Mineralocorticoid receptor stimulation effects on spatial memory in healthy young adults: A study using the virtual Morris Water Maze task.

PubMed

Piber, Dominique; Schultebraucks, Katharina; Mueller, Sven C; Deuter, Christian Eric; Wingenfeld, Katja; Otte, Christian

2016-12-01

Stress hormones such as cortisol are known to influence a wide range of cognitive functions, including hippocampal based spatial memory. In the brain, cortisol acts via two different receptors: the glucocorticoid (GR) and the mineralocorticoid receptor (MR). As the MR has a high density in the hippocampus, we examined the effects of pharmacological MR stimulation on spatial memory. Eighty healthy participants (40 women, 40 men, mean age=23.9years±SD=3.3) completed the virtual Morris Water Maze (vMWM) task to test spatial encoding and spatial memory retrieval after receiving 0.4mg fludrocortisone, a MR agonist, or placebo. There was no effect of MR stimulation on spatial encoding during the vMWM task. However, participants who received fludrocortisone exhibited improved spatial memory retrieval performance. There was neither a main effect of sex nor a sex-by-treatment interaction. In young healthy participants, MR stimulation improved hippocampal based spatial memory retrieval in a virtual Morris Water Maze task. Our study not only confirms the importance of MR function in spatial memory, but suggests beneficial effects of acute MR stimulation on spatial memory retrieval in humans. Copyright © 2016 Elsevier Inc. All rights reserved.

Structural insights into pharmacophore-assisted in silico identification of protein-protein interaction inhibitors for inhibition of human toll-like receptor 4 - myeloid differentiation factor-2 (hTLR4-MD-2) complex.

PubMed

Mishra, Vinita; Pathak, Chandramani

2018-05-29

Toll-like receptor 4 (TLR4) is a member of Toll-Like Receptors (TLRs) family that serves as a receptor for bacterial lipopolysaccharide (LPS). TLR4 alone cannot recognize LPS without aid of co-receptor myeloid differentiation factor-2 (MD-2). Binding of LPS with TLR4 forms a LPS-TLR4-MD-2 complex and directs downstream signaling for activation of immune response, inflammation and NF-κB activation. Activation of TLR4 signaling is associated with various pathophysiological consequences. Therefore, targeting protein-protein interaction (PPI) in TLR4-MD-2 complex formation could be an attractive therapeutic approach for targeting inflammatory disorders. The aim of present study was directed to identify small molecule PPI inhibitors (SMPPIIs) using pharmacophore mapping-based approach of computational drug discovery. Here, we had retrieved the information about the hot spot residues and their pharmacophoric features at both primary (TLR4-MD-2) and dimerization (MD-2-TLR4*) protein-protein interaction interfaces in TLR4-MD-2 homo-dimer complex using in silico methods. Promising candidates were identified after virtual screening, which may restrict TLR4-MD-2 protein-protein interaction. In silico off-target profiling over the virtually screened compounds revealed other possible molecular targets. Two of the virtually screened compounds (C11 and C15) were predicted to have an inhibitory concentration in μM range after HYDE assessment. Molecular dynamics simulation study performed for these two compounds in complex with target protein confirms the stability of the complex. After virtual high throughput screening we found selective hTLR4-MD-2 inhibitors, which may have therapeutic potential to target chronic inflammatory diseases.

Magnetosensitive e-skins with directional perception for augmented reality

PubMed Central

Cañón Bermúdez, Gilbert Santiago; Karnaushenko, Dmitriy D.; Karnaushenko, Daniil; Lebanov, Ana; Bischoff, Lothar; Kaltenbrunner, Martin; Fassbender, Jürgen; Schmidt, Oliver G.; Makarov, Denys

2018-01-01

Electronic skins equipped with artificial receptors are able to extend our perception beyond the modalities that have naturally evolved. These synthetic receptors offer complimentary information on our surroundings and endow us with novel means of manipulating physical or even virtual objects. We realize highly compliant magnetosensitive skins with directional perception that enable magnetic cognition, body position tracking, and touchless object manipulation. Transfer printing of eight high-performance spin valve sensors arranged into two Wheatstone bridges onto 1.7-μm-thick polyimide foils ensures mechanical imperceptibility. This resembles a new class of interactive devices extracting information from the surroundings through magnetic tags. We demonstrate this concept in augmented reality systems with virtual knob-turning functions and the operation of virtual dialing pads, based on the interaction with magnetic fields. This technology will enable a cornucopia of applications from navigation, motion tracking in robotics, regenerative medicine, and sports and gaming to interaction in supplemented reality. PMID:29376121

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

NASA Astrophysics Data System (ADS)

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.

Computational discovery of putative quorum sensing inhibitors against LasR and RhlR receptor proteins of Pseudomonas aeruginosa

NASA Astrophysics Data System (ADS)

Annapoorani, Angusamy; Umamageswaran, Venugopal; Parameswari, Radhakrishnan; Pandian, Shunmugiah Karutha; Ravi, Arumugam Veera

2012-09-01

Drugs have been discovered in the past mainly either by identification of active components from traditional remedies or by unpredicted discovery. A key motivation for the study of structure based virtual screening is the exploitation of such information to design targeted drugs. In this study, structure based virtual screening was used in search for putative quorum sensing inhibitors (QSI) of Pseudomonas aeruginosa. The virtual screening programme Glide version 5.5 was applied to screen 1,920 natural compounds/drugs against LasR and RhlR receptor proteins of P. aeruginosa. Based on the results of in silico docking analysis, five top ranking compounds namely rosmarinic acid, naringin, chlorogenic acid, morin and mangiferin were subjected to in vitro bioassays against laboratory strain PAO1 and two more antibiotic resistant clinical isolates, P. aeruginosa AS1 (GU447237) and P. aeruginosa AS2 (GU447238). Among the five compounds studied, except mangiferin other four compounds showed significant inhibition in the production of protease, elastase and hemolysin. Further, all the five compounds potentially inhibited the biofilm related behaviours. This interaction study provided promising ligands to inhibit the quorum sensing (QS) mediated virulence factors production in P. aeruginosa.

Statistical analysis of EGFR structures' performance in virtual screening

NASA Astrophysics Data System (ADS)

Li, Yan; Li, Xiang; Dong, Zigang

2015-11-01

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.

Virtual Screening of Receptor Sites for Molecularly Imprinted Polymers.

PubMed

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.

In silico approaches to identify novel myeloid cell leukemia-1 (Mcl-1) inhibitors for treatment of cancer.

PubMed

Ren, Ji-Xia; Li, Cheng-Ping; Zhou, Xiu-Ling; Cao, Xue-Song; Xie, Yong

2017-08-22

Myeloid cell leukemia-1 (Mcl-1) has been a validated and attractive target for cancer therapy. Over-expression of Mcl-1 in many cancers allows cancer cells to evade apoptosis and contributes to the resistance to current chemotherapeutics. Here, we identified new Mcl-1 inhibitors using a multi-step virtual screening approach. First, based on two different ligand-receptor complexes, 20 pharmacophore models were established by simultaneously using 'Receptor-Ligand Pharmacophore Generation' method and manual build feature method, and then carefully validated by a test database. Then, pharmacophore-based virtual screening (PB-VS) could be performed by using the 20 pharmacophore models. In addition, docking study was used to predict the possible binding poses of compounds, and the docking parameters were optimized before performing docking-based virtual screening (DB-VS). Moreover, a 3D QSAR model was established by applying the 55 aligned Mcl-1 inhibitors. The 55 inhibitors sharing the same scaffold were docked into the Mcl-1 active site before alignment, then the inhibitors with possible binding conformations were aligned. For the training set, the 3D QSAR model gave a correlation coefficient r 2 of 0.996; for the test set, the correlation coefficient r 2 was 0.812. Therefore, the developed 3D QSAR model was a good model, which could be applied for carrying out 3D QSAR-based virtual screening (QSARD-VS). After the above three virtual screening methods orderly filtering, 23 potential inhibitors with novel scaffolds were identified. Furthermore, we have discussed in detail the mapping results of two potent compounds onto pharmacophore models, 3D QSAR model, and the interactions between the compounds and active site residues.

Ligand-guided optimization of CXCR4 homology models for virtual screening using a multiple chemotype approach

NASA Astrophysics Data System (ADS)

Neves, Marco A. C.; Simões, Sérgio; Sá e Melo, M. Luisa

2010-12-01

CXCR4 is a G-protein coupled receptor for CXCL12 that plays an important role in human immunodeficiency virus infection, cancer growth and metastasization, immune cell trafficking and WHIM syndrome. In the absence of an X-ray crystal structure, theoretical modeling of the CXCR4 receptor remains an important tool for structure-function analysis and to guide the discovery of new antagonists with potential clinical use. In this study, the combination of experimental data and molecular modeling approaches allowed the development of optimized ligand-receptor models useful for elucidation of the molecular determinants of small molecule binding and functional antagonism. The ligand-guided homology modeling approach used in this study explicitly re-shaped the CXCR4 binding pocket in order to improve discrimination between known CXCR4 antagonists and random decoys. Refinement based on multiple test-sets with small compounds from single chemotypes provided the best early enrichment performance. These results provide an important tool for structure-based drug design and virtual ligand screening of new CXCR4 antagonists.

Optimal affinity ranking for automated virtual screening validated in prospective D3R grand challenges

NASA Astrophysics Data System (ADS)

Wingert, Bentley M.; Oerlemans, Rick; Camacho, Carlos J.

2018-01-01

The goal of virtual screening is to generate a substantially reduced and enriched subset of compounds from a large virtual chemistry space. Critical in these efforts are methods to properly rank the binding affinity of compounds. Prospective evaluations of ranking strategies in the D3R grand challenges show that for targets with deep pockets the best correlations (Spearman ρ 0.5) were obtained by our submissions that docked compounds to the holo-receptors with the most chemically similar ligand. On the other hand, for targets with open pockets using multiple receptor structures is not a good strategy. Instead, docking to a single optimal receptor led to the best correlations (Spearman ρ 0.5), and overall performs better than any other method. Yet, choosing a suboptimal receptor for crossdocking can significantly undermine the affinity rankings. Our submissions that evaluated the free energy of congeneric compounds were also among the best in the community experiment. Error bars of around 1 kcal/mol are still too large to significantly improve the overall rankings. Collectively, our top of the line predictions show that automated virtual screening with rigid receptors perform better than flexible docking and other more complex methods.

Anticonvulsant activity of artificial sweeteners: a structural link between sweet-taste receptor T1R3 and brain glutamate receptors.

PubMed

Talevi, Alan; Enrique, Andrea V; Bruno-Blanch, Luis E

2012-06-15

A virtual screening campaign based on application of a topological discriminant function capable of identifying novel anticonvulsant agents indicated several widely-used artificial sweeteners as potential anticonvulsant candidates. Acesulfame potassium, cyclamate and saccharin were tested in the Maximal Electroshock Seizure model (mice, ip), showing moderate anticonvulsant activity. We hypothesized a probable structural link between the receptor responsible of sweet taste and anticonvulsant molecular targets. Bioinformatic tools confirmed a highly significant sequence-similarity between taste-related protein T1R3 and several metabotropic glutamate receptors from different species, including glutamate receptors upregulated in epileptogenesis and certain types of epilepsy. Copyright © 2012 Elsevier Ltd. All rights reserved.

Functional Validation of Virtual Screening for Novel Agents with General Anesthetic Action at Ligand-Gated Ion Channels

PubMed Central

Heusser, Stephanie A.; Howard, Rebecca J.; Borghese, Cecilia M.; Cullins, Madeline A.; Broemstrup, Torben; Lee, Ui S.; Lindahl, Erik; Carlsson, Jens

2013-01-01

GABAA receptors play a crucial role in the actions of general anesthetics. The recently published crystal structure of the general anesthetic propofol bound to Gloeobacter violaceus ligand-gated ion channel (GLIC), a bacterial homolog of GABAA receptors, provided an opportunity to explore structure-based ligand discovery for pentameric ligand-gated ion channels (pLGICs). We used molecular docking of 153,000 commercially available compounds to identify molecules that interact with the propofol binding site in GLIC. In total, 29 compounds were selected for functional testing on recombinant GLIC, and 16 of these compounds modulated GLIC function. Active compounds were also tested on recombinant GABAA receptors, and point mutations around the presumed binding pocket were introduced into GLIC and GABAA receptors to test for binding specificity. The potency of active compounds was only weakly correlated with properties such as lipophilicity or molecular weight. One compound was found to mimic the actions of propofol on GLIC and GABAA, and to be sensitive to mutations that reduce the action of propofol in both receptors. Mutant receptors also provided insight about the position of the binding sites and the relevance of the receptor’s conformation for anesthetic actions. Overall, the findings support the feasibility of the use of virtual screening to discover allosteric modulators of pLGICs, and suggest that GLIC is a valid model system to identify novel GABAA receptor ligands. PMID:23950219

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

NASA Astrophysics Data System (ADS)

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.

Three-dimensional compound comparison methods and their application in drug discovery.

PubMed

Shin, Woong-Hee; Zhu, Xiaolei; Bures, Mark Gregory; Kihara, Daisuke

2015-07-16

Virtual screening has been widely used in the drug discovery process. Ligand-based virtual screening (LBVS) methods compare a library of compounds with a known active ligand. Two notable advantages of LBVS methods are that they do not require structural information of a target receptor and that they are faster than structure-based methods. LBVS methods can be classified based on the complexity of ligand structure information utilized: one-dimensional (1D), two-dimensional (2D), and three-dimensional (3D). Unlike 1D and 2D methods, 3D methods can have enhanced performance since they treat the conformational flexibility of compounds. In this paper, a number of 3D methods will be reviewed. In addition, four representative 3D methods were benchmarked to understand their performance in virtual screening. Specifically, we tested overall performance in key aspects including the ability to find dissimilar active compounds, and computational speed.

Macromolecular Modelling and Docking Simulations for the Discovery of Selective GPER Ligands.

PubMed

Rosano, Camillo; Ponassi, Marco; Santolla, Maria Francesca; Pisano, Assunta; Felli, Lamberto; Vivacqua, Adele; Maggiolini, Marcello; Lappano, Rosamaria

2016-01-01

Estrogens influence multiple physiological processes and are implicated in many diseases as well. Cellular responses to estrogens are mainly mediated by the estrogen receptors (ER)α and ERβ, which act as ligand-activated transcription factors. Recently, a member of the G protein-coupled receptor (GPCR) superfamily, namely GPER/GPR30, has been identified as a further mediator of estrogen signalling in different pathophysiological conditions, including cancer. Today, computational methods are commonly used in all areas of health science research. Among these methods, virtual ligand screening has become an established technique for hit discovery and optimization. The absence of an established three-dimensional structure of GPER promoted studies of structure-based drug design in order to build reliable molecular models of this receptor. Here, we discuss the results obtained through the structure-based virtual ligand screening for GPER, which allowed the identification and synthesis of different selective agonist and antagonist moieties. These compounds led significant advances in our understanding of the GPER function at the cellular, tissue, and organismal levels. In particular, selective GPER ligands were critical toward the evaluation of the role elicited by this receptor in several pathophysiological conditions, including cancer. Considering that structure-based approaches are fundamental in drug discovery, future research breakthroughs with the aid of computer-aided molecular design and chemo-bioinformatics could generate a new class of drugs that, acting through GPER, would be useful in a variety of diseases as well as in innovative anticancer strategies.

Pharmacophore-based virtual screening, biological evaluation and binding mode analysis of a novel protease-activated receptor 2 antagonist

NASA Astrophysics Data System (ADS)

Cho, Nam-Chul; Seo, Seoung-Hwan; Kim, Dohee; Shin, Ji-Sun; Ju, Jeongmin; Seong, Jihye; Seo, Seon Hee; Lee, Iiyoun; Lee, Kyung-Tae; Kim, Yun Kyung; No, Kyoung Tai; Pae, Ae Nim

2016-08-01

Protease-activated receptor 2 (PAR2) is a G protein-coupled receptor, mediating inflammation and pain signaling in neurons, thus it is considered to be a potential therapeutic target for inflammatory diseases. In this study, we performed a ligand-based virtual screening of 1.6 million compounds by employing a common-feature pharmacophore model and two-dimensional similarity search to identify a new PAR2 antagonist. The common-feature pharmacophore model was established based on the biological screening results of our in-house library. The initial virtual screening yielded a total number of 47 hits, and additional biological activity tests including PAR2 antagonism and anti-inflammatory effects resulted in a promising candidate, compound 43, which demonstrated an IC50 value of 8.22 µM against PAR2. In next step, a PAR2 homology model was constructed using the crystal structure of the PAR1 as a template to explore the binding mode of the identified ligands. A molecular docking method was optimized by comparing the binding modes of a known PAR2 agonist GB110 and antagonist GB83, and applied to predict the binding mode of our hit compound 43. In-depth docking analyses revealed that the hydrophobic interaction with Phe2435.39 is crucial for PAR2 ligands to exert antagonistic activity. MD simulation results supported the predicted docking poses that PAR2 antagonist blocked a conformational rearrangement of Na+ allosteric site in contrast to PAR2 agonist that showed Na+ relocation upon GPCR activation. In conclusion, we identified new a PAR2 antagonist together with its binding mode, which provides useful insights for the design and development of PAR2 ligands.

Structure-based discovery and binding site analysis of histamine receptor ligands.

PubMed

Kiss, Róbert; Keserű, György M

2016-12-01

The application of structure-based drug discovery in histamine receptor projects was previously hampered by the lack of experimental structures. The publication of the first X-ray structure of the histamine H1 receptor has been followed by several successful virtual screens and binding site analysis studies of H1-antihistamines. This structure together with several other recently solved aminergic G-protein coupled receptors (GPCRs) enabled the development of more realistic homology models for H2, H3 and H4 receptors. Areas covered: In this paper, the authors review the development of histamine receptor models and their application in drug discovery. Expert opinion: In the authors' opinion, the application of atomistic histamine receptor models has played a significant role in understanding key ligand-receptor interactions as well as in the discovery of novel chemical starting points. The recently solved H1 receptor structure is a major milestone in structure-based drug discovery; however, our analysis also demonstrates that for building H3 and H4 receptor homology models, other GPCRs may be more suitable as templates. For these receptors, the authors envisage that the development of higher quality homology models will significantly contribute to the discovery and optimization of novel H3 and H4 ligands.

Rational Design of a New Class of Toll-Like Receptor 4 (TLR4) Tryptamine Related Agonists by Means of the Structure- and Ligand-Based Virtual Screening for Vaccine Adjuvant Discovery.

PubMed

Honegr, Jan; Dolezal, Rafael; Malinak, David; Benkova, Marketa; Soukup, Ondrej; Almeida, Joyce S F D de; Franca, Tanos C C; Kuca, Kamil; Prymula, Roman

2018-01-04

In order to identify novel lead structures for human toll-like receptor 4 ( h TLR4) modulation virtual high throughput screening by a peta-flops-scale supercomputer has been performed. Based on the in silico studies, a series of 12 compounds related to tryptamine was rationally designed to retain suitable molecular geometry for interaction with the h TLR4 binding site as well as to satisfy general principles of drug-likeness. The proposed compounds were synthesized, and tested by in vitro and ex vivo experiments, which revealed that several of them are capable to stimulate h TLR4 in vitro up to 25% activity of Monophosphoryl lipid A. The specific affinity of the in vitro most potent substance was confirmed by surface plasmon resonance direct-binding experiments. Moreover, two compounds from the series show also significant ability to elicit production of interleukin 6.

Docking and Virtual Screening Strategies for GPCR Drug Discovery.

PubMed

Beuming, Thijs; Lenselink, Bart; Pala, Daniele; McRobb, Fiona; Repasky, Matt; Sherman, Woody

2015-01-01

Progress in structure determination of G protein-coupled receptors (GPCRs) has made it possible to apply structure-based drug design (SBDD) methods to this pharmaceutically important target class. The quality of GPCR structures available for SBDD projects fall on a spectrum ranging from high resolution crystal structures (<2 Å), where all water molecules in the binding pocket are resolved, to lower resolution (>3 Å) where some protein residues are not resolved, and finally to homology models that are built using distantly related templates. Each GPCR project involves a distinct set of opportunities and challenges, and requires different approaches to model the interaction between the receptor and the ligands. In this review we will discuss docking and virtual screening to GPCRs, and highlight several refinement and post-processing steps that can be used to improve the accuracy of these calculations. Several examples are discussed that illustrate specific steps that can be taken to improve upon the docking and virtual screening accuracy. While GPCRs are a unique target class, many of the methods and strategies outlined in this review are general and therefore applicable to other protein families.

Knowledge-Based Methods To Train and Optimize Virtual Screening Ensembles

PubMed Central

2016-01-01

Ensemble docking can be a successful virtual screening technique that addresses the innate conformational heterogeneity of macromolecular drug targets. Yet, lacking a method to identify a subset of conformational states that effectively segregates active and inactive small molecules, ensemble docking may result in the recommendation of a large number of false positives. Here, three knowledge-based methods that construct structural ensembles for virtual screening are presented. Each method selects ensembles by optimizing an objective function calculated using the receiver operating characteristic (ROC) curve: either the area under the ROC curve (AUC) or a ROC enrichment factor (EF). As the number of receptor conformations, N, becomes large, the methods differ in their asymptotic scaling. Given a set of small molecules with known activities and a collection of target conformations, the most resource intense method is guaranteed to find the optimal ensemble but scales as O(2N). A recursive approximation to the optimal solution scales as O(N2), and a more severe approximation leads to a faster method that scales linearly, O(N). The techniques are generally applicable to any system, and we demonstrate their effectiveness on the androgen nuclear hormone receptor (AR), cyclin-dependent kinase 2 (CDK2), and the peroxisome proliferator-activated receptor δ (PPAR-δ) drug targets. Conformations that consisted of a crystal structure and molecular dynamics simulation cluster centroids were used to form AR and CDK2 ensembles. Multiple available crystal structures were used to form PPAR-δ ensembles. For each target, we show that the three methods perform similarly to one another on both the training and test sets. PMID:27097522

DOVIS 2.0: An Efficient and Easy to Use Parallel Virtual Screening Tool Based on AutoDock 4.0

DTIC Science & Technology

2008-09-08

under the GNU General Public License. Background Molecular docking is a computational method that pre- dicts how a ligand interacts with a receptor...Hence, it is an important tool in studying receptor-ligand interactions and plays an essential role in drug design. Particularly, molecular docking has...libraries from OpenBabel and setup a molecular data structure as a C++ object in our program. This makes handling of molecular structures (e.g., atoms

Design, synthesis and screening studies of potent thiazol-2-amine derivatives as fibroblast growth factor receptor 1 inhibitors.

PubMed

Kumar, B V S Suneel; Lakshmi, Narasu; Kumar, M Ravi; Rambabu, Gundla; Manjashetty, Thimmappa H; Arunasree, Kalle M; Sriram, Dharmarajan; Ramkumar, Kavya; Neamati, Nouri; Dayam, Raveendra; Sarma, J A R P

2014-01-01

Fibroblast growth factor receptor 1 (FGFR1) a tyrosine kinase receptor, plays important roles in angiogenesis, embryonic development, cell proliferation, cell differentiation, and wound healing. The FGFR isoforms and their receptors (FGFRs) considered as a potential targets and under intense research to design potential anticancer agents. Fibroblast growth factors (FGF's) and its growth factor receptors (FGFR) plays vital role in one of the critical pathway in monitoring angiogenesis. In the current study, quantitative pharmacophore models were generated and validated using known FGFR1 inhibitors. The pharmacophore models were generated using a set of 28 compounds (training). The top pharmacophore model was selected and validated using a set of 126 compounds (test set) and also using external validation. The validated pharmacophore was considered as a virtual screening query to screen a database of 400,000 virtual molecules and pharmacophore model retrieved 2800 hits. The retrieved hits were subsequently filtered based on the fit value. The selected hits were subjected for docking studies to observe the binding modes of the retrieved hits and also to reduce the false positives. One of the potential hits (thiazole-2-amine derivative) was selected based the pharmacophore fit value, dock score, and synthetic feasibility. A few analogues of the thiazole-2-amine derivative were synthesized. These compounds were screened for FGFR1 activity and anti-proliferative studies. The top active compound showed 56.87% inhibition of FGFR1 activity at 50 µM and also showed good cellular activity. Further optimization of thiazole-2-amine derivatives is in progress.

Magnetically-refreshable receptor platform structures for reusable nano-biosensor chips

NASA Astrophysics Data System (ADS)

Yoo, Haneul; Lee, Dong Jun; Cho, Dong-guk; Park, Juhun; Nam, Ki Wan; Tak Cho, Young; Park, Jae Yeol; Chen, Xing; Hong, Seunghun

2016-01-01

We developed a magnetically-refreshable receptor platform structure which can be integrated with quite versatile nano-biosensor structures to build reusable nano-biosensor chips. This structure allows one to easily remove used receptor molecules from a biosensor surface and reuse the biosensor for repeated sensing operations. Using this structure, we demonstrated reusable immunofluorescence biosensors. Significantly, since our method allows one to place receptor molecules very close to a nano-biosensor surface, it can be utilized to build reusable carbon nanotube transistor-based biosensors which require receptor molecules within a Debye length from the sensor surface. Furthermore, we also show that a single sensor chip can be utilized to detect two different target molecules simply by replacing receptor molecules using our method. Since this method does not rely on any chemical reaction to refresh sensor chips, it can be utilized for versatile biosensor structures and virtually-general receptor molecular species.

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

PubMed Central

Pérez-Regidor, Lucía; Zarioh, Malik; Ortega, Laura; Martín-Santamaría, Sonsoles

2016-01-01

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. PMID:27618029

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

PubMed

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.

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

NASA Astrophysics Data System (ADS)

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.

An infrastructure to mine molecular descriptors for ligand selection on virtual screening.

PubMed

Seus, Vinicius Rosa; Perazzo, Giovanni Xavier; Winck, Ana T; Werhli, Adriano V; Machado, Karina S

2014-01-01

The receptor-ligand interaction evaluation is one important step in rational drug design. The databases that provide the structures of the ligands are growing on a daily basis. This makes it impossible to test all the ligands for a target receptor. Hence, a ligand selection before testing the ligands is needed. One possible approach is to evaluate a set of molecular descriptors. With the aim of describing the characteristics of promising compounds for a specific receptor we introduce a data warehouse-based infrastructure to mine molecular descriptors for virtual screening (VS). We performed experiments that consider as target the receptor HIV-1 protease and different compounds for this protein. A set of 9 molecular descriptors are taken as the predictive attributes and the free energy of binding is taken as a target attribute. By applying the J48 algorithm over the data we obtain decision tree models that achieved up to 84% of accuracy. The models indicate which molecular descriptors and their respective values are relevant to influence good FEB results. Using their rules we performed ligand selection on ZINC database. Our results show important reduction in ligands selection to be applied in VS experiments; for instance, the best selection model picked only 0.21% of the total amount of drug-like ligands.

OpenVirtualToxLab--a platform for generating and exchanging in silico toxicity data.

PubMed

Vedani, Angelo; Dobler, Max; Hu, Zhenquan; Smieško, Martin

2015-01-22

The VirtualToxLab is an in silico technology for estimating the toxic potential--endocrine and metabolic disruption, some aspects of carcinogenicity and cardiotoxicity--of drugs, chemicals and natural products. The technology is based on an automated protocol that simulates and quantifies the binding of small molecules towards a series of currently 16 proteins, known or suspected to trigger adverse effects: 10 nuclear receptors (androgen, estrogen α, estrogen β, glucocorticoid, liver X, mineralocorticoid, peroxisome proliferator-activated receptor γ, progesterone, thyroid α, thyroid β), four members of the cytochrome P450 enzyme family (1A2, 2C9, 2D6, 3A4), a cytosolic transcription factor (aryl hydrocarbon receptor) and a potassium ion channel (hERG). The toxic potential of a compound--its ability to trigger adverse effects--is derived from its computed binding affinities toward these very proteins: the computationally demanding simulations are executed in client-server model on a Linux cluster of the University of Basel. The graphical-user interface supports all computer platforms, allows building and uploading molecular structures, inspecting and downloading the results and, most important, rationalizing any prediction at the atomic level by interactively analyzing the binding mode of a compound with its target protein(s) in real-time 3D. Access to the VirtualToxLab is available free of charge for universities, governmental agencies, regulatory bodies and non-profit organizations. Copyright © 2014 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

A Role for Fragment-Based Drug Design in Developing Novel Lead Compounds for Central Nervous System Targets.

PubMed

Wasko, Michael J; Pellegrene, Kendy A; Madura, Jeffry D; Surratt, Christopher K

2015-01-01

Hundreds of millions of U.S. dollars are invested in the research and development of a single drug. Lead compound development is an area ripe for new design strategies. Therapeutic lead candidates have been traditionally found using high-throughput in vitro pharmacological screening, a costly method for assaying thousands of compounds. This approach has recently been augmented by virtual screening (VS), which employs computer models of the target protein to narrow the search for possible leads. A variant of VS is fragment-based drug design (FBDD), an emerging in silico lead discovery method that introduces low-molecular weight fragments, rather than intact compounds, into the binding pocket of the receptor model. These fragments serve as starting points for "growing" the lead candidate. Current efforts in virtual FBDD within central nervous system (CNS) targets are reviewed, as is a recent rule-based optimization strategy in which new molecules are generated within a 3D receptor-binding pocket using the fragment as a scaffold. This process not only places special emphasis on creating synthesizable molecules but also exposes computational questions worth addressing. Fragment-based methods provide a viable, relatively low-cost alternative for therapeutic lead discovery and optimization that can be applied to CNS targets to augment current design strategies.

A Role for Fragment-Based Drug Design in Developing Novel Lead Compounds for Central Nervous System Targets

PubMed Central

Wasko, Michael J.; Pellegrene, Kendy A.; Madura, Jeffry D.; Surratt, Christopher K.

2015-01-01

Hundreds of millions of U.S. dollars are invested in the research and development of a single drug. Lead compound development is an area ripe for new design strategies. Therapeutic lead candidates have been traditionally found using high-throughput in vitro pharmacological screening, a costly method for assaying thousands of compounds. This approach has recently been augmented by virtual screening (VS), which employs computer models of the target protein to narrow the search for possible leads. A variant of VS is fragment-based drug design (FBDD), an emerging in silico lead discovery method that introduces low-molecular weight fragments, rather than intact compounds, into the binding pocket of the receptor model. These fragments serve as starting points for “growing” the lead candidate. Current efforts in virtual FBDD within central nervous system (CNS) targets are reviewed, as is a recent rule-based optimization strategy in which new molecules are generated within a 3D receptor-binding pocket using the fragment as a scaffold. This process not only places special emphasis on creating synthesizable molecules but also exposes computational questions worth addressing. Fragment-based methods provide a viable, relatively low-cost alternative for therapeutic lead discovery and optimization that can be applied to CNS targets to augment current design strategies. PMID:26441817

Search for β2 Adrenergic Receptor Ligands by Virtual Screening via Grid Computing and Investigation of Binding Modes by Docking and Molecular Dynamics Simulations

PubMed Central

Bai, Qifeng; Shao, Yonghua; Pan, Dabo; Zhang, Yang; Liu, Huanxiang; Yao, Xiaojun

2014-01-01

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. PMID:25229694

Structural basis for ligand recognition at the benzodiazepine binding site of GABAA alpha 3 receptor, and pharmacophore-based virtual screening approach.

PubMed

Vijayan, R S K; Ghoshal, Nanda

2008-10-01

Given the heterogeneity of GABA(A) receptor, the pharmacological significance of identifying subtype selective modulators is increasingly being recognized. Thus, drugs selective for GABA(A) alpha(3) receptors are expected to display fewer side effects than the drugs presently in clinical use. Hence we carried out 3D QSAR (three-dimensional quantitative structure-activity relationship) studies on a series of novel GABA(A) alpha(3) subtype selective modulators to gain more insight into subtype affinity. To identify the 3D functional attributes required for subtype selectivity, a chemical feature-based pharmacophore, primarily based on selective ligands representing diverse structural classes was generated. The obtained pseudo receptor model of the benzodiazepine binding site revealed a binding mode akin to "Message-Address" concept. Scaffold hopping was carried out across multi-conformational May Bridge database for the identification of novel chemotypes. Further a focused data reduction approach was employed to choose a subset of enriched compounds based on "Drug likeness" and "Similarity-based" methods. These results taken together could provide impetus for rational design and optimization of more selective and high affinity leads with a potential to have decreased adverse effects.

The Texas-Indiana Virtual STAR Center: Zebrafish Models for Developmental Toxicity Screening

EPA Pesticide Factsheets

The Texas-Indiana Virtual STAR Center: Zebrafish Models for Developmental Toxicity Screening (Presented by Maria Bondesson Bolin, Ph.D, University of Houston, Center for Nuclear Receptors and Cell Signaling) (3/22/2012)

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

PubMed

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.

Application of Quantitative Structure–Activity Relationship Models of 5-HT1A Receptor Binding to Virtual Screening Identifies Novel and Potent 5-HT1A Ligands

PubMed Central

2015-01-01

The 5-hydroxytryptamine 1A (5-HT1A) serotonin receptor has been an attractive target for treating mood and anxiety disorders such as schizophrenia. We have developed binary classification quantitative structure–activity relationship (QSAR) models of 5-HT1A receptor binding activity using data retrieved from the PDSP Ki database. The prediction accuracy of these models was estimated by external 5-fold cross-validation as well as using an additional validation set comprising 66 structurally distinct compounds from the World of Molecular Bioactivity database. These validated models were then used to mine three major types of chemical screening libraries, i.e., drug-like libraries, GPCR targeted libraries, and diversity libraries, to identify novel computational hits. The five best hits from each class of libraries were chosen for further experimental testing in radioligand binding assays, and nine of the 15 hits were confirmed to be active experimentally with binding affinity better than 10 μM. The most active compound, Lysergol, from the diversity library showed very high binding affinity (Ki) of 2.3 nM against 5-HT1A receptor. The novel 5-HT1A actives identified with the QSAR-based virtual screening approach could be potentially developed as novel anxiolytics or potential antischizophrenic drugs. PMID:24410373

A combined ligand-based and target-based drug design approach for G-protein coupled receptors: application to salvinorin A, a selective kappa opioid receptor agonist

NASA Astrophysics Data System (ADS)

Singh, Nidhi; Chevé, Gwénaël; Ferguson, David M.; McCurdy, Christopher R.

2006-08-01

Combined ligand-based and target-based drug design approaches provide a synergistic advantage over either method individually. Therefore, we set out to develop a powerful virtual screening model to identify novel molecular scaffolds as potential leads for the human KOP (hKOP) receptor employing a combined approach. Utilizing a set of recently reported derivatives of salvinorin A, a structurally unique KOP receptor agonist, a pharmacophore model was developed that consisted of two hydrogen bond acceptor and three hydrophobic features. The model was cross-validated by randomizing the data using the CatScramble technique. Further validation was carried out using a test set that performed well in classifying active and inactive molecules correctly. Simultaneously, a bovine rhodopsin based "agonist-bound" hKOP receptor model was also generated. The model provided more accurate information about the putative binding site of salvinorin A based ligands. Several protein structure-checking programs were used to validate the model. In addition, this model was in agreement with the mutation experiments carried out on KOP receptor. The predictive ability of the model was evaluated by docking a set of known KOP receptor agonists into the active site of this model. The docked scores correlated reasonably well with experimental p K i values. It is hypothesized that the integration of these two independently generated models would enable a swift and reliable identification of new lead compounds that could reduce time and cost of hit finding within the drug discovery and development process, particularly in the case of GPCRs.

Scaffold-based novel SHP2 allosteric inhibitors design using Receptor-Ligand pharmacophore model, virtual screening and molecular dynamics.

PubMed

Jin, Wen-Yan; Ma, Ying; Li, Wei-Ya; Li, Hong-Lian; Wang, Run-Ling

2018-04-01

SHP2 is a potential target for the development of novel therapies for SHP2-dependent cancers. In our research, with the aid of the 'Receptor-Ligand Pharmacophore' technique, a 3D-QSAR method was carried out to explore structure activity relationship of SHP2 allosteric inhibitors. Structure-based drug design was employed to optimize SHP099, an efficacious, potent, and selective SHP2 allosteric inhibitor. A novel class of selective SHP2 allosteric inhibitors was discovered by using the powerful 'SBP', 'ADMET' and 'CDOCKER' techniques. By means of molecular dynamics simulations, it was observed that these novel inhibitors not only had the same function as SHP099 did in inhibiting SHP2, but also had more favorable conformation for binding to the receptor. Thus, this report may provide a new method in discovering novel and selective SHP2 allosteric inhibitors. Copyright © 2018 Elsevier Ltd. All rights reserved.

Identification of novel drug scaffolds for inhibition of SARS-CoV 3-Chymotrypsin-like protease using virtual and high-throughput screenings.

PubMed

Lee, Hyun; Mittal, Anuradha; Patel, Kavankumar; Gatuz, Joseph L; Truong, Lena; Torres, Jaime; Mulhearn, Debbie C; Johnson, Michael E

2014-01-01

We have used a combination of virtual screening (VS) and high-throughput screening (HTS) techniques to identify novel, non-peptidic small molecule inhibitors against human SARS-CoV 3CLpro. A structure-based VS approach integrating docking and pharmacophore based methods was employed to computationally screen 621,000 compounds from the ZINC library. The screening protocol was validated using known 3CLpro inhibitors and was optimized for speed, improved selectivity, and for accommodating receptor flexibility. Subsequently, a fluorescence-based enzymatic HTS assay was developed and optimized to experimentally screen approximately 41,000 compounds from four structurally diverse libraries chosen mainly based on the VS results. False positives from initial HTS hits were eliminated by a secondary orthogonal binding analysis using surface plasmon resonance (SPR). The campaign identified a reversible small molecule inhibitor exhibiting mixed-type inhibition with a K(i) value of 11.1 μM. Together, these results validate our protocols as suitable approaches to screen virtual and chemical libraries, and the newly identified compound reported in our study represents a promising structural scaffold to pursue for further SARS-CoV 3CLpro inhibitor development. Copyright © 2013. Published by Elsevier Ltd.

Assessing an ensemble docking-based virtual screening strategy for kinase targets by considering protein flexibility.

PubMed

Tian, Sheng; Sun, Huiyong; Pan, Peichen; Li, Dan; Zhen, Xuechu; Li, Youyong; Hou, Tingjun

2014-10-27

In this study, to accommodate receptor flexibility, based on multiple receptor conformations, a novel ensemble docking protocol was developed by using the naïve Bayesian classification technique, and it was evaluated in terms of the prediction accuracy of docking-based virtual screening (VS) of three important targets in the kinase family: ALK, CDK2, and VEGFR2. First, for each target, the representative crystal structures were selected by structural clustering, and the capability of molecular docking based on each representative structure to discriminate inhibitors from non-inhibitors was examined. Then, for each target, 50 ns molecular dynamics (MD) simulations were carried out to generate an ensemble of the conformations, and multiple representative structures/snapshots were extracted from each MD trajectory by structural clustering. On average, the representative crystal structures outperform the representative structures extracted from MD simulations in terms of the capabilities to separate inhibitors from non-inhibitors. Finally, by using the naïve Bayesian classification technique, an integrated VS strategy was developed to combine the prediction results of molecular docking based on different representative conformations chosen from crystal structures and MD trajectories. It was encouraging to observe that the integrated VS strategy yields better performance than the docking-based VS based on any single rigid conformation. This novel protocol may provide an improvement over existing strategies to search for more diverse and promising active compounds for a target of interest.

On the TRAIL to successful cancer therapy? Predicting and counteracting resistance against TRAIL-based therapeutics

PubMed Central

Dimberg, Lina Y.; Anderson, Charles K.; Camidge, Ross; Behbakht, Kian; Thorburn, Andrew; Ford, Heide L.

2015-01-01

TRAIL and agonistic antibodies against TRAIL death receptors kill tumor cells while causing virtually no damage to normal cells. Several novel drugs targeting TRAIL receptors are currently in clinical trials. However, TRAIL resistance is a common obstacle in TRAIL based therapy and limits the efficiency of these drugs. In this review article we discuss different mechanisms of TRAIL resistance and how they can be predicted and therapeutically circumvented. In addition, we provide a brief overview of all TRAIL based clinical trials conducted so far. It is apparent that although the effects of TRAIL therapy are disappointingly modest overall, a small subset of patients responds very well to TRAIL. We argue that the true potential of targeting TRAIL death receptors in cancer can only be reached when we find efficient ways to select for those patients that are most likely to benefit from the treatment. To achieve this, it is crucial to identify biomarkers that can help us predict TRAIL sensitivity. PMID:22580613

Exploration of the conformational landscape in pregnane X receptor reveals a new binding pocket

PubMed Central

Chandran, Aneesh

2016-01-01

Abstract Ligand‐regulated pregnane X receptor (PXR), a member of the nuclear receptor superfamily, plays a central role in xenobiotic metabolism. Despite its critical role in drug metabolism, PXR activation can lead to adverse drug‐drug interactions and early stage metabolism of drugs. Activated PXR can induce cancer drug resistance and enhance the onset of malignancy. Since promiscuity in ligand binding makes it difficult to develop competitive inhibitors targeting PXR ligand binding pocket (LBP), it is essential to identify allosteric sites for effective PXR antagonism. Here, molecular dynamics (MD) simulation studies unravelled the existence of two different conformational states, namely “expanded” and “contracted”, in apo PXR ligand binding domain (LBD). Ligand binding events shifted this conformational equilibrium and locked the LBD in a single “ligand‐adaptable” conformational state. Ensemble‐based computational solvent mapping identified a transiently open potential small molecule binding pocket between α5 and α8 helices, named “α8 pocket”, whose opening‐closing mechanism directly correlated with the conformational shift in LBD. A virtual hit identified through structure‐based virtual screening against α8 pocket locks the pocket in its open conformation. MD simulations further revealed that the presence of small molecule at allosteric site disrupts the LBD dynamics and locks the LBD in a “tightly‐contracted” conformation. The molecular details provided here could guide new structural studies to understand PXR activation and antagonism. PMID:27515410

Virtual and biomolecular screening converge on a selective agonist for GPR30.

PubMed

Bologa, Cristian G; Revankar, Chetana M; Young, Susan M; Edwards, Bruce S; Arterburn, Jeffrey B; Kiselyov, Alexander S; Parker, Matthew A; Tkachenko, Sergey E; Savchuck, Nikolay P; Sklar, Larry A; Oprea, Tudor I; Prossnitz, Eric R

2006-04-01

Estrogen is a hormone critical in the development, normal physiology and pathophysiology of numerous human tissues. The effects of estrogen have traditionally been solely ascribed to estrogen receptor alpha (ERalpha) and more recently ERbeta, members of the soluble, nuclear ligand-activated family of transcription factors. We have recently shown that the seven-transmembrane G protein-coupled receptor GPR30 binds estrogen with high affinity and resides in the endoplasmic reticulum, where it activates multiple intracellular signaling pathways. To differentiate between the functions of ERalpha or ERbeta and GPR30, we used a combination of virtual and biomolecular screening to isolate compounds that selectively bind to GPR30. Here we describe the identification of the first GPR30-specific agonist, G-1 (1), capable of activating GPR30 in a complex environment of classical and new estrogen receptors. The development of compounds specific to estrogen receptor family members provides the opportunity to increase our understanding of these receptors and their contribution to estrogen biology.

Screening of synthetic and natural product databases: Identification of novel androgens and antiandrogens.

PubMed

Bobach, Claudia; Tennstedt, Stephanie; Palberg, Kristin; Denkert, Annika; Brandt, Wolfgang; de Meijere, Armin; Seliger, Barbara; Wessjohann, Ludger A

2015-01-27

The androgen receptor is an important pharmaceutical target for a variety of diseases. This paper presents an in silico/in vitro screening procedure to identify new androgen receptor ligands. The two-step virtual screening procedure uses a three-dimensional pharmacophore model and a docking/scoring routine. About 39,000 filtered compounds were docked with PLANTS and scored by Chemplp. Subsequent to virtual screening, 94 compounds, including 28 steroidal and 66 nonsteroidal compounds, were tested by an androgen receptor fluorescence polarization ligand displacement assay. As a result, 30 compounds were identified that show a relative binding affinity of more than 50% in comparison to 100 nM dihydrotestosterone and were classified as androgen receptor binders. For 11 androgen receptor binders of interest IC50 and Ki values were determined. The compound with the highest affinity exhibits a Ki value of 10.8 nM. Subsequent testing of the 11 compounds in a PC-3 and LNCaP multi readout proliferation assay provides insights into the potential mode of action. Further steroid receptor ligand displacement assays and docking studies on estrogen receptors α and β, glucocorticoid receptor, and progesterone receptor gave information about the specificity of the 11 most active compounds. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Conformation guides molecular efficacy in docking screens of activated β-2 adrenergic G protein coupled receptor.

PubMed

Weiss, Dahlia R; Ahn, SeungKirl; Sassano, Maria F; Kleist, Andrew; Zhu, Xiao; Strachan, Ryan; Roth, Bryan L; Lefkowitz, Robert J; Shoichet, Brian K

2013-05-17

A prospective, large library virtual screen against an activated β2-adrenergic receptor (β2AR) structure returned potent agonists to the exclusion of inverse-agonists, providing the first complement to the previous virtual screening campaigns against inverse-agonist-bound G protein coupled receptor (GPCR) structures, which predicted only inverse-agonists. In addition, two hits recapitulated the signaling profile of the co-crystal ligand with respect to the G protein and arrestin mediated signaling. This functional fidelity has important implications in drug design, as the ability to predict ligands with predefined signaling properties is highly desirable. However, the agonist-bound state provides an uncertain template for modeling the activated conformation of other GPCRs, as a dopamine D2 receptor (DRD2) activated model templated on the activated β2AR structure returned few hits of only marginal potency.

Discovery of Dual ETA/ETB Receptor Antagonists from Traditional Chinese Herbs through in Silico and in Vitro Screening

PubMed Central

Wang, Xing; Zhang, Yuxin; Liu, Qing; Ai, Zhixin; Zhang, Yanling; Xiang, Yuhong; Qiao, Yanjiang

2016-01-01

Endothelin-1 receptors (ETAR and ETBR) act as a pivotal regulator in the biological effects of ET-1 and represent a potential drug target for the treatment of multiple cardiovascular diseases. The purpose of the study is to discover dual ETA/ETB receptor antagonists from traditional Chinese herbs. Ligand- and structure-based virtual screening was performed to screen an in-house database of traditional Chinese herbs, followed by a series of in vitro bioassay evaluation. Aristolochic acid A (AAA) was first confirmed to be a dual ETA/ETB receptor antagonist based intracellular calcium influx assay and impedance-based assay. Dose-response curves showed that AAA can block both ETAR and ETBR with IC50 of 7.91 and 7.40 μM, respectively. Target specificity and cytotoxicity bioassay proved that AAA is a selective dual ETA/ETB receptor antagonist and has no significant cytotoxicity on HEK293/ETAR and HEK293/ETBR cells within 24 h. It is a feasible and effective approach to discover bioactive compounds from traditional Chinese herbs using in silico screening combined with in vitro bioassay evaluation. The structural characteristic of AAA for its activity was especially interpreted, which could provide valuable reference for the further structural modification of AAA. PMID:26999111

Structure-Based Virtual Screening for Drug Discovery: Principles, Applications and Recent Advances

PubMed Central

Lionta, Evanthia; Spyrou, George; Vassilatis, Demetrios K.; Cournia, Zoe

2014-01-01

Structure-based drug discovery (SBDD) is becoming an essential tool in assisting fast and cost-efficient lead discovery and optimization. The application of rational, structure-based drug design is proven to be more efficient than the traditional way of drug discovery since it aims to understand the molecular basis of a disease and utilizes the knowledge of the three-dimensional structure of the biological target in the process. In this review, we focus on the principles and applications of Virtual Screening (VS) within the context of SBDD and examine different procedures ranging from the initial stages of the process that include receptor and library pre-processing, to docking, scoring and post-processing of topscoring hits. Recent improvements in structure-based virtual screening (SBVS) efficiency through ensemble docking, induced fit and consensus docking are also discussed. The review highlights advances in the field within the framework of several success studies that have led to nM inhibition directly from VS and provides recent trends in library design as well as discusses limitations of the method. Applications of SBVS in the design of substrates for engineered proteins that enable the discovery of new metabolic and signal transduction pathways and the design of inhibitors of multifunctional proteins are also reviewed. Finally, we contribute two promising VS protocols recently developed by us that aim to increase inhibitor selectivity. In the first protocol, we describe the discovery of micromolar inhibitors through SBVS designed to inhibit the mutant H1047R PI3Kα kinase. Second, we discuss a strategy for the identification of selective binders for the RXRα nuclear receptor. In this protocol, a set of target structures is constructed for ensemble docking based on binding site shape characterization and clustering, aiming to enhance the hit rate of selective inhibitors for the desired protein target through the SBVS process. PMID:25262799

A kinase-focused compound collection: compilation and screening strategy.

PubMed

Sun, Dongyu; Chuaqui, Claudio; Deng, Zhan; Bowes, Scott; Chin, Donovan; Singh, Juswinder; Cullen, Patrick; Hankins, Gretchen; Lee, Wen-Cherng; Donnelly, Jason; Friedman, Jessica; Josiah, Serene

2006-06-01

Lead identification by high-throughput screening of large compound libraries has been supplemented with virtual screening and focused compound libraries. To complement existing approaches for lead identification at Biogen Idec, a kinase-focused compound collection was designed, developed and validated. Two strategies were adopted to populate the compound collection: a ligand shape-based virtual screening and a receptor-based approach (structural interaction fingerprint). Compounds selected with the two approaches were cherry-picked from an existing high-throughput screening compound library, ordered from suppliers and supplemented with specific medicinal compounds from internal programs. Promising hits and leads have been generated from the kinase-focused compound collection against multiple kinase targets. The principle of the collection design and screening strategy was validated and the use of the kinase-focused compound collection for lead identification has been added to existing strategies.

November 6, 2017, Virtual Meeting on the Charge Questions for the Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (FIFRA SAP) Meeting on Endocrine Disruption

EPA Pesticide Factsheets

This virtual FIFRA SAP meeting will be discus questions on Continuing Development of Alternative High-Throughput Screens to Determine Endocrine Disruption, focusing on Androgen Receptor, Steroidogenesis, and Thyroid Pathways

Virtual screening on an α-helix to β-strand switchable region of the FGFR2 extracellular domain revealed positive and negative modulators.

PubMed

Diaz, Constantino; Corentin, Herbert; Thierry, Vermat; Chantal, Alcouffe; Tanguy, Bozec; David, Sibrac; Jean-Marc, Herbert; Pascual, Ferrara; Françoise, Bono; Edgardo, Ferran

2014-11-01

The secondary structure of some protein segments may vary between α-helix and β-strand. To predict these switchable segments, we have developed an algorithm, Switch-P, based solely on the protein sequence. This algorithm was used on the extracellular parts of FGF receptors. For FGFR2, it predicted that β4 and β5 strands of the third Ig-like domain were highly switchable. These two strands possess a high number of somatic mutations associated with cancer. Analysis of PDB structures of FGF receptors confirmed the switchability prediction for β5. We thus evaluated if compound-driven α-helix/β-strand switching of β5 could modulate FGFR2 signaling. We performed the virtual screening of a library containing 1.4 million of chemical compounds with two models of the third Ig-like domain of FGFR2 showing different secondary structures for β5, and we selected 32 compounds. Experimental testing using proliferation assays with FGF7-stimulated SNU-16 cells and a FGFR2-dependent Erk1/2 phosphorylation assay with FGFR2-transfected L6 cells, revealed activators and inhibitors of FGFR2. Our method for the identification of switchable proteinic regions, associated with our virtual screening approach, provides an opportunity to discover new generation of drugs with under-explored mechanism of action. © 2014 Wiley Periodicals, Inc.

Discovery of Tyk2 inhibitors via the virtual site-directed fragment-based drug design.

PubMed

Jang, Woo Dae; Kim, Jun-Tae; Son, Hoon Young; Park, Seung Yeon; Cho, Young Sik; Koo, Tae-sung; Lee, Hyuk; Kang, Nam Sook

2015-09-15

In this study, we synthesized compound 12 with potent Tyk2 inhibitory activity from FBDD study and carried out a cell-based assay for Tyk2/STAT3 signaling activation upon IFNα5 stimulation. Compound 12 completely suppressed the IFNα5-mediated Tyk2/STAT3 signaling pathway as well as the basal levels of pSTAT3. Stimulation with IFNα/β leads to the tyrosine phosphorylation of the JAK1 and Tyk2 receptor-associated kinases with subsequent STATs activation, transmitting signals from the cell surface receptor to the nucleus. In conclusion, the potency of compound 12 to interrupt the signal transmission of Tyk2/STAT3 appeared to be equivalent or superior to that of the reference compound. Copyright © 2015 Elsevier Ltd. All rights reserved.

SABRE: ligand/structure-based virtual screening approach using consensus molecular-shape pattern recognition.

PubMed

Wei, Ning-Ning; Hamza, Adel

2014-01-27

We present an efficient and rational ligand/structure shape-based virtual screening approach combining our previous ligand shape-based similarity SABRE (shape-approach-based routines enhanced) and the 3D shape of the receptor binding site. Our approach exploits the pharmacological preferences of a number of known active ligands to take advantage of the structural diversities and chemical similarities, using a linear combination of weighted molecular shape density. Furthermore, the algorithm generates a consensus molecular-shape pattern recognition that is used to filter and place the candidate structure into the binding pocket. The descriptor pool used to construct the consensus molecular-shape pattern consists of four dimensional (4D) fingerprints generated from the distribution of conformer states available to a molecule and the 3D shapes of a set of active ligands computed using SABRE software. The virtual screening efficiency of SABRE was validated using the Database of Useful Decoys (DUD) and the filtered version (WOMBAT) of 10 DUD targets. The ligand/structure shape-based similarity SABRE algorithm outperforms several other widely used virtual screening methods which uses the data fusion of multiscreening tools (2D and 3D fingerprints) and demonstrates a superior early retrieval rate of active compounds (EF(0.1%) = 69.0% and EF(1%) = 98.7%) from a large size of ligand database (∼95,000 structures). Therefore, our developed similarity approach can be of particular use for identifying active compounds that are similar to reference molecules and predicting activity against other targets (chemogenomics). An academic license of the SABRE program is available on request.

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

PubMed

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 <15.4%) of the individual target inhibitors of the same target pair and 0.58-7.1% of the other 6 targets outside the target pair. COMBI-SVMs showed low dual inhibitor false hit rates (0.006-0.056%, 0.042-0.21%, 0.2-4%) in screening 17 million PubChem compounds, 168,000 MDDR compounds, and 7-8181 MDDR compounds similar to the dual inhibitors. Compared with similarity searching, k-NN and PNN methods, COMBI-SVM produced comparable dual inhibitor yields, similar target selectivity, and lower false hit rate in screening 168,000 MDDR compounds. The annotated classes of many COMBI-SVMs identified MDDR 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.

Molecular Docking and Drug Discovery in β-Adrenergic Receptors.

PubMed

Vilar, Santiago; Sobarzo-Sanchez, Eduardo; Santana, Lourdes; Uriarte, Eugenio

2017-01-01

Evolution in computer engineering, availability of increasing amounts of data and the development of new and fast docking algorithms and software have led to improved molecular simulations with crucial applications in virtual high-throughput screening and drug discovery. Moreover, analysis of protein-ligand recognition through molecular docking has become a valuable tool in drug design. In this review, we focus on the applicability of molecular docking on a particular class of G protein-coupled receptors: the β-adrenergic receptors, which are relevant targets in clinic for the treatment of asthma and cardiovascular diseases. We describe the binding site in β-adrenergic receptors to understand key factors in ligand recognition along with the proteins activation process. Moreover, we focus on the discovery of new lead compounds that bind the receptors, on the evaluation of virtual screening using the active/ inactive binding site states, and on the structural optimization of known families of binders to improve β-adrenergic affinity. We also discussed strengths and challenges related to the applicability of molecular docking in β-adrenergic receptors. Molecular docking is a valuable technique in computational chemistry to deeply analyze ligand recognition and has led to important breakthroughs in drug discovery and design in the field of β-adrenergic receptors. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Contributions of sex, testosterone, and androgen receptor CAG repeat number to virtual Morris water maze performance.

PubMed

Nowak, Nicole T; Diamond, Michael P; Land, Susan J; Moffat, Scott D

2014-03-01

The possibility that androgens contribute to the male advantage typically found on measures of spatial cognition has been investigated using a variety of approaches. To date, evidence to support the notion that androgens affect spatial cognition in healthy young adults is somewhat equivocal. The present study sought to clarify the association between testosterone (T) and spatial performance by extending measurements of androgenicity to include both measures of circulating T as well as an androgen receptor-specific genetic marker. The aims of this study were to assess the contributions of sex, T, and androgen receptor CAG repeat number (CAGr) on virtual Morris water task (vMWT) performance in a group of healthy young men and women. The hypothesis that men would outperform women on vMWT outcomes was supported. Results indicate that CAGr may interact with T to impact navigation performance and suggest that consideration of androgen receptor sensitivity is an important consideration in evaluating hormone-behavior relationships. Copyright © 2013 Elsevier Ltd. All rights reserved.

wFReDoW: A Cloud-Based Web Environment to Handle Molecular Docking Simulations of a Fully Flexible Receptor Model

PubMed Central

De Paris, Renata; Frantz, Fábio A.; Norberto de Souza, Osmar; Ruiz, Duncan D. A.

2013-01-01

Molecular docking simulations of fully flexible protein receptor (FFR) models are coming of age. In our studies, an FFR model is represented by a series of different conformations derived from a molecular dynamic simulation trajectory of the receptor. For each conformation in the FFR model, a docking simulation is executed and analyzed. An important challenge is to perform virtual screening of millions of ligands using an FFR model in a sequential mode since it can become computationally very demanding. In this paper, we propose a cloud-based web environment, called web Flexible Receptor Docking Workflow (wFReDoW), which reduces the CPU time in the molecular docking simulations of FFR models to small molecules. It is based on the new workflow data pattern called self-adaptive multiple instances (P-SaMIs) and on a middleware built on Amazon EC2 instances. P-SaMI reduces the number of molecular docking simulations while the middleware speeds up the docking experiments using a High Performance Computing (HPC) environment on the cloud. The experimental results show a reduction in the total elapsed time of docking experiments and the quality of the new reduced receptor models produced by discarding the nonpromising conformations from an FFR model ruled by the P-SaMI data pattern. PMID:23691504

Selection, application, and validation of a set of molecular descriptors for nuclear receptor ligands.

PubMed

Stewart, Eugene L; Brown, Peter J; Bentley, James A; Willson, Timothy M

2004-08-01

A methodology for the selection and validation of nuclear receptor ligand chemical descriptors is described. After descriptors for a targeted chemical space were selected, a virtual screening methodology utilizing this space was formulated for the identification of potential NR ligands from our corporate collection. Using simple descriptors and our virtual screening method, we are able to quickly identify potential NR ligands from a large collection of compounds. As validation of the virtual screening procedure, an 8, 000-membered NR targeted set and a 24, 000-membered diverse control set of compounds were selected from our in-house general screening collection and screened in parallel across a number of orphan NR FRET assays. For the two assays that provided at least one hit per set by the established minimum pEC(50) for activity, the results showed a 2-fold increase in the hit-rate of the targeted compound set over the diverse set.

[Selection of a melanine concentrating hormone receptor-1 (MCHR1) antagonists' focused library and its biological screening with AequoScreen].

PubMed

Flachner, Beáta; Hajdú, István; Dobi, Krisztina; Lorincz, Zsolt; Cseh, Sándor; Dormán, György

2013-01-01

Target focused libraries can be rapidly selected by 2D virtual screening methods from multimillion compounds' repositories if structures of active compounds are available. In the present study a multi-step virtual and in vitro screening cascade is reported to select Melanin Concentrating Hormone Receptor-1 (MCHR1) antagonists. The 2D similarity search combined with physicochemical parameter filtering is suitable for selecting candidates from multimillion compounds' repository. The seeds of the first round virtual screening were collected from the literature and commercial databases, while the seeds of the second round were the hits of the first round. In vitro screening underlined the efficiency of our approach, as in the second screening round the hit rate (8.6 %) significantly improved compared to the first round (1.9%), reaching the antagonist activity even below 10 nM.

Discovery of novel mGluR1 antagonists: a multistep virtual screening approach based on an SVM model and a pharmacophore hypothesis significantly increases the hit rate and enrichment factor.

PubMed

Li, Guo-Bo; Yang, Ling-Ling; Feng, Shan; Zhou, Jian-Ping; Huang, Qi; Xie, Huan-Zhang; Li, Lin-Li; Yang, Sheng-Yong

2011-03-15

Development of glutamate non-competitive antagonists of mGluR1 (Metabotropic glutamate receptor subtype 1) has increasingly attracted much attention in recent years due to their potential therapeutic application for various nervous disorders. Since there is no crystal structure reported for mGluR1, ligand-based virtual screening (VS) methods, typically pharmacophore-based VS (PB-VS), are often used for the discovery of mGluR1 antagonists. Nevertheless, PB-VS usually suffers a lower hit rate and enrichment factor. In this investigation, we established a multistep ligand-based VS approach that is based on a support vector machine (SVM) classification model and a pharmacophore model. Performance evaluation of these methods in virtual screening against a large independent test set, M-MDDR, show that the multistep VS approach significantly increases the hit rate and enrichment factor compared with the individual SB-VS and PB-VS methods. The multistep VS approach was then used to screen several large chemical libraries including PubChem, Specs, and Enamine. Finally a total of 20 compounds were selected from the top ranking compounds, and shifted to the subsequent in vitro and in vivo studies, which results will be reported in the near future. Copyright © 2011 Elsevier Ltd. All rights reserved.

Creation of a Human Secretome: A Novel Composite Library of Human Secreted Proteins: Validation Using Ovarian Cancer Gene Expression Data and a Virtual Secretome Array.

PubMed

Vathipadiekal, Vinod; Wang, Victoria; Wei, Wei; Waldron, Levi; Drapkin, Ronny; Gillette, Michael; Skates, Steven; Birrer, Michael

2015-11-01

To generate a comprehensive "Secretome" of proteins potentially found in the blood and derive a virtual Affymetrix array. To validate the utility of this database for the discovery of novel serum-based biomarkers using ovarian cancer transcriptomic data. The secretome was constructed by aggregating the data from databases of known secreted proteins, transmembrane or membrane proteins, signal peptides, G-protein coupled receptors, or proteins existing in the extracellular region, and the virtual array was generated by mapping them to Affymetrix probeset identifiers. Whole-genome microarray data from ovarian cancer, normal ovarian surface epithelium, and fallopian tube epithelium were used to identify transcripts upregulated in ovarian cancer. We established the secretome from eight public databases and a virtual array consisting of 16,521 Affymetrix U133 Plus 2.0 probesets. Using ovarian cancer transcriptomic data, we identified candidate blood-based biomarkers for ovarian cancer and performed bioinformatic validation by demonstrating rediscovery of known biomarkers including CA125 and HE4. Two novel top biomarkers (FGF18 and GPR172A) were validated in serum samples from an independent patient cohort. We present the secretome, comprising the most comprehensive resource available for protein products that are potentially found in the blood. The associated virtual array can be used to translate gene-expression data into cancer biomarker discovery. A list of blood-based biomarkers for ovarian cancer detection is reported and includes CA125 and HE4. FGF18 and GPR172A were identified and validated by ELISA as being differentially expressed in the serum of ovarian cancer patients compared with controls. ©2015 American Association for Cancer Research.

Pharmacophore Based 3D-QSAR, Virtual Screening and Docking Studies on Novel Series of HDAC Inhibitors with Thiophen Linker as Anticancer Agents.

PubMed

Patel, Preeti; Singh, Avineesh; Patel, Vijay K; Jain, Deepak K; Veerasamy, Ravichandran; Rajak, Harish

2016-01-01

Histone deacetylase (HDAC) inhibitors can reactivate gene expression and inhibit the growth and survival of cancer cells. To identify the important pharmacophoric features and correlate 3Dchemical structure with biological activity using 3D-QSAR and Pharmacophore modeling studies. The pharmacophore hypotheses were developed using e-pharmacophore script and phase module. Pharmacophore hypothesis represents the 3D arrangement of molecular features necessary for activity. A series of 55 compounds with wellassigned HDAC inhibitory activity were used for 3D-QSAR model development. Best 3D-QSAR model, which is a five partial least square (PLS) factor model with good statistics and predictive ability, acquired Q2 (0.7293), R2 (0.9811), cross-validated coefficient rcv 2=0.9807 and R2 pred=0.7147 with low standard deviation (0.0952). Additionally, the selected pharmacophore model DDRRR.419 was used as a 3D query for virtual screening against the ZINC database. In the virtual screening workflow, docking studies (HTVS, SP and XP) were carried out by selecting multiple receptors (PDB ID: 1T69, 1T64, 4LXZ, 4LY1, 3MAX, 2VQQ, 3C10, 1W22). Finally, six compounds were obtained based on high scoring function (dock score -11.2278-10.2222 kcal/mol) and diverse structures. The structure activity correlation was established using virtual screening, docking, energetic based pharmacophore modelling, pharmacophore, atom based 3D QSAR models and their validation. The outcomes of these studies could be further employed for the design of novel HDAC inhibitors for anticancer activity.

Structure-based drug design: docking and scoring.

PubMed

Kroemer, Romano T

2007-08-01

This review gives an introduction into ligand - receptor docking and illustrates the basic underlying concepts. An overview of different approaches and algorithms is provided. Although the application of docking and scoring has led to some remarkable successes, there are still some major challenges ahead, which are outlined here as well. Approaches to address some of these challenges and the latest developments in the area are presented. Some aspects of the assessment of docking program performance are discussed. A number of successful applications of structure-based virtual screening are described.

Systematic and efficient side chain optimization for molecular docking using a cheapest-path procedure.

PubMed

Schumann, Marcel; Armen, Roger S

2013-05-30

Molecular docking of small-molecules is an important procedure for computer-aided drug design. Modeling receptor side chain flexibility is often important or even crucial, as it allows the receptor to adopt new conformations as induced by ligand binding. However, the accurate and efficient incorporation of receptor side chain flexibility has proven to be a challenge due to the huge computational complexity required to adequately address this problem. Here we describe a new docking approach with a very fast, graph-based optimization algorithm for assignment of the near-optimal set of residue rotamers. We extensively validate our approach using the 40 DUD target benchmarks commonly used to assess virtual screening performance and demonstrate a large improvement using the developed side chain optimization over rigid receptor docking (average ROC AUC of 0.693 vs. 0.623). Compared to numerous benchmarks, the overall performance is better than nearly all other commonly used procedures. Furthermore, we provide a detailed analysis of the level of receptor flexibility observed in docking results for different classes of residues and elucidate potential avenues for further improvement. Copyright © 2013 Wiley Periodicals, Inc.

Improving database enrichment through ensemble docking

NASA Astrophysics Data System (ADS)

Rao, Shashidhar; Sanschagrin, Paul C.; Greenwood, Jeremy R.; Repasky, Matthew P.; Sherman, Woody; Farid, Ramy

2008-09-01

While it may seem intuitive that using an ensemble of multiple conformations of a receptor in structure-based virtual screening experiments would necessarily yield improved enrichment of actives relative to using just a single receptor, it turns out that at least in the p38 MAP kinase model system studied here, a very large majority of all possible ensembles do not yield improved enrichment of actives. However, there are combinations of receptor structures that do lead to improved enrichment results. We present here a method to select the ensembles that produce the best enrichments that does not rely on knowledge of active compounds or sophisticated analyses of the 3D receptor structures. In the system studied here, the small fraction of ensembles of up to 3 receptors that do yield good enrichments of actives were identified by selecting ensembles that have the best mean GlideScore for the top 1% of the docked ligands in a database screen of actives and drug-like "decoy" ligands. Ensembles of two receptors identified using this mean GlideScore metric generally outperform single receptors, while ensembles of three receptors identified using this metric consistently give optimal enrichment factors in which, for example, 40% of the known actives outrank all the other ligands in the database.

Integrating sampling techniques and inverse virtual screening: toward the discovery of artificial peptide-based receptors for ligands.

PubMed

Pérez, Germán M; Salomón, Luis A; Montero-Cabrera, Luis A; de la Vega, José M García; Mascini, Marcello

2016-05-01

A novel heuristic using an iterative select-and-purge strategy is proposed. It combines statistical techniques for sampling and classification by rigid molecular docking through an inverse virtual screening scheme. This approach aims to the de novo discovery of short peptides that may act as docking receptors for small target molecules when there are no data available about known association complexes between them. The algorithm performs an unbiased stochastic exploration of the sample space, acting as a binary classifier when analyzing the entire peptides population. It uses a novel and effective criterion for weighting the likelihood of a given peptide to form an association complex with a particular ligand molecule based on amino acid sequences. The exploratory analysis relies on chemical information of peptides composition, sequence patterns, and association free energies (docking scores) in order to converge to those peptides forming the association complexes with higher affinities. Statistical estimations support these results providing an association probability by improving predictions accuracy even in cases where only a fraction of all possible combinations are sampled. False positives/false negatives ratio was also improved with this method. A simple rigid-body docking approach together with the proper information about amino acid sequences was used. The methodology was applied in a retrospective docking study to all 8000 possible tripeptide combinations using the 20 natural amino acids, screened against a training set of 77 different ligands with diverse functional groups. Afterward, all tripeptides were screened against a test set of 82 ligands, also containing different functional groups. Results show that our integrated methodology is capable of finding a representative group of the top-scoring tripeptides. The associated probability of identifying the best receptor or a group of the top-ranked receptors is more than double and about 10 times higher, respectively, when compared to classical random sampling methods.

Homology Modeling of Class A G Protein-Coupled Receptors

PubMed Central

Costanzi, Stefano

2012-01-01

G protein-coupled receptors (GPCRs) are a large superfamily of membrane bound signaling proteins that hold great pharmaceutical interest. Since experimentally elucidated structures are available only for a very limited number of receptors, homology modeling has become a widespread technique for the construction of GPCR models intended to study the structure-function relationships of the receptors and aid the discovery and development of ligands capable of modulating their activity. Through this chapter, various aspects involved in the constructions of homology models of the serpentine domain of the largest class of GPCRs, known as class A or rhodopsin family, are illustrated. In particular, the chapter provides suggestions, guidelines and critical thoughts on some of the most crucial aspect of GPCR modeling, including: collection of candidate templates and a structure-based alignment of their sequences; identification and alignment of the transmembrane helices of the query receptor to the corresponding domains of the candidate templates; selection of one or more templates receptor; election of homology or de novo modeling for the construction of specific extracellular and intracellular domains; construction of the three-dimensional models, with special consideration to extracellular regions, disulfide bridges, and interhelical cavity; validation of the models through controlled virtual screening experiments. PMID:22323225

Structure-based Virtual Screening and Identification of a Novel Androgen Receptor Antagonist*

PubMed Central

Song, Chin-Hee; Yang, Su Hui; Park, Eunsook; Cho, Suk Hee; Gong, Eun-Yeung; Khadka, Daulat Bikram; Cho, Won-Jea; Lee, Keesook

2012-01-01

Hormonal therapies, mainly combinations of anti-androgens and androgen deprivation, have been the mainstay treatment for advanced prostate cancer because the androgen-androgen receptor (AR) system plays a pivotal role in the development and progression of prostate cancers. However, the emergence of androgen resistance, largely due to inefficient anti-hormone action, limits the therapeutic usefulness of these therapies. Here, we report that 6-(3,4-dihydro-1H-isoquinolin-2-yl)-N-(6-methylpyridin-2-yl)nicotinamide (DIMN) acts as a novel anti-androgenic compound that may be effective in the treatment of both androgen-dependent and androgen-independent prostate cancers. Through AR structure-based virtual screening using the FlexX docking model, fifty-four compounds were selected and further screened for AR antagonism via cell-based tests. One compound, DIMN, showed an antagonistic effect specific to AR with comparable potency to that of the classical AR antagonists, hydroxyflutamide and bicalutamide. Consistent with their anti-androgenic activity, DIMN inhibited the growth of androgen-dependent LNCaP prostate cancer cells. Interestingly, the compound also suppressed the growth of androgen-independent C4–2 and CWR22rv prostate cancer cells, which express a functional AR, but did not suppress the growth of the AR-negative prostate cancer cells PPC-1, DU145, and R3327-AT3.1. Taken together, the results suggest that the synthetic compound DIMN is a novel anti-androgen and strong candidate for useful therapeutic agent against early stage to advanced prostate cancer. PMID:22798067

Discovery of estrogen receptor α modulators from natural compounds in Si-Wu-Tang series decoctions using estrogen-responsive MCF-7 breast cancer cells.

PubMed

Liu, Li; Ma, Hongyue; Tang, Yuping; Chen, Wenxing; Lu, Yin; Guo, Jianming; Duan, Jin-Ao

2012-01-01

The binding between the estrogen receptor α (ER-α) and a variety of compounds in traditional Chinese formulae, Si-Wu-Tang (SWT) series decoctions, was studied using a stably-transfected human breast cancer cell line (MVLN). In 38 compounds tested from SWT series decoctions, the estrogen-like activity of 22 compounds was above 60% in 20 μg mL(-1). Furthermore, theoretical affinity of these compounds was certificated using the functional virtual screen of ER-α modulators by FlexX-Pharm. The accuracy of functional virtual screening of ER-α modulators could reach to 77.27%. The results showed that some compounds, such as organic acids and flavones in SWT series decoctions could be used as selective estrogen receptor modulators (SERMs) and could be selected for further development as potential agents for estrogen related diseases. Copyright © 2011 Elsevier Ltd. All rights reserved.

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

NASA Astrophysics Data System (ADS)

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.

Virtual Screening on MMP-13 Led to Discovering New Inhibitors Including a Non-Zinc Binding and a Micro Molar One: A Successful Example of Receptor Selection According to Cross-Docking Results for a Flexible Enzyme.

PubMed

Ramezani, Mohammad; Shamsara, Jamal

2017-01-01

MMP-13 belongs to a large family of proteases called matrix metalloproteinases (MMPs) that degrades type II collagen, the main structural protein of articular cartilage. The main pathologic role of MMP-13 over expression is to contribute to the development of osteoarthritis. To find new inhibitors with possible selectivity for MMP-13 a structure based virtual screening was employed. The inhibitory activities of 11 inhibitors among 19 purchased compounds were approved by enzyme inhibition assay. Our results demonstrated that the CADD (computer aided drug design) could be successfully applied to find new MMP-13 inhibitors using a receptor structure (PDB code: 3O2X) which had been demonstrated a good performance in a cross-docking study. We discovered inhibitors with new scaffolds for inhibition of MMP-13 and some selectivity features such as proper S1' occupancy and interactions with S1' pocket that could be subjected to a future lead optimization study. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

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

NASA Astrophysics Data System (ADS)

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.

Discovery of potent and novel smoothened antagonists via structure-based virtual screening and biological assays.

PubMed

Lu, Wenfeng; Zhang, Dihua; Ma, Haikuo; Tian, Sheng; Zheng, Jiyue; Wang, Qin; Luo, Lusong; Zhang, Xiaohu

2018-05-23

The Hedgehog (Hh) signaling pathway plays a critical role in controlling patterning, growth and cell migration during embryonic development. Aberrant activation of Hh signaling has been linked to tumorigenesis in various cancers, such as basal cell carcinoma (BCC) and medulloblastoma. As a key member of the Hh pathway, the Smoothened (Smo) receptor, a member of the G protein-coupled receptor (GPCR) family, has emerged as an attractive therapeutic target for the treatment and prevention of human cancers. The recent determination of several crystal structures of Smo in complex with different antagonists offers the possibility to perform structure-based virtual screening for discovering potent Smo antagonists with distinct chemical scaffolds. In this study, based on the two Smo crystal complexes with the best capacity to distinguish the known Smo antagonists from decoys, the molecular docking-based virtual screening was conducted to identify promising Smo antagonists from ChemDiv library. A total of 21 structurally novel and diverse compounds were selected for experimental testing, and six of them exhibited significant inhibitory activity against the Hh pathway activation (IC 50  < 10 μM) in a GRE (Gli-responsive element) reporter gene assay. Specifically, the most potent compound (compound 20: 47 nM) showed comparable Hh signaling inhibition to vismodegib (46 nM). Compound 20 was further confirmed to be a potent Smo antagonist in a fluorescence based competitive binding assay. Optimization using substructure searching method led to the discovery of 12 analogues of compound 20 with decent Hh pathway inhibition activity, including four compounds with IC 50 lower than 1 μM. The important residues uncovered by binding free energy calculation (MM/GBSA) and binding free energy decomposition were highlighted and discussed. These findings suggest that the novel scaffold afforded by compound 20 can be used as a good starting point for further modification/optimization and the clarified interaction patterns may also guide us to find more potent Smo antagonists. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Homology modeling, binding site identification and docking study of human angiotensin II type I (Ang II-AT1) receptor.

PubMed

Vyas, Vivek K; Ghate, Manjunath; Patel, Kinjal; Qureshi, Gulamnizami; Shah, Surmil

2015-08-01

Ang II-AT1 receptors play an important role in mediating virtually all of the physiological actions of Ang II. Several drugs (SARTANs) are available, which can block the AT1 receptor effectively and lower the blood pressure in the patients with hypertension. Currently, there is no experimental Ang II-AT1 structure available; therefore, in this study we modeled Ang II-AT1 receptor structure using homology modeling followed by identification and characterization of binding sites and thereby assessing druggability of the receptor. Homology models were constructed using MODELLER and I-TASSER server, refined and validated using PROCHECK in which 96.9% of 318 residues were present in the favoured regions of the Ramachandran plots. Various Ang II-AT1 receptor antagonist drugs are available in the market as antihypertensive drug, so we have performed docking study with the binding site prediction algorithms to predict different binding pockets on the modeled proteins. The identification of 3D structures and binding sites for various known drugs will guide us for the structure-based drug design of novel compounds as Ang II-AT1 receptor antagonists for the treatment of hypertension. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

A combination of 2D similarity search, pharmacophore, and molecular docking techniques for the identification of vascular endothelial growth factor receptor-2 inhibitors.

PubMed

Ai, Guanhua; Tian, Caiping; Deng, Dawei; Fida, Guissi; Chen, Haiyan; Ma, Yuxiang; Ding, Li; Gu, Yueqing

2015-04-01

The human vascular endothelial growth factor receptor-2 (VEGFR-2) has been an attractive target for the inhibition of angiogenesis. In the current study, we used a hybrid protocol of virtual screening methods to retrieve new VEGFR-2 inhibitors from the Zinc-Specs Database (441 574 compounds). The hybrid protocol included the initial screening of candidates by comparing the 2D similarity to five reported top active inhibitors of 13 VEGFR-2 X-ray crystallography structures, followed by the pharmacophore modeling of virtual screening on the basis of receptor-ligand interactions and further narrowing by LibDOCK to obtain the final hits. Two compounds (AN-919/41439526 and AK-968/40939851) with a high libscore were selected as the final hits for a subsequent cell cytotoxicity study. The two compounds screened exerted significant inhibitory effects on the proliferation of cancer cells (U87 and MCF-7). The results indicated that the hybrid procedure is an effective approach for screening specific receptor inhibitors.

Clustering molecular dynamics trajectories for optimizing docking experiments.

PubMed

De Paris, Renata; Quevedo, Christian V; Ruiz, Duncan D; Norberto de Souza, Osmar; Barros, Rodrigo C

2015-01-01

Molecular dynamics simulations of protein receptors have become an attractive tool for rational drug discovery. However, the high computational cost of employing molecular dynamics trajectories in virtual screening of large repositories threats the feasibility of this task. Computational intelligence techniques have been applied in this context, with the ultimate goal of reducing the overall computational cost so the task can become feasible. Particularly, clustering algorithms have been widely used as a means to reduce the dimensionality of molecular dynamics trajectories. In this paper, we develop a novel methodology for clustering entire trajectories using structural features from the substrate-binding cavity of the receptor in order to optimize docking experiments on a cloud-based environment. The resulting partition was selected based on three clustering validity criteria, and it was further validated by analyzing the interactions between 20 ligands and a fully flexible receptor (FFR) model containing a 20 ns molecular dynamics simulation trajectory. Our proposed methodology shows that taking into account features of the substrate-binding cavity as input for the k-means algorithm is a promising technique for accurately selecting ensembles of representative structures tailored to a specific ligand.

Central serotonin modulates neural responses to virtual violent actions in emotion regulation networks.

PubMed

Wolf, Dhana; Klasen, Martin; Eisner, Patrick; Zepf, Florian D; Zvyagintsev, Mikhail; Palomero-Gallagher, Nicola; Weber, René; Eisert, Albrecht; Mathiak, Klaus

2018-06-08

Disruptions in the cortico-limbic emotion regulation networks have been linked to depression, anxiety, impulsivity, and aggression. Altered transmission of the central nervous serotonin (5-HT) contributes to dysfunctions in the cognitive control of emotions. To date, studies relating to pharmaco-fMRI challenging of the 5-HT system have focused on emotion processing for facial expressions. We investigated effects of a single-dose selective 5-HT reuptake inhibitor (escitalopram) on emotion regulation during virtual violence. For this purpose, 38 male participants played a violent video game during fMRI scanning. The SSRI reduced neural responses to violent actions in right-hemispheric inferior frontal gyrus and medial prefrontal cortex encompassing the anterior cingulate cortex (ACC), but not to non-violent actions. Within the ACC, the drug effect differentiated areas with high inhibitory 5-HT1A receptor density (subgenual s25) from those with a lower density (pregenual p32, p24). This finding links functional responses during virtual violent actions with 5-HT neurotransmission in emotion regulation networks, underpinning the ecological validity of the 5-HT model in aggressive behavior. Available 5-HT receptor density data suggest that this SSRI effect is only observable when inhibitory and excitatory 5-HT receptors are balanced. The observed early functional changes may impact patient groups receiving SSRI treatment.

Selecting an optimal number of binding site waters to improve virtual screening enrichments against the adenosine A2A receptor.

PubMed

Lenselink, Eelke B; Beuming, Thijs; Sherman, Woody; van Vlijmen, Herman W T; IJzerman, Adriaan P

2014-06-23

A major challenge in structure-based virtual screening (VS) involves the treatment of explicit water molecules during docking in order to improve the enrichment of active compounds over decoys. Here we have investigated this in the context of the adenosine A2A receptor, where water molecules have previously been shown to be important for achieving high enrichment rates with docking, and where the positions of some binding site waters are known from a high-resolution crystal structure. The effect of these waters (both their presence and orientations) on VS enrichment was assessed using a carefully curated set of 299 high affinity A2A antagonists and 17,337 decoys. We show that including certain crystal waters greatly improves VS enrichment and that optimization of water hydrogen positions is needed in order to achieve the best results. We also show that waters derived from a molecular dynamics simulation - without any knowledge of crystallographic waters - can improve enrichments to a similar degree as the crystallographic waters, which makes this strategy applicable to structures without experimental knowledge of water positions. Finally, we used decision trees to select an ensemble of structures with different water molecule positions and orientations that outperforms any single structure with water molecules. The approach presented here is validated against independent test sets of A2A receptor antagonists and decoys from the literature. In general, this water optimization strategy could be applied to any target with waters-mediated protein-ligand interactions.

Identification of novel monoamine oxidase B inhibitors by structure-based virtual screening.

PubMed

Geldenhuys, Werner J; Darvesh, Altaf S; Funk, Max O; Van der Schyf, Cornelis J; Carroll, Richard T

2010-09-01

Parkinson's disease is a severe debilitating neurodegenerative disorder. Recently, it was shown that the peroxisome proliferating-activator receptor-gamma agonist pioglitazone protected mice from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity due to its ability to inhibit monoamine oxidase B (MAO-B). Docking studies were initiated to investigate pioglitazone's interactions within the substrate cavity of MAO-B. Modeling studies indicated that the thiazolidinedione (TZD) moiety was a likely candidate for its specificity to MAO-B. To explore this potential novel MAO-B scaffold, we performed a structure-based virtual screen to identify additional MAO-B inhibitors. Our search identified eight novel compounds containing the TZD-moiety that allowed for a limited study to identify structural requirements for binding to MAO-B. Inhibition assays identified two TZDs (A6355 and L136662) which were found to inhibit recombinant human MAO-B with IC(50) values of 82 and 195 nM, respectively. Copyright 2010 Elsevier Ltd. All rights reserved.

Design of Glucagon-Like Peptide-1 Receptor Agonist for Diabetes Mellitus from Traditional Chinese Medicine

PubMed Central

Tang, Hsin-Chieh; Chen, Calvin Yu-Chian

2014-01-01

Glucagon-like peptide-1 (GLP-1) is a promising target for diabetes mellitus (DM) therapy and reduces the occurrence of diabetes due to obesity. However, GLP-1 will be hydrolyzed soon by the enzyme dipeptidyl peptidase-4 (DPP-4). We tried to design small molecular drugs for GLP-1 receptor agonist from the world's largest traditional Chinese medicine (TCM) Database@Taiwan. According to docking results of virtual screening, we selected 2 TCM compounds, wenyujinoside and 28-deglucosylchikusetsusaponin IV, for further molecular dynamics (MD) simulation. GLP-1 was assigned as the control compound. Based on the results of root mean square deviation (RMSD), solvent accessible surface (SAS), mean square deviation (MSD), Gyrate, total energy, root mean square fluctuation (RMSF), matrices of smallest distance of residues, database of secondary structure assignment (DSSP), cluster analysis, and distance of H-bond, we concluded that all the 3 compounds could bind and activate GLP-1 receptor by computational simulation. Wenyujinoside and 28-deglucosylchikusetsusaponin IV were the TCM compounds that could be GLP-1 receptor agonists. PMID:24891870

Design of glucagon-like Peptide-1 receptor agonist for diabetes mellitus from traditional chinese medicine.

PubMed

Tang, Hsin-Chieh; Chen, Calvin Yu-Chian

2014-01-01

Glucagon-like peptide-1 (GLP-1) is a promising target for diabetes mellitus (DM) therapy and reduces the occurrence of diabetes due to obesity. However, GLP-1 will be hydrolyzed soon by the enzyme dipeptidyl peptidase-4 (DPP-4). We tried to design small molecular drugs for GLP-1 receptor agonist from the world's largest traditional Chinese medicine (TCM) Database@Taiwan. According to docking results of virtual screening, we selected 2 TCM compounds, wenyujinoside and 28-deglucosylchikusetsusaponin IV, for further molecular dynamics (MD) simulation. GLP-1 was assigned as the control compound. Based on the results of root mean square deviation (RMSD), solvent accessible surface (SAS), mean square deviation (MSD), Gyrate, total energy, root mean square fluctuation (RMSF), matrices of smallest distance of residues, database of secondary structure assignment (DSSP), cluster analysis, and distance of H-bond, we concluded that all the 3 compounds could bind and activate GLP-1 receptor by computational simulation. Wenyujinoside and 28-deglucosylchikusetsusaponin IV were the TCM compounds that could be GLP-1 receptor agonists.

A new inhibitor of the β-arrestin/AP2 endocytic complex reveals interplay between GPCR internalization and signalling

NASA Astrophysics Data System (ADS)

Beautrait, Alexandre; Paradis, Justine S.; Zimmerman, Brandon; Giubilaro, Jenna; Nikolajev, Ljiljana; Armando, Sylvain; Kobayashi, Hiroyuki; Yamani, Lama; Namkung, Yoon; Heydenreich, Franziska M.; Khoury, Etienne; Audet, Martin; Roux, Philippe P.; Veprintsev, Dmitry B.; Laporte, Stéphane A.; Bouvier, Michel

2017-04-01

In addition to G protein-coupled receptor (GPCR) desensitization and endocytosis, β-arrestin recruitment to ligand-stimulated GPCRs promotes non-canonical signalling cascades. Distinguishing the respective contributions of β-arrestin recruitment to the receptor and β-arrestin-promoted endocytosis in propagating receptor signalling has been limited by the lack of selective analytical tools. Here, using a combination of virtual screening and cell-based assays, we have identified a small molecule that selectively inhibits the interaction between β-arrestin and the β2-adaptin subunit of the clathrin adaptor protein AP2 without interfering with the formation of receptor/β-arrestin complexes. This selective β-arrestin/β2-adaptin inhibitor (Barbadin) blocks agonist-promoted endocytosis of the prototypical β2-adrenergic (β2AR), V2-vasopressin (V2R) and angiotensin-II type-1 (AT1R) receptors, but does not affect β-arrestin-independent (transferrin) or AP2-independent (endothelin-A) receptor internalization. Interestingly, Barbadin fully blocks V2R-stimulated ERK1/2 activation and blunts cAMP accumulation promoted by both V2R and β2AR, supporting the concept of β-arrestin/AP2-dependent signalling for both G protein-dependent and -independent pathways.

A new inhibitor of the β-arrestin/AP2 endocytic complex reveals interplay between GPCR internalization and signalling.

PubMed

Beautrait, Alexandre; Paradis, Justine S; Zimmerman, Brandon; Giubilaro, Jenna; Nikolajev, Ljiljana; Armando, Sylvain; Kobayashi, Hiroyuki; Yamani, Lama; Namkung, Yoon; Heydenreich, Franziska M; Khoury, Etienne; Audet, Martin; Roux, Philippe P; Veprintsev, Dmitry B; Laporte, Stéphane A; Bouvier, Michel

2017-04-18

In addition to G protein-coupled receptor (GPCR) desensitization and endocytosis, β-arrestin recruitment to ligand-stimulated GPCRs promotes non-canonical signalling cascades. Distinguishing the respective contributions of β-arrestin recruitment to the receptor and β-arrestin-promoted endocytosis in propagating receptor signalling has been limited by the lack of selective analytical tools. Here, using a combination of virtual screening and cell-based assays, we have identified a small molecule that selectively inhibits the interaction between β-arrestin and the β2-adaptin subunit of the clathrin adaptor protein AP2 without interfering with the formation of receptor/β-arrestin complexes. This selective β-arrestin/β2-adaptin inhibitor (Barbadin) blocks agonist-promoted endocytosis of the prototypical β2-adrenergic (β2AR), V2-vasopressin (V2R) and angiotensin-II type-1 (AT1R) receptors, but does not affect β-arrestin-independent (transferrin) or AP2-independent (endothelin-A) receptor internalization. Interestingly, Barbadin fully blocks V2R-stimulated ERK1/2 activation and blunts cAMP accumulation promoted by both V2R and β2AR, supporting the concept of β-arrestin/AP2-dependent signalling for both G protein-dependent and -independent pathways.

A new inhibitor of the β-arrestin/AP2 endocytic complex reveals interplay between GPCR internalization and signalling

PubMed Central

Beautrait, Alexandre; Paradis, Justine S.; Zimmerman, Brandon; Giubilaro, Jenna; Nikolajev, Ljiljana; Armando, Sylvain; Kobayashi, Hiroyuki; Yamani, Lama; Namkung, Yoon; Heydenreich, Franziska M.; Khoury, Etienne; Audet, Martin; Roux, Philippe P.; Veprintsev, Dmitry B.; Laporte, Stéphane A.; Bouvier, Michel

2017-01-01

In addition to G protein-coupled receptor (GPCR) desensitization and endocytosis, β-arrestin recruitment to ligand-stimulated GPCRs promotes non-canonical signalling cascades. Distinguishing the respective contributions of β-arrestin recruitment to the receptor and β-arrestin-promoted endocytosis in propagating receptor signalling has been limited by the lack of selective analytical tools. Here, using a combination of virtual screening and cell-based assays, we have identified a small molecule that selectively inhibits the interaction between β-arrestin and the β2-adaptin subunit of the clathrin adaptor protein AP2 without interfering with the formation of receptor/β-arrestin complexes. This selective β-arrestin/β2-adaptin inhibitor (Barbadin) blocks agonist-promoted endocytosis of the prototypical β2-adrenergic (β2AR), V2-vasopressin (V2R) and angiotensin-II type-1 (AT1R) receptors, but does not affect β-arrestin-independent (transferrin) or AP2-independent (endothelin-A) receptor internalization. Interestingly, Barbadin fully blocks V2R-stimulated ERK1/2 activation and blunts cAMP accumulation promoted by both V2R and β2AR, supporting the concept of β-arrestin/AP2-dependent signalling for both G protein-dependent and -independent pathways. PMID:28416805

VirtualToxLab — A platform for estimating the toxic potential of drugs, chemicals and natural products

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vedani, Angelo, E-mail: angelo.vedani@unibas.ch; Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel; Dobler, Max

The VirtualToxLab is an in silico technology for estimating the toxic potential (endocrine and metabolic disruption, some aspects of carcinogenicity and cardiotoxicity) of drugs, chemicals and natural products. The technology is based on an automated protocol that simulates and quantifies the binding of small molecules towards a series of proteins, known or suspected to trigger adverse effects. The toxic potential, a non-linear function ranging from 0.0 (none) to 1.0 (extreme), is derived from the individual binding affinities of a compound towards currently 16 target proteins: 10 nuclear receptors (androgen, estrogen α, estrogen β, glucocorticoid, liver X, mineralocorticoid, peroxisome proliferator-activated receptormore » γ, progesterone, thyroid α, and thyroid β), four members of the cytochrome P450 enzyme family (1A2, 2C9, 2D6, and 3A4), a cytosolic transcription factor (aryl hydrocarbon receptor) and a potassium ion channel (hERG). The interface to the technology allows building and uploading molecular structures, viewing and downloading results and, most importantly, rationalizing any prediction at the atomic level by interactively analyzing the binding mode of a compound with its target protein(s) in real-time 3D. The VirtualToxLab has been used to predict the toxic potential for over 2500 compounds: the results are posted on (http://www.virtualtoxlab.org). The free platform — the OpenVirtualToxLab — is accessible (in client–server mode) over the Internet. It is free of charge for universities, governmental agencies, regulatory bodies and non-profit organizations. -- Highlights: ► In silico technology for estimating the toxic potential of drugs and chemicals. ► Simulation of binding towards 16 proteins suspected to trigger adverse effects. ► Mechanistic interpretation and real-time 3D visualization. ► Accessible over the Internet. ► Free of charge for universities, governmental agencies, regulatory bodies and NPOs.« less

Importance of the pharmacological profile of the bound ligand in enrichment on nuclear receptors: toward the use of experimentally validated decoy ligands.

PubMed

Lagarde, Nathalie; Zagury, Jean-François; Montes, Matthieu

2014-10-27

The evaluation of virtual ligand screening methods is of major importance to ensure their reliability. Taking into account the agonist/antagonist pharmacological profile should improve the quality of the benchmarking data sets since ligand binding can induce conformational changes in the nuclear receptor structure and such changes may vary according to the agonist/antagonist ligand profile. We indeed found that splitting the agonist and antagonist ligands into two separate data sets for a given nuclear receptor target significantly enhances the quality of the evaluation. The pharmacological profile of the ligand bound in the binding site of the target structure was also found to be an additional critical parameter. We also illustrate that active compound data sets for a given pharmacological activity can be used as a set of experimentally validated decoy ligands for another pharmacological activity to ensure a reliable and challenging evaluation of virtual screening methods.

Novel approaches for targeting the adenosine A2A receptor.

PubMed

Yuan, Gengyang; Gedeon, Nicholas G; Jankins, Tanner C; Jones, Graham B

2015-01-01

The adenosine A2A receptor (A2AR) represents a drug target for a wide spectrum of diseases. Approaches for targeting this membrane-bound protein have been greatly advanced by new stabilization techniques. The resulting X-ray crystal structures and subsequent analyses provide deep insight to the A2AR from both static and dynamic perspectives. Application of this, along with other biophysical methods combined with fragment-based drug design (FBDD), has become a standard approach in targeting A2AR. Complementarities of in silico screening based- and biophysical screening assisted- FBDD are likely to feature in future approaches in identifying novel ligands against this key receptor. This review describes evolution of the above approaches for targeting A2AR and highlights key modulators identified. It includes a review of: adenosine receptor structures, homology modeling, X-ray structural analysis, rational drug design, biophysical methods, FBDD and in silico screening. As a drug target, the A2AR is attractive as its function plays a role in a wide spectrum of diseases including oncologic, inflammatory, Parkinson's and cardiovascular diseases. Although traditional approaches such as high-throughput screening and homology model-based virtual screening (VS) have played a role in targeting A2AR, numerous shortcomings have generally restricted their applications to specific ligand families. Using stabilization methods for crystallization, X-ray structures of A2AR have greatly accelerated drug discovery and influenced development of biophysical-in silico hybrid screening methods. Application of these new methods to other ARs and G-protein-coupled receptors is anticipated in the future.

An Unbiased Method To Build Benchmarking Sets for Ligand-Based Virtual Screening and its Application To GPCRs

PubMed Central

2015-01-01

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. PMID:24749745

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

PubMed

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.

Prospective virtual screening for novel p53-MDM2 inhibitors using ultrafast shape recognition

NASA Astrophysics Data System (ADS)

Patil, Sachin P.; Ballester, Pedro J.; Kerezsi, Cassidy R.

2014-02-01

The p53 protein, known as the guardian of genome, is mutated or deleted in approximately 50 % of human tumors. In the rest of the cancers, p53 is expressed in its wild-type form, but its function is inhibited by direct binding with the murine double minute 2 (MDM2) protein. Therefore, inhibition of the p53-MDM2 interaction, leading to the activation of tumor suppressor p53 protein presents a fundamentally novel therapeutic strategy against several types of cancers. The present study utilized ultrafast shape recognition (USR), a virtual screening technique based on ligand-receptor 3D shape complementarity, to screen DrugBank database for novel p53-MDM2 inhibitors. Specifically, using 3D shape of one of the most potent crystal ligands of MDM2, MI-63, as the query molecule, six compounds were identified as potential p53-MDM2 inhibitors. These six USR hits were then subjected to molecular modeling investigations through flexible receptor docking followed by comparative binding energy analysis. These studies suggested a potential role of the USR-selected molecules as p53-MDM2 inhibitors. This was further supported by experimental tests showing that the treatment of human colon tumor cells with the top USR hit, telmisartan, led to a dose-dependent cell growth inhibition in a p53-dependent manner. It is noteworthy that telmisartan has a long history of safe human use as an approved anti-hypertension drug and thus may present an immediate clinical potential as a cancer therapeutic. Furthermore, it could also serve as a structurally-novel lead molecule for the development of more potent, small-molecule p53-MDM2 inhibitors against variety of cancers. Importantly, the present study demonstrates that the adopted USR-based virtual screening protocol is a useful tool for hit identification in the domain of small molecule p53-MDM2 inhibitors.

Decoupling the Functional Pleiotropy of Stem Cell Factor by Tuning c-Kit Signaling

PubMed Central

Ho, Chia Chi M.; Chhabra, Akanksha; Starkl, Philipp; Schnorr, Peter-John; Wilmes, Stephan; Moraga, Ignacio; Kwon, Hye-Sook; Gaudenzio, Nicolas; Sibilano, Riccardo; Wehrman, Tom S.; Gakovic, Milica; Sockolosky, Jonathan T.; Tiffany, Matthew R.; Ring, Aaron M.; Piehler, Jacob; Weissman, Irving L.; Galli, Stephen J.; Shizuru, Judith A.; Garcia, K. Christopher

2017-01-01

SUMMARY Most secreted growth factors and cytokines are functionally pleiotropic because their receptors are expressed on diverse cell types. While important for normal mammalian physiology, pleiotropy limits the efficacy of cytokines and growth factors as therapeutics. Stem cell factor (SCF) is a growth factor that acts through the c-Kit receptor tyrosine kinase to elicit hematopoietic progenitor expansion, but can be toxic when administered in vivo because it concurrently activates mast cells. We engineered a mechanism-based SCF partial agonist that impaired c-Kit dimerization, truncating downstream signaling amplitude. This SCF variant elicited biased activation of hematopoietic progenitors over mast cells in vitro and in vivo. Mouse models of SCF-mediated anaphylaxis, radioprotection, and hematopoietic expansion revealed that this SCF partial agonist retained therapeutic efficacy while exhibiting virtually no anaphylactic off-target effects. The approach of biasing cell activation by tuning signaling thresholds and outputs has applications to many dimeric receptor-ligand systems. PMID:28283060

DOCKTITE-a highly versatile step-by-step workflow for covalent docking and virtual screening in the molecular operating environment.

PubMed

Scholz, Christoph; Knorr, Sabine; Hamacher, Kay; Schmidt, Boris

2015-02-23

The formation of a covalent bond with the target is essential for a number of successful drugs, yet tools for covalent docking without significant restrictions regarding warhead or receptor classes are rare and limited in use. In this work we present DOCKTITE, a highly versatile workflow for covalent docking in the Molecular Operating Environment (MOE) combining automated warhead screening, nucleophilic side chain attachment, pharmacophore-based docking, and a novel consensus scoring approach. The comprehensive validation study includes pose predictions of 35 protein/ligand complexes which resulted in a mean RMSD of 1.74 Å and a prediction rate of 71.4% with an RMSD below 2 Å, a virtual screening with an area under the curve (AUC) for the receiver operating characteristics (ROC) of 0.81, and a significant correlation between predicted and experimental binding affinities (ρ = 0.806, R(2) = 0.649, p < 0.005).

Clustering Molecular Dynamics Trajectories for Optimizing Docking Experiments

PubMed Central

De Paris, Renata; Quevedo, Christian V.; Ruiz, Duncan D.; Norberto de Souza, Osmar; Barros, Rodrigo C.

2015-01-01

Molecular dynamics simulations of protein receptors have become an attractive tool for rational drug discovery. However, the high computational cost of employing molecular dynamics trajectories in virtual screening of large repositories threats the feasibility of this task. Computational intelligence techniques have been applied in this context, with the ultimate goal of reducing the overall computational cost so the task can become feasible. Particularly, clustering algorithms have been widely used as a means to reduce the dimensionality of molecular dynamics trajectories. In this paper, we develop a novel methodology for clustering entire trajectories using structural features from the substrate-binding cavity of the receptor in order to optimize docking experiments on a cloud-based environment. The resulting partition was selected based on three clustering validity criteria, and it was further validated by analyzing the interactions between 20 ligands and a fully flexible receptor (FFR) model containing a 20 ns molecular dynamics simulation trajectory. Our proposed methodology shows that taking into account features of the substrate-binding cavity as input for the k-means algorithm is a promising technique for accurately selecting ensembles of representative structures tailored to a specific ligand. PMID:25873944

Assessment and Challenges of Ligand Docking into Comparative Models of G-Protein Coupled Receptors

PubMed Central

Frimurer, Thomas M.; Meiler, Jens

2013-01-01

The rapidly increasing number of high-resolution X-ray structures of G-protein coupled receptors (GPCRs) creates a unique opportunity to employ comparative modeling and docking to provide valuable insight into the function and ligand binding determinants of novel receptors, to assist in virtual screening and to design and optimize drug candidates. However, low sequence identity between receptors, conformational flexibility, and chemical diversity of ligands present an enormous challenge to molecular modeling approaches. It is our hypothesis that rapid Monte-Carlo sampling of protein backbone and side-chain conformational space with Rosetta can be leveraged to meet this challenge. This study performs unbiased comparative modeling and docking methodologies using 14 distinct high-resolution GPCRs and proposes knowledge-based filtering methods for improvement of sampling performance and identification of correct ligand-receptor interactions. On average, top ranked receptor models built on template structures over 50% sequence identity are within 2.9 Å of the experimental structure, with an average root mean square deviation (RMSD) of 2.2 Å for the transmembrane region and 5 Å for the second extracellular loop. Furthermore, these models are consistently correlated with low Rosetta energy score. To predict their binding modes, ligand conformers of the 14 ligands co-crystalized with the GPCRs were docked against the top ranked comparative models. In contrast to the comparative models themselves, however, it remains difficult to unambiguously identify correct binding modes by score alone. On average, sampling performance was improved by 103 fold over random using knowledge-based and energy-based filters. In assessing the applicability of experimental constraints, we found that sampling performance is increased by one order of magnitude for every 10 residues known to contact the ligand. Additionally, in the case of DOR, knowledge of a single specific ligand-protein contact improved sampling efficiency 7 fold. These findings offer specific guidelines which may lead to increased success in determining receptor-ligand complexes. PMID:23844000

Chemical-Space-Based de Novo Design Method To Generate Drug-Like Molecules.

PubMed

Takeda, Shunichi; Kaneko, Hiromasa; Funatsu, Kimito

2016-10-24

To discover drug compounds in chemical space containing an enormous number of compounds, a structure generator is required to produce virtual drug-like chemical structures. The de novo design algorithm for exploring chemical space (DAECS) visualizes the activity distribution on a two-dimensional plane corresponding to chemical space and generates structures in a target area on a plane selected by the user. In this study, we modify the DAECS to enable the user to select a target area to consider properties other than activity and improve the diversity of the generated structures by visualizing the drug-likeness distribution and the activity distribution, generating structures by substructure-based structural changes, including addition, deletion, and substitution of substructures, as well as the slight structural changes used in the DAECS. Through case studies using ligand data for the human adrenergic alpha2A receptor and the human histamine H1 receptor, the modified DAECS can generate high diversity drug-like structures, and the usefulness of the modification of the DAECS is verified.

Cell-based assays in GPCR drug discovery.

PubMed

Siehler, Sandra

2008-04-01

G protein-coupled receptors (GPCRs) transmit extracellular signals into the intracellular space, and play key roles in the physiological regulation of virtually every cell and tissue. Characteristic for the GPCR superfamily of cell surface receptors are their seven transmembrane-spanning alpha-helices, an extracellular N terminus and intracellular C-terminal tail. Besides transmission of extracellular signals, their activity is modulated by cellular signals in an auto- or transregulatory fashion. The molecular complexity of GPCRs and their regulated signaling networks triggered the interest in academic research groups to explore them further, and their drugability and role in pathophysiology triggers pharmaceutical research towards small molecular weight ligands and therapeutic antibodies. About 30% of marketed drugs target GPCRs, which underlines the importance of this target class. This review describes current and emerging cellular assays for the ligand discovery of GPCRs.

Adoptive therapy with CAR redirected T cells: the challenges in targeting solid tumors.

PubMed

Abken, Hinrich

2015-01-01

Recent spectacular success in the adoptive cell therapy of leukemia and lymphoma with chimeric antigen receptor (CAR)-modified T cells raised the expectations that this therapy may be efficacious in a wide range of cancer entities. The expectations are based on the predefined specificity of CAR T cells by an antibody-derived binding domain that acts independently of the natural T-cell receptor, recognizes targets independently of presentation by the major histocompatibility complex and allows targeting toward virtually any cell surface antigen. We here discuss that targeting CAR T cells toward solid tumors faces certain circumstances critical for the therapeutic success. Targeting tumor stroma and taking advantage of TRUCK cells, in other words, CAR T cells with inducible release of a transgenic payload, are some strategies envisaged to overcome current limitations in the near future.

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

NASA Astrophysics Data System (ADS)

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.

The bitter pill: clinical drugs that activate the human bitter taste receptor TAS2R14.

PubMed

Levit, Anat; Nowak, Stefanie; Peters, Maximilian; Wiener, Ayana; Meyerhof, Wolfgang; Behrens, Maik; Niv, Masha Y

2014-03-01

Bitter taste receptors (TAS2Rs) mediate aversive response to toxic food, which is often bitter. These G-protein-coupled receptors are also expressed in extraoral tissues, and emerge as novel targets for therapeutic indications such as asthma and infection. Our goal was to identify ligands of the broadly tuned TAS2R14 among clinical drugs. Molecular properties of known human bitter taste receptor TAS2R14 agonists were incorporated into pharmacophore- and shape-based models and used to computationally predict additional ligands. Predictions were tested by calcium imaging of TAS2R14-transfected HEK293 cells. In vitro testing of the virtual screening predictions resulted in 30-80% success rates, and 15 clinical drugs were found to activate the TAS2R14. hERG potassium channel, which is predominantly expressed in the heart, emerged as a common off-target of bitter drugs. Despite immense chemical diversity of known TAS2R14 ligands, novel ligands and previously unknown polypharmacology of drugs were unraveled by in vitro screening of computational predictions. This enables rational repurposing of traditional and standard drugs for bitter taste signaling modulation for therapeutic indications.

Discovery of a Small-Molecule Inhibitor of Interleukin 15: Pharmacophore-Based Virtual Screening and Hit Optimization.

PubMed

Quéméner, Agnès; Maillasson, Mike; Arzel, Laurence; Sicard, Benoit; Vomiandry, Romy; Mortier, Erwan; Dubreuil, Didier; Jacques, Yannick; Lebreton, Jacques; Mathé-Allainmat, Monique

2017-07-27

Interleukin (IL)-15 is a pleiotropic cytokine, which is structurally close to IL-2 and shares with it the IL-2 β and γ receptor (R) subunits. By promoting the activation and proliferation of NK, NK-T, and CD8+ T cells, IL-15 plays important roles in innate and adaptative immunity. Moreover, the association of high levels of IL-15 expression with inflammatory and autoimmune diseases has led to the development of various antagonistic approaches targeting IL-15. This study is an original approach aimed at discovering small-molecule inhibitors impeding IL-15/IL-15R interaction. A pharmacophore and docking-based virtual screening of compound libraries led to the selection of 240 high-scoring compounds, 36 of which were found to bind IL-15, to inhibit the binding of IL-15 to the IL-2Rβ chain or the proliferation of IL-15-dependent cells or both. One of them was selected as a hit and optimized by a structure-activity relationship approach, leading to the first small-molecule IL-15 inhibitor with sub-micromolar activity.

Consensus Induced Fit Docking (cIFD): methodology, validation, and application to the discovery of novel Crm1 inhibitors

NASA Astrophysics Data System (ADS)

Kalid, Ori; Toledo Warshaviak, Dora; Shechter, Sharon; Sherman, Woody; Shacham, Sharon

2012-11-01

We present the Consensus Induced Fit Docking (cIFD) approach for adapting a protein binding site to accommodate multiple diverse ligands for virtual screening. This novel approach results in a single binding site structure that can bind diverse chemotypes and is thus highly useful for efficient structure-based virtual screening. We first describe the cIFD method and its validation on three targets that were previously shown to be challenging for docking programs (COX-2, estrogen receptor, and HIV reverse transcriptase). We then demonstrate the application of cIFD to the challenging discovery of irreversible Crm1 inhibitors. We report the identification of 33 novel Crm1 inhibitors, which resulted from the testing of 402 purchased compounds selected from a screening set containing 261,680 compounds. This corresponds to a hit rate of 8.2 %. The novel Crm1 inhibitors reveal diverse chemical structures, validating the utility of the cIFD method in a real-world drug discovery project. This approach offers a pragmatic way to implicitly account for protein flexibility without the additional computational costs of ensemble docking or including full protein flexibility during virtual screening.

Structural and Molecular Modeling Features of P2X Receptors

PubMed Central

Alves, Luiz Anastacio; da Silva, João Herminio Martins; Ferreira, Dinarte Neto Moreira; Fidalgo-Neto, Antonio Augusto; Teixeira, Pedro Celso Nogueira; de Souza, Cristina Alves Magalhães; Caffarena, Ernesto Raúl; de Freitas, Mônica Santos

2014-01-01

Currently, adenosine 5′-triphosphate (ATP) is recognized as the extracellular messenger that acts through P2 receptors. P2 receptors are divided into two subtypes: P2Y metabotropic receptors and P2X ionotropic receptors, both of which are found in virtually all mammalian cell types studied. Due to the difficulty in studying membrane protein structures by X-ray crystallography or NMR techniques, there is little information about these structures available in the literature. Two structures of the P2X4 receptor in truncated form have been solved by crystallography. Molecular modeling has proven to be an excellent tool for studying ionotropic receptors. Recently, modeling studies carried out on P2X receptors have advanced our knowledge of the P2X receptor structure-function relationships. This review presents a brief history of ion channel structural studies and shows how modeling approaches can be used to address relevant questions about P2X receptors. PMID:24637936

Reverse Induced Fit-Driven MAS-Downstream Transduction: Looking for Metabotropic Agonists.

PubMed

Pernomian, Larissa; Gomes, Mayara S; de Paula da Silva, Carlos H Tomich; Rosa, Joaquin M C

2017-01-01

Protective effects of MAS activation have spurred clinical interests in developing MAS agonists. However, current bases that drive this process preclude that physiological concentrations of peptide MAS agonists induce an atypical signaling that does not reach the metabotropic efficacy of constitutive activation. Canonical activation of MAS-coupled G proteins is only achieved by supraphysiological concentrations of peptide MAS agonists or physiological concentrations of chemically modified analogues. These pleiotropic differences are because of two overlapped binding domains: one non-metabotropic site that recognizes peptide agonists and one metabotropic domain that recognizes modified analogues. It is feasible that supraphysiological concentrations of peptide MAS agonists undergo to chemical modifications required for binding to metabotropic domain. Receptor oligomerization enhances pharmacological parameters coupled to metabotropic signaling. The formation of receptor-signalosome complex makes the transduction of agonists more adaptive. Considering the recent identification of MAS-signalosome, we aimed to postulate the reverse induced fit hypothesis in which MAS-signalosome would trigger chemical modifications required for agonists bind to MAS metabotropic domain. Here we cover rational perspectives for developing novel metabotropic MAS agonists in the view of the reverse induced-fit hypothesis. Predicting a 3D model of MAS metabotropic domain may guide the screening of chemical modifications required for metabotropic efficacy. Pharmacophore-based virtual screening would select potential metabotropic MAS agonists from virtual libraries from human proteome. Rational perspectives that consider reverse induced fit hypothesis during MAS activation for developing metabotropic MAS agonists represents the best approach in providing MAS ligands with constitutive efficacy at physiological concentrations. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Improving virtual screening of G protein-coupled receptors via ligand-directed modeling

PubMed Central

Simms, John; Christopoulos, Arthur; Wootten, Denise

2017-01-01

G protein-coupled receptors (GPCRs) play crucial roles in cell physiology and pathophysiology. There is increasing interest in using structural information for virtual screening (VS) of libraries and for structure-based drug design to identify novel agonist or antagonist leads. However, the sparse availability of experimentally determined GPCR/ligand complex structures with diverse ligands impedes the application of structure-based drug design (SBDD) programs directed to identifying new molecules with a select pharmacology. In this study, we apply ligand-directed modeling (LDM) to available GPCR X-ray structures to improve VS performance and selectivity towards molecules of specific pharmacological profile. The described method refines a GPCR binding pocket conformation using a single known ligand for that GPCR. The LDM method is a computationally efficient, iterative workflow consisting of protein sampling and ligand docking. We developed an extensive benchmark comparing LDM-refined binding pockets to GPCR X-ray crystal structures across seven different GPCRs bound to a range of ligands of different chemotypes and pharmacological profiles. LDM-refined models showed improvement in VS performance over origin X-ray crystal structures in 21 out of 24 cases. In all cases, the LDM-refined models had superior performance in enriching for the chemotype of the refinement ligand. This likely contributes to the LDM success in all cases of inhibitor-bound to agonist-bound binding pocket refinement, a key task for GPCR SBDD programs. Indeed, agonist ligands are required for a plethora of GPCRs for therapeutic intervention, however GPCR X-ray structures are mostly restricted to their inactive inhibitor-bound state. PMID:29131821

Identification of the Beer Component Hordenine as Food-Derived Dopamine D2 Receptor Agonist by Virtual Screening a 3D Compound Database

NASA Astrophysics Data System (ADS)

Sommer, Thomas; Hübner, Harald; El Kerdawy, Ahmed; Gmeiner, Peter; Pischetsrieder, Monika; Clark, Timothy

2017-03-01

The dopamine D2 receptor (D2R) is involved in food reward and compulsive food intake. The present study developed a virtual screening (VS) method to identify food components, which may modulate D2R signalling. In contrast to their common applications in drug discovery, VS methods are rarely applied for the discovery of bioactive food compounds. Here, databases were created that exclusively contain substances occurring in food and natural sources (about 13,000 different compounds in total) as the basis for combined pharmacophore searching, hit-list clustering and molecular docking into D2R homology models. From 17 compounds finally tested in radioligand assays to determine their binding affinities, seven were classified as hits (hit rate = 41%). Functional properties of the five most active compounds were further examined in β-arrestin recruitment and cAMP inhibition experiments. D2R-promoted G-protein activation was observed for hordenine, a constituent of barley and beer, with approximately identical ligand efficacy as dopamine (76%) and a Ki value of 13 μM. Moreover, hordenine antagonised D2-mediated β-arrestin recruitment indicating functional selectivity. Application of our databases provides new perspectives for the discovery of bioactive food constituents using VS methods. Based on its presence in beer, we suggest that hordenine significantly contributes to mood-elevating effects of beer.

Discovery and study of novel protein tyrosine phosphatase 1B inhibitors

NASA Astrophysics Data System (ADS)

Zhang, Qian; Chen, Xi; Feng, Changgen

2017-10-01

Protein tyrosine phosphatase 1B (PTP1B) is considered to be a target for therapy of type II diabetes and obesity. So it is of great significance to take advantage of a computer aided drug design protocol involving the structured-based virtual screening with docking simulations for fast searching small molecule PTP1B inhibitors. Based on optimized complex structure of PTP1B bound with specific inhibitor of IX1, structured-based virtual screening against a library of natural products containing 35308 molecules, which was constructed based on Traditional Chinese Medicine database@ Taiwan (TCM database@ Taiwan), was conducted to determine the occurrence of PTP1B inhibitors using the Lubbock module and CDOCKER module from Discovery Studio 3.1 software package. The results were further filtered by predictive ADME simulation and predictive toxic simulation. As a result, 2 good drug-like molecules, namely para-benzoquinone compound 1 and Clavepictine analogue 2 were identified ultimately with the dock score of original inhibitor (IX1) and the receptor as a threshold. Binding model analyses revealed that these two candidate compounds have good interactions with PTP1B. The PTP1B inhibitory activity of compound 2 hasn't been reported before. The optimized compound 2 has higher scores and deserves further study.

Maximal Unbiased Benchmarking Data Sets for Human Chemokine Receptors and Comparative Analysis.

PubMed

Xia, Jie; Reid, Terry-Elinor; Wu, Song; Zhang, Liangren; Wang, Xiang Simon

2018-05-29

Chemokine receptors (CRs) have long been druggable targets for the treatment of inflammatory diseases and HIV-1 infection. As a powerful technique, virtual screening (VS) has been widely applied to identifying small molecule leads for modern drug targets including CRs. For rational selection of a wide variety of VS approaches, ligand enrichment assessment based on a benchmarking data set has become an indispensable practice. However, the lack of versatile benchmarking sets for the whole CRs family that are able to unbiasedly evaluate every single approach including both structure- and ligand-based VS somewhat hinders modern drug discovery efforts. To address this issue, we constructed Maximal Unbiased Benchmarking Data sets for human Chemokine Receptors (MUBD-hCRs) using our recently developed tools of MUBD-DecoyMaker. The MUBD-hCRs encompasses 13 subtypes out of 20 chemokine receptors, composed of 404 ligands and 15756 decoys so far and is readily expandable in the future. It had been thoroughly validated that MUBD-hCRs ligands are chemically diverse while its decoys are maximal unbiased in terms of "artificial enrichment", "analogue bias". In addition, we studied the performance of MUBD-hCRs, in particular CXCR4 and CCR5 data sets, in ligand enrichment assessments of both structure- and ligand-based VS approaches in comparison with other benchmarking data sets available in the public domain and demonstrated that MUBD-hCRs is very capable of designating the optimal VS approach. MUBD-hCRs is a unique and maximal unbiased benchmarking set that covers major CRs subtypes so far.

Structural insights into ligand recognition and selectivity for class A, B, and C GPCRs

PubMed Central

Lee, Sang-Min; Booe, Jason M.; Pioszak, Augen A.

2015-01-01

The G protein-coupled receptor (GPCR) superfamily constitutes the largest collection of cell surface signaling proteins with approximately 800 members in the human genome. GPCRs regulate virtually all aspects of physiology and they are an important class of drug targets with ~30% of drugs on the market targeting a GPCR. Breakthroughs in GPCR structural biology in recent years have significantly expanded our understanding of GPCR structure and function and ushered in a new era of structure-based drug design for GPCRs. Crystal structures for nearly thirty distinct GPCRs are now available including receptors from each of the major classes, A, B, C, and F. These structures provide a foundation for understanding the molecular basis of GPCR pharmacology. Here, we review structural mechanisms of ligand recognition and selectivity of GPCRs with a focus on selected examples from classes A, B, and C, and we highlight major unresolved questions for future structural studies. PMID:25981303

Physics-based scoring of protein-ligand interactions: explicit polarizability, quantum mechanics and free energies.

PubMed

Bryce, Richard A

2011-04-01

The ability to accurately predict the interaction of a ligand with its receptor is a key limitation in computer-aided drug design approaches such as virtual screening and de novo design. In this article, we examine current strategies for a physics-based approach to scoring of protein-ligand affinity, as well as outlining recent developments in force fields and quantum chemical techniques. We also consider advances in the development and application of simulation-based free energy methods to study protein-ligand interactions. Fuelled by recent advances in computational algorithms and hardware, there is the opportunity for increased integration of physics-based scoring approaches at earlier stages in computationally guided drug discovery. Specifically, we envisage increased use of implicit solvent models and simulation-based scoring methods as tools for computing the affinities of large virtual ligand libraries. Approaches based on end point simulations and reference potentials allow the application of more advanced potential energy functions to prediction of protein-ligand binding affinities. Comprehensive evaluation of polarizable force fields and quantum mechanical (QM)/molecular mechanical and QM methods in scoring of protein-ligand interactions is required, particularly in their ability to address challenging targets such as metalloproteins and other proteins that make highly polar interactions. Finally, we anticipate increasingly quantitative free energy perturbation and thermodynamic integration methods that are practical for optimization of hits obtained from screened ligand libraries.

Sensitivity-based virtual fields for the non-linear virtual fields method

NASA Astrophysics Data System (ADS)

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.

A Pipeline To Enhance Ligand Virtual Screening: Integrating Molecular Dynamics and Fingerprints for Ligand and Proteins.

PubMed

Spyrakis, Francesca; Benedetti, Paolo; Decherchi, Sergio; Rocchia, Walter; Cavalli, Andrea; Alcaro, Stefano; Ortuso, Francesco; Baroni, Massimo; Cruciani, Gabriele

2015-10-26

The importance of taking into account protein flexibility in drug design and virtual ligand screening (VS) has been widely debated in the literature, and molecular dynamics (MD) has been recognized as one of the most powerful tools for investigating intrinsic protein dynamics. Nevertheless, deciphering the amount of information hidden in MD simulations and recognizing a significant minimal set of states to be used in virtual screening experiments can be quite complicated. Here we present an integrated MD-FLAP (molecular dynamics-fingerprints for ligand and proteins) approach, comprising a pipeline of molecular dynamics, clustering and linear discriminant analysis, for enhancing accuracy and efficacy in VS campaigns. We first extracted a limited number of representative structures from tens of nanoseconds of MD trajectories by means of the k-medoids clustering algorithm as implemented in the BiKi Life Science Suite ( http://www.bikitech.com [accessed July 21, 2015]). Then, instead of applying arbitrary selection criteria, that is, RMSD, pharmacophore properties, or enrichment performances, we allowed the linear discriminant analysis algorithm implemented in FLAP ( http://www.moldiscovery.com [accessed July 21, 2015]) to automatically choose the best performing conformational states among medoids and X-ray structures. Retrospective virtual screenings confirmed that ensemble receptor protocols outperform single rigid receptor approaches, proved that computationally generated conformations comprise the same quantity/quality of information included in X-ray structures, and pointed to the MD-FLAP approach as a valuable tool for improving VS performances.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Liying; Sedykh, Alexander; Tripathi, Ashutosh

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 bindingmore » 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. • The results have potential applications to green chemistry. • Models are publicly available for virtual screening via a web portal.« less

Virtual screening studies to design potent CDK2-cyclin A inhibitors.

PubMed

Vadivelan, S; Sinha, Barij Nayan; Irudayam, Sheeba Jem; Jagarlapudi, Sarma A R P

2007-01-01

The cell division cycle is controlled by cyclin-dependent kinases (CDK), which consist of a catalytic subunit (CDK1-CDK8) and a regulatory subunit (cyclin A-H). Pharmacophore analysis indicates that the best inhibitor model consists of (1) two hydrogen bond acceptors, (2) one hydrogen bond donor, and (3) one hydrophobic feature. The HypoRefine pharmacophore model gave an enrichment factor of 1.31 and goodness of fit score of 0.76. Docking studies were carried out to explore the structural requirements for the CDK2-cyclin A inhibitors and to construct highly predictive models for the design of new inhibitors. Docking studies demonstrate the important role of hydrogen bond and hydrophobic interactions in determining the inhibitor-receptor binding affinity. The validated pharmacophore model is further used for retrieving the most active hits/lead from a virtual library of molecules. Subsequently, docking studies were performed on the hits, and novel series of potent leads were suggested based on the interaction energy between CDK2-cyclin A and the putative inhibitors.

Docking based virtual screening and molecular dynamics study to identify potential monoacylglycerol lipase inhibitors.

PubMed

Afzal, Obaid; Kumar, Suresh; Kumar, Rajiv; Firoz, Ahmad; Jaggi, Manu; Bawa, Sandhya

2014-08-15

Monoacylglycerol lipase (MAGL) is one of the key enzymes of the endocannabinoid system (ECS). It hydrolyzes one of the major endocannabinoid, 2-arachidonoylglycerol (2-AG), an endogenous full agonist at G protein coupled cannabinoid receptors CB1 and CB2. Numerous studies showed that MGL inhibitors are potentially useful for the treatment of pain, inflammation, cancer and CNS disorders. These provocative findings suggested that pharmacological inhibition of MAGL function may confer significant therapeutic benefits. In this study, we presented hybrid ligand and structure-based approaches to obtain a novel set of virtual leads as MAGL inhibitors. The constraints used in this study, were Glide score, binding free energy estimates and ADME properties to screen the ZINC database, containing approximately 21 million compounds. A total of seven virtual hits were obtained, which showed significant binding affinity towards MAGL protein. Ligand, ZINC24092691 was employed in complex form with the protein MAGL, for molecular dynamics simulation study, because of its excellent glide score, binding free energy and ADME properties. The RMSD of ZINC24092691 was observed to stay at 0.1 nm (1 Å) in most of the trajectories, which further confirmed its ability to inhibit the protein MAGL. The hits were then evaluated for their ability to inhibit human MAGL. The compound ZINC24092691 displayed the noteworthy inhibitory activity reducing MAGL activity to 21.15% at 100 nM concentration, with an IC50 value of 10 nM. Copyright © 2014 Elsevier Ltd. All rights reserved.

Characterization and validation of fluorescent receptor ligands: a case study of the ionotropic serotonin receptor.

PubMed

Hovius, Ruud

2013-01-01

The application of fluorescent receptor ligands has become widespread, incited by two important reasons. "Seeing is believing"-it is possible to visualize in real time in live cells ligand-receptor interactions, and to locate the receptors with subcellular precision allowing one to follow, e.g., internalization of the ligand-receptor complex. The high sensitivity of photon detection permits observation of on the one hand receptor-ligand interactions on cells with low, native receptor abundance, and on the other of individual fluorophores unveiling the stochastic properties of single ligand-receptor complexes.The major bottlenecks that impede extensive use of fluorescent ligands are due to possible dramatic changes of the pharmacological properties of a ligand upon chemical modification and fluorophore conjugation, aggravated by the observation that different fluorophores can provoke very dissimilar effects. This makes it virtually impossible to predict beforehand which labelling strategy to use to produce a fluorescent ligand with the desired qualities.Here, we focus on the design, synthesis, and evaluation of a high-affinity fluorescent antagonist for the ionotropic serotonin type-3 receptor.

Strong homeostatic TCR signals induce formation of self-tolerant virtual memory CD8 T cells.

PubMed

Drobek, Ales; Moudra, Alena; Mueller, Daniel; Huranova, Martina; Horkova, Veronika; Pribikova, Michaela; Ivanek, Robert; Oberle, Susanne; Zehn, Dietmar; McCoy, Kathy D; Draber, Peter; Stepanek, Ondrej

2018-05-11

Virtual memory T cells are foreign antigen-inexperienced T cells that have acquired memory-like phenotype and constitute 10-20% of all peripheral CD8 + T cells in mice. Their origin, biological roles, and relationship to naïve and foreign antigen-experienced memory T cells are incompletely understood. By analyzing T-cell receptor repertoires and using retrogenic monoclonal T-cell populations, we demonstrate that the virtual memory T-cell formation is a so far unappreciated cell fate decision checkpoint. We describe two molecular mechanisms driving the formation of virtual memory T cells. First, virtual memory T cells originate exclusively from strongly self-reactive T cells. Second, the stoichiometry of the CD8 interaction with Lck regulates the size of the virtual memory T-cell compartment via modulating the self-reactivity of individual T cells. Although virtual memory T cells descend from the highly self-reactive clones and acquire a partial memory program, they are not more potent in inducing experimental autoimmune diabetes than naïve T cells. These data underline the importance of the variable level of self-reactivity in polyclonal T cells for the generation of functional T-cell diversity. © 2018 The Authors. Published under the terms of the CC BY 4.0 license.

PoLi: A Virtual Screening Pipeline Based On Template Pocket And Ligand Similarity

PubMed Central

Roy, Ambrish; Srinivasan, Bharath; Skolnick, Jeffrey

2015-01-01

Often in pharmaceutical research, the goal is to identify small molecules that can interact with and appropriately modify the biological behavior of a new protein target. Unfortunately, most proteins lack both known structures and small molecule binders, prerequisites of many virtual screening, VS, approaches. For such proteins, ligand homology modeling, LHM, that copies ligands from homologous and perhaps evolutionarily distant template proteins, has been shown to be a powerful VS approach to identify possible binding ligands. However, if we want to target a specific pocket for which there is no homologous holo template protein structure, then LHM will not work. To address this issue, in a new pocket based approach, PoLi, we generalize LHM by exploiting the fact that the number of distinct small molecule ligand binding pockets in proteins is small. PoLi identifies similar ligand binding pockets in a holo-template protein library, selectively copies relevant parts of template ligands and uses them for VS. In practice, PoLi is a hybrid structure and ligand based VS algorithm that integrates 2D fingerprint-based and 3D shape-based similarity metrics for improved virtual screening performance. On standard DUD and DUD-E benchmark databases, using modeled receptor structures, PoLi achieves an average enrichment factor of 13.4 and 9.6 respectively, in the top 1% of the screened library. In contrast, traditional docking based VS using AutoDock Vina and homology-based VS using FINDSITEfilt have an average enrichment of 1.6 (3.0) and 9.0 (7.9) on the DUD (DUD-E) sets respectively. Experimental validation of PoLi predictions on dihydrofolate reductase, DHFR, using differential scanning fluorimetry, DSF, identifies multiple ligands with diverse molecular scaffolds, thus demonstrating the advantage of PoLi over current state-of-the-art VS methods. PMID:26225536

DOVIS: an implementation for high-throughput virtual screening using AutoDock.

PubMed

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

2008-02-27

Molecular-docking-based virtual screening is an important tool in drug discovery that is used to significantly reduce the number of possible chemical compounds to be investigated. In addition to the selection of a sound docking strategy with appropriate scoring functions, another technical challenge is to in silico screen millions of compounds in a reasonable time. To meet this challenge, it is necessary to use high performance computing (HPC) platforms and techniques. However, the development of an integrated HPC system that makes efficient use of its elements is not trivial. We have developed an application termed DOVIS that uses AutoDock (version 3) as the docking engine and runs in parallel on a Linux cluster. DOVIS can efficiently dock large numbers (millions) of small molecules (ligands) to a receptor, screening 500 to 1,000 compounds per processor per day. Furthermore, in DOVIS, the docking session is fully integrated and automated in that the inputs are specified via a graphical user interface, the calculations are fully integrated with a Linux cluster queuing system for parallel processing, and the results can be visualized and queried. DOVIS removes most of the complexities and organizational problems associated with large-scale high-throughput virtual screening, and provides a convenient and efficient solution for AutoDock users to use this software in a Linux cluster platform.

Structure-based pharmacophore design and virtual screening for novel potential inhibitors of epidermal growth factor receptor as an approach to breast cancer chemotherapy.

PubMed

Mahernia, Shabnam; Hassanzadeh, Malihe; Sharifi, Niusha; Mehravi, Bita; Paytam, Fariba; Adib, Mehdi; Amanlou, Massoud

2018-02-01

Cancer cells are described with features of uncontrolled growth, invasion and metastasis. The epidermal growth factor receptor subfamily of tyrosine kinases (EGFR-TK) plays a crucial regulatory role in the control of cellular proliferation and progression of various cancers. Therefore, its inhibition might lead to the discovery of a new generation of anticancer drugs. In the present study, structure-based pharmacophore modeling, molecular docking and molecular dynamics simulations were applied to identify potential hits, which exhibited good inhibition on the proliferation of MCF-7 breast cancer cell line and favorable binding interactions on EGFR-TK. Selected compounds were examined for their anticancer activity against the Michigan Cancer Foundation-7 (MCF-7) breast cancer cell line which overexpresses EGFR using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) tetrazolium reduction assay. Compounds 1 and 2, with an isoindoline-1-one core, induced significant inhibition of breast cancer cells proliferation with IC[Formula: see text] values 327 and 370 nM, respectively.

Somatostatin receptor immunohistochemistry in neuroendocrine tumors: comparison between manual and automated evaluation

PubMed Central

Daniel, Kaemmerer; Maria, Athelogou; Amelie, Lupp; Isabell, Lenhardt; Stefan, Schulz; Luisa, Peter; Merten, Hommann; Vikas, Prasad; Gerd, Binnig; Paul, Baum Richard

2014-01-01

Background: Manual evaluation of somatostatin receptor (SSTR) immunohistochemistry (IHC) is a time-consuming and cost-intensive procedure. Aim of the study was to compare manual evaluation of SSTR subtype IHC to an automated software-based analysis, and to in-vivo imaging by SSTR-based PET/CT. Methods: We examined 25 gastroenteropancreatic neuroendocrine tumor (GEP-NET) patients and correlated their in-vivo SSTR-PET/CT data (determined by the standardized uptake values SUVmax,-mean) with the corresponding ex-vivo IHC data of SSTR subtype (1, 2A, 4, 5) expression. Exactly the same lesions were imaged by PET/CT, resected and analyzed by IHC in each patient. After manual evaluation, the IHC slides were digitized and automatically evaluated for SSTR expression by Definiens XD software. A virtual IHC score “BB1” was created for comparing the manual and automated analysis of SSTR expression. Results: BB1 showed a significant correlation with the corresponding conventionally determined Her2/neu score of the SSTR-subtypes 2A (rs: 0.57), 4 (rs: 0.44) and 5 (rs: 0.43). BB1 of SSTR2A also significantly correlated with the SUVmax (rs: 0.41) and the SUVmean (rs: 0.50). Likewise, a significant correlation was seen between the conventionally evaluated SSTR2A status and the SUVmax (rs: 0.42) and SUVmean (rs: 0.62).Conclusion: Our data demonstrate that the evaluation of the SSTR status by automated analysis (BB1 score), using digitized histopathology slides (“virtual microscopy”), corresponds well with the SSTR2A, 4 and 5 expression as determined by conventional manual histopathology. The BB1 score also exhibited a significant association to the SSTR-PET/CT data in accordance with the high affinity profile of the SSTR analogues used for imaging. PMID:25197368

Identification of a Novel Class of BRD4 Inhibitors by Computational Screening and Binding Simulations

PubMed Central

2017-01-01

Computational screening is a method to prioritize small-molecule compounds based on the structural and biochemical attributes built from ligand and target information. Previously, we have developed a scalable virtual screening workflow to identify novel multitarget kinase/bromodomain inhibitors. In the current study, we identified several novel N-[3-(2-oxo-pyrrolidinyl)phenyl]-benzenesulfonamide derivatives that scored highly in our ensemble docking protocol. We quantified the binding affinity of these compounds for BRD4(BD1) biochemically and generated cocrystal structures, which were deposited in the Protein Data Bank. As the docking poses obtained in the virtual screening pipeline did not align with the experimental cocrystal structures, we evaluated the predictions of their precise binding modes by performing molecular dynamics (MD) simulations. The MD simulations closely reproduced the experimentally observed protein–ligand cocrystal binding conformations and interactions for all compounds. These results suggest a computational workflow to generate experimental-quality protein–ligand binding models, overcoming limitations of docking results due to receptor flexibility and incomplete sampling, as a useful starting point for the structure-based lead optimization of novel BRD4(BD1) inhibitors. PMID:28884163

Predicting Bone Metastatic Potential of Prostate Cancer via Computational Modeling of TGF-Beta Signaling

DTIC Science & Technology

2008-05-01

receptor trafficking. Smad phosphorylation Although the receptors for TGF-β signal through both Smad2 and Smad3 proteins in epithelial cells, we...select Smad2 to represent the R-Smads, because the two are virtually identical kinetically; furthermore, Smad2 is ~12-fold more abundant than Smad3 (11...the type of R-Smads. For example, regarding nuclear import, it has been proposed that Smad2, Smad3 , and Smad4 enter the nucleus by direct

Sequential Application of Ligand and Structure Based Modeling Approaches to Index Chemicals for Their hH4R Antagonism

PubMed Central

Basile, Livia; Milardi, Danilo; Zeidan, Mouhammed; Raiyn, Jamal; Guccione, Salvatore; Rayan, Anwar

2014-01-01

The human histamine H4 receptor (hH4R), a member of the G-protein coupled receptors (GPCR) family, is an increasingly attractive drug target. It plays a key role in many cell pathways and many hH4R ligands are studied for the treatment of several inflammatory, allergic and autoimmune disorders, as well as for analgesic activity. Due to the challenging difficulties in the experimental elucidation of hH4R structure, virtual screening campaigns are normally run on homology based models. However, a wealth of information about the chemical properties of GPCR ligands has also accumulated over the last few years and an appropriate combination of these ligand-based knowledge with structure-based molecular modeling studies emerges as a promising strategy for computer-assisted drug design. Here, two chemoinformatics techniques, the Intelligent Learning Engine (ILE) and Iterative Stochastic Elimination (ISE) approach, were used to index chemicals for their hH4R bioactivity. An application of the prediction model on external test set composed of more than 160 hH4R antagonists picked from the chEMBL database gave enrichment factor of 16.4. A virtual high throughput screening on ZINC database was carried out, picking ∼4000 chemicals highly indexed as H4R antagonists' candidates. Next, a series of 3D models of hH4R were generated by molecular modeling and molecular dynamics simulations performed in fully atomistic lipid membranes. The efficacy of the hH4R 3D models in discrimination between actives and non-actives were checked and the 3D model with the best performance was chosen for further docking studies performed on the focused library. The output of these docking studies was a consensus library of 11 highly active scored drug candidates. Our findings suggest that a sequential combination of ligand-based chemoinformatics approaches with structure-based ones has the potential to improve the success rate in discovering new biologically active GPCR drugs and increase the enrichment factors in a synergistic manner. PMID:25330207

Sequential application of ligand and structure based modeling approaches to index chemicals for their hH4R antagonism.

PubMed

Pappalardo, Matteo; Shachaf, Nir; Basile, Livia; Milardi, Danilo; Zeidan, Mouhammed; Raiyn, Jamal; Guccione, Salvatore; Rayan, Anwar

2014-01-01

The human histamine H4 receptor (hH4R), a member of the G-protein coupled receptors (GPCR) family, is an increasingly attractive drug target. It plays a key role in many cell pathways and many hH4R ligands are studied for the treatment of several inflammatory, allergic and autoimmune disorders, as well as for analgesic activity. Due to the challenging difficulties in the experimental elucidation of hH4R structure, virtual screening campaigns are normally run on homology based models. However, a wealth of information about the chemical properties of GPCR ligands has also accumulated over the last few years and an appropriate combination of these ligand-based knowledge with structure-based molecular modeling studies emerges as a promising strategy for computer-assisted drug design. Here, two chemoinformatics techniques, the Intelligent Learning Engine (ILE) and Iterative Stochastic Elimination (ISE) approach, were used to index chemicals for their hH4R bioactivity. An application of the prediction model on external test set composed of more than 160 hH4R antagonists picked from the chEMBL database gave enrichment factor of 16.4. A virtual high throughput screening on ZINC database was carried out, picking ∼ 4000 chemicals highly indexed as H4R antagonists' candidates. Next, a series of 3D models of hH4R were generated by molecular modeling and molecular dynamics simulations performed in fully atomistic lipid membranes. The efficacy of the hH4R 3D models in discrimination between actives and non-actives were checked and the 3D model with the best performance was chosen for further docking studies performed on the focused library. The output of these docking studies was a consensus library of 11 highly active scored drug candidates. Our findings suggest that a sequential combination of ligand-based chemoinformatics approaches with structure-based ones has the potential to improve the success rate in discovering new biologically active GPCR drugs and increase the enrichment factors in a synergistic manner.

Hierarchical virtual screening of the dual MMP-2/HDAC-6 inhibitors from natural products based on pharmacophore models and molecular docking.

PubMed

Wang, Yijun; Yang, Limei; Hou, Jiaying; Zou, Qing; Gao, Qi; Yao, Wenhui; Yao, Qizheng; Zhang, Ji

2018-02-12

The dual-target inhibitors tend to improve the response rate in treating tumors, comparing with the single-target inhibitors. Matrix metalloproteinase-2 (MMP-2) and histone deacetylase-6 (HDAC-6) are attractive targets for cancer therapy. In this study, the hierarchical virtual screening of dual MMP-2/HDAC-6 inhibitors from natural products is investigated. The pharmacophore model of MMP-2 inhibitors is built based on ligands, but the pharmacophore model of HDAC-6 inhibitors is built based on the experimental crystal structures of multiple receptor-ligand complexes. The reliability of these two pharmacophore models is validated subsequently. The hierarchical virtual screening, combining these two different pharmacophore models of MMP-2 and HDAC-6 inhibitors with molecular docking, is carried out to identify the dual MMP-2/HDAC-6 inhibitors from a database of natural products. The four potential dual MMP-2/HDAC-6 inhibitors of natural products, STOCK1 N-46177, STOCK1 N-52245, STOCK1 N-55477, and STOCK1 N-69706, are found. The studies of binding modes show that the screened four natural products can simultaneously well bind with the MMP-2 and HDAC-6 active sites by different kinds of interactions, to inhibit the MMP-2 and HDAC-6 activities. In addition, the ADMET properties of screened four natural products are assessed. These found dual MMP-2/HDAC-6 inhibitors of natural products could serve as the lead compounds for designing the new dual MMP-2/HDAC-6 inhibitors having higher biological activities by carrying out structural modifications and optimizations in the future studies.

Current progress in Structure-Based Rational Drug Design marks a new mindset in drug discovery

PubMed Central

Lounnas, Valère; Ritschel, Tina; Kelder, Jan; McGuire, Ross; Bywater, Robert P.; Foloppe, Nicolas

2013-01-01

The past decade has witnessed a paradigm shift in preclinical drug discovery with structure-based drug design (SBDD) making a comeback while high-throughput screening (HTS) methods have continued to generate disappointing results. There is a deficit of information between identified hits and the many criteria that must be fulfilled in parallel to convert them into preclinical candidates that have a real chance to become a drug. This gap can be bridged by investigating the interactions between the ligands and their receptors. Accurate calculations of the free energy of binding are still elusive; however progresses were made with respect to how one may deal with the versatile role of water. A corpus of knowledge combining X-ray structures, bioinformatics and molecular modeling techniques now allows drug designers to routinely produce receptor homology models of increasing quality. These models serve as a basis to establish and validate efficient rationales used to tailor and/or screen virtual libraries with enhanced chances of obtaining hits. Many case reports of successful SBDD show how synergy can be gained from the combined use of several techniques. The role of SBDD with respect to two different classes of widely investigated pharmaceutical targets: (a) protein kinases (PK) and (b) G-protein coupled receptors (GPCR) is discussed. Throughout these examples prototypical situations covering the current possibilities and limitations of SBDD are presented. PMID:24688704

Identification of Breast Cancer Inhibitors Specific for G Protein-Coupled Estrogen Receptor (GPER)-Expressing Cells.

PubMed

Aiello, Francesca; Carullo, Gabriele; Giordano, Francesca; Spina, Elena; Nigro, Alessandra; Garofalo, Antonio; Tassini, Sabrina; Costantino, Gabriele; Vincetti, Paolo; Bruno, Agostino; Radi, Marco

2017-08-22

Together with estrogen receptors ERα and ERβ, the G protein-coupled estrogen receptor (GPER) mediates important pathophysiological signaling pathways induced by estrogens and is currently regarded as a promising target for ER-negative (ER-) and triple-negative (TN) breast cancer. Only a few selective GPER modulators have been reported to date, and their use in cancer cell lines has often led to contradictory results. Herein we report the application of virtual screening and cell-based studies for the identification of new chemical scaffolds with a specific antiproliferative effect against GPER-expressing breast cancer cell lines. Out of the four different scaffolds identified, 8-chloro-4-(4-chlorophenyl)pyrrolo[1,2-a]quinoxaline 14 c was found to be the most promising compound able to induce: 1) antiproliferative activity in GPER-expressing cell lines (MCF7 and SKBR3), similarly to G15; 2) no effect on cells that do not express GPER (HEK293); 3) a decrease in cyclin D1 expression; and 4) a sustained induction of cell-cycle negative regulators p53 and p21. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Cefminox, a Dual Agonist of Prostacyclin Receptor and Peroxisome Proliferator-Activated Receptor-Gamma Identified by Virtual Screening, Has Therapeutic Efficacy against Hypoxia-Induced Pulmonary Hypertension in Rats

PubMed Central

Xia, Jingwen; Yang, Li; Dong, Liang; Niu, Mengjie; Zhang, Shengli; Yang, Zhiwei; Wumaier, Gulinuer; Li, Ying; Wei, Xiaomin; Gong, Yi; Zhu, Ning; Li, Shengqing

2018-01-01

Prostacyclin receptor (IP) and peroxisome proliferator-activated receptor-gamma (PPARγ) are both potential targets for treatment of pulmonary arterial hypertension (PAH). Expression of IP and PPARγ decreases in PAH, suggesting that screening of dual agonists of IP and PPARγ might be an efficient method for drug discovery. Virtual screening (VS) of potential IP–PPARγ dual-targeting agonists was performed in the ZINC database. Ten of the identified compounds were further screened, and cefminox was found to dramatically inhibit growth of PASMCs with no obvious cytotoxicity. Growth inhibition by cefminox was partially reversed by both the IP antagonist RO113842 and the PPARγ antagonist GW9662. Investigation of the underlying mechanisms of action demonstrated that cefminox inhibits the protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway through up-regulation of the expression of phosphatase and tensin homolog (PTEN, which is inhibited by GW9662), and enhances cyclic adenosine monophosphate (cAMP) production in PASMCs (which is inhibited by RO113842). In a rat model of hypoxia-induced pulmonary hypertension, cefminox displayed therapeutic efficacy not inferior to that of the prostacyclin analog iloprost or the PPARγ agonist rosiglitazone. Our results identified cefminox as a dual agonist of IP and PPARγ that significantly inhibits PASMC proliferation by up-regulation of PTEN and cAMP, suggesting that it has potential for treatment of PAH. PMID:29527168

Identification of multi-targeted anti-migraine potential of nystatin and development of its brain targeted chitosan nanoformulation.

PubMed

Girotra, Priti; Thakur, Aman; Kumar, Ajay; Singh, Shailendra Kumar

2017-03-01

The complex pathophysiology involved in migraine necessitates the drug treatment to act on several receptors simultaneously. The present investigation was an attempt to discover the unidentified anti-migraine activity of the already marketed drugs. Shared featured pharmacophore modeling was employed for this purpose on six target receptors (β 2 adrenoceptor, Dopamine D 3 , 5HT 1B , TRPV1, iGluR5 kainate and CGRP), resulting in the generation of five shared featured pharmacophores, which were further subjected to virtual screening of the ligands obtained from Drugbank database. Molecular docking, performed on the obtained hit compounds from virtual screening, indicated nystatin to be the only active lead against the receptors iGluR5 kainate receptor (1VSO), CGRP (3N7R), β 2 adrenoceptor (3NYA) and Dopamine D 3 (3PBL) with a high binding energy of -11.1, -10.9, -10.2 and -12kcal/mole respectively. The anti-migraine activity of nystatin was then adjudged by fabricating its brain targeted chitosan nanoparticles. Its brain targeting efficacy, analyzed qualitatively by confocal laser scanning microscopy, demonstrated a significant amount of drug reaching the brain. The pharmacodynamic models on Swiss male albino mice revealed significant anti-migraine activity of the nanoformulation. The present study reports for the first time the therapeutic potential of nystatin in migraine management, hence opening avenues for its future exploration. Copyright © 2016 Elsevier B.V. All rights reserved.

Virtual Reality as an Adjunctive Non-pharmacologic Analgesic for Acute Burn Pain During Medical Procedures

PubMed Central

Chambers, Gloria T.; Meyer, Walter J.; Arceneaux, Lisa L.; Russell, William J.; Seibel, Eric J.; Richards, Todd L.; Sharar, Sam R.; Patterson, David R.

2015-01-01

Introduction Excessive pain during medical procedures is a widespread problem but is especially problematic during daily wound care of patients with severe burn injuries. Methods Burn patients report 35–50% reductions in procedural pain while in a distracting immersive virtual reality, and fMRI brain scans show associated reductions in pain-related brain activity during VR. VR distraction appears to be most effective for patients with the highest pain intensity levels. VR is thought to reduce pain by directing patients’ attention into the virtual world, leaving less attention available to process incoming neural signals from pain receptors. Conclusions We review evidence from clinical and laboratory research studies exploring Virtual Reality analgesia, concentrating primarily on the work ongoing within our group. We briefly describe how VR pain distraction systems have been tailored to the unique needs of burn patients to date, and speculate about how VR systems could be tailored to the needs of other patient populations in the future. PMID:21264690

Impact of Middle vs. Inferior Total Turbinectomy on Nasal Aerodynamics

PubMed Central

Dayal, Anupriya; Rhee, John S.; Garcia, Guilherme J. M.

2016-01-01

Objectives This computational study aims to: (1) Use virtual surgery to theoretically investigate the maximum possible change in nasal aerodynamics after turbinate surgery; (2) Quantify the relative contributions of the middle and inferior turbinates to nasal resistance and air conditioning; (3) Quantify to what extent total turbinectomy impairs the nasal air conditioning capacity. Study Design Virtual surgery and computational fluid dynamics (CFD). Setting Academic tertiary medical center. Subjects and Methods Ten patients with inferior turbinate hypertrophy were studied. Three-dimensional models of their nasal anatomies were built based on pre-surgery computed tomography scans. Virtual surgery was applied to create models representing either total inferior turbinectomy (TIT) or total middle turbinectomy (TMT). Airflow, heat transfer, and humidity transport were simulated at a 15 L/min steady-state inhalation rate. The surface area stimulated by mucosal cooling was defined as the area where heat fluxes exceed 50 W/cm2. Results In both virtual total turbinectomy models, nasal resistance decreased and airflow increased. However, the surface area where heat fluxes exceed 50 W/cm2 either decreased (TIT) or did not change significantly (TMT), suggesting that total turbinectomy may reduce the stimulation of cold receptors by inspired air. Nasal heating and humidification efficiencies decreased significantly after both TIT and TMT. All changes were greater in the TIT models than in the TMT models. Conclusion TIT yields greater increases in nasal airflow, but also impairs the nasal air conditioning capacity to a greater extent than TMT. Radical resection of the turbinates may decrease the surface area stimulated by mucosal cooling. PMID:27165673

Computer-Aided Drug Design (CADD): Methodological Aspects and Practical Applications in Cancer Research

NASA Astrophysics Data System (ADS)

Gianti, Eleonora

Computer-Aided Drug Design (CADD) has deservedly gained increasing popularity in modern drug discovery (Schneider, G.; Fechner, U. 2005), whether applied to academic basic research or the pharmaceutical industry pipeline. In this work, after reviewing theoretical advancements in CADD, we integrated novel and stateof- the-art methods to assist in the design of small-molecule inhibitors of current cancer drug targets, specifically: Androgen Receptor (AR), a nuclear hormone receptor required for carcinogenesis of Prostate Cancer (PCa); Signal Transducer and Activator of Transcription 5 (STAT5), implicated in PCa progression; and Epstein-Barr Nuclear Antigen-1 (EBNA1), essential to the Epstein Barr Virus (EBV) during latent infections. Androgen Receptor. With the aim of generating binding mode hypotheses for a class (Handratta, V.D. et al. 2005) of dual AR/CYP17 inhibitors (CYP17 is a key enzyme for androgens biosynthesis and therefore implicated in PCa development), we successfully implemented a receptor-based computational strategy based on flexible receptor docking (Gianti, E.; Zauhar, R.J. 2012). Then, with the ultimate goal of identifying novel AR binders, we performed Virtual Screening (VS) by Fragment-Based Shape Signatures, an improved version of the original method developed in our Laboratory (Zauhar, R.J. et al. 2003), and we used the results to fully assess the high-level performance of this innovative tool in computational chemistry. STAT5. The SRC Homology 2 (SH2) domain of STAT5 is responsible for phospho-peptide recognition and activation. As a keystone of Structure-Based Drug Design (SBDD), we characterized key residues responsible for binding. We also generated a model of STAT5 receptor bound to a phospho-peptide ligand, which was validated by docking publicly known STAT5 inhibitors. Then, we performed Shape Signatures- and docking-based VS of the ZINC database (zinc.docking.org), followed by Molecular Mechanics Generalized Born Surface Area (MMGBSA) simulations, paired with Principal Component Analysis (PCA) of top-scoring hits to identify novel lead molecules likely to be active against STAT5. EBNA1 is the only viral protein consistently expressed in the many EBV-associated tumors, and is required for viral genome maintenance during latent infection. To immediately assist SBDD, we computationally identified "druggable" binding sites of EBNA1, and our predictions were later confirmed by experimental evidence (The Wistar Institute proprietary data).

Virtual reality system for treatment of the fear of public speaking using image-based rendering and moving pictures.

PubMed

Lee, Jae M; Ku, Jeong H; Jang, Dong P; Kim, Dong H; Choi, Young H; Kim, In Y; Kim, Sun I

2002-06-01

The fear of speaking is often cited as the world's most common social phobia. The rapid growth of computer technology enabled us to use virtual reality (VR) for the treatment of the fear of public speaking. There have been two techniques used to construct a virtual environment for the treatment of the fear of public speaking: model-based and movie-based. Virtual audiences and virtual environments made by model-based technique are unrealistic and unnatural. The movie-based technique has a disadvantage in that each virtual audience cannot be controlled respectively, because all virtual audiences are included in one moving picture file. To address this disadvantage, this paper presents a virtual environment made by using image-based rendering (IBR) and chroma keying simultaneously. IBR enables us to make the virtual environment realistic because the images are stitched panoramically with the photos taken from a digital camera. And the use of chroma keying allows a virtual audience to be controlled individually. In addition, a real-time capture technique was applied in constructing the virtual environment to give the subjects more interaction, in that they can talk with a therapist or another subject.

Using smartphone technology to deliver a virtual pedestrian environment: usability and validation.

PubMed

Schwebel, David C; Severson, Joan; He, Yefei

2017-09-01

Various programs effectively teach children to cross streets more safely, but all are labor- and cost-intensive. Recent developments in mobile phone technology offer opportunity to deliver virtual reality pedestrian environments to mobile smartphone platforms. Such an environment may offer a cost- and labor-effective strategy to teach children to cross streets safely. This study evaluated usability, feasibility, and validity of a smartphone-based virtual pedestrian environment. A total of 68 adults completed 12 virtual crossings within each of two virtual pedestrian environments, one delivered by smartphone and the other a semi-immersive kiosk virtual environment. Participants completed self-report measures of perceived realism and simulator sickness experienced in each virtual environment, plus self-reported demographic and personality characteristics. All participants followed system instructions and used the smartphone-based virtual environment without difficulty. No significant simulator sickness was reported or observed. Users rated the smartphone virtual environment as highly realistic. Convergent validity was detected, with many aspects of pedestrian behavior in the smartphone-based virtual environment matching behavior in the kiosk virtual environment. Anticipated correlations between personality and kiosk virtual reality pedestrian behavior emerged for the smartphone-based system. A smartphone-based virtual environment can be usable and valid. Future research should develop and evaluate such a training system.

Structural basis for PPAR partial or full activation revealed by a novel ligand binding mode

NASA Astrophysics Data System (ADS)

Capelli, Davide; Cerchia, Carmen; Montanari, Roberta; Loiodice, Fulvio; Tortorella, Paolo; Laghezza, Antonio; Cervoni, Laura; Pochetti, Giorgio; Lavecchia, Antonio

2016-10-01

The peroxisome proliferator-activated receptors (PPARs) are nuclear receptors involved in the regulation of the metabolic homeostasis and therefore represent valuable therapeutic targets for the treatment of metabolic diseases. The development of more balanced drugs interacting with PPARs, devoid of the side-effects showed by the currently marketed PPARγ full agonists, is considered the major challenge for the pharmaceutical companies. Here we present a structure-based virtual screening approach that let us identify a novel PPAR pan-agonist with a very attractive activity profile and its crystal structure in the complex with PPARα and PPARγ, respectively. In PPARα this ligand occupies a new pocket whose filling is allowed by the ligand-induced switching of the F273 side chain from a closed to an open conformation. The comparison between this pocket and the corresponding cavity in PPARγ provides a rationale for the different activation of the ligand towards PPARα and PPARγ, suggesting a novel basis for ligand design.

Identification of novel peroxisome proliferator-activated receptor-gamma (PPARγ) agonists using molecular modeling method

NASA Astrophysics Data System (ADS)

Gee, Veronica M. W.; Wong, Fiona S. L.; Ramachandran, Lalitha; Sethi, Gautam; Kumar, Alan Prem; Yap, Chun Wei

2014-11-01

Peroxisome proliferator-activated receptor-gamma (PPARγ) plays a critical role in lipid and glucose homeostasis. It is the target of many drug discovery studies, because of its role in various disease states including diabetes and cancer. Thiazolidinediones, a synthetic class of agents that work by activation of PPARγ, have been used extensively as insulin-sensitizers for the management of type 2 diabetes. In this study, a combination of QSAR and docking methods were utilised to perform virtual screening of more than 25 million compounds in the ZINC library. The QSAR model was developed using 1,517 compounds and it identified 42,378 potential PPARγ agonists from the ZINC library, and 10,000 of these were selected for docking with PPARγ based on their diversity. Several steps were used to refine the docking results, and finally 30 potentially highly active ligands were identified. Four compounds were subsequently tested for their in vitro activity, and one compound was found to have a K i values of <5 μM.

Structural insight to mutation effects uncover a common allosteric site in class C GPCRs.

PubMed

Harpsøe, Kasper; Boesgaard, Michael W; Munk, Christian; Bräuner-Osborne, Hans; Gloriam, David E

2017-04-15

Class C G protein-coupled receptors (GPCRs) regulate important physiological functions and allosteric modulators binding to the transmembrane domain constitute an attractive and, due to a lack of structural insight, a virtually unexplored potential for therapeutics and the food industry. Combining pharmacological site-directed mutagenesis data with the recent class C GPCR experimental structures will provide a foundation for rational design of new therapeutics. We uncover one common site for both positive and negative modulators with different amino acid layouts that can be utilized to obtain selectivity. Additionally, we show a large potential for structure-based modulator design, especially for four orphan receptors with high similarity to the crystal structures. All collated mutagenesis data is available in the GPCRdb mutation browser at http://gpcrdb.org/mutations/ and can be analyzed online or downloaded in excel format. david.gloriam@sund.ku.dk. Supplementary data are available at Bioinformatics online. © The Author 2016. Published by Oxford University Press.

Rational design of novel TLR4 ligands by in silico screening and their functional and structural characterization in vitro.

PubMed

Honegr, Jan; Malinak, David; Dolezal, Rafael; Soukup, Ondrej; Benkova, Marketa; Hroch, Lukas; Benek, Ondrej; Janockova, Jana; Kuca, Kamil; Prymula, Roman

2018-02-25

The purpose of this study was to identify new small molecules that possess activity on human toll-like receptor 4 associated with the myeloid differentiation protein 2 (hTLR4/MD2). Following current rational drug design principles, we firstly performed a ligand and structure based virtual screening of more than 130 000 compounds to discover until now unknown class of hTLR4/MD2 modulators that could be used as novel type of immunologic adjuvants. The core of the in silico study was molecular docking of flexible ligands in a partially flexible hTLR4/MD2 receptor model using a peta-flops-scale supercomputer. The most promising substances resulting from this study, related to anthracene-succimide hybrids, were synthesized and tested. The best prepared candidate exhibited 80% of Monophosphoryl Lipid A in vitro agonistic activity in cell lines expressing hTLR4/MD2. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Prospects for adoptive immunotherapy of pancreatic cancer using chimeric antigen receptor-engineered T-cells.

PubMed

Alrifai, Doraid; Sarker, Debashis; Maher, John

2016-01-01

Adoptive immunotherapy using chimeric antigen receptor (CAR) engineered T-cells is emerging as a powerful new approach to cancer immunotherapy. CARs are fusion molecules that couple the antibody-like binding of a native cell surface target to the delivery of a bespoke T-cell activating signal. Recent studies undertaken by several centers have demonstrated highly compelling efficacy in patients with acute and chronic B-cell malignancies. However, comparable therapeutic activity has not been achieved in solid tumors. Modern management of pancreatic ductal adenocarcinoma (PDAC) remains ineffective, reflected in the virtual equivalence of annual incidence and mortality statistics for this tumor type. Increasing evidence indicates that these tumors are recognized by the immune system, but deploy powerful evasion strategies that limit natural immune surveillance and render efforts at immunotherapy challenging. Here, we review preclinical and clinical studies that have been initiated or completed in an effort to develop CAR-based immunotherapy for PDAC. We also consider the hurdles to the effective clinical development of this exciting new therapeutic modality.

LS-align: an atom-level, flexible ligand structural alignment algorithm for high-throughput virtual screening.

PubMed

Hu, Jun; Liu, Zi; Yu, Dong-Jun; Zhang, Yang

2018-02-15

Sequence-order independent structural comparison, also called structural alignment, of small ligand molecules is often needed for computer-aided virtual drug screening. Although many ligand structure alignment programs are proposed, most of them build the alignments based on rigid-body shape comparison which cannot provide atom-specific alignment information nor allow structural variation; both abilities are critical to efficient high-throughput virtual screening. We propose a novel ligand comparison algorithm, LS-align, to generate fast and accurate atom-level structural alignments of ligand molecules, through an iterative heuristic search of the target function that combines inter-atom distance with mass and chemical bond comparisons. LS-align contains two modules of Rigid-LS-align and Flexi-LS-align, designed for rigid-body and flexible alignments, respectively, where a ligand-size independent, statistics-based scoring function is developed to evaluate the similarity of ligand molecules relative to random ligand pairs. Large-scale benchmark tests are performed on prioritizing chemical ligands of 102 protein targets involving 1,415,871 candidate compounds from the DUD-E (Database of Useful Decoys: Enhanced) database, where LS-align achieves an average enrichment factor (EF) of 22.0 at the 1% cutoff and the AUC score of 0.75, which are significantly higher than other state-of-the-art methods. Detailed data analyses show that the advanced performance is mainly attributed to the design of the target function that combines structural and chemical information to enhance the sensitivity of recognizing subtle difference of ligand molecules and the introduces of structural flexibility that help capture the conformational changes induced by the ligand-receptor binding interactions. These data demonstrate a new avenue to improve the virtual screening efficiency through the development of sensitive ligand structural alignments. http://zhanglab.ccmb.med.umich.edu/LS-align/. njyudj@njust.edu.cn or zhng@umich.edu. Supplementary data are available at Bioinformatics online.

Fragment-based drug discovery and molecular docking in drug design.

PubMed

Wang, Tao; Wu, Mian-Bin; Chen, Zheng-Jie; Chen, Hua; Lin, Jian-Ping; Yang, Li-Rong

2015-01-01

Fragment-based drug discovery (FBDD) has caused a revolution in the process of drug discovery and design, with many FBDD leads being developed into clinical trials or approved in the past few years. Compared with traditional high-throughput screening, it displays obvious advantages such as efficiently covering chemical space, achieving higher hit rates, and so forth. In this review, we focus on the most recent developments of FBDD for improving drug discovery, illustrating the process and the importance of FBDD. In particular, the computational strategies applied in the process of FBDD and molecular-docking programs are highlighted elaborately. In most cases, docking is used for predicting the ligand-receptor interaction modes and hit identification by structurebased virtual screening. The successful cases of typical significance and the hits identified most recently are discussed.

Learning Rationales and Virtual Reality Technology in Education.

ERIC Educational Resources Information Center

Chiou, Guey-Fa

1995-01-01

Defines and describes virtual reality technology and differentiates between virtual learning environment, learning material, and learning tools. Links learning rationales to virtual reality technology to pave conceptual foundations for application of virtual reality technology education. Constructivism, case-based learning, problem-based learning,…

A web-based platform for virtual screening.

PubMed

Watson, Paul; Verdonk, Marcel; Hartshorn, Michael J

2003-09-01

A fully integrated, web-based, virtual screening platform has been developed to allow rapid virtual screening of large numbers of compounds. ORACLE is used to store information at all stages of the process. The system includes a large database of historical compounds from high throughput screenings (HTS) chemical suppliers, ATLAS, containing over 3.1 million unique compounds with their associated physiochemical properties (ClogP, MW, etc.). The database can be screened using a web-based interface to produce compound subsets for virtual screening or virtual library (VL) enumeration. In order to carry out the latter task within ORACLE a reaction data cartridge has been developed. Virtual libraries can be enumerated rapidly using the web-based interface to the cartridge. The compound subsets can be seamlessly submitted for virtual screening experiments, and the results can be viewed via another web-based interface allowing ad hoc querying of the virtual screening data stored in ORACLE.

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

PubMed Central

Zhou, Nannan; Xu, Yuan; Liu, Xian; Wang, Yulan; Peng, Jianlong; Luo, Xiaomin; Zheng, Mingyue; Chen, Kaixian; Jiang, Hualiang

2015-01-01

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. PMID:26110383

VSDMIP 1.5: an automated structure- and ligand-based virtual screening platform with a PyMOL graphical user interface.

PubMed

Cabrera, Álvaro Cortés; Gil-Redondo, Rubén; Perona, Almudena; Gago, Federico; Morreale, Antonio

2011-09-01

A graphical user interface (GUI) for our previously published virtual screening (VS) and data management platform VSDMIP (Gil-Redondo et al. J Comput Aided Mol Design, 23:171-184, 2009) that has been developed as a plugin for the popular molecular visualization program PyMOL is presented. In addition, a ligand-based VS module (LBVS) has been implemented that complements the already existing structure-based VS (SBVS) module and can be used in those cases where the receptor's 3D structure is not known or for pre-filtering purposes. This updated version of VSDMIP is placed in the context of similar available software and its LBVS and SBVS capabilities are tested here on a reduced set of the Directory of Useful Decoys database. Comparison of results from both approaches confirms the trend found in previous studies that LBVS outperforms SBVS. We also show that by combining LBVS and SBVS, and using a cluster of ~100 modern processors, it is possible to perform complete VS studies of several million molecules in less than a month. As the main processes in VSDMIP are 100% scalable, more powerful processors and larger clusters would notably decrease this time span. The plugin is distributed under an academic license upon request from the authors. © Springer Science+Business Media B.V. 2011

Support vector regression scoring of receptor-ligand complexes for rank-ordering and virtual screening of chemical libraries.

PubMed

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.

Study on virtual instrument developing system based on intelligent virtual control

NASA Astrophysics Data System (ADS)

Tang, Baoping; Cheng, Fabin; Qin, Shuren

2005-01-01

The paper introduces a non-programming developing system of a virtual instument (VI), i.e., a virtual measurement instrument developing system (VMIDS) based on intelligent virtual control (IVC). The background of the IVC-based VMIDS is described briefly, and the hierarchical message bus (HMB)-based software architecture of VMIDS is discussed in detail. The three parts and functions of VMIDS are introduced, and the process of non-programming developing VI is further described.

Walking training associated with virtual reality-based training increases walking speed of individuals with chronic stroke: systematic review with meta-analysis.

PubMed

Rodrigues-Baroni, Juliana M; Nascimento, Lucas R; Ada, Louise; Teixeira-Salmela, Luci F

2014-01-01

To systematically review the available evidence on the efficacy of walking training associated with virtual reality-based training in patients with stroke. The specific questions were: Is walking training associated with virtual reality-based training effective in increasing walking speed after stroke? Is this type of intervention more effective in increasing walking speed, than non-virtual reality-based walking interventions? A systematic review with meta-analysis of randomized clinical trials was conducted. Participants were adults with chronic stroke and the experimental intervention was walking training associated with virtual reality-based training to increase walking speed. The outcome data regarding walking speed were extracted from the eligible trials and were combined using a meta-analysis approach. Seven trials representing eight comparisons were included in this systematic review. Overall, the virtual reality-based training increased walking speed by 0.17 m/s (IC 95% 0.08 to 0.26), compared with placebo/nothing or non-walking interventions. In addition, the virtual reality-based training increased walking speed by 0.15 m/s (IC 95% 0.05 to 0.24), compared with non-virtual reality walking interventions. This review provided evidence that walking training associated with virtual reality-based training was effective in increasing walking speed after stroke, and resulted in better results than non-virtual reality interventions.

Walking training associated with virtual reality-based training increases walking speed of individuals with chronic stroke: systematic review with meta-analysis

PubMed Central

Rodrigues-Baroni, Juliana M.; Nascimento, Lucas R.; Ada, Louise; Teixeira-Salmela, Luci F.

2014-01-01

OBJECTIVE: To systematically review the available evidence on the efficacy of walking training associated with virtual reality-based training in patients with stroke. The specific questions were: Is walking training associated with virtual reality-based training effective in increasing walking speed after stroke? Is this type of intervention more effective in increasing walking speed, than non-virtual reality-based walking interventions? METHOD: A systematic review with meta-analysis of randomized clinical trials was conducted. Participants were adults with chronic stroke and the experimental intervention was walking training associated with virtual reality-based training to increase walking speed. The outcome data regarding walking speed were extracted from the eligible trials and were combined using a meta-analysis approach. RESULTS: Seven trials representing eight comparisons were included in this systematic review. Overall, the virtual reality-based training increased walking speed by 0.17 m/s (IC 95% 0.08 to 0.26), compared with placebo/nothing or non-walking interventions. In addition, the virtual reality-based training increased walking speed by 0.15 m/s (IC 95% 0.05 to 0.24), compared with non-virtual reality walking interventions. CONCLUSIONS: This review provided evidence that walking training associated with virtual reality-based training was effective in increasing walking speed after stroke, and resulted in better results than non-virtual reality interventions. PMID:25590442

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

PubMed

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.

Natural Products based P-glycoprotein Activators for Improved β-amyloid Clearance in Alzheimer's Disease: An in silico Approach.

PubMed

Shinde, Pravin; Vidyasagar, Nikhil; Dhulap, Sivakami; Dhulap, Abhijeet; Hirwani, Raj

2015-01-01

Alzheimer's disease is an age related disorder and is defined to be progressive, irreversible neurodegenerative disease. The potential targets which are associated with the Alzheimer's disease are cholinesterases, N-methyl-D-aspartate receptor, Beta secretase 1, Pregnane X receptor (PXR) and P-glycoprotein (Pgp). P-glycoprotein is a member of the ATP binding cassette (ABC) transporter family, which is an important integral of the blood-brain, blood-cerebrospinal fluid and the blood-testis barrier. Reports from the literature provide evidences that the up-regulation of the efflux pump is liable for a decrease in β -amyloid intracellular accumulation and is an important hallmark in Alzheimer's disease (AD). Thus, targeting β-amyloid clearance by stimulating Pgp could be a useful strategy to prevent Alzheimer's advancement. Currently available drugs provide limited effectiveness and do not assure to cure Alzheimer's disease completely. On the other hand, the current research is now directed towards the development of synthetic or natural based therapeutics which can delay the onset or progression of Alzheimer's disease. Since ancient time medicinal plants such as Withania somnifera, Bacopa monieri, Nerium indicum have been used to prevent neurological disorders including Alzheimer's disease. Till today around 125 Indian medicinal plants have been screened on the basis of ethnopharmacology for their activity against neurological disorders. In this paper, we report bioactives from natural sources which show binding affinity towards the Pgp receptor using ligand based pharmacophore development, virtual screening, molecular docking and molecular dynamics simulation studies for the bioactives possessing acceptable ADME properties. These bioactives can thus be useful to treat Alzheimer's disease.

Effects of virtual reality-based bilateral upper-extremity training on brain activity in post-stroke patients.

PubMed

Lee, Su-Hyun; Kim, Yu-Mi; Lee, Byoung-Hee

2015-07-01

[Purpose] This study investigated the therapeutic effects of virtual reality-based bilateral upper-extremity training on brain activity in patients with stroke. [Subjects and Methods] Eighteen chronic stroke patients were divided into two groups: the virtual reality-based bilateral upper-extremity training group (n = 10) and the bilateral upper-limb training group (n = 8). The virtual reality-based bilateral upper-extremity training group performed bilateral upper-extremity exercises in a virtual reality environment, while the bilateral upper-limb training group performed only bilateral upper-extremity exercise. All training was conducted 30 minutes per day, three times per week for six weeks, followed by brain activity evaluation. [Results] Electroencephalography showed significant increases in concentration in the frontopolar 2 and frontal 4 areas, and significant increases in brain activity in the frontopolar 1 and frontal 3 areas in the virtual reality-based bilateral upper-extremity training group. [Conclusion] Virtual reality-based bilateral upper-extremity training can improve the brain activity of stroke patients. Thus, virtual reality-based bilateral upper-extremity training is feasible and beneficial for improving brain activation in stroke patients.

Nonlinear scoring functions for similarity-based ligand docking and binding affinity prediction.

PubMed

Brylinski, Michal

2013-11-25

A common strategy for virtual screening considers a systematic docking of a large library of organic compounds into the target sites in protein receptors with promising leads selected based on favorable intermolecular interactions. Despite a continuous progress in the modeling of protein-ligand interactions for pharmaceutical design, important challenges still remain, thus the development of novel techniques is required. In this communication, we describe eSimDock, a new approach to ligand docking and binding affinity prediction. eSimDock employs nonlinear machine learning-based scoring functions to improve the accuracy of ligand ranking and similarity-based binding pose prediction, and to increase the tolerance to structural imperfections in the target structures. In large-scale benchmarking using the Astex/CCDC data set, we show that 53.9% (67.9%) of the predicted ligand poses have RMSD of <2 Å (<3 Å). Moreover, using binding sites predicted by recently developed eFindSite, eSimDock models ligand binding poses with an RMSD of 4 Å for 50.0-39.7% of the complexes at the protein homology level limited to 80-40%. Simulations against non-native receptor structures, whose mean backbone rearrangements vary from 0.5 to 5.0 Å Cα-RMSD, show that the ratio of docking accuracy and the estimated upper bound is at a constant level of ∼0.65. Pearson correlation coefficient between experimental and predicted by eSimDock Ki values for a large data set of the crystal structures of protein-ligand complexes from BindingDB is 0.58, which decreases only to 0.46 when target structures distorted to 3.0 Å Cα-RMSD are used. Finally, two case studies demonstrate that eSimDock can be customized to specific applications as well. These encouraging results show that the performance of eSimDock is largely unaffected by the deformations of ligand binding regions, thus it represents a practical strategy for across-proteome virtual screening using protein models. eSimDock is freely available to the academic community as a Web server at http://www.brylinski.org/esimdock .

A Virtual Reality-Based Simulation of Abdominal Surgery

DTIC Science & Technology

1994-06-30

415) 591-7881 In! IhNiI 1 SHORT TITLE: A Virtual Reality -Based Simulation of Abdominal Surgery REPORTING PERIOD: October 31, 1993-June 30, 1994 The...Report - A Virtual Reality -Based Simulation Of Abdominal Surgery Page 2 June 21, 1994 TECHNICAL REPORT SUMMARY Virtual Reality is a marriage between...applications of this technology. Virtual reality systems can be used to teach surgical anatomy, diagnose surgical problems, plan operations. simulate and

Minimalist hybrid ligand/receptor-based pharmacophore model for CXCR4 applied to a small-library of marine natural products led to the identification of phidianidine a as a new CXCR4 ligand exhibiting antagonist activity.

PubMed

Vitale, Rosa Maria; Gatti, Monica; Carbone, Marianna; Barbieri, Federica; Felicità, Vera; Gavagnin, Margherita; Florio, Tullio; Amodeo, Pietro

2013-12-20

Here, we present a minimal hybrid ligand/receptor-based pharmacophore model (PM) for CXCR4, a chemokine receptor deeply involved in several pathologies, such as HIV infection, rheumatoid arthritis, cancer development/progression, and metastasization. This model, considerably simpler than those thus far proposed for this receptor, has been used to search for new CXCR4 inhibitors in a small marine natural product library available at ICB-CNR Institute (Pozzuoli, NA, Italy), since natural products, with their naturally selected chemical and functional diversity, represent a rich source of bioactive scaffolds; computational approaches allow searching for new scaffolds with a minimal waste of possibly precious natural product samples; and our "stripped-down" model substantially increases the probabilities of identifying potential hits even in small-sized libraries. This search, also validated by a systematic virtual screening of the same library, has led to the identification of a new CXCR4 ligand, phidianidine A (PHIA). Docking studies supported PHIA activity and suggested its possible binding modes to CXCR4. Using the CXCR4-expressing/CXCR7-negative GH4C1 cell line we show that PHIA inhibits CXCL12-induced DNA synthesis, cell migration, and ERK1/2 activation. The specificity of these effects was confirmed by the lack of PHIA activity in GH4C1 cells, in which siRNA highly reduces CXCR4 expression and the lack of cytoxicity of PHIA was also verified. Thus, PHIA represents a promising lead for a new family of CXCR4 modulators with wide margins of improvement in potency and specificity offered by the small and very simple underlying PM.

Aberrant ligand-induced activation of G protein-coupled estrogen receptor 1 (GPER) results in developmental malformations during vertebrate embryogenesis.

PubMed

Jayasinghe, B Sumith; Volz, David C

2012-01-01

G protein-coupled estrogen receptor 1 (GPER) is a G protein-coupled receptor (GPCR) unrelated to nuclear estrogen receptors but strongly activated by 17β-estradiol in both mammals and fish. To date, the distribution and functional characterization of GPER within reproductive and nonreproductive vertebrate organs have been restricted to juvenile and adult animals. In contrast, virtually nothing is known about the spatiotemporal distribution and function of GPER during vertebrate embryogenesis. Using zebrafish as an animal model, we investigated the potential functional role and expression of GPER during embryogenesis. Based on real-time PCR and whole-mount in situ hybridization, gper was expressed as early as 1 h postfertilization (hpf) and exhibited strong stage-dependent expression patterns during embryogenesis. At 26 and 38 hpf, gper mRNA was broadly distributed throughout the body, whereas from 50 to 98 hpf, gper expression was increasingly localized to the heart, brain, neuromasts, craniofacial region, and somite boundaries of developing zebrafish. Continuous exposure to a selective GPER agonist (G-1)-but not continuous exposure to a selective GPER antagonist (G-15)-from 5 to 96 hpf, or within three developmental windows ranging from 10 to 72 hpf, resulted in adverse concentration-dependent effects on survival, gross morphology, and somite formation within the trunk of developing zebrafish embryos. Importantly, based on co-exposure studies, G-15 blocked severe G-1-induced developmental toxicity, suggesting that G-1 toxicity is mediated via aberrant activation of GPER. Overall, our findings suggest that xenobiotic-induced GPER activation represents a potentially novel and understudied mechanism of toxicity for environmentally relevant chemicals that affect vertebrate embryogenesis.

From The Cover: Microtransplantation of functional receptors and channels from the Alzheimer's brain to frog oocytes

NASA Astrophysics Data System (ADS)

Miledi, R.; Dueñas, Z.; Martinez-Torres, A.; Kawas, C. H.; Eusebi, F.

2004-02-01

About a decade ago, cell membranes from the electric organ of Torpedo and from the rat brain were transplanted to frog oocytes, which thus acquired functional Torpedo and rat neurotransmitter receptors. Nevertheless, the great potential that this method has for studying human diseases has remained virtually untapped. Here, we show that cell membranes from the postmortem brains of humans that suffered Alzheimer's disease can be microtransplanted to the plasma membrane of Xenopus oocytes. We show also that these postmortem membranes carry neurotransmitter receptors and voltage-operated channels that are still functional, even after they have been kept frozen for many years. This method provides a new and powerful approach to study directly the functional characteristics and structure of receptors, channels, and other membrane proteins of the Alzheimer's brain. This knowledge may help in understanding the basis of Alzheimer's disease and also help in developing new treatments. -aminobutyric acid receptors | sodium channels | calcium channels | postmortem brain

Phosphotyrosine signaling proteins that drive oncogenesis tend to be highly interconnected.

PubMed

Koytiger, Grigoriy; Kaushansky, Alexis; Gordus, Andrew; Rush, John; Sorger, Peter K; MacBeath, Gavin

2013-05-01

Mutation and overexpression of receptor tyrosine kinases or the proteins they regulate serve as oncogenic drivers in diverse cancers. To better understand receptor tyrosine kinase signaling and its link to oncogenesis, we used protein microarrays to systematically and quantitatively measure interactions between virtually every SH2 or PTB domain encoded in the human genome and all known sites of tyrosine phosphorylation on 40 receptor tyrosine kinases and on most of the SH2 and PTB domain-containing adaptor proteins. We found that adaptor proteins, like RTKs, have many high affinity bindings sites for other adaptor proteins. In addition, proteins that drive cancer, including both receptors and adaptor proteins, tend to be much more highly interconnected via networks of SH2 and PTB domain-mediated interactions than nononcogenic proteins. Our results suggest that network topological properties such as connectivity can be used to prioritize new drug targets in this well-studied family of signaling proteins.

Analysis of the murine Dtk gene identifies conservation of genomic structure within a new receptor tyrosine kinase subfamily

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lewis, P.M.; Crosier, K.E.; Crosier, P.S.

The receptor tyrosine kinase Dtk/Tyro 3/Sky/rse/brt/tif is a member of a new subfamily of receptors that also includes Axl/Ufo/Ark and Eyk/Mer. These receptors are characterized by the presence of two immunoglobulin-like loops and two fibronectin type III repeats in their extracellular domains. The structure of the murine Dtk gene has been determined. The gene consists of 21 exons that are distributed over 21 kb of genomic DNA. An isoform of Dtk is generated by differential splicing of exons from the 5{prime} region of the gene. The overall genomic structure of Dtk is virtually identical to that determined for the humanmore » UFO gene. This particular genomic organization is likely to have been duplicated and closely maintained throughout evolution. 38 refs., 3 figs., 1 tab.« less

Protein tyrosine kinase and mitogen-activated protein kinase signalling pathways contribute to differences in heterophil-mediated innate immune responsiveness between two lines of broilers

USDA-ARS?s Scientific Manuscript database

Protein tyrosine phosphorylation mediates signal transduction of cellular processes, with protein tyrosine kinases (PTKs) regulating virtually all signaling events. The mitogen-activated protein kinase (MAPK) super-family consists of three conserved pathways that convert receptor activation into ce...

A method for acetylcholinesterase staining of brain sections previously processed for receptor autoradiography.

PubMed

Lim, M M; Hammock, E A D; Young, L J

2004-02-01

Receptor autoradiography using selective radiolabeled ligands allows visualization of brain receptor distribution and density on film. The resolution of specific brain regions on the film often can be difficult to discern owing to the general spread of the radioactive label and the lack of neuroanatomical landmarks on film. Receptor binding is a chemically harsh protocol that can render the tissue virtually unstainable by Nissl and other conventional stains used to delineate neuroanatomical boundaries of brain regions. We describe a method for acetylcholinesterase (AChE) staining of slides previously processed for receptor binding. AChE staining is a useful tool for delineating major brain nuclei and tracts. AChE staining on sections that have been processed for receptor autoradiography provides a direct comparison of brain regions for more precise neuroanatomical description. We report a detailed thiocholine protocol that is a modification of the Koelle-Friedenwald method to amplify the AChE signal in brain sections previously processed for autoradiography. We also describe several temporal and experimental factors that can affect the density and clarity of the AChE signal when using this protocol.

Serotonin 5-HT7 receptor agents: structure-activity relationships and potential therapeutic applications in central nervous system disorders

PubMed Central

Leopoldo, Marcello; Lacivita, Enza; Berardi, Francesco; Perrone, Roberto; Hedlund, Peter B.

2010-01-01

Since its discovery in the 1940s in serum, the mammalian intestinal mucosa, and in the central nervous system, serotonin (5-HT) has been shown to be involved in virtually all cognitive and behavioral human functions, and alterations in its neurochemistry have been implicated in the etiology of a plethora of neuropsychiatric disorders. The cloning of 5-HT receptor subtypes has been of importance in enabling them to be classified as specific protein molecules encoded by specific genes. The 5-HT7 receptor is the most recently classified member of the serotonin receptor family. Since its identification, it has been the subject of intense research efforts driven by its presence in functionally relevant regions of the brain. The availability of some selective antagonists and agonists, in combination with genetically modified mice lacking the 5-HT7 receptor, has allowed for a better understanding of the pathophysiological role of this receptor. This paper reviews data on localization and pharmacological properties of the 5-HT7 receptor, and summarizes the results of structure-activity relationship studies aimed at the discovery of selective 5-HT7 receptor ligands. Additionally, an overview of the potential therapeutic applications of 5-HT7 receptor agonists and antagonists in central nervous system disorders is presented. PMID:20923682

Photorealistic virtual anatomy based on Chinese Visible Human data.

PubMed

Heng, P A; Zhang, S X; Xie, Y M; Wong, T T; Chui, Y P; Cheng, C Y

2006-04-01

Virtual reality based learning of human anatomy is feasible when a database of 3D organ models is available for the learner to explore, visualize, and dissect in virtual space interactively. In this article, we present our latest work on photorealistic virtual anatomy applications based on the Chinese Visible Human (CVH) data. We have focused on the development of state-of-the-art virtual environments that feature interactive photo-realistic visualization and dissection of virtual anatomical models constructed from ultra-high resolution CVH datasets. We also outline our latest progress in applying these highly accurate virtual and functional organ models to generate realistic look and feel to advanced surgical simulators. (c) 2006 Wiley-Liss, Inc.

A computationally identified compound antagonizes excess FGF-23 signaling in renal tubules and a mouse model of hypophosphatemia

DOE PAGES

Xiao, Zhousheng; Riccardi, Demian; Velazquez, Hector A.; ...

2016-11-22

Fibroblast growth factor–23 (FGF-23) interacts with a binary receptor complex composed of α-Klotho (α-KL) and FGF receptors (FGFRs) to regulate phosphate and vitamin D metabolism in the kidney. Excess FGF-23 production, which causes hypophosphatemia, is genetically inherited or occurs with chronic kidney disease. Among other symptoms, hypophosphatemia causes vitamin D deficiency and the bone-softening disorder rickets. Current therapeutics that target the receptor complex have limited utility clinically. In this paper, using a computationally driven, structure-based, ensemble docking and virtual high-throughput screening approach, we identified four novel compounds predicted to selectively inhibit FGF-23–induced activation of the FGFR/α-KL complex. Additional modeling andmore » functional analysis found that Zinc13407541 bound to FGF-23 and disrupted its interaction with the FGFR1/α-KL complex; experiments in a heterologous cell expression system showed that Zinc13407541 selectivity inhibited α-KL–dependent FGF-23 signaling. Zinc13407541 also inhibited FGF-23 signaling in isolated renal tubules ex vivo and partially reversed the hypophosphatemic effects of excess FGF-23 in a mouse model. Finally, these chemical probes provide a platform to develop lead compounds to treat disorders caused by excess FGF-23.« less

A computationally identified compound antagonizes excess FGF-23 signaling in renal tubules and a mouse model of hypophosphatemia.

PubMed

Xiao, Zhousheng; Riccardi, Demian; Velazquez, Hector A; Chin, Ai L; Yates, Charles R; Carrick, Jesse D; Smith, Jeremy C; Baudry, Jerome; Quarles, L Darryl

2016-11-22

Fibroblast growth factor-23 (FGF-23) interacts with a binary receptor complex composed of α-Klotho (α-KL) and FGF receptors (FGFRs) to regulate phosphate and vitamin D metabolism in the kidney. Excess FGF-23 production, which causes hypophosphatemia, is genetically inherited or occurs with chronic kidney disease. Among other symptoms, hypophosphatemia causes vitamin D deficiency and the bone-softening disorder rickets. Current therapeutics that target the receptor complex have limited utility clinically. Using a computationally driven, structure-based, ensemble docking and virtual high-throughput screening approach, we identified four novel compounds predicted to selectively inhibit FGF-23-induced activation of the FGFR/α-KL complex. Additional modeling and functional analysis found that Zinc13407541 bound to FGF-23 and disrupted its interaction with the FGFR1/α-KL complex; experiments in a heterologous cell expression system showed that Zinc13407541 selectivity inhibited α-KL-dependent FGF-23 signaling. Zinc13407541 also inhibited FGF-23 signaling in isolated renal tubules ex vivo and partially reversed the hypophosphatemic effects of excess FGF-23 in a mouse model. These chemical probes provide a platform to develop lead compounds to treat disorders caused by excess FGF-23. Copyright © 2016, American Association for the Advancement of Science.

A computationally identified compound antagonizes excess FGF-23 signaling in renal tubules and a mouse model of hypophosphatemia

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xiao, Zhousheng; Riccardi, Demian; Velazquez, Hector A.

Fibroblast growth factor–23 (FGF-23) interacts with a binary receptor complex composed of α-Klotho (α-KL) and FGF receptors (FGFRs) to regulate phosphate and vitamin D metabolism in the kidney. Excess FGF-23 production, which causes hypophosphatemia, is genetically inherited or occurs with chronic kidney disease. Among other symptoms, hypophosphatemia causes vitamin D deficiency and the bone-softening disorder rickets. Current therapeutics that target the receptor complex have limited utility clinically. In this paper, using a computationally driven, structure-based, ensemble docking and virtual high-throughput screening approach, we identified four novel compounds predicted to selectively inhibit FGF-23–induced activation of the FGFR/α-KL complex. Additional modeling andmore » functional analysis found that Zinc13407541 bound to FGF-23 and disrupted its interaction with the FGFR1/α-KL complex; experiments in a heterologous cell expression system showed that Zinc13407541 selectivity inhibited α-KL–dependent FGF-23 signaling. Zinc13407541 also inhibited FGF-23 signaling in isolated renal tubules ex vivo and partially reversed the hypophosphatemic effects of excess FGF-23 in a mouse model. Finally, these chemical probes provide a platform to develop lead compounds to treat disorders caused by excess FGF-23.« less

Molecular docking and simulation studies of gustatory receptor of Aedes aegypti: A potent drug target to distract host-seeking behaviour in mosquitoes.

PubMed

Gupta, Krishna Kant; Sethi, Guneswar; Jayaraman, Manikandan

2016-01-01

It is well reported that exhaled CO 2 and skin odour from human being assist female mosquitoes to locate human host. Basically, the receptors for this activity are expressed in cpA neurons. In both Aedes aegypti and Anopheles gambiae, this CO 2-sensitive olfactory neuron detects myriad number of chemicals present in human skin. Therefore, manipulation of gustatory receptors housing these neurons may serve as important targets for behavioural intervention. The study was aimed towards virtual screening of small molecules in the analyzed conserved active site residues of gustatory receptor and molecular dynamics simulation study of optimum protein-ligand complex to identify a suitable lead molecule for distracting host-seeking behaviour of mosquitoes. The conserved residue analysis of gustatory receptor (GR) of Ae. aegypti and An. gambiae was performed. The structure of GR protein from Ae. aegypti was modeled and validated, and then molecular docking was performed to screen 2903 small molecules against the predicted active residues of GR. Further, simulation studies were also carried out to prove protein-ligand stability. The glutamine 154 residue of GR was found to be highly conserved in Ae. aegypti and An. gambiae. Docking results indicated that the dodecanoic acid, 1,2,3-propanetriyl ester (dynasan 112) was interacting with this residue, as it showed better LibDock score than previously reported ethyl acetate used as mosquito repellant. Simulation studies indicated the structural instability of GR protein in docked form with dynasan 112 suggesting its involvement in structural changes. Based on the interaction energies and stability, this compound has been proposed to be used in mosquitoes' repellant. A novel effective odorant acting as inhibitor of GR is proposed based on its stability, docking score, interactions and RMSD, considering ethyl pyruvate as a standard inhibitor. Host preference and host-seeking ability of mosquito vectors play key roles in disease transmission, a clear understanding of these aspects is essential for preventing the spread of the disease.

Water exposure assessment of aryl hydrocarbon receptor agonists in Three Gorges Reservoir, China using SPMD-based virtual organisms.

PubMed

Wang, Jingxian; Bernhöft, Silke; Pfister, Gerd; Schramm, Karl-Werner

2014-10-15

SPMD-based virtual organisms (VOs) were deployed at five to eight sites in the Three Gorges Reservoir (TGR), China for five periods in 2008, 2009 and 2011. The water exposure of aryl hydrocarbon receptor (AhR) agonists was assessed by the VOs. The chosen bioassay response for the extracts of the VOs, the induction of 7-ethoxyresorufin-O-deethylase (EROD) was assayed using a rat hepatoma cell line (H4IIE). The results show that the extracts from the VOs could induce AhR activity significantly, whereas the chemically derived 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) equivalent (TEQcal) accounted for <11% of the observed AhR responses (TEQbio). Unidentified AhR-active compounds represented a greater proportion of the TCDD equivalent in VOs from TGR. High TEQbio value in diluted extract and low TEQbio in concentrated extract of the same sample was observed suggesting potential non-additive effects in the mixture. The levels of AhR agonists in VOs from upstream TGR were in general higher than those from downstream reservoir, indicating urbanization effect on AhR agonist pollution. The temporal variation showed that levels of AhR agonists in 2009 and 2011 were higher than those in 2008, and the potential non-additive effects in the area close to the dam were also obviously higher in 2009 and 2011 than in 2008, indicating big changes in the composition of pollutants in the area after water level reached a maximum of 175 m. Although the aqueous concentration of AhR agonists of 0.8-4.8 pg TCDDL(-1) in TGR was not alarming, the tendency of accumulating high concentration of AhR agonists in VO lipid and existence of possible synergism or antagonism in the water may exhibit a potential hazard to local biota being exposed to AhR agonists. Copyright © 2014 Elsevier B.V. All rights reserved.

The Virtual Desktop: Options and Challenges in Selecting a Secure Desktop Infrastructure Based on Virtualization

DTIC Science & Technology

2011-10-01

Fortunately, some products offer centralized management and deployment tools for local desktop implementation . Figure 5 illustrates the... implementation of a secure desktop infrastructure based on virtualization. It includes an overview of desktop virtualization, including an in-depth...environment in the data centre, whereas LHVD places it on the endpoint itself. Desktop virtualization implementation considerations and potential

Delay-based virtual congestion control in multi-tenant datacenters

NASA Astrophysics Data System (ADS)

Liu, Yuxin; Zhu, Danhong; Zhang, Dong

2018-03-01

With the evolution of cloud computing and virtualization, the congestion control of virtual datacenters has become the basic issue for multi-tenant datacenters transmission. Regarding to the friendly conflict of heterogeneous congestion control among multi-tenant, this paper proposes a delay-based virtual congestion control, which translates the multi-tenant heterogeneous congestion control into delay-based feedback uniformly by setting the hypervisor translation layer, modifying three-way handshake of explicit feedback and packet loss feedback and throttling receive window. The simulation results show that the delay-based virtual congestion control can effectively solve the unfairness of heterogeneous feedback congestion control algorithms.

Fragment-Based Optimization of Small Molecule CXCL12 Inhibitors for Antagonizing the CXCL12/CXCR4 Interaction

PubMed Central

Ziarek, Joshua J.; Liu, Yan; Smith, Emmanuel; Zhang, Guolin; Peterson, Francis C.; Chen, Jun; Yu, Yongping; Chen, Yu; Volkman, Brian F.; Li, Rongshi

2013-01-01

The chemokine CXCL12 and its G protein-coupled receptor (GPCR) CXCR4 are high-priority clinical targets because of their involvement in metastatic cancers (also implicated in autoimmune disease and cardiovascular disease). Because chemokines interact with two distinct sites to bind and activate their receptors, both the GPCRs and chemokines are potential targets for small molecule inhibition. A number of chemokines have been validated as targets for drug development, but virtually all drug discovery efforts focus on the GPCRs. However, all CXCR4 receptor antagonists with the exception of MSX-122 have failed in clinical trials due to unmanageable toxicities, emphasizing the need for alternative strategies to interfere with CXCL12/CXCR4-guided metastatic homing. Although targeting the relatively featureless surface of CXCL12 was presumed to be challenging, focusing efforts at the sulfotyrosine (sY) binding pockets proved successful for procuring initial hits. Using a hybrid structure-based in silico/NMR screening strategy, we recently identified a ligand that occludes the receptor recognition site. From this initial hit, we designed a small fragment library containing only nine tetrazole derivatives using a fragment-based and bioisostere approach to target the sY binding sites of CXCL12. Compound binding modes and affinities were studied by 2D NMR spectroscopy, X-ray crystallography, molecular docking and cell-based functional assays. Our results demonstrate that the sY binding sites are conducive to the development of high affinity inhibitors with better ligand efficiency (LE) than typical protein-protein interaction inhibitors (LE ≤ 0.24). Our novel tetrazole-based fragment 18 was identified to bind the sY21 site with a Kd of 24 μM (LE = 0.30). Optimization of 18 yielded compound 25 which specifically inhibits CXCL12-induced migration with an improvement in potency over the initial hit 9. The fragment from this library that exhibited the highest affinity and ligand efficiency (11: Kd = 13 μM, LE = 0.33) may serve as a starting point for development of inhibitors targeting the sY12 site. PMID:23368099

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

PubMed

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 social virtual environments. The outcome can prove helpful in using low-cost projection-based virtual reality environments for treating individuals with social phobia.

Virtual Reality: Toward Fundamental Improvements in Simulation-Based Training.

ERIC Educational Resources Information Center

Thurman, Richard A.; Mattoon, Joseph S.

1994-01-01

Considers the role and effectiveness of virtual reality in simulation-based training. The theoretical and practical implications of verity, integration, and natural versus artificial interface are discussed; a three-dimensional classification scheme for virtual reality is described; and the relationship between virtual reality and other…

Development of a virtual speaking simulator using Image Based Rendering.

PubMed

Lee, J M; Kim, H; Oh, M J; Ku, J H; Jang, D P; Kim, I Y; Kim, S I

2002-01-01

The fear of speaking is often cited as the world's most common social phobia. The rapid growth of computer technology has enabled the use of virtual reality (VR) for the treatment of the fear of public speaking. There are two techniques for building virtual environments for the treatment of this fear: a model-based and a movie-based method. Both methods have the weakness that they are unrealistic and not controllable individually. To understand these disadvantages, this paper presents a virtual environment produced with Image Based Rendering (IBR) and a chroma-key simultaneously. IBR enables the creation of realistic virtual environments where the images are stitched panoramically with the photos taken from a digital camera. And the use of chroma-keys puts virtual audience members under individual control in the environment. In addition, real time capture technique is used in constructing the virtual environments enabling spoken interaction between the subject and a therapist or another subject.

Molecular Structure and Regulation of P2X Receptors With a Special Emphasis on the Role of P2X2 in the Auditory System.

PubMed

Mittal, Rahul; Chan, Brandon; Grati, M'hamed; Mittal, Jeenu; Patel, Kunal; Debs, Luca H; Patel, Amit P; Yan, Denise; Chapagain, Prem; Liu, Xue Zhong

2016-08-01

The P2X purinergic receptors are cation-selective channels gated by extracellular adenosine 5'-triphosphate (ATP). These purinergic receptors are found in virtually all mammalian cell types and facilitate a number of important physiological processes. Within the past few years, the characterization of crystal structures of the zebrafish P2X4 receptor in its closed and open states has provided critical insights into the mechanisms of ligand binding and channel activation. Understanding of this gating mechanism has facilitated to design and interpret new modeling and structure-function experiments to better elucidate how different agonists and antagonists can affect the receptor with differing levels of potency. This review summarizes the current knowledge on the structure, activation, allosteric modulators, function, and location of the different P2X receptors. Moreover, an emphasis on the P2X2 receptors has been placed in respect to its role in the auditory system. In particular, the discovery of three missense mutations in P2X2 receptors could become important areas of study in the field of gene therapy to treat progressive and noise-induced hearing loss. J. Cell. Physiol. 231: 1656-1670, 2016. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.

Cell-Matrix Interactions in Breast Carcinoma Invasion.

DTIC Science & Technology

1998-01-01

concentrated in hemidesmosomes, adhesive junctions which connect the basement membrane to the intracellular keratin cytoskeleton. In virtually all...fibronectin receptor contribute to the adhesive abnormalities of transformed fibroblasts by overexpressing this integrin in Chinese hamster ovary (CHO) cells...normal breast epithelium , the integrins expressed in breast carcinoma cells are diffusely distributed over the cell surface (Zutter et al., 1990

Projection and Reflection of American Culture via Mass Media--Case Study: Australia.

ERIC Educational Resources Information Center

Breen, Myles P.

The current Australian scene is a good example of how American culture as portrayed in the mass media is reflected by a receptor national culture. Australia, sharing a similar history and a common language with the United States, has virtually no resistance to American culture. Some differences in national characteristics, such as the Australian…

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

PubMed

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.

Realistic terrain visualization based on 3D virtual world technology

NASA Astrophysics Data System (ADS)

Huang, Fengru; Lin, Hui; Chen, Bin; Xiao, Cai

2009-09-01

The rapid advances in information technologies, e.g., network, graphics processing, and virtual world, have provided challenges and opportunities for new capabilities in information systems, Internet applications, and virtual geographic environments, especially geographic visualization and collaboration. In order to achieve meaningful geographic capabilities, we need to explore and understand how these technologies can be used to construct virtual geographic environments to help to engage geographic research. The generation of three-dimensional (3D) terrain plays an important part in geographical visualization, computer simulation, and virtual geographic environment applications. The paper introduces concepts and technologies of virtual worlds and virtual geographic environments, explores integration of realistic terrain and other geographic objects and phenomena of natural geographic environment based on SL/OpenSim virtual world technologies. Realistic 3D terrain visualization is a foundation of construction of a mirror world or a sand box model of the earth landscape and geographic environment. The capabilities of interaction and collaboration on geographic information are discussed as well. Further virtual geographic applications can be developed based on the foundation work of realistic terrain visualization in virtual environments.

Realistic terrain visualization based on 3D virtual world technology

NASA Astrophysics Data System (ADS)

Huang, Fengru; Lin, Hui; Chen, Bin; Xiao, Cai

2010-11-01

The rapid advances in information technologies, e.g., network, graphics processing, and virtual world, have provided challenges and opportunities for new capabilities in information systems, Internet applications, and virtual geographic environments, especially geographic visualization and collaboration. In order to achieve meaningful geographic capabilities, we need to explore and understand how these technologies can be used to construct virtual geographic environments to help to engage geographic research. The generation of three-dimensional (3D) terrain plays an important part in geographical visualization, computer simulation, and virtual geographic environment applications. The paper introduces concepts and technologies of virtual worlds and virtual geographic environments, explores integration of realistic terrain and other geographic objects and phenomena of natural geographic environment based on SL/OpenSim virtual world technologies. Realistic 3D terrain visualization is a foundation of construction of a mirror world or a sand box model of the earth landscape and geographic environment. The capabilities of interaction and collaboration on geographic information are discussed as well. Further virtual geographic applications can be developed based on the foundation work of realistic terrain visualization in virtual environments.

Evolution-based Virtual Content Insertion with Visually Virtual Interactions in Videos

NASA Astrophysics Data System (ADS)

Chang, Chia-Hu; Wu, Ja-Ling

With the development of content-based multimedia analysis, virtual content insertion has been widely used and studied for video enrichment and multimedia advertising. However, how to automatically insert a user-selected virtual content into personal videos in a less-intrusive manner, with an attractive representation, is a challenging problem. In this chapter, we present an evolution-based virtual content insertion system which can insert virtual contents into videos with evolved animations according to predefined behaviors emulating the characteristics of evolutionary biology. The videos are considered not only as carriers of message conveyed by the virtual content but also as the environment in which the lifelike virtual contents live. Thus, the inserted virtual content will be affected by the videos to trigger a series of artificial evolutions and evolve its appearances and behaviors while interacting with video contents. By inserting virtual contents into videos through the system, users can easily create entertaining storylines and turn their personal videos into visually appealing ones. In addition, it would bring a new opportunity to increase the advertising revenue for video assets of the media industry and online video-sharing websites.

Pragmatically on the sense of taste - a short treatise based on culinary art.

PubMed

Waluga, Marek; Jonderko, Krzysztof; Buschhaus, Magdalena

2013-01-01

The sense of taste is essential for proper functioning of the organism. The authors describe, in an accessible way, the complex mechanisms of taste perception. The structure of particular taste receptors, variants of their activation, as well as physical and chemical factors modifying the sensation of taste, are presented. Exquisite culinary examples are given in order to facilitate the reader with the understanding of why, at the level of the cerebral cortex, a virtually infinite number of combinations of taste sensations can be perceived. The discourse is spiced up by reflections of the eminent philosopher of taste, J.A. Brillat-Savarin, who convinces us that food intake should be not only a physiological act, but also a refined pleasure.

Pragmatically on the sense of taste – a short treatise based on culinary art

PubMed Central

Jonderko, Krzysztof; Buschhaus, Magdalena

2013-01-01

The sense of taste is essential for proper functioning of the organism. The authors describe, in an accessible way, the complex mechanisms of taste perception. The structure of particular taste receptors, variants of their activation, as well as physical and chemical factors modifying the sensation of taste, are presented. Exquisite culinary examples are given in order to facilitate the reader with the understanding of why, at the level of the cerebral cortex, a virtually infinite number of combinations of taste sensations can be perceived. The discourse is spiced up by reflections of the eminent philosopher of taste, J.A. Brillat-Savarin, who convinces us that food intake should be not only a physiological act, but also a refined pleasure. PMID:24868281

Research and Development of Web-Based Virtual Online Classroom

ERIC Educational Resources Information Center

Yang, Zongkai; Liu, Qingtang

2007-01-01

To build a web-based virtual learning environment depends on information technologies, concerns technology supporting learning methods and theories. A web-based virtual online classroom is designed and developed based on learning theories and streaming media technologies. And it is composed of two parts: instructional communicating environment…

Combat pneumococcal infections: adhesins as candidates for protein-based vaccine development.

PubMed

Gamez, Gustavo; Hammerschmidt, Sven

2012-03-01

Streptococcus pneumoniae (pneumococcus) is an asymptomatic colonizer of the upper respiratory tract in humans. However, these apparently harmless bacteria have also a high virulence potential and are known as the etiologic agent of respiratory and life-threatening invasive diseases. Dissemination of pneumococci from the nasopharynx into the lungs or bloodstream leads to community-acquired pneumonia, septicaemia and meningitis. Traditionally, pneumococcal diseases are treated with antibiotics and prevented with polysaccharide-based vaccines. However, due to the dramatic increase in antibiotic resistance and limitations of the current available vaccines, the burden of diseases remains high. Thus, combating pneumococcal transmission and infections has emphasized the need for a new generation of protein-based vaccines. Interactions of pneumococci with soluble host proteins or cellular receptors are crucial for adherence, colonization, transmigration of host barriers and immune evasion. Therefore, surface-exposed proteins involved in these pathogenic processes and virtually expressed by all pneumococcal strains and serotypes are the prime potential targets for an immunogenic and highly protective pneumococcal-derived carrier protein of a vaccine. In this review, we will address the state of the art in deciphering, i). the conservation, distribution and pathogenic role of recently discovered pneumococcal adhesins in colonization and invasive diseases, ii). the interactions of these virulence factors with host-proteins and receptors, iii). the subversion of the host immune and cellular responses, and iv). the potential of pneumococcal adhesins as vaccine candidates.

Web-based Three-dimensional Virtual Body Structures: W3D-VBS

PubMed Central

Temkin, Bharti; Acosta, Eric; Hatfield, Paul; Onal, Erhan; Tong, Alex

2002-01-01

Major efforts are being made to improve the teaching of human anatomy to foster cognition of visuospatial relationships. The Visible Human Project of the National Library of Medicine makes it possible to create virtual reality-based applications for teaching anatomy. Integration of traditional cadaver and illustration-based methods with Internet-based simulations brings us closer to this goal. Web-based three-dimensional Virtual Body Structures (W3D-VBS) is a next-generation immersive anatomical training system for teaching human anatomy over the Internet. It uses Visible Human data to dynamically explore, select, extract, visualize, manipulate, and stereoscopically palpate realistic virtual body structures with a haptic device. Tracking user’s progress through evaluation tools helps customize lesson plans. A self-guided “virtual tour” of the whole body allows investigation of labeled virtual dissections repetitively, at any time and place a user requires it. PMID:12223495

Web-based three-dimensional Virtual Body Structures: W3D-VBS.

PubMed

Temkin, Bharti; Acosta, Eric; Hatfield, Paul; Onal, Erhan; Tong, Alex

2002-01-01

Major efforts are being made to improve the teaching of human anatomy to foster cognition of visuospatial relationships. The Visible Human Project of the National Library of Medicine makes it possible to create virtual reality-based applications for teaching anatomy. Integration of traditional cadaver and illustration-based methods with Internet-based simulations brings us closer to this goal. Web-based three-dimensional Virtual Body Structures (W3D-VBS) is a next-generation immersive anatomical training system for teaching human anatomy over the Internet. It uses Visible Human data to dynamically explore, select, extract, visualize, manipulate, and stereoscopically palpate realistic virtual body structures with a haptic device. Tracking user's progress through evaluation tools helps customize lesson plans. A self-guided "virtual tour" of the whole body allows investigation of labeled virtual dissections repetitively, at any time and place a user requires it.

A Small Molecule Agonist of EphA2 Receptor Tyrosine Kinase Inhibits Tumor Cell Migration In Vitro and Prostate Cancer Metastasis In Vivo

PubMed Central

Guo, Hong; Miao, Hui; Tochtrop, Gregory P.; Hsieh, Jer-Tsong; Page, Phillip; Liu, Lili; Lindner, Daniel J.; Acharya, Chayan; MacKerell, Alexander D.; Ficker, Eckhard; Song, Jianxing; Wang, Bingcheng

2012-01-01

During tumor progression, EphA2 receptor can gain ligand-independent pro-oncogenic functions due to Akt activation and reduced ephrin-A ligand engagement. The effects can be reversed by ligand stimulation, which triggers the intrinsic tumor suppressive signaling pathways of EphA2 including inhibition of PI3/Akt and Ras/ERK pathways. These observations argue for development of small molecule agonists for EphA2 as potential tumor intervention agents. Through virtual screening and cell-based assays, we report here the identification and characterization of doxazosin as a novel small molecule agonist for EphA2 and EphA4, but not for other Eph receptors tested. NMR studies revealed extensive contacts of doxazosin with EphA2/A4, recapitulating both hydrophobic and electrostatic interactions recently found in the EphA2/ephrin-A1 complex. Clinically used as an α1-adrenoreceptor antagonist (Cardura®) for treating hypertension and benign prostate hyperplasia, doxazosin activated EphA2 independent of α1-adrenoreceptor. Similar to ephrin-A1, doxazosin inhibited Akt and ERK kinase activities in an EphA2-dependent manner. Treatment with doxazosin triggered EphA2 receptor internalization, and suppressed haptotactic and chemotactic migration of prostate cancer, breast cancer, and glioma cells. Moreover, in an orthotopic xenograft model, doxazosin reduced distal metastasis of human prostate cancer cells and prolonged survival in recipient mice. To our knowledge, doxazosin is the first small molecule agonist of a receptor tyrosine kinase that is capable of inhibiting malignant behaviors in vitro and in vivo. PMID:22916121

Constructing an atomic-resolution model of human P2X7 receptor followed by pharmacophore modeling to identify potential inhibitors.

PubMed

Ahmadi, Mehdi; Nowroozi, Amin; Shahlaei, Mohsen

2015-09-01

The P2X purinoceptor 7 (P2X7R) is a trimeric ATP-activated ion channel gated by extracellular ATP. P2X7R has important role in numerous diseases including pain, neurodegeneration, and inflammatory diseases such as rheumatoid arthritis and osteoarthritis. In this prospective, the discovery of small-molecule inhibitors for P2X7R as a novel therapeutic target has received considerable attention in recent years. At first, 3D structure of P2X7R was built by using homology modeling (HM) and a 50ns molecular dynamics simulation (MDS). Ligand-based quantitative pharmacophore modeling methodology of P2X7R antagonists were developed based on training set of 49 compounds. The best four-feature pharmacophore model, includes two hydrophobic aromatic, one hydrophobic and one aromatic ring features, has the highest correlation coefficient (0.874), cost difference (368.677), low RMSD (2.876), as well as it shows a high goodness of fit and enrichment factor. Consequently, some hit compounds were introduced as final candidates by employing virtual screening and molecular docking procedure simultaneously. Among these compounds, six potential molecule were identified as potential virtual leads which, as such or upon further optimization, can be used to design novel P2X7R inhibitors. Copyright © 2015 Elsevier Inc. All rights reserved.

Virtual reality measures in neuropsychological assessment: a meta-analytic review.

PubMed

Neguț, Alexandra; Matu, Silviu-Andrei; Sava, Florin Alin; David, Daniel

2016-02-01

Virtual reality-based assessment is a new paradigm for neuropsychological evaluation, that might provide an ecological assessment, compared to paper-and-pencil or computerized neuropsychological assessment. Previous research has focused on the use of virtual reality in neuropsychological assessment, but no meta-analysis focused on the sensitivity of virtual reality-based measures of cognitive processes in measuring cognitive processes in various populations. We found eighteen studies that compared the cognitive performance between clinical and healthy controls on virtual reality measures. Based on a random effects model, the results indicated a large effect size in favor of healthy controls (g = .95). For executive functions, memory and visuospatial analysis, subgroup analysis revealed moderate to large effect sizes, with superior performance in the case of healthy controls. Participants' mean age, type of clinical condition, type of exploration within virtual reality environments, and the presence of distractors were significant moderators. Our findings support the sensitivity of virtual reality-based measures in detecting cognitive impairment. They highlight the possibility of using virtual reality measures for neuropsychological assessment in research applications, as well as in clinical practice.

Computational Approaches for Decoding Select Odorant-Olfactory Receptor Interactions Using Mini-Virtual Screening

PubMed Central

Harini, K.; Sowdhamini, Ramanathan

2015-01-01

Olfactory receptors (ORs) belong to the class A G-Protein Coupled Receptor superfamily of proteins. Unlike G-Protein Coupled Receptors, ORs exhibit a combinatorial response to odors/ligands. ORs display an affinity towards a range of odor molecules rather than binding to a specific set of ligands and conversely a single odorant molecule may bind to a number of olfactory receptors with varying affinities. The diversity in odor recognition is linked to the highly variable transmembrane domains of these receptors. The purpose of this study is to decode the odor-olfactory receptor interactions using in silico docking studies. In this study, a ligand (odor molecules) dataset of 125 molecules was used to carry out in silico docking using the GLIDE docking tool (SCHRODINGER Inc Pvt LTD). Previous studies, with smaller datasets of ligands, have shown that orthologous olfactory receptors respond to similarly-tuned ligands, but are dramatically different in their efficacy and potency. Ligand docking results were applied on homologous pairs (with varying sequence identity) of ORs from human and mouse genomes and ligand binding residues and the ligand profile differed among such related olfactory receptor sequences. This study revealed that homologous sequences with high sequence identity need not bind to the same/ similar ligand with a given affinity. A ligand profile has been obtained for each of the 20 receptors in this analysis which will be useful for expression and mutation studies on these receptors. PMID:26221959

Internalization of G-protein-coupled receptors: Implication in receptor function, physiology and diseases.

PubMed

Calebiro, Davide; Godbole, Amod

2018-04-01

G protein-coupled receptors (GPCRs) are the largest family of membrane receptors and mediate the effects of numerous hormones and neurotransmitters. The nearly 1000 GPCRs encoded by the human genome regulate virtually all physiological functions and are implicated in the pathogenesis of prevalent human diseases such as thyroid disorders, hypertension or Parkinson's disease. As a result, 30-50% of all currently prescribed drugs are targeting these receptors. Once activated, GPCRs induce signals at the cell surface. This is often followed by internalization, a process that results in the transfer of receptors from the plasma membrane to membranes of the endosomal compartment. Internalization was initially thought to be mainly implicated in signal desensitization, a mechanism of adaptation to prolonged receptor stimulation. However, several unexpected functions have subsequently emerged. Most notably, accumulating evidence indicates that internalization can induce prolonged receptor signaling on intracellular membranes, which is apparently required for at least some biological effects of hormones like TSH, LH and adrenaline. These findings reveal an even stronger connection between receptor internalization and signaling than previously thought. Whereas new studies are just beginning to reveal an important physiological role for GPCR signaling after internalization and ways to exploit it for therapeutic purposes, future investigations will be required to explore its involvement in human disease. Copyright © 2018 Elsevier Ltd. All rights reserved.

The role of virtual articulator in prosthetic and restorative dentistry.

PubMed

Koralakunte, Pavankumar Ravi; Aljanakh, Mohammad

2014-07-01

Virtual reality is a computer based technology linked with the future of dentistry and dental practice. The virtual articulator is one such application in prosthetic and restorative dentistry based on virtual reality that will significantly reduce the limitations of the mechanical articulator, and by simulation of real patient data, allow analyses with regard to static and dynamic occlusion as well as to jaw relation. It is the purpose of this article to present the concepts and strategies for a future replacement of the mechanical articulator by a virtual one. Also, a brief note on virtual reality haptic system has been highlighted along with newly developed touch enabled virtual articulator.

Interference Cognizant Network Scheduling

NASA Technical Reports Server (NTRS)

Hall, Brendan (Inventor); Bonk, Ted (Inventor); DeLay, Benjamin F. (Inventor); Varadarajan, Srivatsan (Inventor); Smithgall, William Todd (Inventor)

2017-01-01

Systems and methods for interference cognizant network scheduling are provided. In certain embodiments, a method of scheduling communications in a network comprises identifying a bin of a global timeline for scheduling an unscheduled virtual link, wherein a bin is a segment of the timeline; identifying a pre-scheduled virtual link in the bin; and determining if the pre-scheduled and unscheduled virtual links share a port. In certain embodiments, if the unscheduled and pre-scheduled virtual links don't share a port, scheduling transmission of the unscheduled virtual link to overlap with the scheduled transmission of the pre-scheduled virtual link; and if the unscheduled and pre-scheduled virtual links share a port: determining a start time delay for the unscheduled virtual link based on the port; and scheduling transmission of the unscheduled virtual link in the bin based on the start time delay to overlap part of the scheduled transmission of the pre-scheduled virtual link.

New Thermal Taste Actuation Technology for Future Multisensory Virtual Reality and Internet.

PubMed

Karunanayaka, Kasun; Johari, Nurafiqah; Hariri, Surina; Camelia, Hanis; Bielawski, Kevin Stanley; Cheok, Adrian David

2018-04-01

Today's virtual reality (VR) applications such as gaming, multisensory entertainment, remote dining, and online shopping are mainly based on audio, visual, and touch interactions between humans and virtual worlds. Integrating the sense of taste into VR is difficult since humans are dependent on chemical-based taste delivery systems. This paper presents the 'Thermal Taste Machine', a new digital taste actuation technology that can effectively produce and modify thermal taste sensations on the tongue. It modifies the temperature of the surface of the tongue within a short period of time (from 25°C to 40 °C while heating, and from 25°C to 10 °C while cooling). We tested this device on human subjects and described the experience of thermal taste using 20 known (taste and non-taste) sensations. Our results suggested that rapidly heating the tongue produces sweetness, fatty/oiliness, electric taste, warmness, and reduces the sensibility for metallic taste. Similarly, cooling the tongue produced mint taste, pleasantness, and coldness. By conducting another user study on the perceived sweetness of sucrose solutions after the thermal stimulation, we found that heating the tongue significantly enhances the intensity of sweetness for both thermal tasters and non-thermal tasters. Also, we found that faster temperature rises on the tongue produce more intense sweet sensations for thermal tasters. This technology will be useful in two ways: First, it can produce taste sensations without using chemicals for the individuals who are sensitive to thermal taste. Second, the temperature rise of the device can be used as a way to enhance the intensity of sweetness. We believe that this technology can be used to digitally produce and enhance taste sensations in future virtual reality applications. The key novelties of this paper are as follows: 1. Development of a thermal taste actuation technology for stimulating the human taste receptors, 2. Characterization of the thermal taste produced by the device using taste-related sensations and non-taste related sensations, 3. Research on enhancing the intensity for sucrose solutions using thermal stimulation, 4. Research on how different speeds of heating affect the intensity of sweetness produced by thermal stimulation.

A lipid-binding loop of botulinum neurotoxin serotypes B, DC and G is an essential feature to confer their exquisite potency

PubMed Central

Le Blanc, Alexander; Mahrhold, Stefan; Piesker, Janett; Luppa, Peter B.

2018-01-01

The exceptional toxicity of botulinum neurotoxins (BoNTs) is mediated by high avidity binding to complex polysialogangliosides and intraluminal segments of synaptic vesicle proteins embedded in the presynaptic membrane. One peculiarity is an exposed hydrophobic loop in the toxin’s cell binding domain HC, which is located between the ganglioside- and protein receptor-binding sites, and that is particularly pronounced in the serotypes BoNT/B, DC, and G sharing synaptotagmin as protein receptor. Here, we provide evidence that this HC loop is a critical component of their tripartite receptor recognition complex. Binding to nanodisc-embedded receptors and toxicity were virtually abolished in BoNT mutants lacking residues at the tip of the HC loop. Surface plasmon resonance experiments revealed that only insertion of the HC loop into the lipid-bilayer compensates for the entropic penalty inflicted by the dual-receptor binding. Our results represent a new paradigm of how BoNT/B, DC, and G employ ternary interactions with a protein, ganglioside, and lipids to mediate their extraordinary neurotoxicity. PMID:29718991

Nine pairs of megastigmane enantiomers from the leaves of Eucommia ulmoides Oliver.

PubMed

Yan, Jiankun; Shi, Xuliu; Donkor, Paul Owusu; Zhu, Huajie; Gao, Xiumei; Ding, Liqin; Qiu, Feng

2017-10-01

Nine pairs of megastigmane enantiomers (1a/1b-9a/9b), comprising two new compounds (6S,9R)-blumenol C (7b), (6S,9S)-blumenol C (8b), two pairs of enantiomers (+)-(6R)-eucomegastigmane A (1a), (-)-(6S)-eucomegastigmane A (1b), (+)-(3S,4S)-eucomegastigmane B (5a), (-)-(3R,4R)-eucomegastigmane B (5b) isolated by chiral resolution firstly, and twelve known compounds, were isolated from the leaves of Eucommia ulmoides Oliver. Their structures were elucidated based on extensive spectroscopic analysis. Absolute configurations of the megastigmane enantiomers were assigned by comparing experimental ECD and OR with calculated ECD and OR. Docking-based virtual screening of all compounds showed that megastigmane enantiomers have weak intermolecular interactions with the binding site residues of angiotensin-converting enzyme (ACE) and angiotensin II type 1 receptor (AT 1 R).

Tracking single membrane targets of human autoantibodies using single nanoparticle imaging.

PubMed

Jézéquel, Julie; Dupuis, Julien P; Maingret, François; Groc, Laurent

2018-04-21

Over the past decade, an increasing number of neurological and neuropsychiatric diseases have been associated with the expression of autoantibodies directed against neuronal targets, including neurotransmitter receptors. Although cell-based assays are routinely used in clinics to detect the presence of immunoglobulins, such tests often provide heterogeneous outcomes due to their limited sensitivity, especially at low titers. Thus, there is an urging need for new methods allowing the detection of autoantibodies in seropositive patients that cannot always be clinically distinguished from seronegative ones. Here we make a case for single nanoparticle imaging approaches as a highly sensitive antibody detection assay. Through high-affinity interactions between functionalized nanoparticles and autoantibodies that recognize extracellular domains of membrane neuronal targets, single nanoparticle imaging allows a live surface staining of transmembrane proteins and gives access to their surface dynamics. We show here that this method is well-suited to detect low titers of purified immunoglobulin G (IgG) from first-episode psychotic patients and demonstrate that these IgG target glutamatergic N-Methyl-d-Aspartate receptors (NMDAR) in live hippocampal neurons. The molecular behaviors of targeted membrane receptors were indistinguishable from those of endogenous GluN1 NMDAR subunit and were virtually independent of the IgG concentration present in the sample contrary to classical cell-based assays. Single nanoparticle imaging emerges as a real-time sensitive method to detect IgG directed against neuronal surface proteins, which could be used as an additional step to rule out ambiguous seropositivity diagnoses. Copyright © 2018 Elsevier B.V. All rights reserved.

3D pharmacophore-based virtual screening, docking and density functional theory approach towards the discovery of novel human epidermal growth factor receptor-2 (HER2) inhibitors.

PubMed

Gogoi, Dhrubajyoti; Baruah, Vishwa Jyoti; Chaliha, Amrita Kashyap; Kakoti, Bibhuti Bhushan; Sarma, Diganta; Buragohain, Alak Kumar

2016-12-21

Human epidermal growth factor receptor 2 (HER2) is one of the four members of the epidermal growth factor receptor (EGFR) family and is expressed to facilitate cellular proliferation across various tissue types. Therapies targeting HER2, which is a transmembrane glycoprotein with tyrosine kinase activity, offer promising prospects especially in breast and gastric/gastroesophageal cancer patients. Persistence of both primary and acquired resistance to various routine drugs/antibodies is a disappointing outcome in the treatment of many HER2 positive cancer patients and is a challenge that requires formulation of new and improved strategies to overcome the same. Identification of novel HER2 inhibitors with improved therapeutics index was performed with a highly correlating (r=0.975) ligand-based pharmacophore model (Hypo1) in this study. Hypo1 was generated from a training set of 22 compounds with HER2 inhibitory activity and this well-validated hypothesis was subsequently used as a 3D query to screen compounds in a total of four databases of which two were natural product databases. Further, these compounds were analyzed for compliance with Veber's drug-likeness rule and optimum ADMET parameters. The selected compounds were then subjected to molecular docking and Density Functional Theory (DFT) analysis to discern their molecular interactions at the active site of HER2. The findings thus presented would be an important starting point towards the development of novel HER2 inhibitors using well-validated computational techniques. Copyright © 2016 Elsevier Ltd. All rights reserved.

Real-time interactive virtual tour on the World Wide Web (WWW)

NASA Astrophysics Data System (ADS)

Yoon, Sanghyuk; Chen, Hai-jung; Hsu, Tom; Yoon, Ilmi

2003-12-01

Web-based Virtual Tour has become a desirable and demanded application, yet challenging due to the nature of web application's running environment such as limited bandwidth and no guarantee of high computation power on the client side. Image-based rendering approach has attractive advantages over traditional 3D rendering approach in such Web Applications. Traditional approach, such as VRML, requires labor-intensive 3D modeling process, high bandwidth and computation power especially for photo-realistic virtual scenes. QuickTime VR and IPIX as examples of image-based approach, use panoramic photos and the virtual scenes that can be generated from photos directly skipping the modeling process. But, these image-based approaches may require special cameras or effort to take panoramic views and provide only one fixed-point look-around and zooming in-out rather than 'walk around', that is a very important feature to provide immersive experience to virtual tourists. The Web-based Virtual Tour using Tour into the Picture employs pseudo 3D geometry with image-based rendering approach to provide viewers with immersive experience of walking around the virtual space with several snap shots of conventional photos.

A Virtual Campus Based on Human Factor Engineering

ERIC Educational Resources Information Center

Yang, Yuting; Kang, Houliang

2014-01-01

Three Dimensional or 3D virtual reality has become increasingly popular in many areas, especially in building a digital campus. This paper introduces a virtual campus, which is based on a 3D model of The Tourism and Culture College of Yunnan University (TCYU). Production of the virtual campus was aided by Human Factor and Ergonomics (HF&E), an…

Mice with a "monoclonal nose": perturbations in an olfactory map impair odor discrimination.

PubMed

Fleischmann, Alexander; Shykind, Benjamin M; Sosulski, Dara L; Franks, Kevin M; Glinka, Meredith E; Mei, Dan Feng; Sun, Yonghua; Kirkland, Jennifer; Mendelsohn, Monica; Albers, Mark W; Axel, Richard

2008-12-26

We have altered the neural representation of odors in the brain by generating a mouse with a "monoclonal nose" in which greater than 95% of the sensory neurons express a single odorant receptor, M71. As a consequence, the frequency of sensory neurons expressing endogenous receptor genes is reduced 20-fold. We observe that these mice can smell, but odor discrimination and performance in associative olfactory learning tasks are impaired. However, these mice cannot detect the M71 ligand acetophenone despite the observation that virtually all sensory neurons and glomeruli are activated by this odor. The M71 transgenic mice readily detect other odors in the presence of acetophenone. These observations have implications for how receptor activation in the periphery is represented in the brain and how these representations encode odors.

Novel Design Strategy for Checkpoint Kinase 2 Inhibitors Using Pharmacophore Modeling, Combinatorial Fusion, and Virtual Screening

PubMed Central

Wang, Yen-Ling

2014-01-01

Checkpoint kinase 2 (Chk2) has a great effect on DNA-damage and plays an important role in response to DNA double-strand breaks and related lesions. In this study, we will concentrate on Chk2 and the purpose is to find the potential inhibitors by the pharmacophore hypotheses (PhModels), combinatorial fusion, and virtual screening techniques. Applying combinatorial fusion into PhModels and virtual screening techniques is a novel design strategy for drug design. We used combinatorial fusion to analyze the prediction results and then obtained the best correlation coefficient of the testing set (r test) with the value 0.816 by combining the BesttrainBesttest and FasttrainFasttest prediction results. The potential inhibitors were selected from NCI database by screening according to BesttrainBesttest + FasttrainFasttest prediction results and molecular docking with CDOCKER docking program. Finally, the selected compounds have high interaction energy between a ligand and a receptor. Through these approaches, 23 potential inhibitors for Chk2 are retrieved for further study. PMID:24864236

Hierarchical virtual screening approaches in small molecule drug discovery.

PubMed

Kumar, Ashutosh; Zhang, Kam Y J

2015-01-01

Virtual screening has played a significant role in the discovery of small molecule inhibitors of therapeutic targets in last two decades. Various ligand and structure-based virtual screening approaches are employed to identify small molecule ligands for proteins of interest. These approaches are often combined in either hierarchical or parallel manner to take advantage of the strength and avoid the limitations associated with individual methods. Hierarchical combination of ligand and structure-based virtual screening approaches has received noteworthy success in numerous drug discovery campaigns. In hierarchical virtual screening, several filters using ligand and structure-based approaches are sequentially applied to reduce a large screening library to a number small enough for experimental testing. In this review, we focus on different hierarchical virtual screening strategies and their application in the discovery of small molecule modulators of important drug targets. Several virtual screening studies are discussed to demonstrate the successful application of hierarchical virtual screening in small molecule drug discovery. Copyright © 2014 Elsevier Inc. All rights reserved.

Alternative Entry Receptors for Herpes Simplex Virus and Their Roles in Disease

PubMed Central

Taylor, Joann M.; Lin, Erick; Susmarski, Nanette; Yoon, Miri; Zago, Anna; Ware, Carl F.; Pfeffer, Klaus; Miyoshi, Jun; Takai, Yoshimi; Spear, Patricia G.

2007-01-01

SUMMARY Either herpesvirus entry mediator (HVEM, TNFRSF14) or nectin-1 (PVRL1) is sufficient for herpes simplex virus (HSV) infection of cultured cells. The contribution of individual receptors to infection in vivo and to disease is less clear. To assess this, Tnfrsf14 −/− and/or Pvrl1 −/− mice were challenged intravaginally with HSV-2. Infection of the vaginal epithelium occurred in the absence of either HVEM or nectin-1, but was virtually undetectable when both receptors were absent, indicating that either HVEM or nectin-1 was necessary. Absence of nectin-1 (but not HVEM) reduced efficiency of infection of the vaginal epithelium and viral spread to the nervous system, attenuating neurological disease and preventing external lesion development. While nectin-1 proved not to be essential for infection of the nervous system, it is required for the full manifestations of disease. This study illustrates the value of mutant mice for understanding receptor contributions to disease caused by a human virus. PMID:18005714

The serotonin receptor 7 and the structural plasticity of brain circuits

PubMed Central

Volpicelli, Floriana; Speranza, Luisa; di Porzio, Umberto; Crispino, Marianna; Perrone-Capano, Carla

2014-01-01

Serotonin (5-hydroxytryptamine, 5-HT) modulates numerous physiological processes in the nervous system. Together with its function as neurotransmitter, 5-HT regulates neurite outgrowth, dendritic spine shape and density, growth cone motility and synapse formation during development. In the mammalian brain 5-HT innervation is virtually ubiquitous and the diversity and specificity of its signaling and function arise from at least 20 different receptors, grouped in 7 classes. Here we will focus on the role 5-HT7 receptor (5-HT7R) in the correct establishment of neuronal cytoarchitecture during development, as also suggested by its involvement in several neurodevelopmental disorders. The emerging picture shows that this receptor is a key player contributing not only to shape brain networks during development but also to remodel neuronal wiring in the mature brain, thus controlling cognitive and emotional responses. The activation of 5-HT7R might be one of the mechanisms underlying the ability of the CNS to respond to different stimuli by modulation of its circuit configuration. PMID:25309369

Incorporating Virtual Reactions into a Logic-based Ligand-based Virtual Screening Method to Discover New Leads

PubMed Central

Reynolds, Christopher R; Muggleton, Stephen H; Sternberg, Michael J E

2015-01-01

The use of virtual screening has become increasingly central to the drug development pipeline, with ligand-based virtual screening used to screen databases of compounds to predict their bioactivity against a target. These databases can only represent a small fraction of chemical space, and this paper describes a method of exploring synthetic space by applying virtual reactions to promising compounds within a database, and generating focussed libraries of predicted derivatives. A ligand-based virtual screening tool Investigational Novel Drug Discovery by Example (INDDEx) is used as the basis for a system of virtual reactions. The use of virtual reactions is estimated to open up a potential space of 1.21×1012 potential molecules. A de novo design algorithm known as Partial Logical-Rule Reactant Selection (PLoRRS) is introduced and incorporated into the INDDEx methodology. PLoRRS uses logical rules from the INDDEx model to select reactants for the de novo generation of potentially active products. The PLoRRS method is found to increase significantly the likelihood of retrieving molecules similar to known actives with a p-value of 0.016. Case studies demonstrate that the virtual reactions produce molecules highly similar to known actives, including known blockbuster drugs. PMID:26583052

Engineering Laboratory Instruction in Virtual Environment--"eLIVE"

ERIC Educational Resources Information Center

Chaturvedi, Sushil; Prabhakaran, Ramamurthy; Yoon, Jaewan; Abdel-Salam, Tarek

2011-01-01

A novel application of web-based virtual laboratories to prepare students for physical experiments is explored in some detail. The pedagogy of supplementing physical laboratory with web-based virtual laboratories is implemented by developing a web-based tool, designated in this work as "eLIVE", an acronym for Engineering Laboratory…

Simplified Virtualization in a HEP/NP Environment with Condor

NASA Astrophysics Data System (ADS)

Strecker-Kellogg, W.; Caramarcu, C.; Hollowell, C.; Wong, T.

2012-12-01

In this work we will address the development of a simple prototype virtualized worker node cluster, using Scientific Linux 6.x as a base OS, KVM and the libvirt API for virtualization, and the Condor batch software to manage virtual machines. The discussion in this paper provides details on our experience with building, configuring, and deploying the various components from bare metal, including the base OS, creation and distribution of the virtualized OS images and the integration of batch services with the virtual machines. Our focus was on simplicity and interoperability with our existing architecture.

The Role of Virtual Articulator in Prosthetic and Restorative Dentistry

PubMed Central

Aljanakh, Mohammad

2014-01-01

Virtual reality is a computer based technology linked with the future of dentistry and dental practice. The virtual articulator is one such application in prosthetic and restorative dentistry based on virtual reality that will significantly reduce the limitations of the mechanical articulator, and by simulation of real patient data, allow analyses with regard to static and dynamic occlusion as well as to jaw relation. It is the purpose of this article to present the concepts and strategies for a future replacement of the mechanical articulator by a virtual one. Also, a brief note on virtual reality haptic system has been highlighted along with newly developed touch enabled virtual articulator. PMID:25177664

Cognitive training on stroke patients via virtual reality-based serious games.

PubMed

Gamito, Pedro; Oliveira, Jorge; Coelho, Carla; Morais, Diogo; Lopes, Paulo; Pacheco, José; Brito, Rodrigo; Soares, Fabio; Santos, Nuno; Barata, Ana Filipa

2017-02-01

Use of virtual reality environments in cognitive rehabilitation offers cost benefits and other advantages. In order to test the effectiveness of a virtual reality application for neuropsychological rehabilitation, a cognitive training program using virtual reality was applied to stroke patients. A virtual reality-based serious games application for cognitive training was developed, with attention and memory tasks consisting of daily life activities. Twenty stroke patients were randomly assigned to two conditions: exposure to the intervention, and waiting list control. The results showed significant improvements in attention and memory functions in the intervention group, but not in the controls. Overall findings provide further support for the use of VR cognitive training applications in neuropsychological rehabilitation. Implications for Rehabilitation Improvements in memory and attention functions following a virtual reality-based serious games intervention. Training of daily-life activities using a virtual reality application. Accessibility to training contents.

Architecture of web services in the enhancement of real-time 3D video virtualization in cloud environment

NASA Astrophysics Data System (ADS)

Bada, Adedayo; Wang, Qi; Alcaraz-Calero, Jose M.; Grecos, Christos

2016-04-01

This paper proposes a new approach to improving the application of 3D video rendering and streaming by jointly exploring and optimizing both cloud-based virtualization and web-based delivery. The proposed web service architecture firstly establishes a software virtualization layer based on QEMU (Quick Emulator), an open-source virtualization software that has been able to virtualize system components except for 3D rendering, which is still in its infancy. The architecture then explores the cloud environment to boost the speed of the rendering at the QEMU software virtualization layer. The capabilities and inherent limitations of Virgil 3D, which is one of the most advanced 3D virtual Graphics Processing Unit (GPU) available, are analyzed through benchmarking experiments and integrated into the architecture to further speed up the rendering. Experimental results are reported and analyzed to demonstrate the benefits of the proposed approach.

Exploring Virtual Reality for Classroom Use: The Virtual Reality and Education Lab at East Carolina University.

ERIC Educational Resources Information Center

Auld, Lawrence W. S.; Pantelidis, Veronica S.

1994-01-01

Describes the Virtual Reality and Education Lab (VREL) established at East Carolina University to study the implications of virtual reality for elementary and secondary education. Highlights include virtual reality software evaluation; hardware evaluation; computer-based curriculum objectives which could use virtual reality; and keeping current…

Computational modeling-based discovery of novel classes of anti-inflammatory drugs that target lanthionine synthetase C-like protein 2.

PubMed

Lu, Pinyi; Hontecillas, Raquel; Horne, William T; Carbo, Adria; Viladomiu, Monica; Pedragosa, Mireia; Bevan, David R; Lewis, Stephanie N; Bassaganya-Riera, Josep

2012-01-01

Lanthionine synthetase component C-like protein 2 (LANCL2) is a member of the eukaryotic lanthionine synthetase component C-Like protein family involved in signal transduction and insulin sensitization. Recently, LANCL2 is a target for the binding and signaling of abscisic acid (ABA), a plant hormone with anti-diabetic and anti-inflammatory effects. The goal of this study was to determine the role of LANCL2 as a potential therapeutic target for developing novel drugs and nutraceuticals against inflammatory diseases. Previously, we performed homology modeling to construct a three-dimensional structure of LANCL2 using the crystal structure of lanthionine synthetase component C-like protein 1 (LANCL1) as a template. Using this model, structure-based virtual screening was performed using compounds from NCI (National Cancer Institute) Diversity Set II, ChemBridge, ZINC natural products, and FDA-approved drugs databases. Several potential ligands were identified using molecular docking. In order to validate the anti-inflammatory efficacy of the top ranked compound (NSC61610) in the NCI Diversity Set II, a series of in vitro and pre-clinical efficacy studies were performed using a mouse model of dextran sodium sulfate (DSS)-induced colitis. Our findings showed that the lead compound, NSC61610, activated peroxisome proliferator-activated receptor gamma in a LANCL2- and adenylate cyclase/cAMP dependent manner in vitro and ameliorated experimental colitis by down-modulating colonic inflammatory gene expression and favoring regulatory T cell responses. LANCL2 is a novel therapeutic target for inflammatory diseases. High-throughput, structure-based virtual screening is an effective computational-based drug design method for discovering anti-inflammatory LANCL2-based drug candidates.

Computational Modeling-Based Discovery of Novel Classes of Anti-Inflammatory Drugs That Target Lanthionine Synthetase C-Like Protein 2

PubMed Central

Lu, Pinyi; Hontecillas, Raquel; Horne, William T.; Carbo, Adria; Viladomiu, Monica; Pedragosa, Mireia; Bevan, David R.; Lewis, Stephanie N.; Bassaganya-Riera, Josep

2012-01-01

Background Lanthionine synthetase component C-like protein 2 (LANCL2) is a member of the eukaryotic lanthionine synthetase component C-Like protein family involved in signal transduction and insulin sensitization. Recently, LANCL2 is a target for the binding and signaling of abscisic acid (ABA), a plant hormone with anti-diabetic and anti-inflammatory effects. Methodology/Principal Findings The goal of this study was to determine the role of LANCL2 as a potential therapeutic target for developing novel drugs and nutraceuticals against inflammatory diseases. Previously, we performed homology modeling to construct a three-dimensional structure of LANCL2 using the crystal structure of lanthionine synthetase component C-like protein 1 (LANCL1) as a template. Using this model, structure-based virtual screening was performed using compounds from NCI (National Cancer Institute) Diversity Set II, ChemBridge, ZINC natural products, and FDA-approved drugs databases. Several potential ligands were identified using molecular docking. In order to validate the anti-inflammatory efficacy of the top ranked compound (NSC61610) in the NCI Diversity Set II, a series of in vitro and pre-clinical efficacy studies were performed using a mouse model of dextran sodium sulfate (DSS)-induced colitis. Our findings showed that the lead compound, NSC61610, activated peroxisome proliferator-activated receptor gamma in a LANCL2- and adenylate cyclase/cAMP dependent manner in vitro and ameliorated experimental colitis by down-modulating colonic inflammatory gene expression and favoring regulatory T cell responses. Conclusions/Significance LANCL2 is a novel therapeutic target for inflammatory diseases. High-throughput, structure-based virtual screening is an effective computational-based drug design method for discovering anti-inflammatory LANCL2-based drug candidates. PMID:22509338

Facilitating 3D Virtual World Learning Environments Creation by Non-Technical End Users through Template-Based Virtual World Instantiation

ERIC Educational Resources Information Center

Liu, Chang; Zhong, Ying; Ozercan, Sertac; Zhu, Qing

2013-01-01

This paper presents a template-based solution to overcome technical barriers non-technical computer end users face when developing functional learning environments in three-dimensional virtual worlds (3DVW). "iVirtualWorld," a prototype of a platform-independent 3DVW creation tool that implements the proposed solution, facilitates 3DVW…

Pre-Service Teachers' Perspectives on Using Scenario-Based Virtual Worlds in Science Education

ERIC Educational Resources Information Center

Kennedy-Clark, Shannon

2011-01-01

This paper presents the findings of a study on the current knowledge and attitudes of pre-service teachers on the use of scenario-based multi-user virtual environments in science education. The 28 participants involved in the study were introduced to "Virtual Singapura," a multi-user virtual environment, and completed an open-ended questionnaire.…

Shape-Based Virtual Screening with Volumetric Aligned Molecular Shapes

PubMed Central

Koes, David Ryan; Camacho, Carlos J.

2014-01-01

Shape-based virtual screening is an established and effective method for identifying small molecules that are similar in shape and function to a reference ligand. We describe a new method of shape-based virtual screening, volumetric aligned molecular shapes (VAMS). VAMS uses efficient data structures to encode and search molecular shapes. We demonstrate that VAMS is an effective method for shape-based virtual screening and that it can be successfully used as a pre-filter to accelerate more computationally demanding search algorithms. Unique to VAMS is a novel minimum/maximum shape constraint query for precisely specifying the desired molecular shape. Shape constraint searches in VAMS are particularly efficient and millions of shapes can be searched in a fraction of a second. We compare the performance of VAMS with two other shape-based virtual screening algorithms a benchmark of 102 protein targets consisting of more than 32 million molecular shapes and find that VAMS provides a competitive trade-off between run-time performance and virtual screening performance. PMID:25049193

The Role of Semantics in Next-Generation Online Virtual World-Based Retail Store

NASA Astrophysics Data System (ADS)

Sharma, Geetika; Anantaram, C.; Ghosh, Hiranmay

Online virtual environments are increasingly becoming popular for entrepreneurship. While interactions are primarily between avatars, some interactions could occur through intelligent chatbots. Such interactions require connecting to backend business applications to obtain information, carry out real-world transactions etc. In this paper, we focus on integrating business application systems with virtual worlds. We discuss the probable features of a next-generation online virtual world-based retail store and the technologies involved in realizing the features of such a store. In particular, we examine the role of semantics in integrating popular virtual worlds with business applications to provide natural language based interactions.

Designing communication and remote controlling of virtual instrument network system

NASA Astrophysics Data System (ADS)

Lei, Lin; Wang, Houjun; Zhou, Xue; Zhou, Wenjian

2005-01-01

In this paper, a virtual instrument network through the LAN and finally remote control of virtual instruments is realized based on virtual instrument and LabWindows/CVI software platform. The virtual instrument network system is made up of three subsystems. There are server subsystem, telnet client subsystem and local instrument control subsystem. This paper introduced virtual instrument network structure in detail based on LabWindows. Application procedure design of virtual instrument network communication, the Client/the programming mode of the server, remote PC and server communication far realizing, the control power of the workstation is transmitted, server program and so on essential technical were introduced. And virtual instruments network may connect to entire Internet on. Above-mentioned technology, through measuring the application in the electronic measurement virtual instrument network that is already built up, has verified the actual using value of the technology. Experiment and application validate that this design is resultful.

The Effect of Virtual versus Traditional Learning in Achieving Competency-Based Skills

ERIC Educational Resources Information Center

Mosalanejad, Leili; Shahsavari, Sakine; Sobhanian, Saeed; Dastpak, Mehdi

2012-01-01

Background: By rapid developing of the network technology, the internet-based learning methods are substituting the traditional classrooms making them expand to the virtual network learning environment. The purpose of this study was to determine the effectiveness of virtual systems on competency-based skills of first-year nursing students.…

77 FR 5008 - Solios Power Mid-Atlantic Virtual LLC; Supplemental Notice That Initial Market-Based Rate Filing...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-02-01

...-referenced proceeding are accessible in the Commission's eLibrary system by clicking on the appropriate link... Mid-Atlantic Virtual LLC; Supplemental Notice That Initial Market-Based Rate Filing Includes Request... of Solios Power Mid-Atlantic Virtual LLC's application for market-based rate authority, with an...

Intelligent web agents for a 3D virtual community

NASA Astrophysics Data System (ADS)

Dave, T. M.; Zhang, Yanqing; Owen, G. S. S.; Sunderraman, Rajshekhar

2003-08-01

In this paper, we propose an Avatar-based intelligent agent technique for 3D Web based Virtual Communities based on distributed artificial intelligence, intelligent agent techniques, and databases and knowledge bases in a digital library. One of the goals of this joint NSF (IIS-9980130) and ACM SIGGRAPH Education Committee (ASEC) project is to create a virtual community of educators and students who have a common interest in comptuer graphics, visualization, and interactive techniqeus. In this virtual community (ASEC World) Avatars will represent the educators, students, and other visitors to the world. Intelligent agents represented as specially dressed Avatars will be available to assist the visitors to ASEC World. The basic Web client-server architecture of the intelligent knowledge-based avatars is given. Importantly, the intelligent Web agent software system for the 3D virtual community is implemented successfully.

ChemScreener: A Distributed Computing Tool for Scaffold based Virtual Screening.

PubMed

Karthikeyan, Muthukumarasamy; Pandit, Deepak; Vyas, Renu

2015-01-01

In this work we present ChemScreener, a Java-based application to perform virtual library generation combined with virtual screening in a platform-independent distributed computing environment. ChemScreener comprises a scaffold identifier, a distinct scaffold extractor, an interactive virtual library generator as well as a virtual screening module for subsequently selecting putative bioactive molecules. The virtual libraries are annotated with chemophore-, pharmacophore- and toxicophore-based information for compound prioritization. The hits selected can then be further processed using QSAR, docking and other in silico approaches which can all be interfaced within the ChemScreener framework. As a sample application, in this work scaffold selectivity, diversity, connectivity and promiscuity towards six important therapeutic classes have been studied. In order to illustrate the computational power of the application, 55 scaffolds extracted from 161 anti-psychotic compounds were enumerated to produce a virtual library comprising 118 million compounds (17 GB) and annotated with chemophore, pharmacophore and toxicophore based features in a single step which would be non-trivial to perform with many standard software tools today on libraries of this size.

Pharmacophore based approach to design inhibitors in crustaceans: an insight into the molt inhibition response to the receptor guanylyl cyclase.

PubMed

Shrivastava, Sajal; Princy, S Adline

2014-04-01

The first set of competitive inhibitors of molt inhibiting hormone (MIH) has been developed using the effective approaches such as Hip-Hop, virtual screening and manual alterations. Moreover, the conserved residues at 71 and 72 positions in the molt inhibiting hormone is known to be significant for selective inhibition of ecdysteroidogenesis; thus, the information from mutation and solution structure were used to generate common pharmacophore features. The geometry of the final six-feature pharmacophore was also found to be consistent with the homology-modeled MIH structures from various other decapod crustaceans. The Hypo-1, comprising six features hypothesis was carefully selected as a best pharmacophore model for virtual screening created on the basis of rank score and cluster processes. The hypothesis was validated and the database was virtually screened using this 3D query and the compounds were then manually altered to enhance the fit value. The hits obtained were further filtered for drug-likeness, which is expressed as physicochemical properties that contribute to favorable ADME/Tox profiles to eliminate the molecules exhibit toxicity and poor pharmacokinetics. In conclusion, the higher fit values of CI-1 (4.6), CI-4 (4.9) and CI-7 (4.2) in conjunction with better pharmacokinetic profile made these molecules practically helpful tool to increase production by accelerating molt in crustaceans. The use of feeding sub-therapeutic dosages of these growth enhancers can be very effectively implemented and certainly turn out to be a vital part of emerging nutritional strategies for economically important crustacean livestock.

Comparing Science Virtual and Paper-Based Test to Measure Students’ Critical Thinking based on VAK Learning Style Model

NASA Astrophysics Data System (ADS)

Rosyidah, T. H.; Firman, H.; Rusyati, L.

2017-02-01

This research was comparing virtual and paper-based test to measure students’ critical thinking based on VAK (Visual-Auditory-Kynesthetic) learning style model. Quasi experiment method with one group post-test only design is applied in this research in order to analyze the data. There was 40 eight grade students at one of public junior high school in Bandung becoming the sample in this research. The quantitative data was obtained through 26 questions about living thing and environment sustainability which is constructed based on the eight elements of critical thinking and be provided in the form of virtual and paper-based test. Based on analysis of the result, it is shown that within visual, auditory, and kinesthetic were not significantly difference in virtual and paper-based test. Besides, all result was supported by quistionnaire about students’ respond on virtual test which shows 3.47 in the scale of 4. Means that student showed positive respond in all aspet measured, which are interest, impression, and expectation.

Adenosine A2a receptors and O2 sensing in development

PubMed Central

2011-01-01

Reduced mitochondrial oxidative phosphorylation, via activation of adenylate kinase and the resulting exponential rise in the cellular AMP/ATP ratio, appears to be a critical factor underlying O2 sensing in many chemoreceptive tissues in mammals. The elevated AMP/ATP ratio, in turn, activates key enzymes that are involved in physiologic adjustments that tend to balance ATP supply and demand. An example is the conversion of AMP to adenosine via 5′-nucleotidase and the resulting activation of adenosine A2A receptors, which are involved in acute oxygen sensing by both carotid bodies and the brain. In fetal sheep, A2A receptors associated with carotid bodies trigger hypoxic cardiovascular chemoreflexes, while central A2A receptors mediate hypoxic inhibition of breathing and rapid eye movements. A2A receptors are also involved in hypoxic regulation of fetal endocrine systems, metabolism, and vascular tone. In developing lambs, A2A receptors play virtually no role in O2 sensing by the carotid bodies, but brain A2A receptors remain critically involved in the roll-off ventilatory response to hypoxia. In adult mammals, A2A receptors have been implicated in O2 sensing by carotid glomus cells, while central A2A receptors likely blunt hypoxic hyperventilation. In conclusion, A2A receptors are crucially involved in the transduction mechanisms of O2 sensing in fetal carotid bodies and brains. Postnatally, central A2A receptors remain key mediators of hypoxic respiratory depression, but they are less critical for O2 sensing in carotid chemoreceptors, particularly in developing lambs. PMID:21677265

Psychological benefits of virtual reality for patients in rehabilitation therapy.

PubMed

Chen, Chih-Hung; Jeng, Ming-Chang; Fung, Chin-Ping; Doong, Ji-Liang; Chuang, Tien-Yow

2009-05-01

Whether virtual rehabilitation is beneficial has not been determined. To investigate the psychological benefits of virtual reality in rehabilitation. An experimental group underwent therapy with a virtual-reality-based exercise bike, and a control group underwent the therapy without virtual-reality equipment. Hospital laboratory. 30 patients suffering from spinal-cord injury. A designed rehabilitation therapy. Endurance, Borg's rating-of-perceived-exertion scale, the Activation-Deactivation Adjective Check List (AD-ACL), and the Simulator Sickness Questionnaire. The differences between the experimental and control groups were significant for AD-ACL calmness and tension. A virtual-reality-based rehabilitation program can ease patients' tension and induce calm.

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

PubMed

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 better binding affinity compared to the PDB bound inhibitor of falcipain-III. The docking simulation results of falcipain-III with designed leupeptin analogues using Glide compared with AutoDock and find 80% similarity as better binder than leupeptin. These results further highlight new leupeptin analogues as promising future inhibitors for chemotherapeutic prevention of malaria. The result of Glide for falcipain-III has been compared with the result of AutoDock and finds very less differences in their order of binding affinity. Although there are no extra hydrogen bonds, however, equal number of hydrogen bonds with variable strength as compared to leupeptin along with the enhanced hydrophobic and electrostatic interactions in case of analogues supports our study that it holds the ligand molecules strongly within the receptor. The comparative e-pharmacophoric study also suggests and supports our predictions regarding the minimum features required in ligand molecule to behave as falcipain- III inhibitors and is also helpful in screening the large database as future antimalarial inhibitors.

Innovative application of virtual display technique in virtual museum

NASA Astrophysics Data System (ADS)

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.

Assistance Technology Research Center

DTIC Science & Technology

2003-02-01

and perhaps modifying - some social behaviors of people with autism . "* Leveraging ancillary funding from both NIDRR and NSF, Anthrotronix is three...to independence for many individuals with traumatic brain injury, stroke, and autism . This project will develop virtual environments, using the...pentapeptide consensus sequence of the human NMDA receptor NR2a and NR2b subunits. Magnetic resonance imaging (MRI) will be performed for evaluation of

Performance evaluation of structure based and ligand based virtual screening methods on ten selected anti-cancer targets.

PubMed

Ramasamy, Thilagavathi; Selvam, Chelliah

2015-10-15

Virtual screening has become an important tool in drug discovery process. Structure based and ligand based approaches are generally used in virtual screening process. To date, several benchmark sets for evaluating the performance of the virtual screening tool are available. In this study, our aim is to compare the performance of both structure based and ligand based virtual screening methods. Ten anti-cancer targets and their corresponding benchmark sets from 'Demanding Evaluation Kits for Objective In silico Screening' (DEKOIS) library were selected. X-ray crystal structures of protein-ligand complexes were selected based on their resolution. Openeye tools such as FRED, vROCS were used and the results were carefully analyzed. At EF1%, vROCS produced better results but at EF5% and EF10%, both FRED and ROCS produced almost similar results. It was noticed that the enrichment factor values were decreased while going from EF1% to EF5% and EF10% in many cases. Published by Elsevier Ltd.

Ensemble pharmacophore meets ensemble docking: a novel screening strategy for the identification of RIPK1 inhibitors

NASA Astrophysics Data System (ADS)

Fayaz, S. M.; Rajanikant, G. K.

2014-07-01

Programmed cell death has been a fascinating area of research since it throws new challenges and questions in spite of the tremendous ongoing research in this field. Recently, necroptosis, a programmed form of necrotic cell death, has been implicated in many diseases including neurological disorders. Receptor interacting serine/threonine protein kinase 1 (RIPK1) is an important regulatory protein involved in the necroptosis and inhibition of this protein is essential to stop necroptotic process and eventually cell death. Current structure-based virtual screening methods involve a wide range of strategies and recently, considering the multiple protein structures for pharmacophore extraction has been emphasized as a way to improve the outcome. However, using the pharmacophoric information completely during docking is very important. Further, in such methods, using the appropriate protein structures for docking is desirable. If not, potential compound hits, obtained through pharmacophore-based screening, may not have correct ranks and scores after docking. Therefore, a comprehensive integration of different ensemble methods is essential, which may provide better virtual screening results. In this study, dual ensemble screening, a novel computational strategy was used to identify diverse and potent inhibitors against RIPK1. All the pharmacophore features present in the binding site were captured using both the apo and holo protein structures and an ensemble pharmacophore was built by combining these features. This ensemble pharmacophore was employed in pharmacophore-based screening of ZINC database. The compound hits, thus obtained, were subjected to ensemble docking. The leads acquired through docking were further validated through feature evaluation and molecular dynamics simulation.

Differential targeting of Gbetagamma-subunit signaling with small molecules.

PubMed

Bonacci, Tabetha M; Mathews, Jennifer L; Yuan, Chujun; Lehmann, David M; Malik, Sundeep; Wu, Dianqing; Font, Jose L; Bidlack, Jean M; Smrcka, Alan V

2006-04-21

G protein betagamma subunits have potential as a target for therapeutic treatment of a number of diseases. We performed virtual docking of a small-molecule library to a site on Gbetagamma subunits that mediates protein interactions. We hypothesized that differential targeting of this surface could allow for selective modulation of Gbetagamma subunit functions. Several compounds bound to Gbetagamma subunits with affinities from 0.1 to 60 muM and selectively modulated functional Gbetagamma-protein-protein interactions in vitro, chemotactic peptide signaling pathways in HL-60 leukocytes, and opioid receptor-dependent analgesia in vivo. These data demonstrate an approach for modulation of G protein-coupled receptor signaling that may represent an important therapeutic strategy.

Virtual wall-based haptic-guided teleoperated surgical robotic system for single-port brain tumor removal surgery.

PubMed

Seung, Sungmin; Choi, Hongseok; Jang, Jongseong; Kim, Young Soo; Park, Jong-Oh; Park, Sukho; Ko, Seong Young

2017-01-01

This article presents a haptic-guided teleoperation for a tumor removal surgical robotic system, so-called a SIROMAN system. The system was developed in our previous work to make it possible to access tumor tissue, even those that seat deeply inside the brain, and to remove the tissue with full maneuverability. For a safe and accurate operation to remove only tumor tissue completely while minimizing damage to the normal tissue, a virtual wall-based haptic guidance together with a medical image-guided control is proposed and developed. The virtual wall is extracted from preoperative medical images, and the robot is controlled to restrict its motion within the virtual wall using haptic feedback. Coordinate transformation between sub-systems, a collision detection algorithm, and a haptic-guided teleoperation using a virtual wall are described in the context of using SIROMAN. A series of experiments using a simplified virtual wall are performed to evaluate the performance of virtual wall-based haptic-guided teleoperation. With haptic guidance, the accuracy of the robotic manipulator's trajectory is improved by 57% compared to one without. The tissue removal performance is also improved by 21% ( p < 0.05). The experiments show that virtual wall-based haptic guidance provides safer and more accurate tissue removal for single-port brain surgery.

Virtual environments simulation in research reactor

NASA Astrophysics Data System (ADS)

Muhamad, Shalina Bt. Sheik; Bahrin, Muhammad Hannan Bin

2017-01-01

Virtual reality based simulations are interactive and engaging. It has the useful potential in improving safety training. Virtual reality technology can be used to train workers who are unfamiliar with the physical layout of an area. In this study, a simulation program based on the virtual environment at research reactor was developed. The platform used for virtual simulation is 3DVia software for which it's rendering capabilities, physics for movement and collision and interactive navigation features have been taken advantage of. A real research reactor was virtually modelled and simulated with the model of avatars adopted to simulate walking. Collision detection algorithms were developed for various parts of the 3D building and avatars to restrain the avatars to certain regions of the virtual environment. A user can control the avatar to move around inside the virtual environment. Thus, this work can assist in the training of personnel, as in evaluating the radiological safety of the research reactor facility.

Optimizing Virtual Network Functions Placement in Virtual Data Center Infrastructure Using Machine Learning

NASA Astrophysics Data System (ADS)

Bolodurina, I. P.; Parfenov, D. I.

2018-01-01

We have elaborated a neural network model of virtual network flow identification based on the statistical properties of flows circulating in the network of the data center and characteristics that describe the content of packets transmitted through network objects. This enabled us to establish the optimal set of attributes to identify virtual network functions. We have established an algorithm for optimizing the placement of virtual data functions using the data obtained in our research. Our approach uses a hybrid method of visualization using virtual machines and containers, which enables to reduce the infrastructure load and the response time in the network of the virtual data center. The algorithmic solution is based on neural networks, which enables to scale it at any number of the network function copies.

Evaluation of the cognitive effects of travel technique in complex real and virtual environments.

PubMed

Suma, Evan A; Finkelstein, Samantha L; Reid, Myra; V Babu, Sabarish; Ulinski, Amy C; Hodges, Larry F

2010-01-01

We report a series of experiments conducted to investigate the effects of travel technique on information gathering and cognition in complex virtual environments. In the first experiment, participants completed a non-branching multilevel 3D maze at their own pace using either real walking or one of two virtual travel techniques. In the second experiment, we constructed a real-world maze with branching pathways and modeled an identical virtual environment. Participants explored either the real or virtual maze for a predetermined amount of time using real walking or a virtual travel technique. Our results across experiments suggest that for complex environments requiring a large number of turns, virtual travel is an acceptable substitute for real walking if the goal of the application involves learning or reasoning based on information presented in the virtual world. However, for applications that require fast, efficient navigation or travel that closely resembles real-world behavior, real walking has advantages over common joystick-based virtual travel techniques.

Classification and virtual screening of androgen receptor antagonists.

PubMed

Li, Jiazhong; Gramatica, Paola

2010-05-24

Computational tools, such as quantitative structure-activity relationship (QSAR), are highly useful as screening support for prioritization of substances of very high concern (SVHC). From the practical point of view, QSAR models should be effective to pick out more active rather than inactive compounds, expressed as sensitivity in classification works. This research investigates the classification of a big data set of endocrine-disrupting chemicals (EDCs)-androgen receptor (AR) antagonists, mainly aiming to improve the external sensitivity and to screen for potential AR binders. The kNN, lazy IB1, and ADTree methods and the consensus approach were used to build different models, which improve the sensitivity on external chemicals from 57.1% (literature) to 76.4%. Additionally, the models' predictive abilities were further validated on a blind collected data set (sensitivity: 85.7%). Then the proposed classifiers were used: (i) to distinguish a set of AR binders into antagonists and agonists; (ii) to screen a combined estrogen receptor binder database to find out possible chemicals that can bind to both AR and ER; and (iii) to virtually screen our in-house environmental chemical database. The in silico screening results suggest: (i) that some compounds can affect the normal endocrine system through a complex mechanism binding both to ER and AR; (ii) new EDCs, which are nonER binders, but can in silico bind to AR, are recognized; and (iii) about 20% of compounds in a big data set of environmental chemicals are predicted as new AR antagonists. The priority should be given to them to experimentally test the binding activities with AR.

The comparison between science virtual and paper based test in measuring grade 7 students’ critical thinking

NASA Astrophysics Data System (ADS)

Dhitareka, P. H.; Firman, H.; Rusyati, L.

2018-05-01

This research is comparing science virtual and paper-based test in measuring grade 7 students’ critical thinking based on Multiple Intelligences and gender. Quasi experimental method with within-subjects design is conducted in this research in order to obtain the data. The population of this research was all seventh grade students in ten classes of one public secondary school in Bandung. There were 71 students within two classes taken randomly became the sample in this research. The data are obtained through 28 questions with a topic of living things and environmental sustainability constructed based on eight critical thinking elements proposed by Inch then the questions provided in science virtual and paper-based test. The data was analysed by using paired-samples t test when the data are parametric and Wilcoxon signed ranks test when the data are non-parametric. In general comparison, the p-value of the comparison between science virtual and paper-based tests’ score is 0.506, indicated that there are no significance difference between science virtual and paper-based test based on the tests’ score. The results are furthermore supported by the students’ attitude result which is 3.15 from the scale from 1 to 4, indicated that they have positive attitudes towards Science Virtual Test.

Virtual network embedding in cross-domain network based on topology and resource attributes

NASA Astrophysics Data System (ADS)

Zhu, Lei; Zhang, Zhizhong; Feng, Linlin; Liu, Lilan

2018-03-01

Aiming at the network architecture ossification and the diversity of access technologies issues, this paper researches the cross-domain virtual network embedding algorithm. By analysing the topological attribute from the local and global perspective of nodes in the virtual network and the physical network, combined with the local network resource property, we rank the embedding priority of the nodes with PCA and TOPSIS methods. Besides, the link load distribution is considered. Above all, We proposed an cross-domain virtual network embedding algorithm based on topology and resource attributes. The simulation results depicts that our algorithm increases the acceptance rate of multi-domain virtual network requests, compared with the existing virtual network embedding algorithm.

Receptor-mediated internalization of [3H]-neurotensin in synaptosomal preparations from rat neostriatum.

PubMed

Nguyen, Ha Minh Ky; Cahill, Catherine M; McPherson, Peter S; Beaudet, Alain

2002-06-01

Following its binding to somatodendritic receptors, the neuropeptide neurotensin (NT) internalizes via a clathrin-mediated process. In the present study, we investigated whether NT also internalizes presynaptically using synaptosomes from rat neostriatum, a region in which NT1 receptors are virtually all presynaptic. Binding of [(3)H]-NT to striatal synaptosomes in the presence of levocabastine to block NT2 receptors is specific, saturable, and has NT1 binding properties. A significant fraction of the bound radioactivity is resistant to hypertonic acid wash indicating that it is internalized. Internalization of [(3)H]-NT, like that of [(125)I]-transferrin, is blocked by sucrose and low temperature, consistent with endocytosis occurring via a clathrin-dependent pathway. However, contrary to what was reported at the somatodendritic level, neither [(3)H]-NT nor [(125)I]-transferrin internalization in synaptosomes is sensitive to the endocytosis inhibitor phenylarsine oxide. Moreover, treatment of synaptosomes with monensin, which prevents internalized receptors from recycling to the plasma membrane, reduces [(3)H]-NT binding and internalization, suggesting that presynaptic NT1 receptors, in contrast to somatodendritic ones, are recycled back to the plasma membrane. Taken together, these results suggest that NT internalizes in nerve terminals via an endocytic pathway that is related to, but is mechanistically distinct from that responsible for NT internalization in nerve cell bodies.

Welcome to Wonderland: The Influence of the Size and Shape of a Virtual Hand On the Perceived Size and Shape of Virtual Objects

PubMed Central

Linkenauger, Sally A.; Leyrer, Markus; Bülthoff, Heinrich H.; Mohler, Betty J.

2013-01-01

The notion of body-based scaling suggests that our body and its action capabilities are used to scale the spatial layout of the environment. Here we present four studies supporting this perspective by showing that the hand acts as a metric which individuals use to scale the apparent sizes of objects in the environment. However to test this, one must be able to manipulate the size and/or dimensions of the perceiver’s hand which is difficult in the real world due to impliability of hand dimensions. To overcome this limitation, we used virtual reality to manipulate dimensions of participants’ fully-tracked, virtual hands to investigate its influence on the perceived size and shape of virtual objects. In a series of experiments, using several measures, we show that individuals’ estimations of the sizes of virtual objects differ depending on the size of their virtual hand in the direction consistent with the body-based scaling hypothesis. Additionally, we found that these effects were specific to participants’ virtual hands rather than another avatar’s hands or a salient familiar-sized object. While these studies provide support for a body-based approach to the scaling of the spatial layout, they also demonstrate the influence of virtual bodies on perception of virtual environments. PMID:23874681

Cousins Virtual Jane and Virtual Joe, Extraordinary Virtual Helpers

ERIC Educational Resources Information Center

Blignaut, Seugnet; Nagel, Lynette

2009-01-01

Higher education institutions deliver web-based learning with varied success. The success rate of distributed online courses remains low. Factors such as ineffective course facilitation and insufficient communication contribute to the unfulfilled promises of web-based learning. Students consequently feel unmotivated. Instructor control and in the…

Statistical virtual eye model based on wavefront aberration

PubMed Central

Wang, Jie-Mei; Liu, Chun-Ling; Luo, Yi-Ning; Liu, Yi-Guang; Hu, Bing-Jie

2012-01-01

Wavefront aberration affects the quality of retinal image directly. This paper reviews the representation and reconstruction of wavefront aberration, as well as the construction of virtual eye model based on Zernike polynomial coefficients. In addition, the promising prospect of virtual eye model is emphasized. PMID:23173112

Neurosteroid Influences on Sensitivity to Ethanol

PubMed Central

Helms, Christa M.; Rossi, David J.; Grant, Kathleen A.

2011-01-01

This review will highlight a variety of mechanisms by which neurosteroids affect sensitivity to ethanol, including physiological states associated with activity of the hypothalamic–pituitary–adrenal (HPA) and hypothalamic–pituitary–gonadal (HPG) axes, and the effects of chronic exposure to ethanol, in addition to behavioral implications. To date, γ-aminobutyric acid (GABAA) receptor mechanisms are a major focus of the modulation of ethanol effects by neuroactive steroids. While NMDA receptor mechanisms are gaining prominence in the literature, these complex data would be best discussed separately. Accordingly, GABAA receptor mechanisms are emphasized in this review with brief mention of some NMDA receptor mechanisms to point out contrasting neuroactive steroid pharmacology. Overall, the data suggest that neurosteroids are virtually ubiquitous modulators of inhibitory neurotransmission. Neurosteroids appear to affect sensitivity to ethanol in specific brain regions and, consequently, specific behavioral tests, possibly related to the efficacy and potency of ethanol to potentiate the release of GABA and increase neurosteroid concentrations. Although direct interaction of ethanol and neuroactive steroids at common receptor binding sites has been suggested in some studies, this proposition is still controversial. It is currently difficult to assign a specific mechanism by which neuroactive steroids could modulate the effects of ethanol in particular behavioral tasks. PMID:22654852

A virtual maintenance-based approach for satellite assembling and troubleshooting assessment

NASA Astrophysics Data System (ADS)

Geng, Jie; Li, Ying; Wang, Ranran; Wang, Zili; Lv, Chuan; Zhou, Dong

2017-09-01

In this study, a Virtual Maintenance (VM)-based approach for satellite troubleshooting assessment is proposed. By focusing on various elements in satellite assemble troubleshooting, such as accessibility, ergonomics, wiring, and extent of damage, a systematic, quantitative, and objective assessment model is established to decrease subjectivity in satellite assembling and troubleshooting assessment. Afterwards, based on the established assessment model and satellite virtual prototype, an application process of this model suitable for a virtual environment is presented. Finally, according to the application process, all the elements in satellite troubleshooting are analyzed and assessed. The corresponding improvements, which realize the transformation from a conventional way to a virtual simulation and assessment, are suggested, and the flaws in assembling and troubleshooting are revealed. Assembling or troubleshooting schemes can be improved in the early stage of satellite design with the help of a virtual prototype. Repetition in the practical operation is beneficial to companies as risk and cost are effectively reduced.

The Therapeutic Potential of Nociceptin/Orphanin FQ Receptor Agonists as Analgesics without Abuse Liability

PubMed Central

2012-01-01

Although mu opioid (MOP) receptor agonists are the most commonly used analgesics for the treatment of moderate to severe pain in the clinic, the side effects of MOP agonists such as abuse liability limit their value as a medication. Research to identify novel analgesics without adverse effects is pivotal to advance the health care of humans. The nociceptin/orphanin FQ peptide (NOP) receptor, the fourth opioid receptor subtype, mediates distinctive actions in nonhuman primates which suggests the possibility that activity at this receptor may result in strong analgesia in the absence of virtually all of the side effects associated with MOP agonists. The present review highlights the recent progress of pharmacological studies of NOP-related ligands in primates. Selective NOP agonists, either peptidic or nonpeptidic, produce full analgesia in various assays in primates, when delivered systemically or intrathecally. Yet small molecule NOP agonists do not serve as reinforcers, indicating a lack of abuse liability. Given that NOP agonists have low abuse liability and that coactivation of NOP and MOP receptors produces synergistic antinociception, it is worth developing bifunctional NOP/MOP ligands. The outcomes of these studies and recent developments provide new perspectives to establish a translational bridge for understanding the biobehavioral functions of NOP receptors in primates and for facilitating the development of NOP-related ligands as a new generation of analgesics without abuse liability in humans. PMID:23421672

Insights into unbound-bound states of GPR142 receptor in a membrane-aqueous system using molecular dynamics simulations.

PubMed

Kaushik, Aman Chandra; Sahi, Shakti

2018-05-01

G protein coupled receptors (GPCRs) are source machinery in signal transduction pathways and being one of the major therapeutic targets play a significant in drug discovery. GPR142, an orphan GPCR, has been implicated in the regulation of insulin, thereby having a crucial role in Type II diabetes management. Deciphering of the structures of orphan, GPCRs (O-GPCRs) offer better prospects for advancements in research in ion translocation and transduction of extracellular signals. As the crystallographic structure of GPR142 is not available in PDB, therefore, threading and ab initio-based approaches were used for 3D modeling of GPR142. Molecular dynamic simulations (900 ns) were performed on the 3D model of GPR142 and complexes of GPR142 with top five hits, obtained through virtual screening, embedded in lipid bilayer with aqueous system using OPLS force field. Compound 1, 3, and 4 may act as scaffolds for designing potential lead agonists for GPR142. The finding of GPR142 MD simulation study provides more comprehensive representation of the functional properties. The concern for Type II diabetes is increasing worldwide and successful treatment of this disease demands novel drugs with better efficacy.

Novel Hybrid Virtual Screening Protocol Based on Molecular Docking and Structure-Based Pharmacophore for Discovery of Methionyl-tRNA Synthetase Inhibitors as Antibacterial Agents

PubMed Central

Liu, Chi; He, Gu; Jiang, Qinglin; Han, Bo; Peng, Cheng

2013-01-01

Methione tRNA synthetase (MetRS) is an essential enzyme involved in protein biosynthesis in all living organisms and is a potential antibacterial target. In the current study, the structure-based pharmacophore (SBP)-guided method has been suggested to generate a comprehensive pharmacophore of MetRS based on fourteen crystal structures of MetRS-inhibitor complexes. In this investigation, a hybrid protocol of a virtual screening method, comprised of pharmacophore model-based virtual screening (PBVS), rigid and flexible docking-based virtual screenings (DBVS), is used for retrieving new MetRS inhibitors from commercially available chemical databases. This hybrid virtual screening approach was then applied to screen the Specs (202,408 compounds) database, a structurally diverse chemical database. Fifteen hit compounds were selected from the final hits and shifted to experimental studies. These results may provide important information for further research of novel MetRS inhibitors as antibacterial agents. PMID:23839093

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

PubMed

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 environment condition were not significantly different from those for the traditional lab condition. The results of this study suggest that participants were productive and enjoyed the virtual lab condition, indicating the potential of a virtual world based approach as an alternative to conventional approaches for synchronous usability testing. Copyright © 2017 Elsevier Ltd. All rights reserved.

Antigen Receptor Galaxy: A User-Friendly, Web-Based Tool for Analysis and Visualization of T and B Cell Receptor Repertoire Data

PubMed Central

IJspeert, Hanna; van Schouwenburg, Pauline A.; van Zessen, David; Pico-Knijnenburg, Ingrid

2017-01-01

Antigen Receptor Galaxy (ARGalaxy) is a Web-based tool for analyses and visualization of TCR and BCR sequencing data of 13 species. ARGalaxy consists of four parts: the demultiplex tool, the international ImMunoGeneTics information system (IMGT) concatenate tool, the immune repertoire pipeline, and the somatic hypermutation (SHM) and class switch recombination (CSR) pipeline. Together they allow the analysis of all different aspects of the immune repertoire. All pipelines can be run independently or combined, depending on the available data and the question of interest. The demultiplex tool allows data trimming and demultiplexing, whereas with the concatenate tool multiple IMGT/HighV-QUEST output files can be merged into a single file. The immune repertoire pipeline is an extended version of our previously published ImmunoGlobulin Galaxy (IGGalaxy) virtual machine that was developed to visualize V(D)J gene usage. It allows analysis of both BCR and TCR rearrangements, visualizes CDR3 characteristics (length and amino acid usage) and junction characteristics, and calculates the diversity of the immune repertoire. Finally, ARGalaxy includes the newly developed SHM and CSR pipeline to analyze SHM and/or CSR in BCR rearrangements. It analyzes the frequency and patterns of SHM, Ag selection (including BASELINe), clonality (Change-O), and CSR. The functionality of the ARGalaxy tool is illustrated in several clinical examples of patients with primary immunodeficiencies. In conclusion, ARGalaxy is a novel tool for the analysis of the complete immune repertoire, which is applicable to many patient groups with disturbances in the immune repertoire such as autoimmune diseases, allergy, and leukemia, but it can also be used to address basic research questions in repertoire formation and selection. PMID:28416602

The Virtual Earth-Solar Observatory of the SCiESMEX

NASA Astrophysics Data System (ADS)

De la Luz, V.; Gonzalez-Esparza, A.; Cifuentes-Nava, G.

2015-12-01

The Mexican Space Weather Service (SCiESMEX, http://www.sciesmex.unam.mx) started operations in October 2014. The project includes the Virtual Earth-Solar Observatory (VESO, http://www.veso.unam.mx). The VESO is a improved project wich objetive is integrate the space weather instrumentation network from the National Autonomous University of Mexico (UNAM). The network includes the Mexican Array Radiotelescope (MEXART), the Callisto receptor (MEXART), a Neutron Telescope, a Cosmic Ray Telescope. the Schumann Antenna, the National Magnetic Service, and the mexican GPS network (TlalocNet). The VESO facility is located at the Geophysics Institute campus Michoacan (UNAM). We offer the service of data store, real-time data, and quasi real-time data. The hardware of VESO includes a High Performance Computer (HPC) dedicated specially to big data storage.

High-numerical-aperture-based virtual point detectors for photoacoustic tomography

NASA Astrophysics Data System (ADS)

Li, Changhui; Wang, Lihong V.

2008-07-01

The focal point of a high-numerical-aperture (NA) ultrasonic transducer can be used as a virtual point detector. This virtual point detector detects omnidirectionally over a wide acceptance angle. It also combines a large active transducer surface and a small effective virtual detector size. Thus the sensitivity is high compared with that of a real point detector, and the aperture effect is small compared with that of a finite size transducer. We present two kinds of high-NA-based virtual point detectors and their successful application in photoacoustic tomography. They can also be applied in other ultrasound-related fields.

Synchronized Pair Configuration in Virtualization-Based Lab for Learning Computer Networks

ERIC Educational Resources Information Center

Kongcharoen, Chaknarin; Hwang, Wu-Yuin; Ghinea, Gheorghita

2017-01-01

More studies are concentrating on using virtualization-based labs to facilitate computer or network learning concepts. Some benefits are lower hardware costs and greater flexibility in reconfiguring computer and network environments. However, few studies have investigated effective mechanisms for using virtualization fully for collaboration.…

Designing a Virtual-Reality-Based, Gamelike Math Learning Environment

ERIC Educational Resources Information Center

Xu, Xinhao; Ke, Fengfeng

2016-01-01

This exploratory study examined the design issues related to a virtual-reality-based, gamelike learning environment (VRGLE) developed via OpenSimulator, an open-source virtual reality server. The researchers collected qualitative data to examine the VRGLE's usability, playability, and content integration for math learning. They found it important…

Virtualization for Cost-Effective Teaching of Assembly Language Programming

ERIC Educational Resources Information Center

Cadenas, José O.; Sherratt, R. Simon; Howlett, Des; Guy, Chris G.; Lundqvist, Karsten O.

2015-01-01

This paper describes a virtual system that emulates an ARM-based processor machine, created to replace a traditional hardware-based system for teaching assembly language. The virtual system proposed here integrates, in a single environment, all the development tools necessary to deliver introductory or advanced courses on modern assembly language…

Efficacy of a Virtual Teaching Assistant in an Open Laboratory Environment for Electric Circuits

ERIC Educational Resources Information Center

Saleheen, Firdous; Wang, Zicong; Picone, Joseph; Butz, Brian P.; Won, Chang-Hee

2018-01-01

In order to provide an on-demand, open electrical engineering laboratory, we developed an innovative software-based Virtual Open Laboratory Teaching Assistant (VOLTA). This web-based virtual assistant provides laboratory instructions, equipment usage videos, circuit simulation assistance, and hardware implementation diagnostics. VOLTA allows…

Identification of Novel Activators of Constitutive Androstane Receptor from FDA-approved Drugs by Integrated Computational and Biological Approaches

PubMed Central

Lynch, Caitlin; Pan, Yongmei; Li, Linhao; Ferguson, Stephen S.; Xia, Menghang; Swaan, Peter W.; Wang, Hongbing

2012-01-01

Purpose The constitutive androstane receptor (CAR, NR1I3) is a xenobiotic sensor governing the transcription of numerous hepatic genes associated with drug metabolism and clearance. Recent evidence suggests that CAR also modulates energy homeostasis and cancer development. Thus, identification of novel human (h) CAR activators is of both clinical importance and scientific interest. Methods Docking and ligand-based structure-activity models were used for virtual screening of a database containing over 2000 FDA-approved drugs. Identified lead compounds were evaluated in cell-based reporter assays to determine hCAR activation. Potential activators were further tested in human primary hepatocytes (HPHs) for the expression of the prototypical hCAR target gene CYP2B6. Results Nineteen lead compounds with optimal modeling parameters were selected for biological evaluation. Seven of the 19 leads exhibited moderate to potent activation of hCAR. Five out of the seven compounds translocated hCAR from the cytoplasm to the nucleus of HPHs in a concentration-dependent manner. These compounds also induce the expression of CYP2B6 in HPHs with rank-order of efficacies closely resembling that of hCAR activation. Conclusion These results indicate that our strategically integrated approaches are effective in the identification of novel hCAR modulators, which may function as valuable research tools or potential therapeutic molecules. PMID:23090669

Purine ionotropic (P2X) receptors.

PubMed

Köles, L; Fürst, S; Illes, P

2007-01-01

Purinergic signaling is involved in the proper functioning of virtually all organs of the body. Although in some cases purines have a major influence on physiological functions (e.g. thrombocyte aggregation), more often they are just background modulators contributing to fine tuning of biological events. However, under pathological conditions, when a huge amount of adenosine 5'-triphosphate (ATP) can reach the extracellular space, their significance is increasing. ATP and its various degradation products activate membrane receptors divided into two main classes: the metabotropic P2Y and the ionotropic P2X family. This latter group, the purine ionotropic receptor, is the object of this review. After providing a description about the distribution and functional properties of P2X receptors in the body, their pharmacology will be summarized. In the second part of this review, the role of purines in those organ systems and body functions will be highlighted, where the (patho)physiological role of P2X receptors has been suggested or is even well established. Besides the regulation of organ systems, for instance in the cardiovascular, respiratory, genitourinary or gastrointestinal system, some special issues will also be discussed, such as the role of P2X receptors in pain, tumors, central nervous system (CNS) injury and embryonic development. Several examples will indicate that purine ionotropic receptors might serve as attractive targets for pharmacological interventions in various diseases, and that selective ligands for these receptors will probably constitute important future therapeutic tools in humans.

Case-Based Learning in Virtual Groups--Collaborative Problem Solving Activities and Learning Outcomes in a Virtual Professional Training Course

ERIC Educational Resources Information Center

Kopp, Birgitta; Hasenbein, Melanie; Mandl, Heinz

2014-01-01

This article analyzes the collaborative problem solving activities and learning outcomes of five groups that worked on two different complex cases in a virtual professional training course. In this asynchronous virtual learning environment, all knowledge management content was delivered virtually and collaboration took place through forums. To…

[The virtual reality simulation research of China Mechanical Virtual Human based on the Creator/Vega].

PubMed

Wei, Gaofeng; Tang, Gang; Fu, Zengliang; Sun, Qiuming; Tian, Feng

2010-10-01

The China Mechanical Virtual Human (CMVH) is a human musculoskeletal biomechanical simulation platform based on China Visible Human slice images; it has great realistic application significance. In this paper is introduced the construction method of CMVH 3D models. Then a simulation system solution based on Creator/Vega is put forward for the complex and gigantic data characteristics of the 3D models. At last, combined with MFC technology, the CMVH simulation system is developed and a running simulation scene is given. This paper provides a new way for the virtual reality application of CMVH.

Operating Room Performance Improves after Proficiency-Based Virtual Reality Cataract Surgery Training.

PubMed

Thomsen, Ann Sofia Skou; Bach-Holm, Daniella; Kjærbo, Hadi; Højgaard-Olsen, Klavs; Subhi, Yousif; Saleh, George M; Park, Yoon Soo; la Cour, Morten; Konge, Lars

2017-04-01

To investigate the effect of virtual reality proficiency-based training on actual cataract surgery performance. The secondary purpose of the study was to define which surgeons benefit from virtual reality training. Multicenter masked clinical trial. Eighteen cataract surgeons with different levels of experience. Cataract surgical training on a virtual reality simulator (EyeSi) until a proficiency-based test was passed. Technical performance in the operating room (OR) assessed by 3 independent, masked raters using a previously validated task-specific assessment tool for cataract surgery (Objective Structured Assessment of Cataract Surgical Skill). Three surgeries before and 3 surgeries after the virtual reality training were video-recorded, anonymized, and presented to the raters in random order. Novices (non-independently operating surgeons) and surgeons having performed fewer than 75 independent cataract surgeries showed significant improvements in the OR-32% and 38%, respectively-after virtual reality training (P = 0.008 and P = 0.018). More experienced cataract surgeons did not benefit from simulator training. The reliability of the assessments was high with a generalizability coefficient of 0.92 and 0.86 before and after the virtual reality training, respectively. Clinically relevant cataract surgical skills can be improved by proficiency-based training on a virtual reality simulator. Novices as well as surgeons with an intermediate level of experience showed improvement in OR performance score. Copyright © 2017 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

The DRF motif of CXCR6 as chemokine receptor adaptation to adhesion.

PubMed

Koenen, Andrea; Babendreyer, Aaron; Schumacher, Julian; Pasqualon, Tobias; Schwarz, Nicole; Seifert, Anke; Deupi, Xavier; Ludwig, Andreas; Dreymueller, Daniela

2017-01-01

The CXC-chemokine receptor 6 (CXCR6) is a class A GTP-binding protein-coupled receptor (GPCRs) that mediates adhesion of leukocytes by interacting with the transmembrane cell surface-expressed chemokine ligand 16 (CXCL16), and also regulates leukocyte migration by interacting with the soluble shed variant of CXCL16. In contrast to virtually all other chemokine receptors with chemotactic activity, CXCR6 carries a DRF motif instead of the typical DRY motif as a key element in receptor activation and G protein coupling. In this work, modeling analyses revealed that the phenylalanine F3.51 in CXCR6 might have impact on intramolecular interactions including hydrogen bonds by this possibly changing receptor function. Initial investigations with embryonic kidney HEK293 cells and further studies with monocytic THP-1 cells showed that mutation of DRF into DRY does not influence ligand binding, receptor internalization, receptor recycling, and protein kinase B (AKT) signaling. Adhesion was slightly decreased in a time-dependent manner. However, CXCL16-induced calcium signaling and migration were increased. Vice versa, when the DRY motif of the related receptor CX3CR1 was mutated into DRF the migratory response towards CX3CL1 was diminished, indicating that the presence of a DRF motif generally impairs chemotaxis in chemokine receptors. Transmembrane and soluble CXCL16 play divergent roles in homeostasis, inflammation, and cancer, which can be beneficial or detrimental. Therefore, the DRF motif of CXCR6 may display a receptor adaptation allowing adhesion and cell retention by transmembrane CXCL16 but reducing the chemotactic response to soluble CXCL16. This adaptation may avoid permanent or uncontrolled recruitment of inflammatory cells as well as cancer metastasis.

The DRF motif of CXCR6 as chemokine receptor adaptation to adhesion

PubMed Central

Koenen, Andrea; Babendreyer, Aaron; Schumacher, Julian; Pasqualon, Tobias; Schwarz, Nicole; Seifert, Anke; Deupi, Xavier

2017-01-01

The CXC-chemokine receptor 6 (CXCR6) is a class A GTP-binding protein-coupled receptor (GPCRs) that mediates adhesion of leukocytes by interacting with the transmembrane cell surface-expressed chemokine ligand 16 (CXCL16), and also regulates leukocyte migration by interacting with the soluble shed variant of CXCL16. In contrast to virtually all other chemokine receptors with chemotactic activity, CXCR6 carries a DRF motif instead of the typical DRY motif as a key element in receptor activation and G protein coupling. In this work, modeling analyses revealed that the phenylalanine F3.51 in CXCR6 might have impact on intramolecular interactions including hydrogen bonds by this possibly changing receptor function. Initial investigations with embryonic kidney HEK293 cells and further studies with monocytic THP-1 cells showed that mutation of DRF into DRY does not influence ligand binding, receptor internalization, receptor recycling, and protein kinase B (AKT) signaling. Adhesion was slightly decreased in a time-dependent manner. However, CXCL16-induced calcium signaling and migration were increased. Vice versa, when the DRY motif of the related receptor CX3CR1 was mutated into DRF the migratory response towards CX3CL1 was diminished, indicating that the presence of a DRF motif generally impairs chemotaxis in chemokine receptors. Transmembrane and soluble CXCL16 play divergent roles in homeostasis, inflammation, and cancer, which can be beneficial or detrimental. Therefore, the DRF motif of CXCR6 may display a receptor adaptation allowing adhesion and cell retention by transmembrane CXCL16 but reducing the chemotactic response to soluble CXCL16. This adaptation may avoid permanent or uncontrolled recruitment of inflammatory cells as well as cancer metastasis. PMID:28267793

Designing a successful HMD-based experience

NASA Technical Reports Server (NTRS)

Pierce, J. S.; Pausch, R.; Sturgill, C. B.; Christiansen, K. D.; Kaiser, M. K. (Principal Investigator)

1999-01-01

For entertainment applications, a successful virtual experience based on a head-mounted display (HMD) needs to overcome some or all of the following problems: entering a virtual world is a jarring experience, people do not naturally turn their heads or talk to each other while wearing an HMD, putting on the equipment is hard, and people do not realize when the experience is over. In the Electric Garden at SIGGRAPH 97, we presented the Mad Hatter's Tea Party, a shared virtual environment experienced by more than 1,500 SIGGRAPH attendees. We addressed these HMD-related problems with a combination of back story, see-through HMDs, virtual characters, continuity of real and virtual objects, and the layout of the physical and virtual environments.

Building Virtuality into University-Based Human Resources Policy in China's Universities

ERIC Educational Resources Information Center

Guoliang, Zhang

2005-01-01

On the basis of discussing the notion of virtual human resources and its structure, this paper analyzes the necessity of building up virtual university teaching staff and proposes a model for the structural makeup of virtual university teaching staff.

Novel design strategy for checkpoint kinase 2 inhibitors using pharmacophore modeling, combinatorial fusion, and virtual screening.

PubMed

Lin, Chun-Yuan; Wang, Yen-Ling

2014-01-01

Checkpoint kinase 2 (Chk2) has a great effect on DNA-damage and plays an important role in response to DNA double-strand breaks and related lesions. In this study, we will concentrate on Chk2 and the purpose is to find the potential inhibitors by the pharmacophore hypotheses (PhModels), combinatorial fusion, and virtual screening techniques. Applying combinatorial fusion into PhModels and virtual screening techniques is a novel design strategy for drug design. We used combinatorial fusion to analyze the prediction results and then obtained the best correlation coefficient of the testing set (r test) with the value 0.816 by combining the Best(train)Best(test) and Fast(train)Fast(test) prediction results. The potential inhibitors were selected from NCI database by screening according to Best(train)Best(test) + Fast(train)Fast(test) prediction results and molecular docking with CDOCKER docking program. Finally, the selected compounds have high interaction energy between a ligand and a receptor. Through these approaches, 23 potential inhibitors for Chk2 are retrieved for further study.

Randomized Placebo-Controlled Trial of a Gastrin Receptor Antagonist in Barretts Esophagus | Division of Cancer Prevention

Cancer.gov

The incidence of esophageal adenocarcinoma (EAC) has risen five-fold over the past several decades, yet the prognosis for EAC remains extremely poor. As such, EAC represents a very attractive target for chemoprevention. Barrett's esophagus (BE) is the precursor lesion for EAC, and acid reflux is a major risk factor for both BE and EAC. Virtually all patients with BE,

LHCb experience with running jobs in virtual machines

NASA Astrophysics Data System (ADS)

McNab, A.; Stagni, F.; Luzzi, C.

2015-12-01

The LHCb experiment has been running production jobs in virtual machines since 2013 as part of its DIRAC-based infrastructure. We describe the architecture of these virtual machines and the steps taken to replicate the WLCG worker node environment expected by user and production jobs. This relies on the uCernVM system for providing root images for virtual machines. We use the CernVM-FS distributed filesystem to supply the root partition files, the LHCb software stack, and the bootstrapping scripts necessary to configure the virtual machines for us. Using this approach, we have been able to minimise the amount of contextualisation which must be provided by the virtual machine managers. We explain the process by which the virtual machine is able to receive payload jobs submitted to DIRAC by users and production managers, and how this differs from payloads executed within conventional DIRAC pilot jobs on batch queue based sites. We describe our operational experiences in running production on VM based sites managed using Vcycle/OpenStack, Vac, and HTCondor Vacuum. Finally we show how our use of these resources is monitored using Ganglia and DIRAC.

BP-Dock: A Flexible Docking Scheme for Exploring Protein–Ligand Interactions Based on Unbound Structures

PubMed Central

Bolia, Ashini; Gerek, Z. Nevin; Ozkan, S. Banu

2016-01-01

Molecular docking serves as an important tool in modeling protein–ligand interactions. However, it is still challenging to incorporate overall receptor flexibility, especially backbone flexibility, in docking due to the large conformational space that needs to be sampled. To overcome this problem, we developed a novel flexible docking approach, BP-Dock (Backbone Perturbation-Dock) that can integrate both backbone and side chain conformational changes induced by ligand binding through a multi-scale approach. In the BP-Dock method, we mimic the nature of binding-induced events as a first-order approximation by perturbing the residues along the protein chain with a small Brownian kick one at a time. The response fluctuation profile of the chain upon these perturbations is computed using the perturbation response scanning method. These response fluctuation profiles are then used to generate binding-induced multiple receptor conformations for ensemble docking. To evaluate the performance of BP-Dock, we applied our approach on a large and diverse data set using unbound structures as receptors. We also compared the BP-Dock results with bound and unbound docking, where overall receptor flexibility was not taken into account. Our results highlight the importance of modeling backbone flexibility in docking for recapitulating the experimental binding affinities, especially when an unbound structure is used. With BP-Dock, we can generate a wide range of binding site conformations realized in nature even in the absence of a ligand that can help us to improve the accuracy of unbound docking. We expect that our fast and efficient flexible docking approach may further aid in our understanding of protein–ligand interactions as well as virtual screening of novel targets for rational drug design. PMID:24380381

Investigating Research Approaches: Classroom-Based Interaction Studies in Physical and Virtual Contexts

ERIC Educational Resources Information Center

Hartwick, Peggy

2018-01-01

This article investigates research approaches used in traditional classroom-based interaction studies for identifying a suitable research method for studies in three-dimensional virtual learning environments (3DVLEs). As opportunities for language learning and teaching in virtual worlds emerge, so too do new research questions. An understanding of…

Assessment method of digital Chinese dance movements based on virtual reality technology

NASA Astrophysics Data System (ADS)

Feng, Wei; Shao, Shuyuan; Wang, Shumin

2008-03-01

Virtual reality has played an increasing role in such areas as medicine, architecture, aviation, engineering science and advertising. However, in the art fields, virtual reality is still in its infancy in the representation of human movements. Based on the techniques of motion capture and reuse of motion capture data in virtual reality environment, this paper presents an assessment method in order to evaluate the quantification of dancers' basic Arm Position movements in Chinese traditional dance. In this paper, the data for quantifying traits of dance motions are defined and measured on dancing which performed by an expert and two beginners, with results indicating that they are beneficial for evaluating dance skills and distinctiveness, and the assessment method of digital Chinese dance movements based on virtual reality technology is validity and feasibility.

Image Mosaicking Approach for a Double-Camera System in the GaoFen2 Optical Remote Sensing Satellite Based on the Big Virtual Camera.

PubMed

Cheng, Yufeng; Jin, Shuying; Wang, Mi; Zhu, Ying; Dong, Zhipeng

2017-06-20

The linear array push broom imaging mode is widely used for high resolution optical satellites (HROS). Using double-cameras attached by a high-rigidity support along with push broom imaging is one method to enlarge the field of view while ensuring high resolution. High accuracy image mosaicking is the key factor of the geometrical quality of complete stitched satellite imagery. This paper proposes a high accuracy image mosaicking approach based on the big virtual camera (BVC) in the double-camera system on the GaoFen2 optical remote sensing satellite (GF2). A big virtual camera can be built according to the rigorous imaging model of a single camera; then, each single image strip obtained by each TDI-CCD detector can be re-projected to the virtual detector of the big virtual camera coordinate system using forward-projection and backward-projection to obtain the corresponding single virtual image. After an on-orbit calibration and relative orientation, the complete final virtual image can be obtained by stitching the single virtual images together based on their coordinate information on the big virtual detector image plane. The paper subtly uses the concept of the big virtual camera to obtain a stitched image and the corresponding high accuracy rational function model (RFM) for concurrent post processing. Experiments verified that the proposed method can achieve seamless mosaicking while maintaining the geometric accuracy.

Virtual collaboration in the online educational setting: a concept analysis.

PubMed

Breen, Henny

2013-01-01

This study was designed to explore the concept of virtual collaboration within the context of an online learning environment in an academic setting. Rodgers' method of evolutionary concept analysis was used to provide a contextual view of the concept to identify attributes, antecedents, and consequences of virtual collaboration. Commonly used terms to describe virtual collaboration are collaborative and cooperative learning, group work, group interaction, group learning, and teamwork. A constructivist pedagogy, group-based process with a shared purpose, support, and web-based technology is required for virtual collaboration to take place. Consequences of virtual collaboration are higher order thinking and learning to work with others. A comprehensive definition of virtual collaboration is offered as an outcome of this analysis. Clarification of virtual collaboration prior to using it as a pedagogical tool in the online learning environment will enhance nursing education with the changes in nursing curriculum being implemented today. Further research is recommended to describe the developmental stages of the collaborative process among nursing students in online education and how virtual collaboration facilitates collaboration in practice. © 2013 Wiley Periodicals, Inc.

Purinergic P2X receptors: structural models and analysis of ligand-target interaction.

PubMed

Dal Ben, Diego; Buccioni, Michela; Lambertucci, Catia; Marucci, Gabriella; Thomas, Ajiroghene; Volpini, Rosaria

2015-01-07

The purinergic P2X receptors are ligand-gated cation channels activated by the endogenous ligand ATP. They assemble as homo- or heterotrimers from seven cloned subtypes (P2X1-7) and all trimer subunits present a common topology consisting in intracellular N- and C- termini, two transmembrane domains and a large extracellular domain. These membrane proteins are present in virtually all mammalian tissues and regulate a large variety of responses in physio- and pathological conditions. The development of ligands that selectively activate or block specific P2X receptor subtypes hence represents a promising strategy to obtain novel pharmacological tools for the treatment of pain, cancer, inflammation, and neurological, cardiovascular, and endocrine diseases. The publication of the crystal structures of zebrafish P2X4 receptor in inactive and ATP-bound active forms provided structural data for the analysis of the receptor structure, the interpretation of mutagenesis data, and the depiction of ligand binding and receptor activation mechanism. In addition, the availability of ATP-competitive ligands presenting selectivity for P2X receptor subtypes supports the design of new potent and selective ligands with possibly improved pharmacokinetic profiles, with the final aim to obtain new drugs. This study describes molecular modelling studies performed to develop structural models of the human and rat P2X receptors in inactive and active states. These models allowed to analyse the role of some non-conserved residues at ATP binding site and to study the receptor interaction with some non-specific or subtype selective agonists and antagonists. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Evolution of hormone signaling in elasmobranchs by exploitation of promiscuous receptors.

PubMed

Carroll, Sean Michael; Bridgham, Jamie T; Thornton, Joseph W

2008-12-01

Specific interactions among proteins, nucleic acids, and metabolites drive virtually all cellular functions and underlie phenotypic complexity and diversity. Despite the fundamental importance of interactions, the mechanisms and dynamics by which they evolve are poorly understood. Here we describe novel interactions between a lineage-specific hormone and its receptors in elasmobranchs, a subclass of cartilaginous fishes, and infer how these associations evolved using phylogenetic and protein structural analyses. The hormone 1alpha-hydroxycorticosterone (1alpha-B) is a physiologically important steroid synthesized only in elasmobranchs. We show that 1alpha-B modulates gene expression in vitro by activating two paralogous intracellular transcription factors, the mineralocorticoid receptor (MR) and glucocorticoid receptor (GR), in the little skate Leucoraja erinacea; MR serves as a high-sensitivity and GR as a low-sensitivity receptor. Using functional analysis of extant and resurrected ancestral proteins, we show that receptor sensitivity to 1alpha-B evolved millions of years before the hormone itself evolved. The 1alpha-B differs from more ancient corticosteroids only by the addition of a hydroxyl group; the three-dimensional structure of the ancestral receptor shows that the ligand pocket contained ample unoccupied space to accommodate this moiety. Our findings indicate that the interactions between 1alpha-B and elasmobranch GR and MR proteins evolved by molecular exploitation: a novel hormone recruited into new functional partnerships two ancient receptors that had previously interacted with other ligands. The ancestral receptor's promiscuous capacity to fortuitously bind compounds that are slight structural variants of its original ligands set the stage for the evolution of this new interaction.

Migrating EO/IR sensors to cloud-based infrastructure as service architectures

NASA Astrophysics Data System (ADS)

Berglie, Stephen T.; Webster, Steven; May, Christopher M.

2014-06-01

The Night Vision Image Generator (NVIG), a product of US Army RDECOM CERDEC NVESD, is a visualization tool used widely throughout Army simulation environments to provide fully attributed synthesized, full motion video using physics-based sensor and environmental effects. The NVIG relies heavily on contemporary hardware-based acceleration and GPU processing techniques, which push the envelope of both enterprise and commodity-level hypervisor support for providing virtual machines with direct access to hardware resources. The NVIG has successfully been integrated into fully virtual environments where system architectures leverage cloudbased technologies to various extents in order to streamline infrastructure and service management. This paper details the challenges presented to engineers seeking to migrate GPU-bound processes, such as the NVIG, to virtual machines and, ultimately, Cloud-Based IAS architectures. In addition, it presents the path that led to success for the NVIG. A brief overview of Cloud-Based infrastructure management tool sets is provided, and several virtual desktop solutions are outlined. A discrimination is made between general purpose virtual desktop technologies compared to technologies that expose GPU-specific capabilities, including direct rendering and hard ware-based video encoding. Candidate hypervisor/virtual machine configurations that nominally satisfy the virtualized hardware-level GPU requirements of the NVIG are presented , and each is subsequently reviewed in light of its implications on higher-level Cloud management techniques. Implementation details are included from the hardware level, through the operating system, to the 3D graphics APls required by the NVIG and similar GPU-bound tools.

Distributed attitude synchronization of formation flying via consensus-based virtual structure

NASA Astrophysics Data System (ADS)

Cong, Bing-Long; Liu, Xiang-Dong; Chen, Zhen

2011-06-01

This paper presents a general framework for synchronized multiple spacecraft rotations via consensus-based virtual structure. In this framework, attitude control systems for formation spacecrafts and virtual structure are designed separately. Both parametric uncertainty and external disturbance are taken into account. A time-varying sliding mode control (TVSMC) algorithm is designed to improve the robustness of the actual attitude control system. As for the virtual attitude control system, a behavioral consensus algorithm is presented to accomplish the attitude maneuver of the entire formation and guarantee a consistent attitude among the local virtual structure counterparts during the attitude maneuver. A multiple virtual sub-structures (MVSSs) system is introduced to enhance current virtual structure scheme when large amounts of spacecrafts are involved in the formation. The attitude of spacecraft is represented by modified Rodrigues parameter (MRP) for its non-redundancy. Finally, a numerical simulation with three synchronization situations is employed to illustrate the effectiveness of the proposed strategy.

Effects of virtual reality-based training and task-oriented training on balance performance in stroke patients.

PubMed

Lee, Hyung Young; Kim, You Lim; Lee, Suk Min

2015-06-01

[Purpose] This study aimed to investigate the clinical effects of virtual reality-based training and task-oriented training on balance performance in stroke patients. [Subjects and Methods] The subjects were randomly allocated to 2 groups: virtual reality-based training group (n = 12) and task-oriented training group (n = 12). The patients in the virtual reality-based training group used the Nintendo Wii Fit Plus, which provided visual and auditory feedback as well as the movements that enabled shifting of weight to the right and left sides, for 30 min/day, 3 times/week for 6 weeks. The patients in the task-oriented training group practiced additional task-oriented programs for 30 min/day, 3 times/week for 6 weeks. Patients in both groups also underwent conventional physical therapy for 60 min/day, 5 times/week for 6 weeks. [Results] Balance and functional reach test outcomes were examined in both groups. The results showed that the static balance and functional reach test outcomes were significantly higher in the virtual reality-based training group than in the task-oriented training group. [Conclusion] This study suggested that virtual reality-based training might be a more feasible and suitable therapeutic intervention for dynamic balance in stroke patients compared to task-oriented training.

Effects of virtual reality-based training and task-oriented training on balance performance in stroke patients

PubMed Central

Lee, Hyung Young; Kim, You Lim; Lee, Suk Min

2015-01-01

[Purpose] This study aimed to investigate the clinical effects of virtual reality-based training and task-oriented training on balance performance in stroke patients. [Subjects and Methods] The subjects were randomly allocated to 2 groups: virtual reality-based training group (n = 12) and task-oriented training group (n = 12). The patients in the virtual reality-based training group used the Nintendo Wii Fit Plus, which provided visual and auditory feedback as well as the movements that enabled shifting of weight to the right and left sides, for 30 min/day, 3 times/week for 6 weeks. The patients in the task-oriented training group practiced additional task-oriented programs for 30 min/day, 3 times/week for 6 weeks. Patients in both groups also underwent conventional physical therapy for 60 min/day, 5 times/week for 6 weeks. [Results] Balance and functional reach test outcomes were examined in both groups. The results showed that the static balance and functional reach test outcomes were significantly higher in the virtual reality-based training group than in the task-oriented training group. [Conclusion] This study suggested that virtual reality-based training might be a more feasible and suitable therapeutic intervention for dynamic balance in stroke patients compared to task-oriented training. PMID:26180341

Vision-based navigation in a dynamic environment for virtual human

NASA Astrophysics Data System (ADS)

Liu, Yan; Sun, Ji-Zhou; Zhang, Jia-Wan; Li, Ming-Chu

2004-06-01

Intelligent virtual human is widely required in computer games, ergonomics software, virtual environment and so on. We present a vision-based behavior modeling method to realize smart navigation in a dynamic environment. This behavior model can be divided into three modules: vision, global planning and local planning. Vision is the only channel for smart virtual actor to get information from the outside world. Then, the global and local planning module use A* and D* algorithm to find a way for virtual human in a dynamic environment. Finally, the experiments on our test platform (Smart Human System) verify the feasibility of this behavior model.

Advanced Maintenance Simulation by Means of Hand-Based Haptic Interfaces

NASA Astrophysics Data System (ADS)

Nappi, Michele; Paolino, Luca; Ricciardi, Stefano; Sebillo, Monica; Vitiello, Giuliana

Aerospace industry has been involved in virtual simulation for design and testing since the birth of virtual reality. Today this industry is showing a growing interest in the development of haptic-based maintenance training applications, which represent the most advanced way to simulate maintenance and repair tasks within a virtual environment by means of a visual-haptic approach. The goal is to allow the trainee to experiment the service procedures not only as a workflow reproduced at a visual level but also in terms of the kinaesthetic feedback involved with the manipulation of tools and components. This study, conducted in collaboration with aerospace industry specialists, is aimed to the development of an immersive virtual capable of immerging the trainees into a virtual environment where mechanics and technicians can perform maintenance simulation or training tasks by directly manipulating 3D virtual models of aircraft parts while perceiving force feedback through the haptic interface. The proposed system is based on ViRstperson, a virtual reality engine under development at the Italian Center for Aerospace Research (CIRA) to support engineering and technical activities such as design-time maintenance procedure validation, and maintenance training. This engine has been extended to support haptic-based interaction, enabling a more complete level of interaction, also in terms of impedance control, and thus fostering the development of haptic knowledge in the user. The user’s “sense of touch” within the immersive virtual environment is simulated through an Immersion CyberForce® hand-based force-feedback device. Preliminary testing of the proposed system seems encouraging.

Virtual Learning Effectiveness: An Examination of the Process

ERIC Educational Resources Information Center

Stonebraker, Peter W.; Hazeltine, James E.

2004-01-01

This study defines, examines, and measures the effectiveness of a corporate virtual learning program. Initially, distinctions between traditional and virtual learning and university and corporate programs are defined. Then, based on the literature, an integrative model of the perceived effectiveness of a virtual learning environment is developed…

Virtual Reference Services.

ERIC Educational Resources Information Center

Brewer, Sally

2003-01-01

As the need to access information increases, school librarians must create virtual libraries. Linked to reliable reference resources, the virtual library extends the physical collection and library hours and lets students learn to use Web-based resources in a protected learning environment. The growing number of virtual schools increases the need…

Differential Targeting of Gβγ-Subunit Signaling with Small Molecules

NASA Astrophysics Data System (ADS)

Bonacci, Tabetha M.; Mathews, Jennifer L.; Yuan, Chujun; Lehmann, David M.; Malik, Sundeep; Wu, Dianqing; Font, Jose L.; Bidlack, Jean M.; Smrcka, Alan V.

2006-04-01

G protein βγ subunits have potential as a target for therapeutic treatment of a number of diseases. We performed virtual docking of a small-molecule library to a site on Gβγ subunits that mediates protein interactions. We hypothesized that differential targeting of this surface could allow for selective modulation of Gβγ subunit functions. Several compounds bound to Gβγ subunits with affinities from 0.1 to 60 μM and selectively modulated functional Gβγ-protein-protein interactions in vitro, chemotactic peptide signaling pathways in HL-60 leukocytes, and opioid receptor-dependent analgesia in vivo. These data demonstrate an approach for modulation of G protein-coupled receptor signaling that may represent an important therapeutic strategy.

Optimization of N-benzyl-benzoxazol-2-ones as receptor antagonists of macrophage migration inhibitory factor (MIF)

PubMed Central

Hare, Alissa A.; Leng, Lin; Gandavadi, Sunilkumar; Du, Xin; Cournia, Zoe; Bucala, Richard; Jorgensen, William L.

2010-01-01

The cytokine MIF is involved in inflammation and cell proliferation via pathways initiated by its binding to the transmembrane receptor CD74. MIF also exhibits keto-enol tautomerase activity, believed to be vestigial in mammals. Starting from a 1-μM hit from virtual screening, substituted benzoxazol-2-ones have been discovered as antagonists with IC50 values as low as 7.5 nM in a tautomerase assay and 80 nM in a MIF-CD74 binding assay. Additional studies for one of the potent inhibitors demonstrated that it is not a covalent inhibitor of MIF and that it attenuates MIF-dependent ERK1/2 phosphorylation in human synovial fibroblasts. PMID:20728358

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

PubMed

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.

Virtual Screening as a Strategy for the Identification of Xenobiotics Disrupting Corticosteroid Action

PubMed Central

Praxmarer, Lukas; Chantong, Boonrat; Cereghetti, Diego; Winiger, Rahel; Schuster, Daniela; Odermatt, Alex

2012-01-01

Background Impaired corticosteroid action caused by genetic and environmental influence, including exposure to hazardous xenobiotics, contributes to the development and progression of metabolic diseases, cardiovascular complications and immune disorders. Novel strategies are thus needed for identifying xenobiotics that interfere with corticosteroid homeostasis. 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2) and mineralocorticoid receptors (MR) are major regulators of corticosteroid action. 11β-HSD2 converts the active glucocorticoid cortisol to the inactive cortisone and protects MR from activation by glucocorticoids. 11β-HSD2 has also an essential role in the placenta to protect the fetus from high maternal cortisol concentrations. Methods and Principal Findings We employed a previously constructed 3D-structural library of chemicals with proven and suspected endocrine disrupting effects for virtual screening using a chemical feature-based 11β-HSD pharmacophore. We tested several in silico predicted chemicals in a 11β-HSD2 bioassay. The identified antibiotic lasalocid and the silane-coupling agent AB110873 were found to concentration-dependently inhibit 11β-HSD2. Moreover, the silane AB110873 was shown to activate MR and stimulate mitochondrial ROS generation and the production of the proinflammatory cytokine interleukin-6 (IL-6). Finally, we constructed a MR pharmacophore, which successfully identified the silane AB110873. Conclusions Screening of virtual chemical structure libraries can facilitate the identification of xenobiotics inhibiting 11β-HSD2 and/or activating MR. Lasalocid and AB110873 belong to new classes of 11β-HSD2 inhibitors. The silane AB110873 represents to the best of our knowledge the first industrial chemical shown to activate MR. Furthermore, the MR pharmacophore can now be used for future screening purposes. PMID:23056542

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

PubMed

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

2018-06-01

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 VM-shared desktop virtualization system based on OpenStack

NASA Astrophysics Data System (ADS)

Liu, Xi; Zhu, Mingfa; Xiao, Limin; Jiang, Yuanjie

2018-04-01

With the increasing popularity of cloud computing, desktop virtualization is rising in recent years as a branch of virtualization technology. However, existing desktop virtualization systems are mostly designed as a one-to-one mode, which one VM can only be accessed by one user. Meanwhile, previous desktop virtualization systems perform weakly in terms of response time and cost saving. This paper proposes a novel VM-Shared desktop virtualization system based on OpenStack platform. The paper modified the connecting process and the display data transmission process of the remote display protocol SPICE to support VM-Shared function. On the other hand, we propose a server-push display mode to improve user interactive experience. The experimental results show that our system performs well in response time and achieves a low CPU consumption.

Towards Gesture-Based Multi-User Interactions in Collaborative Virtual Environments

NASA Astrophysics Data System (ADS)

Pretto, N.; Poiesi, F.

2017-11-01

We present a virtual reality (VR) setup that enables multiple users to participate in collaborative virtual environments and interact via gestures. A collaborative VR session is established through a network of users that is composed of a server and a set of clients. The server manages the communication amongst clients and is created by one of the users. Each user's VR setup consists of a Head Mounted Display (HMD) for immersive visualisation, a hand tracking system to interact with virtual objects and a single-hand joypad to move in the virtual environment. We use Google Cardboard as a HMD for the VR experience and a Leap Motion for hand tracking, thus making our solution low cost. We evaluate our VR setup though a forensics use case, where real-world objects pertaining to a simulated crime scene are included in a VR environment, acquired using a smartphone-based 3D reconstruction pipeline. Users can interact using virtual gesture-based tools such as pointers and rulers.

Robotic and Virtual Reality BCIs Using Spatial Tactile and Auditory Oddball Paradigms.

PubMed

Rutkowski, Tomasz M

2016-01-01

The paper reviews nine robotic and virtual reality (VR) brain-computer interface (BCI) projects developed by the author, in collaboration with his graduate students, within the BCI-lab research group during its association with University of Tsukuba, Japan. The nine novel approaches are discussed in applications to direct brain-robot and brain-virtual-reality-agent control interfaces using tactile and auditory BCI technologies. The BCI user intentions are decoded from the brainwaves in realtime using a non-invasive electroencephalography (EEG) and they are translated to a symbiotic robot or virtual reality agent thought-based only control. A communication protocol between the BCI output and the robot or the virtual environment is realized in a symbiotic communication scenario using an user datagram protocol (UDP), which constitutes an internet of things (IoT) control scenario. Results obtained from healthy users reproducing simple brain-robot and brain-virtual-agent control tasks in online experiments support the research goal of a possibility to interact with robotic devices and virtual reality agents using symbiotic thought-based BCI technologies. An offline BCI classification accuracy boosting method, using a previously proposed information geometry derived approach, is also discussed in order to further support the reviewed robotic and virtual reality thought-based control paradigms.

Robotic and Virtual Reality BCIs Using Spatial Tactile and Auditory Oddball Paradigms

PubMed Central

Rutkowski, Tomasz M.

2016-01-01

The paper reviews nine robotic and virtual reality (VR) brain–computer interface (BCI) projects developed by the author, in collaboration with his graduate students, within the BCI–lab research group during its association with University of Tsukuba, Japan. The nine novel approaches are discussed in applications to direct brain-robot and brain-virtual-reality-agent control interfaces using tactile and auditory BCI technologies. The BCI user intentions are decoded from the brainwaves in realtime using a non-invasive electroencephalography (EEG) and they are translated to a symbiotic robot or virtual reality agent thought-based only control. A communication protocol between the BCI output and the robot or the virtual environment is realized in a symbiotic communication scenario using an user datagram protocol (UDP), which constitutes an internet of things (IoT) control scenario. Results obtained from healthy users reproducing simple brain-robot and brain-virtual-agent control tasks in online experiments support the research goal of a possibility to interact with robotic devices and virtual reality agents using symbiotic thought-based BCI technologies. An offline BCI classification accuracy boosting method, using a previously proposed information geometry derived approach, is also discussed in order to further support the reviewed robotic and virtual reality thought-based control paradigms. PMID:27999538

Teachers' Conceptions and Their Approaches to Teaching in Virtual Reality and Simulation-Based Learning Environments

ERIC Educational Resources Information Center

Keskitalo, Tuulikki

2011-01-01

This research article focuses on virtual reality (VR) and simulation-based training, with a special focus on the pedagogical use of the Virtual Centre of Wellness Campus known as ENVI (Rovaniemi, Finland). In order to clearly understand how teachers perceive teaching and learning in such environments, this research examines the concepts of…

Personalization of Learning Activities within a Virtual Environment for Training Based on Fuzzy Logic Theory

ERIC Educational Resources Information Center

Mohamed, Fahim; Abdeslam, Jakimi; Lahcen, El Bermi

2017-01-01

Virtual Environments for Training (VET) are useful tools for visualization, discovery as well as for training. VETs are based on virtual reality technique to put learners in training situations that emulate genuine situations. VETs have proven to be advantageous in putting learners into varied training situations to acquire knowledge and…

Can You Skype Me Now? Developing Teachers' Classroom Management Practices through Virtual Coaching

ERIC Educational Resources Information Center

Rock, Marcia L.; Schoenfeld, Naomi; Zigmond, Naomi; Gable, Robert A.; Gregg, Madeleine; Ploessl, Donna M.; Salter, Ashley

2013-01-01

In this article, situated within the context of a larger ongoing study on the efficacy of Web-based virtual coaching, these authors describe a virtual coaching model for maximizing pre- and in-service teachers' effective use of evidence-based classroom management practices. They also provide a brief summary of previous results obtained…

A Practical Guide, with Theoretical Underpinnings, for Creating Effective Virtual Reality Learning Environments

ERIC Educational Resources Information Center

O'Connor, Eileen A.; Domingo, Jelia

2017-01-01

With the advent of open source virtual environments, the associated cost reductions, and the more flexible options, avatar-based virtual reality environments are within reach of educators. By using and repurposing readily available virtual environments, instructors can bring engaging, community-building, and immersive learning opportunities to…

Virtual temporal bone: an interactive 3-dimensional learning aid for cranial base surgery.

PubMed

Kockro, Ralf A; Hwang, Peter Y K

2009-05-01

We have developed an interactive virtual model of the temporal bone for the training and teaching of cranial base surgery. The virtual model was based on the tomographic data of the Visible Human Project. The male Visible Human's computed tomographic data were volumetrically reconstructed as virtual bone tissue, and the individual photographic slices provided the basis for segmentation of the middle and inner ear structures, cranial nerves, vessels, and brainstem. These structures were created by using outlining and tube editing tools, allowing structural modeling either directly on the basis of the photographic data or according to information from textbooks and cadaver dissections. For training and teaching, the virtual model was accessed in the previously described 3-dimensional workspaces of the Dextroscope or Dextrobeam (Volume Interactions Pte, Ltd., Singapore), whose interfaces enable volumetric exploration from any perspective and provide virtual tools for drilling and measuring. We have simulated several cranial base procedures including approaches via the floor of the middle fossa and the lateral petrous bone. The virtual model suitably illustrated the core facts of anatomic spatial relationships while simulating different stages of bone drilling along a variety of surgical corridors. The system was used for teaching during training courses to plan and discuss operative anatomy and strategies. The Virtual Temporal Bone and its surrounding 3-dimensional workspace provide an effective way to study the essential surgical anatomy of this complex region and to teach and train operative strategies, especially when used as an adjunct to cadaver dissections.

Web-Based Testing Tools for Electrical Engineering Courses

DTIC Science & Technology

2001-09-01

ideas of distance learning are based on forming “ virtual teams” [2]. Each team is equipped with the same software packages and share information via...using virtual laboratories where they can simulate a laboratory experience in a web-based environment. They can also control laboratory devices over...possible to create a set of virtual laboratories that allow students to interact with the learning material at the same time that the student is

Virtual TeleRehab: a case study.

PubMed

Pareto, Lena; Johansson, Britt; Zeller, Sally; Sunnerhagen, Katharina S; Rydmark, Martin; Broeren, Jurgen

2011-01-01

We examined the efficacy of a remotely based occupational therapy intervention. A 40-year-old woman who suffered a stroke participated in a telerehabilitation program. The intervention method is based on virtual reality gaming to enhance the training experience and to facilitate the relearning processes. The results indicate that Virtual TeleRehab is an effective method for motivational, economical, and practical reasons by combining game-based rehabilitation in the home with weekly distance meetings.

A virtual university Web system for a medical school.

PubMed

Séka, L P; Duvauferrier, R; Fresnel, A; Le Beux, P

1998-01-01

This paper describes a Virtual Medical University Web Server. This project started in 1994 by the development of the French Radiology Server. The main objective of our Medical Virtual University is to offer not only an initial training (for students) but also the Continuing Professional Education (for practitioners). Our system is based on electronic textbooks, clinical cases (around 4000) and a medical knowledge base called A.D.M. ("Aide au Diagnostic Medical"). We have indexed all electronic textbooks and clinical cases according to the ADM base in order to facilitate the navigation on the system. This system base is supported by a relational database management system. The Virtual Medical University, available on the Web Internet, is presently in the process of external evaluations.

An Integrated In Silico Method to Discover Novel Rock1 Inhibitors: Multi- Complex-Based Pharmacophore, Molecular Dynamics Simulation and Hybrid Protocol Virtual Screening.

PubMed

Chen, Haining; Li, Sijia; Hu, Yajiao; Chen, Guo; Jiang, Qinglin; Tong, Rongsheng; Zang, Zhihe; Cai, Lulu

2016-01-01

Rho-associated, coiled-coil containing protein kinase 1 (ROCK1) is an important regulator of focal adhesion, actomyosin contraction and cell motility. In this manuscript, a combination of the multi-complex-based pharmacophore (MCBP), molecular dynamics simulation and a hybrid protocol of a virtual screening method, comprised of multipharmacophore- based virtual screening (PBVS) and ensemble docking-based virtual screening (DBVS) methods were used for retrieving novel ROCK1 inhibitors from the natural products database embedded in the ZINC database. Ten hit compounds were selected from the hit compounds, and five compounds were tested experimentally. Thus, these results may provide valuable information for further discovery of more novel ROCK1 inhibitors.

Shared protection based virtual network mapping in space division multiplexing optical networks

NASA Astrophysics Data System (ADS)

Zhang, Huibin; Wang, Wei; Zhao, Yongli; Zhang, Jie

2018-05-01

Space Division Multiplexing (SDM) has been introduced to improve the capacity of optical networks. In SDM optical networks, there are multiple cores/modes in each fiber link, and spectrum resources are multiplexed in both frequency and core/modes dimensions. Enabled by network virtualization technology, one SDM optical network substrate can be shared by several virtual networks operators. Similar with point-to-point connection services, virtual networks (VN) also need certain survivability to guard against network failures. Based on customers' heterogeneous requirements on the survivability of their virtual networks, this paper studies the shared protection based VN mapping problem and proposes a Minimum Free Frequency Slots (MFFS) mapping algorithm to improve spectrum efficiency. Simulation results show that the proposed algorithm can optimize SDM optical networks significantly in terms of blocking probability and spectrum utilization.

Virtual Reality for Pediatric Sedation: A Randomized Controlled Trial Using Simulation.

PubMed

Zaveri, Pavan P; Davis, Aisha B; O'Connell, Karen J; Willner, Emily; Aronson Schinasi, Dana A; Ottolini, Mary

2016-02-09

Team training for procedural sedation for pediatric residents has traditionally consisted of didactic presentations and simulated scenarios using high-fidelity mannequins. We assessed the effectiveness of a virtual reality module in teaching preparation for and management of sedation for procedures. After developing a virtual reality environment in Second Life® (Linden Lab, San Francisco, CA) where providers perform and recover patients from procedural sedation, we conducted a randomized controlled trial to assess the effectiveness of the virtual reality module versus a traditional web-based educational module. A 20 question pre- and post-test was administered to assess knowledge change. All subjects participated in a simulated pediatric procedural sedation scenario that was video recorded for review and assessed using a 32-point checklist. A brief survey elicited feedback on the virtual reality module and the simulation scenario. The median score on the assessment checklist was 75% for the intervention group and 70% for the control group (P = 0.32). For the knowledge tests, there was no statistically significant difference between the groups (P = 0.14). Users had excellent reviews of the virtual reality module and reported that the module added to their education. Pediatric residents performed similarly in simulation and on a knowledge test after a virtual reality module compared with a traditional web-based module on procedural sedation. Although users enjoyed the virtual reality experience, these results question the value virtual reality adds in improving the performance of trainees. Further inquiry is needed into how virtual reality provides true value in simulation-based education.

Using Virtual Pets to Increase Fruit and Vegetable Consumption in Children: A Technology-Assisted Social Cognitive Theory Approach.

PubMed

Ahn, Sun Joo Grace; Johnsen, Kyle; Moore, James; Brown, Scott; Biersmith, Melanie; Ball, Catherine

2016-02-01

A virtual pet in the form of a mid-sized dog was developed based on the framework of social cognitive theory and tested as a vehicle for promoting fruit and vegetable (F&V) consumption in children. Three groups of children (N = 68) between the ages of 7 and 13 years were studied: baseline (no treatment), computer only, and virtual dog. Children in the virtual dog condition interacted with the virtual dog for 3 days, setting F&V consumption goals and receiving evaluation and reinforcement based on whether they met their self-set goals. Children vicariously experienced future health outcomes of F&V consumption by seeing, hearing, and feeling their virtual dog's physical and mental health improve or deteriorate based on their F&V consumption in the physical world. Children in the computer only condition interacted with a computer system that presented equivalent features, but without the virtual dog. Children in the baseline condition did not receive any experimental treatment. Results indicated that children in the virtual dog condition chose to be served significantly more F&V than those in the computer only or baseline conditions did. However, children in the virtual dog condition were unable to consume significantly more F&V than those in the computer only condition, although children in those two conditions consumed more F&V than the baseline condition. Food preferences did not differ significantly across the three conditions before and after the experimental treatments. Theoretical and practical potentials of using a virtual pet to promote F&V consumption systematically in children are discussed.

Virtual Reality for Pediatric Sedation: A Randomized Controlled Trial Using Simulation

PubMed Central

Davis, Aisha B; O'Connell, Karen J; Willner, Emily; Aronson Schinasi, Dana A; Ottolini, Mary

2016-01-01

Introduction: Team training for procedural sedation for pediatric residents has traditionally consisted of didactic presentations and simulated scenarios using high-fidelity mannequins. We assessed the effectiveness of a virtual reality module in teaching preparation for and management of sedation for procedures. Methods: After developing a virtual reality environment in Second Life® (Linden Lab, San Francisco, CA) where providers perform and recover patients from procedural sedation, we conducted a randomized controlled trial to assess the effectiveness of the virtual reality module versus a traditional web-based educational module. A 20 question pre- and post-test was administered to assess knowledge change. All subjects participated in a simulated pediatric procedural sedation scenario that was video recorded for review and assessed using a 32-point checklist. A brief survey elicited feedback on the virtual reality module and the simulation scenario. Results: The median score on the assessment checklist was 75% for the intervention group and 70% for the control group (P = 0.32). For the knowledge tests, there was no statistically significant difference between the groups (P = 0.14). Users had excellent reviews of the virtual reality module and reported that the module added to their education. Conclusions: Pediatric residents performed similarly in simulation and on a knowledge test after a virtual reality module compared with a traditional web-based module on procedural sedation. Although users enjoyed the virtual reality experience, these results question the value virtual reality adds in improving the performance of trainees. Further inquiry is needed into how virtual reality provides true value in simulation-based education. PMID:27014520

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

NASA Astrophysics Data System (ADS)

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.

Heterogeneity of NK-2 tachykinin receptors in hamster and rabbit smooth muscles.

PubMed

Maggi, C A; Eglezos, A; Quartara, L; Patacchini, R; Giachetti, A

1992-01-23

The possible existence of NK-2 receptor subtypes in peripheral smooth muscle preparations from rabbit and hamster was investigated by studying the effect of neurokinin A, the selective NK-2 receptor agonist [beta Ala8] neurokinin A (4-10), the selective NK-2 tachykinin receptor antagonists, MEN 10,376, L 659,877 and R 396, and the pseudopeptide derivative of neurokinin A (4-10), MDL 28,564. All experiments were performed in the presence of peptidase inhibitors (captopril, bestatin and thiorphan, 1 microM each). Both neurokinin A and [beta Ala8] neurokinin A (4-10) produced concentration-dependent contractions of the rabbit isolated bronchus and hamster isolated stomach and colon, as well as enhancement of the nerve-mediated twitches of rabbit isolated vas deferens (pars prostatica). MEN 10,376, L 659,877 and R 396 antagonized the effect of the NK-2 receptor selective agonist in all four tissues under study, although marked differences in antagonist potency were evident for the three antagonists. Thus MEN 10,376 was distinctly more potent (about 100 times) in rabbit than in hamster preparations while L 659,877 and R 396 were more potent in hamster than rabbit preparations. MDL 28,564 showed a distinct agonist character in rabbit preparations while it was virtually inactive in hamster preparations, where it antagonized the effect of the NK-2 receptor selective agonist.(ABSTRACT TRUNCATED AT 250 WORDS)

Combined chemical and toxicological long-term monitoring for AhR agonists with SPMD-based virtual organisms in drinking water Danjiangkou Reservoir, China.

PubMed

Wang, Jingxian; Song, Guoqiang; Li, Aimin; Henkelmann, Bernhard; Pfister, Gerd; Tong, Anthony Z; Schramm, Karl-Werner

2014-08-01

SPMD-based virtual organisms (VOs) were employed for time-integrating, long-term sampling combined biological and chemical analyses for exposure assessment of hydrophobic organic pollutants (HOPs) in a drinking water reservoir, China. The SPMDs were deployed at four and five sites in the Danjiangkou (DJK) reservoir over two periods of 26 and 31 d to sequester the hydrophobic contaminants in water. The chosen bioassay response for the extracts of the SPMDs, the induction of 7-ethoxyresorufin-o-deethylase (EROD) was assayed using a rat hepatoma cell line (H4IIE). The known aryl hydrocarbon receptor (AhR) agonists PAHs and PCBs were analyzed by HRGC/HRMS instrument. The cause-effect relationship between the observed AhR activities and chemical concentrations of detected AhR agonists was examined. The results show that the extracts from the SPMD samples could induce AhR activity significantly, whereas the chemically derived 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) equivalent (TEQcal) was not correlated with the bioassay-derived TCDD equivalent (TEQbio). The known AhR agonists could only account for 2-10% of the observed AhR responses among which the contribution of PCBs could almost be neglected. Unidentified AhR-active compounds represented a greater proportion of the TCDD equivalent (TCDD-EQ) in SPMD samples from DJK. Based on the first assessment, the VO followed by the combination of chemical and biological analyses emerges as a resource efficient water monitoring device in ecotoxicological assessment for toxicologically relevant compounds which are readily available for uptake by resident aquatic biota in drinking water resources. Copyright © 2014 Elsevier Ltd. All rights reserved.

Virtual Heritage Tours: Developing Interactive Narrative-Based Environments for Historical Sites

NASA Astrophysics Data System (ADS)

Tuck, Deborah; Kuksa, Iryna

In the last decade there has been a noticeable growth in the use of virtual reality (VR) technologies for reconstructing cultural heritage sites. However, many of these virtual reconstructions evidence little of sites' social histories. Narrating the Past is a research project that aims to re-address this issue by investigating methods for embedding social histories within cultural heritage sites and by creating narrative based virtual environments (VEs) within them. The project aims to enhance the visitor's knowledge and understanding by developing a navigable 3D story space, in which participants are immersed. This has the potential to create a malleable virtual environment allowing the visitor to configure their own narrative paths.

Virtual rehabilitation: What are the practical barriers for home-based research?

PubMed Central

Threapleton, Kate; Drummond, Avril; Standen, Penny

2016-01-01

Virtual reality technologies are becoming increasingly accessible and affordable to deliver, and consequently the interest in applying virtual reality within rehabilitation is growing. This has resulted in the emergence of research exploring the utility of virtual reality and interactive video gaming interventions for home use by patients. The aim of this paper is to highlight the practical factors and difficulties that may be encountered in research in this area, and to make recommendations for addressing these. Whilst this paper focuses on examples drawn mainly from stroke rehabilitation research, many of the issues raised are relevant to other conditions where virtual reality approaches have the potential to be applied to home-based rehabilitation. PMID:29942551

A digital atlas of breast histopathology: an application of web based virtual microscopy

PubMed Central

Lundin, M; Lundin, J; Helin, H; Isola, J

2004-01-01

Aims: To develop an educationally useful atlas of breast histopathology, using advanced web based virtual microscopy technology. Methods: By using a robotic microscope and software adopted and modified from the aerial and satellite imaging industry, a virtual microscopy system was developed that allows fully automated slide scanning and image distribution via the internet. More than 150 slides were scanned at high resolution with an oil immersion ×40 objective (numerical aperture, 1.3) and archived on an image server residing in a high speed university network. Results: A publicly available website was constructed, http://www.webmicroscope.net/breastatlas, which features a comprehensive virtual slide atlas of breast histopathology according to the World Health Organisation 2003 classification. Users can view any part of an entire specimen at any magnification within a standard web browser. The virtual slides are supplemented with concise textual descriptions, but can also be viewed without diagnostic information for self assessment of histopathology skills. Conclusions: Using the technology described here, it is feasible to develop clinically and educationally useful virtual microscopy applications. Web based virtual microscopy will probably become widely used at all levels in pathology teaching. PMID:15563669

The Virtual Climate Data Server (vCDS): An iRODS-Based Data Management Software Appliance Supporting Climate Data Services and Virtualization-as-a-Service in the NASA Center for Climate Simulation

NASA Technical Reports Server (NTRS)

Schnase, John L.; Tamkin, Glenn S.; Ripley, W. David III; Stong, Savannah; Gill, Roger; Duffy, Daniel Q.

2012-01-01

Scientific data services are becoming an important part of the NASA Center for Climate Simulation's mission. Our technological response to this expanding role is built around the concept of a Virtual Climate Data Server (vCDS), repetitive provisioning, image-based deployment and distribution, and virtualization-as-a-service. The vCDS is an iRODS-based data server specialized to the needs of a particular data-centric application. We use RPM scripts to build vCDS images in our local computing environment, our local Virtual Machine Environment, NASA s Nebula Cloud Services, and Amazon's Elastic Compute Cloud. Once provisioned into one or more of these virtualized resource classes, vCDSs can use iRODS s federation capabilities to create an integrated ecosystem of managed collections that is scalable and adaptable to changing resource requirements. This approach enables platform- or software-asa- service deployment of vCDS and allows the NCCS to offer virtualization-as-a-service: a capacity to respond in an agile way to new customer requests for data services.

Determining sensitivity/specificity of virtual reality-based neuropsychological tool for detecting residual abnormalities following sport-related concussion.

PubMed

Teel, Elizabeth; Gay, Michael; Johnson, Brian; Slobounov, Semyon

2016-05-01

Computer-based neuropsychological (NP) evaluation is an effective clinical tool used to assess cognitive function which complements the clinical diagnosis of a concussion. However, some researchers and clinicians argue its lack of ecological validity places limitations on externalizing results to a sensory rich athletic environment. Virtual reality-based NP assessment offers clinical advantages using an immersive environment and evaluating domains not typically assessed by traditional NP assessments. The sensitivity and specificity of detecting lingering cognitive abnormalities was examined on components of a virtual reality-based NP assessment battery to cohort affiliation (concussed vs. controls). Data were retrospectively gathered on 128 controls (no concussion) and 24 concussed college-age athletes on measures of spatial navigation, whole body reaction, attention, and balance in a virtual environment. Concussed athletes were tested within 10 days (M = 8.33, SD = 1.06) of concussion and were clinically asymptomatic at the time of testing. A priori alpha level was set at 0.05 for all tests. Spatial navigation (sensitivity 95.8%/specificity 91.4%, d = 1.89), whole body reaction time (sensitivity 95.2%/specificity 89.1%, d = 1.50) and combined virtual reality modules (sensitivity 95.8%,/specificity 96.1%, d = 3.59) produced high sensitivity/specificity values when determining performance-based variability between groups. Use of a virtual reality-based NP platform can detect lingering cognitive abnormalities resulting from concussion in clinically asymptomatic participants. Virtual reality NP platforms may compliment the traditional concussion assessment battery by providing novel information. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

Hemodynamic Changes Caused by Flow Diverters in Rabbit Aneurysm Models: Comparison of Virtual and Realistic FD Deployments Based on Micro-CT Reconstruction

PubMed Central

Fang, Yibin; Yu, Ying; Cheng, Jiyong; Wang, Shengzhang; Wang, Kuizhong; Liu, Jian-Min; Huang, Qinghai

2013-01-01

Adjusting hemodynamics via flow diverter (FD) implantation is emerging as a novel method of treating cerebral aneurysms. However, most previous FD-related hemodynamic studies were based on virtual FD deployment, which may produce different hemodynamic outcomes than realistic (in vivo) FD deployment. We compared hemodynamics between virtual FD and realistic FD deployments in rabbit aneurysm models using computational fluid dynamics (CFD) simulations. FDs were implanted for aneurysms in 14 rabbits. Vascular models based on rabbit-specific angiograms were reconstructed for CFD studies. Real FD configurations were reconstructed based on micro-CT scans after sacrifice, while virtual FD configurations were constructed with SolidWorks software. Hemodynamic parameters before and after FD deployment were analyzed. According to the metal coverage (MC) of implanted FDs calculated based on micro-CT reconstruction, 14 rabbits were divided into two groups (A, MC >35%; B, MC <35%). Normalized mean wall shear stress (WSS), relative residence time (RRT), inflow velocity, and inflow volume in Group A were significantly different (P<0.05) from virtual FD deployment, but pressure was not (P>0.05). The normalized mean WSS in Group A after realistic FD implantation was significantly lower than that of Group B. All parameters in Group B exhibited no significant difference between realistic and virtual FDs. This study confirmed MC-correlated differences in hemodynamic parameters between realistic and virtual FD deployment. PMID:23823503

Web-Based Virtual Laboratory for Food Analysis Course

NASA Astrophysics Data System (ADS)

Handayani, M. N.; Khoerunnisa, I.; Sugiarti, Y.

2018-02-01

Implementation of learning on food analysis course in Program Study of Agro-industrial Technology Education faced problems. These problems include the availability of space and tools in the laboratory that is not comparable with the number of students also lack of interactive learning tools. On the other hand, the information technology literacy of students is quite high as well the internet network is quite easily accessible on campus. This is a challenge as well as opportunities in the development of learning media that can help optimize learning in the laboratory. This study aims to develop web-based virtual laboratory as one of the alternative learning media in food analysis course. This research is R & D (research and development) which refers to Borg & Gall model. The results showed that assessment’s expert of web-based virtual labs developed, in terms of software engineering aspects; visual communication; material relevance; usefulness and language used, is feasible as learning media. The results of the scaled test and wide-scale test show that students strongly agree with the development of web based virtual laboratory. The response of student to this virtual laboratory was positive. Suggestions from students provided further opportunities for improvement web based virtual laboratory and should be considered for further research.

Immersive Virtual Moon Scene System Based on Panoramic Camera Data of Chang'E-3

NASA Astrophysics Data System (ADS)

Gao, X.; Liu, J.; Mu, L.; Yan, W.; Zeng, X.; Zhang, X.; Li, C.

2014-12-01

The system "Immersive Virtual Moon Scene" is used to show the virtual environment of Moon surface in immersive environment. Utilizing stereo 360-degree imagery from panoramic camera of Yutu rover, the system enables the operator to visualize the terrain and the celestial background from the rover's point of view in 3D. To avoid image distortion, stereo 360-degree panorama stitched by 112 images is projected onto inside surface of sphere according to panorama orientation coordinates and camera parameters to build the virtual scene. Stars can be seen from the Moon at any time. So we render the sun, planets and stars according to time and rover's location based on Hipparcos catalogue as the background on the sphere. Immersing in the stereo virtual environment created by this imaged-based rendering technique, the operator can zoom, pan to interact with the virtual Moon scene and mark interesting objects. Hardware of the immersive virtual Moon system is made up of four high lumen projectors and a huge curve screen which is 31 meters long and 5.5 meters high. This system which take all panoramic camera data available and use it to create an immersive environment, enable operator to interact with the environment and mark interesting objects contributed heavily to establishment of science mission goals in Chang'E-3 mission. After Chang'E-3 mission, the lab with this system will be open to public. Besides this application, Moon terrain stereo animations based on Chang'E-1 and Chang'E-2 data will be showed to public on the huge screen in the lab. Based on the data of lunar exploration，we will made more immersive virtual moon scenes and animations to help the public understand more about the Moon in the future.

Virtual Reality: An Instructional Medium for Visual-Spatial Tasks.

ERIC Educational Resources Information Center

Regian, J. Wesley; And Others

1992-01-01

Describes an empirical exploration of the instructional potential of virtual reality as an interface for simulation-based training. Shows that subjects learned spatial-procedural and spatial-navigational skills in virtual reality. (SR)

Natural gesture interfaces

NASA Astrophysics Data System (ADS)

Starodubtsev, Illya

2017-09-01

The paper describes the implementation of the system of interaction with virtual objects based on gestures. The paper describes the common problems of interaction with virtual objects, specific requirements for the interfaces for virtual and augmented reality.

Research on three-dimensional visualization based on virtual reality and Internet

NASA Astrophysics Data System (ADS)

Wang, Zongmin; Yang, Haibo; Zhao, Hongling; Li, Jiren; Zhu, Qiang; Zhang, Xiaohong; Sun, Kai

2007-06-01

To disclose and display water information, a three-dimensional visualization system based on Virtual Reality (VR) and Internet is researched for demonstrating "digital water conservancy" application and also for routine management of reservoir. To explore and mine in-depth information, after completion of modeling high resolution DEM with reliable quality, topographical analysis, visibility analysis and reservoir volume computation are studied. And also, some parameters including slope, water level and NDVI are selected to classify easy-landslide zone in water-level-fluctuating zone of reservoir area. To establish virtual reservoir scene, two kinds of methods are used respectively for experiencing immersion, interaction and imagination (3I). First virtual scene contains more detailed textures to increase reality on graphical workstation with virtual reality engine Open Scene Graph (OSG). Second virtual scene is for internet users with fewer details for assuring fluent speed.

Social Presence and Transactional Distance as an Antecedent to Knowledge Sharing in Virtual Learning Communities

ERIC Educational Resources Information Center

Karaoglan Yilmaz, Fatma Gizem

2017-01-01

Today, the use of social network-based virtual learning communities is increasing rapidly in terms of knowledge management. An important dynamic of knowledge management processes is the knowledge sharing behaviors (KSB) in community. The purpose of this study is to examine the KSB of the students in a Facebook-based virtual community created…

Applied virtual reality at the Research Triangle Institute

NASA Technical Reports Server (NTRS)

Montoya, R. Jorge

1994-01-01

Virtual Reality (VR) is a way for humans to use computers in visualizing, manipulating and interacting with large geometric data bases. This paper describes a VR infrastructure and its application to marketing, modeling, architectural walk through, and training problems. VR integration techniques used in these applications are based on a uniform approach which promotes portability and reusability of developed modules. For each problem, a 3D object data base is created using data captured by hand or electronically. The object's realism is enhanced through either procedural or photo textures. The virtual environment is created and populated with the data base using software tools which also support interactions with and immersivity in the environment. These capabilities are augmented by other sensory channels such as voice recognition, 3D sound, and tracking. Four applications are presented: a virtual furniture showroom, virtual reality models of the North Carolina Global TransPark, a walk through the Dresden Fraunenkirche, and the maintenance training simulator for the National Guard.

Virtual Technologies to Develop Visual-Spatial Ability in Engineering Students

ERIC Educational Resources Information Center

Roca-González, Cristina; Martin-Gutierrez, Jorge; García-Dominguez, Melchor; Carrodeguas, Mª del Carmen Mato

2017-01-01

The present study assessed a short training experiment to improve spatial abilities using two tools based on virtual technologies: one focused on manipulation of specific geometric virtual pieces, and the other consisting of virtual orienteering game. The two tools can help improve spatial abilities required for many engineering problem-solving…

Managing Global Virtual Teams across Classrooms, Students and Faculty

ERIC Educational Resources Information Center

Shea, Timothy P.; Sherer, Pamela D.; Quilling, Rosemary D.; Blewett, Craig N.

2011-01-01

Virtual teams are becoming commonplace in business today so our business school students should have experience in effectively working in virtual teams. Based on a month-long virtual team project conducted by the authors between classes in South Africa and the United States, this paper discusses the opportunities and challenges of using global…

Virtual Frog Dissection Kit Version 2.2

Science.gov Websites

Virtual Frog Dissection Kit This award-winning interactive program is part of the "Whole Frog " project. You can interactively dissect a (digitized) frog named Fluffy, and play the Virtual Frog animals other than the frog that have a computer-graphics based virtual dissection page. We get frequent

The Study on Virtual Medical Instrument based on LabVIEW.

PubMed

Chengwei, Li; Limei, Zhang; Xiaoming, Hu

2005-01-01

With the increasing performance of computer, the virtual instrument technology has greatly advanced over the years, and then virtual medical instrument technology becomes available. This paper presents the virtual medical instrument, and then as an example, an application of a signal acquisition, processing and analysis system using LabVIEW is also given.

The Problem Patron and the Academic Library Web Site as Virtual Reference Desk.

ERIC Educational Resources Information Center

Taylor, Daniel; Porter, George S.

2002-01-01

Considers problem library patrons in a virtual environment based on experiences at California Institute of Technology's Web site and its use for virtual reference. Discusses the virtual reference desk concept; global visibility and access to the World Wide Web; problematic email; and advantages in the electronic environment. (LRW)

Education about Hallucinations Using an Internet Virtual Reality System: A Qualitative Survey

ERIC Educational Resources Information Center

Yellowlees, Peter M.; Cook, James N.

2006-01-01

Objective: The authors evaluate an Internet virtual reality technology as an education tool about the hallucinations of psychosis. Method: This is a pilot project using Second Life, an Internet-based virtual reality system, in which a virtual reality environment was constructed to simulate the auditory and visual hallucinations of two patients…

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

PubMed

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.

[Use of virtual reality in forensic psychiatry. A new paradigm?].

PubMed

Fromberger, P; Jordan, K; Müller, J L

2014-03-01

For more than 20 years virtual realities (VR) have been successfully used in the assessment and treatment of psychiatric disorders. The most important advantages of VR are the high ecological validity of virtual environments, the entire controllability of virtual stimuli in the virtual environment and the capability to induce the sensation of being in the virtual environment instead of the physical environment. VRs provide the opportunity to face the user with stimuli and situations which are not available or too risky in reality. Despite these advantages VR-based applications have not yet been applied in forensic psychiatry. On the basis of an overview of the recent state-of-the-art in VR-based applications in general psychiatry, the article demonstrates the advantages and possibilities of VR-based applications in forensic psychiatry. Up to now only preliminary studies regarding the VR-based assessment of pedophilic interests exist. These studies demonstrate the potential of ecologically valid VR-based applications for the assessment of forensically relevant disorders. One of the most important advantages is the possibility of VR to assess the behavior of forensic inpatients in crime-related situations without endangering others. This provides completely new possibilities not only regarding the assessment but also for the treatment of forensic inpatients. Before utilizing these possibilities in the clinical practice exhaustive research and development will be necessary. Given the high potential of VR-based applications, this effort would be worth it.

An efficient and scalable deformable model for virtual reality-based medical applications.

PubMed

Choi, Kup-Sze; Sun, Hanqiu; Heng, Pheng-Ann

2004-09-01

Modeling of tissue deformation is of great importance to virtual reality (VR)-based medical simulations. Considerable effort has been dedicated to the development of interactively deformable virtual tissues. In this paper, an efficient and scalable deformable model is presented for virtual-reality-based medical applications. It considers deformation as a localized force transmittal process which is governed by algorithms based on breadth-first search (BFS). The computational speed is scalable to facilitate real-time interaction by adjusting the penetration depth. Simulated annealing (SA) algorithms are developed to optimize the model parameters by using the reference data generated with the linear static finite element method (FEM). The mechanical behavior and timing performance of the model have been evaluated. The model has been applied to simulate the typical behavior of living tissues and anisotropic materials. Integration with a haptic device has also been achieved on a generic personal computer (PC) platform. The proposed technique provides a feasible solution for VR-based medical simulations and has the potential for multi-user collaborative work in virtual environment.

Exploring Design Requirements for Repurposing Dental Virtual Patients From the Web to Second Life: A Focus Group Study

PubMed Central

Antoniou, Panagiotis E; Athanasopoulou, Christina A; Dafli, Eleni

2014-01-01

Background Since their inception, virtual patients have provided health care educators with a way to engage learners in an experience simulating the clinician’s environment without danger to learners and patients. This has led this learning modality to be accepted as an essential component of medical education. With the advent of the visually and audio-rich 3-dimensional multi-user virtual environment (MUVE), a new deployment platform has emerged for educational content. Immersive, highly interactive, multimedia-rich, MUVEs that seamlessly foster collaboration provide a new hotbed for the deployment of medical education content. Objective This work aims to assess the suitability of the Second Life MUVE as a virtual patient deployment platform for undergraduate dental education, and to explore the requirements and specifications needed to meaningfully repurpose Web-based virtual patients in MUVEs. Methods Through the scripting capabilities and available art assets in Second Life, we repurposed an existing Web-based periodontology virtual patient into Second Life. Through a series of point-and-click interactions and multiple-choice queries, the user experienced a specific periodontology case and was asked to provide the optimal responses for each of the challenges of the case. A focus group of 9 undergraduate dentistry students experienced both the Web-based and the Second Life version of this virtual patient. The group convened 3 times and discussed relevant issues such as the group’s computer literacy, the assessment of Second Life as a virtual patient deployment platform, and compared the Web-based and MUVE-deployed virtual patients. Results A comparison between the Web-based and the Second Life virtual patient revealed the inherent advantages of the more experiential and immersive Second Life virtual environment. However, several challenges for the successful repurposing of virtual patients from the Web to the MUVE were identified. The identified challenges for repurposing of Web virtual patients to the MUVE platform from the focus group study were (1) increased case complexity to facilitate the user’s gaming preconception in a MUVE, (2) necessity to decrease textual narration and provide the pertinent information in a more immersive sensory way, and (3) requirement to allow the user to actuate the solutions of problems instead of describing them through narration. Conclusions For a successful systematic repurposing effort of virtual patients to MUVEs such as Second Life, the best practices of experiential and immersive game design should be organically incorporated in the repurposing workflow (automated or not). These findings are pivotal in an era in which open educational content is transferred to and shared among users, learners, and educators of various open repositories/environments. PMID:24927470

Receptor-ligand binding sites and virtual screening.

PubMed

Hattotuwagama, Channa K; Davies, Matthew N; Flower, Darren R

2006-01-01

Within the pharmaceutical industry, the ultimate source of continuing profitability is the unremitting process of drug discovery. To be profitable, drugs must be marketable: legally novel, safe and relatively free of side effects, efficacious, and ideally inexpensive to produce. While drug discovery was once typified by a haphazard and empirical process, it is now increasingly driven by both knowledge of the receptor-mediated basis of disease and how drug molecules interact with receptors and the wider physiome. Medicinal chemistry postulates that to understand a congeneric ligand series, or set thereof, is to understand the nature and requirements of a ligand binding site. Likewise, structural molecular biology posits that to understand a binding site is to understand the nature of ligands bound therein. Reality sits somewhere between these extremes, yet subsumes them both. Complementary to rules of ligand design, arising through decades of medicinal chemistry, structural biology and computational chemistry are able to elucidate the nature of binding site-ligand interactions, facilitating, at both pragmatic and conceptual levels, the drug discovery process.

Teaching Basic Field Skills Using Screen-Based Virtual Reality Landscapes

NASA Astrophysics Data System (ADS)

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 our virtual landscapes are freely available online at www.see.leeds.ac.uk/virtual-landscapes/.

Image-based 3D reconstruction and virtual environmental walk-through

NASA Astrophysics Data System (ADS)

Sun, Jifeng; Fang, Lixiong; Luo, Ying

2001-09-01

We present a 3D reconstruction method, which combines geometry-based modeling, image-based modeling and rendering techniques. The first component is an interactive geometry modeling method which recovery of the basic geometry of the photographed scene. The second component is model-based stereo algorithm. We discus the image processing problems and algorithms of walking through in virtual space, then designs and implement a high performance multi-thread wandering algorithm. The applications range from architectural planning and archaeological reconstruction to virtual environments and cinematic special effects.

Analyzing Members' Motivations to Participate in Role-Playing and Self-Expression Based Virtual Communities

NASA Astrophysics Data System (ADS)

Lee, Young Eun; Saharia, Aditya

With the rapid growth of computer mediated communication technologies in the last two decades, various types of virtual communities have emerged. Some communities provide a role playing arena, enabled by avatars, while others provide an arena for expressing and promoting detailed personal profiles to enhance their offline social networks. Due to different focus of these virtual communities, different factors motivate members to participate in these communities. In this study, we examine differences in members’ motivations to participate in role-playing versus self-expression based virtual communities. To achieve this goal, we apply the Wang and Fesenmaier (2004) framework, which explains members’ participation in terms of their functional, social, psychological, and hedonic needs. The primary contributions of this study are two folds: First, it demonstrates differences between role-playing and self-expression based communities. Second, it provides a comprehensive framework describing members’ motivation to participate in virtual communities.

Efficient Comparison between Windows and Linux Platform Applicable in a Virtual Architectural Walkthrough Application

NASA Astrophysics Data System (ADS)

Thubaasini, P.; Rusnida, R.; Rohani, S. M.

This paper describes Linux, an open source platform used to develop and run a virtual architectural walkthrough application. It proposes some qualitative reflections and observations on the nature of Linux in the concept of Virtual Reality (VR) and on the most popular and important claims associated with the open source approach. The ultimate goal of this paper is to measure and evaluate the performance of Linux used to build the virtual architectural walkthrough and develop a proof of concept based on the result obtain through this project. Besides that, this study reveals the benefits of using Linux in the field of virtual reality and reflects a basic comparison and evaluation between Windows and Linux base operating system. Windows platform is use as a baseline to evaluate the performance of Linux. The performance of Linux is measured based on three main criteria which is frame rate, image quality and also mouse motion.

Sinus Anatomy

MedlinePlus

... ARS HOME ANATOMY Nasal Anatomy Sinus Anatomy Nasal Physiology Nasal Endoscopy Skull Base Anatomy Virtual Anatomy Disclosure ... ANATOMY > Sinus Anatomy Nasal Anatomy Sinus Anatomy Nasal Physiology Nasal Endoscopy Skull Base Anatomy Virtual Anatomy Disclosure ...

Comparison of virtual patient simulation with mannequin-based simulation for improving clinical performances in assessing and managing clinical deterioration: randomized controlled trial.

PubMed

Liaw, Sok Ying; Chan, Sally Wai-Chi; Chen, Fun-Gee; Hooi, Shing Chuan; Siau, Chiang

2014-09-17

Virtual patient simulation has grown substantially in health care education. A virtual patient simulation was developed as a refresher training course to reinforce nursing clinical performance in assessing and managing deteriorating patients. The objective of this study was to describe the development of the virtual patient simulation and evaluate its efficacy, by comparing with a conventional mannequin-based simulation, for improving the nursing students' performances in assessing and managing patients with clinical deterioration. A randomized controlled study was conducted with 57 third-year nursing students who were recruited through email. After a baseline evaluation of all participants' clinical performance in a simulated environment, the experimental group received a 2-hour fully automated virtual patient simulation while the control group received 2-hour facilitator-led mannequin-based simulation training. All participants were then re-tested one day (first posttest) and 2.5 months (second posttest) after the intervention. The participants from the experimental group completed a survey to evaluate their learning experiences with the newly developed virtual patient simulation. Compared to their baseline scores, both experimental and control groups demonstrated significant improvements (P<.001) in first and second post-test scores. While the experimental group had significantly lower (P<.05) second post-test scores compared with the first post-test scores, no significant difference (P=.94) was found between these two scores for the control group. The scores between groups did not differ significantly over time (P=.17). The virtual patient simulation was rated positively. A virtual patient simulation for a refreshing training course on assessing and managing clinical deterioration was developed. Although the randomized controlled study did not show that the virtual patient simulation was superior to mannequin-based simulation, both simulations have demonstrated to be effective refresher learning strategies for improving nursing students' clinical performance. Given the greater resource requirements of mannequin-based simulation, the virtual patient simulation provides a more promising alternative learning strategy to mitigate the decay of clinical performance over time.

Vision-based overlay of a virtual object into real scene for designing room interior

NASA Astrophysics Data System (ADS)

Harasaki, Shunsuke; Saito, Hideo

2001-10-01

In this paper, we introduce a geometric registration method for augmented reality (AR) and an application system, interior simulator, in which a virtual (CG) object can be overlaid into a real world space. Interior simulator is developed as an example of an AR application of the proposed method. Using interior simulator, users can visually simulate the location of virtual furniture and articles in the living room so that they can easily design the living room interior without placing real furniture and articles, by viewing from many different locations and orientations in real-time. In our system, two base images of a real world space are captured from two different views for defining a projective coordinate of object 3D space. Then each projective view of a virtual object in the base images are registered interactively. After such coordinate determination, an image sequence of a real world space is captured by hand-held camera with tracking non-metric measured feature points for overlaying a virtual object. Virtual objects can be overlaid onto the image sequence by taking each relationship between the images. With the proposed system, 3D position tracking device, such as magnetic trackers, are not required for the overlay of virtual objects. Experimental results demonstrate that 3D virtual furniture can be overlaid into an image sequence of the scene of a living room nearly at video rate (20 frames per second).

Xenobiotics and the Glucocorticoid Receptor

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gulliver, Linda S M, E-mail: linda.gulliver@otago.

Glucocorticoid Receptor (GR) is present in virtually every human cell type. Representing a nuclear receptor superfamily, GR has several different isoforms essentially acting as ligand-dependent transcription factors, regulating glucocorticoid-responsive gene expression in both a positive and a negative manner. Although the natural ligand of the Glucocorticoid Receptor, glucocorticoids (GC) represent only some of the multiple ligands for GR. Xenobiotics, ubiquitous in the environment, bind to GR and are also capable of activating or repressing GR gene expression, thereby modulating GR cell and tissue-specific downstream effects in a multitude of ways that include responses to inflammatory, allergic, metabolic, neoplastic and autoimmunemore » processes. Many xenobiotics, if inadequately metabolized by xenobiotic metabolizing enzymes and not wholly eliminated, could have deleterious toxic effects with potentially lethal consequences. This review examines GR, the genomic and non-genomic actions of natural and synthetic GC and the body's handling of xenobiotic compounds, before reviewing what is presently known about GR's interactions with many of the more commonly encountered and some of the less well known GR-associated xenobiotics. GR promiscuity and crosstalk with other signaling pathways is discussed, alongside novel roles for GR that include mood disorder and addiction. A knowledge of GR interactions with xenobiotics is increasingly relevant when considering aging populations and the related prevalence of neoplastic disease, together with growing concerns around human exposure to mixtures of chemicals in the environment. Furthermore, escalating rates of obesity, Type 2 diabetes; autoimmune, allergy, addiction and mood disorder-related pathologies, require novel targeted interventions and GR appears a promising pharmacological candidate. - Highlights: • Biological impact of xenobiotics acting through Glucocorticoid Receptor. • Promiscuity of Glucocorticoid Receptor. • Involvement of Glucocorticoid Receptor in multiple pathologies. • Novel xenobiotic ligands for Glucocorticoid Receptor. • Potential for multifaceted Glucocorticoid Receptor-targeted pharmacological interventions.« less

Role for NK(1) and NK(2) receptors in the motor activity in mouse colon.

PubMed

Mulè, Flavia; Amato, Antonella; Serio, Rosa

2007-09-10

The present study examined the effects induced by endogenous and exogenous activation of NK(1) and NK(2) receptors on the mechanical activity of mouse proximal colon. Experiments were performed in vitro recording the changes in intraluminal pressure from isolated colonic segments. Electrical field stimulation in the presence of atropine and guanethidine produced a small relaxation, followed by nonadrenergic noncholinergic (NANC) contraction. SR140333, NK(1) receptor antagonist, or SR48968, NK(2) receptor antagonist, significantly reduced the contraction, although SR48968 appeared more efficacious. The co-administration of SR140333 and SR48968 virtually abolished the NANC contraction. [Sar(9), Met(O(2))(11)]-substance P, selective NK(1) receptor agonist, induced a concentration-dependent biphasic effect, contraction followed by reduction of the mechanical spontaneous activity. Both effects were antagonized by SR140333, but not by SR48968. [beta-Ala(8)]-neurokinin A (4-10), selective NK(2) receptor agonist, evoked concentration-dependent contraction, which was antagonized by SR48968, but not by SR140333. The contraction induced by [Sar(9), Met(O(2))(11)]-substance P, but not by [beta-Ala(8)]-neurokinin A (4-10), was reduced by tetrodotoxin or atropine, and increased by N(omega)-nitro-L-arginine methyl ester (L-NAME), inhibitor of nitric oxide synthase. The inhibitory effects induced by [Sar(9), Met(O(2))(11)]-substance P were abolished by tetrodotoxin or L-NAME. The results of the present study suggest that in mouse colon both NK(1) and NK(2) receptors are junctionally activated by endogenous tachykinins to cause an additive response. NK(1) receptors appear to be located on cholinergic and on nitrergic neurons as well as on smooth muscle cells, whereas NK(2) receptors seem to be present exclusively on smooth muscle cells.

Opioid Receptor Function Is Regulated by Post-endocytic Peptide Processing*

PubMed Central

Gupta, Achla; Gomes, Ivone; Wardman, Jonathan; Devi, Lakshmi A.

2014-01-01

Most neuroendocrine peptides are generated in the secretory compartment by proteolysis of the precursors at classical cleavage sites consisting of basic residues by well studied endopeptidases belonging to the subtilisin superfamily. In contrast, a subset of bioactive peptides is generated by processing at non-classical cleavage sites that do not contain basic residues. Neither the peptidases responsible for non-classical cleavages nor the compartment involved in such processing has been well established. Members of the endothelin-converting enzyme (ECE) family are considered good candidate enzymes because they exhibit functional properties that are consistent with such a role. In this study we have explored a role for ECE2 in endocytic processing of δ opioid peptides and its effect on modulating δ opioid receptor function by using selective inhibitors of ECE2 that we had identified previously by homology modeling and virtual screening of a library of small molecules. We found that agonist treatment led to intracellular co-localization of ECE2 with δ opioid receptors. Furthermore, selective inhibitors of ECE2 and reagents that increase the pH of the acidic compartment impaired receptor recycling by protecting the endocytosed peptide from degradation. This, in turn, led to a substantial decrease in surface receptor signaling. Finally, we showed that treatment of primary neurons with the ECE2 inhibitor during recycling led to increased intracellular co-localization of the receptors and ECE2, which in turn led to decreased receptor recycling and signaling by the surface receptors. Together, these results support a role for differential modulation of opioid receptor signaling by post-endocytic processing of peptide agonists by ECE2. PMID:24847082

Ionotropic GABA and Glutamate Receptor Mutations and Human Neurologic Diseases.

PubMed

Yuan, Hongjie; Low, Chian-Ming; Moody, Olivia A; Jenkins, Andrew; Traynelis, Stephen F

2015-07-01

The advent of whole exome/genome sequencing and the technology-driven reduction in the cost of next-generation sequencing as well as the introduction of diagnostic-targeted sequencing chips have resulted in an unprecedented volume of data directly linking patient genomic variability to disorders of the brain. This information has the potential to transform our understanding of neurologic disorders by improving diagnoses, illuminating the molecular heterogeneity underlying diseases, and identifying new targets for therapeutic treatment. There is a strong history of mutations in GABA receptor genes being involved in neurologic diseases, particularly the epilepsies. In addition, a substantial number of variants and mutations have been found in GABA receptor genes in patients with autism, schizophrenia, and addiction, suggesting potential links between the GABA receptors and these conditions. A new and unexpected outcome from sequencing efforts has been the surprising number of mutations found in glutamate receptor subunits, with the GRIN2A gene encoding the GluN2A N-methyl-d-aspartate receptor subunit being most often affected. These mutations are associated with multiple neurologic conditions, for which seizure disorders comprise the largest group. The GluN2A subunit appears to be a locus for epilepsy, which holds important therapeutic implications. Virtually all α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor mutations, most of which occur within GRIA3, are from patients with intellectual disabilities, suggesting a link to this condition. Similarly, the most common phenotype for kainate receptor variants is intellectual disability. Herein, we summarize the current understanding of disease-associated mutations in ionotropic GABA and glutamate receptor families, and discuss implications regarding the identification of human mutations and treatment of neurologic diseases. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

Ionotropic GABA and Glutamate Receptor Mutations and Human Neurologic Diseases

PubMed Central

Yuan, Hongjie; Low, Chian-Ming; Moody, Olivia A.; Jenkins, Andrew

2015-01-01

The advent of whole exome/genome sequencing and the technology-driven reduction in the cost of next-generation sequencing as well as the introduction of diagnostic-targeted sequencing chips have resulted in an unprecedented volume of data directly linking patient genomic variability to disorders of the brain. This information has the potential to transform our understanding of neurologic disorders by improving diagnoses, illuminating the molecular heterogeneity underlying diseases, and identifying new targets for therapeutic treatment. There is a strong history of mutations in GABA receptor genes being involved in neurologic diseases, particularly the epilepsies. In addition, a substantial number of variants and mutations have been found in GABA receptor genes in patients with autism, schizophrenia, and addiction, suggesting potential links between the GABA receptors and these conditions. A new and unexpected outcome from sequencing efforts has been the surprising number of mutations found in glutamate receptor subunits, with the GRIN2A gene encoding the GluN2A N-methyl-d-aspartate receptor subunit being most often affected. These mutations are associated with multiple neurologic conditions, for which seizure disorders comprise the largest group. The GluN2A subunit appears to be a locus for epilepsy, which holds important therapeutic implications. Virtually all α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor mutations, most of which occur within GRIA3, are from patients with intellectual disabilities, suggesting a link to this condition. Similarly, the most common phenotype for kainate receptor variants is intellectual disability. Herein, we summarize the current understanding of disease-associated mutations in ionotropic GABA and glutamate receptor families, and discuss implications regarding the identification of human mutations and treatment of neurologic diseases. PMID:25904555

Multiscale virtual particle based elastic network model (MVP-ENM) for normal mode analysis of large-sized biomolecules.

PubMed

Xia, Kelin

2017-12-20

In this paper, a multiscale virtual particle based elastic network model (MVP-ENM) is proposed for the normal mode analysis of large-sized biomolecules. The multiscale virtual particle (MVP) model is proposed for the discretization of biomolecular density data. With this model, large-sized biomolecular structures can be coarse-grained into virtual particles such that a balance between model accuracy and computational cost can be achieved. An elastic network is constructed by assuming "connections" between virtual particles. The connection is described by a special harmonic potential function, which considers the influence from both the mass distributions and distance relations of the virtual particles. Two independent models, i.e., the multiscale virtual particle based Gaussian network model (MVP-GNM) and the multiscale virtual particle based anisotropic network model (MVP-ANM), are proposed. It has been found that in the Debye-Waller factor (B-factor) prediction, the results from our MVP-GNM with a high resolution are as good as the ones from GNM. Even with low resolutions, our MVP-GNM can still capture the global behavior of the B-factor very well with mismatches predominantly from the regions with large B-factor values. Further, it has been demonstrated that the low-frequency eigenmodes from our MVP-ANM are highly consistent with the ones from ANM even with very low resolutions and a coarse grid. Finally, the great advantage of MVP-ANM model for large-sized biomolecules has been demonstrated by using two poliovirus virus structures. The paper ends with a conclusion.

Investigation of MM-PBSA rescoring of docking poses.

PubMed

Thompson, David C; Humblet, Christine; Joseph-McCarthy, Diane

2008-05-01

Target-based virtual screening is increasingly used to generate leads for targets for which high quality three-dimensional (3D) structures are available. To allow large molecular databases to be screened rapidly, a tiered scoring scheme is often employed whereby a simple scoring function is used as a fast filter of the entire database and a more rigorous and time-consuming scoring function is used to rescore the top hits to produce the final list of ranked compounds. Molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) approaches are currently thought to be quite effective at incorporating implicit solvation into the estimation of ligand binding free energies. In this paper, the ability of a high-throughput MM-PBSA rescoring function to discriminate between correct and incorrect docking poses is investigated in detail. Various initial scoring functions are used to generate docked poses for a subset of the CCDC/Astex test set and to dock one set of actives/inactives from the DUD data set. The effectiveness of each of these initial scoring functions is discussed. Overall, the ability of the MM-PBSA rescoring function to (i) regenerate the set of X-ray complexes when docking the bound conformation of the ligand, (ii) regenerate the X-ray complexes when docking conformationally expanded databases for each ligand which include "conformation decoys" of the ligand, and (iii) enrich known actives in a virtual screen for the mineralocorticoid receptor in the presence of "ligand decoys" is assessed. While a pharmacophore-based molecular docking approach, PhDock, is used to carry out the docking, the results are expected to be general to use with any docking method.

Usalpharma: A Cloud-Based Architecture to Support Quality Assurance Training Processes in Health Area Using Virtual Worlds

PubMed Central

García-Peñalvo, Francisco J.; Pérez-Blanco, Jonás Samuel; Martín-Suárez, Ana

2014-01-01

This paper discusses how cloud-based architectures can extend and enhance the functionality of the training environments based on virtual worlds and how, from this cloud perspective, we can provide support to analysis of training processes in the area of health, specifically in the field of training processes in quality assurance for pharmaceutical laboratories, presenting a tool for data retrieval and analysis that allows facing the knowledge discovery in the happenings inside the virtual worlds. PMID:24778593

Virtual Distances Methodology as Verification Technique for AACMMs with a Capacitive Sensor Based Indexed Metrology Platform

PubMed Central

Acero, Raquel; Santolaria, Jorge; Brau, Agustin; Pueo, Marcos

2016-01-01

This paper presents a new verification procedure for articulated arm coordinate measuring machines (AACMMs) together with a capacitive sensor-based indexed metrology platform (IMP) based on the generation of virtual reference distances. The novelty of this procedure lays on the possibility of creating virtual points, virtual gauges and virtual distances through the indexed metrology platform’s mathematical model taking as a reference the measurements of a ball bar gauge located in a fixed position of the instrument’s working volume. The measurements are carried out with the AACMM assembled on the IMP from the six rotating positions of the platform. In this way, an unlimited number and types of reference distances could be created without the need of using a physical gauge, therefore optimizing the testing time, the number of gauge positions and the space needed in the calibration and verification procedures. Four evaluation methods are presented to assess the volumetric performance of the AACMM. The results obtained proved the suitability of the virtual distances methodology as an alternative procedure for verification of AACMMs using the indexed metrology platform. PMID:27869722

Virtual Distances Methodology as Verification Technique for AACMMs with a Capacitive Sensor Based Indexed Metrology Platform.

PubMed

Acero, Raquel; Santolaria, Jorge; Brau, Agustin; Pueo, Marcos

2016-11-18

This paper presents a new verification procedure for articulated arm coordinate measuring machines (AACMMs) together with a capacitive sensor-based indexed metrology platform (IMP) based on the generation of virtual reference distances. The novelty of this procedure lays on the possibility of creating virtual points, virtual gauges and virtual distances through the indexed metrology platform's mathematical model taking as a reference the measurements of a ball bar gauge located in a fixed position of the instrument's working volume. The measurements are carried out with the AACMM assembled on the IMP from the six rotating positions of the platform. In this way, an unlimited number and types of reference distances could be created without the need of using a physical gauge, therefore optimizing the testing time, the number of gauge positions and the space needed in the calibration and verification procedures. Four evaluation methods are presented to assess the volumetric performance of the AACMM. The results obtained proved the suitability of the virtual distances methodology as an alternative procedure for verification of AACMMs using the indexed metrology platform.

Local and global perspectives on the virtual water trade

NASA Astrophysics Data System (ADS)

Tamea, S.; Allamano, P.; Carr, J. A.; Claps, P.; Laio, F.; Ridolfi, L.

2012-11-01

Recent studies on fluxes of virtual water are showing how the global food and goods trade interconnects the water resources of different and distant countries, conditioning the local water balances. This paper presents and discusses the assessment of virtual water fluxes between a single country and its network of trading partners, delineating a country's virtual water budget in space and time (years 1986-2010). The fluxes between the country under study and its importing/exporting partners are visualized with a geographical representation shaping the trade network as a virtual river/delta. Time variations of exchanged fluxes are quantified to show possible trends in the virtual water balance, while characterizing the time evolution of the trade network and its composition in terms of product categories (plant-based, animal-based, luxury and non-edible). The average distance traveled by virtual water to arrive to the place of consumption is also introduced as a new measure for the analysis of globalization of the virtual water trade. Using Italy as an example, we find that food trade has a steadily growing importance compared to domestic production, with a major component represented by plan-based products, and luxury products taking an increasingly larger share (26% in 2010). In 2010 Italy had an average net import of 55 km3 of virtual water (38 km3 in 1986), a value which poses the country among the top net importers in the world. On average each cubic meter of virtual water travels nearly 4000 km before entering Italy, while export goes to relatively closer countries (average distance: 2600 km), with increasing trends in time which are almost unique among the world countries. Analyses proposed for Italy are replicated for 10 other world countries, triggering similar investigations on different socio-economic actualities.

Local and global perspectives on the virtual water trade

NASA Astrophysics Data System (ADS)

Tamea, S.; Allamano, P.; Carr, J. A.; Claps, P.; Laio, F.; Ridolfi, L.

2013-03-01

Recent studies on fluxes of virtual water are showing how the global food and goods trade interconnects the water resources of different and distant countries, conditioning the local water balances. This paper presents and discusses the assessment of virtual water fluxes between a single country and its network of trading partners, delineating a country's virtual water budget in space and time (years 1986-2010). The fluxes between the country under study and its importing/exporting partners are visualized with a geographical representation shaping the trade network as a virtual river/delta. Time variations of exchanged fluxes are quantified to show possible trends in the virtual water balance, while characterizing the time evolution of the trade network and its composition in terms of product categories (plant-based, animal-based, luxury food, and non-edible). The average distance traveled by virtual water to arrive to the place of consumption is also introduced as a new measure for the analysis of globalization of the virtual water trade. Using Italy as an example, we find that food trade has a steadily growing importance compared to domestic production, with a major component represented by plant-based products, and luxury products taking an increasingly larger share (26% in 2010). In 2010 Italy had an average net import of 55 km3 of virtual water (38 km3 in 1986), a value which poses the country among the top net importers in the world. On average each cubic meter of virtual water travels nearly 4000 km before entering Italy, while export goes to relatively closer countries (average distance: 2600 km), with increasing trends in time which are almost unique among the world countries. Analyses proposed for Italy are replicated for 10 other world countries, triggering similar investigations on different socio-economic actualities.

Using Virtual Worlds to Identify Multidimensional Student Engagement in High School Foreign Language Learning Classrooms

ERIC Educational Resources Information Center

Jacob, Laura Beth

2012-01-01

Virtual world environments have evolved from object-oriented, text-based online games to complex three-dimensional immersive social spaces where the lines between reality and computer-generated begin to blur. Educators use virtual worlds to create engaging three-dimensional learning spaces for students, but the impact of virtual worlds in…

Open Source Meets Virtual Reality--An Instructor's Journey Unearths New Opportunities for Learning, Community, and Academia

ERIC Educational Resources Information Center

O'Connor, Eileen A.

2015-01-01

Opening with the history, recent advances, and emerging ways to use avatar-based virtual reality, an instructor who has used virtual environments since 2007 shares how these environments bring more options to community building, teaching, and education. With the open-source movement, where the source code for virtual environments was made…

Virtual Enterprises and Vocational Training.

ERIC Educational Resources Information Center

Kreber, Stefan

2001-01-01

Characteristics of virtual enterprises (client oriented, temporary working organizations that dissolve after solving specific problems, extensive technological applications) can be applied to vocational training. Virtual learning centers can provide web-based training intraorganizationally and interorganizationally via intranets and extranets. (SK)

The Application of Leap Motion in Astronaut Virtual Training

NASA Astrophysics Data System (ADS)

Qingchao, Xie; Jiangang, Chao

2017-03-01

With the development of computer vision, virtual reality has been applied in astronaut virtual training. As an advanced optic equipment to track hand, Leap Motion can provide precise and fluid tracking of hands. Leap Motion is suitable to be used as gesture input device in astronaut virtual training. This paper built an astronaut virtual training based Leap Motion, and established the mathematics model of hands occlusion. At last the ability of Leap Motion to handle occlusion was analysed. A virtual assembly simulation platform was developed for astronaut training, and occlusion gesture would influence the recognition process. The experimental result can guide astronaut virtual training.

Surface functions during mitosis. III. Quantitative analysis of ligand- receptor movement into the cleavage furrow: diffusion vs. flow

PubMed Central

1982-01-01

The surface distribution of concanavalin A (Con A) bound to cell membrane receptors varies dramatically as a function of mitotic phase. The lectin is distributed diffusely on cells labeled and observed between mid-prophase and early anaphase, whereas cells observed in late anaphase or telophase demonstrate a marked accumulation of Con A- receptor complexes over the developing cleavage furrow (Berlin, Oliver, and Walter. 1978. Cell. 15:327-341). In this report, we first use a system based on video intensification fluorescence microscopy to describe the simultaneous changes in cell shape and in lectin-receptor complex topography during progression of single cells through the mitotic cycle. The video analysis establishes that fluorescein succinyl Con A (F-S Con A)-receptor complex redistribution begins coincident with the first appearance of the cleavage furrow and is essentially complete within 2-3 min. This remarkable redistribution of surface fluorescence occurs during only a modest change in cell shape from a sphere to a belted cylinder. It reflects the translocation of complexes and not the accumulation of excess labeled membrane in the cleavage furrow: first, bound fluorescent cholera toxin which faithfully outlines the plasma membrane is not accumulated in the cleavage furrow, and, second, electron microscopy of peroxidase-Con A labeled cells undergoing cleavage shows that there is a high linear density of lectin within the furrow while Con A is virtually eliminated from the poles. The rate of surface movement of F-S Con A was quantitated by photon counting during a repetitive series of laser-excited fluorescence scans across dividing cells. Results were analyzed in terms of two alternative models of movement: a flow model in which complexes moved unidirectionally at constant velocity, and a diffusion model in which complexes could diffuse freely but were trapped at the cleavage furrow. According to these models, the observed rates of accumulation were attainable at either an effective flow velocity of approximately 1 micron/min, or an effective diffusion coefficient of approximately 10(- 9) cm2/s. However, in separate experiments the lectin-receptor diffusion rate measured directly by the method of fluorescence recovery after photobleaching (FRAP) on metaphase cells was only approximately 10(-10) cm2/s. Most importantly, photobleaching experiments during the actual period of F-S Con A accumulation showed that lectin-receptor movement during cleavage occurs unidirectionally. These results rule out diffusion and make a process of oriented flow of ligand-receptor complexes the most likely mechanism for ligand-receptor accumulation in the cleavage furrow. PMID:7119007

HPPD: ligand- and target-based virtual screening on a herbicide target.

PubMed

López-Ramos, Miriam; Perruccio, Francesca

2010-05-24

Hydroxyphenylpyruvate dioxygenase (HPPD) has proven to be a very successful target for the development of herbicides with bleaching properties, and today HPPD inhibitors are well established in the agrochemical market. Syngenta has a long history of HPPD-inhibitor research, and HPPD was chosen as a case study for the validation of diverse ligand- and target-based virtual screening approaches to identify compounds with inhibitory properties. Two-dimensional extended connectivity fingerprints, three-dimensional shape-based tools (ROCS, EON, and Phase-shape) and a pharmacophore approach (Phase) were used as ligand-based methods; Glide and Gold were used as target-based. Both the virtual screening utility and the scaffold-hopping ability of the screening tools were assessed. Particular emphasis was put on the specific pitfalls to take into account for the design of a virtual screening campaign in an agrochemical context, as compared to a pharmaceutical environment.

Application of computer assisted combinatorial chemistry in antivirial, antimalarial and anticancer agents design

NASA Astrophysics Data System (ADS)

Burello, E.; Bologa, C.; Frecer, V.; Miertus, S.

Combinatorial chemistry and technologies have been developed to a stage where synthetic schemes are available for generation of a large variety of organic molecules. The innovative concept of combinatorial design assumes that screening of a large and diverse library of compounds will increase the probability of finding an active analogue among the compounds tested. Since the rate at which libraries are screened for activity currently constitutes a limitation to the use of combinatorial technologies, it is important to be selective about the number of compounds to be synthesized. Early experience with combinatorial chemistry indicated that chemical diversity alone did not result in a significant increase in the number of generated lead compounds. Emphasis has therefore been increasingly put on the use of computer assisted combinatorial chemical techniques. Computational methods are valuable in the design of virtual libraries of molecular models. Selection strategies based on computed physicochemical properties of the models or of a target compound are introduced to reduce the time and costs of library synthesis and screening. In addition, computational structure-based library focusing methods can be used to perform in silico screening of the activity of compounds against a target receptor by docking the ligands into the receptor model. Three case studies are discussed dealing with the design of targeted combinatorial libraries of inhibitors of HIV-1 protease, P. falciparum plasmepsin and human urokinase as potential antivirial, antimalarial and anticancer drugs. These illustrate library focusing strategies.

A Discussion of Knowledge Based Design

NASA Technical Reports Server (NTRS)

Wood, Richard M.; Bauer, Steven X. S.

1999-01-01

A discussion of knowledge and Knowledge- Based design as related to the design of aircraft is presented. The paper discusses the perceived problem with existing design studies and introduces the concepts of design and knowledge for a Knowledge- Based design system. A review of several Knowledge-Based design activities is provided. A Virtual Reality, Knowledge-Based system is proposed and reviewed. The feasibility of Virtual Reality to improve the efficiency and effectiveness of aerodynamic and multidisciplinary design, evaluation, and analysis of aircraft through the coupling of virtual reality technology and a Knowledge-Based design system is also reviewed. The final section of the paper discusses future directions for design and the role of Knowledge-Based design.

Local concurrent error detection and correction in data structures using virtual backpointers

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, C.C.J.; Chen, P.P.; Fuchs, W.K.

1989-11-01

A new technique, based on virtual backpointers, is presented in this paper for local concurrent error detection and correction in linked data structures. Two new data structures utilizing virtual backpointers, the Virtual Double-Linked List and the B-Tree and Virtual Backpointers, are described. For these structures, double errors within a fixed-size checking window can be detected in constant time and single errors detected during forward moves can be corrected in constant time.

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

NASA Astrophysics Data System (ADS)

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.

A Chemocentric Informatics Approach to Drug Discovery: Identification and Experimental Validation of Selective Estrogen Receptor Modulators as ligands of 5-Hydroxytryptamine-6 Receptors and as Potential Cognition Enhancers

PubMed Central

Hajjo, Rima; Setola, Vincent; Roth, Bryan L.; Tropsha, Alexander

2012-01-01

We have devised a chemocentric informatics methodology for drug discovery integrating independent approaches to mining biomolecular databases. As a proof of concept, we have searched for novel putative cognition enhancers. First, we generated Quantitative Structure- Activity Relationship (QSAR) models of compounds binding to 5-hydroxytryptamine-6 receptor (5HT6R), a known target for cognition enhancers, and employed these models for virtual screening to identify putative 5-HT6R actives. Second, we queried chemogenomics data from the Connectivity Map (http://www.broad.mit.edu/cmap/) with the gene expression profile signatures of Alzheimer’s disease patients to identify compounds putatively linked to the disease. Thirteen common hits were tested in 5-HT6R radioligand binding assays and ten were confirmed as actives. Four of them were known selective estrogen receptor modulators that were never reported as 5-HT6R ligands. Furthermore, nine of the confirmed actives were reported elsewhere to have memory-enhancing effects. The approaches discussed herein can be used broadly to identify novel drug-target-disease associations. PMID:22537153

Unconventional binding sites and receptors for VIP and related peptides PACAP and PHI/PHM: an update.

PubMed

Muller, Jean-Marc; Debaigt, Colin; Goursaud, Stéphanie; Montoni, Alicia; Pineau, Nicolas; Meunier, Annie-Claire; Janet, Thierry

2007-09-01

The 28-amino-acid neuropeptide VIP and related peptides PACAP and PHI/PHM modulate virtually all of the vital functions in the body. These peptides are also commonly recognized as major regulators of cell growth and differentiation. Through their trophic and cytoprotective functions, they appear to play major roles in embryonic development, neurogenesis and the progression of a number of cancer types. These peptides bind to three well-characterized subtypes of G-protein coupled receptors: VPAC1 and VPAC2 share a common high affinity in the nanomolar range for VIP and PACAP; a third receptor type, PAC1, has been characterized for its high affinity for PACAP but its low affinity for VIP. Complex effects and pharmacological behaviors of these peptides suggest that multiple subtypes of binding sites may cooperate to mediate their function in target cells and tissues. In this complex response, some of these binding sites correspond to the definition of the conventional receptors cited above, while others display unexpected pharmacological and functional properties. Here we present potential clues that may lead investigators to further characterize the molecular nature and functions of these atypical binding species.

Exploring new scaffolds for angiotensin II receptor antagonism.

PubMed

Kritsi, Eftichia; Matsoukas, Minos-Timotheos; Potamitis, Constantinos; Karageorgos, Vlasios; Detsi, Anastasia; Magafa, Vasilliki; Liapakis, George; Mavromoustakos, Thomas; Zoumpoulakis, Panagiotis

2016-09-15

Nowadays, AT1 receptor (AT1R) antagonists (ARBs) constitute the one of the most prevalent classes of antihypertensive drugs that modulate the renin-angiotensin system (RAS). Their main uses include also treatment of diabetic nephropathy (kidney damage due to diabetes) and congestive heart failure. Towards this direction, our study has been focused on the discovery of novel agents bearing different scaffolds which may evolve as a new class of AT1 receptor antagonists. To fulfill this aim, a combination of computational approaches and biological assays were implemented. Particularly, a pharmacophore model was established and served as a 3D search query to screen the ChEMBL15 database. The reliability and accuracy of virtual screening results were improved by using molecular docking studies. In total, 4 compounds with completely diverse chemical scaffolds from potential ARBs, were picked and tested for their binding affinity to AT1 receptor. Results revealed high nanomolar to micromolar affinity (IC50) for all the compounds. Especially, compound 4 exhibited a binding affinity of 199nM. Molecular dynamics simulations were utilized in an effort to provide a molecular basis of their binding to AT1R in accordance to their biological activities. Copyright © 2016 Elsevier Ltd. All rights reserved.

Visuo-Haptic Mixed Reality with Unobstructed Tool-Hand Integration.

PubMed

Cosco, Francesco; Garre, Carlos; Bruno, Fabio; Muzzupappa, Maurizio; Otaduy, Miguel A

2013-01-01

Visuo-haptic mixed reality consists of adding to a real scene the ability to see and touch virtual objects. It requires the use of see-through display technology for visually mixing real and virtual objects, and haptic devices for adding haptic interaction with the virtual objects. Unfortunately, the use of commodity haptic devices poses obstruction and misalignment issues that complicate the correct integration of a virtual tool and the user's real hand in the mixed reality scene. In this work, we propose a novel mixed reality paradigm where it is possible to touch and see virtual objects in combination with a real scene, using commodity haptic devices, and with a visually consistent integration of the user's hand and the virtual tool. We discuss the visual obstruction and misalignment issues introduced by commodity haptic devices, and then propose a solution that relies on four simple technical steps: color-based segmentation of the hand, tracking-based segmentation of the haptic device, background repainting using image-based models, and misalignment-free compositing of the user's hand. We have developed a successful proof-of-concept implementation, where a user can touch virtual objects and interact with them in the context of a real scene, and we have evaluated the impact on user performance of obstruction and misalignment correction.

Applicability of the "Frame of Reference" approach for environmental monitoring of offshore renewable energy projects.

PubMed

Garel, Erwan; Rey, Cibran Camba; Ferreira, Oscar; van Koningsveld, Mark

2014-08-01

This paper assesses the applicability of the Frame of Reference (FoR) approach for the environmental monitoring of large-scale offshore Marine Renewable Energy (MRE) projects. The focus is on projects harvesting energy from winds, waves and currents. Environmental concerns induced by MRE projects are reported based on a classification scheme identifying stressors, receptors, effects and impacts. Although the potential effects of stressors on most receptors are identified, there are large knowledge gaps regarding the corresponding (positive and negative) impacts. In that context, the development of offshore MRE requires the implementation of fit-for-purpose monitoring activities aimed at environmental protection and knowledge development. Taking European legislation as an example, it is suggested to adopt standardized monitoring protocols for the enhanced usage and utility of environmental indicators. Towards this objective, the use of the FoR approach is advocated since it provides guidance for the definition and use of coherent set of environmental state indicators. After a description of this framework, various examples of applications are provided considering a virtual MRE project located in European waters. Finally, some conclusions and recommendations are provided for the successful implementation of the FoR approach and for future studies. Copyright © 2014 Elsevier Ltd. All rights reserved.

Prospective comparison of virtual fluoroscopy to fluoroscopy and plain radiographs for placement of lumbar pedicle screws.

PubMed

Resnick, Daniel K

2003-06-01

Fluoroscopy-based frameless stereotactic systems provide feedback to the surgeon using virtual fluoroscopic images. The real-life accuracy of these virtual images has not been compared with traditional fluoroscopy in a clinical setting. We prospectively studied 23 consecutive cases. In two cases, registration errors precluded the use of virtual fluoroscopy. Pedicle probes placed with virtual fluoroscopic imaging were imaged with traditional fluoroscopy in the remaining 21 cases. Position of the probes was judged to be ideal, acceptable but not ideal, or not acceptable based on the traditional fluoroscopic images. Virtual fluoroscopy was used to place probes in for 97 pedicles from L1 to the sacrum. Eighty-eight probes were judged to be in ideal position, eight were judged to be acceptable but not ideal, and one probe was judged to be in an unacceptable position. This probe was angled toward an adjacent disc space. Therefore, 96 of 97 probes placed using virtual fluoroscopy were found to be in an acceptable position. The positive predictive value for acceptable screw placement with virtual fluoroscopy compared with traditional fluoroscopy was 99%. A probe placed with virtual fluoroscopic guidance will be judged to be in an acceptable position when imaged with traditional fluoroscopy 99% of the time.

Rendering edge enhancement tactile phenomenon by friction variation in dynamic touch.

PubMed

Abdolvahab, Mohammad

2011-01-04

Variable friction tactile displays have been recently used to render virtual textures and gratings. Neural basis of perceptual mechanism of detection of edge-like features resulting in discrimination of virtual gratings during active touching these tactile actuators is studied using a finite-element biomechanical model of human fingertip. The predicted neural response of the mechanoreceptors, i.e. the computed strain energy density at the location of selected mechanoreceptors as a measure of neural discharge rate of the corresponding receptors, to local reduction of friction between fingerpad and surface are shown to exhibit a similar shape as the edge enhancement phenomenon, particularly in a sudden burst at the boundary of variable friction regions. This phenomenon is supposed to account for the illusion of virtual edges rendered through the modification of contact forces. The presence of this sudden burst under varied model parameters was investigated. It was shown that while the appearance of this phenomenon in simulation results was invariant to model parameters, associated alteration of the edge enhancement ratio might be considered for the purpose of the tuning of the variable friction tactile display. Copyright © 2010 Elsevier Ltd. All rights reserved.

Virtual World Currency Value Fluctuation Prediction System Based on User Sentiment Analysis.

PubMed

Kim, Young Bin; Lee, Sang Hyeok; Kang, Shin Jin; Choi, Myung Jin; Lee, Jung; Kim, Chang Hun

2015-01-01

In this paper, we present a method for predicting the value of virtual currencies used in virtual gaming environments that support multiple users, such as massively multiplayer online role-playing games (MMORPGs). Predicting virtual currency values in a virtual gaming environment has rarely been explored; it is difficult to apply real-world methods for predicting fluctuating currency values or shares to the virtual gaming world on account of differences in domains between the two worlds. To address this issue, we herein predict virtual currency value fluctuations by collecting user opinion data from a virtual community and analyzing user sentiments or emotions from the opinion data. The proposed method is straightforward and applicable to predicting virtual currencies as well as to gaming environments, including MMORPGs. We test the proposed method using large-scale MMORPGs and demonstrate that virtual currencies can be effectively and efficiently predicted with it.

Virtual World Currency Value Fluctuation Prediction System Based on User Sentiment Analysis

PubMed Central

Kim, Young Bin; Lee, Sang Hyeok; Kang, Shin Jin; Choi, Myung Jin; Lee, Jung; Kim, Chang Hun

2015-01-01

In this paper, we present a method for predicting the value of virtual currencies used in virtual gaming environments that support multiple users, such as massively multiplayer online role-playing games (MMORPGs). Predicting virtual currency values in a virtual gaming environment has rarely been explored; it is difficult to apply real-world methods for predicting fluctuating currency values or shares to the virtual gaming world on account of differences in domains between the two worlds. To address this issue, we herein predict virtual currency value fluctuations by collecting user opinion data from a virtual community and analyzing user sentiments or emotions from the opinion data. The proposed method is straightforward and applicable to predicting virtual currencies as well as to gaming environments, including MMORPGs. We test the proposed method using large-scale MMORPGs and demonstrate that virtual currencies can be effectively and efficiently predicted with it. PMID:26241496

Authentication in Virtual Organizations: A Reputation Based PKI Interconnection Model

NASA Astrophysics Data System (ADS)

Wazan, Ahmad Samer; Laborde, Romain; Barrere, Francois; Benzekri, Abdelmalek

Authentication mechanism constitutes a central part of the virtual organization work. The PKI technology is used to provide the authentication in each organization involved in the virtual organization. Different trust models are proposed to interconnect the different PKIs in order to propagate the trust between them. While the existing trust models contain many drawbacks, we propose a new trust model based on the reputation of PKIs.

Adapting Document Similarity Measures for Ligand-Based Virtual Screening.

PubMed

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

2016-04-13

Quantifying the similarity of molecules is considered one of the major tasks in virtual screening. There are many similarity measures that have been proposed for this purpose, some of which have been derived from document and text retrieving areas as most often these similarity methods give good results in document retrieval and can achieve good results in virtual screening. In this work, we propose a similarity measure for ligand-based virtual screening, which has been derived from a text processing similarity measure. It has been adopted to be suitable for virtual screening; we called this proposed measure the Adapted Similarity Measure of Text Processing (ASMTP). For evaluating and testing the proposed ASMTP we conducted several experiments on two different benchmark datasets: the Maximum Unbiased Validation (MUV) and the MDL Drug Data Report (MDDR). The experiments have been conducted by choosing 10 reference structures from each class randomly as queries and evaluate them in the recall of cut-offs at 1% and 5%. The overall obtained results are compared with some similarity methods including the Tanimoto coefficient, which are considered to be the conventional and standard similarity coefficients for fingerprint-based similarity calculations. The achieved results show that the performance of ligand-based virtual screening is better and outperforms the Tanimoto coefficients and other methods.

MIRATE: MIps RATional dEsign Science Gateway.

PubMed

Busato, Mirko; Distefano, Rosario; Bates, Ferdia; Karim, Kal; Bossi, Alessandra Maria; López Vilariño, José Manuel; Piletsky, Sergey; Bombieri, Nicola; Giorgetti, Alejandro

2018-06-13

Molecularly imprinted polymers (MIPs) are high affinity robust synthetic receptors, which can be optimally synthesized and manufactured more economically than their biological equivalents (i.e. antibody). In MIPs production, rational design based on molecular modeling is a commonly employed technique. This mostly aids in (i) virtual screening of functional monomers (FMs), (ii) optimization of monomer-template ratio, and (iii) selectivity analysis. We present MIRATE, an integrated science gateway for the intelligent design of MIPs. By combining and adapting multiple state-of-the-art bioinformatics tools into automated and innovative pipelines, MIRATE guides the user through the entire process of MIPs' design. The platform allows the user to fully customize each stage involved in the MIPs' design, with the main goal to support the synthesis in the wet-laboratory. MIRATE is freely accessible with no login requirement at http://mirate.di.univr.it/. All major browsers are supported.

Sex Differences in Circadian Timing Systems: Implications for Disease

PubMed Central

Bailey, Matthew; Silver, Rae

2014-01-01

Virtually every eukaryotic cell has an endogenous circadian clock and a biological sex. These cell-based clocks have been conceptualized as oscillators whose phase can be reset by internal signals such as hormones, and external cues such as light. The present review highlights the inter-relationship between circadian clocks and sex differences. In mammals, the suprachiasmatic nucleus (SCN) serves as a master clock synchronizing the phase of clocks throughout the body. Gonadal steroid receptors are expressed in almost every site that receives direct SCN input. Here we review sex differences in the circadian timing system in the hypothalamic-pituitary-gonadal axis (HPG), the hypothalamicadrenal-pituitary (HPA) axis, and sleep-arousal systems. We also point to ways in which disruption of circadian rhythms within these systems differs in the sexes and is associated with dysfunction and disease. Understanding sex differentiated circadian timing systems can lead to improved treatment strategies for these conditions. PMID:24287074

Exploring Learner Acceptance of the Use of Virtual Reality in Medical Education: A Case Study of Desktop and Projection-Based Display Systems

ERIC Educational Resources Information Center

Huang, Hsiu-Mei; Liaw, Shu-Sheng; Lai, Chung-Min

2016-01-01

Advanced technologies have been widely applied in medical education, including human-patient simulators, immersive virtual reality Cave Automatic Virtual Environment systems, and video conferencing. Evaluating learner acceptance of such virtual reality (VR) learning environments is a critical issue for ensuring that such technologies are used to…

A comparative analysis of dynamic grids vs. virtual grids using the A3pviGrid framework.

PubMed

Shankaranarayanan, Avinas; Amaldas, Christine

2010-11-01

With the proliferation of Quad/Multi-core micro-processors in mainstream platforms such as desktops and workstations; a large number of unused CPU cycles can be utilized for running virtual machines (VMs) as dynamic nodes in distributed environments. Grid services and its service oriented business broker now termed cloud computing could deploy image based virtualization platforms enabling agent based resource management and dynamic fault management. In this paper we present an efficient way of utilizing heterogeneous virtual machines on idle desktops as an environment for consumption of high performance grid services. Spurious and exponential increases in the size of the datasets are constant concerns in medical and pharmaceutical industries due to the constant discovery and publication of large sequence databases. Traditional algorithms are not modeled at handing large data sizes under sudden and dynamic changes in the execution environment as previously discussed. This research was undertaken to compare our previous results with running the same test dataset with that of a virtual Grid platform using virtual machines (Virtualization). The implemented architecture, A3pviGrid utilizes game theoretic optimization and agent based team formation (Coalition) algorithms to improve upon scalability with respect to team formation. Due to the dynamic nature of distributed systems (as discussed in our previous work) all interactions were made local within a team transparently. This paper is a proof of concept of an experimental mini-Grid test-bed compared to running the platform on local virtual machines on a local test cluster. This was done to give every agent its own execution platform enabling anonymity and better control of the dynamic environmental parameters. We also analyze performance and scalability of Blast in a multiple virtual node setup and present our findings. This paper is an extension of our previous research on improving the BLAST application framework using dynamic Grids on virtualization platforms such as the virtual box.

Cochrane review: virtual reality for stroke rehabilitation.

PubMed

Laver, K; George, S; Thomas, S; Deutsch, J E; Crotty, M

2012-09-01

Virtual reality and interactive video gaming are innovative therapy approaches in the field of stroke rehabilitation. The primary objective of this review was to determine the effectiveness of virtual reality on motor function after stroke. The impact on secondary outcomes including activities of daily living was also assessed. Randomised and quasi-randomised controlled trials that compared virtual reality with an alternative or no intervention were included in the review. The authors searched the Cochrane Stroke Group Trials Register, the Cochrane Central Register of Controlled Trials, electronic databases, trial registers, reference lists, Dissertation Abstracts, conference proceedings and contacted key researchers and virtual reality manufacturers. Search results were independently examined by two review authors to identify studies meeting the inclusion criteria. Nineteen studies with a total of 565 participants were included in the review. Variation in intervention approaches and outcome data collected limited the extent to which studies could be compared. Virtual reality was found to be significantly more effective than conventional therapy in improving upper limb function (standardised mean difference, SMD) 0.53, 95% confidence intervals [CI] 0.25 to 0.81)) based on seven studies, and activities of daily living (ADL) function (SMD 0.81, 95% CI 0.39 to 1.22) based on three studies. No statistically significant effects were found for grip strength (based on two studies) or gait speed (based on three studies). Virtual reality appears to be a promising approach however, further studies are required to confirm these findings.

Virtual Simulations: A Creative, Evidence-Based Approach to Develop and Educate Nurses.

PubMed

Leibold, Nancyruth; Schwarz, Laura

2017-02-01

The use of virtual simulations in nursing is an innovative strategy that is increasing in application. There are several terms related to virtual simulation; although some are used interchangeably, the meanings are not the same. This article presents examples of virtual simulation, virtual worlds, and virtual patients in continuing education, staff development, and academic nursing education. Virtual simulations in nursing use technology to provide safe, as realistic as possible clinical practice for nurses and nursing students. Virtual simulations are useful for learning new skills; practicing a skill that puts content, high-order thinking, and psychomotor elements together; skill competency learning; and assessment for low-volume, high-risk skills. The purpose of this article is to describe the related terms, examples, uses, theoretical frameworks, challenges, and evidence related to virtual simulations in nursing.

Inertial Sensor-Based Touch and Shake Metaphor for Expressive Control of 3D Virtual Avatars

PubMed Central

Patil, Shashidhar; Chintalapalli, Harinadha Reddy; Kim, Dubeom; Chai, Youngho

2015-01-01

In this paper, we present an inertial sensor-based touch and shake metaphor for expressive control of a 3D virtual avatar in a virtual environment. An intuitive six degrees-of-freedom wireless inertial motion sensor is used as a gesture and motion control input device with a sensor fusion algorithm. The algorithm enables user hand motions to be tracked in 3D space via magnetic, angular rate, and gravity sensors. A quaternion-based complementary filter is implemented to reduce noise and drift. An algorithm based on dynamic time-warping is developed for efficient recognition of dynamic hand gestures with real-time automatic hand gesture segmentation. Our approach enables the recognition of gestures and estimates gesture variations for continuous interaction. We demonstrate the gesture expressivity using an interactive flexible gesture mapping interface for authoring and controlling a 3D virtual avatar and its motion by tracking user dynamic hand gestures. This synthesizes stylistic variations in a 3D virtual avatar, producing motions that are not present in the motion database using hand gesture sequences from a single inertial motion sensor. PMID:26094629

Refined docking as a valuable tool for lead optimization: application to histamine H3 receptor antagonists.

PubMed

Levoin, Nicolas; Calmels, Thierry; Poupardin-Olivier, Olivia; Labeeuw, Olivier; Danvy, Denis; Robert, Philippe; Berrebi-Bertrand, Isabelle; Ganellin, C Robin; Schunack, Walter; Stark, Holger; Capet, Marc

2008-10-01

Drug-discovery projects frequently employ structure-based information through protein modeling and ligand docking, and there is a plethora of reports relating successful use of them in virtual screening. Hit/lead optimization, which represents the next step and the longest for the medicinal chemist, is very rarely considered. This is not surprising because lead optimization is a much more complex task. Here, a homology model of the histamine H(3) receptor was built and tested for its ability to discriminate ligands above a defined threshold of affinity. In addition, drug safety is also evaluated during lead optimization, and "antitargets" are studied. So, we have used the same benchmarking procedure with the HERG channel and CYP2D6 enzyme, for which a minimal affinity is strongly desired. For targets and antitargets, we report here an accuracy as high as at least 70%, for ligands being classified above or below the chosen threshold. Such a good result is beyond what could have been predicted, especially, since our test conditions were particularly stringent. First, we measured the accuracy by means of AUC of ROC plots, i. e. considering both false positive and false negatives. Second, we used as datasets extensive chemical libraries (nearly a thousand ligands for H(3)). All molecules considered were true H(3) receptor ligands with moderate to high affinity (from microM to nM range). Third, the database is issued from concrete SAR (Bioprojet H(3) BF2.649 library) and is not simply constituted by few active ligands buried in a chemical catalogue.

Evaluation of pGL1-TNF-alpha therapy in combination with radiation

NASA Technical Reports Server (NTRS)

Li, J.; Andres, M. L.; Fodor, I.; Nelson, G. A.; Gridley, D. S.

1998-01-01

Long-term control of high-grade brain tumors is rarely achieved with current therapeutic regimens. In this study a new plasmid-based human tumor necrosis factor-alpha (TNF-alpha) expression vector was synthesized (pGL1-TNF-alpha) and evaluated together with radiation in the aggressive, rapidly growing C6 rat glioma model. pGL1-TNF-alpha was successfully transfected into C6 cells in vitro using a cationic polyamine method. Expression was detected up to 7 days and averaged 0.4 ng of TNF-alpha in the culture medium from 1x10(5) cells. The expressed protein was biologically functional, as evidenced by growth inhibition of L929, a TNF-alpha-susceptible cell line. Using fluorescence-labeled monoclonal antibodies and laser scanning cytometry, we confirmed that both the P55 and P75 receptors for TNF-alpha were present on the C6 cell membrane. However, the receptors were present at low density and P55 was expressed more than the P75 receptor. These findings were in contrast to results obtained with TNF-alpha-susceptible L929 cells. Tests in athymic mice showed that pGL1-TNF-alpha administered intratumorally 16-18 h before radiation (each modality given three times) significantly inhibited C6 tumor progression (P<0.05). This effect was more than additive, because pGL1-TNF-alpha alone did not slow tumor growth and radiation alone had little effect on tumor growth. These results indicate that pGL1-TNF-alpha has potential to augment the antitumor effects of radiation against a tumor type that is virtually incurable.

Ring-based ultrasonic virtual point detector with applications to photoacoustic tomography

NASA Astrophysics Data System (ADS)

Yang, Xinmai; Li, Meng-Lin; Wang, Lihong V.

2007-06-01

An ultrasonic virtual point detector is constructed using the center of a ring transducer. The virtual point detector provides ideal omnidirectional detection free of any aperture effect. Compared with a real point detector, the virtual one has lower thermal noise and can be scanned with its center inside a physically inaccessible medium. When applied to photoacoustic tomography, the virtual point detector provides both high spatial resolution and high signal-to-noise ratio. It can also be potentially applied to other ultrasound-related technologies.

Simulators and virtual reality in surgical education.

PubMed

Chou, Betty; Handa, Victoria L

2006-06-01

This article explores the pros and cons of virtual reality simulators, their abilities to train and assess surgical skills, and their potential future applications. Computer-based virtual reality simulators and more conventional box trainers are compared and contrasted. The virtual reality simulator provides objective assessment of surgical skills and immediate feedback further to enhance training. With this ability to provide standardized, unbiased assessment of surgical skills, the virtual reality trainer has the potential to be a tool for selecting, instructing, certifying, and recertifying gynecologists.

Spherical harmonics coefficients for ligand-based virtual screening of cyclooxygenase inhibitors.

PubMed

Wang, Quan; Birod, Kerstin; Angioni, Carlo; Grösch, Sabine; Geppert, Tim; Schneider, Petra; Rupp, Matthias; Schneider, Gisbert

2011-01-01

Molecular descriptors are essential for many applications in computational chemistry, such as ligand-based similarity searching. Spherical harmonics have previously been suggested as comprehensive descriptors of molecular structure and properties. We investigate a spherical harmonics descriptor for shape-based virtual screening. We introduce and validate a partially rotation-invariant three-dimensional molecular shape descriptor based on the norm of spherical harmonics expansion coefficients. Using this molecular representation, we parameterize molecular surfaces, i.e., isosurfaces of spatial molecular property distributions. We validate the shape descriptor in a comprehensive retrospective virtual screening experiment. In a prospective study, we virtually screen a large compound library for cyclooxygenase inhibitors, using a self-organizing map as a pre-filter and the shape descriptor for candidate prioritization. 12 compounds were tested in vitro for direct enzyme inhibition and in a whole blood assay. Active compounds containing a triazole scaffold were identified as direct cyclooxygenase-1 inhibitors. This outcome corroborates the usefulness of spherical harmonics for representation of molecular shape in virtual screening of large compound collections. The combination of pharmacophore and shape-based filtering of screening candidates proved to be a straightforward approach to finding novel bioactive chemotypes with minimal experimental effort.

A computer-based training system combining virtual reality and multimedia

NASA Technical Reports Server (NTRS)

Stansfield, Sharon A.

1993-01-01

Training new users of complex machines is often an expensive and time-consuming process. This is particularly true for special purpose systems, such as those frequently encountered in DOE applications. This paper presents a computer-based training system intended as a partial solution to this problem. The system extends the basic virtual reality (VR) training paradigm by adding a multimedia component which may be accessed during interaction with the virtual environment. The 3D model used to create the virtual reality is also used as the primary navigation tool through the associated multimedia. This method exploits the natural mapping between a virtual world and the real world that it represents to provide a more intuitive way for the student to interact with all forms of information about the system.

Assessing Upper Extremity Motor Function in Practice of Virtual Activities of Daily Living

PubMed Central

Adams, Richard J.; Lichter, Matthew D.; Krepkovich, Eileen T.; Ellington, Allison; White, Marga; Diamond, Paul T.

2015-01-01

A study was conducted to investigate the criterion validity of measures of upper extremity (UE) motor function derived during practice of virtual activities of daily living (ADLs). Fourteen hemiparetic stroke patients employed a Virtual Occupational Therapy Assistant (VOTA), consisting of a high-fidelity virtual world and a Kinect™ sensor, in four sessions of approximately one hour in duration. An Unscented Kalman Filter-based human motion tracking algorithm estimated UE joint kinematics in real-time during performance of virtual ADL activities, enabling both animation of the user’s avatar and automated generation of metrics related to speed and smoothness of motion. These metrics, aggregated over discrete sub-task elements during performance of virtual ADLs, were compared to scores from an established assessment of UE motor performance, the Wolf Motor Function Test (WMFT). Spearman’s rank correlation analysis indicates a moderate correlation between VOTA-derived metrics and the time-based WMFT assessments, supporting the criterion validity of VOTA measures as a means of tracking patient progress during an UE rehabilitation program that includes practice of virtual ADLs. PMID:25265612

Assessing upper extremity motor function in practice of virtual activities of daily living.

PubMed

Adams, Richard J; Lichter, Matthew D; Krepkovich, Eileen T; Ellington, Allison; White, Marga; Diamond, Paul T

2015-03-01

A study was conducted to investigate the criterion validity of measures of upper extremity (UE) motor function derived during practice of virtual activities of daily living (ADLs). Fourteen hemiparetic stroke patients employed a Virtual Occupational Therapy Assistant (VOTA), consisting of a high-fidelity virtual world and a Kinect™ sensor, in four sessions of approximately one hour in duration. An unscented Kalman Filter-based human motion tracking algorithm estimated UE joint kinematics in real-time during performance of virtual ADL activities, enabling both animation of the user's avatar and automated generation of metrics related to speed and smoothness of motion. These metrics, aggregated over discrete sub-task elements during performance of virtual ADLs, were compared to scores from an established assessment of UE motor performance, the Wolf Motor Function Test (WMFT). Spearman's rank correlation analysis indicates a moderate correlation between VOTA-derived metrics and the time-based WMFT assessments, supporting the criterion validity of VOTA measures as a means of tracking patient progress during an UE rehabilitation program that includes practice of virtual ADLs.

Hardware assisted hypervisor introspection.

PubMed

Shi, Jiangyong; Yang, Yuexiang; Tang, Chuan

2016-01-01

In this paper, we introduce hypervisor introspection, an out-of-box way to monitor the execution of hypervisors. Similar to virtual machine introspection which has been proposed to protect virtual machines in an out-of-box way over the past decade, hypervisor introspection can be used to protect hypervisors which are the basis of cloud security. Virtual machine introspection tools are usually deployed either in hypervisor or in privileged virtual machines, which might also be compromised. By utilizing hardware support including nested virtualization, EPT protection and #BP, we are able to monitor all hypercalls belongs to the virtual machines of one hypervisor, include that of privileged virtual machine and even when the hypervisor is compromised. What's more, hypercall injection method is used to simulate hypercall-based attacks and evaluate the performance of our method. Experiment results show that our method can effectively detect hypercall-based attacks with some performance cost. Lastly, we discuss our furture approaches of reducing the performance cost and preventing the compromised hypervisor from detecting the existence of our introspector, in addition with some new scenarios to apply our hypervisor introspection system.

Sphingosine-1-Phosphate and the S1P3 Receptor Initiate Neuronal Retraction via RhoA/ROCK Associated with CRMP2 Phosphorylation

PubMed Central

Quarta, Serena; Camprubí-Robles, Maria; Schweigreiter, Rüdiger; Matusica, Dusan; Haberberger, Rainer V.; Proia, Richard L.; Bandtlow, Christine E.; Ferrer-Montiel, Antonio; Kress, Michaela

2017-01-01

The bioactive lipid sphingosine-1-phosphate (S1P) is an important regulator in the nervous system. Here, we explored the role of S1P and its receptors in vitro and in preclinical models of peripheral nerve regeneration. Adult sensory neurons and motor neuron-like cells were exposed to S1P in an in vitro assay, and virtually all neurons responded with a rapid retraction of neurites and growth cone collapse which were associated with RhoA and ROCK activation. The S1P1 receptor agonist SEW2871 neither activated RhoA or neurite retraction, nor was S1P-induced neurite retraction mitigated in S1P1-deficient neurons. Depletion of S1P3 receptors however resulted in a dramatic inhibition of S1P-induced neurite retraction and was on the contrary associated with a significant elongation of neuronal processes in response to S1P. Opposing responses to S1P could be observed in the same neuron population, where S1P could activate S1P1 receptors to stimulate elongation or S1P3 receptors and retraction. S1P was, for the first time in sensory neurons, linked to the phosphorylation of collapsin response-mediated protein-2 (CRMP2), which was inhibited by ROCK inhibition. The improved sensory recovery after crush injury further supported the relevance of a critical role for S1P and receptors in fine-tuning axonal outgrowth in peripheral neurons. PMID:29066950

Sphingosine-1-Phosphate and the S1P3 Receptor Initiate Neuronal Retraction via RhoA/ROCK Associated with CRMP2 Phosphorylation.

PubMed

Quarta, Serena; Camprubí-Robles, Maria; Schweigreiter, Rüdiger; Matusica, Dusan; Haberberger, Rainer V; Proia, Richard L; Bandtlow, Christine E; Ferrer-Montiel, Antonio; Kress, Michaela

2017-01-01

The bioactive lipid sphingosine-1-phosphate (S1P) is an important regulator in the nervous system. Here, we explored the role of S1P and its receptors in vitro and in preclinical models of peripheral nerve regeneration. Adult sensory neurons and motor neuron-like cells were exposed to S1P in an in vitro assay, and virtually all neurons responded with a rapid retraction of neurites and growth cone collapse which were associated with RhoA and ROCK activation. The S1P 1 receptor agonist SEW2871 neither activated RhoA or neurite retraction, nor was S1P-induced neurite retraction mitigated in S1P 1 -deficient neurons. Depletion of S1P 3 receptors however resulted in a dramatic inhibition of S1P-induced neurite retraction and was on the contrary associated with a significant elongation of neuronal processes in response to S1P. Opposing responses to S1P could be observed in the same neuron population, where S1P could activate S1P 1 receptors to stimulate elongation or S1P 3 receptors and retraction. S1P was, for the first time in sensory neurons, linked to the phosphorylation of collapsin response-mediated protein-2 (CRMP2), which was inhibited by ROCK inhibition. The improved sensory recovery after crush injury further supported the relevance of a critical role for S1P and receptors in fine-tuning axonal outgrowth in peripheral neurons.

Evolution of trace amine associated receptor (TAAR) gene family in vertebrates: lineage-specific expansions and degradations of a second class of vertebrate chemosensory receptors expressed in the olfactory epithelium.

PubMed

Hashiguchi, Yasuyuki; Nishida, Mutsumi

2007-09-01

The trace amine-associated receptors (TAARs) form a specific family of G protein-coupled receptors in vertebrates. TAARs were initially considered neurotransmitter receptors, but recent study showed that mouse TAARs function as chemosensory receptors in the olfactory epithelium. To clarify the evolutionary dynamics of the TAAR gene family in vertebrates, near-complete repertoires of TAAR genes and pseudogenes were identified from the genomic assemblies of 4 teleost fishes (zebrafish, fugu, stickleback, and medaka), western clawed frogs, chickens, 3 mammals (humans, mice, and opossum), and sea lampreys. Database searches revealed that fishes had many putatively functional TAAR genes (13-109 genes), whereas relatively small numbers of TAAR genes (3-22 genes) were identified in tetrapods. Phylogenetic analysis of these genes indicated that the TAAR gene family was subdivided into 5 subfamilies that diverged before the divergence of ray-finned fishes and tetrapods. In tetrapods, virtually all TAAR genes were located in 1 specific region of their genomes as a gene cluster; however, in fishes, TAAR genes were scattered throughout more than 2 genomic locations. This possibly reflects a whole-genome duplication that occurred in the common ancestor of ray-finned fishes. Expression analysis of zebrafish and stickleback TAAR genes revealed that many TAARs in these fishes were expressed in the olfactory organ, suggesting the relatively high importance of TAARs as chemosensory receptors in fishes. A possible evolutionary history of the vertebrate TAAR gene family was inferred from the phylogenetic and comparative genomic analyses.

Short-chain free fatty acid receptors FFA2/GPR43 and FFA3/GPR41 as new potential therapeutic targets.

PubMed

Ulven, Trond

2012-01-01

The deorphanization of the free fatty acid (FFA) receptors FFA1 (GPR40), FFA2 (GPR43), FFA3 (GPR41), GPR84, and GPR120 has made clear that the body is capable of recognizing and responding directly to nonesterified fatty acid of virtually any chain length. Colonic fermentation of dietary fiber produces high concentrations of the short-chain fatty acids (SCFAs) acetate, propionate and butyrate, a process which is important to health. The phylogenetically related 7-transmembrane (7TM) receptors free fatty acid receptor 2 (FFA2) and FFA3 are activated by these SCFAs, and several lines of evidence indicate that FFA2 and FFA3 mediate beneficial effects associated with a fiber-rich diet, and that they may be of interest as targets for treatment of inflammatory and metabolic diseases. FFA2 is highly expressed on immune cells, in particular neutrophils, and several studies suggest that the receptor plays a role in diseases involving a dysfunctional neutrophil response, such as inflammatory bowel disease (IBD). Both FFA2 and FFA3 have been implicated in metabolic diseases such as type 2 diabetes and in regulation of appetite. More research is however required to clarify the potential of the receptors as drug targets and establish if activation or inhibition would be the preferred mode of action. The availability of potent and selective receptor modulators is a prerequisite for these studies. The few modulators of FFA2 or FFA3 that have been published hitherto in the peer-reviewed literature in general have properties that make them less than ideal as such tools, but published patent applications indicate that better tool compounds might soon become available which should enable studies critical to validate the receptors as new drug targets.

Signaling network of the Btk family kinases.

PubMed

Qiu, Y; Kung, H J

2000-11-20

The Btk family kinases represent new members of non-receptor tyrosine kinases, which include Btk/Atk, Itk/Emt/Tsk, Bmx/Etk, and Tec. They are characterized by having four structural modules: PH (pleckstrin homology) domain, SH3 (Src homology 3) domain, SH2 (Src homology 2) domain and kinase (Src homology 1) domain. Increasing evidence suggests that, like Src-family kinases, Btk family kinases play central but diverse modulatory roles in various cellular processes. They participate in signal transduction in response to virtually all types of extracellular stimuli which are transmitted by growth factor receptors, cytokine receptors, G-protein coupled receptors, antigen-receptors and integrins. They are regulated by many non-receptor tyrosine kinases such as Src, Jak, Syk and FAK family kinases. In turn, they regulate many of major signaling pathways including those of PI3K, PLCgamma and PKC. Both genetic and biochemical approaches have been used to dissect the signaling pathways and elucidate their roles in growth, differentiation and apoptosis. An emerging new role of this family of kinases is cytoskeletal reorganization and cell motility. The physiological importance of these kinases was amply demonstrated by their link to the development of immunodeficiency diseases, due to germ-line mutations. The present article attempts to review the structure and functions of Btk family kinases by summarizing our current knowledge on the interacting partners associated with the different modules of the kinases and the diverse signaling pathways in which they are involved.

Canoe game-based virtual reality training to improve trunk postural stability, balance, and upper limb motor function in subacute stroke patients: a randomized controlled pilot study.

PubMed

Lee, Myung-Mo; Shin, Doo-Chul; Song, Chang-Ho

2016-07-01

[Purpose] This study was aimed at investigating the preliminary therapeutic efficacy and usefulness of canoe game-based virtual reality training for stroke patients. [Subjects and Methods] Ten stroke patients were randomly assigned to an experimental group (EG; n=5) or a control group (CG; n=5). Patients in both groups participated in a conventional rehabilitation program, but those in the EG additionally participated in a 30-min canoe game-based virtual reality training program 3 days a week for 4 weeks. Therapeutic efficacy was assessed based on trunk postural stability, balance, and upper limb motor function. In addition, the usefulness of canoe game-based virtual reality training was assessed in the EG and therapist group (TG; n=20), which consisted of physical and occupational therapists, by using the System Usability Scale (SUS). [Results] Improvements in trunk postural stability, balance, and upper limb motor function were observed in the EG and CG, but were greater in the EG. The mean SUS scores in the EG and TG were 71 ± 5.2 and 74.2 ± 4.8, respectively. [Conclusion] Canoe game-based virtual reality training is an acceptable and effective intervention for improving trunk postural stability, balance, and upper limb motor function in stroke patients.

The experiment editor: supporting inquiry-based learning with virtual labs

NASA Astrophysics Data System (ADS)

Galan, D.; Heradio, R.; de la Torre, L.; Dormido, S.; Esquembre, F.

2017-05-01

Inquiry-based learning is a pedagogical approach where students are motivated to pose their own questions when facing problems or scenarios. In physics learning, students are turned into scientists who carry out experiments, collect and analyze data, formulate and evaluate hypotheses, and so on. Lab experimentation is essential for inquiry-based learning, yet there is a drawback with traditional hands-on labs in the high costs associated with equipment, space, and maintenance staff. Virtual laboratories are helpful to reduce these costs. This paper enriches the virtual lab ecosystem by providing an integrated environment to automate experimentation tasks. In particular, our environment supports: (i) scripting and running experiments on virtual labs, and (ii) collecting and analyzing data from the experiments. The current implementation of our environment supports virtual labs created with the authoring tool Easy Java/Javascript Simulations. Since there are public repositories with hundreds of freely available labs created with this tool, the potential applicability to our environment is considerable.

BIM based virtual environment for fire emergency evacuation.

PubMed

Wang, Bin; Li, Haijiang; Rezgui, Yacine; Bradley, Alex; Ong, Hoang N

2014-01-01

Recent building emergency management research has highlighted the need for the effective utilization of dynamically changing building information. BIM (building information modelling) can play a significant role in this process due to its comprehensive and standardized data format and integrated process. This paper introduces a BIM based virtual environment supported by virtual reality (VR) and a serious game engine to address several key issues for building emergency management, for example, timely two-way information updating and better emergency awareness training. The focus of this paper lies on how to utilize BIM as a comprehensive building information provider to work with virtual reality technologies to build an adaptable immersive serious game environment to provide real-time fire evacuation guidance. The innovation lies on the seamless integration between BIM and a serious game based virtual reality (VR) environment aiming at practical problem solving by leveraging state-of-the-art computing technologies. The system has been tested for its robustness and functionality against the development requirements, and the results showed promising potential to support more effective emergency management.

Innovative research on the group teaching mode based on the LabVIEW virtual environment

NASA Astrophysics Data System (ADS)

Liang, Pei; Huang, Jie; Gong, Hua-ping; Dong, Qian-min; Dong, Yan-yan; Sun, Cai-xia

2017-08-01

This paper discusses the widely existing problems of increasing demand of professional engineer in electronic science major and the backward of the teaching mode at present. From one specialized course "Virtual Instrument technique and LABVIEW programming", we explore the new group-teaching mode based on the Virtual Instrument technique, and then the Specific measures and implementation procedures and effect of this teaching mode summarized in the end.

Collaborative voxel-based surgical virtual environments.

PubMed

Acosta, Eric; Muniz, Gilbert; Armonda, Rocco; Bowyer, Mark; Liu, Alan

2008-01-01

Virtual Reality-based surgical simulators can utilize Collaborative Virtual Environments (C-VEs) to provide team-based training. To support real-time interactions, C-VEs are typically replicated on each user's local computer and a synchronization method helps keep all local copies consistent. This approach does not work well for voxel-based C-VEs since large and frequent volumetric updates make synchronization difficult. This paper describes a method that allows multiple users to interact within a voxel-based C-VE for a craniotomy simulator being developed. Our C-VE method requires smaller update sizes and provides faster synchronization update rates than volumetric-based methods. Additionally, we address network bandwidth/latency issues to simulate networked haptic and bone drilling tool interactions with a voxel-based skull C-VE.

Planning Image-Based Measurements in Wind Tunnels by Virtual Imaging

NASA Technical Reports Server (NTRS)

Kushner, Laura Kathryn; Schairer, Edward T.

2011-01-01

Virtual imaging is routinely used at NASA Ames Research Center to plan the placement of cameras and light sources for image-based measurements in production wind tunnel tests. Virtual imaging allows users to quickly and comprehensively model a given test situation, well before the test occurs, in order to verify that all optical testing requirements will be met. It allows optimization of the placement of cameras and light sources and leads to faster set-up times, thereby decreasing tunnel occupancy costs. This paper describes how virtual imaging was used to plan optical measurements for three tests in production wind tunnels at NASA Ames.

Designing Virtual Museum Using Web3D Technology

NASA Astrophysics Data System (ADS)

Zhao, Jianghai

VRT was born to have the potentiality of constructing an effective learning environment due to its 3I characteristics: Interaction, Immersion and Imagination. It is now applied in education in a more profound way along with the development of VRT. Virtual Museum is one of the applications. The Virtual Museum is based on the WEB3D technology and extensibility is the most important factor. Considering the advantage and disadvantage of each WEB3D technology, VRML, CULT3D AND VIEWPOINT technologies are chosen. A web chatroom based on flash and ASP technology is also been created in order to make the Virtual Museum an interactive learning environment.

National Mesothelioma Virtual Bank: a standard based biospecimen and clinical data resource to enhance translational research.

PubMed

Amin, Waqas; Parwani, Anil V; Schmandt, Linda; Mohanty, Sambit K; Farhat, Ghada; Pople, Andrew K; Winters, Sharon B; Whelan, Nancy B; Schneider, Althea M; Milnes, John T; Valdivieso, Federico A; Feldman, Michael; Pass, Harvey I; Dhir, Rajiv; Melamed, Jonathan; Becich, Michael J

2008-08-13

Advances in translational research have led to the need for well characterized biospecimens for research. The National Mesothelioma Virtual Bank is an initiative which collects annotated datasets relevant to human mesothelioma to develop an enterprising biospecimen resource to fulfill researchers' need. The National Mesothelioma Virtual Bank architecture is based on three major components: (a) common data elements (based on College of American Pathologists protocol and National North American Association of Central Cancer Registries standards), (b) clinical and epidemiologic data annotation, and (c) data query tools. These tools work interoperably to standardize the entire process of annotation. The National Mesothelioma Virtual Bank tool is based upon the caTISSUE Clinical Annotation Engine, developed by the University of Pittsburgh in cooperation with the Cancer Biomedical Informatics Grid (caBIG, see http://cabig.nci.nih.gov). This application provides a web-based system for annotating, importing and searching mesothelioma cases. The underlying information model is constructed utilizing Unified Modeling Language class diagrams, hierarchical relationships and Enterprise Architect software. The database provides researchers real-time access to richly annotated specimens and integral information related to mesothelioma. The data disclosed is tightly regulated depending upon users' authorization and depending on the participating institute that is amenable to the local Institutional Review Board and regulation committee reviews. The National Mesothelioma Virtual Bank currently has over 600 annotated cases available for researchers that include paraffin embedded tissues, tissue microarrays, serum and genomic DNA. The National Mesothelioma Virtual Bank is a virtual biospecimen registry with robust translational biomedical informatics support to facilitate basic science, clinical, and translational research. Furthermore, it protects patient privacy by disclosing only de-identified datasets to assure that biospecimens can be made accessible to researchers.

Protein tyrosine phosphatases: Ligand interaction analysis and optimisation of virtual screening.

PubMed

Ghattas, Mohammad A; Atatreh, Noor; Bichenkova, Elena V; Bryce, Richard A

2014-07-01

Docking-based virtual screening is an established component of structure-based drug discovery. Nevertheless, scoring and ranking of computationally docked ligand libraries still suffer from many false positives. Identifying optimal docking parameters for a target protein prior to virtual screening can improve experimental hit rates. Here, we examine protocols for virtual screening against the important but challenging class of drug target, protein tyrosine phosphatases. In this study, common interaction features were identified from analysis of protein-ligand binding geometries of more than 50 complexed phosphatase crystal structures. It was found that two interactions were consistently formed across all phosphatase inhibitors: (1) a polar contact with the conserved arginine residue, and (2) at least one interaction with the P-loop backbone amide. In order to investigate the significance of these features on phosphatase-ligand binding, a series of seeded virtual screening experiments were conducted on three phosphatase enzymes, PTP1B, Cdc25b and IF2. It was observed that when the conserved arginine and P-loop amide interactions were used as pharmacophoric constraints during docking, enrichment of the virtual screen significantly increased in the three studied phosphatases, by up to a factor of two in some cases. Additionally, the use of such pharmacophoric constraints considerably improved the ability of docking to predict the inhibitor's bound pose, decreasing RMSD to the crystallographic geometry by 43% on average. Constrained docking improved enrichment of screens against both open and closed conformations of PTP1B. Incorporation of an ordered water molecule in PTP1B screening was also found to generally improve enrichment. The knowledge-based computational strategies explored here can potentially inform structure-based design of new phosphatase inhibitors using docking-based virtual screening. Copyright © 2014 Elsevier Inc. All rights reserved.

Virtual goods recommendations in virtual worlds.

PubMed

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.

Virtual Goods Recommendations in Virtual Worlds

PubMed Central

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. PMID:25834837

The early benefits of a problem-based approach to teaching social inclusion using an online virtual town.

PubMed

Beadle, Mary; Santy, Julie

2008-05-01

This article describes the delivery of a core pre-registration nursing and midwifery module centred on social inclusion. The module was previously delivered using a classroom-based problem-based learning approach. Difficulties with this approach led to changes to the module and its delivery. Logistic issues encouraged the module team to implement a blended learning approach using a virtual town to facilitate online learning and discussion activities. The paper describes and discusses the use of online learning technology to support student nurses and midwives. It highlights the benefits of this approach and outlines some of the experiences of the students including their evaluation of the virtual town. There is also an examination of some of the practical and theoretical issues related to both problem-based learning, online working and using a virtual town to support learning. This article outlines the approach taken and its implications.

Propagation of crises in the virtual water trade network

NASA Astrophysics Data System (ADS)

Tamea, Stefania; Laio, Francesco; Ridolfi, Luca

2015-04-01

The international trade of agricultural goods is associated to the displacement of the water used to produce such goods and embedded in trade as a factor of production. Water virtually exchanged from producing to consuming countries, named virtual water, defines flows across an international network of 'virtual water trade' which enable the assessment of environmental forcings and implications of trade, such as global water savings or country dependencies on foreign water resources. Given the recent expansion of commodity (and virtual water) trade, in both displaced volumes and network structure, concerns have been raised about the exposure to crises of individuals and societies. In fact, if one country had to markedly decrease its export following a socio-economical or environmental crisis, such as a war or a drought, many -if not all- countries would be affected due to a cascade effect within the trade network. The present contribution proposes a mechanistic model describing the propagation of a local crisis into the virtual water trade network, accounting for the network structure and the virtual water balance of all countries. The model, built on data-based assumptions, is tested on the real case study of the Argentinean crisis in 2008-09, when the internal agricultural production (measured as virtual water volume) decreased by 26% and the virtual water export of Argentina dropped accordingly. Crisis propagation and effects on the virtual water trade are correctly captured, showing the way forward to investigations of crises impact and country vulnerability based on the results of the model proposed.

Cheminformatics meets molecular mechanics: a combined application of knowledge-based pose scoring and physical force field-based hit scoring functions improves the accuracy of structure-based virtual screening.

PubMed

Hsieh, Jui-Hua; Yin, Shuangye; Wang, Xiang S; Liu, Shubin; Dokholyan, Nikolay V; Tropsha, Alexander

2012-01-23

Poor performance of scoring functions is a well-known bottleneck in structure-based virtual screening (VS), which is most frequently manifested in the scoring functions' inability to discriminate between true ligands vs known nonbinders (therefore designated as binding decoys). This deficiency leads to a large number of false positive hits resulting from VS. We have hypothesized that filtering out or penalizing docking poses recognized as non-native (i.e., pose decoys) should improve the performance of VS in terms of improved identification of true binders. Using several concepts from the field of cheminformatics, we have developed a novel approach to identifying pose decoys from an ensemble of poses generated by computational docking procedures. We demonstrate that the use of target-specific pose (scoring) filter in combination with a physical force field-based scoring function (MedusaScore) leads to significant improvement of hit rates in VS studies for 12 of the 13 benchmark sets from the clustered version of the Database of Useful Decoys (DUD). This new hybrid scoring function outperforms several conventional structure-based scoring functions, including XSCORE::HMSCORE, ChemScore, PLP, and Chemgauss3, in 6 out of 13 data sets at early stage of VS (up 1% decoys of the screening database). We compare our hybrid method with several novel VS methods that were recently reported to have good performances on the same DUD data sets. We find that the retrieved ligands using our method are chemically more diverse in comparison with two ligand-based methods (FieldScreen and FLAP::LBX). We also compare our method with FLAP::RBLB, a high-performance VS method that also utilizes both the receptor and the cognate ligand structures. Interestingly, we find that the top ligands retrieved using our method are highly complementary to those retrieved using FLAP::RBLB, hinting effective directions for best VS applications. We suggest that this integrative VS approach combining cheminformatics and molecular mechanics methodologies may be applied to a broad variety of protein targets to improve the outcome of structure-based drug discovery studies.

Virtual Education in Universities: A Technological Imperative.

ERIC Educational Resources Information Center

O'Donoghue, John; Singh, Gurmak; Dorward, Lisa

2001-01-01

Discusses virtual universities and virtual classrooms, exploring both the benefits and the disadvantages of technology-based delivery systems. Highlights include competitive pressures to use technology; impacts on students; the need for flexibility to meet unique student needs and learning styles; learning environments; impact on society; and…

Knowledge Searching and Sharing on Virtual Networks.

ERIC Educational Resources Information Center

Helokunnas, Tuija; Herrala, Juha

2001-01-01

Describes searching and sharing of knowledge on virtual networks, based on experiences gained when hosting virtual knowledge networks at Tampere University of Technology in Finland. Discusses information and knowledge management studies; role of information technology in knowledge searching and sharing; implementation and experiences of the…

State Virtual Libraries

ERIC Educational Resources Information Center

Pappas, Marjorie L.

2003-01-01

Virtual library? Electronic library? Digital library? Online information network? These all apply to the growing number of Web-based resource collections managed by consortiums of state library entities. Some, like "INFOhio" and "KYVL" ("Kentucky Virtual Library"), have been available for a few years, but others are just starting. Searching for…

A 3D character animation engine for multimodal interaction on mobile devices

NASA Astrophysics Data System (ADS)

Sandali, Enrico; Lavagetto, Fabio; Pisano, Paolo

2005-03-01

Talking virtual characters are graphical simulations of real or imaginary persons that enable natural and pleasant multimodal interaction with the user, by means of voice, eye gaze, facial expression and gestures. This paper presents an implementation of a 3D virtual character animation and rendering engine, compliant with the MPEG-4 standard, running on Symbian-based SmartPhones. Real-time animation of virtual characters on mobile devices represents a challenging task, since many limitations must be taken into account with respect to processing power, graphics capabilities, disk space and execution memory size. The proposed optimization techniques allow to overcome these issues, guaranteeing a smooth and synchronous animation of facial expressions and lip movements on mobile phones such as Sony-Ericsson's P800 and Nokia's 6600. The animation engine is specifically targeted to the development of new "Over The Air" services, based on embodied conversational agents, with applications in entertainment (interactive story tellers), navigation aid (virtual guides to web sites and mobile services), news casting (virtual newscasters) and education (interactive virtual teachers).

Engaging adolescents in a computer-based weight management program: avatars and virtual coaches could help.

PubMed

LeRouge, Cynthia; Dickhut, Kathryn; Lisetti, Christine; Sangameswaran, Savitha; Malasanos, Toree

2016-01-01

This research focuses on the potential ability of animated avatars (a digital representation of the user) and virtual agents (a digital representation of a coach, buddy, or teacher) to deliver computer-based interventions for adolescents' chronic weight management. An exploration of the acceptance and desire of teens to interact with avatars and virtual agents for self-management and behavioral modification was undertaken. The utilized approach was inspired by community-based participatory research. Data was collected from 2 phases: Phase 1) focus groups with teens, provider interviews, parent interviews; and Phase 2) mid-range prototype assessment by teens and providers. Data from all stakeholder groups expressed great interest in avatars and virtual agents assisting self-management efforts. Adolescents felt the avatars and virtual agents could: 1) reinforce guidance and support, 2) fit within their lifestyle, and 3) help set future goals, particularly after witnessing the effect of their current behavior(s) on the projected physical appearance (external and internal organs) of avatars. Teens wanted 2 virtual characters: a virtual agent to act as a coach or teacher and an avatar (extension of themselves) to serve as a "buddy" for empathic support and guidance and as a surrogate for rewards. Preferred modalities for use include both mobile devices to accommodate access and desktop to accommodate preferences for maximum screen real estate to support virtualization of functions that are more contemplative and complex (e.g., goal setting). Adolescents expressed a desire for limited co-user access, which they could regulate. Data revealed certain barriers and facilitators that could affect adoption and use. The current study extends the support of teens, parents, and providers for adding avatars or virtual agents to traditional computer-based interactions. Data supports the desire for a personal relationship with a virtual character in support of previous studies. The study provides a foundation for further work in the area of avatar-driven motivational interviewing. This study provides evidence supporting the use of avatars and virtual agents, designed using participatory approaches, to be included in the continuum of care. Increased probability of engagement and long-term retention of overweight, obese adolescent users and suggests expanding current chronic care models toward more comprehensive, socio-technical representations. © The Author 2015. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

An information model for a virtual private optical network (OVPN) using virtual routers (VRs)

NASA Astrophysics Data System (ADS)

Vo, Viet Minh Nhat

2002-05-01

This paper describes a virtual private optical network architecture (Optical VPN - OVPN) based on virtual router (VR). It improves over architectures suggested for virtual private networks by using virtual routers with optical networks. The new things in this architecture are necessary changes to adapt to devices and protocols used in optical networks. This paper also presents information models for the OVPN: at the architecture level and at the service level. These are extensions to the DEN (directory enable network) and CIM (Common Information Model) for OVPNs using VRs. The goal is to propose a common management model using policies.

Handheld Micromanipulation with Vision-Based Virtual Fixtures

PubMed Central

Becker, Brian C.; MacLachlan, Robert A.; Hager, Gregory D.; Riviere, Cameron N.

2011-01-01

Precise movement during micromanipulation becomes difficult in submillimeter workspaces, largely due to the destabilizing influence of tremor. Robotic aid combined with filtering techniques that suppress tremor frequency bands increases performance; however, if knowledge of the operator's goals is available, virtual fixtures have been shown to greatly improve micromanipulator precision. In this paper, we derive a control law for position-based virtual fixtures within the framework of an active handheld micromanipulator, where the fixtures are generated in real-time from microscope video. Additionally, we develop motion scaling behavior centered on virtual fixtures as a simple and direct extension to our formulation. We demonstrate that hard and soft (motion-scaled) virtual fixtures outperform state-of-the-art tremor cancellation performance on a set of artificial but medically relevant tasks: holding, move-and-hold, curve tracing, and volume restriction. PMID:23275860

Virtual local target method for avoiding local minimum in potential field based robot navigation.

PubMed

Zou, Xi-Yong; Zhu, Jing

2003-01-01

A novel robot navigation algorithm with global path generation capability is presented. Local minimum is a most intractable but is an encountered frequently problem in potential field based robot navigation. Through appointing appropriately some virtual local targets on the journey, it can be solved effectively. The key concept employed in this algorithm are the rules that govern when and how to appoint these virtual local targets. When the robot finds itself in danger of local minimum, a virtual local target is appointed to replace the global goal temporarily according to the rules. After the virtual target is reached, the robot continues on its journey by heading towards the global goal. The algorithm prevents the robot from running into local minima anymore. Simulation results showed that it is very effective in complex obstacle environments.

Selective Listening Point Audio Based on Blind Signal Separation and Stereophonic Technology

NASA Astrophysics Data System (ADS)

Niwa, Kenta; Nishino, Takanori; Takeda, Kazuya

A sound field reproduction method is proposed that uses blind source separation and a head-related transfer function. In the proposed system, multichannel acoustic signals captured at distant microphones are decomposed to a set of location/signal pairs of virtual sound sources based on frequency-domain independent component analysis. After estimating the locations and the signals of the virtual sources by convolving the controlled acoustic transfer functions with each signal, the spatial sound is constructed at the selected point. In experiments, a sound field made by six sound sources is captured using 48 distant microphones and decomposed into sets of virtual sound sources. Since subjective evaluation shows no significant difference between natural and reconstructed sound when six virtual sources and are used, the effectiveness of the decomposing algorithm as well as the virtual source representation are confirmed.

Visualizing dynamic geosciences phenomena using an octree-based view-dependent LOD strategy within virtual globes

NASA Astrophysics Data System (ADS)

Li, Jing; Wu, Huayi; Yang, Chaowei; Wong, David W.; Xie, Jibo

2011-09-01

Geoscientists build dynamic models to simulate various natural phenomena for a better understanding of our planet. Interactive visualizations of these geoscience models and their outputs through virtual globes on the Internet can help the public understand the dynamic phenomena related to the Earth more intuitively. However, challenges arise when the volume of four-dimensional data (4D), 3D in space plus time, is huge for rendering. Datasets loaded from geographically distributed data servers require synchronization between ingesting and rendering data. Also the visualization capability of display clients varies significantly in such an online visualization environment; some may not have high-end graphic cards. To enhance the efficiency of visualizing dynamic volumetric data in virtual globes, this paper proposes a systematic framework, in which an octree-based multiresolution data structure is implemented to organize time series 3D geospatial data to be used in virtual globe environments. This framework includes a view-dependent continuous level of detail (LOD) strategy formulated as a synchronized part of the virtual globe rendering process. Through the octree-based data retrieval process, the LOD strategy enables the rendering of the 4D simulation at a consistent and acceptable frame rate. To demonstrate the capabilities of this framework, data of a simulated dust storm event are rendered in World Wind, an open source virtual globe. The rendering performances with and without the octree-based LOD strategy are compared. The experimental results show that using the proposed data structure and processing strategy significantly enhances the visualization performance when rendering dynamic geospatial phenomena in virtual globes.

G2H--graphics-to-haptic virtual environment development tool for PC's.

PubMed

Acosta, E; Temkin, B; Krummel, T M; Heinrichs, W L

2000-01-01

For surgical training and preparations, the existing surgical virtual environments have shown great improvement. However, these improvements are more in the visual aspect. The incorporation of haptics into virtual reality base surgical simulations would enhance the sense of realism greatly. To aid in the development of the haptic surgical virtual environment we have created a graphics to haptic, G2H, virtual environment developer tool. G2H transforms graphical virtual environments (created or imported) to haptic virtual environments without programming. The G2H capability has been demonstrated using the complex 3D pelvic model of Lucy 2.0, the Stanford Visible Female. The pelvis was made haptic using G2H without any further programming effort.

[Virtual water content of livestock products in China].

PubMed

Wang, Hong-rui; Wang, Jun-hong

2006-04-01

The paper expatiated the virtual water content concept of livestock products and the study meaning on developing virtual water trade of livestock products in China, then summarized the calculation methods on virtual water and virtual water trade of livestock products. Based on these, the paper analyzed and researched every province virtual water content of livestock products in details, then elicited various situation of every province virtual water content of livestock products in China by year. Moreover, it compared virtual water content of livestock products with local water resources. The study indicated the following results: (1) The virtual water content of livestock products is increasing rapidly in China recently, especially poultry eggs and pork. (2) The distribution of virtual water content of livestock products is not balanced, mainly lies in North China, East China and so on; (3) The increasing production of livestock in Beijing City, Tianjin City, Hebei, Nei Monggol, Liaononing, Jilin, Shandong, Henan and Ningxia province and autonom ous region will bring pressure to local water shortage.

Virtual Network Configuration Management System for Data Center Operations and Management

NASA Astrophysics Data System (ADS)

Okita, Hideki; Yoshizawa, Masahiro; Uehara, Keitaro; Mizuno, Kazuhiko; Tarui, Toshiaki; Naono, Ken

Virtualization technologies are widely deployed in data centers to improve system utilization. However, they increase the workload for operators, who have to manage the structure of virtual networks in data centers. A virtual-network management system which automates the integration of the configurations of the virtual networks is provided. The proposed system collects the configurations from server virtualization platforms and VLAN-supported switches, and integrates these configurations according to a newly developed XML-based management information model for virtual-network configurations. Preliminary evaluations show that the proposed system helps operators by reducing the time to acquire the configurations from devices and correct the inconsistency of operators' configuration management database by about 40 percent. Further, they also show that the proposed system has excellent scalability; the system takes less than 20 minutes to acquire the virtual-network configurations from a large scale network that includes 300 virtual machines. These results imply that the proposed system is effective for improving the configuration management process for virtual networks in data centers.

Validation of a new method for finding the rotational axes of the knee using both marker-based roentgen stereophotogrammetric analysis and 3D video-based motion analysis for kinematic measurements.

PubMed

Roland, Michelle; Hull, M L; Howell, S M

2011-05-01

In a previous paper, we reported the virtual axis finder, which is a new method for finding the rotational axes of the knee. The virtual axis finder was validated through simulations that were subject to limitations. Hence, the objective of the present study was to perform a mechanical validation with two measurement modalities: 3D video-based motion analysis and marker-based roentgen stereophotogrammetric analysis (RSA). A two rotational axis mechanism was developed, which simulated internal-external (or longitudinal) and flexion-extension (FE) rotations. The actual axes of rotation were known with respect to motion analysis and RSA markers within ± 0.0006 deg and ± 0.036 mm and ± 0.0001 deg and ± 0.016 mm, respectively. The orientation and position root mean squared errors for identifying the longitudinal rotation (LR) and FE axes with video-based motion analysis (0.26 deg, 0.28 m, 0.36 deg, and 0.25 mm, respectively) were smaller than with RSA (1.04 deg, 0.84 mm, 0.82 deg, and 0.32 mm, respectively). The random error or precision in the orientation and position was significantly better (p=0.01 and p=0.02, respectively) in identifying the LR axis with video-based motion analysis (0.23 deg and 0.24 mm) than with RSA (0.95 deg and 0.76 mm). There was no significant difference in the bias errors between measurement modalities. In comparing the mechanical validations to virtual validations, the virtual validations produced comparable errors to those of the mechanical validation. The only significant difference between the errors of the mechanical and virtual validations was the precision in the position of the LR axis while simulating video-based motion analysis (0.24 mm and 0.78 mm, p=0.019). These results indicate that video-based motion analysis with the equipment used in this study is the superior measurement modality for use with the virtual axis finder but both measurement modalities produce satisfactory results. The lack of significant differences between validation techniques suggests that the virtual sensitivity analysis previously performed was appropriately modeled. Thus, the virtual axis finder can be applied with a thorough understanding of its errors in a variety of test conditions.

Telemanipulation, telepresence, and virtual reality for surgery in the year 2000

NASA Astrophysics Data System (ADS)

Satava, Richard M.

1995-12-01

The new technologic revolution in medicine is based upon information technologies, and telemanipulation, telepresence and virtual reality are essential components. Telepresence surgery returns the look and feel of `open surgery' to the surgeon and promises enhancement of physical capabilities above normal human performance. Virtual reality provides basic medical education, simulation of surgical procedures, medical forces and disaster medicine practice, and virtual prototyping of medical equipment.

A User-Centric Knowledge Creation Model in a Web of Object-Enabled Internet of Things Environment

PubMed Central

Kibria, Muhammad Golam; Fattah, Sheik Mohammad Mostakim; Jeong, Kwanghyeon; Chong, Ilyoung; Jeong, Youn-Kwae

2015-01-01

User-centric service features in a Web of Object-enabled Internet of Things environment can be provided by using a semantic ontology that classifies and integrates objects on the World Wide Web as well as shares and merges context-aware information and accumulated knowledge. The semantic ontology is applied on a Web of Object platform to virtualize the real world physical devices and information to form virtual objects that represent the features and capabilities of devices in the virtual world. Detailed information and functionalities of multiple virtual objects are combined with service rules to form composite virtual objects that offer context-aware knowledge-based services, where context awareness plays an important role in enabling automatic modification of the system to reconfigure the services based on the context. Converting the raw data into meaningful information and connecting the information to form the knowledge and storing and reusing the objects in the knowledge base can both be expressed by semantic ontology. In this paper, a knowledge creation model that synchronizes a service logistic model and a virtual world knowledge model on a Web of Object platform has been proposed. To realize the context-aware knowledge-based service creation and execution, a conceptual semantic ontology model has been developed and a prototype has been implemented for a use case scenario of emergency service. PMID:26393609

A User-Centric Knowledge Creation Model in a Web of Object-Enabled Internet of Things Environment.

PubMed

Kibria, Muhammad Golam; Fattah, Sheik Mohammad Mostakim; Jeong, Kwanghyeon; Chong, Ilyoung; Jeong, Youn-Kwae

2015-09-18

User-centric service features in a Web of Object-enabled Internet of Things environment can be provided by using a semantic ontology that classifies and integrates objects on the World Wide Web as well as shares and merges context-aware information and accumulated knowledge. The semantic ontology is applied on a Web of Object platform to virtualize the real world physical devices and information to form virtual objects that represent the features and capabilities of devices in the virtual world. Detailed information and functionalities of multiple virtual objects are combined with service rules to form composite virtual objects that offer context-aware knowledge-based services, where context awareness plays an important role in enabling automatic modification of the system to reconfigure the services based on the context. Converting the raw data into meaningful information and connecting the information to form the knowledge and storing and reusing the objects in the knowledge base can both be expressed by semantic ontology. In this paper, a knowledge creation model that synchronizes a service logistic model and a virtual world knowledge model on a Web of Object platform has been proposed. To realize the context-aware knowledge-based service creation and execution, a conceptual semantic ontology model has been developed and a prototype has been implemented for a use case scenario of emergency service.

Research on inosculation between master of ceremonies or players and virtual scene in virtual studio

NASA Astrophysics Data System (ADS)

Li, Zili; Zhu, Guangxi; Zhu, Yaoting

2003-04-01

A technical principle about construction of virtual studio has been proposed where orientation tracker and telemeter has been used for improving conventional BETACAM pickup camera and connecting with the software module of the host. A model of virtual camera named Camera & Post-camera Coupling Pair has been put forward, which is different from the common model in computer graphics and has been bound to real BETACAM pickup camera for shooting. The formula has been educed to compute the foreground frame buffer image and the background frame buffer image of the virtual scene whose boundary is based on the depth information of target point of the real BETACAM pickup camera's projective ray. The effect of real-time consistency has been achieved between the video image sequences of the master of ceremonies or players and the CG video image sequences for the virtual scene in spatial position, perspective relationship and image object masking. The experimental result has shown that the technological scheme of construction of virtual studio submitted in this paper is feasible and more applicative and more effective than the existing technology to establish a virtual studio based on color-key and image synthesis with background using non-linear video editing technique.

Virtual water flows and trade liberalization.

PubMed

Ramirez-Vallejo, J; Rogers, P

2004-01-01

The linkages between agricultural trade and water resources need to be identified and analyzed to better understand the potential impacts that a full liberalization, or lack thereof, will have on water resources. This paper examines trade of virtual water embodied in agricultural products for most countries of the world. The main purpose of the paper, however, is to examine the impact of trade liberalization on virtual-water trade in the future. Based on a simulation of global agricultural trade, a scenario of full liberalization of agriculture was used to assess the net effect of virtual water flows from the relocation of meat and cereals' trade. The paper also identifies the main reasons behind the changes in the magnitude and direction of the net virtual water trade over time, and shows that virtual water trade flows are independent of water resource endowments, contrary to what the Heckscher-Ohlin Theorem states. Finally, based on a formal model, some input demand functions at the country level are estimated. The estimates of the income and agricultural support elasticities of demand for import of virtual water have the expected sign, and are statistically significant. Variables found to have some explanatory power of the variance of virtual water imports are average income; population; agriculture as value added; irrigated area, and exports of goods and services.

The Virtual Care Climate Questionnaire: Development and Validation of a Questionnaire Measuring Perceived Support for Autonomy in a Virtual Care Setting.

PubMed

Smit, Eline Suzanne; Dima, Alexandra Lelia; Immerzeel, Stephanie Annette Maria; van den Putte, Bas; Williams, Geoffrey Colin

2017-05-08

Web-based health behavior change interventions may be more effective if they offer autonomy-supportive communication facilitating the internalization of motivation for health behavior change. Yet, at this moment no validated tools exist to assess user-perceived autonomy-support of such interventions. The aim of this study was to develop and validate the virtual climate care questionnaire (VCCQ), a measure of perceived autonomy-support in a virtual care setting. Items were developed based on existing questionnaires and expert consultation and were pretested among experts and target populations. The virtual climate care questionnaire was administered in relation to Web-based interventions aimed at reducing consumption of alcohol (Study 1; N=230) or cannabis (Study 2; N=228). Item properties, structural validity, and reliability were examined with item-response and classical test theory methods, and convergent and divergent validity via correlations with relevant concepts. In Study 1, 20 of 23 items formed a one-dimensional scale (alpha=.97; omega=.97; H=.66; mean 4.9 [SD 1.0]; range 1-7) that met the assumptions of monotonicity and invariant item ordering. In Study 2, 16 items fitted these criteria (alpha=.92; H=.45; omega=.93; mean 4.2 [SD 1.1]; range 1-7). Only 15 items remained in the questionnaire in both studies, thus we proceeded to the analyses of the questionnaire's reliability and construct validity with a 15-item version of the virtual climate care questionnaire. Convergent validity of the resulting 15-item virtual climate care questionnaire was confirmed by positive associations with autonomous motivation (Study 1: r=.66, P<.001; Study 2: r=.37, P<.001) and perceived competence for reducing alcohol intake (Study 1: r=.52, P<.001). Divergent validity could only be confirmed by the nonsignificant association with perceived competence for learning (Study 2: r=.05, P=.48). The virtual climate care questionnaire accurately assessed participants' perceived autonomy-support offered by two Web-based health behavior change interventions. Overall, the scale showed the expected properties and relationships with relevant concepts, and the studies presented suggest this first version of the virtual climate care questionnaire to be reasonably valid and reliable. As a result, the current version may cautiously be used in future research and practice to measure perceived support for autonomy within a virtual care climate. Future research efforts are required that focus on further investigating the virtual climate care questionnaire's divergent validity, on determining the virtual climate care questionnaire's validity and reliability when used in the context of Web-based interventions aimed at improving nonaddictive or other health behaviors, and on developing and validating a short form virtual climate care questionnaire. ©Eline Suzanne Smit, Alexandra Lelia Dima, Stephanie Annette Maria Immerzeel, Bas van den Putte, Geoffrey Colin Williams. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 08.05.2017.

Computational assessment of model-based wave separation using a database of virtual subjects.

PubMed

Hametner, Bernhard; Schneider, Magdalena; Parragh, Stephanie; Wassertheurer, Siegfried

2017-11-07

The quantification of arterial wave reflection is an important area of interest in arterial pulse wave analysis. It can be achieved by wave separation analysis (WSA) if both the aortic pressure waveform and the aortic flow waveform are known. For better applicability, several mathematical models have been established to estimate aortic flow solely based on pressure waveforms. The aim of this study is to investigate and verify the model-based wave separation of the ARCSolver method on virtual pulse wave measurements. The study is based on an open access virtual database generated via simulations. Seven cardiac and arterial parameters were varied within physiological healthy ranges, leading to a total of 3325 virtual healthy subjects. For assessing the model-based ARCSolver method computationally, this method was used to perform WSA based on the aortic root pressure waveforms of the virtual patients. Asa reference, the values of WSA using both the pressure and flow waveforms provided by the virtual database were taken. The investigated parameters showed a good overall agreement between the model-based method and the reference. Mean differences and standard deviations were -0.05±0.02AU for characteristic impedance, -3.93±1.79mmHg for forward pressure amplitude, 1.37±1.56mmHg for backward pressure amplitude and 12.42±4.88% for reflection magnitude. The results indicate that the mathematical blood flow model of the ARCSolver method is a feasible surrogate for a measured flow waveform and provides a reasonable way to assess arterial wave reflection non-invasively in healthy subjects. Copyright © 2017 Elsevier Ltd. All rights reserved.

Virtually optimized insoles for offloading the diabetic foot: A randomized crossover study.

PubMed

Telfer, S; Woodburn, J; Collier, A; Cavanagh, P R

2017-07-26

Integration of objective biomechanical measures of foot function into the design process for insoles has been shown to provide enhanced plantar tissue protection for individuals at-risk of plantar ulceration. The use of virtual simulations utilizing numerical modeling techniques offers a potential approach to further optimize these devices. In a patient population at-risk of foot ulceration, we aimed to compare the pressure offloading performance of insoles that were optimized via numerical simulation techniques against shape-based devices. Twenty participants with diabetes and at-risk feet were enrolled in this study. Three pairs of personalized insoles: one based on shape data and subsequently manufactured via direct milling; and two were based on a design derived from shape, pressure, and ultrasound data which underwent a finite element analysis-based virtual optimization procedure. For the latter set of insole designs, one pair was manufactured via direct milling, and a second pair was manufactured through 3D printing. The offloading performance of the insoles was analyzed for forefoot regions identified as having elevated plantar pressures. In 88% of the regions of interest, the use of virtually optimized insoles resulted in lower peak plantar pressures compared to the shape-based devices. Overall, the virtually optimized insoles significantly reduced peak pressures by a mean of 41.3kPa (p<0.001, 95% CI [31.1, 51.5]) for milled and 40.5kPa (p<0.001, 95% CI [26.4, 54.5]) for printed devices compared to shape-based insoles. The integration of virtual optimization into the insole design process resulted in improved offloading performance compared to standard, shape-based devices. ISRCTN19805071, www.ISRCTN.org. Copyright © 2017 Elsevier Ltd. All rights reserved.

Digital Immersive Virtual Environments and Instructional Computing

ERIC Educational Resources Information Center

Blascovich, Jim; Beall, Andrew C.

2010-01-01

This article reviews theory and research relevant to the development of digital immersive virtual environment-based instructional computing systems. The review is organized within the context of a multidimensional model of social influence and interaction within virtual environments that models the interaction of four theoretical factors: theory…

ICCE/ICCAI 2000 Full & Short Papers (Virtual Lab/Classroom/School).

ERIC Educational Resources Information Center

2000

This document contains the following full and short papers on virtual laboratories, classrooms, and schools from ICCE/ICCAI 2000 (International Conference on Computers in Education/International Conference on Computer-Assisted Instruction): (1) "A Collaborative Learning Support System Based on Virtual Environment Server for Multiple…

Virtual Learning Environments.

ERIC Educational Resources Information Center

Follows, Scott B.

1999-01-01

Illustrates the possibilities and educational benefits of virtual learning environments (VLEs), based on experiences with "Thirst for Knowledge," a VLE that simulates the workplace of a major company. While working in this virtual office world, students walk through the building, attend meetings, read reports, receive e-mail, answer the telephone,…

Subversion of cytokine networks by virally encoded decoy receptors

PubMed Central

Epperson, Megan L.; Lee, Chung A.; Fremont, Daved H.

2012-01-01

Summary During the course of evolution, viruses have captured or created a diverse array of open reading frames that encode for proteins that serve to evade and sabotage the host innate and adaptive immune responses, which would otherwise lead to their elimination. These viral genomes are some of the best textbooks of immunology ever written. The established arsenal of immunomodulatory proteins encoded by viruses is large and growing and includes specificities for virtually all known inflammatory pathways and targets. The focus of this review is on herpes and poxvirus-encoded cytokine and chemokine binding proteins that serve to undermine the coordination of host immune surveillance. Structural and mechanistic studies of these decoy receptors have provided a wealth of information, not only about viral pathogenesis but also about the inner workings of cytokine signaling networks. PMID:23046131

Population-based respiratory 4D motion atlas construction and its application for VR simulations of liver punctures

NASA Astrophysics Data System (ADS)

Mastmeyer, Andre; Wilms, Matthias; Handels, Heinz

2018-03-01

Virtual reality (VR) training simulators of liver needle insertion in the hepatic area of breathing virtual patients often need 4D image data acquisitions as a prerequisite. Here, first a population-based breathing virtual patient 4D atlas is built and second the requirement of a dose-relevant or expensive acquisition of a 4D CT or MRI data set for a new patient can be mitigated by warping the mean atlas motion. The breakthrough contribution of this work is the construction and reuse of population-based, learned 4D motion models.

Mechanism of Kinect-based virtual reality training for motor functional recovery of upper limbs after subacute stroke.

PubMed

Bao, Xiao; Mao, Yurong; Lin, Qiang; Qiu, Yunhai; Chen, Shaozhen; Li, Le; Cates, Ryan S; Zhou, Shufeng; Huang, Dongfeng

2013-11-05

The Kinect-based virtual reality system for the Xbox 360 enables users to control and interact with the game console without the need to touch a game controller, and provides rehabilitation training for stroke patients with lower limb dysfunctions. However, the underlying mechanism remains unclear. In this study, 18 healthy subjects and five patients after subacute stroke were included. The five patients were scanned using functional MRI prior to training, 3 weeks after training and at a 12-week follow-up, and then compared with healthy subjects. The Fugl-Meyer Assessment and Wolf Motor Function Test scores of the hemiplegic upper limbs of stroke patients were significantly increased 3 weeks after training and at the 12-week follow-up. Functional MRI results showed that contralateral primary sensorimotor cortex was activated after Kinect-based virtual reality training in the stroke patients compared with the healthy subjects. Contralateral primary sensorimotor cortex, the bilateral supplementary motor area and the ipsilateral cerebellum were also activated during hand-clenching in all 18 healthy subjects. Our findings indicate that Kinect-based virtual reality training could promote the recovery of upper limb motor function in subacute stroke patients, and brain reorganization by Kinect-based virtual reality training may be linked to the contralateral sensorimotor cortex.

Mechanism of Kinect-based virtual reality training for motor functional recovery of upper limbs after subacute stroke

PubMed Central

Bao, Xiao; Mao, Yurong; Lin, Qiang; Qiu, Yunhai; Chen, Shaozhen; Li, Le; Cates, Ryan S.; Zhou, Shufeng; Huang, Dongfeng

2013-01-01

The Kinect-based virtual reality system for the Xbox 360 enables users to control and interact with the game console without the need to touch a game controller, and provides rehabilitation training for stroke patients with lower limb dysfunctions. However, the underlying mechanism remains unclear. In this study, 18 healthy subjects and five patients after subacute stroke were included. The five patients were scanned using functional MRI prior to training, 3 weeks after training and at a 12-week follow-up, and then compared with healthy subjects. The Fugl-Meyer Assessment and Wolf Motor Function Test scores of the hemiplegic upper limbs of stroke patients were significantly increased 3 weeks after training and at the 12-week follow-up. Functional MRI results showed that contralateral primary sensorimotor cortex was activated after Kinect-based virtual reality training in the stroke patients compared with the healthy subjects. Contralateral primary sensorimotor cortex, the bilateral supplementary motor area and the ipsilateral cerebellum were also activated during hand-clenching in all 18 healthy subjects. Our findings indicate that Kinect-based virtual reality training could promote the recovery of upper limb motor function in subacute stroke patients, and brain reorganization by Kinect-based virtual reality training may be linked to the contralateral sensorimotor cortex. PMID:25206611

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

PubMed Central

Chen, Can; Wang, Ting; Wu, Fengbo; Huang, Wei; He, Gu; Ouyang, Liang; Xiang, Mingli; Peng, Cheng; Jiang, Qinglin

2014-01-01

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 information for further research on novel PKM2 activators as antitumor agents. PMID:25214764

Virtual reality exposure therapy in anxiety disorders: a quantitative meta-analysis.

PubMed

Opriş, David; Pintea, Sebastian; García-Palacios, Azucena; Botella, Cristina; Szamosközi, Ştefan; David, Daniel

2012-02-01

Virtual reality exposure therapy (VRET) is a promising intervention for the treatment of the anxiety disorders. The main objective of this meta-analysis is to compare the efficacy of VRET, used in a behavioral or cognitive-behavioral framework, with that of the classical evidence-based treatments, in anxiety disorders. A comprehensive search of the literature identified 23 studies (n = 608) that were included in the final analysis. The results show that in the case of anxiety disorders, (1) VRET does far better than the waitlist control; (2) the post-treatment results show similar efficacy between the behavioral and the cognitive behavioral interventions incorporating a virtual reality exposure component and the classical evidence-based interventions, with no virtual reality exposure component; (3) VRET has a powerful real-life impact, similar to that of the classical evidence-based treatments; (4) VRET has a good stability of results over time, similar to that of the classical evidence-based treatments; (5) there is a dose-response relationship for VRET; and (6) there is no difference in the dropout rate between the virtual reality exposure and the in vivo exposure. Implications are discussed. © 2011 Wiley Periodicals, Inc.

Virtual manufacturing in reality

NASA Astrophysics Data System (ADS)

Papstel, Jyri; Saks, Alo

2000-10-01

SMEs play an important role in manufacturing industry. But from time to time there is a shortage in resources to complete the particular order in time. Number of systems is introduced to produce digital information in order to support product and process development activities. Main problem is lack of opportunity for direct data transition within design system modules when needed temporary extension of design capacity (virtuality) or to implement integrated concurrent product development principles. The planning experience in the field is weakly used as well. The concept of virtual manufacturing is a supporting idea to solve this problem. At the same time a number of practical problems should be solved like information conformity, data transfer, unified technological concepts acceptation etc. In the present paper the proposed ways to solve the practical problems of virtual manufacturing are described. General objective is to introduce the knowledge-based CAPP system as missing module for Virtual Manufacturing in the selected product domain. Surface-centered planning concept based on STEP- based modeling principles, and knowledge-based process planning methodology will be used to gain the objectives. As a result the planning module supplied by design data with direct access, and supporting advising environment is expected. Mould producing SME would be as test basis.

[Study on lipid-lowering traditional Chinese medicines based on pharmacophore technology and patent retrieval].

PubMed

Huo, Xiao-qian; He, Yu-su; Qiao, Lian-sheng; Sun, Zhi-yi; Zhang, Yan-ling

2014-12-01

The combined application of statins that inhibit HMG-CoA reductase and fibrates that activate PPAR-α can produce a better lipid-lowering effect than the simple application, but with stronger adverse reactions at the same time. In the treatment of hyperlipidemia, the combined administration of TCMs and HMG-CoA reductase inhibitor in treating hyperlipidemia shows stable efficacy and less adverse reactions, and provides a new option for the combined application of drugs. In this article, the pharmacophore technology was used to search chemical components of TCMs, trace their source herbs, and determine the potential common TCMs that could activate PPAR-α. Because there is no hyperlipidemia-related medication reference in modern TCM classics, to ensure the high safety and efficacy of all selected TCMs, we selected TCMs that are proved to be combined with statins in the World Traditional/Natural Medicine Patent Database, analyzed corresponding drugs in pharmacophore results based on that, and finally obtained common TCMs that can be applied in PPAR-α and combined with statins. Specifically, the pharmacophore model was based on eight receptor-ligand complexes of PPAR-α. The Receptor-Ligand Pharmacophore Generation module in the DS program was used to build the model, optimize with the Screen Library module, and get the best sub-pharmacophore, which consisted of two hydrogen bond acceptor, three hydrophobic groups and 19 excluded volumes, with the identification effectiveness index value N of 2. 82 and the comprehensive evaluation index CAI value of 1. 84. The model was used to screen the TCMD database, hit 5,235 kinds of chemical components and 1 193 natural animals and plants, and finally determine 62 TCMs. Through patent retrieval, we found 38 TCMs; After comparing with the virtual screening results, we finally got seven TCMs.

Performance of HADDOCK and a simple contact-based protein-ligand binding affinity predictor in the D3R Grand Challenge 2

NASA Astrophysics Data System (ADS)

Kurkcuoglu, Zeynep; Koukos, Panagiotis I.; Citro, Nevia; Trellet, Mikael E.; Rodrigues, J. P. G. L. M.; Moreira, Irina S.; Roel-Touris, Jorge; Melquiond, Adrien S. J.; Geng, Cunliang; Schaarschmidt, Jörg; Xue, Li C.; Vangone, Anna; Bonvin, A. M. J. J.

2018-01-01

We present the performance of HADDOCK, our information-driven docking software, in the second edition of the D3R Grand Challenge. In this blind experiment, participants were requested to predict the structures and binding affinities of complexes between the Farnesoid X nuclear receptor and 102 different ligands. The models obtained in Stage1 with HADDOCK and ligand-specific protocol show an average ligand RMSD of 5.1 Å from the crystal structure. Only 6/35 targets were within 2.5 Å RMSD from the reference, which prompted us to investigate the limiting factors and revise our protocol for Stage2. The choice of the receptor conformation appeared to have the strongest influence on the results. Our Stage2 models were of higher quality (13 out of 35 were within 2.5 Å), with an average RMSD of 4.1 Å. The docking protocol was applied to all 102 ligands to generate poses for binding affinity prediction. We developed a modified version of our contact-based binding affinity predictor PRODIGY, using the number of interatomic contacts classified by their type and the intermolecular electrostatic energy. This simple structure-based binding affinity predictor shows a Kendall's Tau correlation of 0.37 in ranking the ligands (7th best out of 77 methods, 5th/25 groups). Those results were obtained from the average prediction over the top10 poses, irrespective of their similarity/correctness, underscoring the robustness of our simple predictor. This results in an enrichment factor of 2.5 compared to a random predictor for ranking ligands within the top 25%, making it a promising approach to identify lead compounds in virtual screening.

Multiple receptor-ligand based pharmacophore modeling and molecular docking to screen the selective inhibitors of matrix metalloproteinase-9 from natural products.

PubMed

Gao, Qi; Wang, Yijun; Hou, Jiaying; Yao, Qizheng; Zhang, Ji

2017-07-01

Matrix metalloproteinase-9 (MMP-9) is an attractive target for cancer therapy. In this study, the pharmacophore model of MMP-9 inhibitors is built based on the experimental binding structures of multiple receptor-ligand complexes. It is found that the pharmacophore model consists of six chemical features, including two hydrogen bond acceptors, one hydrogen bond donor, one ring aromatic regions, and two hydrophobic (HY) features. Among them, the two HY features are especially important because they can enter the S1' pocket of MMP-9 which determines the selectivity of MMP-9 inhibitors. The reliability of pharmacophore model is validated based on the two different decoy sets and relevant experimental data. The virtual screening, combining pharmacophore model with molecular docking, is performed to identify the selective MMP-9 inhibitors from a database of natural products. The four novel MMP-9 inhibitors of natural products, NP-000686, NP-001752, NP-014331, and NP-015905, are found; one of them, NP-000686, is used to perform the experiment of in vitro bioassay inhibiting MMP-9, and the IC 50 value was estimated to be only 13.4 µM, showing the strongly inhibitory activity of NP-000686 against MMP-9, which suggests that our screening results should be reliable. The binding modes of screened inhibitors with MMP-9 active sites were discussed. In addition, the ADMET properties and physicochemical properties of screened four compounds were assessed. The found MMP-9 inhibitors of natural products could serve as the lead compounds for designing the new MMP-9 inhibitors by carrying out structural modifications in the future.

Open Source Virtual Worlds and Low Cost Sensors for Physical Rehab of Patients with Chronic Diseases

NASA Astrophysics Data System (ADS)

Romero, Salvador J.; Fernandez-Luque, Luis; Sevillano, José L.; Vognild, Lars

For patients with chronic diseases, exercise is a key part of rehab to deal better with their illness. Some of them do rehabilitation at home with telemedicine systems. However, keeping to their exercising program is challenging and many abandon the rehabilitation. We postulate that information technologies for socializing and serious games can encourage patients to keep doing physical exercise and rehab. In this paper we present Virtual Valley, a low cost telemedicine system for home exercising, based on open source virtual worlds and utilizing popular low cost motion controllers (e.g. Wii Remote) and medical sensors. Virtual Valley allows patient to socialize, learn, and play group based serious games while exercising.

Virtual Estimator for Piecewise Linear Systems Based on Observability Analysis

PubMed Central

Morales-Morales, Cornelio; Adam-Medina, Manuel; Cervantes, Ilse; Vela-Valdés and, Luis G.; García Beltrán, Carlos Daniel

2013-01-01

This article proposes a virtual sensor for piecewise linear systems based on observability analysis that is in function of a commutation law related with the system's outpu. This virtual sensor is also known as a state estimator. Besides, it presents a detector of active mode when the commutation sequences of each linear subsystem are arbitrary and unknown. For the previous, this article proposes a set of virtual estimators that discern the commutation paths of the system and allow estimating their output. In this work a methodology in order to test the observability for piecewise linear systems with discrete time is proposed. An academic example is presented to show the obtained results. PMID:23447007

Development of virtual environment for treating acrophobia.

PubMed

Ku, J; Jang, D; Shin, M; Jo, H; Ahn, H; Lee, J; Cho, B; Kim, S I

2001-01-01

Virtual Reality (VR) is a new technology that makes humans communicate with computer. It allows the user to see, hear, feel and interact in a three-dimensional virtual world created graphically. Virtual Reality Therapy (VRT), based on this sophisticated technology, has been recently used in the treatment of subjects diagnosed with acrophobia, a disorder that is characterized by marked anxiety upon exposure to heights, avoidance of heights, and a resulting interference in functioning. Conventional virtual reality system for the treatment of acrophobia has a limitation in scope that it is based on over-costly devices or somewhat unrealistic graphic scene. The goal of this study was to develop a inexpensive and more realistic virtual environment for the exposure therapy of acrophobia. We constructed two types virtual environment. One is constituted a bungee-jump tower in the middle of a city. It includes the open lift surrounded by props beside tower that allowed the patient to feel sense of heights. Another is composed of diving boards which have various heights. It provides a view of a lower diving board and people swimming in the pool to serve the patient stimuli upon exposure to heights.

Virtual experiments in electronics: beyond logistics, budgets, and the art of the possible

NASA Astrophysics Data System (ADS)

Chapman, Brian

1999-09-01

It is common and correct to suppose that computers support flexible delivery of educational resources by offering virtual experiments that replicate and substitute for experiments traditionally offered in conventional teaching laboratories. However, traditional methods are limited by logistics, costs, and what is physically possible to accomplish on a laboratory bench. Virtual experiments allow experimental approaches to teaching and learning to transcend these limits. This paper analyses recent and current developments in educational software for 1st- year physics, 2nd-year electronics engineering and 3rd-year communication engineering, based on three criteria: (1)Is the virtual experiment possible in a real laboratory? (2)How direct is the link between the experimental manipulation and the reinforcement of theoretical learning? (3) What impact might the virtual experiment have on the learner's acquisition of practical measurement skills? Virtual experiments allow more flexibility in the directness of the link between experimental manipulation and the theoretical message. However, increasing the directness of this link may reduce or even abolish the measurement processes associated with traditional experiments. Virtual experiments thus pose educational challenges: (a) expanding the design of experimentally based curricula beyond traditional boundaries and (b) ensuring that the learner acquires sufficient experience in making practical measurements.

A sensor network based virtual beam-like structure method for fault diagnosis and monitoring of complex structures with Improved Bacterial Optimization

NASA Astrophysics Data System (ADS)

Wang, H.; Jing, X. J.

2017-02-01

This paper proposes a novel method for the fault diagnosis of complex structures based on an optimized virtual beam-like structure approach. A complex structure can be regarded as a combination of numerous virtual beam-like structures considering the vibration transmission path from vibration sources to each sensor. The structural 'virtual beam' consists of a sensor chain automatically obtained by an Improved Bacterial Optimization Algorithm (IBOA). The biologically inspired optimization method (i.e. IBOA) is proposed for solving the discrete optimization problem associated with the selection of the optimal virtual beam for fault diagnosis. This novel virtual beam-like-structure approach needs less or little prior knowledge. Neither does it require stationary response data, nor is it confined to a specific structure design. It is easy to implement within a sensor network attached to the monitored structure. The proposed fault diagnosis method has been tested on the detection of loosening screws located at varying positions in a real satellite-like model. Compared with empirical methods, the proposed virtual beam-like structure method has proved to be very effective and more reliable for fault localization.

Using Immersive Virtual Reality for Electrical Substation Training

ERIC Educational Resources Information Center

Tanaka, Eduardo H.; Paludo, Juliana A.; Cordeiro, Carlúcio S.; Domingues, Leonardo R.; Gadbem, Edgar V.; Euflausino, Adriana

2015-01-01

Usually, distribution electricians are called upon to solve technical problems found in electrical substations. In this project, we apply problem-based learning to a training program for electricians, with the help of a virtual reality environment that simulates a real substation. Using this virtual substation, users may safely practice maneuvers…

Transforming Professional Healthcare Narratives into Structured Game-Informed-Learning Activities

ERIC Educational Resources Information Center

Begg, Michael; Ellaway, Rachel; Dewhurst, David; Macleod, Hamish

2007-01-01

Noting the dependency of healthcare education on practice-based learning, Michael Begg, Rachel Ellaway, David Dewhurst, and Hamish Macleod suggest that creating a virtual clinical setting for students to interact with virtual patients can begin to address educational demands for clinical experience. They argue that virtual patient simulations that…

Learning to Drive a Wheelchair in Virtual Reality

ERIC Educational Resources Information Center

Inman, Dean P.; Loge, Ken; Cram, Aaron; Peterson, Missy

2011-01-01

This research project studied the effect that a technology-based training program, WheelchairNet, could contribute to the education of children with physical disabilities by providing a chance to practice driving virtual motorized wheelchairs safely within a computer-generated world. Programmers created three virtual worlds for training. Scenarios…

Scenario-Based Spoken Interaction with Virtual Agents

ERIC Educational Resources Information Center

Morton, Hazel; Jack, Mervyn A.

2005-01-01

This paper describes a CALL approach which integrates software for speaker independent continuous speech recognition with embodied virtual agents and virtual worlds to create an immersive environment in which learners can converse in the target language in contextualised scenarios. The result is a self-access learning package: SPELL (Spoken…

E-Learning and Virtual Science Centers

ERIC Educational Resources Information Center

Hin, Leo Tan Wee, Ed.; Subramaniam, R., Ed.

2005-01-01

"E-Learning and Virtual Science Centers" addresses an aspect of Web-based education that has not attracted sufficient attention in the international research literature--that of virtual science centers, the cyberspace annex of traditional science centers. It is the first book to be published on the rapidly advancing field of science education.…

The World's the Limit in the Virtual High School.

ERIC Educational Resources Information Center

Berman, Sheldon; Tinker, Robert

1997-01-01

Assisted by a U.S. Department of Education Technology Innovation Challenge Grant, the Hudson (Massachusetts) Public Schools, the Concord Consortium Educational Technology Lab, and 30 collaborating high schools across the nation have developed a virtual high school over the Internet. Through Internet-based courses, Virtual High School significantly…

Adolescent Attitudes towards Virtual Learning

ERIC Educational Resources Information Center

Pleau, Andrea R.

2012-01-01

This study was designed to examine adolescents' attitudes towards virtual schooling. Virtual schooling may be defined as any public or private organization that delivers instruction via the Internet. The rationale for this study is based on the increased number of adolescents opting to complete some or all of their secondary education through…

When Rural Reality Goes Virtual.

ERIC Educational Resources Information Center

Husain, Dilshad D.

1998-01-01

In rural towns where sparse population and few business are barriers, virtual reality may be the only way to bring work-based learning to students. A partnership between a small-town high school, the Ohio Supercomputer Center, and a high-tech business will enable students to explore the workplace using virtual reality. (JOW)

The Virtual Classroom: A Catalyst for Institutional Transformation

ERIC Educational Resources Information Center

Subramaniam, Nantha Kumar; Kandasamy, Maheswari

2011-01-01

This study explores the use of the virtual classroom which has been created in "myVLE", a learning management system used by the Open University Malaysia (OUM). The virtual classroom in "myVLE" is an asynchronous-based online learning environment that delivers course materials to learners and provides collaboration and…

Virtual Patient Simulations for Medical Education: Increasing Clinical Reasoning Skills through Deliberate Practice

ERIC Educational Resources Information Center

McCoy, Lise

2014-01-01

Virtual Patient Simulations (VPS) are web-based exercises involving simulated patients in virtual environments. This study investigates the utility of VPS for increasing medical student clinical reasoning skills, collaboration, and engagement. Many studies indicate that VPS provide medical students with essential practice in clinical decision…

Virtual Peace Education

ERIC Educational Resources Information Center

Firer, Ruth

2008-01-01

This article is based on the convictions that peace education is the basis for any sustainable non-violent relations between parties in a conflict, and that virtual peace education is almost the only feasible way to practise peace education in an open violent conflict as is the current Israeli/Palestinians one. Moreover, virtual peace education…

Social Impact in Personalised Virtual Professional Development Pathways

ERIC Educational Resources Information Center

Owen, Hazel; Whalley, Rick; Dunmill, Merryn; Eccles, Heather

2018-01-01

This article presents exploratory research into an education-based virtual mentoring provision, the Virtual Professional Learning and Development (VPLD) program, and uses the Elements of Value Pyramid to help frame findings in a way that highlights the participants' (mentors' and mentees') perceived value of working together. Participants were…

Global Team Development. Symposium 7. [AHRD Conference, 2001].

ERIC Educational Resources Information Center

2001

This document contains three papers on global team development. "Virtual Executives: A Paradox with Implications for Development" (Andrea Hornett), which is based on a case study exploring power relationships among members of a virtual team, demonstrates that members of a virtual team describe power differently for situations inside…

Theoretical Bases for Using Virtual Reality in Education

ERIC Educational Resources Information Center

Chen, Chwen Jen

2009-01-01

This article elaborates on how the technical capabilities of virtual reality support the constructivist learning principles. It introduces VRID, a model for instructional design and development that offers explicit guidance on how to produce an educational virtual environment. The define phase of VRID consists of three main tasks: forming a…

Exploring barriers and facilitators to the clinical use of virtual reality for post-stroke unilateral spatial neglect assessment.

PubMed

Ogourtsova, Tatiana; Archambault, Philippe S; Lamontagne, Anouk

2017-11-07

Hemineglect, defined as a failure to attend to the contralesional side of space, is a prevalent and disabling post-stroke deficit. Conventional hemineglect assessments lack sensitivity as they contain mainly non-functional tasks performed in near-extrapersonal space, using static, two-dimensional methods. This is of concern given that hemineglect is a strong predictor for functional deterioration, limited post-stroke recovery, and difficulty in community reintegration. With the emerging field of virtual reality, several virtual tools have been proposed and have reported better sensitivity in neglect-related deficits detection than conventional methods. However, these and future virtual reality-based tools are yet to be implemented in clinical practice. The present study aimed to explore the barriers/facilitators perceived by clinicians in the use of virtual reality for hemineglect assessment; and to identify features of an optimal virtual assessment. A qualitative descriptive process, in the form of focus groups, self-administered questionnaire and individual interviews was used. Two focus groups (n = 11 clinicians) were conducted and experts in the field (n = 3) were individually interviewed. Several barriers and facilitators, including personal, institutional, client suitability, and equipment factors, were identified. Clinicians and experts in the field reported numerous features for the virtual tool optimization. Factors identified through this study lay the foundation for the development of a knowledge translation initiative towards an implementation of a virtual assessment for hemineglect. Addressing the identified barriers/facilitators during implementation and incorporating the optimal features in the design of the virtual assessment could assist and promote its eventual adoption in clinical settings. Implications for rehabilitation A multimodal and active knowledge translation intervention built on the presently identified modifiable factors is suggested to be implemented to support the clinical integration of a virtual reality-based assessment for post-stroke hemineglect. To amplify application and usefulness of a virtual-reality based tool in the assessment of post-stroke hemineglect, optimal features identified in the present study should be incorporated in the design of such technology.

Educational MOO: Text-Based Virtual Reality for Learning in Community. ERIC Digest.

ERIC Educational Resources Information Center

Turbee, Lonnie

MOO stands for "Multi-user domain, Object-Oriented." Early multi-user domains, or "MUDs," began as net-based dungeons-and-dragons type games, but MOOs have evolved from these origins to become some of cyberspace's most fascinating and engaging online communities. MOOs are social environments in a text-based virtual reality…

Creative Writing, Problem-Based Learning, and Game-Based Learning Principles

ERIC Educational Resources Information Center

Trekles, Anastasia M.

2012-01-01

This paper examines how virtual worlds and other advanced social media can be married with problem-based learning to encourage creativity and critical thinking in the English/Language Arts classroom, particularly for middle school, high school, and undergraduate college education. Virtual world experiences such as "Second Life," Jumpstart.com, and…

The Impact of "Virtualization" on Independent Study Course Completion Rates: The British Columbia Open University Experiment

ERIC Educational Resources Information Center

Giguere, Louis

2009-01-01

In 1997 the British Columbia Open University (BCOU) adopted a virtualization strategy based primarily on twinning off-line independent study distance education courses (textbook-based with study guide and telephone and e-mail tutor support) with alternate online versions (textbook-based with integrated conferencing and communications provided…

A Feasibility Study of Virtual Reality-Based Coping Skills Training for Nicotine Dependence

ERIC Educational Resources Information Center

Bordnick, Patrick S.; Traylor, Amy C.; Carter, Brian L.; Graap, Ken M.

2012-01-01

Objective: Virtual reality (VR)-based cue reactivity has been successfully used for the assessment of drug craving. Going beyond assessment of cue reactivity, a novel VR-based treatment approach for smoking cessation was developed and tested for feasibility. Method: In a randomized experiment, 10-week treatment feasibility trial, 46…

Novel Computational Approaches to Drug Discovery

NASA Astrophysics Data System (ADS)

Skolnick, Jeffrey; Brylinski, Michal

2010-01-01

New approaches to protein functional inference based on protein structure and evolution are described. First, FINDSITE, a threading based approach to protein function prediction, is summarized. Then, the results of large scale benchmarking of ligand binding site prediction, ligand screening, including applications to HIV protease, and GO molecular functional inference are presented. A key advantage of FINDSITE is its ability to use low resolution, predicted structures as well as high resolution experimental structures. Then, an extension of FINDSITE to ligand screening in GPCRs using predicted GPCR structures, FINDSITE/QDOCKX, is presented. This is a particularly difficult case as there are few experimentally solved GPCR structures. Thus, we first train on a subset of known binding ligands for a set of GPCRs; this is then followed by benchmarking against a large ligand library. For the virtual ligand screening of a number of Dopamine receptors, encouraging results are seen, with significant enrichment in identified ligands over those found in the training set. Thus, FINDSITE and its extensions represent a powerful approach to the successful prediction of a variety of molecular functions.

Microarray platform for omics analysis

NASA Astrophysics Data System (ADS)

Mecklenburg, Michael; Xie, Bin

2001-09-01

Microarray technology has revolutionized genetic analysis. However, limitations in genome analysis has lead to renewed interest in establishing 'omic' strategies. As we enter the post-genomic era, new microarray technologies are needed to address these new classes of 'omic' targets, such as proteins, as well as lipids and carbohydrates. We have developed a microarray platform that combines self- assembling monolayers with the biotin-streptavidin system to provide a robust, versatile immobilization scheme. A hydrophobic film is patterned on the surface creating an array of tension wells that eliminates evaporation effects thereby reducing the shear stress to which biomolecules are exposed to during immobilization. The streptavidin linker layer makes it possible to adapt and/or develop microarray based assays using virtually any class of biomolecules including: carbohydrates, peptides, antibodies, receptors, as well as them ore traditional DNA based arrays. Our microarray technology is designed to furnish seamless compatibility across the various 'omic' platforms by providing a common blueprint for fabricating and analyzing arrays. The prototype microarray uses a microscope slide footprint patterned with 2 by 96 flat wells. Data on the microarray platform will be presented.

Recent evolution of China's virtual water trade: analysis of selected crops and considerations for policy

NASA Astrophysics Data System (ADS)

Shi, J.; Liu, J.; Pinter, L.

2014-04-01

China has dramatically increased its virtual water import over recent years. Many studies have focused on the quantity of traded virtual water, but very few go into analysing geographic distribution and the properties of China's virtual water trade network. This paper provides a calculation and analysis of the crop-related virtual water trade network of China based on 27 major primary crops between 1986 and 2009. The results show that China is a net importer of virtual water from water-abundant areas of North America and South America, and a net virtual water exporter to water-stressed areas of Asia, Africa, and Europe. Virtual water import is far larger than virtual water export, and in both import and export a small number of trade partners control the supply chain. Grain crops are the major contributors to virtual water trade, and among grain crops, soybeans, mostly imported from the US, Brazil and Argentina, are the most significant. In order to mitigate water scarcity and secure the food supply, virtual water should actively be incorporated into national water management strategies. And the sources of virtual water import need to be further diversified to reduce supply chain risks and increase resilience.

Role of fibroblast growth factor receptor signaling in kidney development

PubMed Central

2011-01-01

Fibroblast growth factor receptors (Fgfrs) consist of four signaling family members and one nonsignaling “decoy” receptor, Fgfr-like 1 (Fgfrl1), all of which are expressed in the developing kidney. Several studies have shown that exogenous fibroblast growth factors (Fgfs) affect growth and maturation of the metanephric mesenchyme (MM) and ureteric bud (UB) in cultured tissues. Transgenic and conditional knockout approaches in whole animals have shown that Fgfr1 and Fgfr2 (predominantly the IIIc isoform) in kidney mesenchyme are critical for early MM and UB formation. Conditional deletion of the ligand, Fgf8, in nephron precursors or global deletion of Fgfrl1 interrupts nephron formation. Fgfr2 (likely the IIIb isoform signaling downstream of Fgf7 and Fgf10) is critical for ureteric morphogenesis. Moreover, Fgfr2 appears to act independently of Frs2α (the major signaling adapter for Fgfrs) in regulating UB branching. Loss of Fgfr2 in the MM leads to many kidney and urinary tract anomalies, including vesicoureteral reflux. Thus Fgfr signaling is critical for patterning of virtually all renal lineages at early and later stages of development. PMID:21613421

Role of fibroblast growth factor receptor signaling in kidney development.

PubMed

Bates, Carlton M

2011-08-01

Fibroblast growth factor receptors (Fgfrs) consist of four signaling family members and one nonsignaling "decoy" receptor, Fgfr-like 1 (Fgfrl1), all of which are expressed in the developing kidney. Several studies have shown that exogenous fibroblast growth factors (Fgfs) affect growth and maturation of the metanephric mesenchyme (MM) and ureteric bud (UB) in cultured tissues. Transgenic and conditional knockout approaches in whole animals have shown that Fgfr1 and Fgfr2 (predominantly the IIIc isoform) in kidney mesenchyme are critical for early MM and UB formation. Conditional deletion of the ligand, Fgf8, in nephron precursors or global deletion of Fgfrl1 interrupts nephron formation. Fgfr2 (likely the IIIb isoform signaling downstream of Fgf7 and Fgf10) is critical for ureteric morphogenesis. Moreover, Fgfr2 appears to act independently of Frs2α (the major signaling adapter for Fgfrs) in regulating UB branching. Loss of Fgfr2 in the MM leads to many kidney and urinary tract anomalies, including vesicoureteral reflux. Thus Fgfr signaling is critical for patterning of virtually all renal lineages at early and later stages of development.

Modeling of Human Prokineticin Receptors: Interactions with Novel Small-Molecule Binders and Potential Off-Target Drugs

PubMed Central

Levit, Anat; Yarnitzky, Talia; Wiener, Ayana; Meidan, Rina; Niv, Masha Y.

2011-01-01

Background and Motivation The Prokineticin receptor (PKR) 1 and 2 subtypes are novel members of family A GPCRs, which exhibit an unusually high degree of sequence similarity. Prokineticins (PKs), their cognate ligands, are small secreted proteins of ∼80 amino acids; however, non-peptidic low-molecular weight antagonists have also been identified. PKs and their receptors play important roles under various physiological conditions such as maintaining circadian rhythm and pain perception, as well as regulating angiogenesis and modulating immunity. Identifying binding sites for known antagonists and for additional potential binders will facilitate studying and regulating these novel receptors. Blocking PKRs may serve as a therapeutic tool for various diseases, including acute pain, inflammation and cancer. Methods and Results Ligand-based pharmacophore models were derived from known antagonists, and virtual screening performed on the DrugBank dataset identified potential human PKR (hPKR) ligands with novel scaffolds. Interestingly, these included several HIV protease inhibitors for which endothelial cell dysfunction is a documented side effect. Our results suggest that the side effects might be due to inhibition of the PKR signaling pathway. Docking of known binders to a 3D homology model of hPKR1 is in agreement with the well-established canonical TM-bundle binding site of family A GPCRs. Furthermore, the docking results highlight residues that may form specific contacts with the ligands. These contacts provide structural explanation for the importance of several chemical features that were obtained from the structure-activity analysis of known binders. With the exception of a single loop residue that might be perused in the future for obtaining subtype-specific regulation, the results suggest an identical TM-bundle binding site for hPKR1 and hPKR2. In addition, analysis of the intracellular regions highlights variable regions that may provide subtype specificity. PMID:22132188

A Framework for Web-Based Interprofessional Education for Midwifery and Medical Students.

PubMed

Reis, Pamela J; Faser, Karl; Davis, Marquietta

2015-01-01

Scheduling interprofessional team-based activities for health sciences students who are geographically dispersed, with divergent and often competing schedules, can be challenging. The use of Web-based technologies such as 3-dimensional (3D) virtual learning environments in interprofessional education is a relatively new phenomenon, which offers promise in helping students come together in online teams when face-to-face encounters are not possible. The purpose of this article is to present the experience of a nurse-midwifery education program in a Southeastern US university in delivering Web-based interprofessional education for nurse-midwifery and third-year medical students utilizing the Virtual Community Clinic Learning Environment (VCCLE). The VCCLE is a 3D, Web-based, asynchronous, immersive clinic environment into which students enter to meet and interact with instructor-controlled virtual patient and virtual preceptor avatars and then move through a classic diagnostic sequence in arriving at a plan of care for women throughout the lifespan. By participating in the problem-based management of virtual patients within the VCCLE, students learn both clinical competencies and competencies for interprofessional collaborative practice, as described by the Interprofessional Education Collaborative Core Competencies for Interprofessional Collaborative Practice. This article is part of a special series of articles that address midwifery innovations in clinical practice, education, interprofessional collaboration, health policy, and global health. © 2015 by the American College of Nurse-Midwives.

Computational predictive models for P-glycoprotein inhibition of in-house chalcone derivatives and drug-bank compounds.

PubMed

Ngo, Trieu-Du; Tran, Thanh-Dao; Le, Minh-Tri; Thai, Khac-Minh

2016-11-01

The human P-glycoprotein (P-gp) efflux pump is of great interest for medicinal chemists because of its important role in multidrug resistance (MDR). Because of the high polyspecificity as well as the unavailability of high-resolution X-ray crystal structures of this transmembrane protein, ligand-based, and structure-based approaches which were machine learning, homology modeling, and molecular docking were combined for this study. In ligand-based approach, individual two-dimensional quantitative structure-activity relationship models were developed using different machine learning algorithms and subsequently combined into the Ensemble model which showed good performance on both the diverse training set and the validation sets. The applicability domain and the prediction quality of the developed models were also judged using the state-of-the-art methods and tools. In our structure-based approach, the P-gp structure and its binding region were predicted for a docking study to determine possible interactions between the ligands and the receptor. Based on these in silico tools, hit compounds for reversing MDR were discovered from the in-house and DrugBank databases through virtual screening using prediction models and molecular docking in an attempt to restore cancer cell sensitivity to cytotoxic drugs.

Cheminformatics-aided discovery of small-molecule Protein-Protein Interaction (PPI) dual inhibitors of Tumor Necrosis Factor (TNF) and Receptor Activator of NF-κB Ligand (RANKL).

PubMed

Melagraki, Georgia; Ntougkos, Evangelos; Rinotas, Vagelis; Papaneophytou, Christos; Leonis, Georgios; Mavromoustakos, Thomas; Kontopidis, George; Douni, Eleni; Afantitis, Antreas; Kollias, George

2017-04-01

We present an in silico drug discovery pipeline developed and applied for the identification and virtual screening of small-molecule Protein-Protein Interaction (PPI) compounds that act as dual inhibitors of TNF and RANKL through the trimerization interface. The cheminformatics part of the pipeline was developed by combining structure-based with ligand-based modeling using the largest available set of known TNF inhibitors in the literature (2481 small molecules). To facilitate virtual screening, the consensus predictive model was made freely available at: http://enalos.insilicotox.com/TNFPubChem/. We thus generated a priority list of nine small molecules as candidates for direct TNF function inhibition. In vitro evaluation of these compounds led to the selection of two small molecules that act as potent direct inhibitors of TNF function, with IC50 values comparable to those of a previously-described direct inhibitor (SPD304), but with significantly reduced toxicity. These molecules were also identified as RANKL inhibitors and validated in vitro with respect to this second functionality. Direct binding of the two compounds was confirmed both for TNF and RANKL, as well as their ability to inhibit the biologically-active trimer forms. Molecular dynamics calculations were also carried out for the two small molecules in each protein to offer additional insight into the interactions that govern TNF and RANKL complex formation. To our knowledge, these compounds, namely T8 and T23, constitute the second and third published examples of dual small-molecule direct function inhibitors of TNF and RANKL, and could serve as lead compounds for the development of novel treatments for inflammatory and autoimmune diseases.

Novel interactive virtual showcase based on 3D multitouch technology

NASA Astrophysics Data System (ADS)

Yang, Tao; Liu, Yue; Lu, You; Wang, Yongtian

2009-11-01

A new interactive virtual showcase is proposed in this paper. With the help of virtual reality technology, the user of the proposed system can watch the virtual objects floating in the air from all four sides and interact with the virtual objects by touching the four surfaces of the virtual showcase. Unlike traditional multitouch system, this system cannot only realize multi-touch on a plane to implement 2D translation, 2D scaling, and 2D rotation of the objects; it can also realize the 3D interaction of the virtual objects by recognizing and analyzing the multi-touch that can be simultaneously captured from the four planes. Experimental results show the potential of the proposed system to be applied in the exhibition of historical relics and other precious goods.

A comparison of older adults' subjective experiences with virtual and real environments during dynamic balance activities.

PubMed

Proffitt, Rachel; Lange, Belinda; Chen, Christina; Winstein, Carolee

2015-01-01

The purpose of this study was to explore the subjective experience of older adults interacting with both virtual and real environments. Thirty healthy older adults engaged with real and virtual tasks of similar motor demands: reaching to a target in standing and stepping stance. Immersive tendencies and absorption scales were administered before the session. Game engagement and experience questionnaires were completed after each task, followed by a semistructured interview at the end of the testing session. Data were analyzed respectively using paired t tests and grounded theory methodology. Participants preferred the virtual task over the real task. They also reported an increase in presence and absorption with the virtual task, describing an external focus of attention. Findings will be used to inform future development of appropriate game-based balance training applications that could be embedded in the home or community settings as part of evidence-based fall prevention programs.

Research on virtual Guzheng based on Kinect

NASA Astrophysics Data System (ADS)

Li, Shuyao; Xu, Kuangyi; Zhang, Heng

2018-05-01

There are a lot of researches on virtual instruments, but there are few on classical Chinese instruments, and the techniques used are very limited. This paper uses Unity 3D and Kinect camera combined with virtual reality technology and gesture recognition method to design a virtual playing system of Guzheng, a traditional Chinese musical instrument, with demonstration function. In this paper, the real scene obtained by Kinect camera is fused with virtual Guzheng in Unity 3D. The depth data obtained by Kinect and the Suzuki85 algorithm are used to recognize the relative position of the user's right hand and the virtual Guzheng, and the hand gesture of the user is recognized by Kinect.

Distribution Locational Real-Time Pricing Based Smart Building Control and Management

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hao, Jun; Dai, Xiaoxiao; Zhang, Yingchen

This paper proposes an real-virtual parallel computing scheme for smart building operations aiming at augmenting overall social welfare. The University of Denver's campus power grid and Ritchie fitness center is used for demonstrating the proposed approach. An artificial virtual system is built in parallel to the real physical system to evaluate the overall social cost of the building operation based on the social science based working productivity model, numerical experiment based building energy consumption model and the power system based real-time pricing mechanism. Through interactive feedback exchanged between the real and virtual system, enlarged social welfare, including monetary cost reductionmore » and energy saving, as well as working productivity improvements, can be achieved.« less

Multi-viewpoint Image Array Virtual Viewpoint Rapid Generation Algorithm Based on Image Layering

NASA Astrophysics Data System (ADS)

Jiang, Lu; Piao, Yan

2018-04-01

The use of multi-view image array combined with virtual viewpoint generation technology to record 3D scene information in large scenes has become one of the key technologies for the development of integrated imaging. This paper presents a virtual viewpoint rendering method based on image layering algorithm. Firstly, the depth information of reference viewpoint image is quickly obtained. During this process, SAD is chosen as the similarity measure function. Then layer the reference image and calculate the parallax based on the depth information. Through the relative distance between the virtual viewpoint and the reference viewpoint, the image layers are weighted and panned. Finally the virtual viewpoint image is rendered layer by layer according to the distance between the image layers and the viewer. This method avoids the disadvantages of the algorithm DIBR, such as high-precision requirements of depth map and complex mapping operations. Experiments show that, this algorithm can achieve the synthesis of virtual viewpoints in any position within 2×2 viewpoints range, and the rendering speed is also very impressive. The average result proved that this method can get satisfactory image quality. The average SSIM value of the results relative to real viewpoint images can reaches 0.9525, the PSNR value can reaches 38.353 and the image histogram similarity can reaches 93.77%.