanced-binding free energy models can have a useful role in early-stage drug-discovery programs.

Virtual screening and pharmacophore design for a novel theoretical inhibitor of macrophage stimulating factor as a metastatic agent.

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Torktaz, Ibrahim; Mohamadhashem, Faezeh; Esmaeili, Abolghasem; Behjati, Mohaddeseh; Sharifzadeh, Sara

2013-01-01

Metastasis is a crucial aspect of cancer. Macrophage stimulating protein (MSP) is a single chain protein and can be cleaved by serum proteases. MSP has several roles in metastasis. In this in silico study, MSP as a metastatic agent was considered as a drug target. Crystallographic structure of MSP was retrieved from protein data bank. To find a chemical inhibitor of MSP, a library of KEGG compounds was screened and 1000 shape complemented ligands were retrieved with FindSite algorithm. Molegro Virtual Docker (MVD) software was used for docking simulation of shape complemented ligands against MSP. Moldock score was used as scoring function for virtual screening and potential inhibitors with more negative binding energy were obtained. PLANS scoring function was used for revaluation of virtual screening data. The top found chemical had binding affinity of -183.55 based on MolDock score and equal to -66.733 PLANTs score to MSP structure. Based on pharmacophore model of potential inhibitor, this study suggests that the chemical which was found in this research and its derivate can be used for subsequent laboratory studies.

A desirability-based multi objective approach for the virtual screening discovery of broad-spectrum anti-gastric cancer agents.

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Yunierkis Perez-Castillo

Full Text Available Gastric cancer is the third leading cause of cancer-related mortality worldwide and despite advances in prevention, diagnosis and therapy, it is still regarded as a global health concern. The efficacy of the therapies for gastric cancer is limited by a poor response to currently available therapeutic regimens. One of the reasons that may explain these poor clinical outcomes is the highly heterogeneous nature of this disease. In this sense, it is essential to discover new molecular agents capable of targeting various gastric cancer subtypes simultaneously. Here, we present a multi-objective approach for the ligand-based virtual screening discovery of chemical compounds simultaneously active against the gastric cancer cell lines AGS, NCI-N87 and SNU-1. The proposed approach relays in a novel methodology based on the development of ensemble models for the bioactivity prediction against each individual gastric cancer cell line. The methodology includes the aggregation of one ensemble per cell line using a desirability-based algorithm into virtual screening protocols. Our research leads to the proposal of a multi-targeted virtual screening protocol able to achieve high enrichment of known chemicals with anti-gastric cancer activity. Specifically, our results indicate that, using the proposed protocol, it is possible to retrieve almost 20 more times multi-targeted compounds in the first 1% of the ranked list than what is expected from a uniform distribution of the active ones in the virtual screening database. More importantly, the proposed protocol attains an outstanding initial enrichment of known multi-targeted anti-gastric cancer agents.

Screening of Potential Lead Molecule as Novel MurE Inhibitor: Virtual Screening, Molecular Dynamics and In Vitro Studies.

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Zaveri, Kunal; Kiranmayi, Patnala

2017-01-01

The prevalence of multi-drug resistance S. aureus is one of the most challenging tasks for the treatment of nosocomial infections. Proteins and enzymes of peptidoglycan biosynthesis pathway are one among the well-studied targets, but many of the enzymes are unexplored as targets. MurE is one such enzyme featured to be a promising target. As MurE plays an important role in ligating the L-lys to stem peptide at third position that is crucial for peptidoglycan synthesis. To screen the potential MurE inhibitor by in silico approach and evaluate the best potential lead molecule by in vitro methods. In the current study, we have employed structure based virtual screening targeting the active site of MurE, followed by Molecular dynamics and in vitro studies. Virtual screening resulted in successful screening of potential lead molecule ((2R)-2-[[1-[(2R)- 2-(benzyloxycarbonylamino) propanoyl] piperidine-4-carbonyl]amino]-5-guanidino-pentan). The molecular dynamics of the MurE and Lead molecule complex emphasizes that lead molecule has shown stable interactions with active site residues Asp 406 and with Glu 460. In vitro studies demonstrate that the lead molecule shows antibacterial activity close to standard antibiotic Vancomycin and higher than that of Ampicillin, Streptomycin and Rifampicin. The MIC of lead molecule at 50μg/mL was observed to be 3.75 μg/mL, MBC being bactericidal with value of 6.25 μg/mL, cytotoxicity showing 34.44% and IC50 of 40.06μg/mL. These results suggest ((2R)-2-[[1-[(2R)-2-(benzyloxycarbonylamino) propanoyl] piperidine-4-carbonyl]amino]-5-guanidino-pentan) as a promising lead molecule for developing a MurE inhibitor against treatment of S. aureus infections. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Virtual Screening and Pharmacophore Design for a Novel Theoretical Inhibitor of Macrophage Stimulating Factor as a Metastatic Agent

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Ibrahim Torktaz

2013-09-01

Full Text Available Introduction: Metastasis is a crucial aspect of cancer. Macrophage stimulating protein (MSP is a single chain protein and can be cleaved by serum proteases. MSP has several roles in metastasis. In this in silico study, MSP as a metastatic agent was considered as a drug target. Methods: Crystallographic structure of MSP was retrieved from protein data bank. To find a chemical inhibitor of MSP, a library of KEGG compounds was screened and 1000 shape complemented ligands were retrieved with FindSite algorithm. Molegro Virtual Docker (MVD software was used for docking simulation of shape complemented ligands against MSP. Moldock score was used as scoring function for virtual screening and potential inhibitors with more negative binding energy were obtained. PLANS scoring function was used for revaluation of virtual screening data. Results: The top found chemical had binding affinity of -183.55 based on MolDock score and equal to -66.733 PLANTs score to MSP structure. Conclusion: Based on pharmacophore model of potential inhibitor, this study suggests that the chemical which was found in this research and its derivate can be used for subsequent laboratory studies.

The Discovery of Aurora Kinase Inhibitor by Multi-Docking-Based Virtual Screening

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Jun-Tae Kim

2014-11-01

Full Text Available We report the discovery of aurora kinase inhibitor using the fragment-based virtual screening by multi-docking strategy. Among a number of fragments collected from eMololecules, we found four fragment molecules showing potent activity (>50% at 100 μM against aurora kinase. Based on the explored fragment scaffold, we selected two compounds in our synthesized library and validated the biological activity against Aurora kinase.

Virtual Reality Skills Training for Health Care Professionals in Alcohol Screening and Brief Intervention

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Fleming, Michael; Olsen, Dale; Stathes, Hilary; Boteler, Laura; Grossberg, Paul; Pfeifer, Judie; Schiro, Stephanie; Banning, Jane; Skochelak, Susan

2009-01-01

Background Educating physicians and other health care professionals to identify and treat patients who drink above recommended limits is an ongoing challenge. Methods An educational Randomized Control Trial (RCT) was conducted to test the ability of a stand alone training simulation to improve the clinical skills of health care professionals in alcohol screening and intervention. The “virtual reality simulation” combines video, voice recognition and non branching logic to create an interactive environment that allows trainees to encounter complex social cues and realistic interpersonal exchanges. The simulation includes 707 questions and statements and 1207 simulated patient responses. Results A sample of 102 health care professionals (10 physicians; 30 physician assistants [PAs] or nurse practitioners [NPs]; 36 medical students; 26 pharmacy, PA or NP students) were randomly assigned to no training (n=51) or a computer based virtual reality intervention (n=51). Subjects in both groups had similar pre-test standardized patient alcohol screening skill scores – 53.2 (experimental) vs. 54.4 (controls), 52.2 vs. 53.7 alcohol brief intervention skills, and 42.9 vs. 43.5 alcohol referral skills. Following repeated practice with the simulation there were significant increases in the scores of the experimental group at 6 months post-randomization compared to the control group for the screening (67.7 vs. 58.1, pvirtual reality simulation to demonstrate an increase in the alcohol screening and brief intervention skills of health care professionals. PMID:19587253

Virtual screening of inorganic materials synthesis parameters with deep learning

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Kim, Edward; Huang, Kevin; Jegelka, Stefanie; Olivetti, Elsa

2017-12-01

Virtual materials screening approaches have proliferated in the past decade, driven by rapid advances in first-principles computational techniques, and machine-learning algorithms. By comparison, computationally driven materials synthesis screening is still in its infancy, and is mired by the challenges of data sparsity and data scarcity: Synthesis routes exist in a sparse, high-dimensional parameter space that is difficult to optimize over directly, and, for some materials of interest, only scarce volumes of literature-reported syntheses are available. In this article, we present a framework for suggesting quantitative synthesis parameters and potential driving factors for synthesis outcomes. We use a variational autoencoder to compress sparse synthesis representations into a lower dimensional space, which is found to improve the performance of machine-learning tasks. To realize this screening framework even in cases where there are few literature data, we devise a novel data augmentation methodology that incorporates literature synthesis data from related materials systems. We apply this variational autoencoder framework to generate potential SrTiO3 synthesis parameter sets, propose driving factors for brookite TiO2 formation, and identify correlations between alkali-ion intercalation and MnO2 polymorph selection.

vSDC: a method to improve early recognition in virtual screening when limited experimental resources are available.

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Chaput, Ludovic; Martinez-Sanz, Juan; Quiniou, Eric; Rigolet, Pascal; Saettel, Nicolas; Mouawad, Liliane

2016-01-01

In drug design, one may be confronted to the problem of finding hits for targets for which no small inhibiting molecules are known and only low-throughput experiments are available (like ITC or NMR studies), two common difficulties encountered in a typical academic setting. Using a virtual screening strategy like docking can alleviate some of the problems and save a considerable amount of time by selecting only top-ranking molecules, but only if the method is very efficient, i.e. when a good proportion of actives are found in the 1-10 % best ranked molecules. The use of several programs (in our study, Gold, Surflex, FlexX and Glide were considered) shows a divergence of the results, which presents a difficulty in guiding the experiments. To overcome this divergence and increase the yield of the virtual screening, we created the standard deviation consensus (SDC) and variable SDC (vSDC) methods, consisting of the intersection of molecule sets from several virtual screening programs, based on the standard deviations of their ranking distributions. SDC allowed us to find hits for two new protein targets by testing only 9 and 11 small molecules from a chemical library of circa 15,000 compounds. Furthermore, vSDC, when applied to the 102 proteins of the DUD-E benchmarking database, succeeded in finding more hits than any of the four isolated programs for 13-60 % of the targets. In addition, when only 10 molecules of each of the 102 chemical libraries were considered, vSDC performed better in the number of hits found, with an improvement of 6-24 % over the 10 best-ranked molecules given by the individual docking programs.Graphical abstractIn drug design, for a given target and a given chemical library, the results obtained with different virtual screening programs are divergent. So how to rationally guide the experimental tests, especially when only a few number of experiments can be made? The variable Standard Deviation Consensus (vSDC) method was developed to

Prospective performance evaluation of selected common virtual screening tools. Case study: Cyclooxygenase (COX) 1 and 2.

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Kaserer, Teresa; Temml, Veronika; Kutil, Zsofia; Vanek, Tomas; Landa, Premysl; Schuster, Daniela

2015-01-01

Computational methods can be applied in drug development for the identification of novel lead candidates, but also for the prediction of pharmacokinetic properties and potential adverse effects, thereby aiding to prioritize and identify the most promising compounds. In principle, several techniques are available for this purpose, however, which one is the most suitable for a specific research objective still requires further investigation. Within this study, the performance of several programs, representing common virtual screening methods, was compared in a prospective manner. First, we selected top-ranked virtual screening hits from the three methods pharmacophore modeling, shape-based modeling, and docking. For comparison, these hits were then additionally predicted by external pharmacophore- and 2D similarity-based bioactivity profiling tools. Subsequently, the biological activities of the selected hits were assessed in vitro, which allowed for evaluating and comparing the prospective performance of the applied tools. Although all methods performed well, considerable differences were observed concerning hit rates, true positive and true negative hits, and hitlist composition. Our results suggest that a rational selection of the applied method represents a powerful strategy to maximize the success of a research project, tightly linked to its aims. We employed cyclooxygenase as application example, however, the focus of this study lied on highlighting the differences in the virtual screening tool performances and not in the identification of novel COX-inhibitors. Copyright © 2015 The Authors. Published by Elsevier Masson SAS.. All rights reserved.

iScreen: world's first cloud-computing web server for virtual screening and de novo drug design based on TCM database@Taiwan.

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Tsai, Tsung-Ying; Chang, Kai-Wei; Chen, Calvin Yu-Chian

2011-06-01

The rapidly advancing researches on traditional Chinese medicine (TCM) have greatly intrigued pharmaceutical industries worldwide. To take initiative in the next generation of drug development, we constructed a cloud-computing system for TCM intelligent screening system (iScreen) based on TCM Database@Taiwan. iScreen is compacted web server for TCM docking and followed by customized de novo drug design. We further implemented a protein preparation tool that both extract protein of interest from a raw input file and estimate the size of ligand bind site. In addition, iScreen is designed in user-friendly graphic interface for users who have less experience with the command line systems. For customized docking, multiple docking services, including standard, in-water, pH environment, and flexible docking modes are implemented. Users can download first 200 TCM compounds of best docking results. For TCM de novo drug design, iScreen provides multiple molecular descriptors for a user's interest. iScreen is the world's first web server that employs world's largest TCM database for virtual screening and de novo drug design. We believe our web server can lead TCM research to a new era of drug development. The TCM docking and screening server is available at http://iScreen.cmu.edu.tw/.

iScreen: world's first cloud-computing web server for virtual screening and de novo drug design based on TCM database@Taiwan

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Tsai, Tsung-Ying; Chang, Kai-Wei; Chen, Calvin Yu-Chian

2011-06-01

The rapidly advancing researches on traditional Chinese medicine (TCM) have greatly intrigued pharmaceutical industries worldwide. To take initiative in the next generation of drug development, we constructed a cloud-computing system for TCM intelligent screening system (iScreen) based on TCM Database@Taiwan. iScreen is compacted web server for TCM docking and followed by customized de novo drug design. We further implemented a protein preparation tool that both extract protein of interest from a raw input file and estimate the size of ligand bind site. In addition, iScreen is designed in user-friendly graphic interface for users who have less experience with the command line systems. For customized docking, multiple docking services, including standard, in-water, pH environment, and flexible docking modes are implemented. Users can download first 200 TCM compounds of best docking results. For TCM de novo drug design, iScreen provides multiple molecular descriptors for a user's interest. iScreen is the world's first web server that employs world's largest TCM database for virtual screening and de novo drug design. We believe our web server can lead TCM research to a new era of drug development. The TCM docking and screening server is available at http://iScreen.cmu.edu.tw/.

Performance of machine-learning scoring functions in structure-based virtual screening.

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Wójcikowski, Maciej; Ballester, Pedro J; Siedlecki, Pawel

2017-04-25

Classical scoring functions have reached a plateau in their performance in virtual screening and binding affinity prediction. Recently, machine-learning scoring functions trained on protein-ligand complexes have shown great promise in small tailored studies. They have also raised controversy, specifically concerning model overfitting and applicability to novel targets. Here we provide a new ready-to-use scoring function (RF-Score-VS) trained on 15 426 active and 893 897 inactive molecules docked to a set of 102 targets. We use the full DUD-E data sets along with three docking tools, five classical and three machine-learning scoring functions for model building and performance assessment. Our results show RF-Score-VS can substantially improve virtual screening performance: RF-Score-VS top 1% provides 55.6% hit rate, whereas that of Vina only 16.2% (for smaller percent the difference is even more encouraging: RF-Score-VS top 0.1% achieves 88.6% hit rate for 27.5% using Vina). In addition, RF-Score-VS provides much better prediction of measured binding affinity than Vina (Pearson correlation of 0.56 and -0.18, respectively). Lastly, we test RF-Score-VS on an independent test set from the DEKOIS benchmark and observed comparable results. We provide full data sets to facilitate further research in this area (http://github.com/oddt/rfscorevs) as well as ready-to-use RF-Score-VS (http://github.com/oddt/rfscorevs_binary).

Virtual target screening to rapidly identify potential protein targets of natural products in drug discovery

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Yuri Pevzner

2014-05-01

Full Text Available Inherent biological viability and diversity of natural products make them a potentially rich source for new therapeutics. However, identification of bioactive compounds with desired therapeutic effects and identification of their protein targets is a laborious, expensive process. Extracts from organism samples may show desired activity in phenotypic assays but specific bioactive compounds must be isolated through further separation methods and protein targets must be identified by more specific phenotypic and in vitro experimental assays. Still, questions remain as to whether all relevant protein targets for a compound have been identified. The desire is to understand breadth of purposing for the compound to maximize its use and intellectual property, and to avoid further development of compounds with insurmountable adverse effects. Previously we developed a Virtual Target Screening system that computationally screens one or more compounds against a collection of virtual protein structures. By scoring each compound-protein interaction, we can compare against averaged scores of synthetic drug-like compounds to determine if a particular protein would be a potential target of a compound of interest. Here we provide examples of natural products screened through our system as we assess advantages and shortcomings of our current system in regards to natural product drug discovery.

Virtual target screening to rapidly identify potential protein targets of natural products in drug discovery

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Yuri Pevzner

2015-08-01

Full Text Available Inherent biological viability and diversity of natural products make them a potentially rich source for new therapeutics. However, identification of bioactive compounds with desired therapeutic effects and identification of their protein targets is a laborious, expensive process. Extracts from organism samples may show desired activity in phenotypic assays but specific bioactive compounds must be isolated through further separation methods and protein targets must be identified by more specific phenotypic and in vitro experimental assays. Still, questions remain as to whether all relevant protein targets for a compound have been identified. The desire is to understand breadth of purposing for the compound to maximize its use and intellectual property, and to avoid further development of compounds with insurmountable adverse effects. Previously we developed a Virtual Target Screening system that computationally screens one or more compounds against a collection of virtual protein structures. By scoring each compound-protein interaction, we can compare against averaged scores of synthetic drug-like compounds to determine if a particular protein would be a potential target of a compound of interest. Here we provide examples of natural products screened through our system as we assess advantages and shortcomings of our current system in regards to natural product drug discovery.

Ligand-based virtual screening and inductive learning for identification of SIRT1 inhibitors in natural products.

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Sun, Yunan; Zhou, Hui; Zhu, Hongmei; Leung, Siu-wai

2016-01-25

Sirtuin 1 (SIRT1) is a nicotinamide adenine dinucleotide-dependent deacetylase, and its dysregulation can lead to ageing, diabetes, and cancer. From 346 experimentally confirmed SIRT1 inhibitors, an inhibitor structure pattern was generated by inductive logic programming (ILP) with DMax Chemistry Assistant software. The pattern contained amide, amine, and hetero-aromatic five-membered rings, each of which had a hetero-atom and an unsubstituted atom at a distance of 2. According to this pattern, a ligand-based virtual screening of 1 444 880 active compounds from Chinese herbs identified 12 compounds as inhibitors of SIRT1. Three compounds (ZINC08790006, ZINC08792229, and ZINC08792355) had high affinity (-7.3, -7.8, and -8.6 kcal/mol, respectively) for SIRT1 as estimated by molecular docking software AutoDock Vina. This study demonstrated a use of ILP and background knowledge in machine learning to facilitate virtual screening.

Large-scale systematic analysis of 2D fingerprint methods and parameters to improve virtual screening enrichments.

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Sastry, Madhavi; Lowrie, Jeffrey F; Dixon, Steven L; Sherman, Woody

2010-05-24

A systematic virtual screening study on 11 pharmaceutically relevant targets has been conducted to investigate the interrelation between 8 two-dimensional (2D) fingerprinting methods, 13 atom-typing schemes, 13 bit scaling rules, and 12 similarity metrics using the new cheminformatics package Canvas. In total, 157 872 virtual screens were performed to assess the ability of each combination of parameters to identify actives in a database screen. In general, fingerprint methods, such as MOLPRINT2D, Radial, and Dendritic that encode information about local environment beyond simple linear paths outperformed other fingerprint methods. Atom-typing schemes with more specific information, such as Daylight, Mol2, and Carhart were generally superior to more generic atom-typing schemes. Enrichment factors across all targets were improved considerably with the best settings, although no single set of parameters performed optimally on all targets. The size of the addressable bit space for the fingerprints was also explored, and it was found to have a substantial impact on enrichments. Small bit spaces, such as 1024, resulted in many collisions and in a significant degradation in enrichments compared to larger bit spaces that avoid collisions.

A Study of Applications of Machine Learning Based Classification Methods for Virtual Screening of Lead Molecules.

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Vyas, Renu; Bapat, Sanket; Jain, Esha; Tambe, Sanjeev S; Karthikeyan, Muthukumarasamy; Kulkarni, Bhaskar D

2015-01-01

The ligand-based virtual screening of combinatorial libraries employs a number of statistical modeling and machine learning methods. A comprehensive analysis of the application of these methods for the diversity oriented virtual screening of biological targets/drug classes is presented here. A number of classification models have been built using three types of inputs namely structure based descriptors, molecular fingerprints and therapeutic category for performing virtual screening. The activity and affinity descriptors of a set of inhibitors of four target classes DHFR, COX, LOX and NMDA have been utilized to train a total of six classifiers viz. Artificial Neural Network (ANN), k nearest neighbor (k-NN), Support Vector Machine (SVM), Naïve Bayes (NB), Decision Tree--(DT) and Random Forest--(RF). Among these classifiers, the ANN was found as the best classifier with an AUC of 0.9 irrespective of the target. New molecular fingerprints based on pharmacophore, toxicophore and chemophore (PTC), were used to build the ANN models for each dataset. A good accuracy of 87.27% was obtained using 296 chemophoric binary fingerprints for the COX-LOX inhibitors compared to pharmacophoric (67.82%) and toxicophoric (70.64%). The methodology was validated on the classical Ames mutagenecity dataset of 4337 molecules. To evaluate it further, selectivity and promiscuity of molecules from five drug classes viz. anti-anginal, anti-convulsant, anti-depressant, anti-arrhythmic and anti-diabetic were studied. The TPC fingerprints computed for each category were able to capture the drug-class specific features using the k-NN classifier. These models can be useful for selecting optimal molecules for drug design.

Discovery of new inhibitors of the bacterial peptidoglycan biosynthesis enzymes MurD and MurF by structure-based virtual screening.

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Turk, Samo; Kovac, Andreja; Boniface, Audrey; Bostock, Julieanne M; Chopra, Ian; Blanot, Didier; Gobec, Stanislav

2009-03-01

The ATP-dependent Mur ligases (MurC, MurD, MurE and MurF) successively add L-Ala, D-Glu, meso-A(2)pm or L-Lys, and D-Ala-D-Ala to the nucleotide precursor UDP-MurNAc, and they represent promising targets for antibacterial drug discovery. We have used the molecular docking programme eHiTS for the virtual screening of 1990 compounds from the National Cancer Institute 'Diversity Set' on MurD and MurF. The 50 top-scoring compounds from screening on each enzyme were selected for experimental biochemical evaluation. Our approach of virtual screening and subsequent in vitro biochemical evaluation of the best ranked compounds has provided four novel MurD inhibitors (best IC(50)=10 microM) and one novel MurF inhibitor (IC(50)=63 microM).

Exploration of natural product ingredients as inhibitors of human HMG-CoA reductase through structure-based virtual screening

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Lin SH

2015-06-01

Full Text Available Shih-Hung Lin,1 Kao-Jean Huang,1,2 Ching-Feng Weng,1 David Shiuan1 1Department of Life Science and Institute of Biotechnology, National Dong Hwa University, Hualien, Taiwan, Republic of China; 2Development Center of Biotechnology, Taipei, Taiwan, Republic of China Abstract: Cholesterol plays an important role in living cells. However, a very high level of cholesterol may lead to atherosclerosis. HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A reductase is the key enzyme in the cholesterol biosynthesis pathway, and the statin-like drugs are inhibitors of human HMG-CoA reductase (hHMGR. The present study aimed to virtually screen for potential hHMGR inhibitors from natural product to discover hypolipidemic drug candidates with fewer side effects and lesser toxicities. We used the 3D structure 1HWK from the PDB (Protein Data Bank database of hHMGR as the target to screen for the strongly bound compounds from the traditional Chinese medicine database. Many interesting molecules including polyphenolic compounds, polisubstituted heterocyclics, and linear lipophilic alcohols were identified and their ADMET (absorption, disrtibution, metabolism, excretion, toxicity properties were predicted. Finally, four compounds were obtained for the in vitro validation experiments. The results indicated that curcumin and salvianolic acid C can effectively inhibit hHMGR, with IC50 (half maximal inhibitory concentration values of 4.3 µM and 8 µM, respectively. The present study also demonstrated the feasibility of discovering new drug candidates through structure-based virtual screening. Keywords: HMG-CoA reductase, virtual screening, curcumin, salvianolic acid C

Virtual screening by a new Clustering-based Weighted Similarity Extreme Learning Machine approach.

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Pasupa, Kitsuchart; Kudisthalert, Wasu

2018-01-01

Machine learning techniques are becoming popular in virtual screening tasks. One of the powerful machine learning algorithms is Extreme Learning Machine (ELM) which has been applied to many applications and has recently been applied to virtual screening. We propose the Weighted Similarity ELM (WS-ELM) which is based on a single layer feed-forward neural network in a conjunction of 16 different similarity coefficients as activation function in the hidden layer. It is known that the performance of conventional ELM is not robust due to random weight selection in the hidden layer. Thus, we propose a Clustering-based WS-ELM (CWS-ELM) that deterministically assigns weights by utilising clustering algorithms i.e. k-means clustering and support vector clustering. The experiments were conducted on one of the most challenging datasets-Maximum Unbiased Validation Dataset-which contains 17 activity classes carefully selected from PubChem. The proposed algorithms were then compared with other machine learning techniques such as support vector machine, random forest, and similarity searching. The results show that CWS-ELM in conjunction with support vector clustering yields the best performance when utilised together with Sokal/Sneath(1) coefficient. Furthermore, ECFP_6 fingerprint presents the best results in our framework compared to the other types of fingerprints, namely ECFP_4, FCFP_4, and FCFP_6.

Ultrafast protein structure-based virtual screening with Panther

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Niinivehmas, Sanna P.; Salokas, Kari; Lätti, Sakari; Raunio, Hannu; Pentikäinen, Olli T.

2015-10-01

Molecular docking is by far the most common method used in protein structure-based virtual screening. This paper presents Panther, a novel ultrafast multipurpose docking tool. In Panther, a simple shape-electrostatic model of the ligand-binding area of the protein is created by utilizing the protein crystal structure. The features of the possible ligands are then compared to the model by using a similarity search algorithm. On average, one ligand can be processed in a few minutes by using classical docking methods, whereas using Panther processing takes Panther protocol can be used in several applications, such as speeding up the early phases of drug discovery projects, reducing the number of failures in the clinical phase of the drug development process, and estimating the environmental toxicity of chemicals. Panther-code is available in our web pages (http://www.jyu.fi/panther) free of charge after registration.

Virtual screening filters for the design of type II p38 MAP kinase inhibitors: a fragment based library generation approach.

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Badrinarayan, Preethi; Sastry, G Narahari

2012-04-01

In this work, we introduce the development and application of a three-step scoring and filtering procedure for the design of type II p38 MAP kinase leads using allosteric fragments extracted from virtual screening hits. The design of the virtual screening filters is based on a thorough evaluation of docking methods, DFG-loop conformation, binding interactions and chemotype specificity of the 138 p38 MAP kinase inhibitors from Protein Data Bank bound to DFG-in and DFG-out conformations using Glide, GOLD and CDOCKER. A 40 ns molecular dynamics simulation with the apo, type I with DFG-in and type II with DFG-out forms was carried out to delineate the effects of structural variations on inhibitor binding. The designed docking-score and sub-structure filters were first tested on a dataset of 249 potent p38 MAP kinase inhibitors from seven diverse series and 18,842 kinase inhibitors from PDB, to gauge their capacity to discriminate between kinase and non-kinase inhibitors and likewise to selectively filter-in target-specific inhibitors. The designed filters were then applied in the virtual screening of a database of ten million (10⁷) compounds resulting in the identification of 100 hits. Based on their binding modes, 98 allosteric fragments were extracted from the hits and a fragment library was generated. New type II p38 MAP kinase leads were designed by tailoring the existing type I ATP site binders with allosteric fragments using a common urea linker. Target specific virtual screening filters can thus be easily developed for other kinases based on this strategy to retrieve target selective compounds. Copyright © 2012 Elsevier Inc. All rights reserved.

Colon cancer screening

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Screening for colon cancer; Colonoscopy - screening; Sigmoidoscopy - screening; Virtual colonoscopy - screening; Fecal immunochemical test; Stool DNA test; sDNA test; Colorectal cancer - screening; Rectal ...

Discovery of covalent inhibitors for MIF tautomerase via cocrystal structures with phantom hits from virtual screening

Energy Technology Data Exchange (ETDEWEB)

McLean, Larry R.; Zhang, Ying; Li, Hua; Li, Ziyu; Lukasczyk, Ulrike; Choi, Yong-Mi; Han, Zuoning; Prisco, Joy; Fordham, Jeremy; Tsay, Joseph T.; Reiling, Stephan; Vaz, Roy J.; Li, Yi; (Sanofi)

2010-10-28

Biochemical and X-ray crystallographic studies confirmed that hydroxyquinoline derivatives identified by virtual screening were actually covalent inhibitors of the MIF tautomerase. Adducts were formed by N-alkylation of the Pro-1 at the catalytic site with a loss of an amino group of the inhibitor.

Identification of LasR Ligands through a Virtual Screening Approach

DEFF Research Database (Denmark)

Skovstrup, Søren; Le Quement, Sebastian Thordal; Hansen, Thomas

2013-01-01

as an attractive therapeutic target for the next generation of antimicrobial agents. In the present study, a virtual screening workflow combining pharmacophore‐ and structure‐based approaches was used to identify new LasR ligands. Five novel inducers and three inhibitors of LasR activity were validated...... experimentally by use of a cell‐based assay. Interestingly, these compounds are molecularly distinct from the native signal molecule, N‐3‐oxododecanoyl‐L‐homoserine lactone (OHN), and may serve as lead structures for the design of new drugs. The binding modes of these compounds to the OHN binding site in Las......R were predicted and used to identify the key interactions that contribute to the induction and inhibition of LasR activity....

Discovery of potent inhibitors of soluble epoxide hydrolase by combinatorial library design and structure-based virtual screening.

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Xing, Li; McDonald, Joseph J; Kolodziej, Steve A; Kurumbail, Ravi G; Williams, Jennifer M; Warren, Chad J; O'Neal, Janet M; Skepner, Jill E; Roberds, Steven L

2011-03-10

Structure-based virtual screening was applied to design combinatorial libraries to discover novel and potent soluble epoxide hydrolase (sEH) inhibitors. X-ray crystal structures revealed unique interactions for a benzoxazole template in addition to the conserved hydrogen bonds with the catalytic machinery of sEH. By exploitation of the favorable binding elements, two iterations of library design based on amide coupling were employed, guided principally by the docking results of the enumerated virtual products. Biological screening of the libraries demonstrated as high as 90% hit rate, of which over two dozen compounds were single digit nanomolar sEH inhibitors by IC(50) determination. In total the library design and synthesis produced more than 300 submicromolar sEH inhibitors. In cellular systems consistent activities were demonstrated with biochemical measurements. The SAR understanding of the benzoxazole template provides valuable insights into discovery of novel sEH inhibitors as therapeutic agents.

Discovering new PI3Kα inhibitors with a strategy of combining ligand-based and structure-based virtual screening.

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Yu, Miao; Gu, Qiong; Xu, Jun

2018-02-01

PI3Kα is a promising drug target for cancer chemotherapy. In this paper, we report a strategy of combing ligand-based and structure-based virtual screening to identify new PI3Kα inhibitors. First, naïve Bayesian (NB) learning models and a 3D-QSAR pharmacophore model were built based upon known PI3Kα inhibitors. Then, the SPECS library was screened by the best NB model. This resulted in virtual hits, which were validated by matching the structures against the pharmacophore models. The pharmacophore matched hits were then docked into PI3Kα crystal structures to form ligand-receptor complexes, which are further validated by the Glide-XP program to result in structural validated hits. The structural validated hits were examined by PI3Kα inhibitory assay. With this screening protocol, ten PI3Kα inhibitors with new scaffolds were discovered with IC 50 values ranging 0.44-31.25 μM. The binding affinities for the most active compounds 33 and 74 were estimated through molecular dynamics simulations and MM-PBSA analyses.

Discovering new PI3Kα inhibitors with a strategy of combining ligand-based and structure-based virtual screening

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Yu, Miao; Gu, Qiong; Xu, Jun

2018-02-01

PI3Kα is a promising drug target for cancer chemotherapy. In this paper, we report a strategy of combing ligand-based and structure-based virtual screening to identify new PI3Kα inhibitors. First, naïve Bayesian (NB) learning models and a 3D-QSAR pharmacophore model were built based upon known PI3Kα inhibitors. Then, the SPECS library was screened by the best NB model. This resulted in virtual hits, which were validated by matching the structures against the pharmacophore models. The pharmacophore matched hits were then docked into PI3Kα crystal structures to form ligand-receptor complexes, which are further validated by the Glide-XP program to result in structural validated hits. The structural validated hits were examined by PI3Kα inhibitory assay. With this screening protocol, ten PI3Kα inhibitors with new scaffolds were discovered with IC50 values ranging 0.44-31.25 μM. The binding affinities for the most active compounds 33 and 74 were estimated through molecular dynamics simulations and MM-PBSA analyses.

Primary Care Screening of Depression and Treatment Engagement in a University Health Center: A Retrospective Analysis

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Klein, Michael C.; Ciotoli, Carlo; Chung, Henry

2011-01-01

Objectives: This retrospective study analyzed a primary care depression screening initiative in a large urban university health center. Depression detection, treatment status, and engagement data are presented. Participants: Participants were 3,713 graduate and undergraduate students who presented consecutively for primary care services between…

Quantitative structure-activity relationship analysis and virtual screening studies for identifying HDAC2 inhibitors from known HDAC bioactive chemical libraries.

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Pham-The, H; Casañola-Martin, G; Diéguez-Santana, K; Nguyen-Hai, N; Ngoc, N T; Vu-Duc, L; Le-Thi-Thu, H

2017-03-01

Histone deacetylases (HDAC) are emerging as promising targets in cancer, neuronal diseases and immune disorders. Computational modelling approaches have been widely applied for the virtual screening and rational design of novel HDAC inhibitors. In this study, different machine learning (ML) techniques were applied for the development of models that accurately discriminate HDAC2 inhibitors form non-inhibitors. The obtained models showed encouraging results, with the global accuracy in the external set ranging from 0.83 to 0.90. Various aspects related to the comparison of modelling techniques, applicability domain and descriptor interpretations were discussed. Finally, consensus predictions of these models were used for screening HDAC2 inhibitors from four chemical libraries whose bioactivities against HDAC1, HDAC3, HDAC6 and HDAC8 have been known. According to the results of virtual screening assays, structures of some hits with pair-isoform-selective activity (between HDAC2 and other HDACs) were revealed. This study illustrates the power of ML-based QSAR approaches for the screening and discovery of potent, isoform-selective HDACIs.

The virtual slide in the promotion of cytologic and hystologic quality in oncologic screenings

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Arrigo Bondi

2010-06-01

Full Text Available A regional experience environment in virtual microscopy and digital pathology comprehending the digital cytology is presented. The project has been conducted in Emilia-Romagna and it has been planned for the promotion and the quality assessment in screening cytology and histology for the prevention of the tumors of uterine cervix, breast and colon-rectum cancers. During the project it has been envisaged the design of a dedicated picture archive and communication system (PACS for cooperative diagnosis, didactics and training, teleconsulting, documentation of rare cases and pilot experiences; furthermore selected cases are catalogued in the PACS with the aim of the check of the diagnostic concordance in the oncologic screening.

Sense of presence and anxiety during virtual social interactions between a human and virtual humans.

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Morina, Nexhmedin; Brinkman, Willem-Paul; Hartanto, Dwi; Emmelkamp, Paul M G

2014-01-01

Virtual reality exposure therapy (VRET) has been shown to be effective in treatment of anxiety disorders. Yet, there is lack of research on the extent to which interaction between the individual and virtual humans can be successfully implanted to increase levels of anxiety for therapeutic purposes. This proof-of-concept pilot study aimed at examining levels of the sense of presence and anxiety during exposure to virtual environments involving social interaction with virtual humans and using different virtual reality displays. A non-clinical sample of 38 participants was randomly assigned to either a head-mounted display (HMD) with motion tracker and sterescopic view condition or a one-screen projection-based virtual reality display condition. Participants in both conditions engaged in free speech dialogues with virtual humans controlled by research assistants. It was hypothesized that exposure to virtual social interactions will elicit moderate levels of sense of presence and anxiety in both groups. Further it was expected that participants in the HMD condition will report higher scores of sense of presence and anxiety than participants in the one-screen projection-based display condition. Results revealed that in both conditions virtual social interactions were associated with moderate levels of sense of presence and anxiety. Additionally, participants in the HMD condition reported significantly higher levels of presence than those in the one-screen projection-based display condition (p = .001). However, contrary to the expectations neither the average level of anxiety nor the highest level of anxiety during exposure to social virtual environments differed between the groups (p = .97 and p = .75, respectively). The findings suggest that virtual social interactions can be successfully applied in VRET to enhance sense of presence and anxiety. Furthermore, our results indicate that one-screen projection-based displays can successfully activate levels of anxiety in

Sense of presence and anxiety during virtual social interactions between a human and virtual humans

Directory of Open Access Journals (Sweden)

Nexhmedin Morina

2014-04-01

Full Text Available Virtual reality exposure therapy (VRET has been shown to be effective in treatment of anxiety disorders. Yet, there is lack of research on the extent to which interaction between the individual and virtual humans can be successfully implanted to increase levels of anxiety for therapeutic purposes. This proof-of-concept pilot study aimed at examining levels of the sense of presence and anxiety during exposure to virtual environments involving social interaction with virtual humans and using different virtual reality displays. A non-clinical sample of 38 participants was randomly assigned to either a head-mounted display (HMD with motion tracker and sterescopic view condition or a one-screen projection-based virtual reality display condition. Participants in both conditions engaged in free speech dialogues with virtual humans controlled by research assistants. It was hypothesized that exposure to virtual social interactions will elicit moderate levels of sense of presence and anxiety in both groups. Further it was expected that participants in the HMD condition will report higher scores of sense of presence and anxiety than participants in the one-screen projection-based display condition. Results revealed that in both conditions virtual social interactions were associated with moderate levels of sense of presence and anxiety. Additionally, participants in the HMD condition reported significantly higher levels of presence than those in the one-screen projection-based display condition (p = .001. However, contrary to the expectations neither the average level of anxiety nor the highest level of anxiety during exposure to social virtual environments differed between the groups (p = .97 and p = .75, respectively. The findings suggest that virtual social interactions can be successfully applied in VRET to enhance sense of presence and anxiety. Furthermore, our results indicate that one-screen projection-based displays can successfully activate levels

Virtual screening for potential inhibitors of Mcl-1 conformations sampled by normal modes, molecular dynamics, and nuclear magnetic resonance

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Glantz-Gashai Y

2017-06-01

Full Text Available Yitav Glantz-Gashai,* Tomer Meirson,* Eli Reuveni, Abraham O Samson Faculty of Medicine in the Galilee, Bar Ilan University, Safed, Israel *These authors contributed equally to this work Abstract: Myeloid cell leukemia-1 (Mcl-1 is often overexpressed in human cancer and is an important target for developing antineoplastic drugs. In this study, a data set containing 2.3 million lead-like molecules and a data set of all the US Food and Drug Administration (FDA-approved drugs are virtually screened for potential Mcl-1 ligands using Protein Data Bank (PDB ID 2MHS. The potential Mcl-1 ligands are evaluated and computationally docked on to three conformation ensembles generated by normal mode analysis (NMA, molecular dynamics (MD, and nuclear magnetic resonance (NMR, respectively. The evaluated potential Mcl-1 ligands are then compared with their clinical use. Remarkably, half of the top 30 potential drugs are used clinically to treat cancer, thus partially validating our virtual screen. The partial validation also favors the idea that the other half of the top 30 potential drugs could be used in the treatment of cancer. The normal mode-, MD-, and NMR-based conformation greatly expand the conformational sampling used herein for in silico identification of potential Mcl-1 inhibitors. Keywords: virtual screening, Mcl-1, molecular dynamics, NMR, normal modes

Novel inhibitors to Taenia solium Cu/Zn superoxide dismutase identified by virtual screening

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García-Gutiérrez, P.; Landa-Piedra, A.; Rodríguez-Romero, A.; Parra-Unda, R.; Rojo-Domínguez, A.

2011-12-01

We describe in this work a successful virtual screening and experimental testing aimed to the identification of novel inhibitors of superoxide dismutase of the worm Taenia solium ( TsCu/Zn-SOD), a human parasite. Conformers from LeadQuest® database of drug-like compounds were selected and then docked on the surface of TsCu/Zn-SOD. Results were screened looking for ligand contacts with receptor side-chains not conserved in the human homologue, with a subsequent development of a score optimization by a set of energy minimization steps, aimed to identify lead compounds for in vitro experiments. Six out of fifty experimentally tested compounds showed μM inhibitory activity toward TsCu/Zn-SOD. Two of them showed species selectivity since did not inhibit the homologous human enzyme when assayed in vitro.

Identification and Validation of a Potent Dual Inhibitor of the P. falciparum M1 and M17 Aminopeptidases Using Virtual Screening.

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Chiara Ruggeri

Full Text Available The Plasmodium falciparum PfA-M1 and PfA-M17 metalloaminopeptidases are validated drug targets for the discovery of antimalarial agents. In order to identify dual inhibitors of both proteins, we developed a hierarchical virtual screening approach, followed by in vitro evaluation of the highest scoring hits. Starting from the ZINC database of purchasable compounds, sequential 3D-pharmacophore and molecular docking steps were applied to filter the virtual 'hits'. At the end of virtual screening, 12 compounds were chosen and tested against the in vitro aminopeptidase activity of both PfA-M1 and PfA-M17. Two molecules showed significant inhibitory activity (low micromolar/nanomolar range against both proteins. Finally, the crystal structure of the most potent compound in complex with both PfA-M1 and PfA-M17 was solved, revealing the binding mode and validating our computational approach.

Virtual screening for HIV protease inhibitors: a comparison of AutoDock 4 and Vina.

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Max W Chang

Full Text Available BACKGROUND: The AutoDock family of software has been widely used in protein-ligand docking research. This study compares AutoDock 4 and AutoDock Vina in the context of virtual screening by using these programs to select compounds active against HIV protease. METHODOLOGY/PRINCIPAL FINDINGS: Both programs were used to rank the members of two chemical libraries, each containing experimentally verified binders to HIV protease. In the case of the NCI Diversity Set II, both AutoDock 4 and Vina were able to select active compounds significantly better than random (AUC = 0.69 and 0.68, respectively; p<0.001. The binding energy predictions were highly correlated in this case, with r = 0.63 and iota = 0.82. For a set of larger, more flexible compounds from the Directory of Universal Decoys, the binding energy predictions were not correlated, and only Vina was able to rank compounds significantly better than random. CONCLUSIONS/SIGNIFICANCE: In ranking smaller molecules with few rotatable bonds, AutoDock 4 and Vina were equally capable, though both exhibited a size-related bias in scoring. However, as Vina executes more quickly and is able to more accurately rank larger molecules, researchers should look to it first when undertaking a virtual screen.

An unbiased method to build benchmarking sets for ligand-based virtual screening and its application to GPCRs.

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Xia, Jie; Jin, Hongwei; Liu, Zhenming; Zhang, Liangren; Wang, Xiang Simon

2014-05-27

Benchmarking data sets have become common in recent years for the purpose of virtual screening, though the main focus had been placed on the structure-based virtual screening (SBVS) approaches. Due to the lack of crystal structures, there is great need for unbiased benchmarking sets to evaluate various ligand-based virtual screening (LBVS) methods for important drug targets such as G protein-coupled receptors (GPCRs). To date these ready-to-apply data sets for LBVS are fairly limited, and the direct usage of benchmarking sets designed for SBVS could bring the biases to the evaluation of LBVS. Herein, we propose an unbiased method to build benchmarking sets for LBVS and validate it on a multitude of GPCRs targets. To be more specific, our methods can (1) ensure chemical diversity of ligands, (2) maintain the physicochemical similarity between ligands and decoys, (3) make the decoys dissimilar in chemical topology to all ligands to avoid false negatives, and (4) maximize spatial random distribution of ligands and decoys. We evaluated the quality of our Unbiased Ligand Set (ULS) and Unbiased Decoy Set (UDS) using three common LBVS approaches, with Leave-One-Out (LOO) Cross-Validation (CV) and a metric of average AUC of the ROC curves. Our method has greatly reduced the "artificial enrichment" and "analogue bias" of a published GPCRs benchmarking set, i.e., GPCR Ligand Library (GLL)/GPCR Decoy Database (GDD). In addition, we addressed an important issue about the ratio of decoys per ligand and found that for a range of 30 to 100 it does not affect the quality of the benchmarking set, so we kept the original ratio of 39 from the GLL/GDD.

Virtual screening and optimization of Type II inhibitors of JAK2 from a natural product library.

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Ma, Dik-Lung; Chan, Daniel Shiu-Hin; Wei, Guo; Zhong, Hai-Jing; Yang, Hui; Leung, Lai To; Gullen, Elizabeth A; Chiu, Pauline; Cheng, Yung-Chi; Leung, Chung-Hang

2014-11-21

Amentoflavone has been identified as a JAK2 inhibitor by structure-based virtual screening of a natural product library. In silico optimization using the DOLPHIN model yielded analogues with enhanced potency against JAK2 activity and HCV activity in cellulo. Molecular modeling and kinetic experiments suggested that the analogues may function as Type II inhibitors of JAK2.

Alternative global goodness metrics and sensitivity analysis: heuristics to check the robustness of conclusions from studies comparing virtual screening methods.

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Sheridan, Robert P

2008-02-01

We introduce two ways of testing the robustness of conclusions from studies comparing virtual screening methods: alternative "global goodness" metrics and sensitivity analysis. While the robustness tests cannot eliminate all biases in virtual screening comparisons, they are useful as a "reality check" for any given study. To illustrate this, we apply them to a set of enrichments published in McGaughey et al. (J. Chem. Inf. Model. 2007, 47, 1504-1519) where 11 target protein/ligand combinations are tested on 2D and 3D similarity methods, plus docking. The major conclusions in that paper, for instance, that ligand-based methods are better than docking methods, hold up. However, some minor conclusions, such as Glide being the best docking method, do not.

Virtual screening for potential inhibitors of bacterial MurC and MurD ligases.

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Tomašić, Tihomir; Kovač, Andreja; Klebe, Gerhard; Blanot, Didier; Gobec, Stanislav; Kikelj, Danijel; Mašič, Lucija Peterlin

2012-03-01

Mur ligases are bacterial enzymes involved in the cytoplasmic steps of peptidoglycan biosynthesis and are viable targets for antibacterial drug discovery. We have performed virtual screening for potential ATP-competitive inhibitors targeting MurC and MurD ligases, using a protocol of consecutive hierarchical filters. Selected compounds were evaluated for inhibition of MurC and MurD ligases, and weak inhibitors possessing dual inhibitory activity have been identified. These compounds represent new scaffolds for further optimisation towards multiple Mur ligase inhibitors with improved inhibitory potency.

Exploration of natural product ingredients as inhibitors of human HMG-CoA reductase through structure-based virtual screening.

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Lin, Shih-Hung; Huang, Kao-Jean; Weng, Ching-Feng; Shiuan, David

2015-01-01

Cholesterol plays an important role in living cells. However, a very high level of cholesterol may lead to atherosclerosis. HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase is the key enzyme in the cholesterol biosynthesis pathway, and the statin-like drugs are inhibitors of human HMG-CoA reductase (hHMGR). The present study aimed to virtually screen for potential hHMGR inhibitors from natural product to discover hypolipidemic drug candidates with fewer side effects and lesser toxicities. We used the 3D structure 1HWK from the PDB (Protein Data Bank) database of hHMGR as the target to screen for the strongly bound compounds from the traditional Chinese medicine database. Many interesting molecules including polyphenolic compounds, polisubstituted heterocyclics, and linear lipophilic alcohols were identified and their ADMET (absorption, disrtibution, metabolism, excretion, toxicity) properties were predicted. Finally, four compounds were obtained for the in vitro validation experiments. The results indicated that curcumin and salvianolic acid C can effectively inhibit hHMGR, with IC50 (half maximal inhibitory concentration) values of 4.3 µM and 8 µM, respectively. The present study also demonstrated the feasibility of discovering new drug candidates through structure-based virtual screening.

Human recombinant beta-secretase immobilized enzyme reactor for fast hits' selection and characterization from a virtual screening library.

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De Simone, Angela; Mancini, Francesca; Cosconati, Sandro; Marinelli, Luciana; La Pietra, Valeria; Novellino, Ettore; Andrisano, Vincenza

2013-01-25

In the present work, a human recombinant BACE1 immobilized enzyme reactor (hrBACE1-IMER) has been applied for the sensitive fast screening of 38 compounds selected through a virtual screening approach. HrBACE1-IMER was inserted into a liquid chromatograph coupled with a fluorescent detector. A fluorogenic peptide substrate (M-2420), containing the β-secretase site of the Swedish mutation of APP, was injected and cleaved in the on-line HPLC-hrBACE1-IMER system, giving rise to the fluorescent product. The compounds of the library were tested for their ability to inhibit BACE1 in the immobilized format and to reduce the area related to the chromatographic peak of the fluorescent enzymatic product. The results were validated in solution by using two different FRET methods. Due to the efficient virtual screening methodology, more than fifty percent of the selected compounds showed a measurable inhibitory activity. One of the most active compound (a bis-indanone derivative) was characterized in terms of IC(50) and K(i) determination on the hrBACE1-IMER. Thus, the hrBACE1-IMER has been confirmed as a valid tool for the throughput screening of different chemical entities with potency lower than 30μM for the fast hits' selection and for mode of action determination. Copyright © 2012 Elsevier B.V. All rights reserved.

Ligand efficiency based approach for efficient virtual screening of compound libraries.

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Ke, Yi-Yu; Coumar, Mohane Selvaraj; Shiao, Hui-Yi; Wang, Wen-Chieh; Chen, Chieh-Wen; Song, Jen-Shin; Chen, Chun-Hwa; Lin, Wen-Hsing; Wu, Szu-Huei; Hsu, John T A; Chang, Chung-Ming; Hsieh, Hsing-Pang

2014-08-18

Here we report for the first time the use of fit quality (FQ), a ligand efficiency (LE) based measure for virtual screening (VS) of compound libraries. The LE based VS protocol was used to screen an in-house database of 125,000 compounds to identify aurora kinase A inhibitors. First, 20 known aurora kinase inhibitors were docked to aurora kinase A crystal structure (PDB ID: 2W1C); and the conformations of docked ligand were used to create a pharmacophore (PH) model. The PH model was used to screen the database compounds, and rank (PH rank) them based on the predicted IC50 values. Next, LE_Scale, a weight-dependant LE function, was derived from 294 known aurora kinase inhibitors. Using the fit quality (FQ = LE/LE_Scale) score derived from the LE_Scale function, the database compounds were reranked (PH_FQ rank) and the top 151 (0.12% of database) compounds were assessed for aurora kinase A inhibition biochemically. This VS protocol led to the identification of 7 novel hits, with compound 5 showing aurora kinase A IC50 = 1.29 μM. Furthermore, testing of 5 against a panel of 31 kinase reveals that it is selective toward aurora kinase A & B, with <50% inhibition for other kinases at 10 μM concentrations and is a suitable candidate for further development. Incorporation of FQ score in the VS protocol not only helped identify a novel aurora kinase inhibitor, 5, but also increased the hit rate of the VS protocol by improving the enrichment factor (EF) for FQ based screening (EF = 828), compared to PH based screening (EF = 237) alone. The LE based VS protocol disclosed here could be applied to other targets for hit identification in an efficient manner. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

A graph-based approach to construct target-focused libraries for virtual screening.

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Naderi, Misagh; Alvin, Chris; Ding, Yun; Mukhopadhyay, Supratik; Brylinski, Michal

2016-01-01

Due to exorbitant costs of high-throughput screening, many drug discovery projects commonly employ inexpensive virtual screening to support experimental efforts. However, the vast majority of compounds in widely used screening libraries, such as the ZINC database, will have a very low probability to exhibit the desired bioactivity for a given protein. Although combinatorial chemistry methods can be used to augment existing compound libraries with novel drug-like compounds, the broad chemical space is often too large to be explored. Consequently, the trend in library design has shifted to produce screening collections specifically tailored to modulate the function of a particular target or a protein family. Assuming that organic compounds are composed of sets of rigid fragments connected by flexible linkers, a molecule can be decomposed into its building blocks tracking their atomic connectivity. On this account, we developed eSynth, an exhaustive graph-based search algorithm to computationally synthesize new compounds by reconnecting these building blocks following their connectivity patterns. We conducted a series of benchmarking calculations against the Directory of Useful Decoys, Enhanced database. First, in a self-benchmarking test, the correctness of the algorithm is validated with the objective to recover a molecule from its building blocks. Encouragingly, eSynth can efficiently rebuild more than 80 % of active molecules from their fragment components. Next, the capability to discover novel scaffolds is assessed in a cross-benchmarking test, where eSynth successfully reconstructed 40 % of the target molecules using fragments extracted from chemically distinct compounds. Despite an enormous chemical space to be explored, eSynth is computationally efficient; half of the molecules are rebuilt in less than a second, whereas 90 % take only about a minute to be generated. eSynth can successfully reconstruct chemically feasible molecules from molecular fragments

Virtual Trackballs Revisited

DEFF Research Database (Denmark)

Henriksen, Knud; Sporring, Jon; Hornbæk, Kasper

2004-01-01

reviews and provides a mathematical foundation for virtual trackballs. The first, but still popular, virtual trackball was described by Chen et al. [CHECK END OF SENTENCE]. We show that the virtual trackball by Chen et al. does not rotate the object along the intended great circular arc on the virtual...... trackball and we give a correction. Another popular virtual trackball is Shoemake's quaternion implementation [CHECK END OF SENTENCE], which we show to be a special case of the virtual trackball by Chen et al.. Shoemake extends the scope of the virtual trackball to the full screen. Unfortunately, Shoemake......'s virtual trackball is inhomogeneous and discontinuous with consequences for usability. Finally, we review Bell's virtual trackball [CHECK END OF SENTENCE] and discuss studies of the usability of virtual trackballs....

Contributions and Limitations of National Cervical Cancer Screening Program in Korea: A Retrospective Observational Study

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Jung Hyun Lee, MPH

2018-03-01

Full Text Available Summary: Purpose: The purpose of this study was to evaluate the contributions and limitations of the cervical cancer screening test with accuracy in Korea. Methods: This was a retrospective observational study. The study population consisted of all participants who underwent cervical cancer screening test from 2009 to 2014. The data were obtained from National Health Information Database (NHID which represents medical use records of most Koreans. As the indices for contributions and limitations of the screening test, crude detection rate, incidence rate of interval cancer, sensitivity, specificity, and positive predictive value were used. Results: The crude detection rate of screening test per 100,000 participants increased from 100.7 in 2009 to 102.1 in 2014. The incidence rate of interval cancer per 100,000 negatives decreased from 13.0 in 2009 to 10.2 in 2014. The sensitivities of screening test were 88.7% in 2009 and 91.2% in 2014, and the specificities were 98.5% in 2009 and 97.7% in 2014. The positive predictive value of screening decreased from 6.2% in 2009 to 4.3% in 2014. Conclusion: The Korean national cervical cancer screening program has improved in accuracy and has contributed to detection of early stage of cervical cancer over the years. Along with efforts to promote participation in cancer screening programs, quality control over the screening program should be enhanced. Keywords: carcinoma in situ, early detection of cancer, Papanicolaou test, sensitivity and specificity, uterine cervical neoplasms

Discovery of new erbB4 inhibitors: Repositioning an orphan chemical library by inverse virtual screening.

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Giordano, Assunta; Forte, Giovanni; Massimo, Luigia; Riccio, Raffaele; Bifulco, Giuseppe; Di Micco, Simone

2018-04-12

Inverse Virtual Screening (IVS) is a docking based approach aimed to the evaluation of the virtual ability of a single compound to interact with a library of proteins. For the first time, we applied this methodology to a library of synthetic compounds, which proved to be inactive towards the target they were initially designed for. Trifluoromethyl-benzenesulfonamides 3-21 were repositioned by means of IVS identifying new lead compounds (14-16, 19 and 20) for the inhibition of erbB4 in the low micromolar range. Among these, compound 20 exhibited an interesting value of IC 50 on MCF7 cell lines, thus validating IVS in lead repurposing. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Machine Learning Approaches Toward Building Predictive Models for Small Molecule Modulators of miRNA and Its Utility in Virtual Screening of Molecular Databases.

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Periwal, Vinita; Scaria, Vinod

2017-01-01

The ubiquitous role of microRNAs (miRNAs) in a number of pathological processes has suggested that they could act as potential drug targets. RNA-binding small molecules offer an attractive means for modulating miRNA function. The availability of bioassay data sets for a variety of biological assays and molecules in public domain provides a new opportunity toward utilizing them to create models and further utilize them for in silico virtual screening approaches to prioritize or assign potential functions for small molecules. Here, we describe a computational strategy based on machine learning for creation of predictive models from high-throughput biological screens for virtual screening of small molecules with the potential to inhibit microRNAs. Such models could be potentially used for computational prioritization of small molecules before performing high-throughput biological assay.

Contact-based ligand-clustering approach for the identification of active compounds in virtual screening

Directory of Open Access Journals (Sweden)

Mantsyzov AB

2012-09-01

Full Text Available Alexey B Mantsyzov,1 Guillaume Bouvier,2 Nathalie Evrard-Todeschi,1 Gildas Bertho11Université Paris Descartes, Sorbonne, Paris, France; 2Institut Pasteur, Paris, FranceAbstract: Evaluation of docking results is one of the most important problems for virtual screening and in silico drug design. Modern approaches for the identification of active compounds in a large data set of docked molecules use energy scoring functions. One of the general and most significant limitations of these methods relates to inaccurate binding energy estimation, which results in false scoring of docked compounds. Automatic analysis of poses using self-organizing maps (AuPosSOM represents an alternative approach for the evaluation of docking results based on the clustering of compounds by the similarity of their contacts with the receptor. A scoring function was developed for the identification of the active compounds in the AuPosSOM clustered dataset. In addition, the AuPosSOM efficiency for the clustering of compounds and the identification of key contacts considered as important for its activity, were also improved. Benchmark tests for several targets revealed that together with the developed scoring function, AuPosSOM represents a good alternative to the energy-based scoring functions for the evaluation of docking results.Keywords: scoring, docking, virtual screening, CAR, AuPosSOM

Discovery of selective inhibitors against EBNA1 via high throughput in silico virtual screening.

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Ning Li

2010-04-01

Full Text Available Epstein-Barr Virus (EBV latent infection is associated with several human malignancies and is a causal agent of lymphoproliferative diseases during immunosuppression. While inhibitors of herpesvirus DNA polymerases, like gancyclovir, reduce EBV lytic cycle infection, these treatments have limited efficacy for treating latent infection. EBNA1 is an EBV-encoded DNA-binding protein required for viral genome maintenance during latent infection.Here, we report the identification of a new class of small molecules that inhibit EBNA1 DNA binding activity. These compounds were identified by virtual screening of 90,000 low molecular mass compounds using computational docking programs with the solved crystal structure of EBNA1. Four structurally related compounds were found to inhibit EBNA1-DNA binding in biochemical assays with purified EBNA1 protein. Compounds had a range of 20-100 microM inhibition of EBNA1 in fluorescence polarization assays and were further validated for inhibition using electrophoresis mobility shift assays. These compounds exhibited no significant inhibition of an unrelated DNA binding protein. Three of these compounds inhibited EBNA1 transcription activation function in cell-based assays and reduced EBV genome copy number when incubated with a Burkitt lymphoma cell line.These experiments provide a proof-of-principle that virtual screening can be used to identify specific inhibitors of EBNA1 that may have potential for treatment of EBV latent infection.

Stepping into the virtual unknown: feasibility study of a virtual reality-based test of ocular misalignment.

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Nesaratnam, N; Thomas, P; Vivian, A

2017-10-01

IntroductionDissociated tests of strabismus provide valuable information for diagnosis and monitoring of ocular misalignment in patients with normal retinal correspondence. However, they are vulnerable to operator error and rely on a fixed head position. Virtual reality headsets obviate the need for head fixation, while providing other clear theoretical advantages, including complete control over the illumination and targets presented for the patient's interaction.PurposeWe compared the performance of a virtual reality-based test of ocular misalignment to that of the traditional Lees screen, to establish the feasibility of using virtual reality technology in ophthalmic settings in the future.MethodsThree patients underwent a traditional Lees screen test, and a virtual reality headset-based test of ocular motility. The virtual reality headset-based programme consisted of an initial test to measure horizontal and vertical deviation, followed by a test for torsion.ResultsThe pattern of deviation obtained using the virtual reality-based test showed agreement with that obtained from the Lees screen for patients with a fourth nerve palsy, comitant esotropia, and restrictive thyroid eye disease.ConclusionsThis study reports the first use of a virtual reality headset in assessing ocular misalignment, and demonstrates that it is a feasible dissociative test of strabismus.

Benchmark of four popular virtual screening programs: construction of the active/decoy dataset remains a major determinant of measured performance.

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Chaput, Ludovic; Martinez-Sanz, Juan; Saettel, Nicolas; Mouawad, Liliane

2016-01-01

In a structure-based virtual screening, the choice of the docking program is essential for the success of a hit identification. Benchmarks are meant to help in guiding this choice, especially when undertaken on a large variety of protein targets. Here, the performance of four popular virtual screening programs, Gold, Glide, Surflex and FlexX, is compared using the Directory of Useful Decoys-Enhanced database (DUD-E), which includes 102 targets with an average of 224 ligands per target and 50 decoys per ligand, generated to avoid biases in the benchmarking. Then, a relationship between these program performances and the properties of the targets or the small molecules was investigated. The comparison was based on two metrics, with three different parameters each. The BEDROC scores with α = 80.5, indicated that, on the overall database, Glide succeeded (score > 0.5) for 30 targets, Gold for 27, FlexX for 14 and Surflex for 11. The performance did not depend on the hydrophobicity nor the openness of the protein cavities, neither on the families to which the proteins belong. However, despite the care in the construction of the DUD-E database, the small differences that remain between the actives and the decoys likely explain the successes of Gold, Surflex and FlexX. Moreover, the similarity between the actives of a target and its crystal structure ligand seems to be at the basis of the good performance of Glide. When all targets with significant biases are removed from the benchmarking, a subset of 47 targets remains, for which Glide succeeded for only 5 targets, Gold for 4 and FlexX and Surflex for 2. The performance dramatic drop of all four programs when the biases are removed shows that we should beware of virtual screening benchmarks, because good performances may be due to wrong reasons. Therefore, benchmarking would hardly provide guidelines for virtual screening experiments, despite the tendency that is maintained, i.e., Glide and Gold display better

LASSO-ligand activity by surface similarity order: a new tool for ligand based virtual screening.

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Reid, Darryl; Sadjad, Bashir S; Zsoldos, Zsolt; Simon, Aniko

2008-01-01

Virtual Ligand Screening (VLS) has become an integral part of the drug discovery process for many pharmaceutical companies. Ligand similarity searches provide a very powerful method of screening large databases of ligands to identify possible hits. If these hits belong to new chemotypes the method is deemed even more successful. eHiTS LASSO uses a new interacting surface point types (ISPT) molecular descriptor that is generated from the 3D structure of the ligand, but unlike most 3D descriptors it is conformation independent. Combined with a neural network machine learning technique, LASSO screens molecular databases at an ultra fast speed of 1 million structures in under 1 min on a standard PC. The results obtained from eHiTS LASSO trained on relatively small training sets of just 2, 4 or 8 actives are presented using the diverse directory of useful decoys (DUD) dataset. It is shown that over a wide range of receptor families, eHiTS LASSO is consistently able to enrich screened databases and provides scaffold hopping ability.

LASSO—ligand activity by surface similarity order: a new tool for ligand based virtual screening

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Reid, Darryl; Sadjad, Bashir S.; Zsoldos, Zsolt; Simon, Aniko

2008-06-01

Virtual Ligand Screening (VLS) has become an integral part of the drug discovery process for many pharmaceutical companies. Ligand similarity searches provide a very powerful method of screening large databases of ligands to identify possible hits. If these hits belong to new chemotypes the method is deemed even more successful. eHiTS LASSO uses a new interacting surface point types (ISPT) molecular descriptor that is generated from the 3D structure of the ligand, but unlike most 3D descriptors it is conformation independent. Combined with a neural network machine learning technique, LASSO screens molecular databases at an ultra fast speed of 1 million structures in under 1 min on a standard PC. The results obtained from eHiTS LASSO trained on relatively small training sets of just 2, 4 or 8 actives are presented using the diverse directory of useful decoys (DUD) dataset. It is shown that over a wide range of receptor families, eHiTS LASSO is consistently able to enrich screened databases and provides scaffold hopping ability.

Fragment-based virtual screening approach and molecular dynamics simulation studies for identification of BACE1 inhibitor leads.

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Manoharan, Prabu; Ghoshal, Nanda

2018-05-01

Traditional structure-based virtual screening method to identify drug-like small molecules for BACE1 is so far unsuccessful. Location of BACE1, poor Blood Brain Barrier permeability and P-glycoprotein (Pgp) susceptibility of the inhibitors make it even more difficult. Fragment-based drug design method is suitable for efficient optimization of initial hit molecules for target like BACE1. We have developed a fragment-based virtual screening approach to identify/optimize the fragment molecules as a starting point. This method combines the shape, electrostatic, and pharmacophoric features of known fragment molecules, bound to protein conjugate crystal structure, and aims to identify both chemically and energetically feasible small fragment ligands that bind to BACE1 active site. The two top-ranked fragment hits were subjected for a 53 ns MD simulation. Principle component analysis and free energy landscape analysis reveal that the new ligands show the characteristic features of established BACE1 inhibitors. The potent method employed in this study may serve for the development of potential lead molecules for BACE1-directed Alzheimer's disease therapeutics.

Discovery of nonsteroidal 17beta-hydroxysteroid dehydrogenase 1 inhibitors by pharmacophore-based screening of virtual compound libraries.

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Schuster, Daniela; Nashev, Lyubomir G; Kirchmair, Johannes; Laggner, Christian; Wolber, Gerhard; Langer, Thierry; Odermatt, Alex

2008-07-24

17Beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) plays a pivotal role in the local synthesis of the most potent estrogen estradiol. Its expression is a prognostic marker for the outcome of patients with breast cancer and inhibition of 17beta-HSD1 is currently under consideration for breast cancer prevention and treatment. We aimed to identify nonsteroidal 17beta-HSD1 inhibitor scaffolds by virtual screening with pharmacophore models built from crystal structures containing steroidal compounds. The most promising model was validated by comparing predicted and experimentally determined inhibitory activities of several flavonoids. Subsequently, a virtual library of nonsteroidal compounds was screened against the 3D pharmacophore. Analysis of 14 selected compounds yielded four that inhibited the activity of human 17beta-HSD1 (IC 50 below 50 microM). Specificity assessment of identified 17beta-HSD1 inhibitors emphasized the importance of including related short-chain dehydrogenase/reductase (SDR) members to analyze off-target effects. Compound 29 displayed at least 10-fold selectivity over the related SDR enzymes tested.

Discovery of novel SERCA inhibitors by virtual screening of a large compound library.

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Elam, Christopher; Lape, Michael; Deye, Joel; Zultowsky, Jodie; Stanton, David T; Paula, Stefan

2011-05-01

Two screening protocols based on recursive partitioning and computational ligand docking methodologies, respectively, were employed for virtual screens of a compound library with 345,000 entries for novel inhibitors of the enzyme sarco/endoplasmic reticulum calcium ATPase (SERCA), a potential target for cancer chemotherapy. A total of 72 compounds that were predicted to be potential inhibitors of SERCA were tested in bioassays and 17 displayed inhibitory potencies at concentrations below 100 μM. The majority of these inhibitors were composed of two phenyl rings tethered to each other by a short link of one to three atoms. Putative interactions between SERCA and the inhibitors were identified by inspection of docking-predicted poses and some of the structural features required for effective SERCA inhibition were determined by analysis of the classification pattern employed by the recursive partitioning models. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

Discovering Novel Alternaria solani Succinate Dehydrogenase Inhibitors by in Silico Modeling and Virtual Screening Strategies to Combat Early Blight

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Sehrish Iftikhar

2017-11-01

Full Text Available Alternaria blight is an important foliage disease caused by Alternaria solani. The enzyme Succinate dehydrogenase (SDH is a potential drug target because of its role in tricarboxylic acid cycle. Hence targeting Alternaria solani SDH enzyme could be efficient tool to design novel fungicides against A. solani. We employed computational methodologies to design new SDH inhibitors using homology modeling; pharmacophore modeling and structure based virtual screening. The three dimensional SDH model showed good stereo-chemical and structural properties. Based on virtual screening results twelve commercially available compounds were purchased and tested in vitro and in vivo. The compounds were found to inhibit mycelial growth of A. solani. Moreover in vitro trials showed that inhibitory effects were enhanced with increase in concentrations. Similarly increased disease control was observed in pre-treated potato tubers. Hence the applied in silico strategy led us to identify novel fungicides.

On various metrics used for validation of predictive QSAR models with applications in virtual screening and focused library design.

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Roy, Kunal; Mitra, Indrani

2011-07-01

Quantitative structure-activity relationships (QSARs) have important applications in drug discovery research, environmental fate modeling, property prediction, etc. Validation has been recognized as a very important step for QSAR model development. As one of the important objectives of QSAR modeling is to predict activity/property/toxicity of new chemicals falling within the domain of applicability of the developed models and QSARs are being used for regulatory decisions, checking reliability of the models and confidence of their predictions is a very important aspect, which can be judged during the validation process. One prime application of a statistically significant QSAR model is virtual screening for molecules with improved potency based on the pharmacophoric features and the descriptors appearing in the QSAR model. Validated QSAR models may also be utilized for design of focused libraries which may be subsequently screened for the selection of hits. The present review focuses on various metrics used for validation of predictive QSAR models together with an overview of the application of QSAR models in the fields of virtual screening and focused library design for diverse series of compounds with citation of some recent examples.

The Role of Affordances in Children's Learning Performance and Efficiency When Using Virtual Manipulative Mathematics Touch-Screen Apps

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Moyer-Packenham, Patricia S.; Bullock, Emma K.; Shumway, Jessica F.; Tucker, Stephen I.; Watts, Christina M.; Westenskow, Arla; Anderson-Pence, Katie L.; Maahs-Fladung, Cathy; Boyer-Thurgood, Jennifer; Gulkilik, Hilal; Jordan, Kerry

2016-01-01

This paper focuses on understanding the role that affordances played in children's learning performance and efficiency during clinical interviews of their interactions with mathematics apps on touch-screen devices. One hundred children, ages 3 to 8, each used six different virtual manipulative mathematics apps during 30-40-min interviews. The…

The influence of negative training set size on machine learning-based virtual screening.

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Kurczab, Rafał; Smusz, Sabina; Bojarski, Andrzej J

2014-01-01

The paper presents a thorough analysis of the influence of the number of negative training examples on the performance of machine learning methods. The impact of this rather neglected aspect of machine learning methods application was examined for sets containing a fixed number of positive and a varying number of negative examples randomly selected from the ZINC database. An increase in the ratio of positive to negative training instances was found to greatly influence most of the investigated evaluating parameters of ML methods in simulated virtual screening experiments. In a majority of cases, substantial increases in precision and MCC were observed in conjunction with some decreases in hit recall. The analysis of dynamics of those variations let us recommend an optimal composition of training data. The study was performed on several protein targets, 5 machine learning algorithms (SMO, Naïve Bayes, Ibk, J48 and Random Forest) and 2 types of molecular fingerprints (MACCS and CDK FP). The most effective classification was provided by the combination of CDK FP with SMO or Random Forest algorithms. The Naïve Bayes models appeared to be hardly sensitive to changes in the number of negative instances in the training set. In conclusion, the ratio of positive to negative training instances should be taken into account during the preparation of machine learning experiments, as it might significantly influence the performance of particular classifier. What is more, the optimization of negative training set size can be applied as a boosting-like approach in machine learning-based virtual screening.

Exploring the Potential of a Global Emerging Contaminant Early Warning Network through the Use of Retrospective Suspect Screening with High-Resolution Mass Spectrometry.

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Alygizakis, Nikiforos A; Samanipour, Saer; Hollender, Juliane; Ibáñez, María; Kaserzon, Sarit; Kokkali, Varvara; van Leerdam, Jan A; Mueller, Jochen F; Pijnappels, Martijn; Reid, Malcolm J; Schymanski, Emma L; Slobodnik, Jaroslav; Thomaidis, Nikolaos S; Thomas, Kevin V

2018-04-13

A key challenge in the environmental and exposure sciences is to establish experimental evidence of the role of chemical exposure in human and environmental systems. High resolution and accurate tandem mass spectrometry (HRMS) is increasingly being used for the analysis of environmental samples. One lauded benefit of HRMS is the possibility to retrospectively process data for (previously omitted) compounds that has led to the archiving of HRMS data. Archived HRMS data affords the possibility of exploiting historical data to rapidly and effectively establish the temporal and spatial occurrence of newly identified contaminants through retrospective suspect screening. We propose to establish a global emerging contaminant early warning network to rapidly assess the spatial and temporal distribution of contaminants of emerging concern in environmental samples through performing retrospective analysis on HRMS data. The effectiveness of such a network is demonstrated through a pilot study, where eight reference laboratories with available archived HRMS data retrospectively screened data acquired from aqueous environmental samples collected in 14 countries on 3 different continents. The widespread spatial occurrence of several surfactants (e.g., polyethylene glycols ( PEGs ) and C12AEO-PEGs ), transformation products of selected drugs (e.g., gabapentin-lactam, metoprolol-acid, carbamazepine-10-hydroxy, omeprazole-4-hydroxy-sulfide, and 2-benzothiazole-sulfonic-acid), and industrial chemicals (3-nitrobenzenesulfonate and bisphenol-S) was revealed. Obtaining identifications of increased reliability through retrospective suspect screening is challenging, and recommendations for dealing with issues such as broad chromatographic peaks, data acquisition, and sensitivity are provided.

Evaluating the predictivity of virtual screening for ABL kinase inhibitors to hinder drug resistance

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Gani, Osman A B S M; Narayanan, Dilip; Engh, Richard A

2013-01-01

decoy sets and tested with virtual screening approaches with and without explicit use of target structures (docking). We show how various scoring functions and choice of inactive ligand sets influence overall and early enrichment of the libraries. Although ligand-based methods, for example principal...... component analyses of chemical properties, can distinguish some decoy sets from active compounds, the addition of target structural information via docking improves enrichment, and explicit consideration of multiple target conformations (i.e. types I and II) achieves best enrichment of active versus...

Combining structure-based pharmacophore modeling, virtual screening, and in silico ADMET analysis to discover novel tetrahydro-quinoline based pyruvate kinase isozyme M2 activators with antitumor activity

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Chen C

2014-09-01

Full Text Available Can Chen,1,2,* Ting Wang,1,3,* Fengbo Wu,1,* Wei Huang,4 Gu He,1 Liang Ouyang,1 Mingli Xiang,1 Cheng Peng,4 Qinglin Jiang1,2 1State Key Laboratory of Biotherapy and Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, 2College of Pharmacy and the First Affiliated Hospital, Chengdu Medical College, Chengdu, 3Department of Cardiology, Genenal Hospital of Chengdu Military Command, Chengdu, 4State Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, People’s Republic of China*These authors contributed equally to this workAbstract: Compared with normal differentiated cells, cancer cells upregulate the expression of pyruvate kinase isozyme M2 (PKM2 to support glycolytic intermediates for anabolic processes, including the synthesis of nucleic acids, amino acids, and lipids. In this study, a combination of the structure-based pharmacophore modeling and a hybrid protocol of virtual screening methods comprised of pharmacophore model-based virtual screening, docking-based virtual screening, and in silico ADMET (absorption, distribution, metabolism, excretion and toxicity analysis were used to retrieve novel PKM2 activators from commercially available chemical databases. Tetrahydroquinoline derivatives were identified as potential scaffolds of PKM2 activators. Thus, the hybrid virtual screening approach was applied to screen the focused tetrahydroquinoline derivatives embedded in the ZINC database. Six hit compounds were selected from the final hits and experimental studies were then performed. Compound 8 displayed a potent inhibitory effect on human lung cancer cells. Following treatment with Compound 8, cell viability, apoptosis, and reactive oxygen species (ROS production were examined in A549 cells. Finally, we evaluated the effects of Compound 8 on mice xenograft tumor models in vivo. These results may provide important

CSBB-ConeExclusion, adapting structure based solution virtual screening to libraries on solid support.

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Shave, Steven; Auer, Manfred

2013-12-23

Combinatorial chemical libraries produced on solid support offer fast and cost-effective access to a large number of unique compounds. If such libraries are screened directly on-bead, the speed at which chemical space can be explored by chemists is much greater than that addressable using solution based synthesis and screening methods. Solution based screening has a large supporting body of software such as structure-based virtual screening tools which enable the prediction of protein-ligand complexes. Use of these techniques to predict the protein bound complexes of compounds synthesized on solid support neglects to take into account the conjugation site on the small molecule ligand. This may invalidate predicted binding modes, the linker may be clashing with protein atoms. We present CSBB-ConeExclusion, a methodology and computer program which provides a measure of the applicability of solution dockings to solid support. Output is given in the form of statistics for each docking pose, a unique 2D visualization method which can be used to determine applicability at a glance, and automatically generated PyMol scripts allowing visualization of protein atom incursion into a defined exclusion volume. CSBB-ConeExclusion is then exemplarically used to determine the optimum attachment point for a purine library targeting cyclin-dependent kinase 2 CDK2.

Search for β2 adrenergic receptor ligands by virtual screening via grid computing and investigation of binding modes by docking and molecular dynamics simulations.

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Qifeng Bai

Full Text Available We designed a program called MolGridCal that can be used to screen small molecule database in grid computing on basis of JPPF grid environment. Based on MolGridCal program, we proposed an integrated strategy for virtual screening and binding mode investigation by combining molecular docking, molecular dynamics (MD simulations and free energy calculations. To test the effectiveness of MolGridCal, we screened potential ligands for β2 adrenergic receptor (β2AR from a database containing 50,000 small molecules. MolGridCal can not only send tasks to the grid server automatically, but also can distribute tasks using the screensaver function. As for the results of virtual screening, the known agonist BI-167107 of β2AR is ranked among the top 2% of the screened candidates, indicating MolGridCal program can give reasonable results. To further study the binding mode and refine the results of MolGridCal, more accurate docking and scoring methods are used to estimate the binding affinity for the top three molecules (agonist BI-167107, neutral antagonist alprenolol and inverse agonist ICI 118,551. The results indicate agonist BI-167107 has the best binding affinity. MD simulation and free energy calculation are employed to investigate the dynamic interaction mechanism between the ligands and β2AR. The results show that the agonist BI-167107 also has the lowest binding free energy. This study can provide a new way to perform virtual screening effectively through integrating molecular docking based on grid computing, MD simulations and free energy calculations. The source codes of MolGridCal are freely available at http://molgridcal.codeplex.com.

Discovery of novel EGFR tyrosine kinase inhibitors by structure-based virtual screening.

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Li, Siyuan; Sun, Xianqiang; Zhao, Hongli; Tang, Yun; Lan, Minbo

2012-06-15

By using of structure-based virtual screening, 13 novel epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors were discovered from 197,116 compounds in the SPECS database here. Among them, 8 compounds significantly inhibited EGFR kinase activity with IC(50) values lower than 10 μM. 3-{[1-(3-Chloro-4-fluorophenyl)-3,5-dioxo-4-pyrazolidinylidene]methyl}phenyl 2-thiophenecarboxylate (13), particularly, was the most potent inhibitor possessing the IC(50) value of 3.5 μM. The docking studies also provide some useful information that the docking models of the 13 compounds are beneficial to find a new path for designing novel EGFR inhibitors. Copyright © 2012 Elsevier Ltd. All rights reserved.

ILP-2 modeling and virtual screening of an FDA-approved library:a possible anticancer therapy.

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Khalili, Saeed; Mohammadpour, Hemn; Shokrollahi Barough, Mahideh; Kokhaei, Parviz

2016-06-23

The members of the inhibitors of apoptosis protein (IAP) family inhibit diverse components of the caspase signaling pathway, notably caspase 3, 7, and 9. ILP-2 (BIRC-8) is the most recently identified member of the IAPs, mainly interacting with caspase 9. This interaction would eventually lead to death resistance in the case of cancerous cells. Therefore, structural modeling of ILP-2 and finding applicable inhibitors of its interaction with caspase 9 are a compelling challenge. Three main protein modeling approaches along with various model refinement measures were harnessed to achieve a reliable 3D model, using state-of-the-art software. Thereafter, the selected model was employed to perform virtual screening of an FDA approved library. A model built by a combinatorial approach (homology and ab initio approaches) was chosen as the best model. Model refinement processes successfully bolstered the model quality. Virtual screening of the compound library introduced several high affinity inhibitor candidates that interact with functional residues of ILP2. Given the 3D structure of the ILP2 molecule, we found promising inhibitory molecules. In addition to high affinity towards the ILP2 molecule, these molecules interact with residues that play pivotal rules in ILP2-caspase interaction. These molecules would inhibit ILP2-caspase interaction and consequently would lead to reactivated cell apoptosis through the caspases pathway.

Structure-Guided Screening for Functionally Selective D2 Dopamine Receptor Ligands from a Virtual Chemical Library.

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Männel, Barbara; Jaiteh, Mariama; Zeifman, Alexey; Randakova, Alena; Möller, Dorothee; Hübner, Harald; Gmeiner, Peter; Carlsson, Jens

2017-10-20

Functionally selective ligands stabilize conformations of G protein-coupled receptors (GPCRs) that induce a preference for signaling via a subset of the intracellular pathways activated by the endogenous agonists. The possibility to fine-tune the functional activity of a receptor provides opportunities to develop drugs that selectively signal via pathways associated with a therapeutic effect and avoid those causing side effects. Animal studies have indicated that ligands displaying functional selectivity at the D 2 dopamine receptor (D 2 R) could be safer and more efficacious drugs against neuropsychiatric diseases. In this work, computational design of functionally selective D 2 R ligands was explored using structure-based virtual screening. Molecular docking of known functionally selective ligands to a D 2 R homology model indicated that such compounds were anchored by interactions with the orthosteric site and extended into a common secondary pocket. A tailored virtual library with close to 13 000 compounds bearing 2,3-dichlorophenylpiperazine, a privileged orthosteric scaffold, connected to diverse chemical moieties via a linker was docked to the D 2 R model. Eighteen top-ranked compounds that occupied both the orthosteric and allosteric site were synthesized, leading to the discovery of 16 partial agonists. A majority of the ligands had comparable maximum effects in the G protein and β-arrestin recruitment assays, but a subset displayed preference for a single pathway. In particular, compound 4 stimulated β-arrestin recruitment (EC 50 = 320 nM, E max = 16%) but had no detectable G protein signaling. The use of structure-based screening and virtual libraries to discover GPCR ligands with tailored functional properties will be discussed.

Women with learning disabilities and access to cervical screening: retrospective cohort study using case control methods

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Reynolds, Fiona; Stanistreet, Debbi; Elton, Peter

2008-01-01

Background Several studies in the UK have suggested that women with learning disabilities may be less likely to receive cervical screening tests and a previous local study in had found that GPs considered screening unnecessary for women with learning disabilities. This study set out to ascertain whether women with learning disabilities are more likely to be ceased from a cervical screening programme than women without; and to examine the reasons given for ceasing women with learning disabilities. It was carried out in Bury, Heywood-and-Middleton and Rochdale. Methods Carried out using retrospective cohort study methods, women with learning disabilities were identified by Read code; and their cervical screening records were compared with the Call-and-Recall records of women without learning disabilities in order to examine their screening histories. Analysis was carried out using case-control methods – 1:2 (women with learning disabilities: women without learning disabilities), calculating odds ratios. Results 267 women's records were compared with the records of 534 women without learning disabilities. Women with learning disabilities had an odds ratio (OR) of 0.48 (Confidence Interval (CI) 0.38 – 0.58; X2: 72.227; p.value learning disabilities. Conclusion The reasons given for ceasing and/or not screening suggest that merely being coded as having a learning disability is not the sole reason for these actions. There are training needs among smear takers regarding appropriate reasons not to screen and providing screening for women with learning disabilities. PMID:18218106

Does breast screening offer a survival benefit? A retrospective comparative study of oncological outcomes of screen-detected and symptomatic early stage breast cancer cases.

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Újhelyi, M; Pukancsik, D; Kelemen, P; Kovács, E; Kenessey, I; Udvarhelyi, N; Bak, M; Kovács, T; Mátrai, Z

2016-12-01

Mammography screening reduces breast cancer mortality by up to 32%. However, some recent studies have questioned the impact of non-palpable breast cancer detection on mortality reduction. The aim of this study was to analyse the clinicopathological and long-term follow-up data of early stage screened and symptomatic breast cancer patients. The institutional prospectively led database was systematically analysed for breast cancer cases diagnosed via the mammography screening program from 2002 to 2009. As a control group, symptomatic early stage breast cancer patients were collected randomly from the same database and matched for age and follow-up period. All medical records were reviewed retrospectively. Data from 298 breast cancer patients were collected from 47,718 mammography screenings. In addition, 331 symptomatic breast cancer patients were randomly selected. The screened group presented a significantly lower median tumour size (P screened group (P screened group did not exhibit better overall (P = 0.717) or disease-free survival (P = 0.081) compared to the symptomatic group. Our results do not suggest that mammography screening does not reduce breast cancer mortality but the mammography screening did not bring any significant improvement in patient overall or disease-free survival for the early stage breast cancer patients compared to the symptomatic group. The drawback of symptomatic early stage tumours compared to non-palpable tumours could be equalized by modern multimodality oncology treatments. Copyright © 2016 Elsevier Ltd, BASO ~ the Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.

Machine-learning scoring functions to improve structure-based binding affinity prediction and virtual screening.

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Ain, Qurrat Ul; Aleksandrova, Antoniya; Roessler, Florian D; Ballester, Pedro J

2015-01-01

Docking tools to predict whether and how a small molecule binds to a target can be applied if a structural model of such target is available. The reliability of docking depends, however, on the accuracy of the adopted scoring function (SF). Despite intense research over the years, improving the accuracy of SFs for structure-based binding affinity prediction or virtual screening has proven to be a challenging task for any class of method. New SFs based on modern machine-learning regression models, which do not impose a predetermined functional form and thus are able to exploit effectively much larger amounts of experimental data, have recently been introduced. These machine-learning SFs have been shown to outperform a wide range of classical SFs at both binding affinity prediction and virtual screening. The emerging picture from these studies is that the classical approach of using linear regression with a small number of expert-selected structural features can be strongly improved by a machine-learning approach based on nonlinear regression allied with comprehensive data-driven feature selection. Furthermore, the performance of classical SFs does not grow with larger training datasets and hence this performance gap is expected to widen as more training data becomes available in the future. Other topics covered in this review include predicting the reliability of a SF on a particular target class, generating synthetic data to improve predictive performance and modeling guidelines for SF development. WIREs Comput Mol Sci 2015, 5:405-424. doi: 10.1002/wcms.1225 For further resources related to this article, please visit the WIREs website.

Structure Based Virtual Screening Studies to Identify Novel Potential Compounds for GPR142 and Their Relative Dynamic Analysis for Study of Type 2 Diabetes

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Aman C. Kaushik

2018-02-01

Full Text Available GPR142 (G protein receptor 142 is a novel orphan GPCR (G protein coupled receptor belonging to “Class A” of GPCR family and expressed in β cells of pancreas. In this study, we reported the structure based virtual screening to identify the hit compounds which can be developed as leads for potential agonists. The results were validated through induced fit docking, pharmacophore modeling, and system biology approaches. Since, there is no solved crystal structure of GPR142, we attempted to predict the 3D structure followed by validation and then identification of active site using threading and ab initio methods. Also, structure based virtual screening was performed against a total of 1171519 compounds from different libraries and only top 20 best hit compounds were screened and analyzed. Moreover, the biochemical pathway of GPR142 complex with screened compound2 was also designed and compared with experimental data. Interestingly, compound2 showed an increase in insulin production via Gq mediated signaling pathway suggesting the possible role of novel GPR142 agonists in therapy against type 2 diabetes.

Structure Based Virtual Screening Studies to Identify Novel Potential Compounds for GPR142 and Their Relative Dynamic Analysis for Study of Type 2 Diabetes

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Kaushik, Aman C.; Kumar, Sanjay; Wei, Dong Q.; Sahi, Shakti

2018-02-01

GPR142 (G protein receptor 142) is a novel orphan GPCR (G protein coupled receptor) belonging to ‘Class A’ of GPCR family and expressed in beta cells of pancreas. In this study, we reported the structure based virtual screening to identify the hit compounds which can be developed as leads for potential agonists. The results were validated through induced fit docking, pharmacophore modeling and system biology approaches. Since, there is no solved crystal structure of GPR142, we attempted to predict the 3D structure followed by validation and then identification of active site using threading and ab initio methods. Also, structure based virtual screening was performed against a total of 1171519 compounds from different libraries and only top 20 best hit compounds were screened and analyzed. Moreover, the biochemical pathway of GPR142 complex with screened compound2 was also designed and compared with experimental data. Interestingly, compound2 showed an increase in insulin production via Gq mediated signaling pathway suggesting the possible role of novel GPR142 agonists in therapy against type 2 diabetes.

Virtual screening of selective inhibitors of phosphopantetheine adenylyltransferase from Mycobacterium tuberculosis

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Podshivalov, D. D.; Timofeev, V. I.; Sidorov-Biryukov, D. D.; Kuranova, I. P.

2017-05-01

Bacterial phosphopantetheine adenylyltransferase from Mycobacterium tuberculosis (PPAT Mt) is a convenient target protein for the directed search for selective inhibitors as potent antituberculosis drugs. Four compounds suitable for the detailed investigation of their interactions with PPAT Mt were found by virtual screening. The active-site region of the enzyme was chosen as the ligand-binding site. The positions of the ligands found by the docking were refined by molecular dynamics simulation. The nearest environment of the ligands, the positions of which in the active site of the enzyme were found in a computational experiment, was analyzed. The compounds under consideration were shown to directly interact with functionally important active-site amino-acid residues and block access of substrates to the active site. Therefore, these compounds can be used for the design of selective inhibitors of PPAT Mt as potent antituberculosis drugs.

High-throughput quantum chemistry and virtual screening for OLED material components

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Halls, Mathew D.; Giesen, David J.; Hughes, Thomas F.; Goldberg, Alexander; Cao, Yixiang

2013-09-01

Computational structure enumeration, analysis using an automated simulation workflow and filtering of large chemical structure libraries to identify lead systems, has become a central paradigm in drug discovery research. Transferring this paradigm to challenges in materials science is now possible due to advances in the speed of computational resources and the efficiency and stability of chemical simulation packages. State-of-the-art software tools that have been developed for drug discovery can be applied to efficiently explore the chemical design space to identify solutions for problems such as organic light-emitting diode material components. In this work, virtual screening for OLED materials based on intrinsic quantum mechanical properties is illustrated. Also, a new approach to more reliably identify candidate systems is introduced that is based on the chemical reaction energetics of defect pathways for OLED materials.

Pharmacophore modeling, virtual screening and molecular docking of ATPase inhibitors of HSP70.

Science.gov (United States)

Sangeetha, K; Sasikala, R P; Meena, K S

2017-10-01

Heat shock protein 70 is an effective anticancer target as it influences many signaling pathways. Hence the study investigated the important pharmacophore feature required for ATPase inhibitors of HSP70 by generating a ligand based pharmacophore model followed by virtual based screening and subsequent validation by molecular docking in Discovery studio V4.0. The most extrapolative pharmacophore model (hypotheses 8) consisted of four hydrogen bond acceptors. Further validation by external test set prediction identified 200 hits from Mini Maybridge, Drug Diverse, SCPDB compounds and Phytochemicals. Consequently, the screened compounds were refined by rule of five, ADMET and molecular docking to retain the best competitive hits. Finally Phytochemical compounds Muricatetrocin B, Diacetylphiladelphicalactone C, Eleutheroside B and 5-(3-{[1-(benzylsulfonyl)piperidin-4-yl]amino}phenyl)- 4-bromo-3-(carboxymethoxy)thiophene-2-carboxylic acid were obtained as leads to inhibit the ATPase activity of HSP70 in our findings and thus can be proposed for further in vitro and in vivo evaluation. Copyright © 2017 Elsevier Ltd. All rights reserved.

Women with learning disabilities and access to cervical screening: retrospective cohort study using case control methods

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Stanistreet Debbi

2008-01-01

Full Text Available Abstract Background Several studies in the UK have suggested that women with learning disabilities may be less likely to receive cervical screening tests and a previous local study in had found that GPs considered screening unnecessary for women with learning disabilities. This study set out to ascertain whether women with learning disabilities are more likely to be ceased from a cervical screening programme than women without; and to examine the reasons given for ceasing women with learning disabilities. It was carried out in Bury, Heywood-and-Middleton and Rochdale. Methods Carried out using retrospective cohort study methods, women with learning disabilities were identified by Read code; and their cervical screening records were compared with the Call-and-Recall records of women without learning disabilities in order to examine their screening histories. Analysis was carried out using case-control methods – 1:2 (women with learning disabilities: women without learning disabilities, calculating odds ratios. Results 267 women's records were compared with the records of 534 women without learning disabilities. Women with learning disabilities had an odds ratio (OR of 0.48 (Confidence Interval (CI 0.38 – 0.58; X2: 72.227; p.value X2: 24.236; p.value X2: 286.341; p.value Conclusion The reasons given for ceasing and/or not screening suggest that merely being coded as having a learning disability is not the sole reason for these actions. There are training needs among smear takers regarding appropriate reasons not to screen and providing screening for women with learning disabilities.

DARC: Mapping Surface Topography by Ray-Casting for Effective Virtual Screening at Protein Interaction Sites.

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Gowthaman, Ragul; Miller, Sven A; Rogers, Steven; Khowsathit, Jittasak; Lan, Lan; Bai, Nan; Johnson, David K; Liu, Chunjing; Xu, Liang; Anbanandam, Asokan; Aubé, Jeffrey; Roy, Anuradha; Karanicolas, John

2016-05-12

Protein-protein interactions represent an exciting and challenging target class for therapeutic intervention using small molecules. Protein interaction sites are often devoid of the deep surface pockets presented by "traditional" drug targets, and crystal structures reveal that inhibitors typically engage these sites using very shallow binding modes. As a consequence, modern virtual screening tools developed to identify inhibitors of traditional drug targets do not perform as well when they are instead deployed at protein interaction sites. To address the need for novel inhibitors of important protein interactions, here we introduce an alternate docking strategy specifically designed for this regime. Our method, termed DARC (Docking Approach using Ray-Casting), matches the topography of a surface pocket "observed" from within the protein to the topography "observed" when viewing a potential ligand from the same vantage point. We applied DARC to carry out a virtual screen against the protein interaction site of human antiapoptotic protein Mcl-1 and found that four of the top-scoring 21 compounds showed clear inhibition in a biochemical assay. The Ki values for these compounds ranged from 1.2 to 21 μM, and each had ligand efficiency comparable to promising small-molecule inhibitors of other protein-protein interactions. These hit compounds do not resemble the natural (protein) binding partner of Mcl-1, nor do they resemble any known inhibitors of Mcl-1. Our results thus demonstrate the utility of DARC for identifying novel inhibitors of protein-protein interactions.

A novel interaction fingerprint derived from per atom score contributions: exhaustive evaluation of interaction fingerprint performance in docking based virtual screening.

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Jasper, Julia B; Humbeck, Lina; Brinkjost, Tobias; Koch, Oliver

2018-03-16

Protein ligand interaction fingerprints are a powerful approach for the analysis and assessment of docking poses to improve docking performance in virtual screening. In this study, a novel interaction fingerprint approach (PADIF, protein per atom score contributions derived interaction fingerprint) is presented which was specifically designed for utilising the GOLD scoring functions' atom contributions together with a specific scoring scheme. This allows the incorporation of known protein-ligand complex structures for a target-specific scoring. Unlike many other methods, this approach uses weighting factors reflecting the relative frequency of a specific interaction in the references and penalizes destabilizing interactions. In addition, and for the first time, an exhaustive validation study was performed that assesses the performance of PADIF and two other interaction fingerprints in virtual screening. Here, PADIF shows superior results, and some rules of thumb for a successful use of interaction fingerprints could be identified.

Structure-based virtual screening and characterization of a novel IL-6 antagonistic compound from synthetic compound database

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Wang J

2016-12-01

Full Text Available Jing Wang,1,* Chunxia Qiao,1,* He Xiao,1 Zhou Lin,1 Yan Li,1 Jiyan Zhang,1 Beifen Shen,1 Tinghuan Fu,2 Jiannan Feng1 1Department of Molecular Immunology, Beijing Institute of Basic Medical Sciences, 2First Affiliated Hospital of PLA General Hospital, Beijing, People’s Republic of China *These authors contributed equally to this work Abstract: According to the three-dimensional (3D complex structure of (hIL-6·hIL-6R·gp 1302 and the binding orientation of hIL-6, three compounds with high affinity to hIL-6R and bioactivity to block hIL-6 in vitro were screened theoretically from the chemical databases, including 3D-Available Chemicals Directory (ACD and MDL Drug Data Report (MDDR, by means of the computer-guided virtual screening method. Using distance geometry, molecular modeling and molecular dynamics trajectory analysis methods, the binding mode and binding energy of the three compounds were evaluated theoretically. Enzyme-linked immunosorbent assay analysis demonstrated that all the three compounds could block IL-6 binding to IL-6R specifically. However, only compound 1 could effectively antagonize the function of hIL-6 and inhibit the proliferation of XG-7 cells in a dose-dependent manner, whereas it showed no cytotoxicity to SP2/0 or L929 cells. These data demonstrated that the compound 1 could be a promising candidate of hIL-6 antagonist. Keywords: virtual screening, structural optimization, human interlukin-6, small molecular antagonist, XG-7 cells, apoptosis

A rational workflow for sequential virtual screening of chemical libraries on searching for new tyrosinase inhibitors.

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Le-Thi-Thu, Huong; Casanola-Martín, Gerardo M; Marrero-Ponce, Yovani; Rescigno, Antonio; Abad, Concepcion; Khan, Mahmud Tareq Hassan

2014-01-01

The tyrosinase is a bifunctional, copper-containing enzyme widely distributed in the phylogenetic tree. This enzyme is involved in the production of melanin and some other pigments in humans, animals and plants, including skin pigmentations in mammals, and browning process in plants and vegetables. Therefore, enzyme inhibitors has been under the attention of the scientist community, due to its broad applications in food, cosmetic, agricultural and medicinal fields, to avoid the undesirable effects of abnormal melanin overproduction. However, the research of novel chemical with antityrosinase activity demands the use of more efficient tools to speed up the tyrosinase inhibitors discovery process. This chapter is focused in the different components of a predictive modeling workflow for the identification and prioritization of potential new compounds with activity against the tyrosinase enzyme. In this case, two structure chemical libraries Spectrum Collection and Drugbank are used in this attempt to combine different virtual screening data mining techniques, in a sequential manner helping to avoid the usually expensive and time consuming traditional methods. Some of the sequential steps summarize here comprise the use of drug-likeness filters, similarity searching, classification and potency QSAR multiclassifier systems, modeling molecular interactions systems, and similarity/diversity analysis. Finally, the methodologies showed here provide a rational workflow for virtual screening hit analysis and selection as a promissory drug discovery strategy for use in target identification phase.

Identification of Mycobacterium tuberculosis BioA inhibitors by using structure-based virtual screening

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Singh S

2018-05-01

Full Text Available Swati Singh,1 Garima Khare,1 Ritika Kar Bahal,1 Prahlad C Ghosh,1 Anil K Tyagi1,2 1Department of Biochemistry, University of Delhi South Campus, New Delhi, India; 2Guru Gobind Singh Indraprastha University, New Delhi, India Background: 7,8-Diaminopelargonic acid synthase (BioA, an enzyme of biotin biosynthesis pathway, is a well-known promising target for anti-tubercular drug development. Methods: In this study, structure-based virtual screening was employed against the active site of BioA to identify new chemical entities for BioA inhibition and top ranking compounds were evaluated for their ability to inhibit BioA enzymatic activity. Results: Seven compounds inhibited BioA enzymatic activity by greater than 60% at 100 µg/mL with most potent compounds being A36, A35 and A65, displaying IC50 values of 10.48 µg/mL (28.94 µM, 33.36 µg/mL (88.16 µM and 39.17 µg/mL (114.42 µM, respectively. Compounds A65 and A35 inhibited Mycobacterium tuberculosis (M. tuberculosis growth with MIC90 of 20 µg/mL and 80 µg/mL, respectively, whereas compound A36 exhibited relatively weak inhibition of M. tuberculosis growth (83% inhibition at 200 µg/mL. Compound A65 emerged as the most potent compound identified in our study that inhibited BioA enzymatic activity and growth of the pathogen and possessed drug-like properties. Conclusion: Our study has identified a few hit molecules against M. tuberculosis BioA that can act as potential candidates for further development of potent anti-tubercular therapeutic agents. Keywords: Mycobacterium tuberculosis, BioA, virtual screening, drug discovery

Identification by virtual screening and in vitro testing of human DOPA decarboxylase inhibitors.

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Frederick Daidone

Full Text Available Dopa decarboxylase (DDC, a pyridoxal 5'-phosphate (PLP enzyme responsible for the biosynthesis of dopamine and serotonin, is involved in Parkinson's disease (PD. PD is a neurodegenerative disease mainly due to a progressive loss of dopamine-producing cells in the midbrain. Co-administration of L-Dopa with peripheral DDC inhibitors (carbidopa or benserazide is the most effective symptomatic treatment for PD. Although carbidopa and trihydroxybenzylhydrazine (the in vivo hydrolysis product of benserazide are both powerful irreversible DDC inhibitors, they are not selective because they irreversibly bind to free PLP and PLP-enzymes, thus inducing diverse side effects. Therefore, the main goals of this study were (a to use virtual screening to identify potential human DDC inhibitors and (b to evaluate the reliability of our virtual-screening (VS protocol by experimentally testing the "in vitro" activity of selected molecules. Starting from the crystal structure of the DDC-carbidopa complex, a new VS protocol, integrating pharmacophore searches and molecular docking, was developed. Analysis of 15 selected compounds, obtained by filtering the public ZINC database, yielded two molecules that bind to the active site of human DDC and behave as competitive inhibitors with K(i values ≥10 µM. By performing in silico similarity search on the latter compounds followed by a substructure search using the core of the most active compound we identified several competitive inhibitors of human DDC with K(i values in the low micromolar range, unable to bind free PLP, and predicted to not cross the blood-brain barrier. The most potent inhibitor with a K(i value of 500 nM represents a new lead compound, targeting human DDC, that may be the basis for lead optimization in the development of new DDC inhibitors. To our knowledge, a similar approach has not been reported yet in the field of DDC inhibitors discovery.

Identification of novel malarial cysteine protease inhibitors using structure-based virtual screening of a focused cysteine protease inhibitor library.

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Shah, Falgun; Mukherjee, Prasenjit; Gut, Jiri; Legac, Jennifer; Rosenthal, Philip J; Tekwani, Babu L; Avery, Mitchell A

2011-04-25

Malaria, in particular that caused by Plasmodium falciparum , is prevalent across the tropics, and its medicinal control is limited by widespread drug resistance. Cysteine proteases of P. falciparum , falcipain-2 (FP-2) and falcipain-3 (FP-3), are major hemoglobinases, validated as potential antimalarial drug targets. Structure-based virtual screening of a focused cysteine protease inhibitor library built with soft rather than hard electrophiles was performed against an X-ray crystal structure of FP-2 using the Glide docking program. An enrichment study was performed to select a suitable scoring function and to retrieve potential candidates against FP-2 from a large chemical database. Biological evaluation of 50 selected compounds identified 21 diverse nonpeptidic inhibitors of FP-2 with a hit rate of 42%. Atomic Fukui indices were used to predict the most electrophilic center and its electrophilicity in the identified hits. Comparison of predicted electrophilicity of electrophiles in identified hits with those in known irreversible inhibitors suggested the soft-nature of electrophiles in the selected target compounds. The present study highlights the importance of focused libraries and enrichment studies in structure-based virtual screening. In addition, few compounds were screened against homologous human cysteine proteases for selectivity analysis. Further evaluation of structure-activity relationships around these nonpeptidic scaffolds could help in the development of selective leads for antimalarial chemotherapy.

Optimization of TRPV6 Calcium Channel Inhibitors Using a 3D Ligand-Based Virtual Screening Method.

OpenAIRE

Simonin Céline; Awale Mahendra; Brand Michael; van Deursen Ruud; Schwartz Julian; Fine Michael; Kovacs Gergely; Häfliger Pascal; Gyimesi Gergely; Sithampari Abilashan; Charles Roch-Philippe; Hediger Matthias A; Reymond Jean-Louis

2015-01-01

Herein we report the discovery of the first potent and selective inhibitor of TRPV6 a calcium channel overexpressed in breast and prostate cancer and its use to test the effect of blocking TRPV6 mediated Ca(2+) influx on cell growth. The inhibitor was discovered through a computational method xLOS a 3D shape and pharmacophore similarity algorithm a type of ligand based virtual screening (LBVS) method described briefly here. Starting with a single weakly active seed molecule two successive rou...

How to Achieve Better Results Using PASS-Based Virtual Screening: Case Study for Kinase Inhibitors

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Pavel V. Pogodin

2018-04-01

Full Text Available Discovery of new pharmaceutical substances is currently boosted by the possibility of utilization of the Synthetically Accessible Virtual Inventory (SAVI library, which includes about 283 million molecules, each annotated with a proposed synthetic one-step route from commercially available starting materials. The SAVI database is well-suited for ligand-based methods of virtual screening to select molecules for experimental testing. In this study, we compare the performance of three approaches for the analysis of structure-activity relationships that differ in their criteria for selecting of “active” and “inactive” compounds included in the training sets. PASS (Prediction of Activity Spectra for Substances, which is based on a modified Naïve Bayes algorithm, was applied since it had been shown to be robust and to provide good predictions of many biological activities based on just the structural formula of a compound even if the information in the training set is incomplete. We used different subsets of kinase inhibitors for this case study because many data are currently available on this important class of drug-like molecules. Based on the subsets of kinase inhibitors extracted from the ChEMBL 20 database we performed the PASS training, and then applied the model to ChEMBL 23 compounds not yet present in ChEMBL 20 to identify novel kinase inhibitors. As one may expect, the best prediction accuracy was obtained if only the experimentally confirmed active and inactive compounds for distinct kinases in the training procedure were used. However, for some kinases, reasonable results were obtained even if we used merged training sets, in which we designated as inactives the compounds not tested against the particular kinase. Thus, depending on the availability of data for a particular biological activity, one may choose the first or the second approach for creating ligand-based computational tools to achieve the best possible results in

Identification of novel human dipeptidyl peptidase-IV inhibitors of natural origin (part I: virtual screening and activity assays.

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Laura Guasch

Full Text Available BACKGROUND: There has been great interest in determining whether natural products show biological activity toward protein targets of pharmacological relevance. One target of particular interest is DPP-IV whose most important substrates are incretins that, among other beneficial effects, stimulates insulin biosynthesis and secretion. Incretins have very short half-lives because of their rapid degradation by DPP-IV and, therefore, inhibiting this enzyme improves glucose homeostasis. As a result, DPP-IV inhibitors are of considerable interest to the pharmaceutical industry. The main goals of this study were (a to develop a virtual screening process to identify potential DPP-IV inhibitors of natural origin; (b to evaluate the reliability of our virtual-screening protocol by experimentally testing the in vitro activity of selected natural-product hits; and (c to use the most active hit for predicting derivatives with higher binding affinities for the DPP-IV binding site. METHODOLOGY/PRINCIPAL FINDINGS: We predicted that 446 out of the 89,165 molecules present in the natural products subset of the ZINC database would inhibit DPP-IV with good ADMET properties. Notably, when these 446 molecules were merged with 2,342 known DPP-IV inhibitors and the resulting set was classified into 50 clusters according to chemical similarity, there were 12 clusters that contained only natural products for which no DPP-IV inhibitory activity has been previously reported. Nine molecules from 7 of these 12 clusters were then selected for in vitro activity testing and 7 out of the 9 molecules were shown to inhibit DPP-IV (where the remaining two molecules could not be solubilized, preventing the evaluation of their DPP-IV inhibitory activity. Then, the hit with the highest activity was used as a lead compound in the prediction of more potent derivatives. CONCLUSIONS/SIGNIFICANCE: We have demonstrated that our virtual-screening protocol was successful in identifying novel

Virtual screening for novel Staphylococcus Aureus NorA efflux pump inhibitors from natural products.

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Thai, Khac-Minh; Ngo, Trieu-Du; Phan, Thien-Vy; Tran, Thanh-Dao; Nguyen, Ngoc-Vinh; Nguyen, Thien-Hai; Le, Minh-Tri

2015-01-01

NorA is a member of the Major Facilitator Superfamily (MFS) drug efflux pumps that have been shown to mediate antibiotic resistance in Staphylococcus aureus (SA). In this study, QSAR analysis, virtual screening and molecular docking were implemented in an effort to discover novel SA NorA efflux pump inhibitors. Originally, a set of 47 structurally diverse compounds compiled from the literature was used to develop linear QSAR models and another set of 15 different compounds were chosen for extra validation. The final model which was estimated by statistical values for the full data set (n = 45, Q(2) = 0.80, RMSE = 0.20) and for the external test set (n = 15, R(2) = 0.60, |res|max = 0.75, |res|min = 0.02) was applied on the collection of 182 flavonoides and the traditional Chinese medicine (TCM) database to screen for novel NorA inhibitors. Finally, 33 lead compounds that met the Lipinski's rules of five/three and had good predicted pIC50 values from in silico screening process were employed to analyze the binding ability by docking studies on NorA homology model in place of its unavailable crystal structures at two active sites, the central channel and the Walker B.

A computational design approach for virtual screening of peptide interactions across K+ channel families

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Craig A. Doupnik

2015-01-01

Full Text Available Ion channels represent a large family of membrane proteins with many being well established targets in pharmacotherapy. The ‘druggability’ of heteromeric channels comprised of different subunits remains obscure, due largely to a lack of channel-specific probes necessary to delineate their therapeutic potential in vivo. Our initial studies reported here, investigated the family of inwardly rectifying potassium (Kir channels given the availability of high resolution crystal structures for the eukaryotic constitutively active Kir2.2 channel. We describe a ‘limited’ homology modeling approach that can yield chimeric Kir channels having an outer vestibule structure representing nearly any known vertebrate or invertebrate channel. These computationally-derived channel structures were tested in silico for ‘docking’ to NMR structures of tertiapin (TPN, a 21 amino acid peptide found in bee venom. TPN is a highly selective and potent blocker for the epithelial rat Kir1.1 channel, but does not block human or zebrafish Kir1.1 channel isoforms. Our Kir1.1 channel-TPN docking experiments recapitulated published in vitro findings for TPN-sensitive and TPN-insensitive channels. Additionally, in silico site-directed mutagenesis identified ‘hot spots’ within the channel outer vestibule that mediate energetically favorable docking scores and correlate with sites previously identified with in vitro thermodynamic mutant-cycle analysis. These ‘proof-of-principle’ results establish a framework for virtual screening of re-engineered peptide toxins for interactions with computationally derived Kir channels that currently lack channel-specific blockers. When coupled with electrophysiological validation, this virtual screening approach may accelerate the drug discovery process, and can be readily applied to other ion channels families where high resolution structures are available.

Design of efficient molecular organic light-emitting diodes by a high-throughput virtual screening and experimental approach

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Gómez-Bombarelli, Rafael; Aguilera-Iparraguirre, Jorge; Hirzel, Timothy D.; Duvenaud, David; MacLaurin, Dougal; Blood-Forsythe, Martin A.; Chae, Hyun Sik; Einzinger, Markus; Ha, Dong-Gwang; Wu, Tony; Markopoulos, Georgios; Jeon, Soonok; Kang, Hosuk; Miyazaki, Hiroshi; Numata, Masaki; Kim, Sunghan; Huang, Wenliang; Hong, Seong Ik; Baldo, Marc; Adams, Ryan P.; Aspuru-Guzik, Alán

2016-10-01

Virtual screening is becoming a ground-breaking tool for molecular discovery due to the exponential growth of available computer time and constant improvement of simulation and machine learning techniques. We report an integrated organic functional material design process that incorporates theoretical insight, quantum chemistry, cheminformatics, machine learning, industrial expertise, organic synthesis, molecular characterization, device fabrication and optoelectronic testing. After exploring a search space of 1.6 million molecules and screening over 400,000 of them using time-dependent density functional theory, we identified thousands of promising novel organic light-emitting diode molecules across the visible spectrum. Our team collaboratively selected the best candidates from this set. The experimentally determined external quantum efficiencies for these synthesized candidates were as large as 22%.

Film-Screen Mammography versus digital storage plate mammography: Hard copy and monitor display of microcalcifications and focal findings - A retrospective clinical and histologic analysis

International Nuclear Information System (INIS)

Schulz-Wendtland, R.; Wenkel, E.; Aichinger, U.; Tartsch, M.; Kuchar, I.; Bautz, W.

2003-01-01

Purpose: A retrospective clinical-histological study to determine the diagnostic accuracy of mammography using conventional screen-film cassettes (hard copy), high-resolution digital phosphor storage plates (hard copy) and monitor display (soft copy) for microcalcifications and focal lesions (BI-RADS TM category 4 or 5). Materials and methods: From April to November 2001, 76 patients underwent conventional film-screen mammography and, after diagnosis and preoperative wire localization, digital mammography with the same exposure parameters. Five investigators retrospectively determined the diagnosis after the operation from randomly distributed mediolateral views (hard-copy reading) and from the monitor display (soft-copy reading). These results were correlated with the final histology. Results: The accuracy of conventional screen-film mammography, digital mammography and monitor-displayed mammography was 67%, 65% and 68% for all findings, (n = 76), 59%, 59% and 68% for microcalcifications (n = 44) and 75%, 72% and 63% for focal lesions (n = 32). The overall results showed no difference. Conclusions: Our findings indicate equivalence of conventional screen-film mammography, high-resolution digital phosphor storage plate mammography and monitor-displayed mammography. (orig.) [de

Virtual Colonoscopy Screening With Ultra Low-Dose CT and Less-Stressful Bowel Preparation: A Computer Simulation Study

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Wang, Jing; Wang, Su; Li, Lihong; Fan, Yi; Lu, Hongbing; Liang, Zhengrong

2008-10-01

Computed tomography colonography (CTC) or CT-based virtual colonoscopy (VC) is an emerging tool for detection of colonic polyps. Compared to the conventional fiber-optic colonoscopy, VC has demonstrated the potential to become a mass screening modality in terms of safety, cost, and patient compliance. However, current CTC delivers excessive X-ray radiation to the patient during data acquisition. The radiation is a major concern for screening application of CTC. In this work, we performed a simulation study to demonstrate a possible ultra low-dose CT technique for VC. The ultra low-dose abdominal CT images were simulated by adding noise to the sinograms of the patient CTC images acquired with normal dose scans at 100 mA s levels. The simulated noisy sinogram or projection data were first processed by a Karhunen-Loeve domain penalized weighted least-squares (KL-PWLS) restoration method and then reconstructed by a filtered backprojection algorithm for the ultra low-dose CT images. The patient-specific virtual colon lumen was constructed and navigated by a VC system after electronic colon cleansing of the orally-tagged residue stool and fluid. By the KL-PWLS noise reduction, the colon lumen can successfully be constructed and the colonic polyp can be detected in an ultra low-dose level below 50 mA s. Polyp detection can be found more easily by the KL-PWLS noise reduction compared to the results using the conventional noise filters, such as Hanning filter. These promising results indicate the feasibility of an ultra low-dose CTC pipeline for colon screening with less-stressful bowel preparation by fecal tagging with oral contrast.

DOVIS 2.0: an efficient and easy to use parallel virtual screening tool based on AutoDock 4.0.

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Jiang, Xiaohui; Kumar, Kamal; Hu, Xin; Wallqvist, Anders; Reifman, Jaques

2008-09-08

Small-molecule docking is an important tool in studying receptor-ligand interactions and in identifying potential drug candidates. Previously, we developed a software tool (DOVIS) to perform large-scale virtual screening of small molecules in parallel on Linux clusters, using AutoDock 3.05 as the docking engine. DOVIS enables the seamless screening of millions of compounds on high-performance computing platforms. In this paper, we report significant advances in the software implementation of DOVIS 2.0, including enhanced screening capability, improved file system efficiency, and extended usability. To keep DOVIS up-to-date, we upgraded the software's docking engine to the more accurate AutoDock 4.0 code. We developed a new parallelization scheme to improve runtime efficiency and modified the AutoDock code to reduce excessive file operations during large-scale virtual screening jobs. We also implemented an algorithm to output docked ligands in an industry standard format, sd-file format, which can be easily interfaced with other modeling programs. Finally, we constructed a wrapper-script interface to enable automatic rescoring of docked ligands by arbitrarily selected third-party scoring programs. The significance of the new DOVIS 2.0 software compared with the previous version lies in its improved performance and usability. The new version makes the computation highly efficient by automating load balancing, significantly reducing excessive file operations by more than 95%, providing outputs that conform to industry standard sd-file format, and providing a general wrapper-script interface for rescoring of docked ligands. The new DOVIS 2.0 package is freely available to the public under the GNU General Public License.

DOVIS 2.0: an efficient and easy to use parallel virtual screening tool based on AutoDock 4.0

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Wallqvist Anders

2008-09-01

Full Text Available Abstract Background Small-molecule docking is an important tool in studying receptor-ligand interactions and in identifying potential drug candidates. Previously, we developed a software tool (DOVIS to perform large-scale virtual screening of small molecules in parallel on Linux clusters, using AutoDock 3.05 as the docking engine. DOVIS enables the seamless screening of millions of compounds on high-performance computing platforms. In this paper, we report significant advances in the software implementation of DOVIS 2.0, including enhanced screening capability, improved file system efficiency, and extended usability. Implementation To keep DOVIS up-to-date, we upgraded the software's docking engine to the more accurate AutoDock 4.0 code. We developed a new parallelization scheme to improve runtime efficiency and modified the AutoDock code to reduce excessive file operations during large-scale virtual screening jobs. We also implemented an algorithm to output docked ligands in an industry standard format, sd-file format, which can be easily interfaced with other modeling programs. Finally, we constructed a wrapper-script interface to enable automatic rescoring of docked ligands by arbitrarily selected third-party scoring programs. Conclusion The significance of the new DOVIS 2.0 software compared with the previous version lies in its improved performance and usability. The new version makes the computation highly efficient by automating load balancing, significantly reducing excessive file operations by more than 95%, providing outputs that conform to industry standard sd-file format, and providing a general wrapper-script interface for rescoring of docked ligands. The new DOVIS 2.0 package is freely available to the public under the GNU General Public License.

Virtual Reality Design: How Head-Mounted Displays Change Design Paradigms of Virtual Reality Worlds

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Christian Stein

2016-09-01

Full Text Available With the upcoming generation of virtual reality HMDs, new virtual worlds, scenarios, and games are created especially for them. These are no longer bound to a remote screen or a relatively static user, but to an HMD as a more immersive device. This article discusses requirements for virtual scenarios implemented in new-generation HMDs to achieve a comfortable user experience. Furthermore, the effects of positional tracking are introduced and the relation between the user’s virtual and physical body is analyzed. The observations made are exemplified by existing software prototypes. They indicate how the term “virtual reality,” with all its loaded connotations, may be reconceptualized to express the peculiarities of HMDs in the context of gaming, entertainment, and virtual experiences.

Virtual Screening of Phytochemicals to Novel Target (HAT) Rtt109 in Pneumocystis Jirovecii using Bioinformatics Tools.

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Sugumar, Ramya; Adithavarman, Abhinand Ponneri; Dakshinamoorthi, Anusha; David, Darling Chellathai; Ragunath, Padmavathi Kannan

2016-03-01

Pneumocystis jirovecii is a fungus that causes Pneumocystis pneumonia in HIV and other immunosuppressed patients. Treatment of Pneumocystis pneumonia with the currently available antifungals is challenging and associated with considerable adverse effects. There is a need to develop drugs against novel targets with minimal human toxicities. Histone Acetyl Transferase (HAT) Rtt109 is a potential therapeutic target in Pneumocystis jirovecii species. HAT is linked to transcription and is required to acetylate conserved lysine residues on histone proteins by transferring an acetyl group from acetyl CoA to form e-N-acetyl lysine. Therefore, inhibitors of HAT can be useful therapeutic options in Pneumocystis pneumonia. To screen phytochemicals against (HAT) Rtt109 using bioinformatics tool. The tertiary structure of Pneumocystis jirovecii (HAT) Rtt109 was modeled by Homology Modeling. The ideal template for modeling was obtained by performing Psi BLAST of the protein sequence. Rtt109-AcCoA/Vps75 protein from Saccharomyces cerevisiae (PDB structure 3Q35) was chosen as the template. The target protein was modeled using Swiss Modeler and validated using Ramachandran plot and Errat 2. Comprehensive text mining was performed to identify phytochemical compounds with antipneumonia and fungicidal properties and these compounds were filtered based on Lipinski's Rule of 5. The chosen compounds were subjected to virtual screening against the target protein (HAT) Rtt109 using Molegro Virtual Docker 4.5. Osiris Property Explorer and Open Tox Server were used to predict ADME-T properties of the chosen phytochemicals. Tertiary structure model of HAT Rtt 109 had a ProSA score of -6.57 and Errat 2 score of 87.34. Structure validation analysis by Ramachandran plot for the model revealed 97% of amino acids were in the favoured region. Of all the phytochemicals subjected to virtual screening against the target protein (HAT) Rtt109, baicalin exhibited highest binding affinity towards the

Discovery of Anti-Hypertensive Oligopeptides from Adlay Based on In Silico Proteolysis and Virtual Screening

Directory of Open Access Journals (Sweden)

Liansheng Qiao

2016-12-01

Full Text Available Adlay (Coix larchryma-jobi L. was the commonly used Traditional Chinese Medicine (TCM with high content of seed storage protein. The hydrolyzed bioactive oligopeptides of adlay have been proven to be anti-hypertensive effective components. However, the structures and anti-hypertensive mechanism of bioactive oligopeptides from adlay were not clear. To discover the definite anti-hypertensive oligopeptides from adlay, in silico proteolysis and virtual screening were implemented to obtain potential oligopeptides, which were further identified by biochemistry assay and molecular dynamics simulation. In this paper, ten sequences of adlay prolamins were collected and in silico hydrolyzed to construct the oligopeptide library with 134 oligopeptides. This library was reverse screened by anti-hypertensive pharmacophore database, which was constructed by our research team and contained ten anti-hypertensive targets. Angiotensin-I converting enzyme (ACE was identified as the main potential target for the anti-hypertensive activity of adlay oligopeptides. Three crystal structures of ACE were utilized for docking studies and 19 oligopeptides were finally identified with potential ACE inhibitory activity. According to mapping features and evaluation indexes of pharmacophore and docking, three oligopeptides were selected for biochemistry assay. An oligopeptide sequence, NPATY (IC50 = 61.88 ± 2.77 µM, was identified as the ACE inhibitor by reverse-phase high performance liquid chromatography (RP-HPLC assay. Molecular dynamics simulation of NPATY was further utilized to analyze interactive bonds and key residues. ALA354 was identified as a key residue of ACE inhibitors. Hydrophobic effect of VAL518 and electrostatic effects of HIS383, HIS387, HIS513 and Zn2+ were also regarded as playing a key role in inhibiting ACE activities. This study provides a research strategy to explore the pharmacological mechanism of Traditional Chinese Medicine (TCM proteins based on

Virtual Prototyping at CERN

Science.gov (United States)

Gennaro, Silvano De

The VENUS (Virtual Environment Navigation in the Underground Sites) project is probably the largest Virtual Reality application to Engineering design in the world. VENUS is just over one year old and offers a fully immersive and stereoscopic "flythru" of the LHC pits for the proposed experiments, including the experimental area equipment and the surface models that are being prepared for a territorial impact study. VENUS' Virtual Prototypes are an ideal replacement for the wooden models traditionally build for the past CERN machines, as they are generated directly from the EUCLID CAD files, therefore they are totally reliable, they can be updated in a matter of minutes, and they allow designers to explore them from inside, in a one-to-one scale. Navigation can be performed on the computer screen, on a stereoscopic large projection screen, or in immersive conditions, with an helmet and 3D mouse. By using specialised collision detection software, the computer can find optimal paths to lower each detector part into the pits and position it to destination, letting us visualize the whole assembly probess. During construction, these paths can be fed to a robot controller, which can operate the bridge cranes and build LHC almost without human intervention. VENUS is currently developing a multiplatform VR browser that will let the whole HEP community access LHC's Virtual Protoypes over the web. Many interesting things took place during the conference on Virtual Reality. For more information please refer to the Virtual Reality section.

Can virtual autopsy with postmortem CT improve clinical diagnosis of cause of death? A retrospective observational cohort study in a Dutch tertiary referral centre

Science.gov (United States)

Sonnemans, Lianne J P; Kubat, Bela; Prokop, Mathias; Klein, Willemijn M

2018-01-01

Objective To investigate whether virtual autopsy with postmortem CT (PMCT) improves clinical diagnosis of the immediate cause of death. Design Retrospective observational cohort study. Inclusion criteria: inhospital and out-of-hospital deaths over the age of 1 year in whom virtual autopsy with PMCT and conventional autopsy were performed. Exclusion criteria: forensic cases, postmortal organ donors and cases with incomplete scanning procedures. Cadavers were examined by virtual autopsy with PMCT prior to conventional autopsy. The clinically determined cause of death was recorded before virtual autopsy and was then adjusted with the findings of virtual autopsy. Using conventional autopsy as reference standard, we investigated the increase in sensitivity for immediate cause of death, type of pathology and anatomical system involved before and after virtual autopsy. Setting Tertiary referral centre. Participants 86 cadavers that underwent conventional and virtual autopsy between July 2012 and June 2016. Intervention PMCT consisted of brain, cervical spine and chest–abdomen–pelvis imaging. Conventional autopsy consisted of thoracoabdominal examination with/without brain autopsy. Primary and secondary outcome measures Increase in sensitivity for the immediate cause of death, type of pathology (infection, haemorrhage, perfusion disorder, other or not assigned) and anatomical system (pulmonary, cardiovascular, gastrointestinal, other or not assigned) involved, before and after virtual autopsy. Results Using PMCT, the sensitivity for immediate cause of death increased with 12% (95% CI 2% to 22%) from 53% (41% to 64%) to 64% (53% to 75%), with 18% (9% to 27%) from 65% (54% to 76%) to 83% (73% to 91%) for type of pathology and with 19% (9% to 30%) from 65% (54% to 76%) to 85% (75% to 92%) for anatomical system. Conclusion While unenhanced PMCT is an insufficient substitute for conventional autopsy, it can improve diagnosis of cause of death over clinical diagnosis alone

Identification of putative estrogen receptor-mediated endocrine disrupting chemicals using QSAR- and structure-based virtual screening approaches

Energy Technology Data Exchange (ETDEWEB)

Zhang, Liying; Sedykh, Alexander; Tripathi, Ashutosh [Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC (United States); Zhu, Hao [The Rutgers Center for Computational and Integrative Biology, Rutgers University, Camden, NJ (United States); Department of Chemistry, Rutgers University, Camden, NJ (United States); Afantitis, Antreas; Mouchlis, Varnavas D.; Melagraki, Georgia [NovaMechanics Ltd., Nicosia (Cyprus); Rusyn, Ivan, E-mail: iir@unc.edu [Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, NC (United States); Tropsha, Alexander, E-mail: alex_tropsha@unc.edu [Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC (United States)

2013-10-01

Identification of endocrine disrupting chemicals is one of the important goals of environmental chemical hazard screening. We report on the development of validated in silico predictors of chemicals likely to cause estrogen receptor (ER)-mediated endocrine disruption to facilitate their prioritization for future screening. A database of relative binding affinity of a large number of ERα and/or ERβ ligands was assembled (546 for ERα and 137 for ERβ). Both single-task learning (STL) and multi-task learning (MTL) continuous quantitative structure–activity relationship (QSAR) models were developed for predicting ligand binding affinity to ERα or ERβ. High predictive accuracy was achieved for ERα binding affinity (MTL R{sup 2} = 0.71, STL R{sup 2} = 0.73). For ERβ binding affinity, MTL models were significantly more predictive (R{sup 2} = 0.53, p < 0.05) than STL models. In addition, docking studies were performed on a set of ER agonists/antagonists (67 agonists and 39 antagonists for ERα, 48 agonists and 32 antagonists for ERβ, supplemented by putative decoys/non-binders) using the following ER structures (in complexes with respective ligands) retrieved from the Protein Data Bank: ERα agonist (PDB ID: 1L2I), ERα antagonist (PDB ID: 3DT3), ERβ agonist (PDB ID: 2NV7), and ERβ antagonist (PDB ID: 1L2J). We found that all four ER conformations discriminated their corresponding ligands from presumed non-binders. Finally, both QSAR models and ER structures were employed in parallel to virtually screen several large libraries of environmental chemicals to derive a ligand- and structure-based prioritized list of putative estrogenic compounds to be used for in vitro and in vivo experimental validation. - Highlights: • This is the largest curated dataset inclusive of ERα and β (the latter is unique). • New methodology that for the first time affords acceptable ERβ models. • A combination of QSAR and docking enables prediction of affinity and function. �

Identification of putative estrogen receptor-mediated endocrine disrupting chemicals using QSAR- and structure-based virtual screening approaches

International Nuclear Information System (INIS)

Zhang, Liying; Sedykh, Alexander; Tripathi, Ashutosh; Zhu, Hao; Afantitis, Antreas; Mouchlis, Varnavas D.; Melagraki, Georgia; Rusyn, Ivan; Tropsha, Alexander

2013-01-01

Identification of endocrine disrupting chemicals is one of the important goals of environmental chemical hazard screening. We report on the development of validated in silico predictors of chemicals likely to cause estrogen receptor (ER)-mediated endocrine disruption to facilitate their prioritization for future screening. A database of relative binding affinity of a large number of ERα and/or ERβ ligands was assembled (546 for ERα and 137 for ERβ). Both single-task learning (STL) and multi-task learning (MTL) continuous quantitative structure–activity relationship (QSAR) models were developed for predicting ligand binding affinity to ERα or ERβ. High predictive accuracy was achieved for ERα binding affinity (MTL R 2 = 0.71, STL R 2 = 0.73). For ERβ binding affinity, MTL models were significantly more predictive (R 2 = 0.53, p < 0.05) than STL models. In addition, docking studies were performed on a set of ER agonists/antagonists (67 agonists and 39 antagonists for ERα, 48 agonists and 32 antagonists for ERβ, supplemented by putative decoys/non-binders) using the following ER structures (in complexes with respective ligands) retrieved from the Protein Data Bank: ERα agonist (PDB ID: 1L2I), ERα antagonist (PDB ID: 3DT3), ERβ agonist (PDB ID: 2NV7), and ERβ antagonist (PDB ID: 1L2J). We found that all four ER conformations discriminated their corresponding ligands from presumed non-binders. Finally, both QSAR models and ER structures were employed in parallel to virtually screen several large libraries of environmental chemicals to derive a ligand- and structure-based prioritized list of putative estrogenic compounds to be used for in vitro and in vivo experimental validation. - Highlights: • This is the largest curated dataset inclusive of ERα and β (the latter is unique). • New methodology that for the first time affords acceptable ERβ models. • A combination of QSAR and docking enables prediction of affinity and function. • The results

Improved genome-scale multi-target virtual screening via a novel collaborative filtering approach to cold-start problem.

Science.gov (United States)

Lim, Hansaim; Gray, Paul; Xie, Lei; Poleksic, Aleksandar

2016-12-13

Conventional one-drug-one-gene approach has been of limited success in modern drug discovery. Polypharmacology, which focuses on searching for multi-targeted drugs to perturb disease-causing networks instead of designing selective ligands to target individual proteins, has emerged as a new drug discovery paradigm. Although many methods for single-target virtual screening have been developed to improve the efficiency of drug discovery, few of these algorithms are designed for polypharmacology. Here, we present a novel theoretical framework and a corresponding algorithm for genome-scale multi-target virtual screening based on the one-class collaborative filtering technique. Our method overcomes the sparseness of the protein-chemical interaction data by means of interaction matrix weighting and dual regularization from both chemicals and proteins. While the statistical foundation behind our method is general enough to encompass genome-wide drug off-target prediction, the program is specifically tailored to find protein targets for new chemicals with little to no available interaction data. We extensively evaluate our method using a number of the most widely accepted gene-specific and cross-gene family benchmarks and demonstrate that our method outperforms other state-of-the-art algorithms for predicting the interaction of new chemicals with multiple proteins. Thus, the proposed algorithm may provide a powerful tool for multi-target drug design.

BET Bromodomain Inhibitors with One-Step Synthesis Discovered from Virtual Screen.

Science.gov (United States)

Ayoub, Alex M; Hawk, Laura M L; Herzig, Ryan J; Jiang, Jiewei; Wisniewski, Andrea J; Gee, Clifford T; Zhao, Peiliang; Zhu, Jin-Yi; Berndt, Norbert; Offei-Addo, Nana K; Scott, Thomas G; Qi, Jun; Bradner, James E; Ward, Timothy R; Schönbrunn, Ernst; Georg, Gunda I; Pomerantz, William C K

2017-06-22

Chemical inhibition of epigenetic regulatory proteins BrdT and Brd4 is emerging as a promising therapeutic strategy in contraception, cancer, and heart disease. We report an easily synthesized dihydropyridopyrimidine pan-BET inhibitor scaffold, which was uncovered via a virtual screen followed by testing in a fluorescence anisotropy assay. Dihydropyridopyimidine 3 was subjected to further characterization and is highly selective for the BET family of bromodomains. Structure-activity relationship data and ligand deconstruction highlight the importance of the substitution of the uracil moiety for potency and selectivity. Compound 3 was also cocrystallized with Brd4 for determining the ligand binding pose and rationalizing subsequent structure-activity data. An additional series of dihydropyridopyrimidines was synthesized to exploit the proximity of a channel near the ZA loop of Brd4, leading to compounds with submicromolar affinity and cellular target engagement. Given these findings, novel and easily synthesized inhibitors are being introduced to the growing field of bromodomain inhibitor development.

BET Bromodomain Inhibitors with One-Step Synthesis Discovered from Virtual Screen

Energy Technology Data Exchange (ETDEWEB)

Ayoub, Alex M.; Hawk, Laura M.L.; Herzig, Ryan J.; Jiang, Jiewei; Wisniewski, Andrea J.; Gee, Clifford T.; Zhao, Peiliang; Zhu, Jin-Yi; Berndt, Norbert; Offei-Addo, Nana K.; Scott, Thomas G.; Qi, Jun; Bradner, James E.; Ward, Timothy R.; Schönbrunn, Ernst; Georg, Gunda I.; Pomerantz, William C.K. (Moffitt); (UMM); (Harvard-Med)

2017-06-06

Chemical inhibition of epigenetic regulatory proteins BrdT and Brd4 is emerging as a promising therapeutic strategy in contraception, cancer, and heart disease. We report an easily synthesized dihydropyridopyrimidine pan-BET inhibitor scaffold, which was uncovered via a virtual screen followed by testing in a fluorescence anisotropy assay. Dihydropyridopyimidine 3 was subjected to further characterization and is highly selective for the BET family of bromodomains. Structure–activity relationship data and ligand deconstruction highlight the importance of the substitution of the uracil moiety for potency and selectivity. Compound 3 was also cocrystallized with Brd4 for determining the ligand binding pose and rationalizing subsequent structure–activity data. An additional series of dihydropyridopyrimidines was synthesized to exploit the proximity of a channel near the ZA loop of Brd4, leading to compounds with submicromolar affinity and cellular target engagement. Given these findings, novel and easily synthesized inhibitors are being introduced to the growing field of bromodomain inhibitor development.

Virtual Screening and Prediction of Site of Metabolism for Cytochrome P450 1A2 Ligands

DEFF Research Database (Denmark)

Vasanthanathan, P.; Hritz, Jozef; Taboureau, Olivier

2009-01-01

questions have been addressed: 1. Binding orientations and conformations were successfully predicted for various substrates. 2. A virtual screen was performed with satisfying enrichment rates. 3. A classification of individual compounds into active and inactive was performed. It was found that while docking...... can be used successfully to address the first two questions, it seems to be more difficult to perform the classification. Different scoring functions were included, and the well-characterized water molecule in the active site was included in various ways. Results are compared to experimental data...

Simultaneous virtual prediction of anti-Escherichia coli activities and ADMET profiles: A chemoinformatic complementary approach for high-throughput screening.

Science.gov (United States)

Speck-Planche, Alejandro; Cordeiro, M N D S

2014-02-10

Escherichia coli remains one of the principal pathogens that cause nosocomial infections, medical conditions that are increasingly common in healthcare facilities. E. coli is intrinsically resistant to many antibiotics, and multidrug-resistant strains have emerged recently. Chemoinformatics has been a great ally of experimental methodologies such as high-throughput screening, playing an important role in the discovery of effective antibacterial agents. However, there is no approach that can design safer anti-E. coli agents, because of the multifactorial nature and complexity of bacterial diseases and the lack of desirable ADMET (absorption, distribution, metabolism, elimination, and toxicity) profiles as a major cause of disapproval of drugs. In this work, we introduce the first multitasking model based on quantitative-structure biological effect relationships (mtk-QSBER) for simultaneous virtual prediction of anti-E. coli activities and ADMET properties of drugs and/or chemicals under many experimental conditions. The mtk-QSBER model was developed from a large and heterogeneous data set of more than 37800 cases, exhibiting overall accuracies of >95% in both training and prediction (validation) sets. The utility of our mtk-QSBER model was demonstrated by performing virtual prediction of properties for the investigational drug avarofloxacin (AVX) under 260 different experimental conditions. Results converged with the experimental evidence, confirming the remarkable anti-E. coli activities and safety of AVX. Predictions also showed that our mtk-QSBER model can be a promising computational tool for virtual screening of desirable anti-E. coli agents, and this chemoinformatic approach could be extended to the search for safer drugs with defined pharmacological activities.

Virtual screening using the ligand ZINC database for novel lipoxygenase-3 inhibitors.

Science.gov (United States)

Monika; Kour, Janmeet; Singh, Kulwinder

2013-01-01

The leukotrienes constitute a group of arachidonic acid-derived compounds with biologic activities suggesting important roles in inflammation and immediate hypersensitivity. Epidermis-type lipoxygenase-3 (ALOXE3), a distinct subclass within the multigene family of mammalian lipoxygenases, is a novel isoenzyme involved in the metabolism of leukotrienes and plays a very important role in skin barrier functions. Lipoxygenase selective inhibitors such as azelastine and zileuton are currently used to reduce inflammatory response. Nausea, pharyngolaryngeal pain, headache, nasal burning and somnolence are the most frequently reported adverse effects of these drugs. Therefore, there is still a need to develop more potent lipoxygenase inhibitors. In this paper, we report the screening of various compounds from the ZINC database (contains over 21 million compounds) using the Molegro Virtual Docker software against the ALOXE3 protein. Screening was performed using molecular constraints tool to filter compounds with physico-chemical properties similar to the 1N8Q bound ligand protocatechuic acid. The analysis resulted in 4319 Lipinski compliant hits which are docked and scored to identify structurally novel ligands that make similar interactions to those of known ligands or may have different interactions with other parts of the binding site. Our screening approach identified four molecules ZINC84299674; ZINC76643455; ZINC84299122 & ZINC75626957 with MolDock score of -128.901, -120.22, -116.873 & - 102.116 kcal/mol, respectively. Their energy scores were better than the 1N8Q bound co-crystallized ligand protocatechuic acid (with MolDock score of -77.225 kcal/mol). All the ligands were docked within the binding pocket forming interactions with amino acid residues.

Discovery of Selective Inhibitors of Imidazoleglycerol-Phosphate Dehydratase from Mycobacterium tuberculosis by Virtual Screening

Science.gov (United States)

Podshivalov, D.; Mandzhieva, Yu. B.; Sidorov-Biryukov, D. D.; Timofeev, V. I.; Kuranova, I. P.

2018-01-01

Bacterial imidazoleglycerol-phosphate dehydratase from Mycobacterium tuberculosis (HisB- Mt) is a convenient target for the discovery of selective inhibitors as potential antituberculosis drugs. The virtual screening was performed to find compounds suitable for the design of selective inhibitors of HisB- Mt. The positions of four ligands, which were selected based on the docking scoring function and docked to the activesite region of the enzyme, were refined by molecular dynamics simulation. The nearest environment of the ligands was determined. These compounds selectively bind to functionally essential active-site residues, thus blocking access of substrates to the active site of the enzyme, and can be used as lead compounds for the design of selective inhibitors of HisB- M.

Identification of critical chemical features for Aurora kinase-B inhibitors using Hip-Hop, virtual screening and molecular docking

Science.gov (United States)

Sakkiah, Sugunadevi; Thangapandian, Sundarapandian; John, Shalini; Lee, Keun Woo

2011-01-01

This study was performed to find the selective chemical features for Aurora kinase-B inhibitors using the potent methods like Hip-Hop, virtual screening, homology modeling, molecular dynamics and docking. The best hypothesis, Hypo1 was validated toward a wide range of test set containing the selective inhibitors of Aurora kinase-B. Homology modeling and molecular dynamics studies were carried out to perform the molecular docking studies. The best hypothesis Hypo1 was used as a 3D query to screen the chemical databases. The screened molecules from the databases were sorted based on ADME and drug like properties. The selective hit compounds were docked and the hydrogen bond interactions with the critical amino acids present in Aurora kinase-B were compared with the chemical features present in the Hypo1. Finally, we suggest that the chemical features present in the Hypo1 are vital for a molecule to inhibit the Aurora kinase-B activity.

Surgical accuracy of three-dimensional virtual planning

DEFF Research Database (Denmark)

Stokbro, Kasper; Aagaard, Esben; Torkov, Peter

2016-01-01

This retrospective study evaluated the precision and positional accuracy of different orthognathic procedures following virtual surgical planning in 30 patients. To date, no studies of three-dimensional virtual surgical planning have evaluated the influence of segmentation on positional accuracy...... and transverse expansion. Furthermore, only a few have evaluated the precision and accuracy of genioplasty in placement of the chin segment. The virtual surgical plan was compared with the postsurgical outcome by using three linear and three rotational measurements. The influence of maxillary segmentation...

Optimizing virtual fragment screening for GPCRs: Identification of novel ligands for the histamine H3 receptor using ligand- and structure-based molecular fingerprints

NARCIS (Netherlands)

Sirci, F.; Istyastono, E.P.; Vischer, H.F.; Nijmeijer, S.; Kuijer, M.; Kooistra, A.J.; Wijtmans, M.; Mannhold, R.; Leurs, R.; de Esch, I.J.P.; de Graaf, C.

2012-01-01

Virtual fragment screening (VFS) is a promising new method that uses computer models to identify small, fragment-like biologically active molecules as useful starting points for fragment-based drug discovery (FBDD). Training sets of true active and inactive fragment-like molecules to construct and

Virtual-screening workflow tutorials and prospective results from the Teach-Discover-Treat competition 2014 against malaria [version 1; referees: 2 approved

Directory of Open Access Journals (Sweden)

Sereina Riniker

2017-07-01

Full Text Available The first challenge in the 2014 competition launched by the Teach-Discover-Treat (TDT initiative asked for the development of a tutorial for ligand-based virtual screening, based on data from a primary phenotypic high-throughput screen (HTS against malaria. The resulting Workflows were applied to select compounds from a commercial database, and a subset of those were purchased and tested experimentally for anti-malaria activity. Here, we present the two most successful Workflows, both using machine-learning approaches, and report the results for the 114 compounds tested in the follow-up screen. Excluding the two known anti-malarials quinidine and amodiaquine and 31 compounds already present in the primary HTS, a high hit rate of 57% was found.

Virtual Reality Interaction Using Mobile Devices

KAUST Repository

Aseeri, Sahar A.

2013-07-01

With the use of an immersive display system such as CAVE system, the user is able to realize a 3D immersive virtual environment realistically. However, interacting with virtual worlds in CAVE systems using traditional input devices to perform easy operations such as manipulation, object selection, and navigation is often difficult. This difficulty could diminish the immersion and sense of presence when it comes to 3D virtual environment tasks. Our research aims to implement and evaluate alternative approaches of interaction with immersive virtual environments on mobile devices for manipulation and object selection tasks. As many researchers have noted, using a mobile device as an interaction device has a number of advantages, including built-in display, built-in control, and touch screen facility. These advantages facilitate simple tasks within immersive virtual environments. This research proposes new methods using mobile devices like Smart-phones to perform di↵erent kinds of interactions both as an input device, (e.g. performing selection and manipulation of objects) and as an output device (e.g. utilizing the screen as an extra view for a virtual camera or information display). Moreover, we developed a prototype system to demonstrate and informally evaluate these methods. The research conclusion suggests using mobile devices as a 3D-controller. This will be a more intuitive approach to interact within the virtual environment.

Sulfonylureas and Glinides as New PPARγ Agonists:. Virtual Screening and Biological Assays

Science.gov (United States)

Scarsi, Marco; Podvinec, Michael; Roth, Adrian; Hug, Hubert; Kersten, Sander; Albrecht, Hugo; Schwede, Torsten; Meyer, Urs A.; Rücker, Christoph

2007-12-01

This work combines the predictive power of computational drug discovery with experimental validation by means of biological assays. In this way, a new mode of action for type 2 diabetes drugs has been unvealed. Most drugs currently employed in the treatment of type 2 diabetes either target the sulfonylurea receptor stimulating insulin release (sulfonylureas, glinides), or target PPARγ improving insulin resistance (thiazolidinediones). Our work shows that sulfonylureas and glinides bind to PPARγ and exhibit PPARγ agonistic activity. This result was predicted in silico by virtual screening and confirmed in vitro by three biological assays. This dual mode of action of sulfonylureas and glinides may open new perspectives for the molecular pharmacology of antidiabetic drugs, since it provides evidence that drugs can be designed which target both the sulfonylurea receptor and PPARγ. Targeting both receptors could in principle allow to increase pancreatic insulin secretion, as well as to improve insulin resistance.

The impact of Down syndrome screening on Taiwanese Down syndrome births: a nationwide retrospective study and a screening result from a single medical centre.

Directory of Open Access Journals (Sweden)

Shin-Yu Lin

Full Text Available A retrospective analysis of the Taiwanese National Birth Defect Registration and Notification System was conducted in order to determine the live birth- and stillbirth rates in infants with Down syndrome, trisomy 18, trisomy 13 and Turner syndrome between 2001 and 2010. The objective was to investigate the impact of Down syndrome screening on the Taiwanese Down syndrome live birth rate. In addition, the results of first-trimester Down syndrome screening between 2006 and 2011, and of second-trimester quadruple testing between 2008 and 2011, were obtained from the National Taiwan University Hospital. All Taiwanese infants born between 2001 and 2010 were included in the first part of the analysis, and women receiving first-trimester Down syndrome screening or second-trimester quadruple testing from the National Taiwan University Hospital were included in the second part. The live birth rate of infants with Down syndrome, per 100 000 live births, decreased from 22.28 in 2001 to 7.79 in 2010. The ratio of liveborn DS to total DS was 48.74% in 2001, and then decreased to 25.88% in 2006, when first-trimester screening was widely introduced in Taiwan. This ratio dropped to 20.64% in 2008, when the second-trimester quadruple test was implemented. The overall positive rate in first-trimester screening in the National Taiwan University Hospital was 3.1%, with a Down syndrome detection rate of 100%; the quadruple test had values of 9.0% and 75%, respectively. The use of first-trimester screening and the second-trimester quadruple test may be responsible for the marked decrease in the Taiwanese Down syndrome live birth rate observed between 2001 and 2010.

Lung cancer incidence and mortality in National Lung Screening Trial participants who underwent low-dose CT prevalence screening: a retrospective cohort analysis of a randomised, multicentre, diagnostic screening trial.

Science.gov (United States)

Patz, Edward F; Greco, Erin; Gatsonis, Constantine; Pinsky, Paul; Kramer, Barnett S; Aberle, Denise R

2016-05-01

Annual low-dose CT screening for lung cancer has been recommended for high-risk individuals, but the necessity of yearly low-dose CT in all eligible individuals is uncertain. This study examined rates of lung cancer in National Lung Screening Trial (NLST) participants who had a negative prevalence (initial) low-dose CT screen to explore whether less frequent screening could be justified in some lower-risk subpopulations. We did a retrospective cohort analysis of data from the NLST, a randomised, multicentre screening trial comparing three annual low-dose CT assessments with three annual chest radiographs for the early detection of lung cancer in high-risk, eligible individuals (aged 55-74 years with at least a 30 pack-year history of cigarette smoking, and, if a former smoker, had quit within the past 15 years), recruited from US medical centres between Aug 5, 2002, and April 26, 2004. Participants were followed up for up to 5 years after their last annual screen. For the purposes of this analysis, our cohort consisted of all NLST participants who had received a low-dose CT prevalence (T0) screen. We determined the frequency, stage, histology, study year of diagnosis, and incidence of lung cancer, as well as overall and lung cancer-specific mortality, and whether lung cancers were detected as a result of screening or within 1 year of a negative screen. We also estimated the effect on mortality if the first annual (T1) screen in participants with a negative T0 screen had not been done. The NLST is registered with ClinicalTrials.gov, number NCT00047385. Our cohort consisted of 26 231 participants assigned to the low-dose CT screening group who had undergone their T0 screen. The 19 066 participants with a negative T0 screen had a lower incidence of lung cancer than did all 26 231 T0-screened participants (371·88 [95% CI 337·97-408·26] per 100 000 person-years vs 661·23 [622·07-702·21]) and had lower lung cancer-related mortality (185·82 [95% CI 162·17

Using Virtual Patient Simulations to Prepare Primary Health Care Professionals to Conduct Substance Use and Mental Health Screening and Brief Intervention.

Science.gov (United States)

Albright, Glenn; Bryan, Craig; Adam, Cyrille; McMillan, Jeremiah; Shockley, Kristen

2017-07-01

Primary health care professionals are in an excellent position to identify, screen, and conduct brief interventions for patients with mental health and substance use disorders. However, discomfort in initiating conversations about behavioral health, time concerns, lack of knowledge about screening tools, and treatment resources are barriers. This study examines the impact of an online simulation where users practice role-playing with emotionally responsive virtual patients to learn motivational interviewing strategies to better manage screening, brief interventions, and referral conversations. Baseline data were collected from 227 participants who were then randomly assigned into the treatment or wait-list control groups. Treatment group participants then completed the simulation, postsimulation survey, and 3-month follow-up survey. Results showed significant increases in knowledge/skill to identify and engage in collaborative decision making with patients. Results strongly suggest that role-play simulation experiences can be an effective means of teaching screening and brief intervention.

Target specific proteochemometric model development for BACE1 - protein flexibility and structural water are critical in virtual screening.

Science.gov (United States)

Manoharan, Prabu; Chennoju, Kiranmai; Ghoshal, Nanda

2015-07-01

BACE1 is an attractive target in Alzheimer's disease (AD) treatment. A rational drug design effort for the inhibition of BACE1 is actively pursued by researchers in both academic and pharmaceutical industries. This continued effort led to the steady accumulation of BACE1 crystal structures, co-complexed with different classes of inhibitors. This wealth of information is used in this study to develop target specific proteochemometric models and these models are exploited for predicting the prospective BACE1 inhibitors. The models developed in this study have performed excellently in predicting the computationally generated poses, separately obtained from single and ensemble docking approaches. The simple protein-ligand contact (SPLC) model outperforms other sophisticated high end models, in virtual screening performance, developed during this study. In an attempt to account for BACE1 protein active site flexibility information in predictive models, we included the change in the area of solvent accessible surface and the change in the volume of solvent accessible surface in our models. The ensemble and single receptor docking results obtained from this study indicate that the structural water mediated interactions improve the virtual screening results. Also, these waters are essential for recapitulating bioactive conformation during docking study. The proteochemometric models developed in this study can be used for the prediction of BACE1 inhibitors, during the early stage of AD drug discovery.

[Virtual reality in neurosurgery].

Science.gov (United States)

Tronnier, V M; Staubert, A; Bonsanto, M M; Wirtz, C R; Kunze, S

2000-03-01

Virtual reality enables users to immerse themselves in a virtual three-dimensional world and to interact in this world. The simulation is different from the kind in computer games, in which the viewer is active but acts in a nonrealistic world, or on the TV screen, where we are passively driven in an active world. In virtual reality elements look realistic, they change their characteristics and have almost real-world unpredictability. Virtual reality is not only implemented in gambling dens and the entertainment industry but also in manufacturing processes (cars, furniture etc.), military applications and medicine. Especially the last two areas are strongly correlated, because telemedicine or telesurgery was originated for military reasons to operate on war victims from a secure distance or to perform surgery on astronauts in an orbiting space station. In medicine and especially neurosurgery virtual-reality methods are used for education, surgical planning and simulation on a virtual patient.

Can virtual autopsy with postmortem CT improve clinical diagnosis of cause of death? A retrospective observational cohort study in a Dutch tertiary referral centre.

Science.gov (United States)

Sonnemans, Lianne J P; Kubat, Bela; Prokop, Mathias; Klein, Willemijn M

2018-03-16

To investigate whether virtual autopsy with postmortem CT (PMCT) improves clinical diagnosis of the immediate cause of death. Retrospective observational cohort study. inhospital and out-of-hospital deaths over the age of 1 year in whom virtual autopsy with PMCT and conventional autopsy were performed. forensic cases, postmortal organ donors and cases with incomplete scanning procedures. Cadavers were examined by virtual autopsy with PMCT prior to conventional autopsy. The clinically determined cause of death was recorded before virtual autopsy and was then adjusted with the findings of virtual autopsy. Using conventional autopsy as reference standard, we investigated the increase in sensitivity for immediate cause of death, type of pathology and anatomical system involved before and after virtual autopsy. Tertiary referral centre. 86 cadavers that underwent conventional and virtual autopsy between July 2012 and June 2016. PMCT consisted of brain, cervical spine and chest-abdomen-pelvis imaging. Conventional autopsy consisted of thoracoabdominal examination with/without brain autopsy. Increase in sensitivity for the immediate cause of death, type of pathology (infection, haemorrhage, perfusion disorder, other or not assigned) and anatomical system (pulmonary, cardiovascular, gastrointestinal, other or not assigned) involved, before and after virtual autopsy. Using PMCT, the sensitivity for immediate cause of death increased with 12% (95% CI 2% to 22%) from 53% (41% to 64%) to 64% (53% to 75%), with 18% (9% to 27%) from 65% (54% to 76%) to 83% (73% to 91%) for type of pathology and with 19% (9% to 30%) from 65% (54% to 76%) to 85% (75% to 92%) for anatomical system. While unenhanced PMCT is an insufficient substitute for conventional autopsy, it can improve diagnosis of cause of death over clinical diagnosis alone and should therefore be considered whenever autopsy is not performed. © Article author(s) (or their employer(s) unless otherwise stated in the text of

Lead identification for the K-Ras protein: virtual screening and combinatorial fragment-based approaches

Directory of Open Access Journals (Sweden)

Pathan AAK

2016-05-01

Full Text Available Akbar Ali Khan Pathan,1,2,* Bhavana Panthi,3,* Zahid Khan,1 Purushotham Reddy Koppula,4–6 Mohammed Saud Alanazi,1 Sachchidanand,3 Narasimha Reddy Parine,1 Mukesh Chourasia3,* 1Genome Research Chair (GRC, Department of Biochemistry, College of Science, King Saud University, 2Integrated Gulf Biosystems, Riyadh, Kingdom of Saudi Arabia; 3Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research, Hajipur, India; 4Department of Internal Medicine, School of Medicine, 5Harry S. Truman Memorial Veterans Affairs Hospital, 6Department of Radiology, School of Medicine, Columbia, MO, USA *These authors contributed equally to this work Objective: Kirsten rat sarcoma (K-Ras protein is a member of Ras family belonging to the small guanosine triphosphatases superfamily. The members of this family share a conserved structure and biochemical properties, acting as binary molecular switches. The guanosine triphosphate-bound active K-Ras interacts with a range of effectors, resulting in the stimulation of downstream signaling pathways regulating cell proliferation, differentiation, and apoptosis. Efforts to target K-Ras have been unsuccessful until now, placing it among high-value molecules against which developing a therapy would have an enormous impact. K-Ras transduces signals when it binds to guanosine triphosphate by directly binding to downstream effector proteins, but in case of guanosine diphosphate-bound conformation, these interactions get disrupted. Methods: In the present study, we targeted the nucleotide-binding site in the “on” and “off” state conformations of the K-Ras protein to find out suitable lead compounds. A structure-based virtual screening approach has been used to screen compounds from different databases, followed by a combinatorial fragment-based approach to design the apposite lead for the K-Ras protein. Results: Interestingly, the designed compounds exhibit a binding preference for the �

FTree query construction for virtual screening: a statistical analysis.

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Gerlach, Christof; Broughton, Howard; Zaliani, Andrea

2008-02-01

FTrees (FT) is a known chemoinformatic tool able to condense molecular descriptions into a graph object and to search for actives in large databases using graph similarity. The query graph is classically derived from a known active molecule, or a set of actives, for which a similar compound has to be found. Recently, FT similarity has been extended to fragment space, widening its capabilities. If a user were able to build a knowledge-based FT query from information other than a known active structure, the similarity search could be combined with other, normally separate, fields like de-novo design or pharmacophore searches. With this aim in mind, we performed a comprehensive analysis of several databases in terms of FT description and provide a basic statistical analysis of the FT spaces so far at hand. Vendors' catalogue collections and MDDR as a source of potential or known "actives", respectively, have been used. With the results reported herein, a set of ranges, mean values and standard deviations for several query parameters are presented in order to set a reference guide for the users. Applications on how to use this information in FT query building are also provided, using a newly built 3D-pharmacophore from 57 5HT-1F agonists and a published one which was used for virtual screening for tRNA-guanine transglycosylase (TGT) inhibitors.

Screening prior to biological therapy in Crohn's disease: adherence to guidelines and prevalence of infections. Results from a multicentre retrospective study.

Science.gov (United States)

van der Have, Mike; Belderbos, Tim D G; Fidder, Herma H; Leenders, Max; Dijkstra, Gerard; Peters, Charlotte P; Eshuis, Emma J; Ponsioen, Cyriel Y; Siersema, Peter D; van Oijen, Martijn G H; Oldenburg, Bas

2014-10-01

Screening for opportunistic infections prior to starting biological therapy in patients with inflammatory bowel disease is recommended. To assess adherence to screening for opportunistic infections prior to starting biological therapy in Crohn's disease patients and its yield. A multicentre retrospective study was conducted in Crohn's disease patients in whom infliximab or adalimumab was started between 2000 and 2010. Screening included tuberculin skin test, interferon-gamma release assay or chest X-ray for tuberculosis. Extended screening included screening for tuberculosis and viral infections. Patients were followed until three months after ending treatment. Primary endpoints were opportunistic and serious infections. 611 patients were included, 91% on infliximab. 463 (76%) patients were screened for tuberculosis, of whom 113 (24%) underwent extended screening. Screening for tuberculosis and hepatitis B increased to, respectively, 90-97% and 36-49% in the last two years. During a median follow-up of two years, 64/611 (9%, 3.4/100 patient-years) opportunistic infections and 26/611 (4%, 1.6/100 patient-years) serious infections were detected. Comorbidity was significantly associated with serious infections (hazard ratio 3.94). Although screening rates for tuberculosis and hepatitis B increased, screening for hepatitis B was still suboptimal. More caution is required when prescribing biologicals in patients with comorbid conditions. Copyright © 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Virtual Screening Techniques to Probe the Antimalarial Activity of some Traditionally Used Phytochemicals.

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Shibi, Indira G; Aswathy, Lilly; Jisha, Radhakrishnan S; Masand, Vijay H; Gajbhiye, Jayant M

2016-01-01

Malaria parasites show resistance to most of the antimalarial drugs and hence developing antimalarials which can act on multitargets rather than a single target will be a promising strategy of drug design. Here we report a new approach by which virtual screening of 292 unique phytochemicals present in 72 traditionally important herbs is used for finding out inhibitors of plasmepsin-2 and falcipain-2 for antimalarial activity against P. falciparum. Initial screenings of the selected molecules by Random Forest algorithm model of Weka using the bioassay datasets AID 504850 and AID 2302 screened 120 out of the total 292 phytochemicals to be active against the targets. Toxtree scan cautioned 21 compounds to be either carcinogenic or mutagenic and were thus removed for further analysis. Out of the remaining 99 compounds, only 46 compounds offered drug-likeness as per the 'rule of five' criteria. Out of ten antimalarial drug targets, only two target proteins such as 3BPF and 3PNR of falcipain-2 and 1PFZ and 2BJU of plasmepsin-2 are selected as targets. The potential binding of the selected 46 compounds to the active sites of these four targets was analyzed using MOE software. The docked conformations and the interactions with the binding pocket residues of the target proteins were understood by 'Ligplot' analysis. It has been found that 8 compounds are dual inhibitors of falcipain-2 and plasmepsin-2, with the best binding energies. Compound 117 (6aR, 12aS)-12a-Hydroxy-9-methoxy-2,3-dimethylenedioxy-8-prenylrotenone (Usaratenoid C) present in the plant Millettia usaramensis showed maximum molecular docking score.

Breast cancer screening with digital breast tomosynthesis.

Science.gov (United States)

Skaane, Per

2017-01-01

To give an overview of studies comparing full-field digital mammography (FFDM) and digital breast tomosynthesis (DBT) in breast cancer screening. The implementation of tomosynthesis in breast imaging is rapidly increasing world-wide. Experimental clinical studies of relevance for DBT screening have shown that tomosynthesis might have a great potential in breast cancer screening, although most of these retrospective reading studies are based on small populations, so that final conclusions are difficult to draw from individual reports. Several retrospective studies and three prospective trials on tomosynthesis in breast cancer screening have been published so far, confirming the great potential of DBT in mammography screening. The main results of these screening studies are presented. The retrospective screening studies from USA have all shown a significant decrease in the recall rate using DBT as adjunct to mammography. Most of these studies have also shown an increase in the cancer detection rate, and the non-significant results in some studies might be explained by a lack of statistical power. All the three prospective European trials have shown a significant increase in the cancer detection rate. The retrospective and the prospective screening studies comparing FFDM and DBT have all demonstrated that tomosynthesis has a great potential for improving breast cancer screening. DBT should be regarded as a better mammogram that could improve or overcome limitations of the conventional mammography, and tomosynthesis might be considered as the new technique in the next future of breast cancer screening.

Discovery of Natural Products as Novel and Potent FXR Antagonists by Virtual Screening

Science.gov (United States)

Diao, Yanyan; Jiang, Jing; Zhang, Shoude; Li, Shiliang; Shan, Lei; Huang, Jin; Zhang, Weidong; Li, Honglin

2018-04-01

Farnesoid X receptor (FXR) is a member of nuclear receptor family involved in multiple physiological processes through regulating specific target genes. The critical role of FXR as a transcriptional regulator makes it a promising target for diverse diseases, especially those related to metabolic disorders such as diabetes and cholestasis. However, the underlying activation mechanism of FXR is still a blur owing to the absence of proper FXR modulators. To identify potential FXR modulators, an in-house natural product database (NPD) containing over 4000 compounds was screened by structure-based virtual screening strategy and subsequent hit-based similarity searching method. After the yeast two-hybrid (Y2H) assay, six natural products were identified as FXR antagonists which blocked the CDCA-induced SRC-1 association. The IC50 values of compounds 2a, a diterpene bearing polycyclic skeleton, and 3a, named daphneone with chain scaffold, are as low as 1.29 μM and 1.79 μM, respectively. Compared to the control compound guggulsterone (IC50 = 6.47 μM), compounds 2a and 3a displayed 5-fold and 3-fold higher antagonistic activities against FXR, respectively. Remarkably, the two representative compounds shared low topological similarities with other reported FXR antagonists. According to the putative binding poses, the molecular basis of these antagonists against FXR was also elucidated in this report.

Rational approach to identify newer caspase-1 inhibitors using pharmacophore based virtual screening, docking and molecular dynamic simulation studies.

Science.gov (United States)

Patel, Shivani; Modi, Palmi; Chhabria, Mahesh

2018-05-01

Caspase-1 is a key endoprotease responsible for the post-translational processing of pro-inflammatory cytokines IL-1β, 18 & 33. Excessive secretion of IL-1β leads to numerous inflammatory and autoimmune diseases. Thus caspase-1 inhibition would be considered as an important therapeutic strategy for development of newer anti-inflammatory agents. Here we have employed an integrated virtual screening by combining pharmacophore mapping and docking to identify small molecules as caspase-1 inhibitors. The ligand based 3D pharmacophore model was generated having the essential structural features of (HBA, HY & RA) using a data set of 27 compounds. A validated pharmacophore hypothesis (Hypo 1) was used to screen ZINC and Minimaybridge chemical databases. The retrieved virtual hits were filtered by ADMET properties and molecular docking analysis. Subsequently, the cross-docking study was also carried out using crystal structure of caspase-1, 3, 7 and 8 to identify the key residual interaction for specific caspase-1 inhibition. Finally, the best mapped and top scored (ZINC00885612, ZINC72003647, BTB04175 and BTB04410) molecules were subjected to molecular dynamics simulation for accessing the dynamic structure of protein after ligand binding. This study identifies the most promising hits, which can be leads for the development of novel caspase-1 inhibitors as anti-inflammatory agents. Copyright © 2018 Elsevier Inc. All rights reserved.

CamMedNP: building the Cameroonian 3D structural natural products database for virtual screening.

Science.gov (United States)

Ntie-Kang, Fidele; Mbah, James A; Mbaze, Luc Meva'a; Lifongo, Lydia L; Scharfe, Michael; Hanna, Joelle Ngo; Cho-Ngwa, Fidelis; Onguéné, Pascal Amoa; Owono Owono, Luc C; Megnassan, Eugene; Sippl, Wolfgang; Efange, Simon M N

2013-04-16

Computer-aided drug design (CADD) often involves virtual screening (VS) of large compound datasets and the availability of such is vital for drug discovery protocols. We present CamMedNP - a new database beginning with more than 2,500 compounds of natural origin, along with some of their derivatives which were obtained through hemisynthesis. These are pure compounds which have been previously isolated and characterized using modern spectroscopic methods and published by several research teams spread across Cameroon. In the present study, 224 distinct medicinal plant species belonging to 55 plant families from the Cameroonian flora have been considered. About 80 % of these have been previously published and/or referenced in internationally recognized journals. For each compound, the optimized 3D structure, drug-like properties, plant source, collection site and currently known biological activities are given, as well as literature references. We have evaluated the "drug-likeness" of this database using Lipinski's "Rule of Five". A diversity analysis has been carried out in comparison with the ChemBridge diverse database. CamMedNP could be highly useful for database screening and natural product lead generation programs.

Identification of AI-2 Quorum Sensing Inhibitors in Vibrio harveyi Through Structure-Based Virtual Screening.

Science.gov (United States)

Jiang, Tianyu; Zhu, Peng; Du, Lupei; Li, Minyong

2018-01-01

Quorum sensing (QS) is a cell-to-cell communication system that regulates gene expression as a result of the production and perception of signal molecules called autoinducers (AIs). AI-2 is a QS autoinducer produced by both Gram-negative and Gram-positive bacteria, in which it regulates intraspecies and interspecies communication. The identification of QS inhibitors is considered a promising strategy for the development of anti-virulence drugs with reduced selective pressure for resistance. Here we describe a high-throughput virtual screening approach to identify AI-2 quorum sensing inhibitors on the basis of Vibrio harveyi LuxPQ crystal structure. Seven potent inhibitors with IC 50 values in the micromolar range were selected with no effect or low effect on V. harveyi growth rate.

Virtual Screening of Acetylcholinesterase Inhibitors Using the Lipinski’s Rule of Five and ZINC Databank

Directory of Open Access Journals (Sweden)

Pablo Andrei Nogara

2015-01-01

Full Text Available Alzheimer’s disease (AD is a progressive and neurodegenerative pathology that can affect people over 65 years of age. It causes several complications, such as behavioral changes, language deficits, depression, and memory impairments. One of the methods used to treat AD is the increase of acetylcholine (ACh in the brain by using acetylcholinesterase inhibitors (AChEIs. In this study, we used the ZINC databank and the Lipinski’s rule of five to perform a virtual screening and a molecular docking (using Auto Dock Vina 1.1.1 aiming to select possible compounds that have quaternary ammonium atom able to inhibit acetylcholinesterase (AChE activity. The molecules were obtained by screening and further in vitro assays were performed to analyze the most potent inhibitors through the IC50 value and also to describe the interaction models between inhibitors and enzyme by molecular docking. The results showed that compound D inhibited AChE activity from different vertebrate sources and butyrylcholinesterase (BChE from Equus ferus (EfBChE, with IC50 ranging from 1.69 ± 0.46 to 5.64 ± 2.47 µM. Compound D interacted with the peripheral anionic subsite in both enzymes, blocking substrate entrance to the active site. In contrast, compound C had higher specificity as inhibitor of EfBChE. In conclusion, the screening was effective in finding inhibitors of AChE and BuChE from different organisms.

SPOT-ligand 2: improving structure-based virtual screening by binding-homology search on an expanded structural template library.

Science.gov (United States)

Litfin, Thomas; Zhou, Yaoqi; Yang, Yuedong

2017-04-15

The high cost of drug discovery motivates the development of accurate virtual screening tools. Binding-homology, which takes advantage of known protein-ligand binding pairs, has emerged as a powerful discrimination technique. In order to exploit all available binding data, modelled structures of ligand-binding sequences may be used to create an expanded structural binding template library. SPOT-Ligand 2 has demonstrated significantly improved screening performance over its previous version by expanding the template library 15 times over the previous one. It also performed better than or similar to other binding-homology approaches on the DUD and DUD-E benchmarks. The server is available online at http://sparks-lab.org . yaoqi.zhou@griffith.edu.au or yuedong.yang@griffith.edu.au. Supplementary data are available at Bioinformatics online. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com

4D Flexible Atom-Pairs: An efficient probabilistic conformational space comparison for ligand-based virtual screening

Science.gov (United States)

2011-01-01

Background The performance of 3D-based virtual screening similarity functions is affected by the applied conformations of compounds. Therefore, the results of 3D approaches are often less robust than 2D approaches. The application of 3D methods on multiple conformer data sets normally reduces this weakness, but entails a significant computational overhead. Therefore, we developed a special conformational space encoding by means of Gaussian mixture models and a similarity function that operates on these models. The application of a model-based encoding allows an efficient comparison of the conformational space of compounds. Results Comparisons of our 4D flexible atom-pair approach with over 15 state-of-the-art 2D- and 3D-based virtual screening similarity functions on the 40 data sets of the Directory of Useful Decoys show a robust performance of our approach. Even 3D-based approaches that operate on multiple conformers yield inferior results. The 4D flexible atom-pair method achieves an averaged AUC value of 0.78 on the filtered Directory of Useful Decoys data sets. The best 2D- and 3D-based approaches of this study yield an AUC value of 0.74 and 0.72, respectively. As a result, the 4D flexible atom-pair approach achieves an average rank of 1.25 with respect to 15 other state-of-the-art similarity functions and four different evaluation metrics. Conclusions Our 4D method yields a robust performance on 40 pharmaceutically relevant targets. The conformational space encoding enables an efficient comparison of the conformational space. Therefore, the weakness of the 3D-based approaches on single conformations is circumvented. With over 100,000 similarity calculations on a single desktop CPU, the utilization of the 4D flexible atom-pair in real-world applications is feasible. PMID:21733172

Creating Virtual-hand and Virtual-face Illusions to Investigate Self-representation.

Science.gov (United States)

Ma, Ke; Lippelt, Dominique P; Hommel, Bernhard

2017-03-01

Studies investigating how people represent themselves and their own body often use variants of "ownership illusions", such as the traditional rubber-hand illusion or the more recently discovered enfacement illusion. However, these examples require rather artificial experimental setups, in which the artificial effector needs to be stroked in synchrony with the participants' real hand or face-a situation in which participants have no control over the stroking or the movements of their real or artificial effector. Here, we describe a technique to establish ownership illusions in a setup that is more realistic, more intuitive, and of presumably higher ecological validity. It allows creating the virtual-hand illusion by having participants control the movements of a virtual hand presented on a screen or in virtual space in front of them. If the virtual hand moves in synchrony with the participants' own real hand, they tend to perceive the virtual hand as part of their own body. The technique also creates the virtual-face illusion by having participants control the movements of a virtual face in front of them, again with the effect that they tend to perceive the face as their own if it moves in synchrony with their real face. Studying the circumstances that illusions of this sort can be created, increased, or reduced provides important information about how people create and maintain representations of themselves.

Machine Learning Consensus Scoring Improves Performance Across Targets in Structure-Based Virtual Screening.

Science.gov (United States)

Ericksen, Spencer S; Wu, Haozhen; Zhang, Huikun; Michael, Lauren A; Newton, Michael A; Hoffmann, F Michael; Wildman, Scott A

2017-07-24

In structure-based virtual screening, compound ranking through a consensus of scores from a variety of docking programs or scoring functions, rather than ranking by scores from a single program, provides better predictive performance and reduces target performance variability. Here we compare traditional consensus scoring methods with a novel, unsupervised gradient boosting approach. We also observed increased score variation among active ligands and developed a statistical mixture model consensus score based on combining score means and variances. To evaluate performance, we used the common performance metrics ROCAUC and EF1 on 21 benchmark targets from DUD-E. Traditional consensus methods, such as taking the mean of quantile normalized docking scores, outperformed individual docking methods and are more robust to target variation. The mixture model and gradient boosting provided further improvements over the traditional consensus methods. These methods are readily applicable to new targets in academic research and overcome the potentially poor performance of using a single docking method on a new target.

The role of affordances in children's learning performance and efficiency when using virtual manipulative mathematics touch-screen apps

Science.gov (United States)

Moyer-Packenham, Patricia S.; Bullock, Emma K.; Shumway, Jessica F.; Tucker, Stephen I.; Watts, Christina M.; Westenskow, Arla; Anderson-Pence, Katie L.; Maahs-Fladung, Cathy; Boyer-Thurgood, Jennifer; Gulkilik, Hilal; Jordan, Kerry

2016-03-01

This paper focuses on understanding the role that affordances played in children's learning performance and efficiency during clinical interviews of their interactions with mathematics apps on touch-screen devices. One hundred children, ages 3 to 8, each used six different virtual manipulative mathematics apps during 30-40-min interviews. The study used a convergent mixed methods design, in which quantitative and qualitative data were collected concurrently to answer the research questions (Creswell and Plano Clark 2011). Videos were used to capture each child's interactions with the virtual manipulative mathematics apps, document learning performance and efficiency, and record children's interactions with the affordances within the apps. Quantitized video data answered the research question on differences in children's learning performance and efficiency between pre- and post-assessments. A Wilcoxon matched pairs signed-rank test was used to explore these data. Qualitative video data was used to identify affordance access by children when using each app, identifying 95 potential helping and hindering affordances among the 18 apps. The results showed that there were changes in children's learning performance and efficiency when children accessed a helping or a hindering affordance. Helping affordances were more likely to be accessed by children who progressed between the pre- and post-assessments, and the same affordances had helping and hindering effects for different children. These results have important implications for the design of virtual manipulative mathematics learning apps.

Computed tomographic characteristics of interval and post screen carcinomas in lung cancer screening

International Nuclear Information System (INIS)

Scholten, Ernst T.; Horeweg, Nanda; Koning, Harry J. de; Vliegenthart, Rozemarijn; Oudkerk, Matthijs; Mali, Willem P.T.M.; Jong, Pim A. de

2015-01-01

To analyse computed tomography (CT) findings of interval and post-screen carcinomas in lung cancer screening. Consecutive interval and post-screen carcinomas from the Dutch-Belgium lung cancer screening trial were included. The prior screening and the diagnostic chest CT were reviewed by two experienced radiologists in consensus with knowledge of the tumour location on the diagnostic CT. Sixty-one participants (53 men) were diagnosed with an interval or post-screen carcinoma. Twenty-two (36 %) were in retrospect visible on the prior screening CT. Detection error occurred in 20 cancers and interpretation error in two cancers. Errors involved intrabronchial tumour (n = 5), bulla with wall thickening (n = 5), lymphadenopathy (n = 3), pleural effusion (n = 1) and intraparenchymal solid nodules (n = 8). These were missed because of a broad pleural attachment (n = 4), extensive reticulation surrounding a nodule (n = 1) and extensive scarring (n = 1). No definite explanation other than human error was found in two cases. None of the interval or post-screen carcinomas involved a subsolid nodule. Interval or post-screen carcinomas that were visible in retrospect were mostly due to detection errors of solid nodules, bulla wall thickening or endobronchial lesions. Interval or post-screen carcinomas without explanation other than human errors are rare. (orig.)

Computed tomographic characteristics of interval and post screen carcinomas in lung cancer screening

Energy Technology Data Exchange (ETDEWEB)

Scholten, Ernst T. [University Medical Centre, Department of Radiology, Utrecht (Netherlands); Kennemer Gasthuis, Department of Radiology, Haarlem (Netherlands); Horeweg, Nanda [Erasmus University Medical Centre, Department of Public Health, Rotterdam (Netherlands); Erasmus University Medical Centre, Department of Pulmonary Medicine, Rotterdam (Netherlands); Koning, Harry J. de [Erasmus University Medical Centre, Department of Public Health, Rotterdam (Netherlands); Vliegenthart, Rozemarijn [University of Groningen, University Medical Centre Groningen, Department of Radiology, Groningen (Netherlands); University of Groningen, University Medical Centre Groningen, Center for Medical Imaging-North East Netherlands, Groningen (Netherlands); Oudkerk, Matthijs [University of Groningen, University Medical Centre Groningen, Center for Medical Imaging-North East Netherlands, Groningen (Netherlands); Mali, Willem P.T.M.; Jong, Pim A. de [University Medical Centre, Department of Radiology, Utrecht (Netherlands)

2015-01-15

To analyse computed tomography (CT) findings of interval and post-screen carcinomas in lung cancer screening. Consecutive interval and post-screen carcinomas from the Dutch-Belgium lung cancer screening trial were included. The prior screening and the diagnostic chest CT were reviewed by two experienced radiologists in consensus with knowledge of the tumour location on the diagnostic CT. Sixty-one participants (53 men) were diagnosed with an interval or post-screen carcinoma. Twenty-two (36 %) were in retrospect visible on the prior screening CT. Detection error occurred in 20 cancers and interpretation error in two cancers. Errors involved intrabronchial tumour (n = 5), bulla with wall thickening (n = 5), lymphadenopathy (n = 3), pleural effusion (n = 1) and intraparenchymal solid nodules (n = 8). These were missed because of a broad pleural attachment (n = 4), extensive reticulation surrounding a nodule (n = 1) and extensive scarring (n = 1). No definite explanation other than human error was found in two cases. None of the interval or post-screen carcinomas involved a subsolid nodule. Interval or post-screen carcinomas that were visible in retrospect were mostly due to detection errors of solid nodules, bulla wall thickening or endobronchial lesions. Interval or post-screen carcinomas without explanation other than human errors are rare. (orig.)

A virtual high-throughput screening approach to the discovery of novel inhibitors of the bacterial leucine transporter, LeuT

DEFF Research Database (Denmark)

Simmons, Katie J; Gotfryd, Kamil; Billesbølle, Christian B

2013-01-01

Abstract Membrane proteins are intrinsically involved in both human and pathogen physiology, and are the target of 60% of all marketed drugs. During the past decade, advances in the studies of membrane proteins using X-ray crystallography, electron microscopy and NMR-based techniques led to the e...... this is a virtual high-throughput screening (vHTS) technique initially developed for soluble proteins. This paper describes application of this technique to the discovery of inhibitors of the leucine transporter (LeuT), a member of the neurotransmitter:sodium symporter (NSS) family....

Assessing adherence to accepted national guidelines for immigrant and refugee screening and vaccines in an urban primary care practice: a retrospective chart review.

Science.gov (United States)

Waldorf, Barbara; Gill, Christopher; Crosby, Sondra S

2014-10-01

In the United States, 38.5 million people are foreign-born, one in three arriving since 2000. Health issues include high rates of hepatitis B, humanimmunodeficiency virus infection, parasitic infections, and M. tuberculosis. We sought to determine rates of provider adherence to accepted national guidelines for immigrant and refugee health screening and vaccines done at the primary care clinics at Boston Medical Center. Randomized, retrospective chart review of foreign born patients in the primary care clinics. We found low screening and immunization rates that do not conform to CDC/ACIP guidelines. Only 43 % of immigrant patients had tuberculosis screening, 36 % were screened for HIV and hepatitis B, and 33 % received tetanus vaccinations. Organizational changes incorporating multi-disciplinary approaches such as creative use of nursing staff, protocols, standing orders, EMR reminders, and web based educational tools can contribute to better outcomes by identifying patients and improving utilization of guidelines.

Interval lung cancer after a negative CT screening examination: CT findings and outcomes in National Lung Screening Trial participants

International Nuclear Information System (INIS)

Gierada, David S.; Pinsky, Paul F.; Duan, Fenghai; Garg, Kavita; Hart, Eric M.; Kazerooni, Ella A.; Nath, Hrudaya; Watts, Jubal R.; Aberle, Denise R.

2017-01-01

This study retrospectively analyses the screening CT examinations and outcomes of the National Lung Screening Trial (NLST) participants who had interval lung cancer diagnosed within 1 year after a negative CT screen and before the next annual screen. The screening CTs of all 44 participants diagnosed with interval lung cancer (cases) were matched with negative CT screens of participants who did not develop lung cancer (controls). A majority consensus process was used to classify each CT screen as positive or negative according to the NLST criteria and to estimate the likelihood that any abnormalities detected retrospectively were due to lung cancer. By retrospective review, 40/44 cases (91%) and 17/44 controls (39%) met the NLST criteria for a positive screen (P < 0.001). Cases had higher estimated likelihood of lung cancer (P < 0.001). Abnormalities included pulmonary nodules ≥4 mm (n = 16), mediastinal (n = 8) and hilar (n = 6) masses, and bronchial lesions (n = 6). Cancers were stage III or IV at diagnosis in 32/44 cases (73%); 37/44 patients (84%) died of lung cancer, compared to 225/649 (35%) for all screen-detected cancers (P < 0.0001). Most cases met the NLST criteria for a positive screen. Awareness of missed abnormalities and interpretation errors may aid lung cancer identification in CT screening. (orig.)

Interval lung cancer after a negative CT screening examination: CT findings and outcomes in National Lung Screening Trial participants

Energy Technology Data Exchange (ETDEWEB)

Gierada, David S. [Washington University School of Medicine, Mallinckrodt Institute of Radiology, Box 8131, St. Louis, MO (United States); Pinsky, Paul F. [National Cancer Institute, Bethesda, MD (United States); Duan, Fenghai [Brown University School of Public Health, Department of Biostatistics and Center for Statistical Sciences, Providence, RI (United States); Garg, Kavita [University of Colorado School of Medicine, Mail Stop F726, Box 6510, Aurora, CO (United States); Hart, Eric M. [Northwestern University, Feinberg School of Medicine, Department of Radiology, Chicago, IL (United States); Kazerooni, Ella A. [University of Michigan Health System, Department of Radiology, Ann Arbor, MI (United States); Nath, Hrudaya; Watts, Jubal R. [University of Alabama at Birmingham School of Medicine, Department of Radiology-JTN370, Birmingham, AL (United States); Aberle, Denise R. [David Geffen School of Medicine at UCLA, Department of Radiological Sciences, Los Angeles, CA (United States)

2017-08-15

This study retrospectively analyses the screening CT examinations and outcomes of the National Lung Screening Trial (NLST) participants who had interval lung cancer diagnosed within 1 year after a negative CT screen and before the next annual screen. The screening CTs of all 44 participants diagnosed with interval lung cancer (cases) were matched with negative CT screens of participants who did not develop lung cancer (controls). A majority consensus process was used to classify each CT screen as positive or negative according to the NLST criteria and to estimate the likelihood that any abnormalities detected retrospectively were due to lung cancer. By retrospective review, 40/44 cases (91%) and 17/44 controls (39%) met the NLST criteria for a positive screen (P < 0.001). Cases had higher estimated likelihood of lung cancer (P < 0.001). Abnormalities included pulmonary nodules ≥4 mm (n = 16), mediastinal (n = 8) and hilar (n = 6) masses, and bronchial lesions (n = 6). Cancers were stage III or IV at diagnosis in 32/44 cases (73%); 37/44 patients (84%) died of lung cancer, compared to 225/649 (35%) for all screen-detected cancers (P < 0.0001). Most cases met the NLST criteria for a positive screen. Awareness of missed abnormalities and interpretation errors may aid lung cancer identification in CT screening. (orig.)

Binding-site assessment by virtual fragment screening.

Directory of Open Access Journals (Sweden)

Niu Huang

2010-04-01

Full Text Available The accurate prediction of protein druggability (propensity to bind high-affinity drug-like small molecules would greatly benefit the fields of chemical genomics and drug discovery. We have developed a novel approach to quantitatively assess protein druggability by computationally screening a fragment-like compound library. In analogy to NMR-based fragment screening, we dock approximately 11,000 fragments against a given binding site and compute a computational hit rate based on the fraction of molecules that exceed an empirically chosen score cutoff. We perform a large-scale evaluation of the approach on four datasets, totaling 152 binding sites. We demonstrate that computed hit rates correlate with hit rates measured experimentally in a previously published NMR-based screening method. Secondly, we show that the in silico fragment screening method can be used to distinguish known druggable and non-druggable targets, including both enzymes and protein-protein interaction sites. Finally, we explore the sensitivity of the results to different receptor conformations, including flexible protein-protein interaction sites. Besides its original aim to assess druggability of different protein targets, this method could be used to identifying druggable conformations of flexible binding site for lead discovery, and suggesting strategies for growing or joining initial fragment hits to obtain more potent inhibitors.

Bioprospecting of Thermostable Cellulolytic Enzymes through Modeling and Virtual Screening Method

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R. Navanietha Krishnaraj

2017-04-01

Full Text Available Cellulolytic enzymes are promising candidates for the use of cellulose in any bioprocess operations and for the disposal of the cellulosic wastes in an environmentally benign manner. Cellulases from thermophiles have the advantage of hydrolyzing cellulose at wider range of operating conditions unlike the normal enzymes. Herein we report the modeled structures of cellulolytic enzymes (endoglucanase, cellobiohydrolase and ß-glucosidase from a thermophilic bacterium,Clostridium thermocellumand their validation using Root Mean Square Deviation (RMSD and Ramachandran plot analyses. Further, the molecular interactions of the modeled enzyme with cellulose were analyzed using molecular docking technique. The results of molecular docking showed that the endoglucanase, cellobiohydrolase and ß-glucosidase had the binding affinities of -10.7, -9.0 and -10.8 kcal/mol, respectively. A correlation between the binding affinity of the endoglucanase with cellulose and the enzyme activity was also demonstrated. The results showed that the binding affinities of cellulases with cellulose could be used as a tool to assess the hydrolytic activity of cellulases. The results obtained could be used in virtual screening of cellulolytic enzymes based on the molecular interactions with the substrate, and aid in developing systems biology models of thermophiles for industrial biotechnology applications.

Identification of Potent Chloride Intracellular Channel Protein 1 Inhibitors from Traditional Chinese Medicine through Structure-Based Virtual Screening and Molecular Dynamics Analysis

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Wei Wang

2017-01-01

Full Text Available Chloride intracellular channel 1 (CLIC1 is involved in the development of most aggressive human tumors, including gastric, colon, lung, liver, and glioblastoma cancers. It has become an attractive new therapeutic target for several types of cancer. In this work, we aim to identify natural products as potent CLIC1 inhibitors from Traditional Chinese Medicine (TCM database using structure-based virtual screening and molecular dynamics (MD simulation. First, structure-based docking was employed to screen the refined TCM database and the top 500 TCM compounds were obtained and reranked by X-Score. Then, 30 potent hits were achieved from the top 500 TCM compounds using cluster and ligand-protein interaction analysis. Finally, MD simulation was employed to validate the stability of interactions between each hit and CLIC1 protein from docking simulation, and Molecular Mechanics/Generalized Born Surface Area (MM-GBSA analysis was used to refine the virtual hits. Six TCM compounds with top MM-GBSA scores and ideal-binding models were confirmed as the final hits. Our study provides information about the interaction between TCM compounds and CLIC1 protein, which may be helpful for further experimental investigations. In addition, the top 6 natural products structural scaffolds could serve as building blocks in designing drug-like molecules for CLIC1 inhibition.

CycloPs: generating virtual libraries of cyclized and constrained peptides including nonnatural amino acids.

Science.gov (United States)

Duffy, Fergal J; Verniere, Mélanie; Devocelle, Marc; Bernard, Elise; Shields, Denis C; Chubb, Anthony J

2011-04-25

We introduce CycloPs, software for the generation of virtual libraries of constrained peptides including natural and nonnatural commercially available amino acids. The software is written in the cross-platform Python programming language, and features include generating virtual libraries in one-dimensional SMILES and three-dimensional SDF formats, suitable for virtual screening. The stand-alone software is capable of filtering the virtual libraries using empirical measurements, including peptide synthesizability by standard peptide synthesis techniques, stability, and the druglike properties of the peptide. The software and accompanying Web interface is designed to enable the rapid generation of large, structurally diverse, synthesizable virtual libraries of constrained peptides quickly and conveniently, for use in virtual screening experiments. The stand-alone software, and the Web interface for evaluating these empirical properties of a single peptide, are available at http://bioware.ucd.ie .

Efficacy of routine pre-radiation dental screening and dental follow-up in head and neck oncology patients on intermediate and late radiation effects. A retrospective evaluation

NARCIS (Netherlands)

Schuurhuis, Jennifer M.; Stokman, Monique A.; Roodenburg, Johannes L. N.; Reintsema, Harry; Langendijk, Johannes A.; Vissink, Arjan; Spijkervet, Frederik K. L.

2011-01-01

Background and purpose: Head-neck radiotherapy is accompanied by a life-long risk of developing severe oral problems. This study retrospectively assessed oral foci detected during pre-radiation dental screening and follow-up in order to assess risk factors for developing oral problems after

Molecular structures enumeration and virtual screening in the chemical space with RetroPath2.0.

Science.gov (United States)

Koch, Mathilde; Duigou, Thomas; Carbonell, Pablo; Faulon, Jean-Loup

2017-12-19

Network generation tools coupled with chemical reaction rules have been mainly developed for synthesis planning and more recently for metabolic engineering. Using the same core algorithm, these tools apply a set of rules to a source set of compounds, stopping when a sink set of compounds has been produced. When using the appropriate sink, source and rules, this core algorithm can be used for a variety of applications beyond those it has been developed for. Here, we showcase the use of the open source workflow RetroPath2.0. First, we mathematically prove that we can generate all structural isomers of a molecule using a reduced set of reaction rules. We then use this enumeration strategy to screen the chemical space around a set of monomers and predict their glass transition temperatures, as well as around aminoglycosides to search structures maximizing antibacterial activity. We also perform a screening around aminoglycosides with enzymatic reaction rules to ensure biosynthetic accessibility. We finally use our workflow on an E. coli model to complete E. coli metabolome, with novel molecules generated using promiscuous enzymatic reaction rules. These novel molecules are searched on the MS spectra of an E. coli cell lysate interfacing our workflow with OpenMS through the KNIME Analytics Platform. We provide an easy to use and modify, modular, and open-source workflow. We demonstrate its versatility through a variety of use cases including molecular structure enumeration, virtual screening in the chemical space, and metabolome completion. Because it is open source and freely available on MyExperiment.org, workflow community contributions should likely expand further the features of the tool, even beyond the use cases presented in the paper.

Combinatorial support vector machines approach for virtual screening of selective multi-target serotonin reuptake inhibitors from large compound libraries.

Science.gov (United States)

Shi, Z; Ma, X H; Qin, C; Jia, J; Jiang, Y Y; Tan, C Y; Chen, Y Z

2012-02-01

Selective multi-target serotonin reuptake inhibitors enhance antidepressant efficacy. Their discovery can be facilitated by multiple methods, including in silico ones. In this study, we developed and tested an in silico method, combinatorial support vector machines (COMBI-SVMs), for virtual screening (VS) multi-target serotonin reuptake inhibitors of seven target pairs (serotonin transporter paired with noradrenaline transporter, H(3) receptor, 5-HT(1A) receptor, 5-HT(1B) receptor, 5-HT(2C) receptor, melanocortin 4 receptor and neurokinin 1 receptor respectively) from large compound libraries. COMBI-SVMs trained with 917-1951 individual target inhibitors correctly identified 22-83.3% (majority >31.1%) of the 6-216 dual inhibitors collected from literature as independent testing sets. COMBI-SVMs showed moderate to good target selectivity in misclassifying as dual inhibitors 2.2-29.8% (majority virtual hits correlate with the reported effects of their predicted targets. COMBI-SVM is potentially useful for searching selective multi-target agents without explicit knowledge of these agents. Copyright © 2011 Elsevier Inc. All rights reserved.

A virtual reality test battery for assessment and screening of spatial neglect.

Science.gov (United States)

Fordell, H; Bodin, K; Bucht, G; Malm, J

2011-03-01

There is a need for improved screening methods for spatial neglect. To construct a VR-test battery and evaluate its accuracy and usability in patients with acute stroke. VR-DiSTRO consists of a standard desktop computer, a CRT monitor and eye shutter stereoscopic glasses, a force feedback interface, and software, developed to create an interactive and immersive 3D experience. VR-tests were developed and validated to the conventional Star Cancellation test, Line bisection, Baking Tray Task (BTT), and Visual Extinction test. A construct validation to The Rivermead Behavioral Inattention Test, used as criterion of visuospatial neglect, was made. Usability was assessed according to ISO 9241-11. Thirty-one patients with stroke were included, 9/31 patients had neglect. The sensitivity was 100% and the specificity 82% for the VR-DiSTRO to correctly identify neglect. VR-BTT and VR-Extinction had the highest correlation (r² = 0.64 and 0.78), as well as high sensitivity and specificity. The kappa values describing the agreement between traditional neglect tests and the corresponding virtual reality test were between 0.47-0.85. Usability was assessed by a questionnaire; 77% reported that the VR-DiSTRO was 'easy' to use. Eighty-eight percent reported that they felt 'focused', 'pleased' or 'alert'. No patient had adverse symptoms. The test session took 15 min. The VR-DiSTRO quickly and with a high accuracy identified visuospatial neglect in patients with stroke in this construct validation. The usability among elderly patients with stroke was high. This VR-test battery has the potential to become an important screening instrument for neglect and a valuable adjunct to the neuropsychological assessment. © 2010 John Wiley & Sons A/S.

Risk prediction models for selection of lung cancer screening candidates: A retrospective validation study.

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Kevin Ten Haaf

2017-04-01

Full Text Available Selection of candidates for lung cancer screening based on individual risk has been proposed as an alternative to criteria based on age and cumulative smoking exposure (pack-years. Nine previously established risk models were assessed for their ability to identify those most likely to develop or die from lung cancer. All models considered age and various aspects of smoking exposure (smoking status, smoking duration, cigarettes per day, pack-years smoked, time since smoking cessation as risk predictors. In addition, some models considered factors such as gender, race, ethnicity, education, body mass index, chronic obstructive pulmonary disease, emphysema, personal history of cancer, personal history of pneumonia, and family history of lung cancer.Retrospective analyses were performed on 53,452 National Lung Screening Trial (NLST participants (1,925 lung cancer cases and 884 lung cancer deaths and 80,672 Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO ever-smoking participants (1,463 lung cancer cases and 915 lung cancer deaths. Six-year lung cancer incidence and mortality risk predictions were assessed for (1 calibration (graphically by comparing the agreement between the predicted and the observed risks, (2 discrimination (area under the receiver operating characteristic curve [AUC] between individuals with and without lung cancer (death, and (3 clinical usefulness (net benefit in decision curve analysis by identifying risk thresholds at which applying risk-based eligibility would improve lung cancer screening efficacy. To further assess performance, risk model sensitivities and specificities in the PLCO were compared to those based on the NLST eligibility criteria. Calibration was satisfactory, but discrimination ranged widely (AUCs from 0.61 to 0.81. The models outperformed the NLST eligibility criteria over a substantial range of risk thresholds in decision curve analysis, with a higher sensitivity for all models and a

Economic evaluation of the breast cancer screening programme in the Basque Country: retrospective cost-effectiveness and budget impact analysis.

Science.gov (United States)

Arrospide, Arantzazu; Rue, Montserrat; van Ravesteyn, Nicolien T; Comas, Merce; Soto-Gordoa, Myriam; Sarriugarte, Garbiñe; Mar, Javier

2016-06-01

Breast cancer screening in the Basque Country has shown 20 % reduction of the number of BC deaths and an acceptable overdiagnosis level (4 % of screen detected BC). The aim of this study was to evaluate the breast cancer early detection programme in the Basque Country in terms of retrospective cost-effectiveness and budget impact from 1996 to 2011. A discrete event simulation model was built to reproduce the natural history of breast cancer (BC). We estimated for lifetime follow-up the total cost of BC (screening, diagnosis and treatment), as well as quality-adjusted life years (QALY), for women invited to participate in the evaluated programme during the 15-year period in the actual screening scenario and in a hypothetical unscreened scenario. An incremental cost-effectiveness ratio was calculated with the use of aggregated costs. Besides, annual costs were considered for budget impact analysis. Both population level and single-cohort analysis were performed. A probabilistic sensitivity analysis was applied to assess the impact of parameters uncertainty. The actual screening programme involved a cost of 1,127 million euros and provided 6.7 million QALYs over the lifetime of the target population, resulting in a gain of 8,666 QALYs for an additional cost of 36.4 million euros, compared with the unscreened scenario. Thus, the incremental cost-effectiveness ratio was 4,214€/QALY. All the model runs in the probabilistic sensitivity analysis resulted in an incremental cost-effectiveness ratio lower than 10,000€/QALY. The screening programme involved an increase of the annual budget of the Basque Health Service by 5.2 million euros from year 2000 onwards. The BC screening programme in the Basque Country proved to be cost-effective during the evaluated period and determined an affordable budget impact. These results confirm the epidemiological benefits related to the centralised screening system and support the continuation of the programme.

A novel anti-tumor inhibitor identified by virtual screen with PLK1 structure and zebrafish assay.

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Jing Lu

Full Text Available Polo-like kinase 1 (PLK1, one of the key regulators of mitosis, is a target for cancer therapy due to its abnormally high activity in several tumors. Plk1 is highly conserved and shares a nearly identical 3-D structure between zebrafish and humans. The initial 10 mitoses of zebrafish embryonic cleavages occur every∼30 minutes, and therefore provide a rapid assay to evaluate mitosis inhibitors including those targeting Plk1. To increase efficiency and specificity, we first performed a computational virtual screen of∼60000 compounds against the human Plk1 3-D structure docked to both its kinase and Polo box domain. 370 candidates with the top free-energy scores were subjected to zebrafish assay and 3 were shown to inhibit cell division. Compared to general screen for compounds inhibiting zebrafish embryonic cleavage, computation increased the efficiency by 11 folds. One of the 3 compounds, named I2, was further demonstrated to effectively inhibit multiple tumor cell proliferation in vitro and PC3 prostate cancer growth in Xenograft mouse model in vivo. Furthermore, I2 inhibited Plk1 enzyme activity in a dose dependent manner. The IC50 values of I2 in these assays are compatible to those of ON-01910, a Plk1 inhibitor currently in Phase III clinic trials. Our studies demonstrate that zebrafish assays coupled with computational screening significantly improves the efficiency of identifying specific regulators of biological targets. The PLK1 inhibitor I2, and its analogs, may have potential in cancer therapeutics.

Poster: Virtual reality interaction using mobile devices

KAUST Repository

Aseeri, Sahar A.

2013-03-01

In this work we aim to implement and evaluate alternative approaches for interacting with virtual environments on mobile devices for navigation, object selection and manipulation. Interaction with objects in virtual worlds using traditional input such as current state-of-the-art devices is often difficult and could diminish the immersion and sense of presence when it comes to 3D virtual environment tasks. We have developed new methods to perform different kinds of interactions using a mobile device (e.g. a smartphone) both as input device, performing selection and manipulation of objects, and as output device, utilizing the screen as an extra view (virtual camera or information display). Our hypothesis is that interaction via mobile devices facilitates simple tasks like the ones described within immersive virtual reality systems. We present here our initial implementation and result. © 2013 IEEE.

Stepwise high-throughput virtual screening of Rho kinase inhibitors from natural product library and potential therapeutics for pulmonary hypertension.

Science.gov (United States)

Su, Hao; Yan, Ji; Xu, Jian; Fan, Xi-Zhen; Sun, Xian-Lin; Chen, Kang-Yu

2015-08-01

Pulmonary hypertension (PH) is a devastating disease characterized by progressive elevation of pulmonary arterial pressure and vascular resistance due to pulmonary vasoconstriction and vessel remodeling. The activation of RhoA/Rho-kinase (ROCK) pathway plays a central role in the pathologic progression of PH and thus the Rho kinase, an essential effector of the ROCK pathway, is considered as a potential therapeutic target to attenuate PH. In the current study, a synthetic pipeline is used to discover new potent Rho inhibitors from various natural products. In the pipeline, the stepwise high-throughput virtual screening, quantitative structure-activity relationship (QSAR)-based rescoring, and kinase assay were integrated. The screening was performed against a structurally diverse, drug-like natural product library, from which six identified compounds were tested to determine their inhibitory potencies agonist Rho by using a standard kinase assay protocol. With this scheme, we successfully identified two potent Rho inhibitors, namely phloretin and baicalein, with activity values of IC50 = 0.22 and 0.95 μM, respectively. Structural examination suggested that complicated networks of non-bonded interactions such as hydrogen bonding, hydrophobic forces, and van der Waals contacts across the complex interfaces of Rho kinase are formed with the screened compounds.

Manually locating physical and virtual reality objects.

Science.gov (United States)

Chen, Karen B; Kimmel, Ryan A; Bartholomew, Aaron; Ponto, Kevin; Gleicher, Michael L; Radwin, Robert G

2014-09-01

In this study, we compared how users locate physical and equivalent three-dimensional images of virtual objects in a cave automatic virtual environment (CAVE) using the hand to examine how human performance (accuracy, time, and approach) is affected by object size, location, and distance. Virtual reality (VR) offers the promise to flexibly simulate arbitrary environments for studying human performance. Previously, VR researchers primarily considered differences between virtual and physical distance estimation rather than reaching for close-up objects. Fourteen participants completed manual targeting tasks that involved reaching for corners on equivalent physical and virtual boxes of three different sizes. Predicted errors were calculated from a geometric model based on user interpupillary distance, eye location, distance from the eyes to the projector screen, and object. Users were 1.64 times less accurate (p virtual versus physical box corners using the hands. Predicted virtual targeting errors were on average 1.53 times (p virtual targets but not significantly different for close-up virtual targets. Target size, location, and distance, in addition to binocular disparity, affected virtual object targeting inaccuracy. Observed virtual box inaccuracy was less than predicted for farther locations, suggesting possible influence of cues other than binocular vision. Human physical interaction with objects in VR for simulation, training, and prototyping involving reaching and manually handling virtual objects in a CAVE are more accurate than predicted when locating farther objects.

Mobile Screens: The Visual Regime of Navigation

NARCIS (Netherlands)

Verhoeff, N.

2012-01-01

In this book on screen media, space, and mobility I compare synchronically, as well as diachronically, diverse and variegated screen media - their technologies and practices – as sites for virtual mobility and navigation. Mobility as a central trope can be found on the multiple levels that are

Pharmacophore-based virtual screening, molecular docking, molecular dynamics simulation, and biological evaluation for the discovery of novel BRD4 inhibitors.

Science.gov (United States)

Yan, Guoyi; Hou, Manzhou; Luo, Jiang; Pu, Chunlan; Hou, Xueyan; Lan, Suke; Li, Rui

2018-02-01

Bromodomain is a recognition module in the signal transduction of acetylated histone. BRD4, one of the bromodomain members, is emerging as an attractive therapeutic target for several types of cancer. Therefore, in this study, an attempt has been made to screen compounds from an integrated database containing 5.5 million compounds for BRD4 inhibitors using pharmacophore-based virtual screening, molecular docking, and molecular dynamics simulations. As a result, two molecules of twelve hits were found to be active in bioactivity tests. Among the molecules, compound 5 exhibited potent anticancer activity, and the IC 50 values against human cancer cell lines MV4-11, A375, and HeLa were 4.2, 7.1, and 11.6 μm, respectively. After that, colony formation assay, cell cycle, apoptosis analysis, wound-healing migration assay, and Western blotting were carried out to learn the bioactivity of compound 5. © 2017 John Wiley & Sons A/S.

Shattering the Screen: Embodied Narrative in Digital Media

Directory of Open Access Journals (Sweden)

Russell J. Cook

2017-03-01

Full Text Available This illustrated phenomenological inquiry into storytelling in screen media identifies important media transformations of experience. Viewers embody, or situate their experienced selves, according to screen requirements. A viewer’s compelled perspective on the screen causes fundamental spatio-temporal transformations of narrative experience, including horizontal stretching of screen space and time compression or leakage. Virtual media have the potential, as yet unrealized, to break out of the screen and to restore narrative to its primordial, experiential roots.

Identification of STAT1 and STAT3 specific inhibitors using comparative virtual screening and docking validation.

Directory of Open Access Journals (Sweden)

Malgorzata Szelag

Full Text Available Signal transducers and activators of transcription (STATs facilitate action of cytokines, growth factors and pathogens. STAT activation is mediated by a highly conserved SH2 domain, which interacts with phosphotyrosine motifs for specific STAT-receptor contacts and STAT dimerization. The active dimers induce gene transcription in the nucleus by binding to a specific DNA-response element in the promoter of target genes. Abnormal activation of STAT signaling pathways is implicated in many human diseases, like cancer, inflammation and auto-immunity. Searches for STAT-targeting compounds, exploring the phosphotyrosine (pTyr-SH2 interaction site, yielded many small molecules for STAT3 but sparsely for other STATs. However, many of these inhibitors seem not STAT3-specific, thereby questioning the present modeling and selection strategies of SH2 domain-based STAT inhibitors. We generated new 3D structure models for all human (hSTATs and developed a comparative in silico docking strategy to obtain further insight into STAT-SH2 cross-binding specificity of a selection of previously identified STAT3 inhibitors. Indeed, by primarily targeting the highly conserved pTyr-SH2 binding pocket the majority of these compounds exhibited similar binding affinity and tendency scores for all STATs. By comparative screening of a natural product library we provided initial proof for the possibility to identify STAT1 as well as STAT3-specific inhibitors, introducing the 'STAT-comparative binding affinity value' and 'ligand binding pose variation' as selection criteria. In silico screening of a multi-million clean leads (CL compound library for binding of all STATs, likewise identified potential specific inhibitors for STAT1 and STAT3 after docking validation. Based on comparative virtual screening and docking validation, we developed a novel STAT inhibitor screening tool that allows identification of specific STAT1 and STAT3 inhibitory compounds. This could increase our

Virtual reality boosts performance at AREVA Projects

International Nuclear Information System (INIS)

Bernasconi, F.

2017-01-01

AREVA Projects is one of the 6 business units of New AREVA and it is dedicated to engineering works in a vast fan of activities from mining to waste management via uranium chemistry and nuclear fuel recycling. AREVA projects has opted for innovation to improve performance. Since 2012 virtual reality has been used through the creation of a room equipped with a high-definition screen and stereoscopic goggles. At the beginning virtual reality was used to test and validate procedures for handling equipment thanks to a dynamical digital simulation of this equipment. Now virtual reality is massively used to validate the design phase of projects without having to fabricate a physical mock-up which saves time. The next step in the use of virtual reality is the implementation of a new version of devices like helmets, gloves... that will allow a better interaction with the virtual world. The continuously increasing of computer power is always pushing back the limits of what is possible in virtual reality. (A.C.)

[Virtual microscopy in pathology teaching and postgraduate training (continuing education)].

Science.gov (United States)

Sinn, H P; Andrulis, M; Mogler, C; Schirmacher, P

2008-11-01

As with conventional microscopy, virtual microscopy permits histological tissue sections to be viewed on a computer screen with a free choice of viewing areas and a wide range of magnifications. This, combined with the possibility of linking virtual microscopy to E-Learning courses, make virtual microscopy an ideal tool for teaching and postgraduate training in pathology. Uses of virtual microscopy in pathology teaching include blended learning with the presentation of digital teaching slides in the internet parallel to presentation in the histology lab, extending student access to histology slides beyond the lab. Other uses are student self-learning in the Internet, as well as the presentation of virtual slides in the classroom with or without replacing real microscopes. Successful integration of virtual microscopy depends on its embedding in the virtual classroom and the creation of interactive E-learning content. Applications derived from this include the use of virtual microscopy in video clips, podcasts, SCORM modules and the presentation of virtual microscopy using interactive whiteboards in the classroom.

Cognitive evaluation for the diagnosis of Alzheimer's disease based on Turing Test and Virtual Environments.

Science.gov (United States)

Fernandez Montenegro, Juan Manuel; Argyriou, Vasileios

2017-05-01

Alzheimer's screening tests are commonly used by doctors to diagnose the patient's condition and stage as early as possible. Most of these tests are based on pen-paper interaction and do not embrace the advantages provided by new technologies. This paper proposes novel Alzheimer's screening tests based on virtual environments and game principles using new immersive technologies combined with advanced Human Computer Interaction (HCI) systems. These new tests are focused on the immersion of the patient in a virtual room, in order to mislead and deceive the patient's mind. In addition, we propose two novel variations of Turing Test proposed by Alan Turing as a method to detect dementia. As a result, four tests are introduced demonstrating the wide range of screening mechanisms that could be designed using virtual environments and game concepts. The proposed tests are focused on the evaluation of memory loss related to common objects, recent conversations and events; the diagnosis of problems in expressing and understanding language; the ability to recognize abnormalities; and to differentiate between virtual worlds and reality, or humans and machines. The proposed screening tests were evaluated and tested using both patients and healthy adults in a comparative study with state-of-the-art Alzheimer's screening tests. The results show the capacity of the new tests to distinguish healthy people from Alzheimer's patients. Copyright © 2017. Published by Elsevier Inc.

Post-mortem virtual estimation of free abdominal blood volume

International Nuclear Information System (INIS)

Ampanozi, Garyfalia; Hatch, Gary M.; Ruder, Thomas D.; Flach, Patricia M.; Germerott, Tanja; Thali, Michael J.; Ebert, Lars C.

2012-01-01

Purpose: The purpose of this retrospective study was to examine the reliability of virtually estimated abdominal blood volume using segmentation from postmortem computed tomography (PMCT) data. Materials and methods: Twenty-one cases with free abdominal blood were investigated by PMCT and autopsy. The volume of the blood was estimated using a manual segmentation technique (Amira, Visage Imaging, Germany) and the results were compared to autopsy data. Six of 21 cases had undergone additional post-mortem computed tomographic angiography (PMCTA). Results: The virtually estimated abdominal blood volumes did not differ significantly from those measured at autopsy. Additional PMCTA did not bias data significantly. Conclusion: Virtual estimation of abdominal blood volume is a reliable technique. The virtual blood volume estimation is a useful tool to deliver additional information in cases where autopsy is not performed or in cases where a postmortem angiography is performed

Virtual reality and laparoscopic surgery.

Science.gov (United States)

Coleman, J; Nduka, C C; Darzi, A

1994-12-01

The nature of laparoscopic surgery makes it likely to benefit from current and future developments in virtual reality and telepresence technology. High-definition screens, three-dimensional sensory feedback and remote dextrous manipulation will be the next major developments in laparoscopic surgery. Simulators may be used in surgical training and in the evaluation of surgical capability.

Virtual screening of natural inhibitors to the predicted HBx protein structure of Hepatitis B Virus using molecular docking for identification of potential lead molecules for liver cancer

Science.gov (United States)

Pathak, Rajesh Kumar; Baunthiyal, Mamta; Taj, Gohar; Kumar, Anil

2014-01-01

The HBx protein in Hepatitis B Virus (HBV) is a potential target for anti-liver cancer molecules. Therefore, it is of interest to screen known natural compounds against the HBx protein using molecular docking. However, the structure of HBx is not yet known. Therefore, the predicted structure of HBx using threading in LOMET was used for docking against plant derived natural compounds (curcumin, oleanolic acid, resveratrol, bilobetin, luteoline, ellagic acid, betulinic acid and rutin) by Molegro Virtual Docker. The screening identified rutin with binding energy of -161.65 Kcal/mol. Thus, twenty derivatives of rutin were further designed and screened against HBx. These in silico experiments identified compounds rutin01 (-163.16 Kcal/mol) and rutin08 (- 165.76 Kcal/mol) for further consideration and downstream validation. PMID:25187683

Missing depth cues in virtual reality limit performance and quality of three dimensional reaching movements.

Science.gov (United States)

Gerig, Nicolas; Mayo, Johnathan; Baur, Kilian; Wittmann, Frieder; Riener, Robert; Wolf, Peter

2018-01-01

Goal-directed reaching for real-world objects by humans is enabled through visual depth cues. In virtual environments, the number and quality of available visual depth cues is limited, which may affect reaching performance and quality of reaching movements. We assessed three-dimensional reaching movements in five experimental groups each with ten healthy volunteers. Three groups used a two-dimensional computer screen and two groups used a head-mounted display. The first screen group received the typically recreated visual depth cues, such as aerial and linear perspective, occlusion, shadows, and texture gradients. The second screen group received an abstract minimal rendering lacking those. The third screen group received the cues of the first screen group and absolute depth cues enabled by retinal image size of a known object, which realized with visual renderings of the handheld device and a ghost handheld at the target location. The two head-mounted display groups received the same virtually recreated visual depth cues as the second or the third screen group respectively. Additionally, they could rely on stereopsis and motion parallax due to head-movements. All groups using the screen performed significantly worse than both groups using the head-mounted display in terms of completion time normalized by the straight-line distance to the target. Both groups using the head-mounted display achieved the optimal minimum in number of speed peaks and in hand path ratio, indicating that our subjects performed natural movements when using a head-mounted display. Virtually recreated visual depth cues had a minor impact on reaching performance. Only the screen group with rendered handhelds could outperform the other screen groups. Thus, if reaching performance in virtual environments is in the main scope of a study, we suggest applying a head-mounted display. Otherwise, when two-dimensional screens are used, achievable performance is likely limited by the reduced depth

Virtual Mirror gaming in libraries

NARCIS (Netherlands)

Speelman, M.; Kröse, B.; Nijholt, A.; Poppe, R.

2008-01-01

This paper presents a study on a natural interface game in the context of a library. We developed a camera-based Virtual Mirror (VM) game, in which the player can see himself on the screen as if he looks at a mirror image. We present an overview of the different aspects of VM games and technologies

Virtual Reality: Is It Real Or Not?

Directory of Open Access Journals (Sweden)

S. Serap Kurbanoğlu

1996-01-01

Full Text Available In this paper virtual reality technology and how libraries might be affected by this technology are examined. Virtual reality sets out to address a problem. The problem is that of user-friendliness of computer systems. Needless to say, the current generation of computers still involves a barrier between human and machine. This is keyboard or mouse on the human side, and the screen on the computer side. If computers are really going to become a part of everyone’s normal day to day experiences, they, must allow users to visualise information in a way familiar to them, not the way the computers forces them to. Virtual reality provides such a way. With the increasing amounts of information available in electronic form, it is clear that virtual reality technology will have a profound impact on libraries.

Virtual screening using combinatorial cyclic peptide libraries reveals protein interfaces readily targetable by cyclic peptides.

Science.gov (United States)

Duffy, Fergal J; O'Donovan, Darragh; Devocelle, Marc; Moran, Niamh; O'Connell, David J; Shields, Denis C

2015-03-23

Protein-protein and protein-peptide interactions are responsible for the vast majority of biological functions in vivo, but targeting these interactions with small molecules has historically been difficult. What is required are efficient combined computational and experimental screening methods to choose among a number of potential protein interfaces worthy of targeting lead macrocyclic compounds for further investigation. To achieve this, we have generated combinatorial 3D virtual libraries of short disulfide-bonded peptides and compared them to pharmacophore models of important protein-protein and protein-peptide structures, including short linear motifs (SLiMs), protein-binding peptides, and turn structures at protein-protein interfaces, built from 3D models available in the Protein Data Bank. We prepared a total of 372 reference pharmacophores, which were matched against 108,659 multiconformer cyclic peptides. After normalization to exclude nonspecific cyclic peptides, the top hits notably are enriched for mimetics of turn structures, including a turn at the interaction surface of human α thrombin, and also feature several protein-binding peptides. The top cyclic peptide hits also cover the critical "hot spot" interaction sites predicted from the interaction crystal structure. We have validated our method by testing cyclic peptides predicted to inhibit thrombin, a key protein in the blood coagulation pathway of important therapeutic interest, identifying a cyclic peptide inhibitor with lead-like activity. We conclude that protein interfaces most readily targetable by cyclic peptides and related macrocyclic drugs may be identified computationally among a set of candidate interfaces, accelerating the choice of interfaces against which lead compounds may be screened.

The Virtual and the Real in Planning and Urban Design: Perspectives, Practices and Applications

NARCIS (Netherlands)

Yamu, Claudia; Poplin, Alenka; Devisch, Oswald; de Roo, Gert

2018-01-01

The Virtual and the Real: Perspectives, Practices and Applications for the Built Environment explores the merging relationship between physical and virtual spaces in planning and urban design. Technological advances such as smart sensors, interactive screens, locative media and evolving computation

Glenn Reconfigurable User-interface and Virtual reality Exploration (GURVE) Laboratory

Data.gov (United States)

Federal Laboratory Consortium — The GRUVE (Glenn Reconfigurable User-interface and Virtual reality Exploration) Lab is a reconfigurable, large screen display facility at Nasa Glenn Research Center....

Modeling of luminance distribution in CAVE-type virtual reality systems

Science.gov (United States)

Meironke, Michał; Mazikowski, Adam

2017-08-01

At present, one of the most advanced virtual reality systems are CAVE-type (Cave Automatic Virtual Environment) installations. Such systems are usually consisted of four, five or six projection screens and in case of six screens arranged in form of a cube. Providing the user with a high level of immersion feeling in such systems is largely dependent of optical properties of the system. The modeling of physical phenomena plays nowadays a huge role in the most fields of science and technology. It allows to simulate work of device without a need to make any changes in the physical constructions. In this paper distribution of luminance in CAVE-type virtual reality systems were modelled. Calculations were performed for the model of 6-walled CAVE-type installation, based on Immersive 3D Visualization Laboratory, situated at the Faculty of Electronics, Telecommunications and Informatics at the Gdańsk University of Technology. Tests have been carried out for two different scattering distribution of the screen material in order to check how these characteristicinfluence on the luminance distribution of the whole CAVE. The basis assumption and simplification of modeled CAVE-type installation and results were presented. The brief discussion about the results and usefulness of developed model were also carried out.

Octopus: a platform for the virtual high-throughput screening of a pool of compounds against a set of molecular targets.

Science.gov (United States)

Maia, Eduardo Habib Bechelane; Campos, Vinícius Alves; Dos Reis Santos, Bianca; Costa, Marina Santos; Lima, Iann Gabriel; Greco, Sandro J; Ribeiro, Rosy I M A; Munayer, Felipe M; da Silva, Alisson Marques; Taranto, Alex Gutterres

2017-01-01

Octopus is an automated workflow management tool that is scalable for virtual high-throughput screening (vHTS). It integrates MOPAC2016, MGLTools, PyMOL, and AutoDock Vina. In contrast to other platforms, Octopus can perform docking simulations of an unlimited number of compounds into a set of molecular targets. After generating the ligands in a drawing package in the Protein Data Bank (PDB) format, Octopus can carry out geometry refinement using the semi-empirical method PM7 implemented in MOPAC2016. Docking simulations can be performed using AutoDock Vina and can utilize the Our Own Molecular Targets (OOMT) databank. Finally, the proposed software compiles the best binding energies into a standard table. Here, we describe two successful case studies that were verified by biological assay. In the first case study, the vHTS process was carried out for 22 (phenylamino)urea derivatives. The vHTS process identified a metalloprotease with the PDB code 1GKC as a molecular target for derivative LE&007. In a biological assay, compound LE&007 was found to inhibit 80% of the activity of this enzyme. In the second case study, compound Tx001 was submitted to the Octopus routine, and the results suggested that Plasmodium falciparum ATP6 (PfATP6) as a molecular target for this compound. Following an antimalarial assay, Tx001 was found to have an inhibitory concentration (IC 50 ) of 8.2 μM against PfATP6. These successful examples illustrate the utility of this software for finding appropriate molecular targets for compounds. Hits can then be identified and optimized as new antineoplastic and antimalarial drugs. Finally, Octopus has a friendly Linux-based user interface, and is available at www.drugdiscovery.com.br . Graphical Abstract Octopus: A platform for inverse virtual screening (IVS) to search new molecular targets for drugs.

Uniqueness of Experience and Virtual Playworlds: Playing Is Not Just for Fun

Science.gov (United States)

Talamo, Alessandra; Pozzi, Simone; Mellini, Barbara

2010-01-01

Social interactions within virtual communities are often described solely as being online experiences. Such descriptions are limited, for they fail to reference life external to the screen. The terms "virtual" and "real" have a negative connotation for many people and can even be interpreted to mean that something is "false" or "inauthentic."…

Integration of ligand and structure-based virtual screening for identification of leading anabolic steroids.

Science.gov (United States)

Alvarez-Ginarte, Yoanna María; Montero-Cabrera, Luis Alberto; García-de la Vega, José Manuel; Bencomo-Martínez, Alberto; Pupo, Amaury; Agramonte-Delgado, Alina; Marrero-Ponce, Yovani; Ruiz-García, José Alberto; Mikosch, Hans

2013-11-01

Parallel ligand- and structure-based virtual screenings of 269 steroids with anabolic activity evaluated in vivo were performed. The quantitative structure-activity relationship (QSAR) model expressed by selected descriptors as the octanol-water partition coefficient, the molar volume and the quantum mechanical calculated charge values on atoms C1, C2, C5, C9, C10, C14 and C17 of the steroid skeleton, expresses structural features of anabolic steroids (AS) contributing to the transport and steroid-receptor interaction. On the other hand, computational simulations of a candidate ligand binding to a receptor study (a "docking" procedure) predict the association of these AS with the human androgen receptor (AR). Fourteen compounds were identified as lead; the most potent was the 7α-methylestr-4-en-3, 17-dione. It was concluded that a good anabolic activity requires hydrogen bonding interactions between both Arg752 and Gln711 residues in the cycles A with O3 atom of the steroid and either Asn705 and Thr877 residues in the cycles D of steroid with O17 atom. Copyright © 2013 Elsevier Ltd. All rights reserved.

Retrospective study evaluating the performance of a first-trimester combined screening for trisomy 21 in an Italian unselected population

Science.gov (United States)

Padula, Francesco; Cignini, Pietro; Giannarelli, Diana; Brizzi, Cristiana; Coco, Claudio; D’Emidio, Laura; Giorgio, Elsa; Giorlandino, Maurizio; Mangiafico, Lucia; Mastrandrea, Marialuisa; Milite, Vincenzo; Mobili, Luisa; Nanni, Cinzia; Raffio, Raffaella; Taramanni, Cinzia; Vigna, Roberto; Mesoraca, Alvaro; Bizzoco, Domenico; Gabrielli, Ivan; Di Giacomo, Gianluca; Barone, Maria Antonietta; Cima, Antonella; Giorlandino, Francesca Romana; Emili, Sabrina; Cupellaro, Marina; Giorlandino, Claudio

2014-01-01

Objectives to assess the performance of a combined first-trimester screening for trisomy 21 in an unselected Italian population referred to a specialized private center for prenatal medicine. Methods a retrospective validation of first-trimester screening algorithms [risk calculation based on maternal age and nuchal translucency (NT) alone, maternal age and serum parameters (free β-hCG and PAPP-A) alone and a combination of both] for fetal aneuploidies evaluated in an unselected Italian population at Artemisia Fetal-Maternal Medical Centre in Rome. All measurements were performed between 11+0 and 13+6 weeks of gestation, between April 2007 and December 2008. Results of 3,610 single fetuses included in the study, we had a complete follow-up on 2,984. Fourteen of 17 cases of trisomy 21 were detected when a cut-off of 1:300 was applied [detection rate (DR) 82.4%, 95% confidence interval (CI) 64.2–100; false-positive rate (FPR) 4.7%, 95% CI 3.9–5.4; false-negative rate (FNR) 17.6%, 95% CI 0–35.8%]. Conclusion in our study population the detection rate for trisomy 21, using the combined risk calculation based on maternal age, fetal NT, maternal PAPP-A and free β-hCG levels, was superior to the application of either parameter alone. The algorithm has been validated for first trimester screening in the Italian population. PMID:26266002

Study of cognitive and technological prerequisites for virtual laboratories and collaborative virtual environments for radiopharmacy

International Nuclear Information System (INIS)

Melo, Roberto Correia de

2009-01-01

This academic work explains a general view of virtual laboratories (VL) and collaborative virtual environments (CVE) (called, together, a VL/CVE set), focusing their technological features and analyzing the common cognitive features of their users. Also is presented a detailed description of VL/CVE VirRAD (Virtual Radiopharmacy), created specially to connect and support the international radiopharmacy community around the world, and is explained an analysis of their users' cognitive profile, under the perspective of two of the most important cognitive theories of the 20th century: multiple intelligences, by Howard Gardner, and mindful learning, by Ellen Langer. Conclusions from this study has been incorporated, as feature enhancements, to a software prototype created based upon VirRAD software solution, and the hardcopy of their screens is exposed at the end of this work. It is also an essential idea that the conclusions of this work are relevant to any VL/CVE environment. (author)

Machine Learning-based Virtual Screening and Its Applications to Alzheimer's Drug Discovery: A Review.

Science.gov (United States)

Carpenter, Kristy A; Huang, Xudong

2018-06-07

Virtual Screening (VS) has emerged as an important tool in the drug development process, as it conducts efficient in silico searches over millions of compounds, ultimately increasing yields of potential drug leads. As a subset of Artificial Intelligence (AI), Machine Learning (ML) is a powerful way of conducting VS for drug leads. ML for VS generally involves assembling a filtered training set of compounds, comprised of known actives and inactives. After training the model, it is validated and, if sufficiently accurate, used on previously unseen databases to screen for novel compounds with desired drug target binding activity. The study aims to review ML-based methods used for VS and applications to Alzheimer's disease (AD) drug discovery. To update the current knowledge on ML for VS, we review thorough backgrounds, explanations, and VS applications of the following ML techniques: Naïve Bayes (NB), k-Nearest Neighbors (kNN), Support Vector Machines (SVM), Random Forests (RF), and Artificial Neural Networks (ANN). All techniques have found success in VS, but the future of VS is likely to lean more heavily toward the use of neural networks - and more specifically, Convolutional Neural Networks (CNN), which are a subset of ANN that utilize convolution. We additionally conceptualize a work flow for conducting ML-based VS for potential therapeutics of for AD, a complex neurodegenerative disease with no known cure and prevention. This both serves as an example of how to apply the concepts introduced earlier in the review and as a potential workflow for future implementation. Different ML techniques are powerful tools for VS, and they have advantages and disadvantages albeit. ML-based VS can be applied to AD drug development. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Virtual planning of complex head and neck reconstruction results in satisfactory match between real outcomes and virtual models.

Science.gov (United States)

Hanken, Henning; Schablowsky, Clemens; Smeets, Ralf; Heiland, Max; Sehner, Susanne; Riecke, Björn; Nourwali, Ibrahim; Vorwig, Oliver; Gröbe, Alexander; Al-Dam, Ahmed

2015-04-01

The reconstruction of large facial bony defects using microvascular transplants requires extensive surgery to achieve full rehabilitation of form and function. The purpose of this study is to measure the agreement between virtual plans and the actual results of maxillofacial reconstruction. This retrospective cohort study included 30 subjects receiving maxillofacial reconstruction with a preoperative virtual planning. Parameters including defect size, position, angle and volume of the transplanted segments were compared between the virtual plan and the real outcome using paired t test. A total of 63 bone segments were transplanted. The mean differences between the virtual planning and the postoperative situation were for the defect sizes 1.17 mm (95 % confidence interval (CI) (-.21 to 2.56 mm); p = 0.094), for the resection planes 1.69 mm (95 % CI (1.26-2.11); p = 0.033) and 10.16° (95 % CI (8.36°-11.96°); p satisfactory postoperative results are the basis for an optimal functional and aesthetic reconstruction in a single surgical procedure. The technique should be further investigated in larger study populations and should be further improved.

Effectiveness of selective risk based screening for Gestational Diabetes (GDM) in Malaysia: A retrospective cohort study based on the National Obstetric Registry (NOR) of Malaysia.

Science.gov (United States)

Muniswaran, G; Soelar, S A; Karalasingam, S D; Bujang, M A; Jeganathan, R; Suharjono, H

2017-02-01

Gestational diabetes (GDM) has significant maternal and foetal implications. screening allows active interventions which significantly improves pregnancy outcomes. Despite World Health Organization (WHO), FIGO and National Institute of clinical Excellence (NIcE) recommendations for universal screening especially among high risk population; Malaysia currently adopts a selective risk based screening for GDM. the objective is to audit the effectiveness of the current practice of selective risk based screening in detection of GDM in Malaysia. this is a retrospective cohort study based on the National Obstetric Registry (NOR) which comprises of 14 major tertiary hospitals in Malaysia. the study period was from 1st January 2011 till 31st December 2012 and a total of 22,044 patients with GDM were analysed. Logistic regression analysis was used to calculate the crude odd ratio. the incidence of GDM in Malaysia is 8.4%. Maternal age of ≥25, booking bMI ≥27kg/m2, booking weight ≥80kg and previous hypertension are non-significant risk of developing GDM in Malaysia. Parity 5 and more was only associated with an odds-ratio of 1.02 (95% confidence Interval: 0.90-1.17) as compared to parity below 5. the association of women with previous stillbirth with GDM was not significant. current risk based screening for GDM based on maternal age, booking bMI, weight and hypertension is inappropriate. An ideal screening tool should precede disease complications, which is the novel objective of screening. Universal screening for GDM in Malaysia may be a more accurate measure, especially with regards to reducing maternal and foetal complications.

The Uncanny Valley and Nonverbal Communication in Virtual Characters

DEFF Research Database (Denmark)

Tinwell, Angela; Grimshaw, Mark Nicholas; Abdel Nabi, Debbie

2014-01-01

This chapter provides an overview of a current research project investigating the Uncanny Valley phenomenon in realistic, human-like virtual characters. !e research methods used in this Work include a retrospective of both empirical studies and philosophical writings on the Uncanny. No other...... research has explored the notion that realistic, human-like, virtual characters are regarded less favorably due to a perceived diminished degree of responsiveness in facial expression, specifically, nonverbal communication (NVC) in the upper face region. So far, this research project has provided the first...... empirical evidence to test the Uncanny Valley phenomenon in the domain of animated video game characters with speech, as opposed to just still, unresponsive images, as used in previous studies. Based on the results of these experiments, a conceptual framework of the Uncanny Valley in virtual characters has...

Prostate Cancer Screening in Jamaica: Results of the Largest National Screening Clinic Prostate Cancer Screening in Jamaica: Results of the Largest National Screening Clinic

International Nuclear Information System (INIS)

Morrison, B. F.; Aiken, W.; Mayhew, R.; Gordon, Y.; Reid, M.

2016-01-01

Prostate cancer is highly prevalent in Jamaica and is the leading cause of cancer-related deaths. Our aim was to evaluate the patterns of screening in the largest organized screening clinic in Jamaica at the Jamaica Cancer Society. A retrospective analysis of all men presenting for screening at the Jamaica Cancer Society from 1995 to 2005 was done. All patients had digital rectal examinations (DRE) and prostate specific antigen (PSA) tests done. Results of prostate biopsies were noted. 1117 men of mean age 59.9 ± 8.2 years presented for screening. The median documented PSA was 1.6 ng/mL (maximum of 5170 ng/mL). Most patients presented for only 1 screen. There was a gradual reduction in the mean age of presentation for screening over the period. Prostate biopsies were requested on 11% of screening visits; however, only 59% of these were done. 5.6% of all persons screened were found to have cancer. Of the cancers diagnosed, Gleason 6 adenocarcinoma was the commonest grade and median PSA was 8.9 ng/mL (range 1.5-1059 ng/mL). Older men tend to screen for prostate cancer in Jamaica. However, compliance with regular maintenance visits and requests for confirmatory biopsies are poor. Screening needs intervention in the Jamaican population.

Speculations on the representation of architecture in virtual reality

DEFF Research Database (Denmark)

Hermund, Anders; Klint, Lars; Bundgård, Ture Slot

2017-01-01

to the visual field of perception. However, this should not necessarily imply an acceptance of the dominance of vision over the other senses, and the much-criticized retinal architecture with its inherent loss of plasticity. Recent neurology studies indicate that 3D representation models in virtual reality......This paper discusses the present and future possibilities of representation models of architecture in new media such as virtual reality, seen in the broader context of tradition, perception, and neurology. Through comparative studies of real and virtual scenarios using eye tracking, the paper...... are less demanding on the brain’s working memory than 3D models seen on flat two-dimensional screens. This paper suggests that virtual reality representational architectural models can, if used correctly, significantly improve the imaginative role of architectural representation....

A retrospective study of the performance of radiographers in interpreting screening mammograms

International Nuclear Information System (INIS)

Moran, S.; Warren-Forward, H.

2011-01-01

Purpose: This paper provides data on the continued success of radiographers in reviewing mammograms with similar accuracy to screen readers. Method: The participants consisted of 7 radiographers and 2 current official screen readers. Two hundred and fifty sets of mammograms from 2003 were used in this study. Each participant reviewed each set of mammograms as a Rescreen or Recall. Patient outcomes were assessed by following up the results of any histology or pathology tests in 2003 or the 2005/2006 screening results. Results: The screen reader's sensitivities ranged from 79% to 93% and the specificities ranged from 82% to 84%. The radiographer values ranged from 57% to 97% and 63% to 80% respectively. Conclusion: The sensitivity and specificity values attained by some radiographers were equivalent to those of both the screen readers. Accuracy rates of the radiographers suggest that screen reading by selected and appropriately trained radiographers should be achievable in Australia.

From AISR to the Virtual Observatory

Science.gov (United States)

Szalay, Alexander S.

2014-01-01

The talk will provide a retrospective on important results enabled by the NASA AISR program. The program had a unique approach to funding research at the intersection of astrophysics, applied computer science and statistics. It had an interdisciplinary angle, encouraged high risk, high return projects. Without this program the Virtual Observatory would have never been started. During its existence the program has funded some of the most innovative applied computer science projects in astrophysics.

Investigation of tracking systems properties in CAVE-type virtual reality systems

Science.gov (United States)

Szymaniak, Magda; Mazikowski, Adam; Meironke, Michał

2017-08-01

In recent years, many scientific and industrial centers in the world developed a virtual reality systems or laboratories. One of the most advanced solutions are Immersive 3D Visualization Lab (I3DVL), a CAVE-type (Cave Automatic Virtual Environment) laboratory. It contains two CAVE-type installations: six-screen installation arranged in a form of a cube, and four-screen installation, a simplified version of the previous one. The user feeling of "immersion" and interaction with virtual world depend on many factors, in particular on the accuracy of the tracking system of the user. In this paper properties of the tracking systems applied in I3DVL was investigated. For analysis two parameters were selected: the accuracy of the tracking system and the range of detection of markers by the tracking system in space of the CAVE. Measurements of system accuracy were performed for six-screen installation, equipped with four tracking cameras for three axes: X, Y, Z. Rotation around the Y axis was also analyzed. Measured tracking system shows good linear and rotating accuracy. The biggest issue was the range of the monitoring of markers inside the CAVE. It turned out, that the tracking system lose sight of the markers in the corners of the installation. For comparison, for a simplified version of CAVE (four-screen installation), equipped with eight tracking cameras, this problem was not occur. Obtained results will allow for improvement of cave quality.

GPCRs from fusarium graminearum detection, modeling and virtual screening - the search for new routes to control head blight disease.

Science.gov (United States)

Bresso, Emmanuel; Togawa, Roberto; Hammond-Kosack, Kim; Urban, Martin; Maigret, Bernard; Martins, Natalia Florencio

2016-12-15

Fusarium graminearum (FG) is one of the major cereal infecting pathogens causing high economic losses worldwide and resulting in adverse effects on human and animal health. Therefore, the development of new fungicides against FG is an important issue to reduce cereal infection and economic impact. In the strategy for developing new fungicides, a critical step is the identification of new targets against which innovative chemicals weapons can be designed. As several G-protein coupled receptors (GPCRs) are implicated in signaling pathways critical for the fungi development and survival, such proteins could be valuable efficient targets to reduce Fusarium growth and therefore to prevent food contamination. In this study, GPCRs were predicted in the FG proteome using a manually curated pipeline dedicated to the identification of GPCRs. Based on several successive filters, the most appropriate GPCR candidate target for developing new fungicides was selected. Searching for new compounds blocking this particular target requires the knowledge of its 3D-structure. As no experimental X-Ray structure of the selected protein was available, a 3D model was built by homology modeling. The model quality and stability was checked by 100 ns of molecular dynamics simulations. Two stable conformations representative of the conformational families of the protein were extracted from the 100 ns simulation and were used for an ensemble docking campaign. The model quality and stability was checked by 100 ns of molecular dynamics simulations previously to the virtual screening step. The virtual screening step comprised the exploration of a chemical library with 11,000 compounds that were docked to the GPCR model. Among these compounds, we selected the ten top-ranked nontoxic molecules proposed to be experimentally tested to validate the in silico simulation. This study provides an integrated process merging genomics, structural bioinformatics and drug design for proposing innovative

Retrospective dosimetry of Chernobyl liquidators

International Nuclear Information System (INIS)

Chumak, V.V.; Bakhanova, E.V.; Sholom, S.V.; Pasalskaya, L.F.; Bouville, A.; Krjuchkov, V.P.

2000-01-01

The numerous cohort of Chernobyl liquidators is a very attractive subject for epidemiological follow up due to high levels of exposure, age-gender distribution and availability of patients for medical examination. However, dosimetric information related to this population is incomplete, in many cases the quality of available dose records is doubtful and uncertainties of all dose values are not determined. Naive attempts to evaluate average doses on the basis of such factors as 'distance from the reactor' obviously fail due to large variation of tasks and workplace contamination. Therefore, prior to any sensible consideration of liquidators as a subject of epidemiological study, their doses should be evaluated (reevaluated) using the methods of retrospective dosimetry. Retrospective dosimetry in general got significant development over the last decade. However, most of the retrospective dosimetry techniques are time consuming, expensive and possess sensitivity threshold. Therefore, application of retrospective dosimetry for the needs of epidemiological follow up studies requires development of certain strategy. This strategy depends, of coarse, on the epidemiological design of the study, availability of resources and dosimetric information related to the time of clean up. One of the strategies of application of retrospective dosimetry may be demonstrated on the example of a cohort study with occasional nested case control consideration. In this case, the tools are needed for validation of existing dose records (of not always known quality), screening of the study cohort with express dosimetric method called to determine possible dose ranges, and 'state-of-the-art' assessment of individual doses for selected subjects (cases and controls). Verification of dose records involves analysis of the statistical regularities of dose distributions and detection of possible extraneous admixtures (presumably falsified dose records). This work is performed on impersonified data

Population-based V3 genotypic tropism assay: a retrospective analysis using screening samples from the A4001029 and MOTIVATE studies.

Science.gov (United States)

McGovern, Rachel A; Thielen, Alexander; Mo, Theresa; Dong, Winnie; Woods, Conan K; Chapman, Douglass; Lewis, Marilyn; James, Ian; Heera, Jayvant; Valdez, Hernan; Harrigan, P Richard

2010-10-23

The MOTIVATE-1 and 2 studies compared maraviroc (MVC) along with optimized background therapy (OBT) vs. placebo along with OBT in treatment-experienced patients screened as having R5-HIV (original Monogram Trofile). A subset screened with non-R5 HIV were treated with MVC or placebo along with OBT in a sister safety trial, A4001029. This analysis retrospectively examined the performance of population-based sequence analysis of HIV-1 env V3-loop to predict coreceptor tropism. Triplicate V3-loop sequences were generated using stored screening plasma samples and data was processed using custom software ('ReCall'), blinded to clinical response. Tropism was inferred using geno2pheno ('g2p'; 5% false positive rate). Primary outcomes were viral load changes after starting maraviroc; and concordance with prior screening Trofile results. Genotype and Trofile results were available for 1164 individuals with virological outcome data (N = 169 non-R5 by Trofile). Compared with Trofile, V3 genotyping had a specificity of 92.6% and a sensitivity of 67.4% for detecting non-R5 virus. However, when compared with clinical outcome, virological responses were consistently similar between Trofile and V3 genotype at weeks 8 and 24 following the initiation of therapy for patients categorized as R5. Despite differences in sensitivity for predicting non-R5 HIV, week 8 and 24 week virological responses were similar in this treatment-experienced population. These findings suggest the potential utility of V3 genotyping as an accessible assay to select patients who may benefit from maraviroc treatment. Optimization of the predictive tropism algorithm may lead to further improvement in the clinical utility of HIV genotypic tropism assays.

DockoMatic: automated peptide analog creation for high throughput virtual screening.

Science.gov (United States)

Jacob, Reed B; Bullock, Casey W; Andersen, Tim; McDougal, Owen M

2011-10-01

The purpose of this manuscript is threefold: (1) to describe an update to DockoMatic that allows the user to generate cyclic peptide analog structure files based on protein database (pdb) files, (2) to test the accuracy of the peptide analog structure generation utility, and (3) to evaluate the high throughput capacity of DockoMatic. The DockoMatic graphical user interface interfaces with the software program Treepack to create user defined peptide analogs. To validate this approach, DockoMatic produced cyclic peptide analogs were tested for three-dimensional structure consistency and binding affinity against four experimentally determined peptide structure files available in the Research Collaboratory for Structural Bioinformatics database. The peptides used to evaluate this new functionality were alpha-conotoxins ImI, PnIA, and their published analogs. Peptide analogs were generated by DockoMatic and tested for their ability to bind to X-ray crystal structure models of the acetylcholine binding protein originating from Aplysia californica. The results, consisting of more than 300 simulations, demonstrate that DockoMatic predicts the binding energy of peptide structures to within 3.5 kcal mol(-1), and the orientation of bound ligand compares to within 1.8 Å root mean square deviation for ligand structures as compared to experimental data. Evaluation of high throughput virtual screening capacity demonstrated that Dockomatic can collect, evaluate, and summarize the output of 10,000 AutoDock jobs in less than 2 hours of computational time, while 100,000 jobs requires approximately 15 hours and 1,000,000 jobs is estimated to take up to a week. Copyright © 2011 Wiley Periodicals, Inc.

IVSPlat 1.0: an integrated virtual screening platform with a molecular graphical interface.

Science.gov (United States)

Sun, Yin Xue; Huang, Yan Xin; Li, Feng Li; Wang, Hong Yan; Fan, Cong; Bao, Yong Li; Sun, Lu Guo; Ma, Zhi Qiang; Kong, Jun; Li, Yu Xin

2012-01-05

The virtual screening (VS) of lead compounds using molecular docking and pharmacophore detection is now an important tool in drug discovery. VS tasks typically require a combination of several software tools and a molecular graphics system. Thus, the integration of all the requisite tools in a single operating environment could reduce the complexity of running VS experiments. However, only a few freely available integrated software platforms have been developed. A free open-source platform, IVSPlat 1.0, was developed in this study for the management and automation of VS tasks. We integrated several VS-related programs into a molecular graphics system to provide a comprehensive platform for the solution of VS tasks based on molecular docking, pharmacophore detection, and a combination of both methods. This tool can be used to visualize intermediate and final results of the VS execution, while also providing a clustering tool for the analysis of VS results. A case study was conducted to demonstrate the applicability of this platform. IVSPlat 1.0 provides a plug-in-based solution for the management, automation, and visualization of VS tasks. IVSPlat 1.0 is an open framework that allows the integration of extra software to extend its functionality and modified versions can be freely distributed. The open source code and documentation are available at http://kyc.nenu.edu.cn/IVSPlat/.

Virtual surgical planning in endoscopic skull base surgery.

Science.gov (United States)

Haerle, Stephan K; Daly, Michael J; Chan, Harley H L; Vescan, Allan; Kucharczyk, Walter; Irish, Jonathan C

2013-12-01

Skull base surgery (SBS) involves operative tasks in close proximity to critical structures in a complex three-dimensional (3D) anatomy. The aim was to investigate the value of virtual planning (VP) based on preoperative magnetic resonance imaging (MRI) for surgical planning in SBS and to compare the effects of virtual planning with 3D contours between the expert and the surgeon in training. Retrospective analysis. Twelve patients with manually segmented anatomical structures based on preoperative MRI were evaluated by eight surgeons in a randomized order using a validated National Aeronautics and Space Administration Task Load Index (NASA-TLX) questionnaire. Multivariate analysis revealed significant reduction of workload when using VP (PNASA-TLX differences (P.05). Preoperative anatomical segmentation with virtual surgical planning using contours in endoscopic SBS significantly reduces the workload for the expert and the surgeon in training. Copyright © 2013 The American Laryngological, Rhinological and Otological Society, Inc.

Congenital cataract screening in maternity wards is effective

DEFF Research Database (Denmark)

Magnusson, Gunilla; Bizjajeva, Svetlana; Haargaard, Birgitte

2013-01-01

AIM: To study which eye-screening protocol prevails in Swedish maternity/neonatal wards, evaluate efficacy in a prospective study, and compare results with earlier Swedish retrospective results. METHODS: Surveys were sent in 2006 to maternity/neonatal and women's health departments regarding...... with earlier retrospective results was performed. RESULTS: Eye screening is routine protocol at a rate of 90% of Swedish maternity wards. Sixty-one children were included in the study. An increase was shown in case referrals from maternity wards compared to ten years ago (64% versus 50%). Detection...

Comparative analysis of pharmacophore screening tools.

NARCIS (Netherlands)

Sanders, M.P.A.; Barbosa, A.J.; Zarzycka, B.; Nicolaes, G.A.; Klomp, J.P.G.; Vlieg, J. de; Rio, A. Del

2012-01-01

The pharmacophore concept is of central importance in computer-aided drug design (CADD) mainly because of its successful application in medicinal chemistry and, in particular, high-throughput virtual screening (HTVS). The simplicity of the pharmacophore definition enables the complexity of molecular

A retrospective cohort study on the association between periapical abscess, advanced periodontal disease, and the national oral health screening program among Korean adults.

Science.gov (United States)

Ha, Jung-Eun; Jung, Se-Hwan; Jin, Bo-Hyoung; Lee, Byoung-Jin; Bae, Kwang-Hak

2013-09-01

The National Oral Health Screening Program (NOHSP) is a general population-based program in Korea. The objective of this study was to assess the association between participation in the NOHSP and dental visit for periapical abscess (PA) and advanced periodontal disease (APD) among Korean adults. Data were obtained for subjects from the National Health Insurance database. The authors conducted a retrospective cohort study of 9358 randomly selected subjects who were between 40 and 64 years old in 2002. The outcomes of dental visit for PA or APD from the years 2003 to 2007 were compared between the screening and nonscreening groups. The nonscreening group had 19% higher risk of PA and 15% higher risk of APD. This study suggests that the NOHSP may decrease the risk of dental visit because of PA and APD by preventing the progress of lesion to the advanced stage among Korean adults.

Primary care colorectal cancer screening correlates with breast cancer screening: implications for colorectal cancer screening improvement interventions.

Science.gov (United States)

Weiss, Jennifer M; Pandhi, Nancy; Kraft, Sally; Potvien, Aaron; Carayon, Pascale; Smith, Maureen A

2018-04-25

National colorectal cancer (CRC) screening rates have plateaued. To optimize interventions targeting those unscreened, a better understanding is needed of how this preventive service fits in with multiple preventive and chronic care needs managed by primary care providers (PCPs). This study examines whether PCP practices of other preventive and chronic care needs correlate with CRC screening. We performed a retrospective cohort study of 90 PCPs and 33,137 CRC screening-eligible patients. Five PCP quality metrics (breast cancer screening, cervical cancer screening, HgbA1c and LDL testing, and blood pressure control) were measured. A baseline correlation test was performed between these metrics and PCP CRC screening rates. Multivariable logistic regression with clustering at the clinic-level estimated odds ratios and 95% confidence intervals for these PCP quality metrics, patient and PCP characteristics, and their relationship to CRC screening. PCP CRC screening rates have a strong correlation with breast cancer screening rates (r = 0.7414, p < 0.001) and a weak correlation with the other quality metrics. In the final adjusted model, the only PCP quality metric that significantly predicted CRC screening was breast cancer screening (OR 1.25; 95% CI 1.11-1.42; p < 0.001). PCP CRC screening rates are highly concordant with breast cancer screening. CRC screening is weakly concordant with cervical cancer screening and chronic disease management metrics. Efforts targeting PCPs to increase CRC screening rates could be bundled with breast cancer screening improvement interventions to increase their impact and success.

A Prospective Virtual Screening Study: Enriching Hit Rates and Designing Focus Libraries To Find Inhibitors of PI3Kδ and PI3Kγ.

Science.gov (United States)

Damm-Ganamet, Kelly L; Bembenek, Scott D; Venable, Jennifer W; Castro, Glenda G; Mangelschots, Lieve; Peeters, Daniëlle C G; Mcallister, Heather M; Edwards, James P; Disepio, Daniel; Mirzadegan, Taraneh

2016-05-12

Here, we report a high-throughput virtual screening (HTVS) study using phosphoinositide 3-kinase (both PI3Kγ and PI3Kδ). Our initial HTVS results of the Janssen corporate database identified small focused libraries with hit rates at 50% inhibition showing a 50-fold increase over those from a HTS (high-throughput screen). Further, applying constraints based on "chemically intuitive" hydrogen bonds and/or positional requirements resulted in a substantial improvement in the hit rates (versus no constraints) and reduced docking time. While we find that docking scoring functions are not capable of providing a reliable relative ranking of a set of compounds, a prioritization of groups of compounds (e.g., low, medium, and high) does emerge, which allows for the chemistry efforts to be quickly focused on the most viable candidates. Thus, this illustrates that it is not always necessary to have a high correlation between a computational score and the experimental data to impact the drug discovery process.

VecScreen_plus_taxonomy: imposing a tax(onomy) increase on vector contamination screening.

Science.gov (United States)

Schäffer, Alejandro A; Nawrocki, Eric P; Choi, Yoon; Kitts, Paul A; Karsch-Mizrachi, Ilene; McVeigh, Richard

2018-03-01

Nucleic acid sequences in public databases should not contain vector contamination, but many sequences in GenBank do (or did) contain vectors. The National Center for Biotechnology Information uses the program VecScreen to screen submitted sequences for contamination. Additional tools are needed to distinguish true-positive (contamination) from false-positive (not contamination) VecScreen matches. A principal reason for false-positive VecScreen matches is that the sequence and the matching vector subsequence originate from closely related or identical organisms (for example, both originate in Escherichia coli). We collected information on the taxonomy of sources of vector segments in the UniVec database used by VecScreen. We used that information in two overlapping software pipelines for retrospective analysis of contamination in GenBank and for prospective analysis of contamination in new sequence submissions. Using the retrospective pipeline, we identified and corrected over 8000 contaminated sequences in the nonredundant nucleotide database. The prospective analysis pipeline has been in production use since April 2017 to evaluate some new GenBank submissions. Data on the sources of UniVec entries were included in release 10.0 (ftp://ftp.ncbi.nih.gov/pub/UniVec/). The main software is freely available at https://github.com/aaschaffer/vecscreen_plus_taxonomy. aschaffe@helix.nih.gov. Supplementary data are available at Bioinformatics online. Published by Oxford University Press 2017. This work is written by US Government employees and are in the public domain in the US.

Virtual environments for scene of crime reconstruction and analysis

Science.gov (United States)

Howard, Toby L. J.; Murta, Alan D.; Gibson, Simon

2000-02-01

This paper describes research conducted in collaboration with Greater Manchester Police (UK), to evalute the utility of Virtual Environments for scene of crime analysis, forensic investigation, and law enforcement briefing and training. We present an illustrated case study of the construction of a high-fidelity virtual environment, intended to match a particular real-life crime scene as closely as possible. We describe and evaluate the combination of several approaches including: the use of the Manchester Scene Description Language for constructing complex geometrical models; the application of a radiosity rendering algorithm with several novel features based on human perceptual consideration; texture extraction from forensic photography; and experiments with interactive walkthroughs and large-screen stereoscopic display of the virtual environment implemented using the MAVERIK system. We also discuss the potential applications of Virtual Environment techniques in the Law Enforcement and Forensic communities.

Constructing and Validating High-Performance MIEC-SVM Models in Virtual Screening for Kinases: A Better Way for Actives Discovery.

Science.gov (United States)

Sun, Huiyong; Pan, Peichen; Tian, Sheng; Xu, Lei; Kong, Xiaotian; Li, Youyong; Dan Li; Hou, Tingjun

2016-04-22

The MIEC-SVM approach, which combines molecular interaction energy components (MIEC) derived from free energy decomposition and support vector machine (SVM), has been found effective in capturing the energetic patterns of protein-peptide recognition. However, the performance of this approach in identifying small molecule inhibitors of drug targets has not been well assessed and validated by experiments. Thereafter, by combining different model construction protocols, the issues related to developing best MIEC-SVM models were firstly discussed upon three kinase targets (ABL, ALK, and BRAF). As for the investigated targets, the optimized MIEC-SVM models performed much better than the models based on the default SVM parameters and Autodock for the tested datasets. Then, the proposed strategy was utilized to screen the Specs database for discovering potential inhibitors of the ALK kinase. The experimental results showed that the optimized MIEC-SVM model, which identified 7 actives with IC50 < 10 μM from 50 purchased compounds (namely hit rate of 14%, and 4 in nM level) and performed much better than Autodock (3 actives with IC50 < 10 μM from 50 purchased compounds, namely hit rate of 6%, and 2 in nM level), suggesting that the proposed strategy is a powerful tool in structure-based virtual screening.

Inhibitor candidates's identification of HCV's RNA polymerase NS5B using virtual screening against iPPI-library

Science.gov (United States)

Sulistyawati, Indah; Sulistyo Dwi K., P.; Ichsan, Mochammad

2016-03-01

Hepatitis C is one of the major causes of chronic liver failure that caused by Hepatitis C Virus (HCV). Preventing the progression of HCV's replication through the inhibition of The RNA polymerase NS5B of Hepatitis C virus (NS5B) can be achieved via 4 binding regions: Site I (Thumb I), Site II (Thumb II), Site III (Palm I), and Site IV (Palm II). The aim of this research is to identify a candidate of NS5B inhibitor as an alternative for Hepatitis C treatment. An NS5B's 3D structure (PDB ID = 3D5M) used in this study has met some criteria of a good model to be used in virtual screening againts iPPI-lib using MTiOpenScreen webserver. The top two natural compounds resulted here then docked using Pyrix 0.8 and discovered trans-6-Benzamido-2-methyldecahydroisoquinoline (-9,1kcal/mol) and 2,4-dichloro-5-[4-(2 methoxyphenyl) piperazine-1-carbonyl]-N-[3-(trifluoromethyl)phenyl] benzenesulfonamide (9,4 kcal/mol) can bind to Tyr448 similar with all three established inhibitors, such as setrobuvir (-11,4 kcal/mol; site 3 inhibitor), CHEMBL379677 (-9,1 kcal/mol; site 1 inhibitor), and nesbuvir (-7,7 kcal/mol; site 4 inhibitor). The results of this study are relatively still needs to be tested, both in vitro and in vivo, in order to obtain more comprehensive knowledges as a follow-up of this predictive study.

Representability of algebraic topology for biomolecules in machine learning based scoring and virtual screening.

Science.gov (United States)

Cang, Zixuan; Mu, Lin; Wei, Guo-Wei

2018-01-01

This work introduces a number of algebraic topology approaches, including multi-component persistent homology, multi-level persistent homology, and electrostatic persistence for the representation, characterization, and description of small molecules and biomolecular complexes. In contrast to the conventional persistent homology, multi-component persistent homology retains critical chemical and biological information during the topological simplification of biomolecular geometric complexity. Multi-level persistent homology enables a tailored topological description of inter- and/or intra-molecular interactions of interest. Electrostatic persistence incorporates partial charge information into topological invariants. These topological methods are paired with Wasserstein distance to characterize similarities between molecules and are further integrated with a variety of machine learning algorithms, including k-nearest neighbors, ensemble of trees, and deep convolutional neural networks, to manifest their descriptive and predictive powers for protein-ligand binding analysis and virtual screening of small molecules. Extensive numerical experiments involving 4,414 protein-ligand complexes from the PDBBind database and 128,374 ligand-target and decoy-target pairs in the DUD database are performed to test respectively the scoring power and the discriminatory power of the proposed topological learning strategies. It is demonstrated that the present topological learning outperforms other existing methods in protein-ligand binding affinity prediction and ligand-decoy discrimination.

Representability of algebraic topology for biomolecules in machine learning based scoring and virtual screening

Science.gov (United States)

Mu, Lin

2018-01-01

This work introduces a number of algebraic topology approaches, including multi-component persistent homology, multi-level persistent homology, and electrostatic persistence for the representation, characterization, and description of small molecules and biomolecular complexes. In contrast to the conventional persistent homology, multi-component persistent homology retains critical chemical and biological information during the topological simplification of biomolecular geometric complexity. Multi-level persistent homology enables a tailored topological description of inter- and/or intra-molecular interactions of interest. Electrostatic persistence incorporates partial charge information into topological invariants. These topological methods are paired with Wasserstein distance to characterize similarities between molecules and are further integrated with a variety of machine learning algorithms, including k-nearest neighbors, ensemble of trees, and deep convolutional neural networks, to manifest their descriptive and predictive powers for protein-ligand binding analysis and virtual screening of small molecules. Extensive numerical experiments involving 4,414 protein-ligand complexes from the PDBBind database and 128,374 ligand-target and decoy-target pairs in the DUD database are performed to test respectively the scoring power and the discriminatory power of the proposed topological learning strategies. It is demonstrated that the present topological learning outperforms other existing methods in protein-ligand binding affinity prediction and ligand-decoy discrimination. PMID:29309403

Discovery of Novel Inhibitors of Indoleamine 2,3-Dioxygenase 1 Through Structure-Based Virtual Screening

Directory of Open Access Journals (Sweden)

Guoqing Zhang

2018-03-01

Full Text Available Indoleamine 2,3-dioxygenase 1 (IDO1 is an intracellular monomeric heme-containing enzyme that catalyzes the first and the rate limiting step in catabolism of tryptophan via the kynurenine (KYN pathway, which plays a significant role in the proliferation and differentiation of T cells. IDO1 has been proven to be an attractive target for anticancer therapy and chronic viral infections. In the present study, a class of IDO1 inhibitors with novel scaffolds were identified by virtual screening and biochemical validation, in which the compound DC-I028 shows moderate IDO1 inhibitory activity with an IC50 of 21.61 μM on enzymatic level and 89.11 μM on HeLa cell. In the following hit expansion stage, DC-I02806, an analog of DC-I028, showed better inhibitory activity with IC50 about 18 μM on both enzymatic level and cellular level. The structure–activity relationship (SAR of DC-I028 and its analogs was then discussed based on the molecular docking result. The novel IDO1 inhibitors of DC-I028 and its analogs may provide useful clues for IDO1 inhibitor development.

Discovery of Novel Inhibitors of Indoleamine 2,3-Dioxygenase 1 Through Structure-Based Virtual Screening

Science.gov (United States)

Zhang, Guoqing; Xing, Jing; Wang, Yulan; Wang, Lihao; Ye, Yan; Lu, Dong; Zhao, Jihui; Luo, Xiaomin; Zheng, Mingyue; Yan, Shiying

2018-01-01

Indoleamine 2,3-dioxygenase 1 (IDO1) is an intracellular monomeric heme-containing enzyme that catalyzes the first and the rate limiting step in catabolism of tryptophan via the kynurenine (KYN) pathway, which plays a significant role in the proliferation and differentiation of T cells. IDO1 has been proven to be an attractive target for anticancer therapy and chronic viral infections. In the present study, a class of IDO1 inhibitors with novel scaffolds were identified by virtual screening and biochemical validation, in which the compound DC-I028 shows moderate IDO1 inhibitory activity with an IC50 of 21.61 μM on enzymatic level and 89.11 μM on HeLa cell. In the following hit expansion stage, DC-I02806, an analog of DC-I028, showed better inhibitory activity with IC50 about 18 μM on both enzymatic level and cellular level. The structure–activity relationship (SAR) of DC-I028 and its analogs was then discussed based on the molecular docking result. The novel IDO1 inhibitors of DC-I028 and its analogs may provide useful clues for IDO1 inhibitor development. PMID:29651242

Combined Ligand/Structure-Based Virtual Screening and Molecular Dynamics Simulations of Steroidal Androgen Receptor Antagonists

Directory of Open Access Journals (Sweden)

Yuwei Wang

2017-01-01

Full Text Available The antiandrogens, such as bicalutamide, targeting the androgen receptor (AR, are the main endocrine therapies for prostate cancer (PCa. But as drug resistance to antiandrogens emerges in advanced PCa, there presents a high medical need for exploitation of novel AR antagonists. In this work, the relationships between the molecular structures and antiandrogenic activities of a series of 7α-substituted dihydrotestosterone derivatives were investigated. The proposed MLR model obtained high predictive ability. The thoroughly validated QSAR model was used to virtually screen new dihydrotestosterones derivatives taken from PubChem, resulting in the finding of novel compounds CID_70128824, CID_70127147, and CID_70126881, whose in silico bioactivities are much higher than the published best one, even higher than bicalutamide. In addition, molecular docking, molecular dynamics (MD simulations, and MM/GBSA have been employed to analyze and compare the binding modes between the novel compounds and AR. Through the analysis of the binding free energy and residue energy decomposition, we concluded that the newly discovered chemicals can in silico bind to AR with similar position and mechanism to the reported active compound and the van der Waals interaction is the main driving force during the binding process.

The occurrence of high-risk factors for hearing loss in very-low-birth-weight neonates: a retrospective exploratory study of targeted hearing screening.

Science.gov (United States)

Kanji, Amisha; Khoza-Shangase, Katijah

2012-12-01

The current study aimed at determining the type and frequency of high-risk factors for hearing loss in a group of very-low-birth-weight (VLBW) neonates in a tertiary hospital in South Africa with the objective of collating evidence that could be used in arguing for or against revisiting targeted hearing screening in developing countries. Furthermore, the study aimed at investigating the relationship between the identified high-risk factors and hearing screening results. In a retrospective data review design, data were collated from files from the VLBW project; this included hearing screening records, as well as records from participant medical and audiology files. Records of 86 neonates with birth weights ranging between 680 g and 1500 g were reviewed. Findings indicated that neonatal jaundice, exposure to human immunodeficiency virus (HIV), mechanical or assisted ventilation, and neonatal intensive care unit stay greater than 48 hours were the most frequently occurring high-risk factors for hearing loss in the current sample. These factors are consistent with those listed in the high-risk register of the Health Professions Council of South Africa for the South African context. Findings confirm the complexity of risk factors, and the influence that a variety of factors such as poor follow-up or return rate might have on the implementation of early hearing detection and intervention. The importance of establishing context-specific risk factors for effective implementation of targeted screening protocols where niversal newborn hearing screening is not yet a reality was highlighted by the current study.

Ocular effects of virtual reality headset wear in young adults

OpenAIRE

Turnbull, Philip R. K.; Phillips, John R.

2017-01-01

Virtual Reality (VR) headsets create immersion by displaying images on screens placed very close to the eyes, which are viewed through high powered lenses. Here we investigate whether this viewing arrangement alters the binocular status of the eyes, and whether it is likely to provide a stimulus for myopia development. We compared binocular status after 40-minute trials in indoor and outdoor environments, in both real and virtual worlds. We also measured the change in thickness of the ocular ...

Speculations on the representation of architecture in virtual reality

DEFF Research Database (Denmark)

Hermund, Anders; Klint, Lars; Bundgård, Ture Slot

2017-01-01

to the visual field of perception. However, this should not necessarily imply an acceptance of the dominance of vision over the other senses, and the much-criticized retinal architecture with its inherent loss of plasticity. Recent neurology studies indicate that 3D representation models in virtual reality...... are less demanding on the brain’s working memory than 3D models seen on flat two-dimensional screens. This paper suggests that virtual reality representational architectural models can, if used correctly, significantly improve the imaginative role of architectural representation....

DockoMatic 2.0: high throughput inverse virtual screening and homology modeling.

Science.gov (United States)

Bullock, Casey; Cornia, Nic; Jacob, Reed; Remm, Andrew; Peavey, Thomas; Weekes, Ken; Mallory, Chris; Oxford, Julia T; McDougal, Owen M; Andersen, Timothy L

2013-08-26

DockoMatic is a free and open source application that unifies a suite of software programs within a user-friendly graphical user interface (GUI) to facilitate molecular docking experiments. Here we describe the release of DockoMatic 2.0; significant software advances include the ability to (1) conduct high throughput inverse virtual screening (IVS); (2) construct 3D homology models; and (3) customize the user interface. Users can now efficiently setup, start, and manage IVS experiments through the DockoMatic GUI by specifying receptor(s), ligand(s), grid parameter file(s), and docking engine (either AutoDock or AutoDock Vina). DockoMatic automatically generates the needed experiment input files and output directories and allows the user to manage and monitor job progress. Upon job completion, a summary of results is generated by Dockomatic to facilitate interpretation by the user. DockoMatic functionality has also been expanded to facilitate the construction of 3D protein homology models using the Timely Integrated Modeler (TIM) wizard. The wizard TIM provides an interface that accesses the basic local alignment search tool (BLAST) and MODELER programs and guides the user through the necessary steps to easily and efficiently create 3D homology models for biomacromolecular structures. The DockoMatic GUI can be customized by the user, and the software design makes it relatively easy to integrate additional docking engines, scoring functions, or third party programs. DockoMatic is a free comprehensive molecular docking software program for all levels of scientists in both research and education.

Screening of a virtual mirror-image library of natural products.

Science.gov (United States)

Noguchi, Taro; Oishi, Shinya; Honda, Kaori; Kondoh, Yasumitsu; Saito, Tamio; Ohno, Hiroaki; Osada, Hiroyuki; Fujii, Nobutaka

2016-06-08

We established a facile access to an unexplored mirror-image library of chiral natural product derivatives using d-protein technology. In this process, two chemical syntheses of mirror-image substances including a target protein and hit compound(s) allow the lead discovery from a virtual mirror-image library without the synthesis of numerous mirror-image compounds.

Effect of adding screening ultrasonography to screening mammography on patient recall and cancer detection rates: A retrospective study in Japan

International Nuclear Information System (INIS)

Tohno, Eriko; Umemoto, Takeshi; Sasaki, Kyoko; Morishima, Isamu; Ueno, Ei

2013-01-01

Purpose: To determine whether adding screening ultrasonography to screening mammography can reduce patient recall rates and increase cancer detection rates. Materials and methods: We analyzed the results of mammography and ultrasonography breast screenings performed at the Total Health Evaluation Center Tsukuba, Japan, between April 2011 and March 2012. We also reviewed the modalities and results of diagnostic examinations from women with mammographic abnormalities who visited the Tsukuba Medical Center Hospital for further testing. Results: Of 11,753 women screened, cancer was diagnosed in 10 (0.22%) of the 4529 participants who underwent mammography alone, 23 (0.37%) of the 6250 participants who underwent ultrasonography alone, and 5 (0.51%) of the 974 participants who underwent mammography and ultrasonography. The recall rate due to mammographic abnormalities was 4.9% for women screened only with mammography and 2.6% for those screened with both modalities. The cancer detection rate was 0.22% for women screened only with mammography (positive predictive value, 4.5%) and 0.31% for those screened with both modalities (positive predictive value, 12.0%). Of the 211 lesions presenting as mammographic abnormalities investigated further, diagnostic ultrasonography found no abnormalities in 63 (29.9%) and benign findings in 69 (33.7%). The rest 36.4% needed mammography, cytological or histological examinations or follow-up in addition to diagnostic ultrasonography. Conclusions: It is possible to reduce the recall rate in screening mammography by combining mammography and ultrasonography for breast screening

Computation-based virtual screening for designing novel antimalarial drugs by targeting falcipain-III: a structure-based drug designing approach.

Science.gov (United States)

Kesharwani, Rajesh Kumar; Singh, Durg Vijay; Misra, Krishna

2013-01-01

Cysteine proteases (falcipains), a papain-family of enzymes of Plasmodium falciparum, are responsible for haemoglobin degradation and thus necessary for its survival during asexual life cycle phase inside the human red blood cells while remaining non-functional for the human body. Therefore, these can act as potential targets for designing antimalarial drugs. The P. falciparum cysteine proteases, falcipain-II and falcipain- III are the enzymes which initiate the haemoglobin degradation, therefore, have been selected as targets. In the present study, we have designed new leupeptin analogues and subjected to virtual screening using Glide at the active site cavity of falcipain-II and falcipain-III to select the best docked analogues on the basis of Glide score and also compare with the result of AutoDock. The proposed analogues can be synthesized and tested in vivo as future potent antimalarial drugs. Protein falcipain-II and falcipain-III together with bounds inhibitors epoxysuccinate E64 (E64) and leupeptin respectively were retrieved from protein data bank (PDB) and latter leupeptin was used as lead molecule to design new analogues by using Ligbuilder software and refined the molecules on the basis of Lipinski rule of five and fitness score parameters. All the designed leupeptin analogues were screened via docking simulation at the active site cavity of falcipain-II and falcipain-III by using Glide software and AutoDock. The 104 new leupeptin-based antimalarial ligands were designed using structure-based drug designing approach with the help of Ligbuilder and subjected for virtual screening via docking simulation method against falcipain-II and falcipain-III receptor proteins. The Glide docking results suggest that the ligands namely result_037 shows good binding and other two, result_044 and result_042 show nearly similar binding than naturally occurring PDB bound ligand E64 against falcipain-II and in case of falcipain-III, 15 designed leupeptin analogues having

Ecological validity of virtual reality daily living activities screening for early dementia: longitudinal study.

Science.gov (United States)

Tarnanas, Ioannis; Schlee, Winfried; Tsolaki, Magda; Müri, René; Mosimann, Urs; Nef, Tobias

2013-08-06

Dementia is a multifaceted disorder that impairs cognitive functions, such as memory, language, and executive functions necessary to plan, organize, and prioritize tasks required for goal-directed behaviors. In most cases, individuals with dementia experience difficulties interacting with physical and social environments. The purpose of this study was to establish ecological validity and initial construct validity of a fire evacuation Virtual Reality Day-Out Task (VR-DOT) environment based on performance profiles as a screening tool for early dementia. The objectives were (1) to examine the relationships among the performances of 3 groups of participants in the VR-DOT and traditional neuropsychological tests employed to assess executive functions, and (2) to compare the performance of participants with mild Alzheimer's-type dementia (AD) to those with amnestic single-domain mild cognitive impairment (MCI) and healthy controls in the VR-DOT and traditional neuropsychological tests used to assess executive functions. We hypothesized that the 2 cognitively impaired groups would have distinct performance profiles and show significantly impaired independent functioning in ADL compared to the healthy controls. The study population included 3 groups: 72 healthy control elderly participants, 65 amnestic MCI participants, and 68 mild AD participants. A natural user interface framework based on a fire evacuation VR-DOT environment was used for assessing physical and cognitive abilities of seniors over 3 years. VR-DOT focuses on the subtle errors and patterns in performing everyday activities and has the advantage of not depending on a subjective rating of an individual person. We further assessed functional capacity by both neuropsychological tests (including measures of attention, memory, working memory, executive functions, language, and depression). We also evaluated performance in finger tapping, grip strength, stride length, gait speed, and chair stands separately and

Colorectal Cancer Screening (PDQ®)—Patient Version

Science.gov (United States)

There are five types of tests that are used to screen for colorectal cancer: fecal occult blood test, sigmoidoscopy, colonoscopy, virtual colonoscopy, and DNA stool test. Learn more about these and other tests in this expert-reviewed summary.

Seamless 3D interaction for virtual tables, projection planes, and CAVEs

Science.gov (United States)

Encarnacao, L. M.; Bimber, Oliver; Schmalstieg, Dieter; Barton, Robert J., III

2000-08-01

The Virtual Table presents stereoscopic graphics to a user in a workbench-like setting. This device shares with other large- screen display technologies (such as data walls and surround- screen projection systems) the lack of human-centered unencumbered user interfaces and 3D interaction technologies. Such shortcomings present severe limitations to the application of virtual reality (VR) technology to time- critical applications as well as employment scenarios that involve heterogeneous groups of end-users without high levels of computer familiarity and expertise. Traditionally such employment scenarios are common in planning-related application areas such as mission rehearsal and command and control. For these applications, a high grade of flexibility with respect to the system requirements (display and I/O devices) as well as to the ability to seamlessly and intuitively switch between different interaction modalities and interaction are sought. Conventional VR techniques may be insufficient to meet this challenge. This paper presents novel approaches for human-centered interfaces to Virtual Environments focusing on the Virtual Table visual input device. It introduces new paradigms for 3D interaction in virtual environments (VE) for a variety of application areas based on pen-and-clipboard, mirror-in-hand, and magic-lens metaphors, and introduces new concepts for combining VR and augmented reality (AR) techniques. It finally describes approaches toward hybrid and distributed multi-user interaction environments and concludes by hypothesizing on possible use cases for defense applications.

Discovery of small molecules binding to the normal conformation of prion by combining virtual screening and multiple biological activity evaluation methods

Science.gov (United States)

Li, Lanlan; Wei, Wei; Jia, Wen-Juan; Zhu, Yongchang; Zhang, Yan; Chen, Jiang-Huai; Tian, Jiaqi; Liu, Huanxiang; He, Yong-Xing; Yao, Xiaojun

2017-12-01

Conformational conversion of the normal cellular prion protein, PrPC, into the misfolded isoform, PrPSc, is considered to be a central event in the development of fatal neurodegenerative diseases. Stabilization of prion protein at the normal cellular form (PrPC) with small molecules is a rational and efficient strategy for treatment of prion related diseases. However, few compounds have been identified as potent prion inhibitors by binding to the normal conformation of prion. In this work, to rational screening of inhibitors capable of stabilizing cellular form of prion protein, multiple approaches combining docking-based virtual screening, steady-state fluorescence quenching, surface plasmon resonance and thioflavin T fluorescence assay were used to discover new compounds interrupting PrPC to PrPSc conversion. Compound 3253-0207 that can bind to PrPC with micromolar affinity and inhibit prion fibrillation was identified from small molecule databases. Molecular dynamics simulation indicated that compound 3253-0207 can bind to the hotspot residues in the binding pocket composed by β1, β2 and α2, which are significant structure moieties in conversion from PrPC to PrPSc.

Identification of novel antitubulin agents by using a virtual screening approach based on a 7-point pharmacophore model of the tubulin colchi-site.

Science.gov (United States)

Massarotti, Alberto; Theeramunkong, Sewan; Mesenzani, Ornella; Caldarelli, Antonio; Genazzani, Armando A; Tron, Gian Cesare

2011-12-01

Tubulin inhibition represents an established target in the field of anticancer research, and over the last 20 years, an intensive search for new antimicrotubule agents has occurred. Indeed, in silico models have been presented that might aid the discovery of novel agents. Among these, a 7-point pharmacophore model has been recently proposed. As a formal proof of this model, we carried out a ligand-based virtual screening on the colchicine-binding site. In vitro testing demonstrated that two compounds displayed a cytotoxic profile on neuroblastoma cancer cells (SH-SY5H) and one had an antitubulinic profile. © 2011 John Wiley & Sons A/S.

Identification of Mycobacterium tuberculosis BioA inhibitors by using structure-based virtual screening

Science.gov (United States)

Singh, Swati; Khare, Garima; Bahal, Ritika Kar; Ghosh, Prahlad C; Tyagi, Anil K

2018-01-01

Background 7,8-Diaminopelargonic acid synthase (BioA), an enzyme of biotin biosynthesis pathway, is a well-known promising target for anti-tubercular drug development. Methods In this study, structure-based virtual screening was employed against the active site of BioA to identify new chemical entities for BioA inhibition and top ranking compounds were evaluated for their ability to inhibit BioA enzymatic activity. Results Seven compounds inhibited BioA enzymatic activity by greater than 60% at 100 μg/mL with most potent compounds being A36, A35 and A65, displaying IC50 values of 10.48 μg/mL (28.94 μM), 33.36 μg/mL (88.16 μM) and 39.17 μg/mL (114.42 μM), respectively. Compounds A65 and A35 inhibited Mycobacterium tuberculosis (M. tuberculosis) growth with MIC90 of 20 μg/mL and 80 μg/mL, respectively, whereas compound A36 exhibited relatively weak inhibition of M. tuberculosis growth (83% inhibition at 200 μg/mL). Compound A65 emerged as the most potent compound identified in our study that inhibited BioA enzymatic activity and growth of the pathogen and possessed drug-like properties. Conclusion Our study has identified a few hit molecules against M. tuberculosis BioA that can act as potential candidates for further development of potent anti-tubercular therapeutic agents. PMID:29750019

Virtual reality interventions for rehabilitation: considerations for developing protocols.

Science.gov (United States)

Boechler, Patricia; Krol, Andrea; Raso, Jim; Blois, Terry

2009-01-01

This paper is a preliminary report on a work in progress that explores the existence of practice effects in early use of virtual reality environments for rehabilitation purposes and the effects of increases in level of difficulty as defined by rate of on-screen objects.

Grasping trajectories in a virtual environment adhere to Weber's law.

Science.gov (United States)

Ozana, Aviad; Berman, Sigal; Ganel, Tzvi

2018-06-01

Virtual-reality and telerobotic devices simulate local motor control of virtual objects within computerized environments. Here, we explored grasping kinematics within a virtual environment and tested whether, as in normal 3D grasping, trajectories in the virtual environment are performed analytically, violating Weber's law with respect to object's size. Participants were asked to grasp a series of 2D objects using a haptic system, which projected their movements to a virtual space presented on a computer screen. The apparatus also provided object-specific haptic information upon "touching" the edges of the virtual targets. The results showed that grasping movements performed within the virtual environment did not produce the typical analytical trajectory pattern obtained during 3D grasping. Unlike as in 3D grasping, grasping trajectories in the virtual environment adhered to Weber's law, which indicates relative resolution in size processing. In addition, the trajectory patterns differed from typical trajectories obtained during 3D grasping, with longer times to complete the movement, and with maximum grip apertures appearing relatively early in the movement. The results suggest that grasping movements within a virtual environment could differ from those performed in real space, and are subjected to irrelevant effects of perceptual information. Such atypical pattern of visuomotor control may be mediated by the lack of complete transparency between the interface and the virtual environment in terms of the provided visual and haptic feedback. Possible implications of the findings to movement control within robotic and virtual environments are further discussed.

Hsp90 inhibitors, part 1: definition of 3-D QSAutogrid/R models as a tool for virtual screening.

Science.gov (United States)

Ballante, Flavio; Caroli, Antonia; Wickersham, Richard B; Ragno, Rino

2014-03-24

The multichaperone heat shock protein (Hsp) 90 complex mediates the maturation and stability of a variety of oncogenic signaling proteins. For this reason, Hsp90 has emerged as a promising target for anticancer drug development. Herein, we describe a complete computational procedure for building several 3-D QSAR models used as a ligand-based (LB) component of a comprehensive ligand-based (LB) and structure-based (SB) virtual screening (VS) protocol to identify novel molecular scaffolds of Hsp90 inhibitors. By the application of the 3-D QSAutogrid/R method, eight SB PLS 3-D QSAR models were generated, leading to a final multiprobe (MP) 3-D QSAR pharmacophoric model capable of recognizing the most significant chemical features for Hsp90 inhibition. Both the monoprobe and multiprobe models were optimized, cross-validated, and tested against an external test set. The obtained statistical results confirmed the models as robust and predictive to be used in a subsequent VS.

Virtual Paint for Android

OpenAIRE

Miloeski, Aleksandar

2017-01-01

The aim of this thesis is to create a functional application for the Android environment that allows the user to do simple virtual drawings without the use of the touch screen, but rather through hand motions caught by the camera. There is a variety of approaches to this end, which vary by complexity and performance. This piece of work attempts to find a middle ground among the existing algorithms, as well as to build on and improve them specifically for this particular task. The idea is ...

Encompassing receptor flexibility in virtual screening using ensemble docking-based hybrid QSAR: discovery of novel phytochemicals for BACE1 inhibition.

Science.gov (United States)

Chakraborty, Sandipan; Ramachandran, Balaji; Basu, Soumalee

2014-10-01

Mimicking receptor flexibility during receptor-ligand binding is a challenging task in computational drug design since it is associated with a large increase in the conformational search space. In the present study, we have devised an in silico design strategy incorporating receptor flexibility in virtual screening to identify potential lead compounds as inhibitors for flexible proteins. We have considered BACE1 (β-secretase), a key target protease from a therapeutic perspective for Alzheimer's disease, as the highly flexible receptor. The protein undergoes significant conformational transitions from open to closed form upon ligand binding, which makes it a difficult target for inhibitor design. We have designed a hybrid structure-activity model containing both ligand based descriptors and energetic descriptors obtained from molecular docking based on a dataset of structurally diverse BACE1 inhibitors. An ensemble of receptor conformations have been used in the docking study, further improving the prediction ability of the model. The designed model that shows significant prediction ability judged by several statistical parameters has been used to screen an in house developed 3-D structural library of 731 phytochemicals. 24 highly potent, novel BACE1 inhibitors with predicted activity (Ki) ≤ 50 nM have been identified. Detailed analysis reveals pharmacophoric features of these novel inhibitors required to inhibit BACE1.

Virtual Training of the Myosignal.

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Bernhard Terlaak

Full Text Available To investigate which of three virtual training methods produces the largest learning effects on discrete and continuous myocontrol. The secondary objective was to examine the relation between myocontrol and manual motor control tests.A cohort analytic study.University laboratory.3 groups of 12 able-bodied participants (N = 36.Participants trained the control over their myosignals on 3 consecutive days. Training was done with either myosignal feedback on a computer screen, a virtual myoelectric prosthetic hand or a computer game. Participants performed 2 myocontrol tests and 2 manual motor control tests before the first and after the last training session. They were asked to open and close a virtual prosthetic hand on 3 different velocities as a discrete myocontrol test and followed a line with their myosignals for 30 seconds as a continuous myocontrol test. The motor control tests were a pegboard and grip-force test.Discrete myocontrol test: mean velocities. Continuous myocontrol test: error and error SD. Pegboard test: time to complete. Grip-force test: produced forces.No differences in learning effects on myocontrol were found for the different virtual training methods. Discrete myocontrol ability did not significantly improve as a result of training. Continuous myocontrol ability improved significantly as a result of training, both on average control and variability. All correlations between the motor control and myocontrol test outcome measures were below .50.Three different virtual training methods showed comparable results when learning myocontrol. Continuous myocontrol was improved by training while discrete myocontrol was not. Myocontrol ability could not be predicted by the manual motor control tests.

Evaluation of a focused virtual library of heterobifunctional ligands for Clostridium difficile toxins.

Science.gov (United States)

Sanhueza, Carlos A; Cartmell, Jonathan; El-Hawiet, Amr; Szpacenko, Adam; Kitova, Elena N; Daneshfar, Rambod; Klassen, John S; Lang, Dean E; Eugenio, Luiz; Ng, Kenneth K-S; Kitov, Pavel I; Bundle, David R

2015-01-07

A focused library of virtual heterobifunctional ligands was generated in silico and a set of ligands with recombined fragments was synthesized and evaluated for binding to Clostridium difficile toxins. The position of the trisaccharide fragment was used as a reference for filtering docked poses during virtual screening to match the trisaccharide ligand in a crystal structure. The peptoid, a diversity fragment probing the protein surface area adjacent to a known binding site, was generated by a multi-component Ugi reaction. Our approach combines modular fragment-based design with in silico screening of synthetically feasible compounds and lays the groundwork for future efforts in development of composite bifunctional ligands for large clostridial toxins.

How effective is a virtual consultation process in facilitating multidisciplinary decision-making for malignant epidural spinal cord compression?

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Fitzpatrick, David; Grabarz, Daniel; Wang, Lisa; Bezjak, Andrea; Fehlings, Michael G; Fosker, Christopher; Rampersaud, Raja; Wong, Rebecca K S

2012-10-01

The purpose of this study was to assess the accuracy of a virtual consultation (VC) process in determining treatment strategy for patients with malignant epidural spinal cord compression (MESCC). A prospective clinical database was maintained for patients with MESCC. A virtual consultation process (involving exchange of key predetermined clinical information and diagnostic imaging) facilitated rapid decision-making between oncologists and spinal surgeons. Diagnostic imaging was reviewed retrospectively (by R.R.) for surgical opinions in all patients. The primary outcome was the accuracy of virtual consultation opinion in predicting the final treatment recommendation. After excluding 20 patients who were referred directly to the spinal surgeon, 125 patients were eligible for virtual consultation. Of the 46 patients who had a VC, surgery was recommended in 28 patients and actually given to 23. A retrospective review revealed that 5/79 patients who did not have a VC would have been considered surgical candidates. The overall accuracy of the virtual consultation process was estimated at 92%. The VC process for MESCC patients provides a reliable means of arriving at a multidisciplinary opinion while minimizing patient transfer. This can potentially shorten treatment decision time and enhance clinical outcomes. Copyright © 2012 Elsevier Inc. All rights reserved.

Combinatorial Pharmacophore-Based 3D-QSAR Analysis and Virtual Screening of FGFR1 Inhibitors

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Nannan Zhou

2015-06-01

Full Text Available The fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR signaling pathway plays crucial roles in cell proliferation, angiogenesis, migration, and survival. Aberration in FGFRs correlates with several malignancies and disorders. FGFRs have proved to be attractive targets for therapeutic intervention in cancer, and it is of high interest to find FGFR inhibitors with novel scaffolds. In this study, a combinatorial three-dimensional quantitative structure-activity relationship (3D-QSAR model was developed based on previously reported FGFR1 inhibitors with diverse structural skeletons. This model was evaluated for its prediction performance on a diverse test set containing 232 FGFR inhibitors, and it yielded a SD value of 0.75 pIC50 units from measured inhibition affinities and a Pearson’s correlation coefficient R2 of 0.53. This result suggests that the combinatorial 3D-QSAR model could be used to search for new FGFR1 hit structures and predict their potential activity. To further evaluate the performance of the model, a decoy set validation was used to measure the efficiency of the model by calculating EF (enrichment factor. Based on the combinatorial pharmacophore model, a virtual screening against SPECS database was performed. Nineteen novel active compounds were successfully identified, which provide new chemical starting points for further structural optimization of FGFR1 inhibitors.

Cognitive assessment and rehabilitation in virtual reality: theoretical review and practical implications

Directory of Open Access Journals (Sweden)

Negut, A.

2014-07-01

Full Text Available Virtual reality scenarios have been developed in order to assess cognitive functioning such as: memory, attention and executive function. Most scenarios replicate everyday situations like shopping activities, navigation through a park or a street, learning objects in an apartment or virtual office, or sitting and solving tasks in a classroom or apartment. Results of these studies support the use of virtual reality scenarios in neurocognitive assessment. Virtual scenarios that are used in cognitive training include a wide range of contexts from everyday life such as: a store, a kitchen, a city, as well as exercises like touching a ball on a screen for movement coordination, collecting a coconut and positioning it in a basket. Overall, virtual reality-based assessment or rehabilitation tools seem to be valid, reliable and efficient with an increased level of ecological validity.

Virtual Screening for Potential Inhibitors of NS3 Protein of Zika Virus

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Maheswata Sahoo

2016-09-01

Full Text Available Zika virus (ZIKV is a mosquito borne pathogen, belongs to Flaviviridae family having a positive-sense single-stranded RNA genome, currently known for causing large epidemics in Brazil. Its infection can cause microcephaly, a serious birth defect during pregnancy. The recent outbreak of ZIKV in February 2016 in Brazil realized it as a major health risk, demands an enhanced surveillance and a need to develop novel drugs against ZIKV. Amodiaquine, prochlorperazine, quinacrine, and berberine are few promising drugs approved by Food and Drug Administration against dengue virus which also belong to Flaviviridae family. In this study, we performed molecular docking analysis of these drugs against nonstructural 3 (NS3 protein of ZIKV. The protease activity of NS3 is necessary for viral replication and its prohibition could be considered as a strategy for treatment of ZIKV infection. Amongst these four drugs, berberine has shown highest binding affinity of –5.8 kcal/mol and it is binding around the active site region of the receptor. Based on the properties of berberine, more similar compounds were retrieved from ZINC database and a structure-based virtual screening was carried out by AutoDock Vina in PyRx 0.8. Best 10 novel drug-like compounds were identified and amongst them ZINC53047591 (2-(benzylsulfanyl-3-cyclohexyl-3H-spiro[benzo[h]quinazoline-5,1'-cyclopentan]-4(6H-one was found to interact with NS3 protein with binding energy of –7.1 kcal/mol and formed H-bonds with Ser135 and Asn152 amino acid residues. Observations made in this study may extend an assuring platform for developing anti-viral competitive inhibitors against ZIKV infection.

Virtually teaching virtual leadership

DEFF Research Database (Denmark)

Henriksen, Thomas Duus; Nielsen, Rikke Kristine; Børgesen, Kenneth

2017-01-01

This paper seeks to investigate the challenges to virtual collaboration and leadership on basis of findings from a virtual course on collaboration and leadership. The course used for this experiment was designed as a practical approach, which allowed participants to experience curriculum phenomena....... This experimental course provided insights into the challenges involved in virtual processes, and those experiences where used for addressing the challenges that virtual leadership is confronted with. Emphasis was placed on the reduction of undesired virtual distance and its consequences through affinity building....... We found that student scepticism appeared when a breakdown resulted in increasing virtual distance, and raises questions on how leaders might translate or upgrade their understandings of leadership to handling such increased distance through affinity building....

Virtual screening of compounds derived from Garcinia pedunculata as an inhibitor of gamma hemolysin component A of Staphylococcus aureus

Directory of Open Access Journals (Sweden)

Tarali Chowdhury

2014-03-01

Full Text Available With the emergence of multi-drug resistant pathogens at alarming frequency, there has been an increase interest in the development of novel drugs from natural resources. The use of higher plants and preparations made from them to treat infections is a longstanding practice in a large part of the population, especially in the developing countries, where there is dependence on traditional medicine for a variety of ailments. The virtual screening method was used in this study to analyze the docking and inhibitory activities of some natural bioactive compounds present within Garcinia pedunculata against hemolysin toxin of Staphylococcus aureus, gamma-hemolysin component A hlgA. The study resulted in identifying compounds 1,3,6,7-tetrahydroxy-xanthone and garcinone D with high binding affinity towards the target protein revealing them as potent inhibitors that could be further used to create new drug source in the treatment of staphyloccocal infections.

Target-specific support vector machine scoring in structure-based virtual screening: computational validation, in vitro testing in kinases, and effects on lung cancer cell proliferation.

Science.gov (United States)

Li, Liwei; Khanna, May; Jo, Inha; Wang, Fang; Ashpole, Nicole M; Hudmon, Andy; Meroueh, Samy O

2011-04-25

We assess the performance of our previously reported structure-based support vector machine target-specific scoring function across 41 targets, 40 among them from the Directory of Useful Decoys (DUD). The area under the curve of receiver operating characteristic plots (ROC-AUC) revealed that scoring with SVM-SP resulted in consistently better enrichment over all target families, outperforming Glide and other scoring functions, most notably among kinases. In addition, SVM-SP performance showed little variation among protein classes, exhibited excellent performance in a test case using a homology model, and in some cases showed high enrichment even with few structures used to train a model. We put SVM-SP to the test by virtual screening 1125 compounds against two kinases, EGFR and CaMKII. Among the top 25 EGFR compounds, three compounds (1-3) inhibited kinase activity in vitro with IC₅₀ of 58, 2, and 10 μM. In cell cultures, compounds 1-3 inhibited nonsmall cell lung carcinoma (H1299) cancer cell proliferation with similar IC₅₀ values for compound 3. For CaMKII, one compound inhibited kinase activity in a dose-dependent manner among 20 tested with an IC₅₀ of 48 μM. These results are encouraging given that our in-house library consists of compounds that emerged from virtual screening of other targets with pockets that are different from typical ATP binding sites found in kinases. In light of the importance of kinases in chemical biology, these findings could have implications in future efforts to identify chemical probes of kinases within the human kinome.

A virtual reality endoscopic simulator augments general surgery resident cancer education as measured by performance improvement.

Science.gov (United States)

White, Ian; Buchberg, Brian; Tsikitis, V Liana; Herzig, Daniel O; Vetto, John T; Lu, Kim C

2014-06-01

Colorectal cancer is the second most common cause of death in the USA. The need for screening colonoscopies, and thus adequately trained endoscopists, particularly in rural areas, is on the rise. Recent increases in required endoscopic cases for surgical resident graduation by the Surgery Residency Review Committee (RRC) further emphasize the need for more effective endoscopic training during residency to determine if a virtual reality colonoscopy simulator enhances surgical resident endoscopic education by detecting improvement in colonoscopy skills before and after 6 weeks of formal clinical endoscopic training. We conducted a retrospective review of prospectively collected surgery resident data on an endoscopy simulator. Residents performed four different clinical scenarios on the endoscopic simulator before and after a 6-week endoscopic training course. Data were collected over a 5-year period from 94 different residents performing a total of 795 colonoscopic simulation scenarios. Main outcome measures included time to cecal intubation, "red out" time, and severity of simulated patient discomfort (mild, moderate, severe, extreme) during colonoscopy scenarios. Average time to intubation of the cecum was 6.8 min for those residents who had not undergone endoscopic training versus 4.4 min for those who had undergone endoscopic training (p Virtual reality endoscopic simulation is an effective tool for both augmenting surgical resident endoscopy cancer education and measuring improvement in resident performance after formal clinical endoscopic training.

Efficacy of routine pre-radiation dental screening and dental follow-up in head and neck oncology patients on intermediate and late radiation effects. A retrospective evaluation.

Science.gov (United States)

Schuurhuis, Jennifer M; Stokman, Monique A; Roodenburg, Johannes L N; Reintsema, Harry; Langendijk, Johannes A; Vissink, Arjan; Spijkervet, Frederik K L

2011-12-01

Head-neck radiotherapy is accompanied by a life-long risk of developing severe oral problems. This study retrospectively assessed oral foci detected during pre-radiation dental screening and follow-up in order to assess risk factors for developing oral problems after radiotherapy. Charts of 185 consecutive head-neck cancer patients, subjected to a pre-radiation dental screening in the University Medical Center Groningen, the Netherlands, between January 2004 and December 2008 were reviewed. Eighty (partially) dentulous patients scheduled for curative head-neck radiotherapy met the inclusion criteria. Oral foci were found in 76% of patients, predominantly periodontal disease. Osteoradionecrosis had developed in 9 out of 80 patients (11%). Overall, patients presenting with periodontal pockets ≥ 6mm at dental screening had an increased risk (19%) of developing osteoradionecrosis compared to the total group of patients. Patients in whom periodontal disease treatment was composed of initial periodontal in stead of removal of the affected teeth, the risk of developing osteoradionecrosis was even higher, viz. 33%. A worse periodontal condition at dental screening and initial periodontal therapy to safeguard these patients to develop severe oral sequelae after radiotherapy were shown to be major risk factors of developing osteoradionecrosis. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Efficacy of routine pre-radiation dental screening and dental follow-up in head and neck oncology patients on intermediate and late radiation effects. A retrospective evaluation

International Nuclear Information System (INIS)

Schuurhuis, Jennifer M.; Stokman, Monique A.; Roodenburg, Johannes L.N.; Reintsema, Harry; Langendijk, Johannes A.; Vissink, Arjan; Spijkervet, Frederik K.L.

2011-01-01

Background and purpose: Head–neck radiotherapy is accompanied by a life-long risk of developing severe oral problems. This study retrospectively assessed oral foci detected during pre-radiation dental screening and follow-up in order to assess risk factors for developing oral problems after radiotherapy. Materials and methods: Charts of 185 consecutive head–neck cancer patients, subjected to a pre-radiation dental screening in University Medical Center Groningen, the Netherlands, between January 2004 and December 2008 were reviewed. Eighty (partially) dentulous patients scheduled for curative head–neck radiotherapy met the inclusion criteria. Results: Oral foci were found in 76% of patients, predominantly periodontal disease. Osteoradionecrosis had developed in 9 out of 80 patients (11%). Overall, patients presenting with periodontal pockets ⩾6 mm at dental screening had an increased risk (19%) of developing osteoradionecrosis compared to the total group of patients. Patients in whom periodontal disease treatment was composed of initial periodontal in stead of removal of the affected teeth, the risk of developing osteoradionecrosis was even higher, viz. 33%. Conclusions: A worse periodontal condition at dental screening and initial periodontal therapy to safeguard these patients to develop severe oral sequelae after radiotherapy were shown to be major risk factors of developing osteoradionecrosis.

Detection of the antiviral activity of epicatechin isolated from Salacia crassifolia (Celastraceae) against Mayaro virus based on protein C homology modelling and virtual screening.

Science.gov (United States)

Ferreira, P G; Ferraz, A C; Figueiredo, J E; Lima, C F; Rodrigues, V G; Taranto, A G; Ferreira, J M S; Brandão, G C; Vieira-Filho, S A; Duarte, L P; de Brito Magalhães, C L; de Magalhães, J C

2018-02-24

Mayaro fever, caused by Mayaro virus (MAYV) is a sub-lethal disease with symptoms that are easily confused with those of dengue fever, except for polyarthralgia, which may culminate in physical incapacitation. Recently, outbreaks of MAYV have been documented in metropolitan areas, and to date, there is no therapy or vaccine available. Moreover, there is no information regarding the three-dimensional structure of the viral proteins of MAYV, which is important in the search for antivirals. In this work, we constructed a three-dimensional model of protein C of MAYV by homology modelling, and this was employed in a manner similar to that of receptors in virtual screening studies to evaluate 590 molecules as prospective antiviral agents. In vitro bioassays were utilized to confirm the potential antiviral activity of the flavonoid epicatechin isolated from Salacia crassifolia (Celastraceae). The virtual screening showed that six flavonoids were promising ligands for protein C. The bioassays showed potent antiviral action of epicatechin, which protected the cells from almost all of the effects of viral infection. An effective concentration (EC 50 ) of 0.247 μmol/mL was observed with a selectivity index (SI) of 7. The cytotoxicity assay showed that epicatechin has low toxicity, with a 50% cytotoxic concentration (CC 50 ) greater than 1.723 µmol/mL. Epicatechin was found to be twice as potent as the reference antiviral ribavirin. Furthermore, a replication kinetics assay showed a strong inhibitory effect of epicatechin on MAYV growth, with a reduction of at least four logs in virus production. Our results indicate that epicatechin is a promising candidate for further testing as an antiviral agent against Mayaro virus and other alphaviruses.

A retrospective study on findings of canine hip dysplasia screening in Kenya

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Peter Kimeli

2015-11-01

Full Text Available Aim: The current study was undertaken to evaluate the findings of canine hip dysplasia screening in Kenya. Materials and Methods: Records for 591 dogs were included in this study. The data was obtained from the national screening office, Kenya Veterinary Board, for the period between the years 1998 and 2014. Monthly screening records were assessed and information relating to year of evaluation, breed, sex, age, and hip score captured. Descriptive statistics of hip scores was computed based on year, sex, age, and breed. Results: A total of 591 records from the year 1998 to 2014 were retrieved at the National Screening Centre, the Kenya Veterinary Board. Each record was examined and data pertaining to year of screening, the breed, sex, age of the dogs, and the total hip score were recorded. The highest number of dogs screened for hip dysplasia (HD was in the year 2009 and the lowest in the year 1998. More females than males were screened for HD and the mean age of all the dogs was 22.9±12.7 months. The most common breeds of dogs screened during the study period were German Shepherd (67.0%, Rottweiler (15.6%, and Labrador Retriever (12.2%. The mean hip score for the 591 dogs was 15.1±10.9 and the median 12.0. The mean hip scores per breed were; German Shepherd (16.3±12.1; Golden Retriever (16.0; Hungarian Vizla (15.0; Labrador Retriever (3.0±6.7; Great Dane (13.3±3.2; Rottweiler (12.2±8.2; Doberman (10.3±4.2; Rhodesian Ridgeback (9.6±3.8; and Boxer (9.3±0.6. Based on the hip score, moderate to severe HD was diagnosed in 16.6% of the dogs, mild HD in 32.7%, Borderline HD in 37.7%, fair HD in 6.9%, and good HD in 6.1%. Conclusion: Canine HD is a common occurrence in Kenya with most dogs suffering mild to border line HD. In addition, German Shepherd and Golden Retriever appear to be the most affected breeds. It is therefore recommended that stringent measures be imposed to dog breeding programs to avoid transmission of this undesirable trait

Successful application of virtual screening and molecular dynamics simulations against antimalarial molecular targets

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Renata Rachide Nunes

Full Text Available The main challenge in the control of malaria has been the emergence of drug-resistant parasites. The presence of drug-resistant Plasmodium sp. has raised the need for new antimalarial drugs. Molecular modelling techniques have been used as tools to develop new drugs. In this study, we employed virtual screening of a pyrazol derivative (Tx001 against four malaria targets: plasmepsin-IV, plasmepsin-II, falcipain-II, and PfATP6. The receiver operating characteristic curves and area under the curve (AUC were established for each molecular target. The AUC values obtained for plasmepsin-IV, plasmepsin-II, and falcipain-II were 0.64, 0.92, and 0.94, respectively. All docking simulations were carried out using AutoDock Vina software. The ligand Tx001 exhibited a better interaction with PfATP6 than with the reference compound (-12.2 versus -6.8 Kcal/mol. The Tx001-PfATP6 complex was submitted to molecular dynamics simulations in vacuum implemented on an NAMD program. The ligand Tx001 docked at the same binding site as thapsigargin, which is a natural inhibitor of PfATP6. Compound TX001 was evaluated in vitro with a P. falciparum strain (W2 and a human cell line (WI-26VA4. Tx001 was discovered to be active against P. falciparum (IC50 = 8.2 µM and inactive against WI-26VA4 (IC50 > 200 µM. Further ligand optimisation cycles generated new prospects for docking and biological assays.

Virtual CT-colonoscopy. Examination technique, limitations, and prospects

International Nuclear Information System (INIS)

Springer, P.; Dessl, A.; Giacomuzzi, S.M.; Stoehr, B.; Stoeger, A.; Bodner, G.; Buchberger, W.

1997-01-01

Virtual CT-colonoscopy is a post-processing method which allows for reconstruction of inner bowel surface structures from helical CT datasets. The reconstructed images simulate the views which are known from fiberoptic endoscopy. Since colorectal cancer is the second main cause of death in USA and Europe today and since recent screening recommendations are often ignored by the public, a non-invasive or minimal-invasive procedure for colonic evaluation would offer some benefits. Virtual CT-colonoscopy generally involves three essential steps: patient preparation with cleansing of the bowel and administration of an air enema, helical CT-examination by using appropriate scan parameters, and interactive 3D rendering of the volume dataset. Although recent studies have demonstrated that polypoid lesions of about 5 mm size are well detectable and although virtual colonoscopy offers many advantages over fiberoptic endoscopy, some technical and clinical limitations must still be noted. Thus, the current inability of virtual colonoscopy to provide texture and color leads to problems in identifying flat lesions; the presence of retained or adherent fecal matter may result to false positive diagnosis and collapsed segments of bowel may cause problems as they cannot subsequently be evaluated during image reconstruction. Virtual endoscopy is still in its infancy and further technical and clinical development are necessary. (orig./AJ) [de

Haptic Systems for Post-Stroke Rehabilitation: from Virtual Reality to Remote Rehabilitation

OpenAIRE

Daud, Omar Andres

2011-01-01

Haptic devices are becoming a common and significant tool in the perspective of robotic neurorehabilitation for motor learning, particularly in post-stroke patients. As a standard approach, this kind of devices are used in a local environment, where the patient interacts with a virtual environment recreated in the computer's screen. In this sense, a general framework for virtual reality based rehabilitation was developed. All the features of the framework, such as the control loop and the ext...

Docking ligands into flexible and solvated macromolecules. 7. Impact of protein flexibility and water molecules on docking-based virtual screening accuracy.

Science.gov (United States)

Therrien, Eric; Weill, Nathanael; Tomberg, Anna; Corbeil, Christopher R; Lee, Devin; Moitessier, Nicolas

2014-11-24

The use of predictive computational methods in the drug discovery process is in a state of continual growth. Over the last two decades, an increasingly large number of docking tools have been developed to identify hits or optimize lead molecules through in-silico screening of chemical libraries to proteins. In recent years, the focus has been on implementing protein flexibility and water molecules. Our efforts led to the development of Fitted first reported in 2007 and further developed since then. In this study, we wished to evaluate the impact of protein flexibility and occurrence of water molecules on the accuracy of the Fitted docking program to discriminate active compounds from inactive compounds in virtual screening (VS) campaigns. For this purpose, a total of 171 proteins cocrystallized with small molecules representing 40 unique enzymes and receptors as well as sets of known ligands and decoys were selected from the Protein Data Bank (PDB) and the Directory of Useful Decoys (DUD), respectively. This study revealed that implementing displaceable crystallographic or computationally placed particle water molecules and protein flexibility can improve the enrichment in active compounds. In addition, an informed decision based on library diversity or research objectives (hit discovery vs lead optimization) on which implementation to use may lead to significant improvements.

Virtual Reality Exploration and Planning for Precision Colorectal Surgery.

Science.gov (United States)

Guerriero, Ludovica; Quero, Giuseppe; Diana, Michele; Soler, Luc; Agnus, Vincent; Marescaux, Jacques; Corcione, Francesco

2018-06-01

Medical software can build a digital clone of the patient with 3-dimensional reconstruction of Digital Imaging and Communication in Medicine images. The virtual clone can be manipulated (rotations, zooms, etc), and the various organs can be selectively displayed or hidden to facilitate a virtual reality preoperative surgical exploration and planning. We present preliminary cases showing the potential interest of virtual reality in colorectal surgery for both cases of diverticular disease and colonic neoplasms. This was a single-center feasibility study. The study was conducted at a tertiary care institution. Two patients underwent a laparoscopic left hemicolectomy for diverticular disease, and 1 patient underwent a laparoscopic right hemicolectomy for cancer. The 3-dimensional virtual models were obtained from preoperative CT scans. The virtual model was used to perform preoperative exploration and planning. Intraoperatively, one of the surgeons was manipulating the virtual reality model, using the touch screen of a tablet, which was interactively displayed to the surgical team. The main outcome was evaluation of the precision of virtual reality in colorectal surgery planning and exploration. In 1 patient undergoing laparoscopic left hemicolectomy, an abnormal origin of the left colic artery beginning as an extremely short common trunk from the inferior mesenteric artery was clearly seen in the virtual reality model. This finding was missed by the radiologist on CT scan. The precise identification of this vascular variant granted a safe and adequate surgery. In the remaining cases, the virtual reality model helped to precisely estimate the vascular anatomy, providing key landmarks for a safer dissection. A larger sample size would be necessary to definitively assess the efficacy of virtual reality in colorectal surgery. Virtual reality can provide an enhanced understanding of crucial anatomical details, both preoperatively and intraoperatively, which could

Validation of virtual learning object to support the teaching of nursing care systematization

Directory of Open Access Journals (Sweden)

Pétala Tuani Candido de Oliveira Salvador

Full Text Available ABSTRACT Objective: to describe the content validation process of a Virtual Learning Object to support the teaching of nursing care systematization to nursing professionals. Method: methodological study, with quantitative approach, developed according to the methodological reference of Pasquali's psychometry and conducted from March to July 2016, from two-stage Delphi procedure. Results: in the Delphi 1 stage, eight judges evaluated the Virtual Object; in Delphi 2 stage, seven judges evaluated it. The seven screens of the Virtual Object were analyzed as to the suitability of its contents. The Virtual Learning Object to support the teaching of nursing care systematization was considered valid in its content, with a Total Content Validity Coefficient of 0.96. Conclusion: it is expected that the Virtual Object can support the teaching of nursing care systematization in light of appropriate and effective pedagogical approaches.

Computational redesign of bacterial biotin carboxylase inhibitors using structure-based virtual screening of combinatorial libraries.

Science.gov (United States)

Brylinski, Michal; Waldrop, Grover L

2014-04-02

As the spread of antibiotic resistant bacteria steadily increases, there is an urgent need for new antibacterial agents. Because fatty acid synthesis is only used for membrane biogenesis in bacteria, the enzymes in this pathway are attractive targets for antibacterial agent development. Acetyl-CoA carboxylase catalyzes the committed and regulated step in fatty acid synthesis. In bacteria, the enzyme is composed of three distinct protein components: biotin carboxylase, biotin carboxyl carrier protein, and carboxyltransferase. Fragment-based screening revealed that amino-oxazole inhibits biotin carboxylase activity and also exhibits antibacterial activity against Gram-negative organisms. In this report, we redesigned previously identified lead inhibitors to expand the spectrum of bacteria sensitive to the amino-oxazole derivatives by including Gram-positive species. Using 9,411 small organic building blocks, we constructed a diverse combinatorial library of 1.2×10⁸ amino-oxazole derivatives. A subset of 9×10⁶ of these compounds were subjected to structure-based virtual screening against seven biotin carboxylase isoforms using similarity-based docking by eSimDock. Potentially broad-spectrum antibiotic candidates were selected based on the consensus ranking by several scoring functions including non-linear statistical models implemented in eSimDock and traditional molecular mechanics force fields. The analysis of binding poses of the top-ranked compounds docked to biotin carboxylase isoforms suggests that: (1) binding of the amino-oxazole anchor is stabilized by a network of hydrogen bonds to residues 201, 202 and 204; (2) halogenated aromatic moieties attached to the amino-oxazole scaffold enhance interactions with a hydrophobic pocket formed by residues 157, 169, 171 and 203; and (3) larger substituents reach deeper into the binding pocket to form additional hydrogen bonds with the side chains of residues 209 and 233. These structural insights into drug

Study on the Mechanisms of Active Compounds in Traditional Chinese Medicine for the Treatment of Influenza Virus by Virtual Screening.

Science.gov (United States)

Ai, Haixin; Wu, Xuewei; Qi, Mengyuan; Zhang, Li; Hu, Huan; Zhao, Qi; Zhao, Jian; Liu, Hongsheng

2018-06-01

In recent years, new strains of influenza virus such as H7N9, H10N8, H5N6 and H5N8 had continued to emerge. There was an urgent need for discovery of new anti-influenza virus drugs as well as accurate and efficient large-scale inhibitor screening methods. In this study, we focused on six influenza virus proteins that could be anti-influenza drug targets, including neuraminidase (NA), hemagglutinin (HA), matrix protein 1 (M1), M2 proton channel (M2), nucleoprotein (NP) and non-structural protein 1 (NS1). Structure-based molecular docking was utilized to identify potential inhibitors for these drug targets from 13144 compounds in the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform. The results showed that 56 compounds could inhibit more than two drug targets simultaneously. Further, we utilized reverse docking to study the interaction of these compounds with host targets. Finally, the 22 compound inhibitors could stably bind to host targets with high binding free energy. The results showed that the Chinese herbal medicines had a multi-target effect, which could directly inhibit influenza virus by the target viral protein and indirectly inhibit virus by the human target protein. This method was of great value for large-scale virtual screening of new anti-influenza virus compounds.

Virtual screening studies of Chinese medicine Coptidis Rhizoma as alpha7 nicotinic acetylcholine receptor agonists for treatment of Alzheimer's disease

Science.gov (United States)

Xiang, Li; Xu, Youdong; Zhang, Yan; Meng, Xianli; Wang, Ping

2015-04-01

Alzheimer's disease (AD) is an age-related neurodegenerative disease. Extensive in vitro and in vivo experiments have proved that the decreased activity of the cholinergic neuron is responsible for the memory and cognition deterioration. The alpha7 nicotinic acetylcholine receptor (α7-nAChR) is proposed to a drug target of AD, and compounds which acting as α7-nAChR agonists are considered as candidates in AD treatment. Chinese medicine CoptidisRhizoma and its compounds are reported in various anti-AD effects. In this study, virtual screening, docking approaches and hydrogen bond analyses were applied to screen potential α7-nAChR agonists from CoptidisRhizome. The 3D structure of the protein was obtained from PDB database. 87 reported compounds were included in this research and their structures were accessed by NCBI Pubchem. Docking analysis of the compounds was performed using AutoDock 4.2 and AutoDock Vina. The images of the binding modes hydrogen bonds and the hydrophobic interaction were rendered with PyMOL1.5.0.4. and LigPlot+ respectively. Finally, N-tran-feruloyltyramine, isolariciresinol, flavanone, secoisolariciresinol, (+)-lariciresinol and dihydrochalcone, exhibited the lowest docking energy of protein-ligand complex. The results indicate these 6 compounds are potential α7 nAChR agonists, and expected to be effective in AD treatment.

An investigation of the efficacy of collaborative virtual reality systems for moderated remote usability testing.

Science.gov (United States)

Chalil Madathil, Kapil; Greenstein, Joel S

2017-11-01

Collaborative virtual reality-based systems have integrated high fidelity voice-based communication, immersive audio and screen-sharing tools into virtual environments. Such three-dimensional collaborative virtual environments can mirror the collaboration among usability test participants and facilitators when they are physically collocated, potentially enabling moderated usability tests to be conducted effectively when the facilitator and participant are located in different places. We developed a virtual collaborative three-dimensional remote moderated usability testing laboratory and employed it in a controlled study to evaluate the effectiveness of moderated usability testing in a collaborative virtual reality-based environment with two other moderated usability testing methods: the traditional lab approach and Cisco WebEx, a web-based conferencing and screen sharing approach. Using a mixed methods experimental design, 36 test participants and 12 test facilitators were asked to complete representative tasks on a simulated online shopping website. The dependent variables included the time taken to complete the tasks; the usability defects identified and their severity; and the subjective ratings on the workload index, presence and satisfaction questionnaires. Remote moderated usability testing methodology using a collaborative virtual reality system performed similarly in terms of the total number of defects identified, the number of high severity defects identified and the time taken to complete the tasks with the other two methodologies. The overall workload experienced by the test participants and facilitators was the least with the traditional lab condition. No significant differences were identified for the workload experienced with the virtual reality and the WebEx conditions. However, test participants experienced greater involvement and a more immersive experience in the virtual environment than in the WebEx condition. The ratings for the virtual

Screen-film mammography versus full-field digital mammography in a population-based screening program: The Sogn and Fjordane study

International Nuclear Information System (INIS)

Juel, Inger-Marie; Johannessen, Gunnar; Skaane, Per; Roth Hoff, Solveig; Hofvind, Solveig

2010-01-01

Background: Studies comparing analog and digital mammography in breast cancer screening have shown conflicting results. Little is known about the use of digital photon-counting detectors. Purpose: To retrospectively compare performance indicators in screen-film (SFM) and full-field digital mammography (FFDM) using a photon-counting detector in a population-based screening program. Material and Methods: The Norwegian Social Science Data Services approved the study, which was part of the Norwegian Breast Cancer Screening Program. The program invites women aged 50-69 years to two-view mammography biannually. The study period was January 2005 to June 2006 for SFM and August 2006 to December 2007 for FFDM. Independent double reading was performed using a five-point rating scale for probability of cancer. Recalls due to abnormal mammography were retrospectively reviewed by an expert panel. Performance indicators for the two techniques were compared. Attendance rate was 83.6% (7442/8901) for SFM and 82.0% (6932/8451) for FFDM. Results: The recall rate due to abnormal mammography, cancer detection rate and positive predictive value did not differ significantly between SFM and FFDM: recall 2.3% (174/7442) versus 2.4% (168/6932), cancer detection 0.39% (29/7442) versus 0.48% (33/6932), positive predictive value 16.7% (29/174) versus 19.6% (33/168), respectively (P>0.05 for all). The recall rate due to technically inadequate mammograms was 0.3% (19/7442) for SFM and 0.01% (1/6932) for FFDM. In the retrospective review, a significantly higher proportion of calcifications and asymmetric density were categorized as normal or definitively benign in FFDM compared with SFM. The average glandular dose was 2.17 mGy for SFM and 1.25 mGy for FFDM. Conclusion: Performance indicators show that FFDM using photon-counting detector is suitable for breast cancer screening. The lower radiation dose and lower recalls due to technically inadequate mammograms are of importance in mammography

Value of Virtual Colonoscopy with 64 Row CT in Evaluation of Colorectal Cancer

International Nuclear Information System (INIS)

Zaleska-Dorobisz, Urszula; Łasecki, Mateusz; Nienartowicz, Ewa; Pelak, Joanna; Słonina, Joanna; Olchowy, Cyprian; Ścieżka, Marek; Sąsiadek, Marek

2014-01-01

Virtual colonoscopy (VC) enables three-dimensional view of walls and internal lumen of the colon as a result of reconstruction of multislice CT images. The role of VC in diagnosis of the colon abnormalities systematically increases, and in many medical centers all over the world is carried out as a screening test of patients with high risk of colorectal cancer. We analyzed results of virtual colonoscopy of 360 patients with clinical suspicion of colorectal cancer. Sensitivity and specificity of CT colonoscopy for detection of colon cancers and polyps were assessed. Results of our research have shown high diagnostic efficiency of CT colonoscopy in detection of focal lesions in large intestine of 10 mm or more diameter. Sensitivity was 85.7%, specificity 89.2%. Virtual colonoscopy is noninvasive and well tolerated by patients imaging method, which permits for early detection of the large intestine lesions with specificity and sensitivity similar to classical colonoscopy in screening exams in patients suspected for colorectal cancer. Good preparation of the patients for the examination is very important for proper diagnosis and interpretation of this imaginge procedure

AMMOS: Automated Molecular Mechanics Optimization tool for in silico Screening

Directory of Open Access Journals (Sweden)

Pajeva Ilza

2008-10-01

Full Text Available Abstract Background Virtual or in silico ligand screening combined with other computational methods is one of the most promising methods to search for new lead compounds, thereby greatly assisting the drug discovery process. Despite considerable progresses made in virtual screening methodologies, available computer programs do not easily address problems such as: structural optimization of compounds in a screening library, receptor flexibility/induced-fit, and accurate prediction of protein-ligand interactions. It has been shown that structural optimization of chemical compounds and that post-docking optimization in multi-step structure-based virtual screening approaches help to further improve the overall efficiency of the methods. To address some of these points, we developed the program AMMOS for refining both, the 3D structures of the small molecules present in chemical libraries and the predicted receptor-ligand complexes through allowing partial to full atom flexibility through molecular mechanics optimization. Results The program AMMOS carries out an automatic procedure that allows for the structural refinement of compound collections and energy minimization of protein-ligand complexes using the open source program AMMP. The performance of our package was evaluated by comparing the structures of small chemical entities minimized by AMMOS with those minimized with the Tripos and MMFF94s force fields. Next, AMMOS was used for full flexible minimization of protein-ligands complexes obtained from a mutli-step virtual screening. Enrichment studies of the selected pre-docked complexes containing 60% of the initially added inhibitors were carried out with or without final AMMOS minimization on two protein targets having different binding pocket properties. AMMOS was able to improve the enrichment after the pre-docking stage with 40 to 60% of the initially added active compounds found in the top 3% to 5% of the entire compound collection

Virtual goods recommendations in virtual worlds.

Science.gov (United States)

Chen, Kuan-Yu; Liao, Hsiu-Yu; Chen, Jyun-Hung; Liu, Duen-Ren

2015-01-01

Virtual worlds (VWs) are computer-simulated environments which allow users to create their own virtual character as an avatar. With the rapidly growing user volume in VWs, platform providers launch virtual goods in haste and stampede users to increase sales revenue. However, the rapidity of development incurs virtual unrelated items which will be difficult to remarket. It not only wastes virtual global companies' intelligence resources, but also makes it difficult for users to find suitable virtual goods fit for their virtual home in daily virtual life. In the VWs, users decorate their houses, visit others' homes, create families, host parties, and so forth. Users establish their social life circles through these activities. This research proposes a novel virtual goods recommendation method based on these social interactions. The contact strength and contact influence result from interactions with social neighbors and influence users' buying intention. Our research highlights the importance of social interactions in virtual goods recommendation. The experiment's data were retrieved from an online VW platform, and the results show that the proposed method, considering social interactions and social life circle, has better performance than existing recommendation methods.

Pharmacophore screening of the protein data bank for specific binding site chemistry.

Science.gov (United States)

Campagna-Slater, Valérie; Arrowsmith, Andrew G; Zhao, Yong; Schapira, Matthieu

2010-03-22

A simple computational approach was developed to screen the Protein Data Bank (PDB) for putative pockets possessing a specific binding site chemistry and geometry. The method employs two commonly used 3D screening technologies, namely identification of cavities in protein structures and pharmacophore screening of chemical libraries. For each protein structure, a pocket finding algorithm is used to extract potential binding sites containing the correct types of residues, which are then stored in a large SDF-formatted virtual library; pharmacophore filters describing the desired binding site chemistry and geometry are then applied to screen this virtual library and identify pockets matching the specified structural chemistry. As an example, this approach was used to screen all human protein structures in the PDB and identify sites having chemistry similar to that of known methyl-lysine binding domains that recognize chromatin methylation marks. The selected genes include known readers of the histone code as well as novel binding pockets that may be involved in epigenetic signaling. Putative allosteric sites were identified on the structures of TP53BP1, L3MBTL3, CHEK1, KDM4A, and CREBBP.

Expanded Newborn Screening Program in Saudi Arabia: Incidence of screened disorders.

Science.gov (United States)

Alfadhel, Majid; Al Othaim, Ali; Al Saif, Saif; Al Mutairi, Fuad; Alsayed, Moeenaldeen; Rahbeeni, Zuhair; Alzaidan, Hamad; Alowain, Mohammed; Al-Hassnan, Zuhair; Saeedi, Mohamad; Aljohery, Saeed; Alasmari, Ali; Faqeih, Eissa; Alwakeel, Mansour; AlMashary, Maher; Almohameed, Sulaiman; Alzahrani, Mohammed; Migdad, Abeer; Al-Dirbashi, Osama Y; Rashed, Mohamed; Alamoudi, Mohamed; Jacob, Minnie; Alahaidib, Lujane; El-Badaoui, Fahd; Saadallah, Amal; Alsulaiman, Ayman; Eyaid, Wafaa; Al-Odaib, Ali

2017-06-01

To address the implementation of the National Newborn Screening Program (NBS) in Saudi Arabia and stratify the incidence of the screened disorders. A retrospective study conducted between 1 August 2005 and 31 December 2012, total of 775 000 newborns were screened from 139 hospitals distributed among all regions of Saudi Arabia. The NBS Program screens for 16 disorders from a selective list of inborn errors of metabolism (IEM) and endocrine disorders. Heel prick dry blood spot samples were obtained from all newborns for biochemical and immunoassay testing. Recall screening testing was performed for Initial positive results and confirmed by specific biochemical assays. A total of 743 cases were identified giving an overall incidence of 1:1043. Frequently detected disorders nationwide were congenital hypothyroidism and congenital adrenal hyperplasia with an incidence of 1:7175 and 1:7908 correspondingly. The highest incidence among the IEM was propionic acidaemia with an incidence rate of 1:14 000. The article highlights the experience of the NBS Program in Saudi Arabia and providing data on specific regional incidences of all the screened disorders included in the programme; and showed that the incidence of these disorders is one of the highest reported so far world-wide. © 2017 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).

Virtual visits and Hangouts – how cool is CERN…

CERN Multimedia

Joannah Caborn Wengler

2012-01-01

New media are really making the world smaller. Using a simple lap-top and Vidyo® or Google Hangouts, you can visit experiments’ control rooms and ask physicists those questions you always wanted to ask, all from the comfort of your own home. Here’s how a few people connected with CERN recently.   Students from the Al-Quds University in the Palestinian West Bank participating in the ATLAS virtual visit. It was an old-fashioned aeroplane which took Kate Shaw of the Udine ICTP (Italy) ATLAS group to give a particle physics master class to about 20 students from Al-Quds University in the Palestinian West Bank, but it was via the ether that they were able to take a virtual visit of the ATLAS control room on 2 April. Without having to deal with with the complications of international air travel, they were able to see the experts, monitors and screens via two remote controlled cameras mounted on the ceiling of the ATLAS control room. By the door there is another screen, w...

A Combined Pharmacophore Modeling, 3D QSAR and Virtual Screening Studies on Imidazopyridines as B-Raf Inhibitors

Directory of Open Access Journals (Sweden)

Huiding Xie

2015-05-01

Full Text Available B-Raf kinase is an important target in treatment of cancers. In order to design and find potent B-Raf inhibitors (BRIs, 3D pharmacophore models were created using the Genetic Algorithm with Linear Assignment of Hypermolecular Alignment of Database (GALAHAD. The best pharmacophore model obtained which was used in effective alignment of the data set contains two acceptor atoms, three donor atoms and three hydrophobes. In succession, comparative molecular field analysis (CoMFA and comparative molecular similarity indices analysis (CoMSIA were performed on 39 imidazopyridine BRIs to build three dimensional quantitative structure-activity relationship (3D QSAR models based on both pharmacophore and docking alignments. The CoMSIA model based on the pharmacophore alignment shows the best result (q2 = 0.621, r2pred = 0.885. This 3D QSAR approach provides significant insights that are useful for designing potent BRIs. In addition, the obtained best pharmacophore model was used for virtual screening against the NCI2000 database. The hit compounds were further filtered with molecular docking, and their biological activities were predicted using the CoMSIA model, and three potential BRIs with new skeletons were obtained.

A Combined Pharmacophore Modeling, 3D QSAR and Virtual Screening Studies on Imidazopyridines as B-Raf Inhibitors.

Science.gov (United States)

Xie, Huiding; Chen, Lijun; Zhang, Jianqiang; Xie, Xiaoguang; Qiu, Kaixiong; Fu, Jijun

2015-05-29

B-Raf kinase is an important target in treatment of cancers. In order to design and find potent B-Raf inhibitors (BRIs), 3D pharmacophore models were created using the Genetic Algorithm with Linear Assignment of Hypermolecular Alignment of Database (GALAHAD). The best pharmacophore model obtained which was used in effective alignment of the data set contains two acceptor atoms, three donor atoms and three hydrophobes. In succession, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed on 39 imidazopyridine BRIs to build three dimensional quantitative structure-activity relationship (3D QSAR) models based on both pharmacophore and docking alignments. The CoMSIA model based on the pharmacophore alignment shows the best result (q(2) = 0.621, r(2)(pred) = 0.885). This 3D QSAR approach provides significant insights that are useful for designing potent BRIs. In addition, the obtained best pharmacophore model was used for virtual screening against the NCI2000 database. The hit compounds were further filtered with molecular docking, and their biological activities were predicted using the CoMSIA model, and three potential BRIs with new skeletons were obtained.

Virtual marketing in virtual enterprises

OpenAIRE

Ale Ebrahim, Nader; Fattahi, Hamaid Ali; Golnam, Arash

2008-01-01

Virtualization caused tremendous evolution in the economics of marketing channels, patterns of physical distribution and the structure of distributors and developed a new concept that is known as virtual marketing (VM). VM combines the powerful technologies of interactive marketing and virtual reality. Virtual enterprise (VE) refers to an organization not having a clear physical locus. In other words, VE is an organization distributed geographically and whose work is coordinated through e...

Discovery of DNA Topoisomerase I Inhibitors with Low-Cytotoxicity Based on Virtual Screening from Natural Products

Directory of Open Access Journals (Sweden)

Lan-Ting Xin

2017-07-01

Full Text Available Currently, DNA topoisomerase I (Topo I inhibitors constitute a family of antitumor agents with demonstrated clinical effects on human malignancies. However, the clinical uses of these agents have been greatly limited due to their severe toxic effects. Therefore, it is urgent to find and develop novel low toxic Topo I inhibitors. In recent years, during our ongoing research on natural antitumor products, a collection of low cytotoxic or non-cytotoxic compounds with various structures were identified from marine invertebrates, plants, and their symbiotic microorganisms. In the present study, new Topo I inhibitors were discovered from low cytotoxic and non-cytotoxic natural products by virtual screening with docking simulations in combination with bioassay test. In total, eight potent Topo I inhibitors were found from 138 low cytotoxic or non-cytotoxic compounds from coral-derived fungi and plants. All of these Topo I inhibitors demonstrated activities against Topo I-mediated relaxation of supercoiled DNA at the concentrations of 5–100 µM. Notably, the flavonoids showed higher Topo I inhibitory activities than other compounds. These newly discovered Topo I inhibitors exhibited structurally diverse and could be considered as a good starting point for the development of new antitumor lead compounds.

Novel colchicine-site binders with a cyclohexanedione scaffold identified through a ligand-based virtual screening approach.

Science.gov (United States)

Canela, María-Dolores; Pérez-Pérez, María-Jesús; Noppen, Sam; Sáez-Calvo, Gonzalo; Díaz, J Fernando; Camarasa, María-José; Liekens, Sandra; Priego, Eva-María

2014-05-22

Vascular disrupting agents (VDAs) constitute an innovative anticancer therapy that targets the tumor endothelium, leading to tumor necrosis. Our approach for the identification of new VDAs has relied on a ligand 3-D shape similarity virtual screening (VS) approach using the ROCS program as the VS tool and as query colchicine and TN-16, which both bind the α,β-tubulin dimer. One of the hits identified, using TN-16 as query, has been explored by the synthesis of its structural analogues, leading to 2-(1-((2-methoxyphenyl)amino)ethylidene)-5-phenylcyclohexane-1,3-dione (compound 16c) with an IC50 = 0.09 ± 0.01 μM in HMEC-1 and BAEC, being 100-fold more potent than the initial hit. Compound 16c caused cell cycle arrest in the G2/M phase and interacted with the colchicine-binding site in tubulin, as confirmed by a competition assay with N,N'-ethylenebis(iodoacetamide) and by fluorescence spectroscopy. Moreover, 16c destroyed an established endothelial tubular network at 1 μM and inhibited the migration and invasion of human breast carcinoma cells at 0.4 μM. In conclusion, our approach has led to a new chemotype of promising antiproliferative compounds with antimitotic and potential VDA properties.

The virtual dental home: a critique.

Science.gov (United States)

Friedman, Jay W; Nash, David A; Mathu-Muju, Kavita R

2017-09-01

The Virtual Dental Home is a concept of the Pacific Center for Special Care of the Arthur A. Dugoni School of Dentistry in San Francisco. It is designed to improve access to dental care for underserved populations, specifically children and institutionalized adults. This article describes the development and implementation of the Virtual Dental Home, subsequently critiquing the concept. The criteria for a dental home are not met by the program. It is the equivalent of a traditional public oral health prevention and screening program, with the additional dimension of allowing dental hygienists and assistants to place interim glass ionomer restorations in dental cavities. The critique questions the need to insert a "cloud" dentist into the process. The routine utilization of radiographs is also challenged. The VDH not only lacks the attributes of a dental home, it has not been shown to be as efficient and effective as traditional programs staffed by dental hygienists and dental therapists. The article concludes by describing how programs utilizing dental therapists could address the deficiencies of the Virtual Dental Home, effectively improving access to oral health care for underserved populations. © 2017 American Association of Public Health Dentistry.

Virtual Presenters: Towards Interactive Virtual Presentations

NARCIS (Netherlands)

Nijholt, Antinus; Cappellini, V.; Hemsley, J.

2005-01-01

We discuss having virtual presenters in virtual environments that present information to visitors of these environments. Some current research is surveyed and we will look in particular to our research in the context of a virtual meeting room where a virtual presenter uses speech, gestures, pointing

Value of audits in breast cancer screening quality assurance programmes

NARCIS (Netherlands)

Geertse, Tanya D.; Holland, Roland; Timmers, Janine M. H.; Paap, Ellen; Pijnappel, Ruud M.; Broeders, Mireille J. M.; den Heeten, Gerard J.

2015-01-01

Our aim was to retrospectively evaluate the results of all audits performed in the past and to assess their value in the quality assurance of the Dutch breast cancer screening programme. The audit team of the Dutch Reference Centre for Screening (LRCB) conducts triennial audits of all 17 reading

Improved Resident Adherence to AAA Screening Guidelines via an Electronic Reminder.

Science.gov (United States)

Sypert, David; Van Dyke, Kenneth; Dhillon, Namrata; Elliott, John O; Jordan, Kim

The 2014 United States Preventive Services Task Force systematic review found abdominal aortic aneurysm (AAA) screening decreased related mortality by close to half. Despite the simplicity of screening, research suggests poor adherence to the recommended AAA screening guidelines. Using the quality improvement plan-study-do-act cycle, we retrospectively established poor adherence to AAA screening and poor documentation of smoking history in our resident clinic. An electronic reminder was prospectively implemented into our electronic medical record (EMR) with the goal of improving screening rates. After 1 year, a retrospective chart review was conducted. Comparisons of the pre- and post-electronic reminder intervention data were made using chi-square tests and odds ratios (OR). The purposeful AAA screening rate improved 27.8% during the intervention, 40.3% (95% confidence interval [CI]: 28.6-52.0%) versus 12.5% (95% CI: 3.1-21.9%), p = .002, suggesting patients were more likely to be screened as a result of the electronic reminder, OR = 4.73 (95% CI: 1.77-12.65). This improvement translates to a large effect size, Cohen's d = 0.86 (95% CI: 0.31-1.40). Electronic reminders are a simple EMR addition that can provide evidence-based education while improving adherence rates with preventive health screening measures.

Virtual Worlds for Virtual Organizing

Science.gov (United States)

Rhoten, Diana; Lutters, Wayne

The members and resources of a virtual organization are dispersed across time and space, yet they function as a coherent entity through the use of technologies, networks, and alliances. As virtual organizations proliferate and become increasingly important in society, many may exploit the technical architecture s of virtual worlds, which are the confluence of computer-mediated communication, telepresence, and virtual reality originally created for gaming. A brief socio-technical history describes their early origins and the waves of progress followed by stasis that brought us to the current period of renewed enthusiasm. Examination of contemporary examples demonstrates how three genres of virtual worlds have enabled new arenas for virtual organizing: developer-defined closed worlds, user-modifiable quasi-open worlds, and user-generated open worlds. Among expected future trends are an increase in collaboration born virtually rather than imported from existing organizations, a tension between high-fidelity recreations of the physical world and hyper-stylized imaginations of fantasy worlds, and the growth of specialized worlds optimized for particular sectors, companies, or cultures.

Screening for Intellectual Disability Using High-Resolution CMA Technology in a Retrospective Cohort from Central Brazil

Science.gov (United States)

Pereira, Rodrigo Roncato; Pinto, Irene Plaza; Minasi, Lysa Bernardes; de Melo, Aldaires Vieira; da Cruz e Cunha, Damiana Mirian; Cruz, Alex Silva; Ribeiro, Cristiano Luiz; da Silva, Cláudio Carlos; de Melo e Silva, Daniela; da Cruz, Aparecido Divino

2014-01-01

Intellectual disability is a complex, variable, and heterogeneous disorder, representing a disabling condition diagnosed worldwide, and the etiologies are multiple and highly heterogeneous. Microscopic chromosomal abnormalities and well-characterized genetic conditions are the most common causes of intellectual disability. Chromosomal Microarray Analysis analyses have made it possible to identify putatively pathogenic copy number variation that could explain the molecular etiology of intellectual disability. The aim of the current study was to identify possible submicroscopic genomic alterations using a high-density chromosomal microarray in a retrospective cohort of patients with otherwise undiagnosable intellectual disabilities referred by doctors from the public health system in Central Brazil. The CytoScan HD technology was used to detect changes in the genome copy number variation of patients who had intellectual disability and a normal karyotype. The analysis detected 18 CNVs in 60% of patients. Pathogenic CNVs represented about 22%, so it was possible to propose the etiology of intellectual disability for these patients. Likely pathogenic and unknown clinical significance CNVs represented 28% and 50%, respectively. Inherited and de novo CNVs were equally distributed. We report the nature of CNVs in patients from Central Brazil, representing a population not yet screened by microarray technologies. PMID:25061755

Decision PBL: A 4-year retrospective case study of the use of virtual patients in problem-based learning.

Science.gov (United States)

Ellaway, Rachel H; Poulton, Terry; Jivram, Trupti

2015-01-01

In 2009, St George's University of London (SGUL) replaced their paper-based problem-based learning (PBL) cases with virtual patients for intermediate-level undergraduate students. This involved the development of Decision-Problem-Based Learning (D-PBL), a variation on progressive-release PBL that uses virtual patients instead of paper cases, and focuses on patient management decisions and their consequences. Using a case study method, this paper describes four years of developing and running D-PBL at SGUL from individual activities up to the ways in which D-PBL functioned as an educational system. A number of broad issues were identified: the importance of debates and decision-making in making D-PBL activities engaging and rewarding; the complexities of managing small group dynamics; the time taken to complete D-PBL activities; the changing role of the facilitator; and the erosion of the D-PBL process over time. A key point in understanding this work is the construction and execution of the D-PBL activity, as much of the value of this approach arises from the actions and interactions of students, their facilitators and the virtual patients rather than from the design of the virtual patients alone. At a systems level D-PBL needs to be periodically refreshed to retain its effectiveness.

The CAVE (TM) automatic virtual environment: Characteristics and applications

Science.gov (United States)

Kenyon, Robert V.

1995-01-01

Virtual reality may best be defined as the wide-field presentation of computer-generated, multi-sensory information that tracks a user in real time. In addition to the more well-known modes of virtual reality -- head-mounted displays and boom-mounted displays -- the Electronic Visualization Laboratory at the University of Illinois at Chicago recently introduced a third mode: a room constructed from large screens on which the graphics are projected on to three walls and the floor. The CAVE is a multi-person, room sized, high resolution, 3D video and audio environment. Graphics are rear projected in stereo onto three walls and the floor, and viewed with stereo glasses. As a viewer wearing a location sensor moves within its display boundaries, the correct perspective and stereo projections of the environment are updated, and the image moves with and surrounds the viewer. The other viewers in the CAVE are like passengers in a bus, along for the ride. 'CAVE,' the name selected for the virtual reality theater, is both a recursive acronym (Cave Automatic Virtual Environment) and a reference to 'The Simile of the Cave' found in Plato's 'Republic,' in which the philosopher explores the ideas of perception, reality, and illusion. Plato used the analogy of a person facing the back of a cave alive with shadows that are his/her only basis for ideas of what real objects are. Rather than having evolved from video games or flight simulation, the CAVE has its motivation rooted in scientific visualization and the SIGGRAPH 92 Showcase effort. The CAVE was designed to be a useful tool for scientific visualization. The Showcase event was an experiment; the Showcase chair and committee advocated an environment for computational scientists to interactively present their research at a major professional conference in a one-to-many format on high-end workstations attached to large projection screens. The CAVE was developed as a 'virtual reality theater' with scientific content and

The assessment of virtual reality for human anatomy instruction

Science.gov (United States)

Benn, Karen P.

1994-01-01

This research project seeks to meet the objective of science training by developing, assessing, and validating virtual reality as a human anatomy training medium. In ideal situations, anatomic models, computer-based instruction, and cadaver dissection are utilized to augment the traditional methods of instruction. At many institutions, lack of financial resources limits anatomy instruction to textbooks and lectures. However, human anatomy is three dimensional, unlike the one dimensional depiction found in textbooks and the two dimensional depiction found on the computer. Virtual reality is a breakthrough technology that allows one to step through the computer screen into a three dimensional world. This technology offers many opportunities to enhance science education. Therefore, a virtual testing environment of the abdominopelvic region of a human cadaver was created to study the placement of body parts within the nine anatomical divisions of the abdominopelvic region and the four abdominal quadrants.

The value of screening tests in the detection of prostate cancer. Part I: Results of a retrospective evaluation of 1726 men.

Science.gov (United States)

Bangma, C H; Kranse, R; Blijenberg, B G; Schröder, F H

1995-12-01

The ratio between free and total prostate-specific antigen (PSA) in serum (F/T ratio) was shown to improve the differentiation between prostate carcinoma and benign conditions in selected series of patients. In this study the F/T ratio was analyzed for its ability to improve the specificity of total serum PSA, digital rectal examination (DRE), and transrectal ultrasonography (TRUS) for the detection of prostate cancer in an unselected screening population of men identified in the Rotterdam population. In 1726 men between 55 and 76 years old, 67 prostate carcinomas were detected by DRE, TRUS, and total serum PSA (Abbott IMx, Hybritech Tandem E). The DELFIA ProStatus PSA EQM and ProStatus PSA Free/Total assays (Wallac) were applied in retrospect to determine total and free serum PSA. Age, total prostate and inner zone volumes were taken into consideration. Sixty-seven carcinomas were detected, two by TRUS and three by DRE alone. Total serum PSA was the most important single predictor of prostate cancer, followed by DRE. The F/T ratio increased the specificity of total serum PSA in the PSA range between 4.0 and 10.0 ng/mL. However, this improved specificity was not significant, nor for gland volumes restricted to 50 mL or less. The combination of total serum PSA and DRE remains the standard for detection of prostate carcinoma in a screening population. Their specificity may be improved minimally by the F/T ratio, but not significantly in a sample of 1726 screened men. The threshold of the F/T ratio, and the optimal PSA range for its application, remains to be assessed prospectively.

The Development of Target-Specific Pose Filter Ensembles To Boost Ligand Enrichment for Structure-Based Virtual Screening.

Science.gov (United States)

Xia, Jie; Hsieh, Jui-Hua; Hu, Huabin; Wu, Song; Wang, Xiang Simon

2017-06-26

Structure-based virtual screening (SBVS) has become an indispensable technique for hit identification at the early stage of drug discovery. However, the accuracy of current scoring functions is not high enough to confer success to every target and thus remains to be improved. Previously, we had developed binary pose filters (PFs) using knowledge derived from the protein-ligand interface of a single X-ray structure of a specific target. This novel approach had been validated as an effective way to improve ligand enrichment. Continuing from it, in the present work we attempted to incorporate knowledge collected from diverse protein-ligand interfaces of multiple crystal structures of the same target to build PF ensembles (PFEs). Toward this end, we first constructed a comprehensive data set to meet the requirements of ensemble modeling and validation. This set contains 10 diverse targets, 118 well-prepared X-ray structures of protein-ligand complexes, and large benchmarking actives/decoys sets. Notably, we designed a unique workflow of two-layer classifiers based on the concept of ensemble learning and applied it to the construction of PFEs for all of the targets. Through extensive benchmarking studies, we demonstrated that (1) coupling PFE with Chemgauss4 significantly improves the early enrichment of Chemgauss4 itself and (2) PFEs show greater consistency in boosting early enrichment and larger overall enrichment than our prior PFs. In addition, we analyzed the pairwise topological similarities among cognate ligands used to construct PFEs and found that it is the higher chemical diversity of the cognate ligands that leads to the improved performance of PFEs. Taken together, the results so far prove that the incorporation of knowledge from diverse protein-ligand interfaces by ensemble modeling is able to enhance the screening competence of SBVS scoring functions.

2-D tiles declustering method based on virtual devices

Science.gov (United States)

Li, Zhongmin; Gao, Lu

2009-10-01

Generally, 2-D spatial data are divided as a series of tiles according to the plane grid. To satisfy the effect of vision, the tiles in the query window including the view point would be displayed quickly at the screen. Aiming at the performance difference of real storage devices, we propose a 2-D tiles declustering method based on virtual device. Firstly, we construct a group of virtual devices which have same storage performance and non-limited capacity, then distribute the tiles into M virtual devices according to the query window of 2-D tiles. Secondly, we equably map the tiles in M virtual devices into M equidistant intervals in [0, 1) using pseudo-random number generator. Finally, we devide [0, 1) into M intervals according to the tiles distribution percentage of every real storage device, and distribute the tiles in each interval in the corresponding real storage device. We have designed and realized a prototype GlobeSIGht, and give some related test results. The results show that the average response time of each tile in the query window including the view point using 2-D tiles declustering method based on virtual device is more efficient than using other methods.

Natural interaction for mobile virtual reality

OpenAIRE

Prosenik, Uroš

2016-01-01

Virtual reality (VR) has recently become a real hit. Also, an increasing number of mobile devices that are used for everyday needs support and are powerful enough to run VR applications. As a result, the market is growing in number of VR glasses, which project the image from mobile device screens to user eyes. These glasses can be from different manufacturers and different shapes. Many VR glasses do not provide any additional controllers for interaction with the mobile device. The user is lim...

Adenoma detection in patients undergoing a comprehensive colonoscopy screening

International Nuclear Information System (INIS)

Raju, Gottumukkala S; Vadyala, Vikram; Slack, Rebecca; Krishna, Somashekar G; Ross, William A; Lynch, Patrick M; Bresalier, Robert S; Hawk, Ernest; Stroehlein, John R

2013-01-01

Measures shown to improve the adenoma detection during colonoscopy (excellent bowel preparation, cecal intubation, cap fitted colonoscope to examine behind folds, patient position change to optimize colon distention, trained endoscopy team focusing on detection of subtle flat lesions, and incorporation of optimum endoscopic examination with adequate withdrawal time) are applicable to clinical practice and, if incorporated are projected to facilitate comprehensive colonoscopy screening program for colon cancer prevention. To determine adenoma and serrated polyp detection rate under conditions designed to optimize quality parameters for comprehensive screening colonoscopy. Retrospective analysis of data obtained from a comprehensive colon cancer screening program designed to optimize quality parameters. Academic medical center. Three hundred and forty-three patients between the ages of 50 years and 75 years who underwent first screening colonoscopy between 2009 and 2011 among 535 consecutive patients undergoing colonoscopy. Comprehensive colonoscopy screening program was utilized to screen all patients. Cecal intubation was successful in 98.8% of patients. The Boston Bowel Preparation Scale for quality of colonoscopy was 8.97 (95% confidence interval [CI]; 8.94, 9.00). The rate of adenoma detection was 60% and serrated lesion (defined as serrated adenomas or hyperplastic polyps proximal to the splenic flexure) detection was 23%. The rate of precancerous lesion detection (adenomas and serrated lesions) was 66%. The mean number of adenomas per screening procedure was 1.4 (1.2, 1.6) and the mean number of precancerous lesions (adenomas or serrated lesions) per screening procedure was 1.6 (1.4, 1.8). Retrospective study and single endoscopist experience. A comprehensive colonoscopy screening program results in high-quality screening with high detection of adenomas, advanced adenomas, serrated adenomas, and multiple adenomas

Communication situation and positioning in virtual meetings - rhetorical implications for interpersonal management communication

DEFF Research Database (Denmark)

Winther, Frederikke; Nielsen, Rikke Kristine; Henriksen, Thomas Duus

2017-01-01

, a living room or just a plain white wall. Seen from a rhetorical perspective, the communication situation in a virtual meeting consists of all the participants’ individual frameworks on a screen which must converge into a context suitable for interpersonal communication, interaction and collaboration....... It is argued, that virtual leadership must respond to the situation with rhetorical sensitivity by corresponding attentively and carefully to the conditions, positions and experiences of the particular followers in order to evoke their responsiveness and build commitment....

Virtual colonoscopy: clinical application

International Nuclear Information System (INIS)

Laghi, A.

2005-01-01

Virtual colonoscopy (VC), also known as computed tomography Colonography (CTC), is a non-invasive test for the examination of the colon based on volumetric, thin-collimation CT acquisition of a cleansed and air-distended colon. The technique is easy, less labour-intensive than barium enema and conventional colonoscopy, and is inherently safer. Several studies demonstrate the ability of VC in the detection of colonic neoplastic lesions, not only large carcinomas, but also polyps. Currently, the most widely accepted clinical indication is incomplete or unsuccessful colonoscopy, which may be the result of redundant colon, patient intolerance to the procedure, spasm not resolving even with the use of spasmolytics, obstructing colo-rectal cancer. VC is also used to detect cancer in frail and immobile patients to avoid sedation during colonoscopy or the turning required during barium enema. The use of VC in patients under surveillance following colo-rectal cancer surgery is under investigation. Further studies are necessary in order to assess the cost-effectiveness of this approach. For colo-rectal cancer screening, a practical approach is to consider VC as a currently credible alternative screening method and as a reasonable alternative to the other colo-rectal cancer screening tests when a patient is unable or unwilling to undergo conventional colonoscopy. (orig.)

Virtual colonoscopy: clinical application

Energy Technology Data Exchange (ETDEWEB)

Laghi, A. [Univ. of Rome La Sapienza, Polo Didattico Pontino, Latina (Italy)

2005-11-15

Virtual colonoscopy (VC), also known as computed tomography Colonography (CTC), is a non-invasive test for the examination of the colon based on volumetric, thin-collimation CT acquisition of a cleansed and air-distended colon. The technique is easy, less labour-intensive than barium enema and conventional colonoscopy, and is inherently safer. Several studies demonstrate the ability of VC in the detection of colonic neoplastic lesions, not only large carcinomas, but also polyps. Currently, the most widely accepted clinical indication is incomplete or unsuccessful colonoscopy, which may be the result of redundant colon, patient intolerance to the procedure, spasm not resolving even with the use of spasmolytics, obstructing colo-rectal cancer. VC is also used to detect cancer in frail and immobile patients to avoid sedation during colonoscopy or the turning required during barium enema. The use of VC in patients under surveillance following colo-rectal cancer surgery is under investigation. Further studies are necessary in order to assess the cost-effectiveness of this approach. For colo-rectal cancer screening, a practical approach is to consider VC as a currently credible alternative screening method and as a reasonable alternative to the other colo-rectal cancer screening tests when a patient is unable or unwilling to undergo conventional colonoscopy. (orig.)

Mastoidectomy performance assessment of virtual simulation training using final-product analysis

DEFF Research Database (Denmark)

Andersen, Steven A W; Cayé-Thomasen, Per; Sørensen, Mads S

2015-01-01

a modified Welling scale. The simulator gathered basic metrics on time, steps, and volumes in relation to the on-screen tutorial and collisions with vital structures. RESULTS: Substantial inter-rater reliability (kappa = 0.77) for virtual simulation and moderate inter-rater reliability (kappa = 0.......59) for dissection final-product assessment was found. The simulation and dissection performance scores had significant correlation (P = .014). None of the basic simulator metrics correlated significantly with the final-product score except for number of steps completed in the simulator. CONCLUSIONS: A modified...... version of a validated final-product performance assessment tool can be used to assess mastoidectomy on virtual temporal bones. Performance assessment of virtual mastoidectomy could potentially save the use of cadaveric temporal bones for more advanced training when a basic level of competency...

Assessing subacute mild traumatic brain injury with a portable virtual reality balance device.

Science.gov (United States)

Wright, W Geoffrey; McDevitt, Jane; Tierney, Ryan; Haran, F Jay; Appiah-Kubi, Kwadwo Osei; Dumont, Alex

2017-07-01

Balance impairment is a common sensorimotor symptom in mild traumatic brain injury (mTBI). We designed an affordable, portable virtual reality (VR)-based balance screening device (Virtual Environment TBI Screen [VETS]), which will be validated relative to the Neurocom Sensory Organization Test (SOT) to determine if it can replace commonly used postural assessments. This preliminary study examines healthy adults (n = 56) and adults with mTBI (n = 11). Participants performed six upright postural tasks on the VETS and the SOT. Analysis of variance was used to determine between-group differences. Pearson's correlations were used to establish construct validity. Known-groups approach was used to establish classification accuracy. The mTBI cohort performed significantly worse than the healthy cohort on the new device (p = 0.001). The new device has 91.0% accuracy and an ROC curve with a significant area-under-the-curve (AUC = 0.865, p virtual reality can be economically integrated into the clinical setting for easy testing of postural control in neurologically impaired populations. Tailoring postural assessments to include tasks that rely on visual and vestibular integration will increase the accuracy of detecting balance impairment following mild traumatic brain injury.

Sensorial Virtualization: Coupling Gaming and Virtual Environment

NARCIS (Netherlands)

Garbaya, S.; Miraoui, C.; Wendrich, Robert E.; Lim, T.; Stanescu, I.A.; Hauge, J.B.

2014-01-01

Virtual reality and virtualization are currently used to design complex systems and demonstrate that they represent the functionalities of real systems. However, the design refinement of the virtual environment (VE) and distributed virtual environment (DVE) are still time consuming and costly, as it

MLViS: A Web Tool for Machine Learning-Based Virtual Screening in Early-Phase of Drug Discovery and Development.

Science.gov (United States)

Korkmaz, Selcuk; Zararsiz, Gokmen; Goksuluk, Dincer

2015-01-01

Virtual screening is an important step in early-phase of drug discovery process. Since there are thousands of compounds, this step should be both fast and effective in order to distinguish drug-like and nondrug-like molecules. Statistical machine learning methods are widely used in drug discovery studies for classification purpose. Here, we aim to develop a new tool, which can classify molecules as drug-like and nondrug-like based on various machine learning methods, including discriminant, tree-based, kernel-based, ensemble and other algorithms. To construct this tool, first, performances of twenty-three different machine learning algorithms are compared by ten different measures, then, ten best performing algorithms have been selected based on principal component and hierarchical cluster analysis results. Besides classification, this application has also ability to create heat map and dendrogram for visual inspection of the molecules through hierarchical cluster analysis. Moreover, users can connect the PubChem database to download molecular information and to create two-dimensional structures of compounds. This application is freely available through www.biosoft.hacettepe.edu.tr/MLViS/.

Virtually impossible: limiting Australian children and adolescents daily screen based media use.

Science.gov (United States)

Houghton, Stephen; Hunter, Simon C; Rosenberg, Michael; Wood, Lisa; Zadow, Corinne; Martin, Karen; Shilton, Trevor

2015-01-22

Paediatric recommendations to limit children's and adolescents' screen based media use (SBMU) to less than two hours per day appear to have gone unheeded. Given the associated adverse physical and mental health outcomes of SBMU it is understandable that concern is growing worldwide. However, because the majority of studies measuring SBMU have focused on TV viewing, computer use, video game playing, or a combination of these the true extent of total SBMU (including non-sedentary hand held devices) and time spent on specific screen activities remains relatively unknown. This study assesses the amount of time Australian children and adolescents spend on all types of screens and specific screen activities. We administered an online instrument specifically developed to gather data on all types of SBMU and SBMU activities to 2,620 (1373 males and 1247 females) 8 to 16 year olds from 25 Australian government and non-government primary and secondary schools. We found that 45% of 8 year olds to 80% of 16 year olds exceeded the recommended Social Networking, and Web Use) exceeded the media are central in the everyday lives of children and adolescents. In any reappraisal of SBMU exposure times, researchers, educators and health professionals need to take cognizance of the extent to which SBMU differs across specific screen activity, sex, and age.

Man-system interface based on automatic speech recognition: integration to a virtual control desk

Energy Technology Data Exchange (ETDEWEB)

Jorge, Carlos Alexandre F.; Mol, Antonio Carlos A.; Pereira, Claudio M.N.A.; Aghina, Mauricio Alves C., E-mail: calexandre@ien.gov.b, E-mail: mol@ien.gov.b, E-mail: cmnap@ien.gov.b, E-mail: mag@ien.gov.b [Instituto de Engenharia Nuclear (IEN/CNEN-RJ), Rio de Janeiro, RJ (Brazil); Nomiya, Diogo V., E-mail: diogonomiya@gmail.co [Universidade Federal do Rio de Janeiro (UFRJ), RJ (Brazil)

2009-07-01

This work reports the implementation of a man-system interface based on automatic speech recognition, and its integration to a virtual nuclear power plant control desk. The later is aimed to reproduce a real control desk using virtual reality technology, for operator training and ergonomic evaluation purpose. An automatic speech recognition system was developed to serve as a new interface with users, substituting computer keyboard and mouse. They can operate this virtual control desk in front of a computer monitor or a projection screen through spoken commands. The automatic speech recognition interface developed is based on a well-known signal processing technique named cepstral analysis, and on artificial neural networks. The speech recognition interface is described, along with its integration with the virtual control desk, and results are presented. (author)

Man-system interface based on automatic speech recognition: integration to a virtual control desk

International Nuclear Information System (INIS)

Jorge, Carlos Alexandre F.; Mol, Antonio Carlos A.; Pereira, Claudio M.N.A.; Aghina, Mauricio Alves C.; Nomiya, Diogo V.

2009-01-01

This work reports the implementation of a man-system interface based on automatic speech recognition, and its integration to a virtual nuclear power plant control desk. The later is aimed to reproduce a real control desk using virtual reality technology, for operator training and ergonomic evaluation purpose. An automatic speech recognition system was developed to serve as a new interface with users, substituting computer keyboard and mouse. They can operate this virtual control desk in front of a computer monitor or a projection screen through spoken commands. The automatic speech recognition interface developed is based on a well-known signal processing technique named cepstral analysis, and on artificial neural networks. The speech recognition interface is described, along with its integration with the virtual control desk, and results are presented. (author)

Virtual interactive presence and augmented reality (VIPAR) for remote surgical assistance.

Science.gov (United States)

Shenai, Mahesh B; Dillavou, Marcus; Shum, Corey; Ross, Douglas; Tubbs, Richard S; Shih, Alan; Guthrie, Barton L

2011-03-01

Surgery is a highly technical field that combines continuous decision-making with the coordination of spatiovisual tasks. We designed a virtual interactive presence and augmented reality (VIPAR) platform that allows a remote surgeon to deliver real-time virtual assistance to a local surgeon, over a standard Internet connection. The VIPAR system consisted of a "local" and a "remote" station, each situated over a surgical field and a blue screen, respectively. Each station was equipped with a digital viewpiece, composed of 2 cameras for stereoscopic capture, and a high-definition viewer displaying a virtual field. The virtual field was created by digitally compositing selected elements within the remote field into the local field. The viewpieces were controlled by workstations mutually connected by the Internet, allowing virtual remote interaction in real time. Digital renderings derived from volumetric MRI were added to the virtual field to augment the surgeon's reality. For demonstration, a fixed-formalin cadaver head and neck were obtained, and a carotid endarterectomy (CEA) and pterional craniotomy were performed under the VIPAR system. The VIPAR system allowed for real-time, virtual interaction between a local (resident) and remote (attending) surgeon. In both carotid and pterional dissections, major anatomic structures were visualized and identified. Virtual interaction permitted remote instruction for the local surgeon, and MRI augmentation provided spatial guidance to both surgeons. Camera resolution, color contrast, time lag, and depth perception were identified as technical issues requiring further optimization. Virtual interactive presence and augmented reality provide a novel platform for remote surgical assistance, with multiple applications in surgical training and remote expert assistance.

Virtual Class Support at the Virtual Machine Level

DEFF Research Database (Denmark)

Nielsen, Anders Bach; Ernst, Erik

2009-01-01

This paper describes how virtual classes can be supported in a virtual machine.  Main-stream virtual machines such as the Java Virtual Machine and the .NET platform dominate the world today, and many languages are being executed on these virtual machines even though their embodied design choices...... conflict with the design choices of the virtual machine.  For instance, there is a non-trivial mismatch between the main-stream virtual machines mentioned above and dynamically typed languages.  One language concept that creates an even greater mismatch is virtual classes, in particular because fully...... general support for virtual classes requires generation of new classes at run-time by mixin composition.  Languages like CaesarJ and ObjectTeams can express virtual classes restricted to the subset that does not require run-time generation of classes, because of the restrictions imposed by the Java...

Toward the virtual screening of potential drugs in the homology modeled NAD+ dependent DNA ligase from Mycobacterium tuberculosis.

Science.gov (United States)

Singh, Vijai; Somvanshi, Pallavi

2010-02-01

DNA ligase is an important enzyme and it plays vital role in the replication and repair; also catalyzes nick joining between adjacent bases of DNA. The NAD(+) dependent DNA ligase is selectively present in eubacteria and few viruses; but missing in humans. Homology modeling was used to generate 3-D structure of NAD(+) dependent DNA ligase (LigA) of Mycobacterium tuberculosis using the known template (PDB: 2OWO). Furthermore, the stereochemical quality and torsion angle of 3-D structure was validated. Numerous effective drugs were selected and the active amino acid residue in LigA was targeted and virtual screening through molecular docking was done. In this analysis, four drugs Chloroquine, Hydroxychloroquine, Putrienscine and Adriamycin were found more potent in inhibition of M. tuberculosis through the robust binding affinity between protein-drug interactions in comparison with the other studied drugs. A phylogenetic tree was constructed and it was observed that homology of LigA in M. tuberculosis resembled with other Mycobacterium species. The conserved active amino acids of LigA may be useful to target these drugs. These findings could be used as the starting point of a rational design of novel antibacterial drugs and its analogs.

Using Virtual Reality For Outreach Purposes in Planetology

Science.gov (United States)

Civet, François; Le Mouélic, Stéphane; Le Menn, Erwan; Beaunay, Stéphanie

2016-10-01

2016 has been a year marked by a technological breakthrough : the availability for the first time to the general public of technologically mature virtual reality devices. Virtual Reality consists in visually immerging a user in a 3D environment reproduced either from real and/or imaginary data, with the possibility to move and eventually interact with the different elements. In planetology, most of the places will remain inaccessible to the public for a while, but a fleet of dedicated spacecraft's such as orbiters, landers and rovers allow the possibility to virtually reconstruct the environments, using image processing, cartography and photogrammetry. Virtual reality can then bridge the gap to virtually "send" any user into the place and enjoy the exploration.We are investigating several type of devices to render orbital or ground based data of planetological interest, mostly from Mars. The most simple system consists of a "cardboard" headset, on which the user can simply use his cellphone as the screen. A more comfortable experience is obtained with more complex systems such as the HTC vive or Oculus Rift headsets, which include a tracking system important to minimize motion sickness. The third environment that we have developed is based on the CAVE concept, were four 3D video projectors are used to project on three 2x3m walls plus the ground. These systems can be used for scientific data analysis, but also prove to be perfectly suited for outreach and education purposes.

Development and experimental test of support vector machines virtual screening method for searching Src inhibitors from large compound libraries

Directory of Open Access Journals (Sweden)

Han Bucong

2012-11-01

Full Text Available Abstract Background Src plays various roles in tumour progression, invasion, metastasis, angiogenesis and survival. It is one of the multiple targets of multi-target kinase inhibitors in clinical uses and trials for the treatment of leukemia and other cancers. These successes and appearances of drug resistance in some patients have raised significant interest and efforts in discovering new Src inhibitors. Various in-silico methods have been used in some of these efforts. It is desirable to explore additional in-silico methods, particularly those capable of searching large compound libraries at high yields and reduced false-hit rates. Results We evaluated support vector machines (SVM as virtual screening tools for searching Src inhibitors from large compound libraries. SVM trained and tested by 1,703 inhibitors and 63,318 putative non-inhibitors correctly identified 93.53%~ 95.01% inhibitors and 99.81%~ 99.90% non-inhibitors in 5-fold cross validation studies. SVM trained by 1,703 inhibitors reported before 2011 and 63,318 putative non-inhibitors correctly identified 70.45% of the 44 inhibitors reported since 2011, and predicted as inhibitors 44,843 (0.33% of 13.56M PubChem, 1,496 (0.89% of 168 K MDDR, and 719 (7.73% of 9,305 MDDR compounds similar to the known inhibitors. Conclusions SVM showed comparable yield and reduced false hit rates in searching large compound libraries compared to the similarity-based and other machine-learning VS methods developed from the same set of training compounds and molecular descriptors. We tested three virtual hits of the same novel scaffold from in-house chemical libraries not reported as Src inhibitor, one of which showed moderate activity. SVM may be potentially explored for searching Src inhibitors from large compound libraries at low false-hit rates.

Development and experimental test of support vector machines virtual screening method for searching Src inhibitors from large compound libraries.

Science.gov (United States)

Han, Bucong; Ma, Xiaohua; Zhao, Ruiying; Zhang, Jingxian; Wei, Xiaona; Liu, Xianghui; Liu, Xin; Zhang, Cunlong; Tan, Chunyan; Jiang, Yuyang; Chen, Yuzong

2012-11-23

Src plays various roles in tumour progression, invasion, metastasis, angiogenesis and survival. It is one of the multiple targets of multi-target kinase inhibitors in clinical uses and trials for the treatment of leukemia and other cancers. These successes and appearances of drug resistance in some patients have raised significant interest and efforts in discovering new Src inhibitors. Various in-silico methods have been used in some of these efforts. It is desirable to explore additional in-silico methods, particularly those capable of searching large compound libraries at high yields and reduced false-hit rates. We evaluated support vector machines (SVM) as virtual screening tools for searching Src inhibitors from large compound libraries. SVM trained and tested by 1,703 inhibitors and 63,318 putative non-inhibitors correctly identified 93.53%~ 95.01% inhibitors and 99.81%~ 99.90% non-inhibitors in 5-fold cross validation studies. SVM trained by 1,703 inhibitors reported before 2011 and 63,318 putative non-inhibitors correctly identified 70.45% of the 44 inhibitors reported since 2011, and predicted as inhibitors 44,843 (0.33%) of 13.56M PubChem, 1,496 (0.89%) of 168 K MDDR, and 719 (7.73%) of 9,305 MDDR compounds similar to the known inhibitors. SVM showed comparable yield and reduced false hit rates in searching large compound libraries compared to the similarity-based and other machine-learning VS methods developed from the same set of training compounds and molecular descriptors. We tested three virtual hits of the same novel scaffold from in-house chemical libraries not reported as Src inhibitor, one of which showed moderate activity. SVM may be potentially explored for searching Src inhibitors from large compound libraries at low false-hit rates.

DARC 2.0: Improved Docking and Virtual Screening at Protein Interaction Sites.

Directory of Open Access Journals (Sweden)

Ragul Gowthaman

Full Text Available Over the past decade, protein-protein interactions have emerged as attractive but challenging targets for therapeutic intervention using small molecules. Due to the relatively flat surfaces that typify protein interaction sites, modern virtual screening tools developed for optimal performance against "traditional" protein targets perform less well when applied instead at protein interaction sites. Previously, we described a docking method specifically catered to the shallow binding modes characteristic of small-molecule inhibitors of protein interaction sites. This method, called DARC (Docking Approach using Ray Casting, operates by comparing the topography of the protein surface when "viewed" from a vantage point inside the protein against the topography of a bound ligand when "viewed" from the same vantage point. Here, we present five key enhancements to DARC. First, we use multiple vantage points to more accurately determine protein-ligand surface complementarity. Second, we describe a new scheme for rapidly determining optimal weights in the DARC scoring function. Third, we incorporate sampling of ligand conformers "on-the-fly" during docking. Fourth, we move beyond simple shape complementarity and introduce a term in the scoring function to capture electrostatic complementarity. Finally, we adjust the control flow in our GPU implementation of DARC to achieve greater speedup of these calculations. At each step of this study, we evaluate the performance of DARC in a "pose recapitulation" experiment: predicting the binding mode of 25 inhibitors each solved in complex with its distinct target protein (a protein interaction site. Whereas the previous version of DARC docked only one of these inhibitors to within 2 Å RMSD of its position in the crystal structure, the newer version achieves this level of accuracy for 12 of the 25 complexes, corresponding to a statistically significant performance improvement (p < 0.001. Collectively then, we find

Human agency beliefs influence behaviour during virtual social interactions.

Science.gov (United States)

Caruana, Nathan; Spirou, Dean; Brock, Jon

2017-01-01

In recent years, with the emergence of relatively inexpensive and accessible virtual reality technologies, it is now possible to deliver compelling and realistic simulations of human-to-human interaction. Neuroimaging studies have shown that, when participants believe they are interacting via a virtual interface with another human agent, they show different patterns of brain activity compared to when they know that their virtual partner is computer-controlled. The suggestion is that users adopt an "intentional stance" by attributing mental states to their virtual partner. However, it remains unclear how beliefs in the agency of a virtual partner influence participants' behaviour and subjective experience of the interaction. We investigated this issue in the context of a cooperative "joint attention" game in which participants interacted via an eye tracker with a virtual onscreen partner, directing each other's eye gaze to different screen locations. Half of the participants were correctly informed that their partner was controlled by a computer algorithm ("Computer" condition). The other half were misled into believing that the virtual character was controlled by a second participant in another room ("Human" condition). Those in the "Human" condition were slower to make eye contact with their partner and more likely to try and guide their partner before they had established mutual eye contact than participants in the "Computer" condition. They also responded more rapidly when their partner was guiding them, although the same effect was also found for a control condition in which they responded to an arrow cue. Results confirm the influence of human agency beliefs on behaviour in this virtual social interaction context. They further suggest that researchers and developers attempting to simulate social interactions should consider the impact of agency beliefs on user experience in other social contexts, and their effect on the achievement of the application's goals.

Human agency beliefs influence behaviour during virtual social interactions

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Nathan Caruana

2017-09-01

Full Text Available In recent years, with the emergence of relatively inexpensive and accessible virtual reality technologies, it is now possible to deliver compelling and realistic simulations of human-to-human interaction. Neuroimaging studies have shown that, when participants believe they are interacting via a virtual interface with another human agent, they show different patterns of brain activity compared to when they know that their virtual partner is computer-controlled. The suggestion is that users adopt an “intentional stance” by attributing mental states to their virtual partner. However, it remains unclear how beliefs in the agency of a virtual partner influence participants’ behaviour and subjective experience of the interaction. We investigated this issue in the context of a cooperative “joint attention” game in which participants interacted via an eye tracker with a virtual onscreen partner, directing each other’s eye gaze to different screen locations. Half of the participants were correctly informed that their partner was controlled by a computer algorithm (“Computer” condition. The other half were misled into believing that the virtual character was controlled by a second participant in another room (“Human” condition. Those in the “Human” condition were slower to make eye contact with their partner and more likely to try and guide their partner before they had established mutual eye contact than participants in the “Computer” condition. They also responded more rapidly when their partner was guiding them, although the same effect was also found for a control condition in which they responded to an arrow cue. Results confirm the influence of human agency beliefs on behaviour in this virtual social interaction context. They further suggest that researchers and developers attempting to simulate social interactions should consider the impact of agency beliefs on user experience in other social contexts, and their effect

A QSAR approach for virtual screening of lead-like molecules en route to antitumor and antibiotic drugs from marine and microbial natural products

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Florbela Pereira

2014-05-01

Figure 1. The unreported 15 lead antibiotic MNPs and MbNPs from AntiMarin database, using the best Rfs antibiotic model with a probability of being antibiotic greater than or equal to 0.8. Figure 2. The selected 4 lead antitumor MNPs and MbNPs from the AntiMarin database, using the best Rfs antitumor model with a probability of being antitumor greater than or equal to 0.8. The present work corroborates by one side the results of our previous work6 and enables the presentation of a new set of possible lead like bioactive compounds. Additionally, it is shown the usefulness of quantum-chemical descriptors in the discrimination of biological active and inactive compounds. The use of the εHOMO quantum-chemical descriptor in the discrimination of large scale data sets of lead-like or drug-like compounds has never been reported. This approach results in the reduction, in great extent, of the number of compounds used in real screens, and it reinforces the results of our previous work. Furthermore, besides the virtual screening, the computational methods can be very useful to build appropriate databases, allowing for effective shortcuts of NP extracts dereplication procedures, which will certainly result in increasing the efficiency of drug discovery.

Grid heterogeneity in in-silico experiments: an exploration of drug screening using DOCK on cloud environments.

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Yim, Wen-Wai; Chien, Shu; Kusumoto, Yasuyuki; Date, Susumu; Haga, Jason

2010-01-01

Large-scale in-silico screening is a necessary part of drug discovery and Grid computing is one answer to this demand. A disadvantage of using Grid computing is the heterogeneous computational environments characteristic of a Grid. In our study, we have found that for the molecular docking simulation program DOCK, different clusters within a Grid organization can yield inconsistent results. Because DOCK in-silico virtual screening (VS) is currently used to help select chemical compounds to test with in-vitro experiments, such differences have little effect on the validity of using virtual screening before subsequent steps in the drug discovery process. However, it is difficult to predict whether the accumulation of these discrepancies over sequentially repeated VS experiments will significantly alter the results if VS is used as the primary means for identifying potential drugs. Moreover, such discrepancies may be unacceptable for other applications requiring more stringent thresholds. This highlights the need for establishing a more complete solution to provide the best scientific accuracy when executing an application across Grids. One possible solution to platform heterogeneity in DOCK performance explored in our study involved the use of virtual machines as a layer of abstraction. This study investigated the feasibility and practicality of using virtual machine and recent cloud computing technologies in a biological research application. We examined the differences and variations of DOCK VS variables, across a Grid environment composed of different clusters, with and without virtualization. The uniform computer environment provided by virtual machines eliminated inconsistent DOCK VS results caused by heterogeneous clusters, however, the execution time for the DOCK VS increased. In our particular experiments, overhead costs were found to be an average of 41% and 2% in execution time for two different clusters, while the actual magnitudes of the execution time

Microsoft Virtualization Master Microsoft Server, Desktop, Application, and Presentation Virtualization

CERN Document Server

Olzak, Thomas; Boomer, Jason; Keefer, Robert M

2010-01-01

Microsoft Virtualization helps you understand and implement the latest virtualization strategies available with Microsoft products. This book focuses on: Server Virtualization, Desktop Virtualization, Application Virtualization, and Presentation Virtualization. Whether you are managing Hyper-V, implementing desktop virtualization, or even migrating virtual machines, this book is packed with coverage on all aspects of these processes. Written by a talented team of Microsoft MVPs, Microsoft Virtualization is the leading resource for a full installation, migration, or integration of virtual syste

Virtual Library: An essential component of virtual education

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M zarghani

2015-06-01

Full Text Available Abstract Introduction: Library is one of the essential elements of universities which provide some important educational needs of students. Virtual education can not be exempted and virtual libraries are important support for virtual training programs. The purpose of this study is to evaluate the viewpoint of administrators and students in virtual education centers about the virtual library, its role and resources. Methods: This study was a descriptive survey. The research instrument was a researcher made questionnaire that its validity and reliability was confirmed. The study population consisted of 19 virtual training centers in Tehran city. Out of 19 centers, simple randomized sampling was done in five Centers. The sample size was 360 students. Data collection was conducted online and descriptive statistics using SPSS 18 and Excel software were used. Results: The results showed that viewpoints of administrators and students about the mission and services of virtual libraries in some cases were similar and in some cases were different. One of the administrators’ reasons for setting up a virtual learning system was lifelong learning, and lack of knowledge about virtual libraries was the reason for inadequate use of virtual libraries. The best format of virtual library from the administrators’ and students’ viewpoint, was portal document format (PDF. Conclusion: One of the most important function of a virtual library, is lifelong learning and empowering users to provide information and educational needs. The main reason for not setting up a virtual library is t lack of knowledge about it.

Virtual reality 3D headset based on DMD light modulators

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Bernacki, Bruce E.; Evans, Allan; Tang, Edward

2014-06-01

We present the design of an immersion-type 3D headset suitable for virtual reality applications based upon digital micromirror devices (DMD). Current methods for presenting information for virtual reality are focused on either polarizationbased modulators such as liquid crystal on silicon (LCoS) devices, or miniature LCD or LED displays often using lenses to place the image at infinity. LCoS modulators are an area of active research and development, and reduce the amount of viewing light by 50% due to the use of polarization. Viewable LCD or LED screens may suffer low resolution, cause eye fatigue, and exhibit a "screen door" or pixelation effect due to the low pixel fill factor. Our approach leverages a mature technology based on silicon micro mirrors delivering 720p resolution displays in a small form-factor with high fill factor. Supporting chip sets allow rapid integration of these devices into wearable displays with high-definition resolution and low power consumption, and many of the design methods developed for DMD projector applications can be adapted to display use. Potential applications include night driving with natural depth perception, piloting of UAVs, fusion of multiple sensors for pilots, training, vision diagnostics and consumer gaming. Our design concept is described in which light from the DMD is imaged to infinity and the user's own eye lens forms a real image on the user's retina resulting in a virtual retinal display.

Virtual Reality and the Virtual Library.

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Oppenheim, Charles

1993-01-01

Explains virtual reality, including proper and improper uses of the term, and suggests ways that libraries might be affected by it. Highlights include elements of virtual reality systems; possible virtual reality applications, including architecture, the chemical industry, transport planning, armed forces, and entertainment; and the virtual…

From virtual environment to virtual community

NARCIS (Netherlands)

Nijholt, Antinus; Terano, Takao; Nishida, Toyoaki; Namatame, Akira; Tsumoto, Syusaku; Ohsawa, Yukido; Washio, Takashi

2001-01-01

We discuss a virtual reality theater environment and its transition to a virtual community by adding domain agents and by allowing multiple users to visit this environment. The environment has been built using VRML (Virtual Reality Modeling Language). We discuss how our ideas about this environment

In silico structure-based drug screening of novel antimycobacterial pharmacophores by DOCK-GOLD tandem screening

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Junichi Taira

2017-01-01

Full Text Available Background: Enzymes responsible for cell wall development in Mycobacterium tuberculosis are considered as potential targets of anti-tuberculosis (TB agents. Mycobacterial cyclopropane mycolic acid synthase 1 (CmaA1 is essential for mycobacterial survival because of its critical role in synthesizing mycolic acids. Materials and Methods: We screened compounds that were capable of interacting with the mycobacterial CmaA1 active site using a virtual compound library with an in silico structure-based drug screening (SBDS. Following the selection of such compounds, their antimycobacterial activity was examined. Results: With the in silico SBDS, for which we also used DOCK-GOLD programs and screening methods that utilized the structural similarity between the selected active compounds, we identified two compounds with potent inhibitory effects on mycobacterial growth. The antimycobacterial effect of the compounds was comparable to that of isoniazid, which is used as a first-line anti-TB drug. Conclusion: The compounds identified through SBDS were expected to be a novel class of anti-TB pharmacophores.

NMR-Fragment Based Virtual Screening: A Brief Overview.

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Singh, Meenakshi; Tam, Benjamin; Akabayov, Barak

2018-01-25

Fragment-based drug discovery (FBDD) using NMR has become a central approach over the last twenty years for development of small molecule inhibitors against biological macromolecules, to control a variety of cellular processes. Yet, several considerations should be taken into account for obtaining a therapeutically relevant agent. In this review, we aim to list the considerations that make NMR fragment screening a successful process for yielding potent inhibitors. Factors that may govern the competence of NMR in fragment based drug discovery are discussed, as well as later steps that involve optimization of hits obtained by NMR-FBDD.

NMR-Fragment Based Virtual Screening: A Brief Overview

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Meenakshi Singh

2018-01-01

Full Text Available Fragment-based drug discovery (FBDD using NMR has become a central approach over the last twenty years for development of small molecule inhibitors against biological macromolecules, to control a variety of cellular processes. Yet, several considerations should be taken into account for obtaining a therapeutically relevant agent. In this review, we aim to list the considerations that make NMR fragment screening a successful process for yielding potent inhibitors. Factors that may govern the competence of NMR in fragment based drug discovery are discussed, as well as later steps that involve optimization of hits obtained by NMR-FBDD.

Virtual cathode microwave generation using inhomogeneous magnetic field and wave guide wall configuration

International Nuclear Information System (INIS)

Thode, L.E.; Kwan, T.J.T.

1984-01-01

Microwave generation from a virtual cathode system is investigated using two-dimensional particle-in-cell simulation. In the typical virtual cathode geometry, the electron beam diode is separated from the output waveguide by a ground plane which is a thin foil or screen. By lowering the diode impedance sufficiently, it is possible to form a virtual cathode in the waveguide region a short distance from the ground plane. In this configuration two mechanisms can lead to microwave generation: 1) electron bunching due to reflection between the real and virtual cathode and 2) electron bunching due to virtual cathode oscillation. Both mechanisms are typically present, but it appears possible to make one mechanism dominant by adjusting the output waveguide radius. Although such a configuration might generate 1-10 GW output, electron deposition into the ground plane, waveguide wall, and output window causes breakdown. To overcome these disadvantages, the authors have investigated a configuration with no ground plane coupled with the use of an inhomogeneous external magnetic field and waveguide wall

Virtual reality for the treatment of autism.

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Strickland, D

1997-01-01

Autism is a mental disorder which has received attention in several unrelated studies using virtual reality. One of the first attempts was to diagnose children with special needs at Tokyo University using a sandbox playing technique. Although operating the computer controls proved to be too difficult for the individuals with autism in the Tokyo study, research at the University of Nottingham, UK, is successful in using VR as a learning aid for children with a variety of disorders including autism. Both centers used flat screen computer systems with virtual scenes. Another study which concentrated on using VR as a learning aid with an immersive headset system is described in detail in this chapter. Perhaps because of the seriousness of the disorder and the lack of effective treatments, autism has received more study than attention deficit disorders, although both would appear to benefit from many of the same technology features.

3D multiplayer virtual pets game using Google Card Board

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Herumurti, Darlis; Riskahadi, Dimas; Kuswardayan, Imam

2017-08-01

Virtual Reality (VR) is a technology which allows user to interact with the virtual environment. This virtual environment is generated and simulated by computer. This technology can make user feel the sensation when they are in the virtual environment. The VR technology provides real virtual environment view for user and it is not viewed from screen. But it needs another additional device to show the view of virtual environment. This device is known as Head Mounted Device (HMD). Oculust Rift and Microsoft Hololens are the most famous HMD devices used in VR. And in 2014, Google Card Board was introduced at Google I/O developers conference. Google Card Board is VR platform which allows user to enjoy the VR with simple and cheap way. In this research, we explore Google Card Board to develop simulation game of raising pet. The Google Card Board is used to create view for the VR environment. The view and control in VR environment is built using Unity game engine. And the simulation process is designed using Finite State Machine (FSM). This FSM can help to design the process clearly. So the simulation process can describe the simulation of raising pet well. Raising pet is fun activity. But sometimes, there are many conditions which cause raising pet become difficult to do, i.e. environment condition, disease, high cost, etc. this research aims to explore and implement Google Card Board in simulation of raising pet.

A virtual control room with an embedded, interactive nuclear reactor simulator

International Nuclear Information System (INIS)

Markidis, S.; Rizwan, U.

2006-01-01

The use of virtual nuclear control room can be an effective and powerful tool for training personnel working in the nuclear power plants. Operators could experience and simulate the functioning of the plant, even in critical situations, without being in a real power plant or running any risk. 3D models can be exported to Virtual Reality formats and then displayed in the Virtual Reality environment providing an immersive 3D experience. However, two major limitations of this approach are that 3D models exhibit static textures, and they are not fully interactive and therefore cannot be used effectively in training personnel. In this paper we first describe a possible solution for embedding the output of a computer application in a 3D virtual scene, coupling real-world applications and VR systems. The VR system reported here grabs the output of an application running on an X server; creates a texture with the output and then displays it on a screen or a wall in the virtual reality environment. We then propose a simple model for providing interaction between the user in the VR system and the running simulator. This approach is based on the use of internet-based application that can be commanded by a laptop or tablet-pc added to the virtual environment. (authors)

Exploring the Molecular Basis for Selective Binding of Homoserine Dehydrogenase from Mycobacterium leprae TN toward Inhibitors: A Virtual Screening Study

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Dongling Zhan

2014-01-01

Full Text Available Homoserine dehydrogenase (HSD from Mycobacterium leprae TN is an antifungal target for antifungal properties including efficacy against the human pathogen. The 3D structure of HSD has been firmly established by homology modeling methods. Using the template, homoserine dehydrogenase from Thiobacillus denitrificans (PDB Id 3MTJ, a sequence identity of 40% was found and molecular dynamics simulation was used to optimize a reliable structure. The substrate and co-factor-binding regions in HSD were identified. In order to determine the important residues of the substrate (l-aspartate semialdehyde (l-ASA binding, the ASA was docked to the protein; Thr163, Asp198, and Glu192 may be important because they form a hydrogen bond with HSD through AutoDock 4.2 software. neuraminidaseAfter use of a virtual screening technique of HSD, the four top-scoring docking hits all seemed to cation–π ion pair with the key recognition residue Lys107, and Lys207. These ligands therefore seemed to be new chemotypes for HSD. Our results may be helpful for further experimental investigations.

Discovery of Novel Inhibitors for Nek6 Protein through Homology Model Assisted Structure Based Virtual Screening and Molecular Docking Approaches

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P. Srinivasan

2014-01-01

Full Text Available Nek6 is a member of the NIMA (never in mitosis, gene A-related serine/threonine kinase family that plays an important role in the initiation of mitotic cell cycle progression. This work is an attempt to emphasize the structural and functional relationship of Nek6 protein based on homology modeling and binding pocket analysis. The three-dimensional structure of Nek6 was constructed by molecular modeling studies and the best model was further assessed by PROCHECK, ProSA, and ERRAT plot in order to analyze the quality and consistency of generated model. The overall quality of computed model showed 87.4% amino acid residues under the favored region. A 3 ns molecular dynamics simulation confirmed that the structure was reliable and stable. Two lead compounds (Binding database ID: 15666, 18602 were retrieved through structure-based virtual screening and induced fit docking approaches as novel Nek6 inhibitors. Hence, we concluded that the potential compounds may act as new leads for Nek6 inhibitors designing.

Virtual microscopy and digital pathology in training and education.

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Hamilton, Peter W; Wang, Yinhai; McCullough, Stephen J

2012-04-01

Traditionally, education and training in pathology has been delivered using textbooks, glass slides and conventional microscopy. Over the last two decades, the number of web-based pathology resources has expanded dramatically with centralized pathological resources being delivered to many students simultaneously. Recently, whole slide imaging technology allows glass slides to be scanned and viewed on a computer screen via dedicated software. This technology is referred to as virtual microscopy and has created enormous opportunities in pathological training and education. Students are able to learn key histopathological skills, e.g. to identify areas of diagnostic relevance from an entire slide, via a web-based computer environment. Students no longer need to be in the same room as the slides. New human-computer interfaces are also being developed using more natural touch technology to enhance the manipulation of digitized slides. Several major initiatives are also underway introducing online competency and diagnostic decision analysis using virtual microscopy and have important future roles in accreditation and recertification. Finally, researchers are investigating how pathological decision-making is achieved using virtual microscopy and modern eye-tracking devices. Virtual microscopy and digital pathology will continue to improve how pathology training and education is delivered. © 2012 The Authors APMIS © 2012 APMIS.

Augmented Virtuality: A Real-time Process for Presenting Real-world Visual Sensory Information in an Immersive Virtual Environment for Planetary Exploration

Science.gov (United States)

McFadden, D.; Tavakkoli, A.; Regenbrecht, J.; Wilson, B.

2017-12-01

Virtual Reality (VR) and Augmented Reality (AR) applications have recently seen an impressive growth, thanks to the advent of commercial Head Mounted Displays (HMDs). This new visualization era has opened the possibility of presenting researchers from multiple disciplines with data visualization techniques not possible via traditional 2D screens. In a purely VR environment researchers are presented with the visual data in a virtual environment, whereas in a purely AR application, a piece of virtual object is projected into the real world with which researchers could interact. There are several limitations to the purely VR or AR application when taken within the context of remote planetary exploration. For example, in a purely VR environment, contents of the planet surface (e.g. rocks, terrain, or other features) should be created off-line from a multitude of images using image processing techniques to generate 3D mesh data that will populate the virtual surface of the planet. This process usually takes a tremendous amount of computational resources and cannot be delivered in real-time. As an alternative, video frames may be superimposed on the virtual environment to save processing time. However, such rendered video frames will lack 3D visual information -i.e. depth information. In this paper, we present a technique to utilize a remotely situated robot's stereoscopic cameras to provide a live visual feed from the real world into the virtual environment in which planetary scientists are immersed. Moreover, the proposed technique will blend the virtual environment with the real world in such a way as to preserve both the depth and visual information from the real world while allowing for the sensation of immersion when the entire sequence is viewed via an HMD such as Oculus Rift. The figure shows the virtual environment with an overlay of the real-world stereoscopic video being presented in real-time into the virtual environment. Notice the preservation of the object

Detection of flat colorectal polyps at screening CT colonography in comparison with conventional polypoid lesions

Energy Technology Data Exchange (ETDEWEB)

Sakamoto, Takashi; Urata, Joji [Diagnostic Imaging Center, Saiseikai Kumamoto Hospital, Kumamoto (Japan); Mitsuzaki, Katsuhiko; Matsuda, Katsuhiko; Kawakami, Megumi [Medical Examination Center, Saiseikai Kumamoto Hospital, Kumamoto (Japan); Utsunomiya, Daisuke; Yamamura, Sadahiro; Yamashita, Yasuyuki [Diagnostic Radiology, Faculty of Life Sciences, Kumamoto Univ., Kumamoto (Japan)], e-mail: utsunomi@kumamoto-u.ac.jp

2012-09-15

Background: Although the screening of small, flat polyps is clinically important, the role of CT colonography (CTC) screening in their detection has not been thoroughly investigated. Purpose: To evaluate the detection capability and usefulness of CTC in the screening of flat and polypoid lesions by comparing CTC with optic colonoscopy findings as the gold standard. Material and Methods: We evaluated the CTC detection capability for flat colorectal polyps with a flat surface and a height not exceeding 3 mm (n = 42) by comparing to conventional polypoid lesions (n = 418) according to the polyp diameter. Four types of reconstruction images including multiplanar reconstruction, volume rendering, virtual gross pathology, and virtual endoscopic images were used for visual analysis. We compared the abilities of the four reconstructions for polyp visualization. Results: Detection sensitivity for flat polyps was 31.3 %, 44.4 %, and 87.5 % for lesions measuring 2-3 mm, 4-5 mm, and {>=}6 mm, respectively; the corresponding sensitivity for polypoid lesions was 47.6 %, 79.0 %, and 91.7 %. The overall sensitivity for flat lesions (47.6%) was significantly lower than polypoid lesions (64.1%). Virtual endoscopic imaging showed best visualization among the four reconstructions. Colon cancers were detected in eight patients by optic colonoscopy, and CTC detected colon cancers in all eight patients. Conclusion: CTC using 64-row multidetector CT is useful for colon cancer screening to detect colorectal polyps while the detection of small, flat lesions is still challenging.

Light cones in relativity: Real, complex, and virtual, with applications

International Nuclear Information System (INIS)

Adamo, T. M.; Newman, E. T.

2011-01-01

We study geometric structures associated with shear-free null geodesic congruences in Minkowski space-time and asymptotically shear-free null geodesic congruences in asymptotically flat space-times. We show how in both the flat and asymptotically flat settings, complexified future null infinity I C + acts as a ''holographic screen,'' interpolating between two dual descriptions of the null geodesic congruence. One description constructs a complex null geodesic congruence in a complex space-time whose source is a complex worldline, a virtual source as viewed from the holographic screen. This complex null geodesic congruence intersects the real asymptotic boundary when its source lies on a particular open-string type structure in the complex space-time. The other description constructs a real, twisting, shear-free or asymptotically shear-free null geodesic congruence in the real space-time, whose source (at least in Minkowski space) is in general a closed-string structure: the caustic set of the congruence. Finally we show that virtually all of the interior space-time physical quantities that are identified at null infinity I + (center of mass, spin, angular momentum, linear momentum, and force) are given kinematic meaning and dynamical descriptions in terms of the complex worldline.

Discovery of Specific Inhibitors for Intestinal E. coli  β-Glucuronidase through In Silico Virtual Screening

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Ta-Chun Cheng

2015-01-01

Full Text Available Glucuronidation is a major metabolism process of detoxification for carcinogens, 4-(methylnitrosamino-1-(3-pyridy-1-butanone (NNK and 1,2-dimethylhydrazine (DMH, of reactive oxygen species (ROS. However, intestinal E. coli   β-glucuronidase (eβG has been considered pivotal to colorectal carcinogenesis. Specific inhibition of eβG may prevent reactivating the glucuronide-carcinogen and protect the intestine from ROS-mediated carcinogenesis. In order to develop specific eβG inhibitors, we found that 59 candidate compounds obtained from the initial virtual screening had high inhibition specificity against eβG but not human βG. In particular, we found that compounds 7145 and 4041 with naphthalenylidene-benzenesulfonamide (NYBS are highly effective and selective to inhibit eβG activity. Compound 4041  (IC50=2.8 μM shows a higher inhibiting ability than compound 7145  (IC50=31.6 μM against eβG. Furthermore, the molecular docking analysis indicates that compound 4041 has two hydrophobic contacts to residues L361 and I363 in the bacterial loop, but 7145 has one contact to L361. Only compound 4041 can bind to key residue (E413 at active site of eβG via hydrogen-bonding interactions. These novel NYBS-based eβG specific inhibitors may provide as novel candidate compounds, which specifically inhibit eβG to reduce eβG-based carcinogenesis and intestinal injury.

Retrospective dosimetry using EPR and TL techniques: a status report

Energy Technology Data Exchange (ETDEWEB)

Haskell, E.H.

1996-12-31

Methods of retrospective dosimetry, including luminescence and electron paramagnetic resonance spectroscopy (EPR), rely on measurement of accident dose absorbed by naturally occurring materials - ceramics in the case of both thermoluminescence (TL) and optically stimulated luminescence (OSL) and organic materials and bio- minerals in the case of EPR. Each of these methods relies on measurement of radiation defects resulting from accidental exposure. Since defects also result from natural sources of radiation over the lifetime of a sample, analysis is usually restricted to materials for which the natural dose may be determined and subtracted from the measured cumulative dose. Luminescence dating techniques rely heavily on an accurate assessment of cumulative dose from natural radiation sources, and dating research has provided us with the bulk of our knowledge in this area. Virtually all of the work on natural dose determination can be directly applied to retrospective techniques. With EPR techniques the cumulative dose from diagnostic x- rays is also of importance.

Retrospective dosimetry using EPR and TL techniques: a status report

International Nuclear Information System (INIS)

Haskell, E.H.

1996-01-01

Methods of retrospective dosimetry, including luminescence and electron paramagnetic resonance spectroscopy (EPR), rely on measurement of accident dose absorbed by naturally occurring materials - ceramics in the case of both thermoluminescence (TL) and optically stimulated luminescence (OSL) and organic materials and bio- minerals in the case of EPR. Each of these methods relies on measurement of radiation defects resulting from accidental exposure. Since defects also result from natural sources of radiation over the lifetime of a sample, analysis is usually restricted to materials for which the natural dose may be determined and subtracted from the measured cumulative dose. Luminescence dating techniques rely heavily on an accurate assessment of cumulative dose from natural radiation sources, and dating research has provided us with the bulk of our knowledge in this area. Virtually all of the work on natural dose determination can be directly applied to retrospective techniques. With EPR techniques the cumulative dose from diagnostic x- rays is also of importance

Analysis of the social network development of a virtual community for Australian intensive care professionals.

Science.gov (United States)

Rolls, Kaye Denise; Hansen, Margaret; Jackson, Debra; Elliott, Doug

2014-11-01

Social media platforms can create virtual communities, enabling healthcare professionals to network with a broad range of colleagues and facilitate knowledge exchange. In 2003, an Australian state health department established an intensive care mailing list to address the professional isolation experienced by senior intensive care nurses. This article describes the social network created within this virtual community by examining how the membership profile evolved from 2003 to 2009. A retrospective descriptive design was used. The data source was a deidentified member database. Since 2003, 1340 healthcare professionals subscribed to the virtual community with 78% of these (n = 1042) still members at the end of 2009. The membership profile has evolved from a single-state nurse-specific network to an Australia-wide multidisciplinary and multiorganizational intensive care network. The uptake and retention of membership by intensive care clinicians indicated that they appeared to value involvement in this virtual community. For healthcare organizations, a virtual community may be a communications option for minimizing professional and organizational barriers and promoting knowledge flow. Further research is, however, required to demonstrate a link between these broader social networks, enabling the exchange of knowledge and improved patient outcomes.

Support vector regression scoring of receptor-ligand complexes for rank-ordering and virtual screening of chemical libraries.

Science.gov (United States)

Li, Liwei; Wang, Bo; Meroueh, Samy O

2011-09-26

The community structure-activity resource (CSAR) data sets are used to develop and test a support vector machine-based scoring function in regression mode (SVR). Two scoring functions (SVR-KB and SVR-EP) are derived with the objective of reproducing the trend of the experimental binding affinities provided within the two CSAR data sets. The features used to train SVR-KB are knowledge-based pairwise potentials, while SVR-EP is based on physicochemical properties. SVR-KB and SVR-EP were compared to seven other widely used scoring functions, including Glide, X-score, GoldScore, ChemScore, Vina, Dock, and PMF. Results showed that SVR-KB trained with features obtained from three-dimensional complexes of the PDBbind data set outperformed all other scoring functions, including best performing X-score, by nearly 0.1 using three correlation coefficients, namely Pearson, Spearman, and Kendall. It was interesting that higher performance in rank ordering did not translate into greater enrichment in virtual screening assessed using the 40 targets of the Directory of Useful Decoys (DUD). To remedy this situation, a variant of SVR-KB (SVR-KBD) was developed by following a target-specific tailoring strategy that we had previously employed to derive SVM-SP. SVR-KBD showed a much higher enrichment, outperforming all other scoring functions tested, and was comparable in performance to our previously derived scoring function SVM-SP.

Virtual Team Governance: Addressing the Governance Mechanisms and Virtual Team Performance

Science.gov (United States)

Zhan, Yihong; Bai, Yu; Liu, Ziheng

As technology has improved and collaborative software has been developed, virtual teams with geographically dispersed members spread across diverse physical locations have become increasingly prominent. Virtual team is supported by advancing communication technologies, which makes virtual teams able to largely transcend time and space. Virtual teams have changed the corporate landscape, which are more complex and dynamic than traditional teams since the members of virtual teams are spread on diverse geographical locations and their roles in the virtual team are different. Therefore, how to realize good governance of virtual team and arrive at good virtual team performance is becoming critical and challenging. Good virtual team governance is essential for a high-performance virtual team. This paper explores the performance and the governance mechanism of virtual team. It establishes a model to explain the relationship between the performance and the governance mechanisms in virtual teams. This paper is focusing on managing virtual teams. It aims to find the strategies to help business organizations to improve the performance of their virtual teams and arrive at the objectives of good virtual team management.

Performance of computer-aided detection in false-negative screening mammograms of breast cancers

International Nuclear Information System (INIS)

Han, Boo Kyung; Kim, Ji Young; Shin, Jung Hee; Choe, Yeon Hyeon

2004-01-01

To analyze retrospectively the abnormalities visible on the false-negative screening mammograms of patients with breast cancer and to determine the performance of computer-aided detection (CAD) in the detection of cancers. Of 108 consecutive cases of breast cancer diagnosed over a period of 6 years, of which previous screening mammograms were available, 32 retrospectively visible abnormalities (at which locations cancer later developed) were found in the previous mammograms, and which were originally reported as negative. These 32 patients ranged in age from 38 to 72 years (mean 52 years). We analyzed their previous mammographic findings, and assessed the ability of CAD to mark cancers in previous mammograms, according to the clinical presentation, the type of abnormalities and the mammographic parenchymal density. In these 32 previous mammograms of breast cancers (20 asymptomatic, 12 symptomatic), the retrospectively visible abnormalities were identified as densities in 22, calcifications in 8, and densities with calcifications in 2. CAD marked abnormalities in 20 (63%) of the 32 cancers with false-negative screening mammograms; 14 (70%) of the 20 subsequent screening-detected cancers, 5 (50%) of the 10 interval cancers, and 1 (50%) of the 2 cancers palpable after the screening interval. CAD marked 12 (50%) of the 24 densities and 9 (90%) of the 10 calcifications. CAD marked abnormalities in 7 (50%) of the 14 predominantly fatty breasts, and 13 (72%) of the 18 dense breasts. CAD-assisted diagnosis could potentially decrease the number of false-negative mammograms caused by the failure to recognize the cancer in the screening program, although its usefulness in the prevention of interval cancers appears to be limited

Domestic violence screening in pregnancy.

Science.gov (United States)

Bunn, Mikiko Yazawa; Higa, Nicole A; Parker, Willie J; Kaneshiro, Bliss

2009-11-01

Domestic violence is an important health concern that has been shown to have adverse effects on maternal and neonatal outcomes. The objectives of this study were to compare the prevalence of prenatal screening for domestic violence in a hospital-based resident clinic setting with screening practices in private obstetric offices in Honolulu, Hawai'i and to explore physician attitudes towards domestic violence screening during pregnancy. A retrospective chart review was conducted at Queen's Medical Center in Honolulu, Hawai'i in women who delivered between 2003 and 2004. A 6 item written survey was also given to all attending and resident physicians with obstetric privileges. Descriptive statistics including frequency measures were generated and chi square tests were used to compare categorical variables. A total of 270 charts were reviewed. There was a statistically significant difference (p obstetric practices (39.3 percent) that were screened for domestic violence. While the majority of respondents (77.6%) to the domestic violence survey were aware that the American College of Obstetricians and Gynecologists recommends domestic violence screening in pregnancy most respondents (69.0 percent) indicated that they "never or rarely" screened their patients for domestic violence. Despite professional recommendations and an awareness of these recommendations, between 2003 and 2004, routine prenatal screening for domestic violence was markedly lacking for patients in this study population.

Research on tactical information display technology for interactive virtual cockpit

Science.gov (United States)

Sun, Zhongyun; Tian, Tao; Su, Feng

2018-04-01

Based on a fact that traditional tactical information display technology suffers from disadvantages of a large number of data to be transferred and low plotting efficiency in an interactive virtual cockpit, a GID protocol-based simulation has been designed. This method dissolves complex tactical information screens into basic plotting units. The indication of plotting units is controlled via the plotting commands, which solves the incompatibility between the tactical information display in traditional simulation and the desktop-based virtual simulation training system. Having been used in desktop systems for helicopters, fighters, and transporters, this method proves to be scientific and reasonable in design and simple and efficient in usage, which exerts a significant value in establishing aviation equipment technology support training products.

Short Term Motor-Skill Acquisition Improves with Size of Self-Controlled Virtual Hands.

Science.gov (United States)

Ossmy, Ori; Mukamel, Roy

2017-01-01

Visual feedback in general, and from the body in particular, is known to influence the performance of motor skills in humans. However, it is unclear how the acquisition of motor skills depends on specific visual feedback parameters such as the size of performing effector. Here, 21 healthy subjects physically trained to perform sequences of finger movements with their right hand. Through the use of 3D Virtual Reality devices, visual feedback during training consisted of virtual hands presented on the screen, tracking subject's hand movements in real time. Importantly, the setup allowed us to manipulate the size of the displayed virtual hands across experimental conditions. We found that performance gains increase with the size of virtual hands. In contrast, when subjects trained by mere observation (i.e., in the absence of physical movement), manipulating the size of the virtual hand did not significantly affect subsequent performance gains. These results demonstrate that when it comes to short-term motor skill learning, the size of visual feedback matters. Furthermore, these results suggest that highest performance gains in individual subjects are achieved when the size of the virtual hand matches their real hand size. These results may have implications for optimizing motor training schemes.

Short Term Motor-Skill Acquisition Improves with Size of Self-Controlled Virtual Hands.

Directory of Open Access Journals (Sweden)

Ori Ossmy

Full Text Available Visual feedback in general, and from the body in particular, is known to influence the performance of motor skills in humans. However, it is unclear how the acquisition of motor skills depends on specific visual feedback parameters such as the size of performing effector. Here, 21 healthy subjects physically trained to perform sequences of finger movements with their right hand. Through the use of 3D Virtual Reality devices, visual feedback during training consisted of virtual hands presented on the screen, tracking subject's hand movements in real time. Importantly, the setup allowed us to manipulate the size of the displayed virtual hands across experimental conditions. We found that performance gains increase with the size of virtual hands. In contrast, when subjects trained by mere observation (i.e., in the absence of physical movement, manipulating the size of the virtual hand did not significantly affect subsequent performance gains. These results demonstrate that when it comes to short-term motor skill learning, the size of visual feedback matters. Furthermore, these results suggest that highest performance gains in individual subjects are achieved when the size of the virtual hand matches their real hand size. These results may have implications for optimizing motor training schemes.

Effect of viewing angle on arm reaching while standing in a virtual environment: potential for virtual rehabilitation.

Science.gov (United States)

Ustinova, K I; Perkins, J; Szostakowski, L; Tamkei, L S; Leonard, W A

2010-02-01

Functional arm movements, such as reaching while standing, are planned and executed according to our perception of body position in space and are relative to environmental objects. The angle under which the environment is observed is one component used in creating this perception. This suggests that manipulation of viewing angle may modulate whole body movement to affect performance. We tested this by comparing its effect on reaching in a virtually generated environment. Eleven young healthy individuals performed forward and lateral reaches in the virtual environment, presented on a flat screen in third-person perspective. Participants saw a computer-generated model (avatar) of themselves standing in a courtyard facing a semi-circular hedge with flowers. The image was presented in five different viewing angles ranging from seeing the avatar from behind (0 degrees), to viewing from overhead (90 degrees). Participants attempted to touch the furthest flower possible without losing balance or stepping. Kinematic data were collected to analyze endpoint displacement, arm-postural coordination and center of mass (COM) displacement. Results showed that reach distance was greatest with angular perspectives of approximately 45-77.5 degrees , which are larger than those used in analogous real world situations. Larger reaches were characterized by increased involvement of leg and trunk body segments, altered inter-segmental coordination, and decreased inter-segmental movement time lag. Thus a viewing angle can be a critical visuomotor variable modulating motor coordination of the whole body and related functional performance. These results can be used in designing virtual reality games, in ergonomic design, teleoperation training, and in designing virtual rehabilitation programs that re-train functional movement in vulnerable individuals. Copyright 2009 Elsevier B.V. All rights reserved.

VIRTUAL REALITY HYPNOSIS.

Science.gov (United States)

Askay, Shelley Wiechman; Patterson, David R; Sharar, Sam R

2009-03-01

Scientific evidence for the viability of hypnosis as a treatment for pain has flourished over the past two decades (Rainville, Duncan, Price, Carrier and Bushnell, 1997; Montgomery, DuHamel and Redd, 2000; Lang and Rosen, 2002; Patterson and Jensen, 2003). However its widespread use has been limited by factors such as the advanced expertise, time and effort required by clinicians to provide hypnosis, and the cognitive effort required by patients to engage in hypnosis.The theory in developing virtual reality hypnosis was to apply three-dimensional, immersive, virtual reality technology to guide the patient through the same steps used when hypnosis is induced through an interpersonal process. Virtual reality replaces many of the stimuli that the patients have to struggle to imagine via verbal cueing from the therapist. The purpose of this paper is to explore how virtual reality may be useful in delivering hypnosis, and to summarize the scientific literature to date. We will also explore various theoretical and methodological issues that can guide future research.In spite of the encouraging scientific and clinical findings, hypnosis for analgesia is not universally used in medical centres. One reason for the slow acceptance is the extensive provider training required in order for hypnosis to be an effective pain management modality. Training in hypnosis is not commonly offered in medical schools or even psychology graduate curricula. Another reason is that hypnosis requires far more time and effort to administer than an analgesic pill or injection. Hypnosis requires training, skill and patience to deliver in medical centres that are often fast-paced and highly demanding of clinician time. Finally, the attention and cognitive effort required for hypnosis may be more than patients in an acute care setting, who may be under the influence of opiates and benzodiazepines, are able to impart. It is a challenge to make hypnosis a standard part of care in this environment

Low-cost, smartphone based frequency doubling technology visual field testing using virtual reality (Conference Presentation)

Science.gov (United States)

Alawa, Karam A.; Sayed, Mohamed; Arboleda, Alejandro; Durkee, Heather A.; Aguilar, Mariela C.; Lee, Richard K.

2017-02-01

Glaucoma is the leading cause of irreversible blindness worldwide. Due to its wide prevalence, effective screening tools are necessary. The purpose of this project is to design and evaluate a system that enables portable, cost effective, smartphone based visual field screening based on frequency doubling technology. The system is comprised of an Android smartphone to display frequency doubling stimuli and handle processing, a Bluetooth remote for user input, and a virtual reality headset to simulate the exam. The LG Nexus 5 smartphone and BoboVR Z3 virtual reality headset were used for their screen size and lens configuration, respectively. The system is capable of running the C-20, N-30, 24-2, and 30-2 testing patterns. Unlike the existing system, the smartphone FDT tests both eyes concurrently by showing the same background to both eyes but only displaying the stimulus to one eye at a time. Both the Humphrey Zeiss FDT and the smartphone FDT were tested on five subjects without a history of ocular disease with the C-20 testing pattern. The smartphone FDT successfully produced frequency doubling stimuli at the correct spatial and temporal frequency. Subjects could not tell which eye was being tested. All five subjects preferred the smartphone FDT to the Humphrey Zeiss FDT due to comfort and ease of use. The smartphone FDT is a low-cost, portable visual field screening device that can be used as a screening tool for glaucoma.

Practicality of profile-wire screen in reducing entrainment and impingement

International Nuclear Information System (INIS)

Hanson, B.N.; Bason, W.H.; Beitz, B.E.; Charles, K.E.

1978-01-01

Experimental studies indicated that 1.01-mm slot profile-wire well screen operated at an intake velocity of 15.24 cm/s virtually eliminated impingement of fishes larger than 15 mm fork length (FL). Intake velocities as high as 53.34 cm/s produced low impingement. Tests of fish less than 40 mm FL held near a functioning intake (15.24 cm/s) for as long as 3 hr yielded no impingement or stress. Many striped bass between 8 and 17 mm FL were capable of resisting impingement at more than 30.48 cm/s velocity for longer than 30 min; larger specimens (12 to 17 mm) showed excellent ability to escape when impinged. The screen excluded virtually all striped bass eggs from the cooling water. Preliminary egg mortality studies indicate that at least 95% survival can be expected at an approach velocity of 15.24 cm/s and impingement durations up to 2 min. Fouling studies showed that screens were highly resistant to clogging, essentially self-cleaning in a current, and easily backwashed. In-situ studies in the Chesapeake and Delaware Canal have shown that a 61.0- x 76.2-cm, 1.01-mm-slot screen is capable of providing its designed capacity for weeks without backwashing or cleaning. Biofouling proved to be the greatest operational problem. Entrainment samples from the in-situ intake have shown significant reductions in organisms/m 3 of filtered versus ambient water

Innovative application of virtual display technique in virtual museum

Science.gov (United States)

Zhang, Jiankang

2017-09-01

Virtual museum refers to display and simulate the functions of real museum on the Internet in the form of 3 Dimensions virtual reality by applying interactive programs. Based on Virtual Reality Modeling Language, virtual museum building and its effective interaction with the offline museum lie in making full use of 3 Dimensions panorama technique, virtual reality technique and augmented reality technique, and innovatively taking advantages of dynamic environment modeling technique, real-time 3 Dimensions graphics generating technique, system integration technique and other key virtual reality techniques to make sure the overall design of virtual museum.3 Dimensions panorama technique, also known as panoramic photography or virtual reality, is a technique based on static images of the reality. Virtual reality technique is a kind of computer simulation system which can create and experience the interactive 3 Dimensions dynamic visual world. Augmented reality, also known as mixed reality, is a technique which simulates and mixes the information (visual, sound, taste, touch, etc.) that is difficult for human to experience in reality. These technologies make virtual museum come true. It will not only bring better experience and convenience to the public, but also be conducive to improve the influence and cultural functions of the real museum.

Realistic Visualization of Virtual Views and Virtual Cinema

DEFF Research Database (Denmark)

Livatino, Salvatore

2005-01-01

Realistic Virtual View Visualization is a new field of research which has received increasing attention in recent years. It is strictly related to the increased popularity of virtual reality and the spread of its applications, among which virtual photography and cinematography. The use of computer...... generated characters, "virtual actors", in the motion picture production increases every day. While the most known computer graphics techniques have largely been adopted successfully in nowadays fictions, it still remains very challenging to implement virtual actors which would resemble, visually, human...... beings. Interestingly, film directors have been looking at the recent progress achieved by the research community in the field of realistic visualization of virtual views, and they have successfully implemented state of the art research approaches in their productions. An innovative concept...

Humiliation in the virtual world: Definitions and conceptualization

OpenAIRE

Dilmaç, Julie Alev

2014-01-01

The cyberspace represents a platform for social relations which permit to be in touch with the World, to be “seen” by others and to “see” others. As new technologies emerge, ways of viewing are revised, especially through screens: though it has facilitated communication, the main innovation of the virtual world has been seeing, hearing and showing everything with the individual at the center of permanent interactions. But this overexposure can be dangerous: in attempting to be as much a part ...

Interrater Reliability of the Power Mobility Road Test in the Virtual Reality-Based Simulator-2.

Science.gov (United States)

Kamaraj, Deepan C; Dicianno, Brad E; Mahajan, Harshal P; Buhari, Alhaji M; Cooper, Rory A

2016-07-01

To assess interrater reliability of the Power Mobility Road Test (PMRT) when administered through the Virtual Reality-based SIMulator-version 2 (VRSIM-2). Within-subjects repeated-measures design. Participants interacted with VRSIM-2 through 2 display options (desktop monitor vs immersive virtual reality screens) using 2 control interfaces (roller system vs conventional movement-sensing joystick), providing 4 different driving scenarios (driving conditions 1-4). Participants performed 3 virtual driving sessions for each of the 2 display screens and 1 session through a real-world driving course (driving condition 5). The virtual PMRT was conducted in a simulated indoor office space, and an equivalent course was charted in an open space for the real-world assessment. After every change in driving condition, participants completed a self-reported workload assessment questionnaire, the Task Load Index, developed by the National Aeronautics and Space Administration. A convenience sample of electric-powered wheelchair (EPW) athletes (N=21) recruited at the 31st National Veterans Wheelchair Games. Not applicable. Total composite PMRT score. The PMRT had high interrater reliability (intraclass correlation coefficient [ICC]>.75) between the 2 raters in all 5 driving conditions. Post hoc analyses revealed that the reliability analyses had >80% power to detect high ICCs in driving conditions 1 and 4. The PMRT has high interrater reliability in conditions 1 and 4 and could be used to assess EPW driving performance virtually in VRSIM-2. However, further psychometric assessment is necessary to assess the feasibility of administering the PMRT using the different interfaces of VRSIM-2. Copyright © 2016 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.

Virtual Trondheim: A Virtual Environment for Tourism and Education

OpenAIRE

Jose, Dawn Alphonse

2015-01-01

The purpose of this study is to investigate whether educational activities in tourism can be supported by virtual reality technologies, using virtual world frameworks. Settings of virtual world of SecondLife and a recent Virtual Reality technology known as Oculus Rift were used in the thesis work with the city of Trondheim as the main context. Theoretical studies on Virtual Reality systems were conducted and data for the research were obtained through empirical studies condu...

Personal Virtual Libraries

Science.gov (United States)

Pappas, Marjorie L.

2004-01-01

Virtual libraries are becoming more and more common. Most states have a virtual library. A growing number of public libraries have a virtual presence on the Web. Virtual libraries are a growing addition to school library media collections. The next logical step would be personal virtual libraries. A personal virtual library (PVL) is a collection…

High throughput virtual screening and in silico ADMET analysis for rapid and efficient identification of potential PAP248-286 aggregation inhibitors as anti-HIV agents

Science.gov (United States)

Malik, Ruchi; Bunkar, Devendra; Choudhary, Bhanwar Singh; Srivastava, Shubham; Mehta, Pakhuri; Sharma, Manish

2016-10-01

Human semen is principal vehicle for transmission of HIV-1 and other enveloped viruses. Several endogenous peptides present in semen, including a 39-amino acid fragments of prostatic acid phosphatase (PAP248-286) assemble into amyloid fibrils named as semen-derived enhancer of viral infection (SEVI) that promote virion attachment to target cells which dramatically enhance HIV virus infection by up to 105-fold. Epigallocatechin-3-gallate (EGCG), a polyphenolic compound, is the major catechin found in green tea which disaggregates existing SEVI fibers, and inhibits the formation of SEVI fibers. The aim of this study was to screen a number of relevant polyphenols to develop a rational approach for designing PAP248-286 aggregation inhibitors as potential anti-HIV agents. The molecular docking based virtual screening results showed that polyphenolic compounds 2-6 possessed good docking score and interacted well with the active site residues of PAP248-286. Amino acid residues of binding site namely; Lys255, Ser256, Leu258 and Asn265 are involved in binding of these compounds. In silico ADMET prediction studies on these hits were also found to be promising. Polyphenolic compounds 2-6 identified as hits may act as novel leads for inhibiting aggregation of PAP248-286 into SEVI.

Digital mammography in a screening programme and its implications for pathology: a comparative study.

LENUS (Irish Health Repository)

Feeley, Linda

2011-03-01

Most studies comparing full-field digital mammography (FFDM) with conventional screen-film mammography (SFM) have been radiology-based. The pathological implications of FFDM have received little attention in the literature, especially in the context of screening programmes. The primary objective of this retrospective study is to compare FFDM with SFM in a population-based screening programme with regard to a number of pathological parameters.

Motion-Computerized Tomographic Colography is a Better Method for Screening for Polyps: Arguments for the Motion

Directory of Open Access Journals (Sweden)

Benoit C Pineau

2003-01-01

Full Text Available Colorectal cancer is an important public health problem that is amenable to prevention and early treatment. Traditional screening techniques - fecal occult blood testing, flexible sigmoidoscopy, barium enema and colonoscopy - each have limitations in terms of diagnostic accuracy, cost and/or patient acceptability. Compliance with recommendations for screening has been poor, in part, because of negative perceptions about the available modalities. Virtual colonoscopy, or computerized tomographic colography, is a minimally invasive technique that safely evaluates the entire colon and does not require sedation. Thorough cleansing as well as immobilization and air insufflation of the colon is crucial to a successful examination. Sensitivity and specificity rates are reasonable, compared with conventional colonoscopy, and it has been shown that the latter technique can be averted in over two-thirds of cases, with few false-negative examinations. Most patients find virtual colonoscopy more acceptable than the conventional technique, and would prefer it if a repeat procedure were warranted. An economic analysis that found that computerized tomographic colography was less cost effective than conventional colonoscopy did not consider the indirect costs of the latter, which is an important limitation. Virtual colonoscopy is a novel radiological technique that may revolutionize screening for colorectal cancer.

Virtual Screening of Peptide and Peptidomimetic Fragments Targeted to Inhibit Bacterial Dithiol Oxidase DsbA.

Directory of Open Access Journals (Sweden)

Wilko Duprez

Full Text Available Antibacterial drugs with novel scaffolds and new mechanisms of action are desperately needed to address the growing problem of antibiotic resistance. The periplasmic oxidative folding system in Gram-negative bacteria represents a possible target for anti-virulence antibacterials. By targeting virulence rather than viability, development of resistance and side effects (through killing host native microbiota might be minimized. Here, we undertook the design of peptidomimetic inhibitors targeting the interaction between the two key enzymes of oxidative folding, DsbA and DsbB, with the ultimate goal of preventing virulence factor assembly. Structures of DsbB--or peptides--complexed with DsbA revealed key interactions with the DsbA active site cysteine, and with a hydrophobic groove adjacent to the active site. The present work aimed to discover peptidomimetics that target the hydrophobic groove to generate non-covalent DsbA inhibitors. The previously reported structure of a Proteus mirabilis DsbA active site cysteine mutant, in a non-covalent complex with the heptapeptide PWATCDS, was used as an in silico template for virtual screening of a peptidomimetic fragment library. The highest scoring fragment compound and nine derivatives were synthesized and evaluated for DsbA binding and inhibition. These experiments discovered peptidomimetic fragments with inhibitory activity at millimolar concentrations. Although only weakly potent relative to larger covalent peptide inhibitors that interact through the active site cysteine, these fragments offer new opportunities as templates to build non-covalent inhibitors. The results suggest that non-covalent peptidomimetics may need to interact with sites beyond the hydrophobic groove in order to produce potent DsbA inhibitors.

Wireless virtualization

CERN Document Server

Wen, Heming; Le-Ngoc, Tho

2013-01-01

This SpringerBriefs is an overview of the emerging field of wireless access and mobile network virtualization. It provides a clear and relevant picture of the current virtualization trends in wireless technologies by summarizing and comparing different architectures, techniques and technologies applicable to a future virtualized wireless network infrastructure. The readers are exposed to a short walkthrough of the future Internet initiative and network virtualization technologies in order to understand the potential role of wireless virtualization in the broader context of next-generation ubiq

Newborn screening for proximal urea cycle disorders: Current evidence supporting recommendations for newborn screening.

Science.gov (United States)

Merritt, J Lawrence; Brody, Linnea L; Pino, Gisele; Rinaldo, Piero

2018-04-20

Current newborn screening (NBS) for urea cycle disorders (UCD) is incomplete as only distal UCDs are included in most NBS programs by measuring elevated amino acid concentrations. NBS for the proximal UCDs involves the detection in NBS spots of low citrulline values, a finding which is often overlooked because it is considered to be inadequate. We retrospectively analyzed NBS blood spots from known UCD patients comparing the utility of the Region 4 Stork (R4S) interpretive tools to conventional cutoff based interpretation. This study shows the utility of R4S tools in detecting all UCDs, and provides evidence to support the nomination to add proximal UCDs to the recommended uniform screening panel. Copyright © 2018 Elsevier Inc. All rights reserved.

Virtual colonoscopy

Science.gov (United States)

Colonoscopy - virtual; CT colonography; Computed tomographic colonography; Colography - virtual ... Differences between virtual and conventional colonoscopy include: VC can view the colon from many different angles. This is not as easy ...

Possible applications of the LEAP motion controller for more interactive simulated experiments in augmented or virtual reality

Science.gov (United States)

Wozniak, Peter; Vauderwange, Oliver; Mandal, Avikarsha; Javahiraly, Nicolas; Curticapean, Dan

2016-09-01

Practical exercises are a crucial part of many curricula. Even simple exercises can improve the understanding of the underlying subject. Most experimental setups require special hardware. To carry out e. g. a lens experiments the students need access to an optical bench, various lenses, light sources, apertures and a screen. In our previous publication we demonstrated the use of augmented reality visualization techniques in order to let the students prepare with a simulated experimental setup. Within the context of our intended blended learning concept we want to utilize augmented or virtual reality techniques for stationary laboratory exercises. Unlike applications running on mobile devices, stationary setups can be extended more easily with additional interfaces and thus allow for more complex interactions and simulations in virtual reality (VR) and augmented reality (AR). The most significant difference is the possibility to allow interactions beyond touching a screen. The LEAP Motion controller is a small inexpensive device that allows for the tracking of the user's hands and fingers in three dimensions. It is conceivable to allow the user to interact with the simulation's virtual elements by the user's very hand position, movement and gesture. In this paper we evaluate possible applications of the LEAP Motion controller for simulated experiments in augmented and virtual reality. We pay particular attention to the devices strengths and weaknesses and want to point out useful and less useful application scenarios.

Virtual Exploratories

DEFF Research Database (Denmark)

Jensen, Sisse Siggaard

2006-01-01

-systems, the paper introduces the designing strategy referred to as virtual exploratories. Some of the advanced virtual worlds may inspire the design of such provoking and challenging virtual exploratories, and especially the Massively Multi-User Online Role-Playing Games (MMORPGS). However, if we have to learn from...... the design and activity of the advanced virtual worlds and role-playing games, then the empirical research on the actors’ activity, while they are acting, is an important precondition to it. A step towards the conception of such a designing strategy for virtual exploratories is currently pursued....... [1] The research project: Actors and Avatars Communicating in Virtual Worlds – an Empirical Analysis of Actors’ Sense-making Strategies When Based on a Communication Theoretical Approach’ (2006-2007) is supported...

“Cinematic” Gravity’s Rainbow: Indiscernibility of the Actual and the Virtual

Directory of Open Access Journals (Sweden)

Grmusa Lovorka Gruic

2017-11-01

Full Text Available Acknowledging that all media interpenetrate without any one being privileged as original, this paper focuses on the influence and omnipresence of screen technologies, cinematography in particular, asserting its capacities to act as a dominant technological and cultural force, which surveys and controls the economy, affects human consciousness, and implements its own ideologically tainted reality. More specifically, the analysis demonstrates the impact of cinematography within Thomas Pynchon’s Gravity’s Rainbow, emphasizing intermedial reflexivity from screen to paper, its unfolding and animation, representations and mutations, but also the notion that virtuality dominates actuality (Virilio, The Vision 63, or, in Deleuze’s terms, the two coalesce within the crystal-image, for the real and the imaginary, the actual and the virtual, although distinct, are indiscernible (Deleuze, Cinema 2 68-69. The study is grounded in Paul Virilio’s theoretical framework and his criticism of the colonization of the real by the virtual, and in Gilles Deleuze’s account on cinematic taxonomy and how cinematography partakes in the emergence of a new notion of reality and history. By appropriating, repurposing, and reshaping the techniques, forms, and contents of cinematography, and at the same time being critical of its effects, Pynchon uses paper surface for transition of his ideas, validating the repercussions of intermediation as a cultural force and unveiling literature’s performativity, its ability to shelter/entertain the “cinematic,” which in turn revolutionizes and animates fiction.

Viscosity Measurement: A Virtual Experiment - Abstract of Issues 9907W

Science.gov (United States)

Papadopoulos, N.; Pitta, A. T.; Markopoulos, N.; Limniou, M.; Lemos, M. A. N. D. A.; Lemos, F.; Freire, F. G.

1999-11-01

Viscosity Measurement: A Virtual Experiment simulates a series of viscosity experiments. Viscosity is an important subject in chemistry and chemical engineering. It is important when dealing with intermolecular forces in liquids and gases and it has enormous relevance in all technological aspects of equipment dealing with liquids or gases. Most university-level chemistry courses include viscosity to some extent. Viscosity Measurement includes three virtual experiments: an Ostwald viscometer simulator, a falling-ball viscometer simulator, and a balance simulator for a simple determination of the density of a liquid. The Ostwald viscometer simulator and the balance simulator allow the student to find out how composition and temperature influence the density and viscosity of an ethanol-water mixture. The falling-ball viscometer simulator allows the student to determine experimentally the size and density of the ball required to measure viscosity of various liquids. Each virtual experiment includes a corresponding theoretical section. Support from the program is sufficient to enable the students to carry out a virtual experiment sensibly and on their own. Preparation is not essential. Students can use the program unsupervised, thus saving staff time and allowing flexibility in students' time. The design of the program interface plays a key role in the success of a simulated experiment. Direct manipulation has greater intuitive appeal than alternative interface forms such as menus and has been observed to provide performance and learning advantages (1). We tried to design an interface that is visually attractive, is user friendly with simple and intuitive navigation, and provides appropriate schematic animations to clarify the principles of the laboratory procedures. The opening screen presents the virtual experiments that can be selected. Clicking an icon takes the student to the appropriate section. Viscosity Measurement allows the student to concentrate on the

Screening of allyl alcohol resistant mutant of Rhizopus oryzae and ...

African Journals Online (AJOL)

Ethanol is a main by-product in the fermentation broth of Rhizopus oryzae during the production of high-optical purity L-lactic acid. By screening the lower activity of alcohol dehydrogenase (ADH) mutant, thus decreasing the flux of pyruvic acid to ethanol may be a virtual method for increasing the conversion rate of glucose ...

STUDY ON VIRTUAL COLONOSCOPY

Directory of Open Access Journals (Sweden)

Aithagani Rama Chandraiah

2016-10-01

Full Text Available BACKGROUND Current options available in the investigations of colorectal carcinoma include screening using digital rectal examination, sigmoidoscopy, barium enema and fiberoptic colonoscopy, virtual colonoscopy. The aim of the study was to prospectively evaluate patient acceptance of virtual colonoscopy compared with that of conventional colonoscopy when performed in patients with or suspected of having colorectal disease. MATERIALS AND METHODS The study had been conducted on patients attending Department of Radiology for a period of 1 year. Patients with primary or secondary complaints of pain abdomen, lump in abdomen, bleeding per rectum, loose motions/constipation, altered bowel habits, loss of appetite and weight and anaemia, so total number of cases were 51. RESULTS In our study, the patients were in age groups of 21-70 years. Both sexes were represented in our study. Male preponderance was noted in 51 patients. Cases of adenoma were more commonly found 37 (72.78%. The sensitivity of the CT colonography for the polyps more than 10 mm is 100%, polyps 6-9 mm is 90%, less than 6 mm is 80%. Our study consists of 51 patients; among them, 30 patients showed acceptance for CT colonography, 10 patients for optical colonoscopy. Our study consists of 51 patients, the polyps (more than 10 mm detected in 2D viewing were 24, 2D and 3D viewing of 24, the polyps (less than 10 mm detected in 2D viewing were 15, 2D and 3D viewing were 17. 3D viewing resulted in increased sensitivity for identification of patients with larger polyps more than 1 cm, (70-85% sensitivity and patients with smaller polyps less than 1 cm (increased sensitivity 75-88%. CONCLUSIONS Multislice CT (64 colonography is a good alternative to other colorectal screening tests because it has high sensitivity for polyps 10 mm or more in diameter is relatively safe, clinical effective, minimally invasive, cost effective and filter for therapeutic optical colonoscopy.

Sensitivity-based virtual fields for the non-linear virtual fields method

Science.gov (United States)

Marek, Aleksander; Davis, Frances M.; Pierron, Fabrice

2017-09-01

The virtual fields method is an approach to inversely identify material parameters using full-field deformation data. In this manuscript, a new set of automatically-defined virtual fields for non-linear constitutive models has been proposed. These new sensitivity-based virtual fields reduce the influence of noise on the parameter identification. The sensitivity-based virtual fields were applied to a numerical example involving small strain plasticity; however, the general formulation derived for these virtual fields is applicable to any non-linear constitutive model. To quantify the improvement offered by these new virtual fields, they were compared with stiffness-based and manually defined virtual fields. The proposed sensitivity-based virtual fields were consistently able to identify plastic model parameters and outperform the stiffness-based and manually defined virtual fields when the data was corrupted by noise.

The design of light pipe with microstructures for touch screen

Science.gov (United States)

Yang, Bo; Lu, Kan; Liu, Pengfei; Wei, Xiaona

2010-11-01

Touch screen has a very wide range of applications. Most of them are used in public information inquiries, for instance, service inquiries in telecommunication bureau, tax bureau, bank system, electric department, etc...Touch screen can also be used for entertainment and virtual reality applications too. Traditionally, touch screen was composed of pairs of infrared LED and correspondent receivers which were all installed in the screen frame. Arrays of LED were set in the adjacent sides of the frame of an infrared touch screen while arrays of the infrared receivers were fixed in each opposite side, so that the infrared detecting network was formed. While the infrared touch screen has some technical limitations nowadays such as the low resolution, limitations of touching methods and fault response due to environmental disturbances. The plastic material has a relatively high absorption rate for infrared light, which greatly limits the size of the touch screen. Our design uses laser diode as source and change the traditional inner structure of touch screen by using a light pipe with microstructures. The geometric parameters of the light pipe and the microstructures were obtained through equation solving. Simulation results prove that the design method for touch screen proposed in this paper could achieve high resolution and large size of touch screen.

On virtual displacement and virtual work in Lagrangian dynamics

International Nuclear Information System (INIS)

Ray, Subhankar; Shamanna, J

2006-01-01

The confusion and ambiguity encountered by students in understanding virtual displacement and virtual work is discussed in this paper. A definition of virtual displacement is presented that allows one to express them explicitly for holonomic (velocity independent), non-holonomic (velocity dependent), scleronomous (time independent) and rheonomous (time dependent) constraints. It is observed that for holonomic, scleronomous constraints, the virtual displacements are the displacements allowed by the constraints. However, this is not so for a general class of constraints. For simple physical systems, it is shown that the work done by the constraint forces on virtual displacements is zero. This motivates Lagrange's extension of d'Alembert's principle to a system of particles in constrained motion. However, a similar zero work principle does not hold for the allowed displacements. It is also demonstrated that d'Alembert's principle of zero virtual work is necessary for the solvability of a constrained mechanical problem. We identify this special class of constraints, physically realized and solvable, as the ideal constraints. The concept of virtual displacement and the principle of zero virtual work by constraint forces are central to both Lagrange's method of undetermined multipliers and Lagrange's equations in generalized coordinates

Virtual Reality

Science.gov (United States)

1993-04-01

until exhausted. SECURITY CLASSIFICATION OF THIS PAGE All other editions are obsolete. UNCLASSIFIED " VIRTUAL REALITY JAMES F. DAILEY, LIEUTENANT COLONEL...US" This paper reviews the exciting field of virtual reality . The author describes the basic concepts of virtual reality and finds that its numerous...potential benefits to society could revolutionize everyday life. The various components that make up a virtual reality system are described in detail

Framework for Virtual Cognitive Experiment in Virtual Geographic Environments

Directory of Open Access Journals (Sweden)

Fan Zhang

2018-01-01

Full Text Available Virtual Geographic Environment Cognition is the attempt to understand the human cognition of surface features, geographic processes, and human behaviour, as well as their relationships in the real world. From the perspective of human cognition behaviour analysis and simulation, previous work in Virtual Geographic Environments (VGEs has focused mostly on representing and simulating the real world to create an ‘interpretive’ virtual world and improve an individual’s active cognition. In terms of reactive cognition, building a user ‘evaluative’ environment in a complex virtual experiment is a necessary yet challenging task. This paper discusses the outlook of VGEs and proposes a framework for virtual cognitive experiments. The framework not only employs immersive virtual environment technology to create a realistic virtual world but also involves a responsive mechanism to record the user’s cognitive activities during the experiment. Based on the framework, this paper presents two potential implementation methods: first, training a deep learning model with several hundred thousand street view images scored by online volunteers, with further analysis of which visual factors produce a sense of safety for the individual, and second, creating an immersive virtual environment and Electroencephalogram (EEG-based experimental paradigm to both record and analyse the brain activity of a user and explore what type of virtual environment is more suitable and comfortable. Finally, we present some preliminary findings based on the first method.

Homology modeling and virtual screening to discover potent inhibitors targeting the imidazole glycerophosphate dehydratase protein in Staphylococcus xylosus

Science.gov (United States)

Chen, Xing-Ru; Wang, Xiao-Ting; Hao, Mei-Qi; Zhou, Yong-Hui; Cui, Wen-Qiang; Xing, Xiao-Xu; Xu, Chang-Geng; Bai, Jing-Wen; Li, Yan-Hua

2017-11-01

The imidazole glycerophosphate dehydratase (IGPD) protein is a therapeutic target for herbicide discovery. It is also regarded as a possible target in Staphylococcus xylosus (S. xylosus) for solving mastitis in the dairy cow. The 3D structure of IGPD protein is essential for discovering novel inhibitors during high-throughput virtual screening. However, to date, the 3D structure of IGPD protein of S. xylosus has not been solved. In this study, a series of computational techniques including homology modeling, Ramachandran Plots, and Verify 3D were performed in order to construct an appropriate 3D model of IGPD protein of S. xylosus. Nine hits were identified from 2500 compounds by docking studies. Then, these 9 compounds were first tested in vitro in S. xylosus biofilm formation using crystal violet staining. One of the potential compounds, baicalin was shown to significantly inhibit S. xylosus biofilm formation. Finally, the baicalin was further evaluated, which showed better inhibition of biofilm formation capability in S. xylosus by scanning electron microscopy. Hence, we have predicted the structure of IGPD protein of S. xylosus using computational techniques. We further discovered the IGPD protein was targeted by baicalin compound which inhibited the biofilm formation in S. xylosus. Our findings here would provide implications for the further development of novel IGPD inhibitors for the treatment of dairy mastitis.

Active Learning Environments with Robotic Tangibles: Children's Physical and Virtual Spatial Programming Experiences

Science.gov (United States)

Burleson, Winslow S.; Harlow, Danielle B.; Nilsen, Katherine J.; Perlin, Ken; Freed, Natalie; Jensen, Camilla Nørgaard; Lahey, Byron; Lu, Patrick; Muldner, Kasia

2018-01-01

As computational thinking becomes increasingly important for children to learn, we must develop interfaces that leverage the ways that young children learn to provide opportunities for them to develop these skills. Active Learning Environments with Robotic Tangibles (ALERT) and Robopad, an analogous on-screen virtual spatial programming…

Upgrade of ductal carcinoma in situ on core biopsies to invasive disease at final surgery: a retrospective review across the Scottish Breast Screening Programme.

Science.gov (United States)

Sim, Y T; Litherland, J; Lindsay, E; Hendry, P; Brauer, K; Dobson, H; Cordiner, C; Gagliardi, T; Smart, L

2015-05-01

To identify factors affecting upgrade rates from B5a (non-invasive) preoperative core biopsies to invasive disease at surgery and ways to improve screening performance. This was a retrospective analysis of 1252 cases of B5a biopsies across all six Scottish Breast Screening Programmes (BSPs), ranging between 2004 and 2012. Final surgical histopathology was correlated with radiological and biopsy factors. Data were analysed using basic Microsoft Excel and standard Chi-squared test used for evaluating statistical significance. B5a upgrade rates for the units ranged from 19.2% to 29.2%, with an average of 23.6%. Mean sizes of invasive tumours were small (3-11 mm). The upgrade rate was significantly higher for cases where the main mammographic abnormality was mass, distortion, or asymmetry, compared with micro-calcification alone (33.2% versus 21.7%, p = 0.0004). The upgrade rate was significantly lower with the use of large-volume vacuum-assisted biopsy (VAB) devices than 14 G core needles (19.9% versus 26%, p = 0.013); in stereotactic than ultrasound-guided biopsies (21.2% versus 36.1%, p Scottish BSPs, including first-line biopsy technique and/or device; and it is of interest that a few centres maintain low upgrade rates despite not using VAB routinely for biopsy of micro-calcification. Copyright © 2015 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

A comparison of two different T-grain films in rare-earth screens with a standard film-screen combination for intravenous pyelography and bone examinations

International Nuclear Information System (INIS)

Logan, H.; Daly, L.; Masterson, J.

1989-01-01

T-grain film is claimed to give significantly improved image quality, allowing use of faster screens without loss of quality, thus reducing radiation dose. We tested this claim for two systems. In each case comparison was made with our usual screen-film combination, Agfa Curix RP1 film with Kodak Xomatic Regular screens (a nominally 200 speed system). The systems tested were Kodak TMatG in Kodak Lanex Medium screens (300 speed) and Agfa STG in Kodak Lanex Regular screens (400 speed). The Agfa STG-Lanex Regular system performed less well than the standard system for intravenous pyelograms (IVPs), bones and soft-tissue detail. Its speed advantage was not apparent below 70 kV. The Kodak TMatG-Lanex Medium system was better than the standard system for IVPs but not as good for bones. It gave virtually no speed advantage below 90 kV. Kodak T-grain film in a medium-speed, rare-earth screen was found to be better than the standard system for IVPs. Agfa T-grain film in a fast rare-earth screen was unsatisfactory for IVPs. Neither combination was as good as the standard system for bones. (author)

Virtualization Security Combining Mandatory Access Control and Virtual Machine Introspection

OpenAIRE

Win, Thu Yein; Tianfield, Huaglory; Mair, Quentin

2014-01-01

Virtualization has become a target for attacks in cloud computing environments. Existing approaches to protecting the virtualization environment against the attacks are limited in protection scope and are with high overheads. This paper proposes a novel virtualization security solution which aims to provide comprehensive protection of the virtualization environment.

Women with learning disabilities and access to cervical screening: retrospective cohort study using case control methods

OpenAIRE

Reynolds, Fiona; Stanistreet, Debbi; Elton, Peter

2008-01-01

Abstract Background Several studies in the UK have suggested that women with learning disabilities may be less likely to receive cervical screening tests and a previous local study in had found that GPs considered screening unnecessary for women with learning disabilities. This study set out to ascertain whether women with learning disabilities are more likely to be ceased from a cervical screening programme than women without; and to examine the reasons given for ceasing women with learning ...

Evaluation of two-year Jewish genetic disease screening program in Atlanta: insight into community genetic screening approaches.