WorldWideScience

Sample records for discovery computational screening

  1. Discovery of technical methanation catalysts based on computational screening

    DEFF Research Database (Denmark)

    Sehested, Jens; Larsen, Kasper Emil; Kustov, Arkadii

    2007-01-01

    Methanation is a classical reaction in heterogeneous catalysis and significant effort has been put into improving the industrially preferred nickel-based catalysts. Recently, a computational screening study showed that nickel-iron alloys should be more active than the pure nickel catalyst and at ...

  2. RAS - Screens & Assays - Drug Discovery

    Science.gov (United States)

    The RAS Drug Discovery group aims to develop assays that will reveal aspects of RAS biology upon which cancer cells depend. Successful assay formats are made available for high-throughput screening programs to yield potentially effective drug compounds.

  3. Computational methods in drug discovery

    Directory of Open Access Journals (Sweden)

    Sumudu P. Leelananda

    2016-12-01

    Full Text Available The process for drug discovery and development is challenging, time consuming and expensive. Computer-aided drug discovery (CADD tools can act as a virtual shortcut, assisting in the expedition of this long process and potentially reducing the cost of research and development. Today CADD has become an effective and indispensable tool in therapeutic development. The human genome project has made available a substantial amount of sequence data that can be used in various drug discovery projects. Additionally, increasing knowledge of biological structures, as well as increasing computer power have made it possible to use computational methods effectively in various phases of the drug discovery and development pipeline. The importance of in silico tools is greater than ever before and has advanced pharmaceutical research. Here we present an overview of computational methods used in different facets of drug discovery and highlight some of the recent successes. In this review, both structure-based and ligand-based drug discovery methods are discussed. Advances in virtual high-throughput screening, protein structure prediction methods, protein–ligand docking, pharmacophore modeling and QSAR techniques are reviewed.

  4. Discovery of earth-abundant nitride semiconductors by computational screening and high-pressure synthesis

    Science.gov (United States)

    Hinuma, Yoyo; Hatakeyama, Taisuke; Kumagai, Yu; Burton, Lee A.; Sato, Hikaru; Muraba, Yoshinori; Iimura, Soshi; Hiramatsu, Hidenori; Tanaka, Isao; Hosono, Hideo; Oba, Fumiyasu

    2016-01-01

    Nitride semiconductors are attractive because they can be environmentally benign, comprised of abundant elements and possess favourable electronic properties. However, those currently commercialized are mostly limited to gallium nitride and its alloys, despite the rich composition space of nitrides. Here we report the screening of ternary zinc nitride semiconductors using first-principles calculations of electronic structure, stability and dopability. This approach identifies as-yet-unreported CaZn2N2 that has earth-abundant components, smaller carrier effective masses than gallium nitride and a tunable direct bandgap suited for light emission and harvesting. High-pressure synthesis realizes this phase, verifying the predicted crystal structure and band-edge red photoluminescence. In total, we propose 21 promising systems, including Ca2ZnN2, Ba2ZnN2 and Zn2PN3, which have not been reported as semiconductors previously. Given the variety in bandgaps of the identified compounds, the present study expands the potential suitability of nitride semiconductors for a broader range of electronic, optoelectronic and photovoltaic applications. PMID:27325228

  5. Computational methods in drug discovery

    OpenAIRE

    Sumudu P. Leelananda; Steffen Lindert

    2016-01-01

    The process for drug discovery and development is challenging, time consuming and expensive. Computer-aided drug discovery (CADD) tools can act as a virtual shortcut, assisting in the expedition of this long process and potentially reducing the cost of research and development. Today CADD has become an effective and indispensable tool in therapeutic development. The human genome project has made available a substantial amount of sequence data that can be used in various drug discovery project...

  6. Pharmacological screening technologies for venom peptide discovery.

    Science.gov (United States)

    Prashanth, Jutty Rajan; Hasaballah, Nojod; Vetter, Irina

    2017-12-01

    Venomous animals occupy one of the most successful evolutionary niches and occur on nearly every continent. They deliver venoms via biting and stinging apparatuses with the aim to rapidly incapacitate prey and deter predators. This has led to the evolution of venom components that act at a number of biological targets - including ion channels, G-protein coupled receptors, transporters and enzymes - with exquisite selectivity and potency, making venom-derived components attractive pharmacological tool compounds and drug leads. In recent years, plate-based pharmacological screening approaches have been introduced to accelerate venom-derived drug discovery. A range of assays are amenable to this purpose, including high-throughput electrophysiology, fluorescence-based functional and binding assays. However, despite these technological advances, the traditional activity-guided fractionation approach is time-consuming and resource-intensive. The combination of screening techniques suitable for miniaturization with sequence-based discovery approaches - supported by advanced proteomics, mass spectrometry, chromatography as well as synthesis and expression techniques - promises to further improve venom peptide discovery. Here, we discuss practical aspects of establishing a pipeline for venom peptide drug discovery with a particular emphasis on pharmacology and pharmacological screening approaches. This article is part of the Special Issue entitled 'Venom-derived Peptides as Pharmacological Tools.' Copyright © 2017 Elsevier Ltd. All rights reserved.

  7. Cloud computing approaches to accelerate drug discovery value chain.

    Science.gov (United States)

    Garg, Vibhav; Arora, Suchir; Gupta, Chitra

    2011-12-01

    Continued advancements in the area of technology have helped high throughput screening (HTS) evolve from a linear to parallel approach by performing system level screening. Advanced experimental methods used for HTS at various steps of drug discovery (i.e. target identification, target validation, lead identification and lead validation) can generate data of the order of terabytes. As a consequence, there is pressing need to store, manage, mine and analyze this data to identify informational tags. This need is again posing challenges to computer scientists to offer the matching hardware and software infrastructure, while managing the varying degree of desired computational power. Therefore, the potential of "On-Demand Hardware" and "Software as a Service (SAAS)" delivery mechanisms cannot be denied. This on-demand computing, largely referred to as Cloud Computing, is now transforming the drug discovery research. Also, integration of Cloud computing with parallel computing is certainly expanding its footprint in the life sciences community. The speed, efficiency and cost effectiveness have made cloud computing a 'good to have tool' for researchers, providing them significant flexibility, allowing them to focus on the 'what' of science and not the 'how'. Once reached to its maturity, Discovery-Cloud would fit best to manage drug discovery and clinical development data, generated using advanced HTS techniques, hence supporting the vision of personalized medicine.

  8. Computational neuropharmacology: dynamical approaches in drug discovery.

    Science.gov (United States)

    Aradi, Ildiko; Erdi, Péter

    2006-05-01

    Computational approaches that adopt dynamical models are widely accepted in basic and clinical neuroscience research as indispensable tools with which to understand normal and pathological neuronal mechanisms. Although computer-aided techniques have been used in pharmaceutical research (e.g. in structure- and ligand-based drug design), the power of dynamical models has not yet been exploited in drug discovery. We suggest that dynamical system theory and computational neuroscience--integrated with well-established, conventional molecular and electrophysiological methods--offer a broad perspective in drug discovery and in the search for novel targets and strategies for the treatment of neurological and psychiatric diseases.

  9. Computer-Assisted Discovery and Proof

    Energy Technology Data Exchange (ETDEWEB)

    Bailey, David H.; Borwein, Jonathan M.

    2007-12-10

    With the advent of powerful, widely-available mathematical software, combined with ever-faster computer hardware, we are approaching a day when both the discovery and proof of mathematical facts can be done in a computer-assisted manner. his article presents several specific examples of this new paradigm in action.

  10. Computer-Aided Drug Discovery in Plant Pathology.

    Science.gov (United States)

    Shanmugam, Gnanendra; Jeon, Junhyun

    2017-12-01

    Control of plant diseases is largely dependent on use of agrochemicals. However, there are widening gaps between our knowledge on plant diseases gained from genetic/mechanistic studies and rapid translation of the knowledge into target-oriented development of effective agrochemicals. Here we propose that the time is ripe for computer-aided drug discovery/design (CADD) in molecular plant pathology. CADD has played a pivotal role in development of medically important molecules over the last three decades. Now, explosive increase in information on genome sequences and three dimensional structures of biological molecules, in combination with advances in computational and informational technologies, opens up exciting possibilities for application of CADD in discovery and development of agrochemicals. In this review, we outline two categories of the drug discovery strategies: structure- and ligand-based CADD, and relevant computational approaches that are being employed in modern drug discovery. In order to help readers to dive into CADD, we explain concepts of homology modelling, molecular docking, virtual screening, and de novo ligand design in structure-based CADD, and pharmacophore modelling, ligand-based virtual screening, quantitative structure activity relationship modelling and de novo ligand design for ligand-based CADD. We also provide the important resources available to carry out CADD. Finally, we present a case study showing how CADD approach can be implemented in reality for identification of potent chemical compounds against the important plant pathogens, Pseudomonas syringae and Colletotrichum gloeosporioides .

  11. Hierarchical virtual screening approaches in small molecule drug discovery.

    Science.gov (United States)

    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.

  12. Rough – Granular Computing knowledge discovery models

    Directory of Open Access Journals (Sweden)

    Mohammed M. Eissa

    2016-11-01

    Full Text Available Medical domain has become one of the most important areas of research in order to richness huge amounts of medical information about the symptoms of diseases and how to distinguish between them to diagnose it correctly. Knowledge discovery models play vital role in refinement and mining of medical indicators to help medical experts to settle treatment decisions. This paper introduces four hybrid Rough – Granular Computing knowledge discovery models based on Rough Sets Theory, Artificial Neural Networks, Genetic Algorithm and Rough Mereology Theory. A comparative analysis of various knowledge discovery models that use different knowledge discovery techniques for data pre-processing, reduction, and data mining supports medical experts to extract the main medical indicators, to reduce the misdiagnosis rates and to improve decision-making for medical diagnosis and treatment. The proposed models utilized two medical datasets: Coronary Heart Disease dataset and Hepatitis C Virus dataset. The main purpose of this paper was to explore and evaluate the proposed models based on Granular Computing methodology for knowledge extraction according to different evaluation criteria for classification of medical datasets. Another purpose is to make enhancement in the frame of KDD processes for supervised learning using Granular Computing methodology.

  13. Bead-based screening in chemical biology and drug discovery

    DEFF Research Database (Denmark)

    Komnatnyy, Vitaly V.; Nielsen, Thomas Eiland; Qvortrup, Katrine

    2018-01-01

    libraries for early drug discovery. Among the various library forms, the one-bead-one-compound (OBOC) library, where each bead carries many copies of a single compound, holds the greatest potential for the rapid identification of novel hits against emerging drug targets. However, this potential has not yet...... been fully realized due to a number of technical obstacles. In this feature article, we review the progress that has been made towards bead-based library screening and applications to the discovery of bioactive compounds. We identify the key challenges of this approach and highlight key steps needed......High-throughput screening is an important component of the drug discovery process. The screening of libraries containing hundreds of thousands of compounds requires assays amanable to miniaturisation and automization. Combinatorial chemistry holds a unique promise to deliver structural diverse...

  14. Pulsar discovery by global volunteer computing.

    Science.gov (United States)

    Knispel, B; Allen, B; Cordes, J M; Deneva, J S; Anderson, D; Aulbert, C; Bhat, N D R; Bock, O; Bogdanov, S; Brazier, A; Camilo, F; Champion, D J; Chatterjee, S; Crawford, F; Demorest, P B; Fehrmann, H; Freire, P C C; Gonzalez, M E; Hammer, D; Hessels, J W T; Jenet, F A; Kasian, L; Kaspi, V M; Kramer, M; Lazarus, P; van Leeuwen, J; Lorimer, D R; Lyne, A G; Machenschalk, B; McLaughlin, M A; Messenger, C; Nice, D J; Papa, M A; Pletsch, H J; Prix, R; Ransom, S M; Siemens, X; Stairs, I H; Stappers, B W; Stovall, K; Venkataraman, A

    2010-09-10

    Einstein@Home aggregates the computer power of hundreds of thousands of volunteers from 192 countries to mine large data sets. It has now found a 40.8-hertz isolated pulsar in radio survey data from the Arecibo Observatory taken in February 2007. Additional timing observations indicate that this pulsar is likely a disrupted recycled pulsar. PSR J2007+2722's pulse profile is remarkably wide with emission over almost the entire spin period; the pulsar likely has closely aligned magnetic and spin axes. The massive computing power provided by volunteers should enable many more such discoveries.

  15. Computer screens and brain cancer

    International Nuclear Information System (INIS)

    Wood, A.W.

    1995-01-01

    Australia, both in the media and at the federal government level, over possible links between screen-based computer use and cancer, brain tumour in particular. The screen emissions assumed to be the sources of the putative hazard are the magnetic fields responsible for horizontal and vertical scanning of the display. Time-varying fluctuations in these magnetic fields induce electrical current flows in exposed tissues. This paper estimates that the induced current densities in the brain of the computer user are up to 1 mA/m 2 (due to the vertical flyback). Corresponding values for other electrical appliances or installations are in general much less than this. The epidemiological literature shows no obvious signs of a sudden increase in brain tumour incidence, but the widespread use of computers is a relatively recent phenomenon. The occupational use of other equipment based on cathode ray tubes (such as TV repair) has a much longer history and has been statistically linked to brain tumour in some studies. A number of factors make this an unreliable indicator of the risk from computer screens, however. 42 refs., 3 tabs., 2 figs

  16. Discovery Mondays: 'The Grid: a universal computer'

    CERN Multimedia

    2006-01-01

    How can one store and analyse the 15 million billion pieces of data that the LHC will produce each year with a computer that isn't the size of a sky-scraper? The IT experts have found the answer: the Grid, which will harness the power of tens of thousands of computers in the world by putting them together on one network and making them work like a single computer achieving a power that has not yet been matched. The Grid, inspired from the Web, already exists - in fact, several of them exist in the field of science. The European EGEE project, led by CERN, contributes not only to the study of particle physics but to medical research as well, notably in the study of malaria and avian flu. The next Discovery Monday invites you to explore this futuristic computing technology. The 'Grid Masters' of CERN have prepared lively animations to help you understand how the Grid works. Children can practice saving the planet on the Grid video game. You will also discover other applications such as UNOSAT, a United Nations...

  17. Computational discovery of extremal microstructure families

    Science.gov (United States)

    Chen, Desai; Skouras, Mélina; Zhu, Bo; Matusik, Wojciech

    2018-01-01

    Modern fabrication techniques, such as additive manufacturing, can be used to create materials with complex custom internal structures. These engineered materials exhibit a much broader range of bulk properties than their base materials and are typically referred to as metamaterials or microstructures. Although metamaterials with extraordinary properties have many applications, designing them is very difficult and is generally done by hand. We propose a computational approach to discover families of microstructures with extremal macroscale properties automatically. Using efficient simulation and sampling techniques, we compute the space of mechanical properties covered by physically realizable microstructures. Our system then clusters microstructures with common topologies into families. Parameterized templates are eventually extracted from families to generate new microstructure designs. We demonstrate these capabilities on the computational design of mechanical metamaterials and present five auxetic microstructure families with extremal elastic material properties. Our study opens the way for the completely automated discovery of extremal microstructures across multiple domains of physics, including applications reliant on thermal, electrical, and magnetic properties. PMID:29376124

  18. Bacterial contamination of computer touch screens.

    Science.gov (United States)

    Gerba, Charles P; Wuollet, Adam L; Raisanen, Peter; Lopez, Gerardo U

    2016-03-01

    The goal of this study was to determine the occurrence of opportunistic bacterial pathogens on the surfaces of computer touch screens used in hospitals and grocery stores. Opportunistic pathogenic bacteria were isolated on touch screens in hospitals; Clostridium difficile and vancomycin-resistant Enterococcus and in grocery stores; methicillin-resistant Staphylococcus aureus. Enteric bacteria were more common on grocery store touch screens than on hospital computer touch screens. Published by Elsevier Inc.

  19. From virtuality to reality - Virtual screening in lead discovery and lead optimization: a medicinal chemistry perspective.

    Science.gov (United States)

    Rester, Ulrich

    2008-07-01

    Drug discovery and development is an interdisciplinary, expensive and time-consuming process. Scientific advancements during the past two decades have altered the way pharmaceutical research produces novel bio-active molecules. Advances in computational techniques and hardware solutions have enabled in silico methods, and in particular virtual screening, to speed up modern lead identification and lead optimization. Recent successes have proven the power of combining virtual screening with complementary and synergistic biophysical methods, such as X-ray crystallography, NMR spectroscopy and isothermal titration calorimetry (ITC). This review addresses key issues, challenges and recent improvements of virtual screening methods and strategies. Examples highlighting the impact of an integrated virtual screening and biophysical characterization platform in the lead identification and optimization process are presented and discussed.

  20. OPENING REMARKS: Scientific Discovery through Advanced Computing

    Science.gov (United States)

    Strayer, Michael

    2006-01-01

    as the national and regional electricity grid, carbon sequestration, virtual engineering, and the nuclear fuel cycle. The successes of the first five years of SciDAC have demonstrated the power of using advanced computing to enable scientific discovery. One measure of this success could be found in the President’s State of the Union address in which President Bush identified ‘supercomputing’ as a major focus area of the American Competitiveness Initiative. Funds were provided in the FY 2007 President’s Budget request to increase the size of the NERSC-5 procurement to between 100-150 teraflops, to upgrade the LCF Cray XT3 at Oak Ridge to 250 teraflops and acquire a 100 teraflop IBM BlueGene/P to establish the Leadership computing facility at Argonne. We believe that we are on a path to establish a petascale computing resource for open science by 2009. We must develop software tools, packages, and libraries as well as the scientific application software that will scale to hundreds of thousands of processors. Computer scientists from universities and the DOE’s national laboratories will be asked to collaborate on the development of the critical system software components such as compilers, light-weight operating systems and file systems. Standing up these large machines will not be business as usual for ASCR. We intend to develop a series of interconnected projects that identify cost, schedule, risks, and scope for the upgrades at the LCF at Oak Ridge, the establishment of the LCF at Argonne, and the development of the software to support these high-end computers. The critical first step in defining the scope of the project is to identify a set of early application codes for each leadership class computing facility. These codes will have access to the resources during the commissioning phase of the facility projects and will be part of the acceptance tests for the machines. Applications will be selected, in part, by breakthrough science, scalability, and

  1. Studying Scientific Discovery by Computer Simulation.

    Science.gov (United States)

    1983-03-30

    Mendel’s laws of inheritance, the law of Gay- Lussac for gaseous reactions, tile law of Dulong and Petit, the derivation of atomic weights by Avogadro...neceseary mid identify by block number) scientific discovery -ittri sic properties physical laws extensive terms data-driven heuristics intensive...terms theory-driven heuristics conservation laws 20. ABSTRACT (Continue on revere. side It necessary and identify by block number) Scientific discovery

  2. Integration of distributed computing into the drug discovery process.

    Science.gov (United States)

    von Korff, Modest; Rufener, Christian; Stritt, Manuel; Freyss, Joel; Bär, Roman; Sander, Thomas

    2011-02-01

    Grid computing offers an opportunity to gain massive computing power at low costs. We give a short introduction into the drug discovery process and exemplify the use of grid computing for image processing, docking and 3D pharmacophore descriptor calculations. The principle of a grid and its architecture are briefly explained. More emphasis is laid on the issues related to a company-wide grid installation and embedding the grid into the research process. The future of grid computing in drug discovery is discussed in the expert opinion section. Most needed, besides reliable algorithms to predict compound properties, is embedding the grid seamlessly into the discovery process. User friendly access to powerful algorithms without any restrictions, that is, by a limited number of licenses, has to be the goal of grid computing in drug discovery.

  3. Virtual drug discovery: beyond computational chemistry?

    Science.gov (United States)

    Gilardoni, Francois; Arvanites, Anthony C

    2010-02-01

    This editorial looks at how a fully integrated structure that performs all aspects in the drug discovery process, under one company, is slowly disappearing. The steps in the drug discovery paradigm have been slowly increasing toward virtuality or outsourcing at various phases of product development in a company's candidate pipeline. Each step in the process, such as target identification and validation and medicinal chemistry, can be managed by scientific teams within a 'virtual' company. Pharmaceutical companies to biotechnology start-ups have been quick in adopting this new research and development business strategy in order to gain flexibility, access the best technologies and technical expertise, and decrease product developmental costs. In today's financial climate, the term virtual drug discovery has an organizational meaning. It represents the next evolutionary step in outsourcing drug development.

  4. Virtual Screening as a Technique for PPAR Modulator Discovery

    Directory of Open Access Journals (Sweden)

    Stephanie N. Lewis

    2010-01-01

    agonists have therapeutic applications as insulin sensitizers in type 2 diabetes or as anti-inflammatories. VS is a cost- and time-effective means for identifying small molecules that have therapeutic potential. Our long-term goal is to devise computational approaches for testing the PPARγ-binding activity of extensive naturally occurring compound libraries prior to testing agonist activity using ligand-binding and reporter assays. This review summarizes the high potential for obtaining further fundamental understanding of PPARγ biology and development of novel therapies for treating chronic inflammatory diseases through evolution and implementation of computational screening processes for immunotherapeutics in conjunction with experimental methods for calibration and validation of results.

  5. Berkeley Lab Computing Sciences: Accelerating Scientific Discovery

    International Nuclear Information System (INIS)

    Hules, John A.

    2008-01-01

    Scientists today rely on advances in computer science, mathematics, and computational science, as well as large-scale computing and networking facilities, to increase our understanding of ourselves, our planet, and our universe. Berkeley Lab's Computing Sciences organization researches, develops, and deploys new tools and technologies to meet these needs and to advance research in such areas as global climate change, combustion, fusion energy, nanotechnology, biology, and astrophysics

  6. Novel opportunities for computational biology and sociology in drug discovery

    Science.gov (United States)

    Yao, Lixia

    2009-01-01

    Drug discovery today is impossible without sophisticated modeling and computation. In this review we touch on previous advances in computational biology and by tracing the steps involved in pharmaceutical development, we explore a range of novel, high value opportunities for computational innovation in modeling the biological process of disease and the social process of drug discovery. These opportunities include text mining for new drug leads, modeling molecular pathways and predicting the efficacy of drug cocktails, analyzing genetic overlap between diseases and predicting alternative drug use. Computation can also be used to model research teams and innovative regions and to estimate the value of academy-industry ties for scientific and human benefit. Attention to these opportunities could promise punctuated advance, and will complement the well-established computational work on which drug discovery currently relies. PMID:19674801

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

    Science.gov (United States)

    Karthikeyan, Muthukumarasamy; Vyas, Renu

    2015-01-01

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

  8. Incorporation of protein flexibility and conformational energy penalties in docking screens to improve ligand discovery

    Science.gov (United States)

    Fischer, Marcus; Coleman, Ryan G.; Fraser, James S.; Shoichet, Brian K.

    2014-07-01

    Proteins fluctuate between alternative conformations, which presents a challenge for ligand discovery because such flexibility is difficult to treat computationally owing to problems with conformational sampling and energy weighting. Here we describe a flexible docking method that samples and weights protein conformations using experimentally derived conformations as a guide. The crystallographically refined occupancies of these conformations, which are observable in an apo receptor structure, define energy penalties for docking. In a large prospective library screen, we identified new ligands that target specific receptor conformations of a cavity in cytochrome c peroxidase, and we confirm both ligand pose and associated receptor conformation predictions by crystallography. The inclusion of receptor flexibility led to ligands with new chemotypes and physical properties. By exploiting experimental measures of loop and side-chain flexibility, this method can be extended to the discovery of new ligands for hundreds of targets in the Protein Data Bank for which similar experimental information is available.

  9. Emerging Computational Methods for the Rational Discovery of Allosteric Drugs.

    Science.gov (United States)

    Wagner, Jeffrey R; Lee, Christopher T; Durrant, Jacob D; Malmstrom, Robert D; Feher, Victoria A; Amaro, Rommie E

    2016-06-08

    Allosteric drug development holds promise for delivering medicines that are more selective and less toxic than those that target orthosteric sites. To date, the discovery of allosteric binding sites and lead compounds has been mostly serendipitous, achieved through high-throughput screening. Over the past decade, structural data has become more readily available for larger protein systems and more membrane protein classes (e.g., GPCRs and ion channels), which are common allosteric drug targets. In parallel, improved simulation methods now provide better atomistic understanding of the protein dynamics and cooperative motions that are critical to allosteric mechanisms. As a result of these advances, the field of predictive allosteric drug development is now on the cusp of a new era of rational structure-based computational methods. Here, we review algorithms that predict allosteric sites based on sequence data and molecular dynamics simulations, describe tools that assess the druggability of these pockets, and discuss how Markov state models and topology analyses provide insight into the relationship between protein dynamics and allosteric drug binding. In each section, we first provide an overview of the various method classes before describing relevant algorithms and software packages.

  10. Discovery and Development of ATP-Competitive mTOR Inhibitors Using Computational Approaches.

    Science.gov (United States)

    Luo, Yao; Wang, Ling

    2017-11-16

    The mammalian target of rapamycin (mTOR) is a central controller of cell growth, proliferation, metabolism, and angiogenesis. This protein is an attractive target for new anticancer drug development. Significant progress has been made in hit discovery, lead optimization, drug candidate development and determination of the three-dimensional (3D) structure of mTOR. Computational methods have been applied to accelerate the discovery and development of mTOR inhibitors helping to model the structure of mTOR, screen compound databases, uncover structure-activity relationship (SAR) and optimize the hits, mine the privileged fragments and design focused libraries. Besides, computational approaches were also applied to study protein-ligand interactions mechanisms and in natural product-driven drug discovery. Herein, we survey the most recent progress on the application of computational approaches to advance the discovery and development of compounds targeting mTOR. Future directions in the discovery of new mTOR inhibitors using computational methods are also discussed. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  11. Computer Screen Use Detection Using Smart Eyeglasses

    Directory of Open Access Journals (Sweden)

    Florian Wahl

    2017-05-01

    Full Text Available Screen use can influence the circadian phase and cause eye strain. Smart eyeglasses with an integrated color light sensor can detect screen use. We present a screen use detection approach based on a light sensor embedded into the bridge of smart eyeglasses. By calculating the light intensity at the user’s eyes for different screens and content types, we found only computer screens to have a significant impact on the circadian phase. Our screen use detection is based on ratios between color channels and used a linear support vector machine to detect screen use. We validated our detection approach in three studies. A test bench was built to detect screen use under different ambient light sources and intensities in a controlled environment. In a lab study, we evaluated recognition performance for different ambient light intensities. By using participant-independent models, we achieved an ROC AUC above 0.9 for ambient light intensities below 200 lx. In a study of typical ADLs, screen use was detected with an average ROC AUC of 0.83 assuming screen use for 30% of the time.

  12. Pulsar discovery by global volunteer computing

    NARCIS (Netherlands)

    Knispel, B.; Allen, B.; Cordes, J.M.; Deneva, J.S.; Anderson, D.; Aulbert, C.; Bhat, N.D.R.; Bock, O.; Bogdanov, S.; Brazier, A.; Camilo, F.; Champion, D.J.; Chatterjee, S.; Crawford, F.; Demorest, P.B.; Fehrmann, H.; Freire, P.C.C.; Gonzalez, M.E.; Hammer, D.; Hessels, J.W.T.; Jenet, F.A.; Kasian, L.; Kaspi, V.M.; Kramer, M.; Lazarus, P.; van Leeuwen, J.; Lorimer, D.R.; Lyne, A.G.; Machenschalk, B.; McLaughlin, M.A.; Messenger, C.; Nice, D.J.; Papa, M.A.; Pletsch, H.J.; Prix, R.; Ransom, S.M.; Siemens, X.; Stairs, I.H.; Stappers, B.W.; Stovall, K.; Venkataraman, A.

    2010-01-01

    Einstein@Home aggregates the computer power of hundreds of thousands of volunteers from 192 countries to mine large data sets. It has now found a 40.8-hertz isolated pulsar in radio survey data from the Arecibo Observatory taken in February 2007. Additional timing observations indicate that this

  13. Screening applications in drug discovery based on microfluidic technology.

    Science.gov (United States)

    Eribol, P; Uguz, A K; Ulgen, K O

    2016-01-01

    Microfluidics has been the focus of interest for the last two decades for all the advantages such as low chemical consumption, reduced analysis time, high throughput, better control of mass and heat transfer, downsizing a bench-top laboratory to a chip, i.e., lab-on-a-chip, and many others it has offered. Microfluidic technology quickly found applications in the pharmaceutical industry, which demands working with leading edge scientific and technological breakthroughs, as drug screening and commercialization are very long and expensive processes and require many tests due to unpredictable results. This review paper is on drug candidate screening methods with microfluidic technology and focuses specifically on fabrication techniques and materials for the microchip, types of flow such as continuous or discrete and their advantages, determination of kinetic parameters and their comparison with conventional systems, assessment of toxicities and cytotoxicities, concentration generations for high throughput, and the computational methods that were employed. An important conclusion of this review is that even though microfluidic technology has been in this field for around 20 years there is still room for research and development, as this cutting edge technology requires ingenuity to design and find solutions for each individual case. Recent extensions of these microsystems are microengineered organs-on-chips and organ arrays.

  14. Screening applications in drug discovery based on microfluidic technology

    Science.gov (United States)

    Eribol, P.; Uguz, A. K.; Ulgen, K. O.

    2016-01-01

    Microfluidics has been the focus of interest for the last two decades for all the advantages such as low chemical consumption, reduced analysis time, high throughput, better control of mass and heat transfer, downsizing a bench-top laboratory to a chip, i.e., lab-on-a-chip, and many others it has offered. Microfluidic technology quickly found applications in the pharmaceutical industry, which demands working with leading edge scientific and technological breakthroughs, as drug screening and commercialization are very long and expensive processes and require many tests due to unpredictable results. This review paper is on drug candidate screening methods with microfluidic technology and focuses specifically on fabrication techniques and materials for the microchip, types of flow such as continuous or discrete and their advantages, determination of kinetic parameters and their comparison with conventional systems, assessment of toxicities and cytotoxicities, concentration generations for high throughput, and the computational methods that were employed. An important conclusion of this review is that even though microfluidic technology has been in this field for around 20 years there is still room for research and development, as this cutting edge technology requires ingenuity to design and find solutions for each individual case. Recent extensions of these microsystems are microengineered organs-on-chips and organ arrays. PMID:26865904

  15. Computer-aided discovery of antimicrobial agents as potential enoyl ...

    African Journals Online (AJOL)

    Computer-aided discovery of antimicrobial agents as potential enoyl acyl carrier protein reductase inhibitors. ... Conclusion: Overall, the newly discovered hits can act as a good starting point in the future for the development of safe and potent antibacterial agents. Keywords: Enoyl acyl carrier protein reductase, saFabI, ...

  16. Recent development of computational resources for new antibiotics discovery

    DEFF Research Database (Denmark)

    Kim, Hyun Uk; Blin, Kai; Lee, Sang Yup

    2017-01-01

    Understanding a complex working mechanism of biosynthetic gene clusters (BGCs) encoding secondary metabolites is a key to discovery of new antibiotics. Computational resources continue to be developed in order to better process increasing volumes of genome and chemistry data, and thereby better...

  17. The Computer Revolution in Science: Steps towards the realization of computer-supported discovery environments

    NARCIS (Netherlands)

    de Jong, Hidde; Rip, Arie

    1997-01-01

    The tools that scientists use in their search processes together form so-called discovery environments. The promise of artificial intelligence and other branches of computer science is to radically transform conventional discovery environments by equipping scientists with a range of powerful

  18. Contributions of computational chemistry and biophysical techniques to fragment-based drug discovery.

    Science.gov (United States)

    Gozalbes, Rafael; Carbajo, Rodrigo J; Pineda-Lucena, Antonio

    2010-01-01

    In the last decade, fragment-based drug discovery (FBDD) has evolved from a novel approach in the search of new hits to a valuable alternative to the high-throughput screening (HTS) campaigns of many pharmaceutical companies. The increasing relevance of FBDD in the drug discovery universe has been concomitant with an implementation of the biophysical techniques used for the detection of weak inhibitors, e.g. NMR, X-ray crystallography or surface plasmon resonance (SPR). At the same time, computational approaches have also been progressively incorporated into the FBDD process and nowadays several computational tools are available. These stretch from the filtering of huge chemical databases in order to build fragment-focused libraries comprising compounds with adequate physicochemical properties, to more evolved models based on different in silico methods such as docking, pharmacophore modelling, QSAR and virtual screening. In this paper we will review the parallel evolution and complementarities of biophysical techniques and computational methods, providing some representative examples of drug discovery success stories by using FBDD.

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

    Directory of Open Access Journals (Sweden)

    Yuri Pevzner

    2014-05-01

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

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

    Directory of Open Access Journals (Sweden)

    Yuri Pevzner

    2015-08-01

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

  1. Toxicophore exploration as a screening technology for drug design and discovery: techniques, scope and limitations.

    Science.gov (United States)

    Singh, Pankaj Kumar; Negi, Arvind; Gupta, Pawan Kumar; Chauhan, Monika; Kumar, Raj

    2016-08-01

    Toxicity is a common drawback of newly designed chemotherapeutic agents. With the exception of pharmacophore-induced toxicity (lack of selectivity at higher concentrations of a drug), the toxicity due to chemotherapeutic agents is based on the toxicophore moiety present in the drug. To date, methodologies implemented to determine toxicophores may be broadly classified into biological, bioanalytical and computational approaches. The biological approach involves analysis of bioactivated metabolites, whereas the computational approach involves a QSAR-based method, mapping techniques, an inverse docking technique and a few toxicophore identification/estimation tools. Being one of the major steps in drug discovery process, toxicophore identification has proven to be an essential screening step in drug design and development. The paper is first of its kind, attempting to cover and compare different methodologies employed in predicting and determining toxicophores with an emphasis on their scope and limitations. Such information may prove vital in the appropriate selection of methodology and can be used as screening technology by researchers to discover the toxicophoric potentials of their designed and synthesized moieties. Additionally, it can be utilized in the manipulation of molecules containing toxicophores in such a manner that their toxicities might be eliminated or removed.

  2. Early phase drug discovery: cheminformatics and computational techniques in identifying lead series.

    Science.gov (United States)

    Duffy, Bryan C; Zhu, Lei; Decornez, Hélène; Kitchen, Douglas B

    2012-09-15

    Early drug discovery processes rely on hit finding procedures followed by extensive experimental confirmation in order to select high priority hit series which then undergo further scrutiny in hit-to-lead studies. The experimental cost and the risk associated with poor selection of lead series can be greatly reduced by the use of many different computational and cheminformatic techniques to sort and prioritize compounds. We describe the steps in typical hit identification and hit-to-lead programs and then describe how cheminformatic analysis assists this process. In particular, scaffold analysis, clustering and property calculations assist in the design of high-throughput screening libraries, the early analysis of hits and then organizing compounds into series for their progression from hits to leads. Additionally, these computational tools can be used in virtual screening to design hit-finding libraries and as procedures to help with early SAR exploration. Copyright © 2012 Elsevier Ltd. All rights reserved.

  3. Computational Discovery of Materials Using the Firefly Algorithm

    Science.gov (United States)

    Avendaño-Franco, Guillermo; Romero, Aldo

    Our current ability to model physical phenomena accurately, the increase computational power and better algorithms are the driving forces behind the computational discovery and design of novel materials, allowing for virtual characterization before their realization in the laboratory. We present the implementation of a novel firefly algorithm, a population-based algorithm for global optimization for searching the structure/composition space. This novel computation-intensive approach naturally take advantage of concurrency, targeted exploration and still keeping enough diversity. We apply the new method in both periodic and non-periodic structures and we present the implementation challenges and solutions to improve efficiency. The implementation makes use of computational materials databases and network analysis to optimize the search and get insights about the geometric structure of local minima on the energy landscape. The method has been implemented in our software PyChemia, an open-source package for materials discovery. We acknowledge the support of DMREF-NSF 1434897 and the Donors of the American Chemical Society Petroleum Research Fund for partial support of this research under Contract 54075-ND10.

  4. Advances in Predictive Toxicology for Discovery Safety through High Content Screening.

    Science.gov (United States)

    Persson, Mikael; Hornberg, Jorrit J

    2016-12-19

    High content screening enables parallel acquisition of multiple molecular and cellular readouts. In particular the predictive toxicology field has progressed from the advances in high content screening, as more refined end points that report on cellular health can be studied in combination, at the single cell level, and in relatively high throughput. Here, we discuss how high content screening has become an essential tool for Discovery Safety, the discipline that integrates safety and toxicology in the drug discovery process to identify and mitigate safety concerns with the aim to design drug candidates with a superior safety profile. In addition to customized mechanistic assays to evaluate target safety, routine screening assays can be applied to identify risk factors for frequently occurring organ toxicities. We discuss the current state of high content screening assays for hepatotoxicity, cardiotoxicity, neurotoxicity, nephrotoxicity, and genotoxicity, including recent developments and current advances.

  5. The development of high-content screening (HCS) technology and its importance to drug discovery.

    Science.gov (United States)

    Fraietta, Ivan; Gasparri, Fabio

    2016-01-01

    High-content screening (HCS) was introduced about twenty years ago as a promising analytical approach to facilitate some critical aspects of drug discovery. Its application has spread progressively within the pharmaceutical industry and academia to the point that it today represents a fundamental tool in supporting drug discovery and development. Here, the authors review some of significant progress in the HCS field in terms of biological models and assay readouts. They highlight the importance of high-content screening in drug discovery, as testified by its numerous applications in a variety of therapeutic areas: oncology, infective diseases, cardiovascular and neurodegenerative diseases. They also dissect the role of HCS technology in different phases of the drug discovery pipeline: target identification, primary compound screening, secondary assays, mechanism of action studies and in vitro toxicology. Recent advances in cellular assay technologies, such as the introduction of three-dimensional (3D) cultures, induced pluripotent stem cells (iPSCs) and genome editing technologies (e.g., CRISPR/Cas9), have tremendously expanded the potential of high-content assays to contribute to the drug discovery process. Increasingly predictive cellular models and readouts, together with the development of more sophisticated and affordable HCS readers, will further consolidate the role of HCS technology in drug discovery.

  6. Discovery of novel bacterial toxins by genomics and computational biology.

    Science.gov (United States)

    Doxey, Andrew C; Mansfield, Michael J; Montecucco, Cesare

    2018-06-01

    Hundreds and hundreds of bacterial protein toxins are presently known. Traditionally, toxin identification begins with pathological studies of bacterial infectious disease. Following identification and cultivation of a bacterial pathogen, the protein toxin is purified from the culture medium and its pathogenic activity is studied using the methods of biochemistry and structural biology, cell biology, tissue and organ biology, and appropriate animal models, supplemented by bioimaging techniques. The ongoing and explosive development of high-throughput DNA sequencing and bioinformatic approaches have set in motion a revolution in many fields of biology, including microbiology. One consequence is that genes encoding novel bacterial toxins can be identified by bioinformatic and computational methods based on previous knowledge accumulated from studies of the biology and pathology of thousands of known bacterial protein toxins. Starting from the paradigmatic cases of diphtheria toxin, tetanus and botulinum neurotoxins, this review discusses traditional experimental approaches as well as bioinformatics and genomics-driven approaches that facilitate the discovery of novel bacterial toxins. We discuss recent work on the identification of novel botulinum-like toxins from genera such as Weissella, Chryseobacterium, and Enteroccocus, and the implications of these computationally identified toxins in the field. Finally, we discuss the promise of metagenomics in the discovery of novel toxins and their ecological niches, and present data suggesting the existence of uncharacterized, botulinum-like toxin genes in insect gut metagenomes. Copyright © 2018. Published by Elsevier Ltd.

  7. Dynamic Docking: A Paradigm Shift in Computational Drug Discovery

    Directory of Open Access Journals (Sweden)

    Dario Gioia

    2017-11-01

    Full Text Available Molecular docking is the methodology of choice for studying in silico protein-ligand binding and for prioritizing compounds to discover new lead candidates. Traditional docking simulations suffer from major limitations, mostly related to the static or semi-flexible treatment of ligands and targets. They also neglect solvation and entropic effects, which strongly limits their predictive power. During the last decade, methods based on full atomistic molecular dynamics (MD have emerged as a valid alternative for simulating macromolecular complexes. In principle, compared to traditional docking, MD allows the full exploration of drug-target recognition and binding from both the mechanistic and energetic points of view (dynamic docking. Binding and unbinding kinetic constants can also be determined. While dynamic docking is still too computationally expensive to be routinely used in fast-paced drug discovery programs, the advent of faster computing architectures and advanced simulation methodologies are changing this scenario. It is feasible that dynamic docking will replace static docking approaches in the near future, leading to a major paradigm shift in in silico drug discovery. Against this background, we review the key achievements that have paved the way for this progress.

  8. OPENING REMARKS: SciDAC: Scientific Discovery through Advanced Computing

    Science.gov (United States)

    Strayer, Michael

    2005-01-01

    Good morning. Welcome to SciDAC 2005 and San Francisco. SciDAC is all about computational science and scientific discovery. In a large sense, computational science characterizes SciDAC and its intent is change. It transforms both our approach and our understanding of science. It opens new doors and crosses traditional boundaries while seeking discovery. In terms of twentieth century methodologies, computational science may be said to be transformational. There are a number of examples to this point. First are the sciences that encompass climate modeling. The application of computational science has in essence created the field of climate modeling. This community is now international in scope and has provided precision results that are challenging our understanding of our environment. A second example is that of lattice quantum chromodynamics. Lattice QCD, while adding precision and insight to our fundamental understanding of strong interaction dynamics, has transformed our approach to particle and nuclear science. The individual investigator approach has evolved to teams of scientists from different disciplines working side-by-side towards a common goal. SciDAC is also undergoing a transformation. This meeting is a prime example. Last year it was a small programmatic meeting tracking progress in SciDAC. This year, we have a major computational science meeting with a variety of disciplines and enabling technologies represented. SciDAC 2005 should position itself as a new corner stone for Computational Science and its impact on science. As we look to the immediate future, FY2006 will bring a new cycle to SciDAC. Most of the program elements of SciDAC will be re-competed in FY2006. The re-competition will involve new instruments for computational science, new approaches for collaboration, as well as new disciplines. There will be new opportunities for virtual experiments in carbon sequestration, fusion, and nuclear power and nuclear waste, as well as collaborations

  9. Search of computers for discovery of electronic evidence

    Directory of Open Access Journals (Sweden)

    Pisarić Milana M.

    2015-01-01

    Full Text Available In order to address the specific nature of criminal activities committed using computer networks and systems, the efforts of states to adapt or complement the existing criminal law with purposeful provisions is understandable. To create an appropriate legal framework for supressing cybercrime, except the rules of substantive criminal law predict certain behavior as criminal offenses against the confidentiality, integrity and availability of computer data, computer systems and networks, it is essential that the provisions of the criminal procedure law contain adequate powers of competent authorities for detecting sources of illegal activities, or the collection of data on the committed criminal offense and offender, which can be used as evidence in criminal proceedings, taking into account the specificities of cyber crime and the environment within which the illegal activity is undertaken. Accordingly, the provisions of the criminal procedural law should be designed to be able to overcome certain challenges in discovering and proving high technology crime, and the provisions governing search of computer for discovery of electronic evidence is of special importance.

  10. Scientific Discovery through Advanced Computing in Plasma Science

    Science.gov (United States)

    Tang, William

    2005-03-01

    Advanced computing is generally recognized to be an increasingly vital tool for accelerating progress in scientific research during the 21st Century. For example, the Department of Energy's ``Scientific Discovery through Advanced Computing'' (SciDAC) Program was motivated in large measure by the fact that formidable scientific challenges in its research portfolio could best be addressed by utilizing the combination of the rapid advances in super-computing technology together with the emergence of effective new algorithms and computational methodologies. The imperative is to translate such progress into corresponding increases in the performance of the scientific codes used to model complex physical systems such as those encountered in high temperature plasma research. If properly validated against experimental measurements and analytic benchmarks, these codes can provide reliable predictive capability for the behavior of a broad range of complex natural and engineered systems. This talk reviews recent progress and future directions for advanced simulations with some illustrative examples taken from the plasma science applications area. Significant recent progress has been made in both particle and fluid simulations of fine-scale turbulence and large-scale dynamics, giving increasingly good agreement between experimental observations and computational modeling. This was made possible by the combination of access to powerful new computational resources together with innovative advances in analytic and computational methods for developing reduced descriptions of physics phenomena spanning a huge range in time and space scales. In particular, the plasma science community has made excellent progress in developing advanced codes for which computer run-time and problem size scale well with the number of processors on massively parallel machines (MPP's). A good example is the effective usage of the full power of multi-teraflop (multi-trillion floating point computations

  11. GENIUS In Silico Screening Technology for HCV Drug Discovery.

    Science.gov (United States)

    Patil, Vaishali M; Masand, Neeraj; Gupta, Satya P

    2016-01-01

    The various reported in silico screening protocols such as molecular docking are associated with various drawbacks as well as benefits. In molecular docking, on interaction with ligand, the protein or receptor molecule gets activated by adopting conformational changes. These conformational changes cannot be utilized to predict the 3D structure of a protein-ligand complex from unbound protein conformations rigid docking, which necessitates the demand for understanding protein flexibility. Therefore, efficiency and accuracy of docking should be achieved and various available/developed protocols may be adopted. One such protocol is GENIUS induced-fit docking and it is used effectively for the development of anti-HCV NS3-4A serine protease inhibitors. The present review elaborates the GENIUS docking protocol along with its benefits and drawbacks.

  12. Computational screening of mixed metal halide ammines

    DEFF Research Database (Denmark)

    Jensen, Peter Bjerre; Lysgaard, Steen; Quaade, Ulrich

    2013-01-01

    Metal halide ammines, e.g. Mg(NH3)6Cl2 and Sr(NH3)8Cl2, can reversibly store ammonia, with high volumetric hydrogen storage capacities. The storage in the halide ammines is very safe, and the salts are therefore highly relevant as a carbon-free energy carrier in future transportation infrastructure...... selection. The GA is evolving from an initial (random) population and selecting those with highest fitness, a function based on e.g. stability, release temperature and storage capacity. The search space includes all alkaline, alkaline earth, 3d and 4d metals and the four lightest halides. In total...... the search spaces consists of millions combinations, which makes a GA ideal, to reduce the number of necessary calculations. We are screening for a one step release from either a hexa or octa ammine, and we have found promising candidates, which will be further investigated ? both computationally...

  13. A Fully Automated High-Throughput Flow Cytometry Screening System Enabling Phenotypic Drug Discovery.

    Science.gov (United States)

    Joslin, John; Gilligan, James; Anderson, Paul; Garcia, Catherine; Sharif, Orzala; Hampton, Janice; Cohen, Steven; King, Miranda; Zhou, Bin; Jiang, Shumei; Trussell, Christopher; Dunn, Robert; Fathman, John W; Snead, Jennifer L; Boitano, Anthony E; Nguyen, Tommy; Conner, Michael; Cooke, Mike; Harris, Jennifer; Ainscow, Ed; Zhou, Yingyao; Shaw, Chris; Sipes, Dan; Mainquist, James; Lesley, Scott

    2018-05-01

    The goal of high-throughput screening is to enable screening of compound libraries in an automated manner to identify quality starting points for optimization. This often involves screening a large diversity of compounds in an assay that preserves a connection to the disease pathology. Phenotypic screening is a powerful tool for drug identification, in that assays can be run without prior understanding of the target and with primary cells that closely mimic the therapeutic setting. Advanced automation and high-content imaging have enabled many complex assays, but these are still relatively slow and low throughput. To address this limitation, we have developed an automated workflow that is dedicated to processing complex phenotypic assays for flow cytometry. The system can achieve a throughput of 50,000 wells per day, resulting in a fully automated platform that enables robust phenotypic drug discovery. Over the past 5 years, this screening system has been used for a variety of drug discovery programs, across many disease areas, with many molecules advancing quickly into preclinical development and into the clinic. This report will highlight a diversity of approaches that automated flow cytometry has enabled for phenotypic drug discovery.

  14. Stem cells: a model for screening, discovery and development of drugs.

    Science.gov (United States)

    Kitambi, Satish Srinivas; Chandrasekar, Gayathri

    2011-01-01

    The identification of normal and cancerous stem cells and the recent advances made in isolation and culture of stem cells have rapidly gained attention in the field of drug discovery and regenerative medicine. The prospect of performing screens aimed at proliferation, directed differentiation, and toxicity and efficacy studies using stem cells offers a reliable platform for the drug discovery process. Advances made in the generation of induced pluripotent stem cells from normal or diseased tissue serves as a platform to perform drug screens aimed at developing cell-based therapies against conditions like Parkinson's disease and diabetes. This review discusses the application of stem cells and cancer stem cells in drug screening and their role in complementing, reducing, and replacing animal testing. In addition to this, target identification and major advances in the field of personalized medicine using induced pluripotent cells are also discussed.

  15. High-Throughput Screening Using Mass Spectrometry within Drug Discovery.

    Science.gov (United States)

    Rohman, Mattias; Wingfield, Jonathan

    2016-01-01

    In order to detect a biochemical analyte with a mass spectrometer (MS) it is necessary to ionize the analyte of interest. The analyte can be ionized by a number of different mechanisms, however, one common method is electrospray ionization (ESI). Droplets of analyte are sprayed through a highly charged field, the droplets pick up charge, and this is transferred to the analyte. High levels of salt in the assay buffer will potentially steal charge from the analyte and suppress the MS signal. In order to avoid this suppression of signal, salt is often removed from the sample prior to injection into the MS. Traditional ESI MS relies on liquid chromatography (LC) to remove the salt and reduce matrix effects, however, this is a lengthy process. Here we describe the use of RapidFire™ coupled to a triple-quadrupole MS for high-throughput screening. This system uses solid-phase extraction to de-salt samples prior to injection, reducing processing time such that a sample is injected into the MS ~every 10 s.

  16. Computer-Aided Experiment Planning toward Causal Discovery in Neuroscience.

    Science.gov (United States)

    Matiasz, Nicholas J; Wood, Justin; Wang, Wei; Silva, Alcino J; Hsu, William

    2017-01-01

    Computers help neuroscientists to analyze experimental results by automating the application of statistics; however, computer-aided experiment planning is far less common, due to a lack of similar quantitative formalisms for systematically assessing evidence and uncertainty. While ontologies and other Semantic Web resources help neuroscientists to assimilate required domain knowledge, experiment planning requires not only ontological but also epistemological (e.g., methodological) information regarding how knowledge was obtained. Here, we outline how epistemological principles and graphical representations of causality can be used to formalize experiment planning toward causal discovery. We outline two complementary approaches to experiment planning: one that quantifies evidence per the principles of convergence and consistency, and another that quantifies uncertainty using logical representations of constraints on causal structure. These approaches operationalize experiment planning as the search for an experiment that either maximizes evidence or minimizes uncertainty. Despite work in laboratory automation, humans must still plan experiments and will likely continue to do so for some time. There is thus a great need for experiment-planning frameworks that are not only amenable to machine computation but also useful as aids in human reasoning.

  17. The history of cosmic baryons: discoveries using advanced computing

    International Nuclear Information System (INIS)

    Norman, Michael L

    2005-01-01

    We live in the era of the cosmological concordance model. This refers to the precise set of cosmological parameters which describe the average composition, geometry, and expansion rate of the universe we inhabit. Due to recent observational, theoretical, and computational advances, these parameters are now known to approximately 10% accuracy, and new efforts are underway to increase precision tenfold. It is found that we live in a spatially flat, dark matter-dominated universe whose rate of expansion is accelerating due to an unseen, unknown dark energy field. Baryons-the stuff of stars, galaxies, and us-account for only 4% of the total mass-energy inventory. And yet, it is through the astronomical study of baryons that we infer the rest. In this talk I will highlight the important role advanced scientific computing has played in getting us to the concordance model, and also the computational discoveries that have been made about the history of cosmic baryons using hydrodynamical cosmological simulations. I will conclude by discussing the central role that very large scale simulations of cosmological structure formation will play in deciphering the results of upcoming dark energy surveys

  18. How Phenotypic Screening Influenced Drug Discovery: Lessons from Five Years of Practice.

    Science.gov (United States)

    Haasen, Dorothea; Schopfer, Ulrich; Antczak, Christophe; Guy, Chantale; Fuchs, Florian; Selzer, Paul

    Since 2011, phenotypic screening has been a trend in the pharmaceutical industry as well as in academia. This renaissance was triggered by analyses that suggested that phenotypic screening is a superior strategy to discover first-in-class drugs. Despite these promises and considerable investments, pharmaceutical research organizations have encountered considerable challenges with the approach. Few success stories have emerged in the past 5 years and companies are questioning their investment in this area. In this contribution, we outline what we have learned about success factors and challenges of phenotypic screening. We then describe how our efforts in phenotypic screening have influenced our approach to drug discovery in general. We predict that concepts from phenotypic screening will be incorporated into target-based approaches and will thus remain influential beyond the current trend.

  19. Discovery of novel selenium derivatives as Pin1 inhibitors by high-throughput screening

    International Nuclear Information System (INIS)

    Subedi, Amit; Shimizu, Takeshi; Ryo, Akihide; Sanada, Emiko; Watanabe, Nobumoto; Osada, Hiroyuki

    2016-01-01

    Peptidyl prolyl cis/trans isomerization by Pin1 regulates various oncogenic signals during cancer progression, and its inhibition through multiple approaches has established Pin1 as a therapeutic target. However, lack of simplified screening systems has limited the discovery of potent Pin1 inhibitors. We utilized phosphorylation-dependent binding of Pin1 to its specific substrate to develop a screening system for Pin1 inhibitors. Using this system, we screened a chemical library, and identified a novel selenium derivative as Pin1 inhibitor. Based on structure-activity guided chemical synthesis, we developed more potent Pin1 inhibitors that inhibited cancer cell proliferation. -- Highlights: •Novel screening for Pin1 inhibitors based on Pin1 binding is developed. •A novel selenium compound is discovered as Pin1 inhibitor. •Activity guided chemical synthesis of selenium derivatives resulted potent Pin1 inhibitors.

  20. Stem cells: a model for screening, discovery and development of drugs

    Directory of Open Access Journals (Sweden)

    Kitambi SS

    2011-09-01

    Full Text Available Satish Srinivas Kitambi1, Gayathri Chandrasekar21Department of Medical Biochemistry and Biophysics; 2Department of Biosciences, Karolinska Institutet, Stockholm, SwedenAbstract: The identification of normal and cancerous stem cells and the recent advances made in isolation and culture of stem cells have rapidly gained attention in the field of drug discovery and regenerative medicine. The prospect of performing screens aimed at proliferation, directed differentiation, and toxicity and efficacy studies using stem cells offers a reliable platform for the drug discovery process. Advances made in the generation of induced pluripotent stem cells from normal or diseased tissue serves as a platform to perform drug screens aimed at developing cell-based therapies against conditions like Parkinson's disease and diabetes. This review discusses the application of stem cells and cancer stem cells in drug screening and their role in complementing, reducing, and replacing animal testing. In addition to this, target identification and major advances in the field of personalized medicine using induced pluripotent cells are also discussed.Keywords: therapeutics, stem cells, cancer stem cells, screening models, drug development, high throughput screening

  1. Stem cells: a model for screening, discovery and development of drugs

    OpenAIRE

    Kitambi, Satish Srinivas; Chandrasekar, Gayathri

    2011-01-01

    Satish Srinivas Kitambi1, Gayathri Chandrasekar21Department of Medical Biochemistry and Biophysics; 2Department of Biosciences, Karolinska Institutet, Stockholm, SwedenAbstract: The identification of normal and cancerous stem cells and the recent advances made in isolation and culture of stem cells have rapidly gained attention in the field of drug discovery and regenerative medicine. The prospect of performing screens aimed at proliferation, directed differentiation, and toxicity and efficac...

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

    Directory of Open Access Journals (Sweden)

    Jun-Tae Kim

    2014-11-01

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

  3. A fully automated primary screening system for the discovery of therapeutic antibodies directly from B cells.

    Science.gov (United States)

    Tickle, Simon; Howells, Louise; O'Dowd, Victoria; Starkie, Dale; Whale, Kevin; Saunders, Mark; Lee, David; Lightwood, Daniel

    2015-04-01

    For a therapeutic antibody to succeed, it must meet a range of potency, stability, and specificity criteria. Many of these characteristics are conferred by the amino acid sequence of the heavy and light chain variable regions and, for this reason, can be screened for during antibody selection. However, it is important to consider that antibodies satisfying all these criteria may be of low frequency in an immunized animal; for this reason, it is essential to have a mechanism that allows for efficient sampling of the immune repertoire. UCB's core antibody discovery platform combines high-throughput B cell culture screening and the identification and isolation of single, antigen-specific IgG-secreting B cells through a proprietary technique called the "fluorescent foci" method. Using state-of-the-art automation to facilitate primary screening, extremely efficient interrogation of the natural antibody repertoire is made possible; more than 1 billion immune B cells can now be screened to provide a useful starting point from which to identify the rare therapeutic antibody. This article will describe the design, construction, and commissioning of a bespoke automated screening platform and two examples of how it was used to screen for antibodies against two targets. © 2014 Society for Laboratory Automation and Screening.

  4. Integrating medicinal chemistry, organic/combinatorial chemistry, and computational chemistry for the discovery of selective estrogen receptor modulators with Forecaster, a novel platform for drug discovery.

    Science.gov (United States)

    Therrien, Eric; Englebienne, Pablo; Arrowsmith, Andrew G; Mendoza-Sanchez, Rodrigo; Corbeil, Christopher R; Weill, Nathanael; Campagna-Slater, Valérie; Moitessier, Nicolas

    2012-01-23

    As part of a large medicinal chemistry program, we wish to develop novel selective estrogen receptor modulators (SERMs) as potential breast cancer treatments using a combination of experimental and computational approaches. However, one of the remaining difficulties nowadays is to fully integrate computational (i.e., virtual, theoretical) and medicinal (i.e., experimental, intuitive) chemistry to take advantage of the full potential of both. For this purpose, we have developed a Web-based platform, Forecaster, and a number of programs (e.g., Prepare, React, Select) with the aim of combining computational chemistry and medicinal chemistry expertise to facilitate drug discovery and development and more specifically to integrate synthesis into computer-aided drug design. In our quest for potent SERMs, this platform was used to build virtual combinatorial libraries, filter and extract a highly diverse library from the NCI database, and dock them to the estrogen receptor (ER), with all of these steps being fully automated by computational chemists for use by medicinal chemists. As a result, virtual screening of a diverse library seeded with active compounds followed by a search for analogs yielded an enrichment factor of 129, with 98% of the seeded active compounds recovered, while the screening of a designed virtual combinatorial library including known actives yielded an area under the receiver operating characteristic (AU-ROC) of 0.78. The lead optimization proved less successful, further demonstrating the challenge to simulate structure activity relationship studies.

  5. Computer Simulation of Breast Cancer Screening

    National Research Council Canada - National Science Library

    Boone, John

    1999-01-01

    Breast cancer will affect approximately 12.5% of the women in the United States, and currently mammographic screening is considered the best way to reduce mortality from this disease through early detection...

  6. Computer-Aided Solvent Screening for Biocatalysis

    DEFF Research Database (Denmark)

    Abildskov, Jens; Leeuwen, M.B. van; Boeriu, C.G.

    2013-01-01

    constrained properties related to chemical reaction equilibrium, substrate and product solubility, water solubility, boiling points, toxicity and others. Two examples are provided, covering the screening of solvents for lipase-catalyzed transesterification of octanol and inulin with vinyl laurate....... Esterification of acrylic acid with octanol is also addressed. Solvents are screened and candidates identified, confirming existing experimental results. Although the examples involve lipases, the method is quite general, so there seems to be no preclusion against application to other biocatalysts....

  7. Cardiac Arrhythmia: In vivo screening in the zebrafish to overcome complexity in drug discovery.

    Science.gov (United States)

    Macrae, Calum A

    2010-07-01

    IMPORTANCE OF THE FIELD: Cardiac arrhythmias remain a major challenge for modern drug discovery. Clinical events are paroxysmal, often rare and may be asymptomatic until a highly morbid complication. Target selection is often based on limited information and though highly specific agents are identified in screening, the final efficacy is often compromised by unanticipated systemic responses, a narrow therapeutic index and substantial toxicities. AREAS COVERED IN THIS REVIEW: Our understanding of complexity of arrhythmogenesis has grown dramatically over the last two decades, and the range of potential disease mechanisms now includes pathways previously thought only tangentially involved in arrhythmia. This review surveys the literature on arrhythmia mechanisms from 1965 to the present day, outlines the complex biology underlying potentially each and every rhythm disturbance, and highlights the problems for rational target identification. The rationale for in vivo screening is described and the utility of the zebrafish for this approach and for complementary work in functional genomics is discussed. Current limitations of the model in this setting and the need for careful validation in new disease areas are also described. WHAT THE READER WILL GAIN: An overview of the complex mechanisms underlying most clinical arrhythmias, and insight into the limits of ion channel conductances as drug targets. An introduction to the zebrafish as a model organism, in particular for cardiovascular biology. Potential approaches to overcoming the hurdles to drug discovery in the face of complex biology including in vivo screening of zebrafish genetic disease models. TAKE HOME MESSAGE: In vivo screening in faithful disease models allows the effects of drugs on integrative physiology and disease biology to be captured during the screening process, in a manner agnostic to potential drug target or targets. This systematic strategy bypasses current gaps in our understanding of disease

  8. A new in vivo screening paradigm to accelerate antimalarial drug discovery.

    Directory of Open Access Journals (Sweden)

    María Belén Jiménez-Díaz

    Full Text Available The emergence of resistance to available antimalarials requires the urgent development of new medicines. The recent disclosure of several thousand compounds active in vitro against the erythrocyte stage of Plasmodium falciparum has been a major breakthrough, though converting these hits into new medicines challenges current strategies. A new in vivo screening concept was evaluated as a strategy to increase the speed and efficiency of drug discovery projects in malaria. The new in vivo screening concept was developed based on human disease parameters, i.e. parasitemia in the peripheral blood of patients on hospital admission and parasite reduction ratio (PRR, which were allometrically down-scaled into P. berghei-infected mice. Mice with an initial parasitemia (P0 of 1.5% were treated orally for two consecutive days and parasitemia measured 24 h after the second dose. The assay was optimized for detection of compounds able to stop parasite replication (PRR = 1 or induce parasite clearance (PRR >1 with statistical power >99% using only two mice per experimental group. In the P. berghei in vivo screening assay, the PRR of a set of eleven antimalarials with different mechanisms of action correlated with human-equivalent data. Subsequently, 590 compounds from the Tres Cantos Antimalarial Set with activity in vitro against P. falciparum were tested at 50 mg/kg (orally in an assay format that allowed the evaluation of hundreds of compounds per month. The rate of compounds with detectable efficacy was 11.2% and about one third of active compounds showed in vivo efficacy comparable with the most potent antimalarials used clinically. High-throughput, high-content in vivo screening could rapidly select new compounds, dramatically speeding up the discovery of new antimalarial medicines. A global multilateral collaborative project aimed at screening the significant chemical diversity within the antimalarial in vitro hits described in the literature is a

  9. A New In Vivo Screening Paradigm to Accelerate Antimalarial Drug Discovery

    Science.gov (United States)

    Jiménez-Díaz, María Belén; Viera, Sara; Ibáñez, Javier; Mulet, Teresa; Magán-Marchal, Noemí; Garuti, Helen; Gómez, Vanessa; Cortés-Gil, Lorena; Martínez, Antonio; Ferrer, Santiago; Fraile, María Teresa; Calderón, Félix; Fernández, Esther; Shultz, Leonard D.; Leroy, Didier; Wilson, David M.; García-Bustos, José Francisco; Gamo, Francisco Javier; Angulo-Barturen, Iñigo

    2013-01-01

    The emergence of resistance to available antimalarials requires the urgent development of new medicines. The recent disclosure of several thousand compounds active in vitro against the erythrocyte stage of Plasmodium falciparum has been a major breakthrough, though converting these hits into new medicines challenges current strategies. A new in vivo screening concept was evaluated as a strategy to increase the speed and efficiency of drug discovery projects in malaria. The new in vivo screening concept was developed based on human disease parameters, i.e. parasitemia in the peripheral blood of patients on hospital admission and parasite reduction ratio (PRR), which were allometrically down-scaled into P. berghei-infected mice. Mice with an initial parasitemia (P0) of 1.5% were treated orally for two consecutive days and parasitemia measured 24 h after the second dose. The assay was optimized for detection of compounds able to stop parasite replication (PRR = 1) or induce parasite clearance (PRR >1) with statistical power >99% using only two mice per experimental group. In the P. berghei in vivo screening assay, the PRR of a set of eleven antimalarials with different mechanisms of action correlated with human-equivalent data. Subsequently, 590 compounds from the Tres Cantos Antimalarial Set with activity in vitro against P. falciparum were tested at 50 mg/kg (orally) in an assay format that allowed the evaluation of hundreds of compounds per month. The rate of compounds with detectable efficacy was 11.2% and about one third of active compounds showed in vivo efficacy comparable with the most potent antimalarials used clinically. High-throughput, high-content in vivo screening could rapidly select new compounds, dramatically speeding up the discovery of new antimalarial medicines. A global multilateral collaborative project aimed at screening the significant chemical diversity within the antimalarial in vitro hits described in the literature is a feasible task

  10. An Algorithm for Computing Screened Coulomb Scattering in Geant4

    OpenAIRE

    Mendenhall, Marcus H.; Weller, Robert A.

    2004-01-01

    An algorithm has been developed for the Geant4 Monte-Carlo package for the efficient computation of screened Coulomb interatomic scattering. It explicitly integrates the classical equations of motion for scattering events, resulting in precise tracking of both the projectile and the recoil target nucleus. The algorithm permits the user to plug in an arbitrary screening function, such as Lens-Jensen screening, which is good for backscattering calculations, or Ziegler-Biersack-Littmark screenin...

  11. Discoveries and application of prostate-specific antigen, and some proposals to optimize prostate cancer screening

    Directory of Open Access Journals (Sweden)

    Tokudome S

    2016-05-01

    Full Text Available Shinkan Tokudome,1 Ryosuke Ando,2 Yoshiro Koda,3 1Department of Nutritional Epidemiology, National Institute of Health and Nutrition, Shinjuku-ku, Tokyo, 2Department of Nephro-urology, Nagoya City University Graduate School of Medical Sciences, Mizuho-ku, Nagoya, 3Department of Forensic Medicine and Human Genetics, Kurume University School of Medicine, Kurume, Japan Abstract: The discoveries and application of prostate-specific antigen (PSA have been much appreciated because PSA-based screening has saved millions of lives of prostate cancer (PCa patients. Historically speaking, Flocks et al first identified antigenic properties in prostate tissue in 1960. Then, Barnes et al detected immunologic characteristics in prostatic fluid in 1963. Hara et al characterized γ-semino-protein in semen in 1966, and it has been proven to be identical to PSA. Subsequently, Ablin et al independently reported the presence of precipitation antigens in the prostate in 1970. Wang et al purified the PSA in 1979, and Kuriyama et al first applied an enzyme-linked immunosorbent assay for PSA in 1980. However, the positive predictive value with a cutoff figure of 4.0 ng/mL appeared substantially low (~30%. There are overdiagnoses and overtreatments for latent/low-risk PCa. Controversies exist in the PCa mortality-reducing effects of PSA screening between the European Randomized Study of Screening for Prostate Cancer (ERSPC and the US Prostate, Lung, Colorectal, and Ovarian (PLCO Cancer Screening Trial. For optimizing PCa screening, PSA-related items may require the following: 1 adjustment of the cutoff values according to age, as well as setting limits to age and screening intervals; 2 improving test performance using doubling time, density, and ratio of free: total PSA; and 3 fostering active surveillance for low-risk PCa with monitoring by PSA value. Other items needing consideration may include the following: 1 examinations of cell proliferation and cell cycle markers

  12. UCLA's Molecular Screening Shared Resource: enhancing small molecule discovery with functional genomics and new technology.

    Science.gov (United States)

    Damoiseaux, Robert

    2014-05-01

    The Molecular Screening Shared Resource (MSSR) offers a comprehensive range of leading-edge high throughput screening (HTS) services including drug discovery, chemical and functional genomics, and novel methods for nano and environmental toxicology. The MSSR is an open access environment with investigators from UCLA as well as from the entire globe. Industrial clients are equally welcome as are non-profit entities. The MSSR is a fee-for-service entity and does not retain intellectual property. In conjunction with the Center for Environmental Implications of Nanotechnology, the MSSR is unique in its dedicated and ongoing efforts towards high throughput toxicity testing of nanomaterials. In addition, the MSSR engages in technology development eliminating bottlenecks from the HTS workflow and enabling novel assays and readouts currently not available.

  13. Biophysical Screening of a Focused Library for the Discovery of CYP121 Inhibitors as Novel Antimycobacterials.

    Science.gov (United States)

    Brengel, Christian; Thomann, Andreas; Schifrin, Alexander; Allegretta, Giuseppe; Kamal, Ahmed A M; Haupenthal, Jörg; Schnorr, Isabell; Cho, Sang Hyun; Franzblau, Scott G; Empting, Martin; Eberhard, Jens; Hartmann, Rolf W

    2017-10-09

    The development of novel antimycobacterial agents against Mycobacterium tuberculosis (Mtb) is urgently required due to the appearance of multidrug resistance (MDR) combined with complicated long-term treatment. CYP121 was shown to be a promising novel target for inhibition of mycobacterial growth. In this study, we describe the rational discovery of new CYP121 inhibitors by a systematic screening based on biophysical and microbiological methods. The best hits originating from only one structural class gave initial information about molecular motifs required for binding and activity. The initial screening procedure was followed by mode-of-action studies and further biological characterizations. The results demonstrate superior antimycobacterial efficacy and a decreased toxicity profile of our frontrunner compound relative to the reference compound econazole. Due to its low molecular weight, promising biological profile, and physicochemical properties, this compound is an excellent starting point for further rational optimization. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  14. Accelerated oral nanomedicine discovery from miniaturized screening to clinical production exemplified by paediatric HIV nanotherapies

    Science.gov (United States)

    Giardiello, Marco; Liptrott, Neill J.; McDonald, Tom O.; Moss, Darren; Siccardi, Marco; Martin, Phil; Smith, Darren; Gurjar, Rohan; Rannard, Steve P.; Owen, Andrew

    2016-10-01

    Considerable scope exists to vary the physical and chemical properties of nanoparticles, with subsequent impact on biological interactions; however, no accelerated process to access large nanoparticle material space is currently available, hampering the development of new nanomedicines. In particular, no clinically available nanotherapies exist for HIV populations and conventional paediatric HIV medicines are poorly available; one current paediatric formulation utilizes high ethanol concentrations to solubilize lopinavir, a poorly soluble antiretroviral. Here we apply accelerated nanomedicine discovery to generate a potential aqueous paediatric HIV nanotherapy, with clinical translation and regulatory approval for human evaluation. Our rapid small-scale screening approach yields large libraries of solid drug nanoparticles (160 individual components) targeting oral dose. Screening uses 1 mg of drug compound per library member and iterative pharmacological and chemical evaluation establishes potential candidates for progression through to clinical manufacture. The wide applicability of our strategy has implications for multiple therapy development programmes.

  15. Established and Emerging Trends in Computational Drug Discovery in the Structural Genomics Era

    DEFF Research Database (Denmark)

    Taboureau, Olivier; Baell, Jonathan B.; Fernández-Recio, Juan

    2012-01-01

    Bioinformatics and chemoinformatics approaches contribute to hit discovery, hit-to-lead optimization, safety profiling, and target identification and enhance our overall understanding of the health and disease states. A vast repertoire of computational methods has been reported and increasingly...

  16. Ebola virus: A gap in drug design and discovery - experimental and computational perspective.

    Science.gov (United States)

    Balmith, Marissa; Faya, Mbuso; Soliman, Mahmoud E S

    2017-03-01

    The Ebola virus, formally known as the Ebola hemorrhagic fever, is an acute viral syndrome causing sporadic outbreaks that have ravaged West Africa. Due to its extreme virulence and highly transmissible nature, Ebola has been classified as a category A bioweapon organism. Only recently have vaccine or drug regimens for the Ebola virus been developed, including Zmapp and peptides. In addition, existing drugs which have been repurposed toward anti-Ebola virus activity have been re-examined and are seen to be promising candidates toward combating Ebola. Drug development involving computational tools has been widely employed toward target-based drug design. Screening large libraries have greatly stimulated research toward effective anti-Ebola virus drug regimens. Current emphasis has been placed on the investigation of host proteins and druggable viral targets. There is a huge gap in the literature regarding guidelines in the discovery of Ebola virus inhibitors, which may be due to the lack of information on the Ebola drug targets, binding sites, and mechanism of action of the virus. This review focuses on Ebola virus inhibitors, drugs which could be repurposed to combat the Ebola virus, computational methods which study drug-target interactions as well as providing further insight into the mode of action of the Ebola virus. © 2016 John Wiley & Sons A/S.

  17. Do Computers Write on Electric Screens?

    Directory of Open Access Journals (Sweden)

    Samuel Goyet

    2016-09-01

    Full Text Available How do we, humans, communicate with computers, or computational machines? What are the activities do humans and machines share, what are the meeting points between the two? Eventually, how can we build concepts of these meeting points that leaves space for the proper mode of existence of both humans and machines, without subduing one to the other? Computers are machines that operates on a scale different from humans: the calculus done by machines is too fast and untangible for humans. This is why computers activities has to be textualized, put into a form that can be understand for humans. For instance into a graphical interface, or a command line. More generally, this article tackles the problem of interface between humans and machines, the way the relation between humans and machines has been conceptualized. It is inspired both by philosophy of the modes of existence – since computers are machines with their own mode of existence – and semiotics, since computers activities have to be converted in some sort of signs that can be read by humans.

  18. Drug discovery for male subfertility using high-throughput screening: a new approach to an unsolved problem.

    Science.gov (United States)

    Martins da Silva, Sarah J; Brown, Sean G; Sutton, Keith; King, Louise V; Ruso, Halil; Gray, David W; Wyatt, Paul G; Kelly, Mark C; Barratt, Christopher L R; Hope, Anthony G

    2017-05-01

    Can pharma drug discovery approaches be utilized to transform investigation into novel therapeutics for male infertility? High-throughput screening (HTS) is a viable approach to much-needed drug discovery for male factor infertility. There is both huge demand and a genuine clinical need for new treatment options for infertile men. However, the time, effort and resources required for drug discovery are currently exorbitant, due to the unique challenges of the cellular, physical and functional properties of human spermatozoa and a lack of appropriate assay platform. Spermatozoa were obtained from healthy volunteer research donors and subfertile patients undergoing IVF/ICSI at a hospital-assisted reproductive techniques clinic between January 2012 and November 2016. A HTS assay was developed and validated using intracellular calcium ([Ca2+]i) as a surrogate for motility in human spermatozoa. Calcium fluorescence was detected using a Flexstation microplate reader (384-well platform) and compared with responses evoked by progesterone, a compound known to modify a number of biologically relevant behaviours in human spermatozoa. Hit compounds identified following single point drug screen (10 μM) of an ion channel-focussed library assembled by the University of Dundee Drug Discovery Unit were rescreened to ensure potency using standard 10 point half-logarithm concentration curves, and tested for purity and integrity using liquid chromatography and mass spectrometry. Hit compounds were grouped by structure activity relationships and five representative compounds then further investigated for direct effects on spermatozoa, using computer-assisted sperm assessment, sperm penetration assay and whole-cell patch clamping. Of the 3242 ion channel library ligands screened, 384 compounds (11.8%) elicited a statistically significant increase in calcium fluorescence, with greater than 3× median absolute deviation above the baseline. Seventy-four compounds eliciting ≥50% increase

  19. SCREENING CHEMICALS FOR ESTROGEN RECEPTOR BIOACTIVITY USING A COMPUTATIONAL MODEL

    Science.gov (United States)

    The U.S. Environmental Protection Agency (EPA) is considering the use high-throughput and computational methods for regulatory applications in the Endocrine Disruptor Screening Program (EDSP). To use these new tools for regulatory decision making, computational methods must be a...

  20. Computational and Experimental Approaches to Cancer Biomarker Discovery

    DEFF Research Database (Denmark)

    Krzystanek, Marcin

    of a patient’s response to a particular treatment, thus helping to avoid unnecessary treatment and unwanted side effects in non-responding individuals.Currently biomarker discovery is facilitated by recent advances in high-throughput technologies when association between a given biological phenotype...... and the state or level of a large number of molecular entities is investigated. Such associative analysis could be confounded by several factors, leading to false discoveries. For example, it is assumed that with the exception of the true biomarkers most molecular entities such as gene expression levels show...... random distribution in a given cohort. However, gene expression levels may also be affected by technical bias when the actual measurement technology or sample handling may introduce a systematic error. If the distribution of systematic errors correlates with the biological phenotype then the risk...

  1. High Throughput Screening in Duchenne Muscular Dystrophy: From Drug Discovery to Functional Genomics

    Directory of Open Access Journals (Sweden)

    Thomas J.J. Gintjee

    2014-11-01

    Full Text Available Centers for the screening of biologically active compounds and genomic libraries are becoming common in the academic setting and have enabled researchers devoted to developing strategies for the treatment of diseases or interested in studying a biological phenomenon to have unprecedented access to libraries that, until few years ago, were accessible only by pharmaceutical companies. As a result, new drugs and genetic targets have now been identified for the treatment of Duchenne muscular dystrophy (DMD, the most prominent of the neuromuscular disorders affecting children. Although the work is still at an early stage, the results obtained to date are encouraging and demonstrate the importance that these centers may have in advancing therapeutic strategies for DMD as well as other diseases. This review will provide a summary of the status and progress made toward the development of a cure for this disorder and implementing high-throughput screening (HTS technologies as the main source of discovery. As more academic institutions are gaining access to HTS as a valuable discovery tool, the identification of new biologically active molecules is likely to grow larger. In addition, the presence in the academic setting of experts in different aspects of the disease will offer the opportunity to develop novel assays capable of identifying new targets to be pursued as potential therapeutic options. These assays will represent an excellent source to be used by pharmaceutical companies for the screening of larger libraries providing the opportunity to establish strong collaborations between the private and academic sectors and maximizing the chances of bringing into the clinic new drugs for the treatment of DMD.

  2. High throughput screening in duchenne muscular dystrophy: from drug discovery to functional genomics.

    Science.gov (United States)

    Gintjee, Thomas J J; Magh, Alvin S H; Bertoni, Carmen

    2014-11-14

    Centers for the screening of biologically active compounds and genomic libraries are becoming common in the academic setting and have enabled researchers devoted to developing strategies for the treatment of diseases or interested in studying a biological phenomenon to have unprecedented access to libraries that, until few years ago, were accessible only by pharmaceutical companies. As a result, new drugs and genetic targets have now been identified for the treatment of Duchenne muscular dystrophy (DMD), the most prominent of the neuromuscular disorders affecting children. Although the work is still at an early stage, the results obtained to date are encouraging and demonstrate the importance that these centers may have in advancing therapeutic strategies for DMD as well as other diseases. This review will provide a summary of the status and progress made toward the development of a cure for this disorder and implementing high-throughput screening (HTS) technologies as the main source of discovery. As more academic institutions are gaining access to HTS as a valuable discovery tool, the identification of new biologically active molecules is likely to grow larger. In addition, the presence in the academic setting of experts in different aspects of the disease will offer the opportunity to develop novel assays capable of identifying new targets to be pursued as potential therapeutic options. These assays will represent an excellent source to be used by pharmaceutical companies for the screening of larger libraries providing the opportunity to establish strong collaborations between the private and academic sectors and maximizing the chances of bringing into the clinic new drugs for the treatment of DMD.

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

    Directory of Open Access Journals (Sweden)

    Lucía Pérez-Regidor

    2016-09-01

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

  4. Molecular-Simulation-Driven Fragment Screening for the Discovery of New CXCL12 Inhibitors.

    Science.gov (United States)

    Martinez-Rosell, Gerard; Harvey, Matt J; De Fabritiis, Gianni

    2018-03-26

    Fragment-based drug discovery (FBDD) has become a mainstream approach in drug design because it allows the reduction of the chemical space and screening libraries while identifying fragments with high protein-ligand efficiency interactions that can later be grown into drug-like leads. In this work, we leverage high-throughput molecular dynamics (MD) simulations to screen a library of 129 fragments for a total of 5.85 ms against the CXCL12 monomer, a chemokine involved in inflammation and diseases such as cancer. Our in silico binding assay was able to recover binding poses, affinities, and kinetics for the selected library and was able to predict 8 mM-affinity fragments with ligand efficiencies higher than 0.3. All of the fragment hits present a similar chemical structure, with a hydrophobic core and a positively charged group, and bind to either sY7 or H1S68 pockets, where they share pharmacophoric properties with experimentally resolved natural binders. This work presents a large-scale screening assay using an exclusive combination of thousands of short MD adaptive simulations analyzed with a Markov state model (MSM) framework.

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

    International Nuclear Information System (INIS)

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

    2015-01-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2015-01-15

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

  7. Computational tools for high-throughput discovery in biology

    OpenAIRE

    Jones, Neil Christopher

    2007-01-01

    High throughput data acquisition technology has inarguably transformed the landscape of the life sciences, in part by making possible---and necessary---the computational disciplines of bioinformatics and biomedical informatics. These fields focus primarily on developing tools for analyzing data and generating hypotheses about objects in nature, and it is in this context that we address three pressing problems in the fields of the computational life sciences which each require computing capaci...

  8. Computational methods for a three-dimensional model of the petroleum-discovery process

    Science.gov (United States)

    Schuenemeyer, J.H.; Bawiec, W.J.; Drew, L.J.

    1980-01-01

    A discovery-process model devised by Drew, Schuenemeyer, and Root can be used to predict the amount of petroleum to be discovered in a basin from some future level of exploratory effort: the predictions are based on historical drilling and discovery data. Because marginal costs of discovery and production are a function of field size, the model can be used to make estimates of future discoveries within deposit size classes. The modeling approach is a geometric one in which the area searched is a function of the size and shape of the targets being sought. A high correlation is assumed between the surface-projection area of the fields and the volume of petroleum. To predict how much oil remains to be found, the area searched must be computed, and the basin size and discovery efficiency must be estimated. The basin is assumed to be explored randomly rather than by pattern drilling. The model may be used to compute independent estimates of future oil at different depth intervals for a play involving multiple producing horizons. We have written FORTRAN computer programs that are used with Drew, Schuenemeyer, and Root's model to merge the discovery and drilling information and perform the necessary computations to estimate undiscovered petroleum. These program may be modified easily for the estimation of remaining quantities of commodities other than petroleum. ?? 1980.

  9. NCI Program for Natural Product Discovery: A Publicly-Accessible Library of Natural Product Fractions for High-Throughput Screening.

    Science.gov (United States)

    Thornburg, Christopher C; Britt, John R; Evans, Jason R; Akee, Rhone K; Whitt, James A; Trinh, Spencer K; Harris, Matthew J; Thompson, Jerell R; Ewing, Teresa L; Shipley, Suzanne M; Grothaus, Paul G; Newman, David J; Schneider, Joel P; Grkovic, Tanja; O'Keefe, Barry R

    2018-06-13

    The US National Cancer Institute's (NCI) Natural Product Repository is one of the world's largest, most diverse collections of natural products containing over 230,000 unique extracts derived from plant, marine, and microbial organisms that have been collected from biodiverse regions throughout the world. Importantly, this national resource is available to the research community for the screening of extracts and the isolation of bioactive natural products. However, despite the success of natural products in drug discovery, compatibility issues that make extracts challenging for liquid handling systems, extended timelines that complicate natural product-based drug discovery efforts and the presence of pan-assay interfering compounds have reduced enthusiasm for the high-throughput screening (HTS) of crude natural product extract libraries in targeted assay systems. To address these limitations, the NCI Program for Natural Product Discovery (NPNPD), a newly launched, national program to advance natural product discovery technologies and facilitate the discovery of structurally defined, validated lead molecules ready for translation will create a prefractionated library from over 125,000 natural product extracts with the aim of producing a publicly-accessible, HTS-amenable library of >1,000,000 fractions. This library, representing perhaps the largest accumulation of natural-product based fractions in the world, will be made available free of charge in 384-well plates for screening against all disease states in an effort to reinvigorate natural product-based drug discovery.

  10. Exploiting pluripotent stem cell technology for drug discovery, screening, safety, and toxicology assessments.

    Science.gov (United States)

    McGivern, Jered V; Ebert, Allison D

    2014-04-01

    In order for the pharmaceutical industry to maintain a constant flow of novel drugs and therapeutics into the clinic, compounds must be thoroughly validated for safety and efficacy in multiple biological and biochemical systems. Pluripotent stem cells, because of their ability to develop into any cell type in the body and recapitulate human disease, may be an important cellular system to add to the drug development repertoire. This review will discuss some of the benefits of using pluripotent stem cells for drug discovery and safety studies as well as some of the recent applications of stem cells in drug screening studies. We will also address some of the hurdles that need to be overcome in order to make stem cell-based approaches an efficient and effective tool in the quest to produce clinically successful drug compounds. Copyright © 2013 Elsevier B.V. All rights reserved.

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

    Science.gov (United States)

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

    2018-01-01

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

  12. Opportunities for discovery: Theory and computation in Basic Energy Sciences

    Energy Technology Data Exchange (ETDEWEB)

    Harmon, Bruce; Kirby, Kate; McCurdy, C. William

    2005-01-11

    New scientific frontiers, recent advances in theory, and rapid increases in computational capabilities have created compelling opportunities for theory and computation to advance the scientific mission of the Office of Basic Energy Sciences (BES). The prospects for success in the experimental programs of BES will be enhanced by pursuing these opportunities. This report makes the case for an expanded research program in theory and computation in BES. The Subcommittee on Theory and Computation of the Basic Energy Sciences Advisory Committee was charged with identifying current and emerging challenges and opportunities for theoretical research within the scientific mission of BES, paying particular attention to how computing will be employed to enable that research. A primary purpose of the Subcommittee was to identify those investments that are necessary to ensure that theoretical research will have maximum impact in the areas of importance to BES, and to assure that BES researchers will be able to exploit the entire spectrum of computational tools, including leadership class computing facilities. The Subcommittee s Findings and Recommendations are presented in Section VII of this report.

  13. Computational discovery of picomolar Q(o) site inhibitors of cytochrome bc1 complex.

    Science.gov (United States)

    Hao, Ge-Fei; Wang, Fu; Li, Hui; Zhu, Xiao-Lei; Yang, Wen-Chao; Huang, Li-Shar; Wu, Jia-Wei; Berry, Edward A; Yang, Guang-Fu

    2012-07-11

    A critical challenge to the fragment-based drug discovery (FBDD) is its low-throughput nature due to the necessity of biophysical method-based fragment screening. Herein, a method of pharmacophore-linked fragment virtual screening (PFVS) was successfully developed. Its application yielded the first picomolar-range Q(o) site inhibitors of the cytochrome bc(1) complex, an important membrane protein for drug and fungicide discovery. Compared with the original hit compound 4 (K(i) = 881.80 nM, porcine bc(1)), the most potent compound 4f displayed 20 507-fold improved binding affinity (K(i) = 43.00 pM). Compound 4f was proved to be a noncompetitive inhibitor with respect to the substrate cytochrome c, but a competitive inhibitor with respect to the substrate ubiquinol. Additionally, we determined the crystal structure of compound 4e (K(i) = 83.00 pM) bound to the chicken bc(1) at 2.70 Å resolution, providing a molecular basis for understanding its ultrapotency. To our knowledge, this study is the first application of the FBDD method in the discovery of picomolar inhibitors of a membrane protein. This work demonstrates that the novel PFVS approach is a high-throughput drug discovery method, independent of biophysical screening techniques.

  14. Computational Screening of MOFs for Acetylene Separation.

    Science.gov (United States)

    Nemati Vesali Azar, Ayda; Keskin, Seda

    2018-01-01

    Efficient separation of acetylene (C 2 H 2 ) from CO 2 and CH 4 is important to meet the requirement of high-purity acetylene in various industrial applications. Metal organic frameworks (MOFs) are great candidates for adsorption-based C 2 H 2 /CO 2 and C 2 H 2 /CH 4 separations due to their unique properties such as wide range of pore sizes and tunable chemistries. Experimental studies on the limited number of MOFs revealed that MOFs offer remarkable C 2 H 2 /CO 2 and C 2 H 2 /CH 4 selectivities based on single-component adsorption data. We performed the first large-scale molecular simulation study to investigate separation performances of 174 different MOF structures for C 2 H 2 /CO 2 and C 2 H 2 /CH 4 mixtures. Using the results of molecular simulations, several adsorbent performance evaluation metrics, such as selectivity, working capacity, adsorbent performance score, sorbent selection parameter, and regenerability were computed for each MOF. Based on these metrics, the best adsorbent candidates were identified for both separations. Results showed that the top three most promising MOF adsorbents exhibit C 2 H 2 /CO 2 selectivities of 49, 47, 24 and C 2 H 2 /CH 4 selectivities of 824, 684, 638 at 1 bar, 298 K and these are the highest C 2 H 2 selectivities reported to date in the literature. Structure-performance analysis revealed that the best MOF adsorbents have pore sizes between 4 and 11 Å, surface areas in the range of 600-1,200 m 2 /g and porosities between 0.4 and 0.6 for selective separation of C 2 H 2 from CO 2 and CH 4 . These results will guide the future studies for the design of new MOFs with high C 2 H 2 separation potentials.

  15. Computational Screening of MOFs for Acetylene Separation

    Science.gov (United States)

    Nemati Vesali Azar, Ayda; Keskin, Seda

    2018-02-01

    Efficient separation of acetylene (C2H2) from CO2 and CH4 is important to meet the requirement of high-purity acetylene in various industrial applications. Metal organic frameworks (MOFs) are great candidates for adsorption-based C2H2/CO2 and C2H2/CH4 separations due to their unique properties such as wide range of pore sizes and tunable chemistries. Experimental studies on the limited number of MOFs revealed that MOFs offer remarkable C2H2/CO2 and C2H2/CH4 selectivities based on single-component adsorption data. We performed the first large-scale molecular simulation study to investigate separation performances of 174 different MOF structures for C2H2/CO2 and C2H2/CH4 mixtures. Using the results of molecular simulations, several adsorbent performance evaluation metrics, such as selectivity, working capacity, adsorbent performance score, sorbent selection parameter and regenerability were computed for each MOF. Based on these metrics, the best adsorbent candidates were identified for both separations. Results showed that the top three most promising MOF adsorbents exhibit C2H2/CO2 selectivities of 49, 47, 24 and C2H2/CH4 selectivities of 824, 684, 638 at 1 bar, 298 K and these are the highest C2H2 selectivities reported to date in the literature. Structure-performance analysis revealed that the best MOF adsorbents have pore sizes between 4-11 Å, surface areas in the range of 600-1,200 m2/g and porosities between 0.4-0.6 for selective separation of C2H2 from CO2 and CH4. These results will guide the future studies for the design of new MOFs with high C2H2 separation potentials.

  16. Computational Screening of MOFs for Acetylene Separation

    Directory of Open Access Journals (Sweden)

    Ayda Nemati Vesali Azar

    2018-02-01

    Full Text Available Efficient separation of acetylene (C2H2 from CO2 and CH4 is important to meet the requirement of high-purity acetylene in various industrial applications. Metal organic frameworks (MOFs are great candidates for adsorption-based C2H2/CO2 and C2H2/CH4 separations due to their unique properties such as wide range of pore sizes and tunable chemistries. Experimental studies on the limited number of MOFs revealed that MOFs offer remarkable C2H2/CO2 and C2H2/CH4 selectivities based on single-component adsorption data. We performed the first large-scale molecular simulation study to investigate separation performances of 174 different MOF structures for C2H2/CO2 and C2H2/CH4 mixtures. Using the results of molecular simulations, several adsorbent performance evaluation metrics, such as selectivity, working capacity, adsorbent performance score, sorbent selection parameter, and regenerability were computed for each MOF. Based on these metrics, the best adsorbent candidates were identified for both separations. Results showed that the top three most promising MOF adsorbents exhibit C2H2/CO2 selectivities of 49, 47, 24 and C2H2/CH4 selectivities of 824, 684, 638 at 1 bar, 298 K and these are the highest C2H2 selectivities reported to date in the literature. Structure-performance analysis revealed that the best MOF adsorbents have pore sizes between 4 and 11 Å, surface areas in the range of 600–1,200 m2/g and porosities between 0.4 and 0.6 for selective separation of C2H2 from CO2 and CH4. These results will guide the future studies for the design of new MOFs with high C2H2 separation potentials.

  17. Phenotypic Screening Approaches to Develop Aurora Kinase Inhibitors: Drug Discovery Perspectives.

    Science.gov (United States)

    Marugán, Carlos; Torres, Raquel; Lallena, María José

    2015-01-01

    Targeting mitotic regulators as a strategy to fight cancer implies the development of drugs against key proteins, such as Aurora-A and -B. Current drugs, which target mitosis through a general mechanism of action (stabilization/destabilization of microtubules), have several side effects (neutropenia, alopecia, and emesis). Pharmaceutical companies aim at avoiding these unwanted effects by generating improved and selective drugs that increase the quality of life of the patients. However, the development of these drugs is an ambitious task that involves testing thousands of compounds through biochemical and cell-based assays. In addition, molecules usually target complex biological processes, involving several proteins and different molecular pathways, further emphasizing the need for high-throughput screening techniques and multiplexing technologies in order to identify drugs with the desired phenotype. We will briefly describe two multiplexing technologies [high-content imaging (HCI) and flow cytometry] and two key processes for drug discovery research (assay development and validation) following our own published industry quality standards. We will further focus on HCI as a useful tool for phenotypic screening and will provide a concrete example of HCI assay to detect Aurora-A or -B selective inhibitors discriminating the off-target effects related to the inhibition of other cell cycle or non-cell cycle key regulators. Finally, we will describe other assays that can help to characterize the in vitro pharmacology of the inhibitors.

  18. Phenotypic screening approaches to develop Aurora kinase inhibitors: Drug Discovery perspectives

    Directory of Open Access Journals (Sweden)

    Carlos eMarugán

    2016-01-01

    Full Text Available Targeting mitotic regulators as a strategy to fight cancer implies the development of drugs against key proteins such as Aurora A and B. Current drugs which target mitosis through a general mechanism of action (stabilization/destabilization of microtubules, have several side effects (neutropenia, alopecia, emesis. Pharmaceutical companies aim at avoiding these unwanted effects by generating improved and selective drugs that increase the quality of life of the patients. However, the development of these drugs is an ambitious task that involves testing thousands of compounds through biochemical and cell-based assays. In addition, molecules usually target complex biological processes, involving several proteins and different molecular pathways, further emphasizing the need for high-throughput screening techniques and multiplexing technologies in order to identify drugs with the desired phenotype.We will briefly describe two multiplexing technologies (high-content imaging, microarrays and flow cytometry and two key processes for drug discovery research (assay development and validation following our own published industry quality standards. We will further focus on high-content imaging as a useful tool for phenotypic screening and will provide a concrete example of high-content imaging assay to detect Aurora A or B selective inhibitors discriminating the off-target effects related to inhibition of other cell cycle or non-cell cycle key regulators. Finally, we will describe other assays that can help to characterize the in vitro pharmacology of the inhibitors.

  19. Radiation levels from computer monitor screens within Benue State ...

    African Journals Online (AJOL)

    Investigation of possible presence of soft X-ray levels from Computer Screens at distances of 0.5m and 1.0m was carried out within Benue State University, Makurdi, using ten different monitor models. Radiation measurement was carried out using a portable digital radiation meter, INSPECTOR 06250 (SE international Inc.

  20. An algorithm for computing screened Coulomb scattering in GEANT4

    Energy Technology Data Exchange (ETDEWEB)

    Mendenhall, Marcus H. [Vanderbilt University Free Electron Laser Center, P.O. Box 351816 Station B, Nashville, TN 37235-1816 (United States)]. E-mail: marcus.h.mendenhall@vanderbilt.edu; Weller, Robert A. [Department of Electrical Engineering and Computer Science, Vanderbilt University, P.O. Box 351821 Station B, Nashville, TN 37235-1821 (United States)]. E-mail: robert.a.weller@vanderbilt.edu

    2005-01-01

    An algorithm has been developed for the GEANT4 Monte-Carlo package for the efficient computation of screened Coulomb interatomic scattering. It explicitly integrates the classical equations of motion for scattering events, resulting in precise tracking of both the projectile and the recoil target nucleus. The algorithm permits the user to plug in an arbitrary screening function, such as Lens-Jensen screening, which is good for backscattering calculations, or Ziegler-Biersack-Littmark screening, which is good for nuclear straggling and implantation problems. This will allow many of the applications of the TRIM and SRIM codes to be extended into the much more general GEANT4 framework where nuclear and other effects can be included.

  1. An algorithm for computing screened Coulomb scattering in GEANT4

    International Nuclear Information System (INIS)

    Mendenhall, Marcus H.; Weller, Robert A.

    2005-01-01

    An algorithm has been developed for the GEANT4 Monte-Carlo package for the efficient computation of screened Coulomb interatomic scattering. It explicitly integrates the classical equations of motion for scattering events, resulting in precise tracking of both the projectile and the recoil target nucleus. The algorithm permits the user to plug in an arbitrary screening function, such as Lens-Jensen screening, which is good for backscattering calculations, or Ziegler-Biersack-Littmark screening, which is good for nuclear straggling and implantation problems. This will allow many of the applications of the TRIM and SRIM codes to be extended into the much more general GEANT4 framework where nuclear and other effects can be included

  2. SSTRAP: A computational model for genomic motif discovery ...

    African Journals Online (AJOL)

    Computational methods can potentially provide high-quality prediction of biological molecules such as DNA binding sites and Transcription factors and therefore reduce the time needed for experimental verification and challenges associated with experimental methods. These biological molecules or motifs have significant ...

  3. Ontology-Driven Discovery of Scientific Computational Entities

    Science.gov (United States)

    Brazier, Pearl W.

    2010-01-01

    Many geoscientists use modern computational resources, such as software applications, Web services, scientific workflows and datasets that are readily available on the Internet, to support their research and many common tasks. These resources are often shared via human contact and sometimes stored in data portals; however, they are not necessarily…

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

    Science.gov (United States)

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

    2011-05-01

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

  5. Bond-based linear indices in QSAR: computational discovery of novel anti-trichomonal compounds

    Science.gov (United States)

    Marrero-Ponce, Yovani; Meneses-Marcel, Alfredo; Rivera-Borroto, Oscar M.; García-Domenech, Ramón; De Julián-Ortiz, Jesus Vicente; Montero, Alina; Escario, José Antonio; Barrio, Alicia Gómez; Pereira, David Montero; Nogal, Juan José; Grau, Ricardo; Torrens, Francisco; Vogel, Christian; Arán, Vicente J.

    2008-08-01

    Trichomonas vaginalis ( Tv) is the causative agent of the most common, non-viral, sexually transmitted disease in women and men worldwide. Since 1959, metronidazole (MTZ) has been the drug of choice in the systemic treatment of trichomoniasis. However, resistance to MTZ in some patients and the great cost associated with the development of new trichomonacidals make necessary the development of computational methods that shorten the drug discovery pipeline. Toward this end, bond-based linear indices, new TOMOCOMD-CARDD molecular descriptors, and linear discriminant analysis were used to discover novel trichomonacidal chemicals. The obtained models, using non-stochastic and stochastic indices, are able to classify correctly 89.01% (87.50%) and 82.42% (84.38%) of the chemicals in the training (test) sets, respectively. These results validate the models for their use in the ligand-based virtual screening. In addition, they show large Matthews' correlation coefficients ( C) of 0.78 (0.71) and 0.65 (0.65) for the training (test) sets, correspondingly. The result of predictions on the 10% full-out cross-validation test also evidences the robustness of the obtained models. Later, both models are applied to the virtual screening of 12 compounds already proved against Tv. As a result, they correctly classify 10 out of 12 (83.33%) and 9 out of 12 (75.00%) of the chemicals, respectively; which is the most important criterion for validating the models. Besides, these classification functions are applied to a library of seven chemicals in order to find novel antitrichomonal agents. These compounds are synthesized and tested for in vitro activity against Tv. As a result, experimental observations approached to theoretical predictions, since it was obtained a correct classification of 85.71% (6 out of 7) of the chemicals. Moreover, out of the seven compounds that are screened, synthesized and biologically assayed, six compounds (VA7-34, VA7-35, VA7-37, VA7-38, VA7-68, VA7-70) show

  6. A high content screening assay to predict human drug-induced liver injury during drug discovery.

    Science.gov (United States)

    Persson, Mikael; Løye, Anni F; Mow, Tomas; Hornberg, Jorrit J

    2013-01-01

    Adverse drug reactions are a major cause for failures of drug development programs, drug withdrawals and use restrictions. Early hazard identification and diligent risk avoidance strategies are therefore essential. For drug-induced liver injury (DILI), this is difficult using conventional safety testing. To reduce the risk for DILI, drug candidates with a high risk need to be identified and deselected. And, to produce drug candidates without that risk associated, risk factors need to be assessed early during drug discovery, such that lead series can be optimized on safety parameters. This requires methods that allow for medium-to-high throughput compound profiling and that generate quantitative results suitable to establish structure-activity-relationships during lead optimization programs. We present the validation of such a method, a novel high content screening assay based on six parameters (nuclei counts, nuclear area, plasma membrane integrity, lysosomal activity, mitochondrial membrane potential (MMP), and mitochondrial area) using ~100 drugs of which the clinical hepatotoxicity profile is known. We find that a 100-fold TI between the lowest toxic concentration and the therapeutic Cmax is optimal to classify compounds as hepatotoxic or non-hepatotoxic, based on the individual parameters. Most parameters have ~50% sensitivity and ~90% specificity. Drugs hitting ≥2 parameters at a concentration below 100-fold their Cmax are typically hepatotoxic, whereas non-hepatotoxic drugs typically hit based on nuclei count, MMP and human Cmax, we identified an area without a single false positive, while maintaining 45% sensitivity. Hierarchical clustering using the multi-parametric dataset roughly separates toxic from non-toxic compounds. We employ the assay in discovery projects to prioritize novel compound series during hit-to-lead, to steer away from a DILI risk during lead optimization, for risk assessment towards candidate selection and to provide guidance of safe

  7. WISDOM-II: Screening against multiple targets implicated in malaria using computational grid infrastructures

    Directory of Open Access Journals (Sweden)

    Kenyon Colin

    2009-05-01

    Full Text Available Abstract Background Despite continuous efforts of the international community to reduce the impact of malaria on developing countries, no significant progress has been made in the recent years and the discovery of new drugs is more than ever needed. Out of the many proteins involved in the metabolic activities of the Plasmodium parasite, some are promising targets to carry out rational drug discovery. Motivation Recent years have witnessed the emergence of grids, which are highly distributed computing infrastructures particularly well fitted for embarrassingly parallel computations like docking. In 2005, a first attempt at using grids for large-scale virtual screening focused on plasmepsins and ended up in the identification of previously unknown scaffolds, which were confirmed in vitro to be active plasmepsin inhibitors. Following this success, a second deployment took place in the fall of 2006 focussing on one well known target, dihydrofolate reductase (DHFR, and on a new promising one, glutathione-S-transferase. Methods In silico drug design, especially vHTS is a widely and well-accepted technology in lead identification and lead optimization. This approach, therefore builds, upon the progress made in computational chemistry to achieve more accurate in silico docking and in information technology to design and operate large scale grid infrastructures. Results On the computational side, a sustained infrastructure has been developed: docking at large scale, using different strategies in result analysis, storing of the results on the fly into MySQL databases and application of molecular dynamics refinement are MM-PBSA and MM-GBSA rescoring. The modeling results obtained are very promising. Based on the modeling results, In vitro results are underway for all the targets against which screening is performed. Conclusion The current paper describes the rational drug discovery activity at large scale, especially molecular docking using FlexX software

  8. Depression screening using the Patient Health Questionnaire-9 administered on a touch screen computer.

    Science.gov (United States)

    Fann, Jesse R; Berry, Donna L; Wolpin, Seth; Austin-Seymour, Mary; Bush, Nigel; Halpenny, Barbara; Lober, William B; McCorkle, Ruth

    2009-01-01

    To (1) evaluate the feasibility of touch screen depression screening in cancer patients using the Patient Health Questionnaire-9 (PHQ-9), (2) evaluate the construct validity of the PHQ-9 using the touch screen modality, and (3) examine the prevalence and severity of depression using this screening modality. The PHQ-9 was placed in a web-based survey within a study of the clinical impact of computerized symptom and quality of life screening. Patients in medical oncology, radiation oncology, and hematopoietic stem cell transplantation (HSCT) clinics used the program on a touch screen computer in waiting rooms prior to therapy (T1) and during therapy (T2). Responses of depressed mood or anhedonia (PHQ-2 cardinal depression symptoms) triggered additional items. PHQ-9 scores were provided to the oncology team in real time. Among 342 patients enrolled, 33 (9.6%) at T1 and 69 (20.2%) at T2 triggered the full PHQ-9 by endorsing at least one cardinal symptom. Feasibility was high, with at least 97% completing the PHQ-2 and at least 96% completing the PHQ-9 when triggered and a mean completion time of about 2 min. The PHQ-9 had good construct validity. Medical oncology patients had the highest percent of positive screens (12.9%) at T1, while HSCT patients had the highest percent (30.5%) at T2. Using this method, 21 (6.1%) at T1 and 54 (15.8%) at T2 of the total sample had moderate to severe depression. The PHQ-9 administered on a touch screen computer is feasible and provides valid depression data in a diverse cancer population. (c) 2008 John Wiley & Sons, Ltd.

  9. Research Update: Computational materials discovery in soft matter

    Directory of Open Access Journals (Sweden)

    Tristan Bereau

    2016-05-01

    Full Text Available Soft matter embodies a wide range of materials, which all share the common characteristics of weak interaction energies determining their supramolecular structure. This complicates structure-property predictions and hampers the direct application of data-driven approaches to their modeling. We present several aspects in which these methods play a role in designing soft-matter materials: drug design as well as information-driven computer simulations, e.g., histogram reweighting. We also discuss recent examples of rational design of soft-matter materials fostered by physical insight and assisted by data-driven approaches. We foresee the combination of data-driven and physical approaches a promising strategy to move the field forward.

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

    Science.gov (United States)

    Carpenter, Kristy A; Huang, Xudong

    2018-06-07

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

  11. Arecibo PALFA survey and Einstein@Home: binary pulsar discovery by volunteer computing

    NARCIS (Netherlands)

    Knispel, B.; Lazarus, P.; Allen, B.; Anderson, D.; Aulbert, C.; Bhat, N.D.R.; Bock, O.; Bogdanov, S.; Brazier, A.; Camilo, F.; Chatterjee, S.; Cordes, J.M.; Crawford, F.; Deneva, J.S.; Desvignes, G.; Fehrmann, H.; Freire, P.C.C.; Hammer, D.; Hessels, J.W.T.; Jenet, F.A.; Kaspi, V.M.; Kramer, M.; van Leeuwen, J.; Lorimer, D.R.; Lyne, A.G.; Machenschalk, B.; McLaughlin, M.A.; Messenger, C.; Nice, D.J.; Papa, M.A.; Pletsch, H.J.; Prix, R.; Ransom, S.M.; Siemens, X.; Stairs, I.H.; Stappers, B.W.; Stovall, K.; Venkataraman, A.

    2011-01-01

    We report the discovery of the 20.7 ms binary pulsar J1952+2630, made using the distributed computing project Einstein@Home in Pulsar ALFA survey observations with the Arecibo telescope. Follow-up observations with the Arecibo telescope confirm the binary nature of the system. We obtain a circular

  12. Decision trees and integrated features for computer aided mammographic screening

    Energy Technology Data Exchange (ETDEWEB)

    Kegelmeyer, W.P. Jr.; Groshong, B.; Allmen, M.; Woods, K.

    1997-02-01

    Breast cancer is a serious problem, which in the United States causes 43,000 deaths a year, eventually striking 1 in 9 women. Early detection is the only effective countermeasure, and mass mammography screening is the only reliable means for early detection. Mass screening has many shortcomings which could be addressed by a computer-aided mammographic screening system. Accordingly, we have applied the pattern recognition methods developed in earlier investigations of speculated lesions in mammograms to the detection of microcalcifications and circumscribed masses, generating new, more rigorous and uniform methods for the detection of both those signs. We have also improved the pattern recognition methods themselves, through the development of a new approach to combinations of multiple classifiers.

  13. A Novel Strategy for Mechanism Based Computational Drug Discovery

    Science.gov (United States)

    Subha, Kalyaanamoorthy; Kumar, Gopal Ramesh; Rajalakshmi, Rajasekaran; Aravindhan, Ganesan

    2010-01-01

    Glioma, the common brain tumor, which arises from the glial cells, offers worse prognosis and therapy than any other tumors. Despite the genetic and pathological diversities of malignant gliomas, common signaling pathways that drive cellular proliferation, survival, invasion and angiogenesis have been identified. Very often, various tyrosine kinase receptors are inappropriately activated in human brain tumors and contribute to tumor malignancy. During such tumourous states where multiple pathways are involved, a few of them are responsbile for cell differentiation, proliferation and anti-apoptosis. Computational simulation studies of normal EGFR signaling in glioma together with the mutant EGFR mediated signaling and the MAPK signaling in glioma were carried out. There were no significant cross talks observed between the mutant EGFR and the MAPK pathways and thus from the simulation results, we propose a novel concept of ‘multiple-targeting’ that combines EGFR and Ras targeted therapy thereby providing a better therapeutic value against glioma. Diallyl Disulfide (DADS) that has been commonly used for Ras inhibition in glioma was taken for analyses and the effect of inhibiting the EGFR downstream signaling protein with this DADS was analyzed using the simulation and docking studies. PMID:24179383

  14. A Novel Strategy for Mechanism Based Computational Drug Discovery

    Directory of Open Access Journals (Sweden)

    Kalyaanamoorthy Subha

    2010-01-01

    Full Text Available Glioma, the common brain tumor, which arises from the glial cells, offers worse prognosis and therapy than any other tumors. Despite the genetic and pathological diversities of malignant gliomas, common signaling pathways that drive cellular proliferation, survival, invasion and angiogenesis have been identified. Very often, various tyrosine kinase receptors are inappropriately activated in human brain tumors and contribute to tumor malignancy. During such tumourous states where multiple pathways are involved, a few of them are responsbile for cell differentiation, proliferation and anti-apoptosis. Computational simulation studies of normal EGFR signaling in glioma together with the mutant EGFR mediated signaling and the MAPK signaling in glioma were carried out. There were no significant cross talks observed between the mutant EGFR and the MAPK pathways and thus from the simulation results, we propose a novel concept of ‘multiple-targeting’ that combines EGFR and Ras targeted therapy thereby providing a better therapeutic value against glioma. Diallyl Disulfide (DADS that has been commonly used for Ras inhibition in glioma was taken for analyses and the effect of inhibiting the EGFR downstream signaling protein with this DADS was analyzed using the simulation and docking studies.

  15. Physicochemical Profiles of the Marketed Agrochemicals and Clues for Agrochemical Lead Discovery and Screening Library Development.

    Science.gov (United States)

    Rao, Hanbing; Huangfu, Changxin; Wang, Yanying; Wang, Xianxiang; Tang, Tiansheng; Zeng, Xianyin; Li, Zerong; Chen, Yuzong

    2015-05-01

    Combinatorial chemistry, high-throughput and virtual screening technologies have been extensively used for discovering agrochemical leads from chemical libraries. The knowledge of the physicochemical properties of the marketed agrochemicals is useful for guiding the design and selection of such libraries. Since the earlier profiling of marketed agrochemicals, the number and types of marketed agrochemicals have significantly increased. Recent studies have shown the change of some physicochemical properties of oral drugs with time. There is a need to also profile the physicochemical properties of the marketed agrochemicals. In this work, we analyzed the key physicochemical properties of 1751 marketed agrochemicals in comparison with the previously-analyzed herbicides and insecticides, 106 391 natural products and 57 548 diverse synthetic libraries compounds. Our study revealed the distribution profiles and evolution trend of different types of agrochemicals that in many respects are broadly similar to the reported profiles for oral drugs, with the most marked difference being that agrochemicals have a lower number of hydrogen bond donors. The derived distribution patterns provided the rule of thumb guidelines for selecting potential agrochemical leads and also provided clues for further improving the libraries for agrochemical lead discovery. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  16. Individual Stochastic Screening for the Development of Computer Graphics

    Directory of Open Access Journals (Sweden)

    Maja Turčić¹*

    2012-12-01

    Full Text Available With the emergence of new tools and media, art and design have developed into digital computer-generated works. This article presents a sequence of creating art graphics because their original authors have not published the procedures. The goal is to discover the mathematics of an image and the programming libretto with the purpose of organizing a structural base of computer graphics. We will elaborate the procedures used to produce graphics known throughout the history of art, but that are nowadays also found in design and security graphics. The results are closely related graphics obtained by changing parameters that initiate them. The aim is to control the graphics, i.e. to use controlled stochastic to achieve desired solutions. Since the artists from the past have never published the procedures of screening methods, their ideas have remained “only” the works of art. In this article we will present the development of the algorithm that, more or less successfully, simulates those screening solutions. It has been proven that mathematically defined graphical elements serve as screening elements. New technological and mathematical solutions are introduced in the reproduction with individual screening elements to be used in printing.

  17. SWEETLEAD: an in silico database of approved drugs, regulated chemicals, and herbal isolates for computer-aided drug discovery.

    Directory of Open Access Journals (Sweden)

    Paul A Novick

    Full Text Available In the face of drastically rising drug discovery costs, strategies promising to reduce development timelines and expenditures are being pursued. Computer-aided virtual screening and repurposing approved drugs are two such strategies that have shown recent success. Herein, we report the creation of a highly-curated in silico database of chemical structures representing approved drugs, chemical isolates from traditional medicinal herbs, and regulated chemicals, termed the SWEETLEAD database. The motivation for SWEETLEAD stems from the observance of conflicting information in publicly available chemical databases and the lack of a highly curated database of chemical structures for the globally approved drugs. A consensus building scheme surveying information from several publicly accessible databases was employed to identify the correct structure for each chemical. Resulting structures are filtered for the active pharmaceutical ingredient, standardized, and differing formulations of the same drug were combined in the final database. The publically available release of SWEETLEAD (https://simtk.org/home/sweetlead provides an important tool to enable the successful completion of computer-aided repurposing and drug discovery campaigns.

  18. An update on the use of C. elegans for preclinical drug discovery: screening and identifying anti-infective drugs.

    Science.gov (United States)

    Kim, Wooseong; Hendricks, Gabriel Lambert; Lee, Kiho; Mylonakis, Eleftherios

    2017-06-01

    The emergence of antibiotic-resistant and -tolerant bacteria is a major threat to human health. Although efforts for drug discovery are ongoing, conventional bacteria-centered screening strategies have thus far failed to yield new classes of effective antibiotics. Therefore, new paradigms for discovering novel antibiotics are of critical importance. Caenorhabditis elegans, a model organism used for in vivo, offers a promising solution for identification of anti-infective compounds. Areas covered: This review examines the advantages of C. elegans-based high-throughput screening over conventional, bacteria-centered in vitro screens. It discusses major anti-infective compounds identified from large-scale C. elegans-based screens and presents the first clinically-approved drugs, then known bioactive compounds, and finally novel small molecules. Expert opinion: There are clear advantages of using a C. elegans-infection based screening method. A C. elegans-based screen produces an enriched pool of non-toxic, efficacious, potential anti-infectives, covering: conventional antimicrobial agents, immunomodulators, and anti-virulence agents. Although C. elegans-based screens do not denote the mode of action of hit compounds, this can be elucidated in secondary studies by comparing the results to target-based screens, or conducting subsequent target-based screens, including the genetic knock-down of host or bacterial genes.

  19. Statistical screening of input variables in a complex computer code

    International Nuclear Information System (INIS)

    Krieger, T.J.

    1982-01-01

    A method is presented for ''statistical screening'' of input variables in a complex computer code. The object is to determine the ''effective'' or important input variables by estimating the relative magnitudes of their associated sensitivity coefficients. This is accomplished by performing a numerical experiment consisting of a relatively small number of computer runs with the code followed by a statistical analysis of the results. A formula for estimating the sensitivity coefficients is derived. Reference is made to an earlier work in which the method was applied to a complex reactor code with good results

  20. The University of Kansas High-Throughput Screening Laboratory. Part II: enabling collaborative drug-discovery partnerships through cutting-edge screening technology.

    Science.gov (United States)

    McDonald, Peter R; Roy, Anuradha; Chaguturu, Rathnam

    2011-07-01

    The University of Kansas High-Throughput Screening (KU HTS) core is a state-of-the-art drug-discovery facility with an entrepreneurial open-service policy, which provides centralized resources supporting public- and private-sector research initiatives. The KU HTS core was established in 2002 at the University of Kansas with support from an NIH grant and the state of Kansas. It collaborates with investigators from national and international academic, nonprofit and pharmaceutical organizations in executing HTS-ready assay development and screening of chemical libraries for target validation, probe selection, hit identification and lead optimization. This is part two of a contribution from the KU HTS laboratory.

  1. Software Infrastructure for Computer-aided Drug Discovery and Development, a Practical Example with Guidelines.

    Science.gov (United States)

    Moretti, Loris; Sartori, Luca

    2016-09-01

    In the field of Computer-Aided Drug Discovery and Development (CADDD) the proper software infrastructure is essential for everyday investigations. The creation of such an environment should be carefully planned and implemented with certain features in order to be productive and efficient. Here we describe a solution to integrate standard computational services into a functional unit that empowers modelling applications for drug discovery. This system allows users with various level of expertise to run in silico experiments automatically and without the burden of file formatting for different software, managing the actual computation, keeping track of the activities and graphical rendering of the structural outcomes. To showcase the potential of this approach, performances of five different docking programs on an Hiv-1 protease test set are presented. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  2. Computer-aided drug discovery [v1; ref status: indexed, http://f1000r.es/5ij

    Directory of Open Access Journals (Sweden)

    Jürgen Bajorath

    2015-08-01

    Full Text Available Computational approaches are an integral part of interdisciplinary drug discovery research. Understanding the science behind computational tools, their opportunities, and limitations is essential to make a true impact on drug discovery at different levels. If applied in a scientifically meaningful way, computational methods improve the ability to identify and evaluate potential drug molecules, but there remain weaknesses in the methods that preclude naïve applications. Herein, current trends in computer-aided drug discovery are reviewed, and selected computational areas are discussed. Approaches are highlighted that aid in the identification and optimization of new drug candidates. Emphasis is put on the presentation and discussion of computational concepts and methods, rather than case studies or application examples. As such, this contribution aims to provide an overview of the current methodological spectrum of computational drug discovery for a broad audience.

  3. Discovery of Selective Nanobodies against α-elapitoxin Dpp2c from Black Mamba through Phage Display Screening

    DEFF Research Database (Denmark)

    Milbo, Christina; Laustsen, Andreas Hougaard; Lohse, Brian

    Feared for its highly neurotoxic venom and rapid attack technique, the Black mamba (Dendroaspis polylepis) is Africa’s largest venomous snake. The clinical manifestations of a bitefrom D. polylepis include flaccid paralysis leading to respiratory failure and death due to postsynaptic blockade of ......-neurotoxins. Here, we report the discovery of selective nanobodies targeting α-elapitoxin Dpp2c from D. polylepis through phage display screening....

  4. Functional Metagenomics: Construction and High-Throughput Screening of Fosmid Libraries for Discovery of Novel Carbohydrate-Active Enzymes.

    Science.gov (United States)

    Ufarté, Lisa; Bozonnet, Sophie; Laville, Elisabeth; Cecchini, Davide A; Pizzut-Serin, Sandra; Jacquiod, Samuel; Demanèche, Sandrine; Simonet, Pascal; Franqueville, Laure; Veronese, Gabrielle Potocki

    2016-01-01

    Activity-based metagenomics is one of the most efficient approaches to boost the discovery of novel biocatalysts from the huge reservoir of uncultivated bacteria. In this chapter, we describe a highly generic procedure of metagenomic library construction and high-throughput screening for carbohydrate-active enzymes. Applicable to any bacterial ecosystem, it enables the swift identification of functional enzymes that are highly efficient, alone or acting in synergy, to break down polysaccharides and oligosaccharides.

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

    Directory of Open Access Journals (Sweden)

    Ning Li

    2010-04-01

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

  6. Computational methods for 2D materials: discovery, property characterization, and application design.

    Science.gov (United States)

    Paul, J T; Singh, A K; Dong, Z; Zhuang, H; Revard, B C; Rijal, B; Ashton, M; Linscheid, A; Blonsky, M; Gluhovic, D; Guo, J; Hennig, R G

    2017-11-29

    The discovery of two-dimensional (2D) materials comes at a time when computational methods are mature and can predict novel 2D materials, characterize their properties, and guide the design of 2D materials for applications. This article reviews the recent progress in computational approaches for 2D materials research. We discuss the computational techniques and provide an overview of the ongoing research in the field. We begin with an overview of known 2D materials, common computational methods, and available cyber infrastructures. We then move onto the discovery of novel 2D materials, discussing the stability criteria for 2D materials, computational methods for structure prediction, and interactions of monolayers with electrochemical and gaseous environments. Next, we describe the computational characterization of the 2D materials' electronic, optical, magnetic, and superconducting properties and the response of the properties under applied mechanical strain and electrical fields. From there, we move on to discuss the structure and properties of defects in 2D materials, and describe methods for 2D materials device simulations. We conclude by providing an outlook on the needs and challenges for future developments in the field of computational research for 2D materials.

  7. Computer screen photo-excited surface plasmon resonance imaging.

    Science.gov (United States)

    Filippini, Daniel; Winquist, Fredrik; Lundström, Ingemar

    2008-09-12

    Angle and spectra resolved surface plasmon resonance (SPR) images of gold and silver thin films with protein deposits is demonstrated using a regular computer screen as light source and a web camera as detector. The screen provides multiple-angle illumination, p-polarized light and controlled spectral radiances to excite surface plasmons in a Kretchmann configuration. A model of the SPR reflectances incorporating the particularities of the source and detector explain the observed signals and the generation of distinctive SPR landscapes is demonstrated. The sensitivity and resolution of the method, determined in air and solution, are 0.145 nm pixel(-1), 0.523 nm, 5.13x10(-3) RIU degree(-1) and 6.014x10(-4) RIU, respectively, encouraging results at this proof of concept stage and considering the ubiquity of the instrumentation.

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

    Directory of Open Access Journals (Sweden)

    Abreu Rui MV

    2010-10-01

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

  9. Lung cancer screening beyond low-dose computed tomography: the role of novel biomarkers.

    Science.gov (United States)

    Hasan, Naveed; Kumar, Rohit; Kavuru, Mani S

    2014-10-01

    Lung cancer is the most common and lethal malignancy in the world. The landmark National lung screening trial (NLST) showed a 20% relative reduction in mortality in high-risk individuals with screening low-dose computed tomography. However, the poor specificity and low prevalence of lung cancer in the NLST provide major limitations to its widespread use. Furthermore, a lung nodule on CT scan requires a nuanced and individualized approach towards management. In this regard, advances in high through-put technology (molecular diagnostics, multi-gene chips, proteomics, and bronchoscopic techniques) have led to discovery of lung cancer biomarkers that have shown potential to complement the current screening standards. Early detection of lung cancer can be achieved by analysis of biomarkers from tissue samples within the respiratory tract such as sputum, saliva, nasal/bronchial airway epithelial cells and exhaled breath condensate or through peripheral biofluids such as blood, serum and urine. Autofluorescence bronchoscopy has been employed in research setting to identify pre-invasive lesions not identified on CT scan. Although these modalities are not yet commercially available in clinic setting, they will be available in the near future and clinicians who care for patients with lung cancer should be aware. In this review, we present up-to-date state of biomarker development, discuss their clinical relevance and predict their future role in lung cancer management.

  10. Sign use and cognition in automated scientific discovery: are computers only special kinds of signs?

    Science.gov (United States)

    Giza, Piotr

    2018-04-01

    James Fetzer criticizes the computational paradigm, prevailing in cognitive science by questioning, what he takes to be, its most elementary ingredient: that cognition is computation across representations. He argues that if cognition is taken to be a purposive, meaningful, algorithmic problem solving activity, then computers are incapable of cognition. Instead, they appear to be signs of a special kind, that can facilitate computation. He proposes the conception of minds as semiotic systems as an alternative paradigm for understanding mental phenomena, one that seems to overcome the difficulties of computationalism. Now, I argue, that with computer systems dealing with scientific discovery, the matter is not so simple as that. The alleged superiority of humans using signs to stand for something other over computers being merely "physical symbol systems" or "automatic formal systems" is only easy to establish in everyday life, but becomes far from obvious when scientific discovery is at stake. In science, as opposed to everyday life, the meaning of symbols is, apart from very low-level experimental investigations, defined implicitly by the way the symbols are used in explanatory theories or experimental laws relevant to the field, and in consequence, human and machine discoverers are much more on a par. Moreover, the great practical success of the genetic programming method and recent attempts to apply it to automatic generation of cognitive theories seem to show, that computer systems are capable of very efficient problem solving activity in science, which is neither purposive nor meaningful, nor algorithmic. This, I think, undermines Fetzer's argument that computer systems are incapable of cognition because computation across representations is bound to be a purposive, meaningful, algorithmic problem solving activity.

  11. Efficacy of computer-aided detection system for screening mammography

    International Nuclear Information System (INIS)

    Saito, Mioko; Ohnuki, Koji; Yamada, Takayuki; Saito, Haruo; Ishibashi, Tadashi; Ohuchi, Noriaki; Takahashi, Shoki

    2002-01-01

    A study was conducted to evaluate the efficacy of a computer-aided detection (CAD) system for screening mammography (MMG). Screening mammograms of 2,231 women aged over 50 yr were examined. Medio-lateral oblique (MLO) images were obtained, and two expert observers interpreted the mammograms by consensus. First, each mammogram was interpreted without the assistance of CAD, followed immediately by a re-evaluation of areas marked by the CAD system. Data were recorded to measure the effect of CAD on the recall rate, cancer detection rate and detection rate of masses, microcalcifications and other findings. The CAD system increased the recall rate from 2.3% to 2.6%. Six recalled cases were diagnosed as breast cancer pathologically, and CAD detected all of these lesions. Seven additional cases in which CAD detected abnormal findings had no malignancy. The detection rate of CAD for microcalcifications was high (95.0%). However, the detection rate for mass lesions and other findings was low (29.2% and 25.0% respectively). The false positivity rate was 0.13/film for microcalcifications, and 0.25/film for mass lesions. The efficacy of the CAD system for detecting microcalcifications on screening mammograms was confirmed. However, the low detection rate of mass lesions and relatively high rate of false positivity need to be further improved. (author)

  12. A Performance/Cost Evaluation for a GPU-Based Drug Discovery Application on Volunteer Computing

    Science.gov (United States)

    Guerrero, Ginés D.; Imbernón, Baldomero; García, José M.

    2014-01-01

    Bioinformatics is an interdisciplinary research field that develops tools for the analysis of large biological databases, and, thus, the use of high performance computing (HPC) platforms is mandatory for the generation of useful biological knowledge. The latest generation of graphics processing units (GPUs) has democratized the use of HPC as they push desktop computers to cluster-level performance. Many applications within this field have been developed to leverage these powerful and low-cost architectures. However, these applications still need to scale to larger GPU-based systems to enable remarkable advances in the fields of healthcare, drug discovery, genome research, etc. The inclusion of GPUs in HPC systems exacerbates power and temperature issues, increasing the total cost of ownership (TCO). This paper explores the benefits of volunteer computing to scale bioinformatics applications as an alternative to own large GPU-based local infrastructures. We use as a benchmark a GPU-based drug discovery application called BINDSURF that their computational requirements go beyond a single desktop machine. Volunteer computing is presented as a cheap and valid HPC system for those bioinformatics applications that need to process huge amounts of data and where the response time is not a critical factor. PMID:25025055

  13. A Performance/Cost Evaluation for a GPU-Based Drug Discovery Application on Volunteer Computing

    Directory of Open Access Journals (Sweden)

    Ginés D. Guerrero

    2014-01-01

    Full Text Available Bioinformatics is an interdisciplinary research field that develops tools for the analysis of large biological databases, and, thus, the use of high performance computing (HPC platforms is mandatory for the generation of useful biological knowledge. The latest generation of graphics processing units (GPUs has democratized the use of HPC as they push desktop computers to cluster-level performance. Many applications within this field have been developed to leverage these powerful and low-cost architectures. However, these applications still need to scale to larger GPU-based systems to enable remarkable advances in the fields of healthcare, drug discovery, genome research, etc. The inclusion of GPUs in HPC systems exacerbates power and temperature issues, increasing the total cost of ownership (TCO. This paper explores the benefits of volunteer computing to scale bioinformatics applications as an alternative to own large GPU-based local infrastructures. We use as a benchmark a GPU-based drug discovery application called BINDSURF that their computational requirements go beyond a single desktop machine. Volunteer computing is presented as a cheap and valid HPC system for those bioinformatics applications that need to process huge amounts of data and where the response time is not a critical factor.

  14. Discovery of novel-scaffold monoamine transporter ligands via in silico screening with the S1 pocket of the serotonin transporter.

    Science.gov (United States)

    Nolan, Tammy L; Geffert, Laura M; Kolber, Benedict J; Madura, Jeffry D; Surratt, Christopher K

    2014-09-17

    Discovery of new inhibitors of the plasmalemmal monoamine transporters (MATs) continues to provide pharmacotherapeutic options for depression, addiction, attention deficit disorders, psychosis, narcolepsy, and Parkinson's disease. The windfall of high-resolution MAT structural information afforded by X-ray crystallography has enabled the construction of credible computational models. Elucidation of lead compounds, creation of compound structure-activity series, and pharmacologic testing are staggering expenses that could be reduced by using a MAT computational model for virtual screening (VS) of structural libraries containing millions of compounds. Here, VS of the PubChem small molecule structural database using the S1 (primary substrate) ligand pocket of a serotonin transporter homology model yielded 19 prominent "hit" compounds. In vitro pharmacology of these VS hits revealed four structurally unique MAT substrate uptake inhibitors with high nanomolar affinity at one or more of the three MATs. In vivo characterization of three of these hits revealed significant activity in a mouse model of acute depression at doses that did not elicit untoward locomotor effects. This constitutes the first report of MAT inhibitor discovery using exclusively the primary substrate pocket as a VS tool. Novel-scaffold MAT inhibitors offer hope of new medications that lack the many classic adverse effects of existing antidepressant drugs.

  15. A reliable computational workflow for the selection of optimal screening libraries.

    Science.gov (United States)

    Gilad, Yocheved; Nadassy, Katalin; Senderowitz, Hanoch

    2015-01-01

    The experimental screening of compound collections is a common starting point in many drug discovery projects. Successes of such screening campaigns critically depend on the quality of the screened library. Many libraries are currently available from different vendors yet the selection of the optimal screening library for a specific project is challenging. We have devised a novel workflow for the rational selection of project-specific screening libraries. The workflow accepts as input a set of virtual candidate libraries and applies the following steps to each library: (1) data curation; (2) assessment of ADME/T profile; (3) assessment of the number of promiscuous binders/frequent HTS hitters; (4) assessment of internal diversity; (5) assessment of similarity to known active compound(s) (optional); (6) assessment of similarity to in-house or otherwise accessible compound collections (optional). For ADME/T profiling, Lipinski's and Veber's rule-based filters were implemented and a new blood brain barrier permeation model was developed and validated (85 and 74 % success rate for training set and test set, respectively). Diversity and similarity descriptors which demonstrated best performances in terms of their ability to select either diverse or focused sets of compounds from three databases (Drug Bank, CMC and CHEMBL) were identified and used for diversity and similarity assessments. The workflow was used to analyze nine common screening libraries available from six vendors. The results of this analysis are reported for each library providing an assessment of its quality. Furthermore, a consensus approach was developed to combine the results of these analyses into a single score for selecting the optimal library under different scenarios. We have devised and tested a new workflow for the rational selection of screening libraries under different scenarios. The current workflow was implemented using the Pipeline Pilot software yet due to the usage of generic

  16. Discovery of novel inhibitors for DHODH via virtual screening and X-ray crystallographic structures

    Energy Technology Data Exchange (ETDEWEB)

    McLean, Larry R.; Zhang, Ying; Degnen, William; Peppard, Jane; Cabel, Dasha; Zou, Chao; Tsay, Joseph T.; Subramaniam, Arun; Vaz, Roy J.; Li, Yi (Sanofi)

    2010-10-28

    Amino-benzoic acid derivatives 1-4 were found to be inhibitors for DHODH by virtual screening, biochemical, and X-ray crystallographic studies. X-ray structures showed that 1 and 2 bind to DHODH as predicted by virtual screening, but 3 and 4 were found to be structurally different from the corresponding compounds initially identified by virtual screening.

  17. Using Just-in-Time Information to Support Scientific Discovery Learning in a Computer-Based Simulation

    Science.gov (United States)

    Hulshof, Casper D.; de Jong, Ton

    2006-01-01

    Students encounter many obstacles during scientific discovery learning with computer-based simulations. It is hypothesized that an effective type of support, that does not interfere with the scientific discovery learning process, should be delivered on a "just-in-time" base. This study explores the effect of facilitating access to…

  18. Integration of lyoplate based flow cytometry and computational analysis for standardized immunological biomarker discovery.

    Directory of Open Access Journals (Sweden)

    Federica Villanova

    Full Text Available Discovery of novel immune biomarkers for monitoring of disease prognosis and response to therapy in immune-mediated inflammatory diseases is an important unmet clinical need. Here, we establish a novel framework for immunological biomarker discovery, comparing a conventional (liquid flow cytometry platform (CFP and a unique lyoplate-based flow cytometry platform (LFP in combination with advanced computational data analysis. We demonstrate that LFP had higher sensitivity compared to CFP, with increased detection of cytokines (IFN-γ and IL-10 and activation markers (Foxp3 and CD25. Fluorescent intensity of cells stained with lyophilized antibodies was increased compared to cells stained with liquid antibodies. LFP, using a plate loader, allowed medium-throughput processing of samples with comparable intra- and inter-assay variability between platforms. Automated computational analysis identified novel immunophenotypes that were not detected with manual analysis. Our results establish a new flow cytometry platform for standardized and rapid immunological biomarker discovery with wide application to immune-mediated diseases.

  19. Integration of lyoplate based flow cytometry and computational analysis for standardized immunological biomarker discovery.

    Science.gov (United States)

    Villanova, Federica; Di Meglio, Paola; Inokuma, Margaret; Aghaeepour, Nima; Perucha, Esperanza; Mollon, Jennifer; Nomura, Laurel; Hernandez-Fuentes, Maria; Cope, Andrew; Prevost, A Toby; Heck, Susanne; Maino, Vernon; Lord, Graham; Brinkman, Ryan R; Nestle, Frank O

    2013-01-01

    Discovery of novel immune biomarkers for monitoring of disease prognosis and response to therapy in immune-mediated inflammatory diseases is an important unmet clinical need. Here, we establish a novel framework for immunological biomarker discovery, comparing a conventional (liquid) flow cytometry platform (CFP) and a unique lyoplate-based flow cytometry platform (LFP) in combination with advanced computational data analysis. We demonstrate that LFP had higher sensitivity compared to CFP, with increased detection of cytokines (IFN-γ and IL-10) and activation markers (Foxp3 and CD25). Fluorescent intensity of cells stained with lyophilized antibodies was increased compared to cells stained with liquid antibodies. LFP, using a plate loader, allowed medium-throughput processing of samples with comparable intra- and inter-assay variability between platforms. Automated computational analysis identified novel immunophenotypes that were not detected with manual analysis. Our results establish a new flow cytometry platform for standardized and rapid immunological biomarker discovery with wide application to immune-mediated diseases.

  20. A Survey on Data Storage and Information Discovery in the WSANs-Based Edge Computing Systems.

    Science.gov (United States)

    Ma, Xingpo; Liang, Junbin; Liu, Renping; Ni, Wei; Li, Yin; Li, Ran; Ma, Wenpeng; Qi, Chuanda

    2018-02-10

    In the post-Cloud era, the proliferation of Internet of Things (IoT) has pushed the horizon of Edge computing, which is a new computing paradigm with data are processed at the edge of the network. As the important systems of Edge computing, wireless sensor and actuator networks (WSANs) play an important role in collecting and processing the sensing data from the surrounding environment as well as taking actions on the events happening in the environment. In WSANs, in-network data storage and information discovery schemes with high energy efficiency, high load balance and low latency are needed because of the limited resources of the sensor nodes and the real-time requirement of some specific applications, such as putting out a big fire in a forest. In this article, the existing schemes of WSANs on data storage and information discovery are surveyed with detailed analysis on their advancements and shortcomings, and possible solutions are proposed on how to achieve high efficiency, good load balance, and perfect real-time performances at the same time, hoping that it can provide a good reference for the future research of the WSANs-based Edge computing systems.

  1. Computational Design and Discovery of Ni-Based Alloys and Coatings: Thermodynamic Approaches Validated by Experiments

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Zi-Kui [Pennsylvania State University; Gleeson, Brian [University of Pittsburgh; Shang, Shunli [Pennsylvania State University; Gheno, Thomas [University of Pittsburgh; Lindwall, Greta [Pennsylvania State University; Zhou, Bi-Cheng [Pennsylvania State University; Liu, Xuan [Pennsylvania State University; Ross, Austin [Pennsylvania State University

    2018-04-23

    This project developed computational tools that can complement and support experimental efforts in order to enable discovery and more efficient development of Ni-base structural materials and coatings. The project goal was reached through an integrated computation-predictive and experimental-validation approach, including first-principles calculations, thermodynamic CALPHAD (CALculation of PHAse Diagram), and experimental investigations on compositions relevant to Ni-base superalloys and coatings in terms of oxide layer growth and microstructure stabilities. The developed description included composition ranges typical for coating alloys and, hence, allow for prediction of thermodynamic properties for these material systems. The calculation of phase compositions, phase fraction, and phase stabilities, which are directly related to properties such as ductility and strength, was a valuable contribution, along with the collection of computational tools that are required to meet the increasing demands for strong, ductile and environmentally-protective coatings. Specifically, a suitable thermodynamic description for the Ni-Al-Cr-Co-Si-Hf-Y system was developed for bulk alloy and coating compositions. Experiments were performed to validate and refine the thermodynamics from the CALPHAD modeling approach. Additionally, alloys produced using predictions from the current computational models were studied in terms of their oxidation performance. Finally, results obtained from experiments aided in the development of a thermodynamic modeling automation tool called ESPEI/pycalphad - for more rapid discovery and development of new materials.

  2. A Survey on Data Storage and Information Discovery in the WSANs-Based Edge Computing Systems

    Science.gov (United States)

    Liang, Junbin; Liu, Renping; Ni, Wei; Li, Yin; Li, Ran; Ma, Wenpeng; Qi, Chuanda

    2018-01-01

    In the post-Cloud era, the proliferation of Internet of Things (IoT) has pushed the horizon of Edge computing, which is a new computing paradigm with data processed at the edge of the network. As the important systems of Edge computing, wireless sensor and actuator networks (WSANs) play an important role in collecting and processing the sensing data from the surrounding environment as well as taking actions on the events happening in the environment. In WSANs, in-network data storage and information discovery schemes with high energy efficiency, high load balance and low latency are needed because of the limited resources of the sensor nodes and the real-time requirement of some specific applications, such as putting out a big fire in a forest. In this article, the existing schemes of WSANs on data storage and information discovery are surveyed with detailed analysis on their advancements and shortcomings, and possible solutions are proposed on how to achieve high efficiency, good load balance, and perfect real-time performances at the same time, hoping that it can provide a good reference for the future research of the WSANs-based Edge computing systems. PMID:29439442

  3. Computational medicinal chemistry in fragment-based drug discovery: what, how and when.

    Science.gov (United States)

    Rabal, Obdulia; Urbano-Cuadrado, Manuel; Oyarzabal, Julen

    2011-01-01

    The use of fragment-based drug discovery (FBDD) has increased in the last decade due to the encouraging results obtained to date. In this scenario, computational approaches, together with experimental information, play an important role to guide and speed up the process. By default, FBDD is generally considered as a constructive approach. However, such additive behavior is not always present, therefore, simple fragment maturation will not always deliver the expected results. In this review, computational approaches utilized in FBDD are reported together with real case studies, where applicability domains are exemplified, in order to analyze them, and then, maximize their performance and reliability. Thus, a proper use of these computational tools can minimize misleading conclusions, keeping the credit on FBDD strategy, as well as achieve higher impact in the drug-discovery process. FBDD goes one step beyond a simple constructive approach. A broad set of computational tools: docking, R group quantitative structure-activity relationship, fragmentation tools, fragments management tools, patents analysis and fragment-hopping, for example, can be utilized in FBDD, providing a clear positive impact if they are utilized in the proper scenario - what, how and when. An initial assessment of additive/non-additive behavior is a critical point to define the most convenient approach for fragments elaboration.

  4. A Survey on Data Storage and Information Discovery in the WSANs-Based Edge Computing Systems

    Directory of Open Access Journals (Sweden)

    Xingpo Ma

    2018-02-01

    Full Text Available In the post-Cloud era, the proliferation of Internet of Things (IoT has pushed the horizon of Edge computing, which is a new computing paradigm with data processed at the edge of the network. As the important systems of Edge computing, wireless sensor and actuator networks (WSANs play an important role in collecting and processing the sensing data from the surrounding environment as well as taking actions on the events happening in the environment. In WSANs, in-network data storage and information discovery schemes with high energy efficiency, high load balance and low latency are needed because of the limited resources of the sensor nodes and the real-time requirement of some specific applications, such as putting out a big fire in a forest. In this article, the existing schemes of WSANs on data storage and information discovery are surveyed with detailed analysis on their advancements and shortcomings, and possible solutions are proposed on how to achieve high efficiency, good load balance, and perfect real-time performances at the same time, hoping that it can provide a good reference for the future research of the WSANs-based Edge computing systems.

  5. Advantages of crystallographic fragment screening: functional and mechanistic insights from a powerful platform for efficient drug discovery.

    Science.gov (United States)

    Patel, Disha; Bauman, Joseph D; Arnold, Eddy

    2014-01-01

    X-ray crystallography has been an under-appreciated screening tool for fragment-based drug discovery due to the perception of low throughput and technical difficulty. Investigators in industry and academia have overcome these challenges by taking advantage of key factors that contribute to a successful crystallographic screening campaign. Efficient cocktail design and soaking methodologies have evolved to maximize throughput while minimizing false positives/negatives. In addition, technical improvements at synchrotron beamlines have dramatically increased data collection rates thus enabling screening on a timescale comparable to other techniques. The combination of available resources and efficient experimental design has resulted in many successful crystallographic screening campaigns. The three-dimensional crystal structure of the bound fragment complexed to its target, a direct result of the screening effort, enables structure-based drug design while revealing insights regarding protein dynamics and function not readily obtained through other experimental approaches. Furthermore, this "chemical interrogation" of the target protein crystals can lead to the identification of useful reagents for improving diffraction resolution or compound solubility. Copyright © 2014. Published by Elsevier Ltd.

  6. Advantages of Crystallographic Fragment Screening: Functional and Mechanistic Insights from a Powerful Platform for Efficient Drug Discovery

    Science.gov (United States)

    Patel, Disha; Bauman, Joseph D.; Arnold, Eddy

    2015-01-01

    X-ray crystallography has been an under-appreciated screening tool for fragment-based drug discovery due to the perception of low throughput and technical difficulty. Investigators in industry and academia have overcome these challenges by taking advantage of key factors that contribute to a successful crystallographic screening campaign. Efficient cocktail design and soaking methodologies have evolved to maximize throughput while minimizing false positives/negatives. In addition, technical improvements at synchrotron beamlines have dramatically increased data collection rates thus enabling screening on a timescale comparable to other techniques. The combination of available resources and efficient experimental design has resulted in many successful crystallographic screening campaigns. The three-dimensional crystal structure of the bound fragment complexed to its target, a direct result of the screening effort, enables structure-based drug design while revealing insights regarding protein dynamics and function not readily obtained through other experimental approaches. Furthermore, this “chemical interrogation” of the target protein crystals can lead to the identification of useful reagents for improving diffraction resolution or compound solubility. PMID:25117499

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

    Science.gov (United States)

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

    2012-01-01

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

  8. Antiprotozoan lead discovery by aligning dry and wet screening: prediction, synthesis, and biological assay of novel quinoxalinones.

    Science.gov (United States)

    Martins Alho, Miriam A; Marrero-Ponce, Yovani; Barigye, Stephen J; Meneses-Marcel, Alfredo; Machado Tugores, Yanetsy; Montero-Torres, Alina; Gómez-Barrio, Alicia; Nogal, Juan J; García-Sánchez, Rory N; Vega, María Celeste; Rolón, Miriam; Martínez-Fernández, Antonio R; Escario, José A; Pérez-Giménez, Facundo; Garcia-Domenech, Ramón; Rivera, Norma; Mondragón, Ricardo; Mondragón, Mónica; Ibarra-Velarde, Froylán; Lopez-Arencibia, Atteneri; Martín-Navarro, Carmen; Lorenzo-Morales, Jacob; Cabrera-Serra, Maria Gabriela; Piñero, Jose; Tytgat, Jan; Chicharro, Roberto; Arán, Vicente J

    2014-03-01

    Protozoan parasites have been one of the most significant public health problems for centuries and several human infections caused by them have massive global impact. Most of the current drugs used to treat these illnesses have been used for decades and have many limitations such as the emergence of drug resistance, severe side-effects, low-to-medium drug efficacy, administration routes, cost, etc. These drugs have been largely neglected as models for drug development because they are majorly used in countries with limited resources and as a consequence with scarce marketing possibilities. Nowadays, there is a pressing need to identify and develop new drug-based antiprotozoan therapies. In an effort to overcome this problem, the main purpose of this study is to develop a QSARs-based ensemble classifier for antiprotozoan drug-like entities from a heterogeneous compounds collection. Here, we use some of the TOMOCOMD-CARDD molecular descriptors and linear discriminant analysis (LDA) to derive individual linear classification functions in order to discriminate between antiprotozoan and non-antiprotozoan compounds as a way to enable the computational screening of virtual combinatorial datasets and/or drugs already approved. Firstly, we construct a wide-spectrum benchmark database comprising of 680 organic chemicals with great structural variability (254 of them antiprotozoan agents and 426 to drugs having other clinical uses). This series of compounds was processed by a k-means cluster analysis in order to design training and predicting sets. In total, seven discriminant functions were obtained, by using the whole set of atom-based linear indices. All the LDA-based QSAR models show accuracies above 85% in the training set and values of Matthews correlation coefficients (C) vary from 0.70 to 0.86. The external validation set shows rather-good global classifications of around 80% (92.05% for best equation). Later, we developed a multi-agent QSAR classification system, in

  9. Discovery of replicating circular RNAs by RNA-seq and computational algorithms.

    Directory of Open Access Journals (Sweden)

    Zhixiang Zhang

    2014-12-01

    Full Text Available Replicating circular RNAs are independent plant pathogens known as viroids, or act to modulate the pathogenesis of plant and animal viruses as their satellite RNAs. The rate of discovery of these subviral pathogens was low over the past 40 years because the classical approaches are technical demanding and time-consuming. We previously described an approach for homology-independent discovery of replicating circular RNAs by analysing the total small RNA populations from samples of diseased tissues with a computational program known as progressive filtering of overlapping small RNAs (PFOR. However, PFOR written in PERL language is extremely slow and is unable to discover those subviral pathogens that do not trigger in vivo accumulation of extensively overlapping small RNAs. Moreover, PFOR is yet to identify a new viroid capable of initiating independent infection. Here we report the development of PFOR2 that adopted parallel programming in the C++ language and was 3 to 8 times faster than PFOR. A new computational program was further developed and incorporated into PFOR2 to allow the identification of circular RNAs by deep sequencing of long RNAs instead of small RNAs. PFOR2 analysis of the small RNA libraries from grapevine and apple plants led to the discovery of Grapevine latent viroid (GLVd and Apple hammerhead viroid-like RNA (AHVd-like RNA, respectively. GLVd was proposed as a new species in the genus Apscaviroid, because it contained the typical structural elements found in this group of viroids and initiated independent infection in grapevine seedlings. AHVd-like RNA encoded a biologically active hammerhead ribozyme in both polarities, and was not specifically associated with any of the viruses found in apple plants. We propose that these computational algorithms have the potential to discover novel circular RNAs in plants, invertebrates and vertebrates regardless of whether they replicate and/or induce the in vivo accumulation of small

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

    Science.gov (United States)

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

    2011-03-10

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

  11. Computational Materials Science and Chemistry: Accelerating Discovery and Innovation through Simulation-Based Engineering and Science

    Energy Technology Data Exchange (ETDEWEB)

    Crabtree, George [Argonne National Lab. (ANL), Argonne, IL (United States); Glotzer, Sharon [University of Michigan; McCurdy, Bill [University of California Davis; Roberto, Jim [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)

    2010-07-26

    This report is based on a SC Workshop on Computational Materials Science and Chemistry for Innovation on July 26-27, 2010, to assess the potential of state-of-the-art computer simulations to accelerate understanding and discovery in materials science and chemistry, with a focus on potential impacts in energy technologies and innovation. The urgent demand for new energy technologies has greatly exceeded the capabilities of today's materials and chemical processes. To convert sunlight to fuel, efficiently store energy, or enable a new generation of energy production and utilization technologies requires the development of new materials and processes of unprecedented functionality and performance. New materials and processes are critical pacing elements for progress in advanced energy systems and virtually all industrial technologies. Over the past two decades, the United States has developed and deployed the world's most powerful collection of tools for the synthesis, processing, characterization, and simulation and modeling of materials and chemical systems at the nanoscale, dimensions of a few atoms to a few hundred atoms across. These tools, which include world-leading x-ray and neutron sources, nanoscale science facilities, and high-performance computers, provide an unprecedented view of the atomic-scale structure and dynamics of materials and the molecular-scale basis of chemical processes. For the first time in history, we are able to synthesize, characterize, and model materials and chemical behavior at the length scale where this behavior is controlled. This ability is transformational for the discovery process and, as a result, confers a significant competitive advantage. Perhaps the most spectacular increase in capability has been demonstrated in high performance computing. Over the past decade, computational power has increased by a factor of a million due to advances in hardware and software. This rate of improvement, which shows no sign of

  12. Computer-Aided Drug Design Applied to Marine Drug Discovery: Meridianins as Alzheimer's Disease Therapeutic Agents.

    Science.gov (United States)

    Llorach-Pares, Laura; Nonell-Canals, Alfons; Sanchez-Martinez, Melchor; Avila, Conxita

    2017-11-27

    Computer-aided drug discovery/design (CADD) techniques allow the identification of natural products that are capable of modulating protein functions in pathogenesis-related pathways, constituting one of the most promising lines followed in drug discovery. In this paper, we computationally evaluated and reported the inhibitory activity found in meridianins A-G, a group of marine indole alkaloids isolated from the marine tunicate Aplidium , against various protein kinases involved in Alzheimer's disease (AD), a neurodegenerative pathology characterized by the presence of neurofibrillary tangles (NFT). Balance splitting between tau kinase and phosphate activities caused tau hyperphosphorylation and, thereby, its aggregation and NTF formation. Inhibition of specific kinases involved in its phosphorylation pathway could be one of the key strategies to reverse tau hyperphosphorylation and would represent an approach to develop drugs to palliate AD symptoms. Meridianins bind to the adenosine triphosphate (ATP) binding site of certain protein kinases, acting as ATP competitive inhibitors. These compounds show very promising scaffolds to design new drugs against AD, which could act over tau protein kinases Glycogen synthetase kinase-3 Beta (GSK3β) and Casein kinase 1 delta (CK1δ, CK1D or KC1D), and dual specificity kinases as dual specificity tyrosine phosphorylation regulated kinase 1 (DYRK1A) and cdc2-like kinases (CLK1). This work is aimed to highlight the role of CADD techniques in marine drug discovery and to provide precise information regarding the binding mode and strength of meridianins against several protein kinases that could help in the future development of anti-AD drugs.

  13. Discovery of resources using MADM approaches for parallel and distributed computing

    Directory of Open Access Journals (Sweden)

    Mandeep Kaur

    2017-06-01

    Full Text Available Grid, a form of parallel and distributed computing, allows the sharing of data and computational resources among its users from various geographical locations. The grid resources are diverse in terms of their underlying attributes. The majority of the state-of-the-art resource discovery techniques rely on the static resource attributes during resource selection. However, the matching resources based on the static resource attributes may not be the most appropriate resources for the execution of user applications because they may have heavy job loads, less storage space or less working memory (RAM. Hence, there is a need to consider the current state of the resources in order to find the most suitable resources. In this paper, we have proposed a two-phased multi-attribute decision making (MADM approach for discovery of grid resources by using P2P formalism. The proposed approach considers multiple resource attributes for decision making of resource selection and provides the best suitable resource(s to grid users. The first phase describes a mechanism to discover all matching resources and applies SAW method to shortlist the top ranked resources, which are communicated to the requesting super-peer. The second phase of our proposed methodology applies integrated MADM approach (AHP enriched PROMETHEE-II on the list of selected resources received from different super-peers. The pairwise comparison of the resources with respect to their attributes is made and the rank of each resource is determined. The top ranked resource is then communicated to the grid user by the grid scheduler. Our proposed methodology enables the grid scheduler to allocate the most suitable resource to the user application and also reduces the search complexity by filtering out the less suitable resources during resource discovery.

  14. Pattern recognition algorithms for data mining scalability, knowledge discovery and soft granular computing

    CERN Document Server

    Pal, Sankar K

    2004-01-01

    Pattern Recognition Algorithms for Data Mining addresses different pattern recognition (PR) tasks in a unified framework with both theoretical and experimental results. Tasks covered include data condensation, feature selection, case generation, clustering/classification, and rule generation and evaluation. This volume presents various theories, methodologies, and algorithms, using both classical approaches and hybrid paradigms. The authors emphasize large datasets with overlapping, intractable, or nonlinear boundary classes, and datasets that demonstrate granular computing in soft frameworks.Organized into eight chapters, the book begins with an introduction to PR, data mining, and knowledge discovery concepts. The authors analyze the tasks of multi-scale data condensation and dimensionality reduction, then explore the problem of learning with support vector machine (SVM). They conclude by highlighting the significance of granular computing for different mining tasks in a soft paradigm.

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

    Directory of Open Access Journals (Sweden)

    Craig A. Doupnik

    2015-01-01

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

  16. Drug discovery for Duchenne muscular dystrophy via utrophin promoter activation screening.

    Directory of Open Access Journals (Sweden)

    Catherine Moorwood

    Full Text Available Duchenne muscular dystrophy (DMD is a devastating muscle wasting disease caused by mutations in dystrophin, a muscle cytoskeletal protein. Utrophin is a homologue of dystrophin that can functionally compensate for its absence when expressed at increased levels in the myofibre, as shown by studies in dystrophin-deficient mice. Utrophin upregulation is therefore a promising therapeutic approach for DMD. The use of a small, drug-like molecule to achieve utrophin upregulation offers obvious advantages in terms of delivery and bioavailability. Furthermore, much of the time and expense involved in the development of a new drug can be eliminated by screening molecules that are already approved for clinical use.We developed and validated a cell-based, high-throughput screening assay for utrophin promoter activation, and used it to screen the Prestwick Chemical Library of marketed drugs and natural compounds. Initial screening produced 20 hit molecules, 14 of which exhibited dose-dependent activation of the utrophin promoter and were confirmed as hits. Independent validation demonstrated that one of these compounds, nabumetone, is able to upregulate endogenous utrophin mRNA and protein, in C2C12 muscle cells.We have developed a cell-based, high-throughput screening utrophin promoter assay. Using this assay, we identified and validated a utrophin promoter-activating drug, nabumetone, for which pharmacokinetics and safety in humans are already well described, and which represents a lead compound for utrophin upregulation as a therapy for DMD.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2010-10-28

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

  18. Developing computer-based training programs for basic mammalian histology: Didactic versus discovery-based design

    Science.gov (United States)

    Fabian, Henry Joel

    Educators have long tried to understand what stimulates students to learn. The Swiss psychologist and zoologist, Jean Claude Piaget, suggested that students are stimulated to learn when they attempt to resolve confusion. He reasoned that students try to explain the world with the knowledge they have acquired in life. When they find their own explanations to be inadequate to explain phenomena, students find themselves in a temporary state of confusion. This prompts students to seek more plausible explanations. At this point, students are primed for learning (Piaget 1964). The Piagetian approach described above is called learning by discovery. To promote discovery learning, a teacher must first allow the student to recognize his misconception and then provide a plausible explanation to replace that misconception (Chinn and Brewer 1993). One application of this method is found in the various learning cycles, which have been demonstrated to be effective means for teaching science (Renner and Lawson 1973, Lawson 1986, Marek and Methven 1991, and Glasson & Lalik 1993). In contrast to the learning cycle, tutorial computer programs are generally not designed to correct student misconceptions, but rather follow a passive, didactic method of teaching. In the didactic or expositional method, the student is told about a phenomenon, but is neither encouraged to explore it, nor explain it in his own terms (Schneider and Renner 1980).

  19. DOE High Performance Computing Operational Review (HPCOR): Enabling Data-Driven Scientific Discovery at HPC Facilities

    Energy Technology Data Exchange (ETDEWEB)

    Gerber, Richard; Allcock, William; Beggio, Chris; Campbell, Stuart; Cherry, Andrew; Cholia, Shreyas; Dart, Eli; England, Clay; Fahey, Tim; Foertter, Fernanda; Goldstone, Robin; Hick, Jason; Karelitz, David; Kelly, Kaki; Monroe, Laura; Prabhat,; Skinner, David; White, Julia

    2014-10-17

    U.S. Department of Energy (DOE) High Performance Computing (HPC) facilities are on the verge of a paradigm shift in the way they deliver systems and services to science and engineering teams. Research projects are producing a wide variety of data at unprecedented scale and level of complexity, with community-specific services that are part of the data collection and analysis workflow. On June 18-19, 2014 representatives from six DOE HPC centers met in Oakland, CA at the DOE High Performance Operational Review (HPCOR) to discuss how they can best provide facilities and services to enable large-scale data-driven scientific discovery at the DOE national laboratories. The report contains findings from that review.

  20. A High Throughput, 384-Well, Semi-Automated, Hepatocyte Intrinsic Clearance Assay for Screening New Molecular Entities in Drug Discovery.

    Science.gov (United States)

    Heinle, Lance; Peterkin, Vincent; de Morais, Sonia M; Jenkins, Gary J; Badagnani, Ilaria

    2015-01-01

    A high throughput, semi-automated clearance screening assay in hepatocytes was developed allowing a scientist to generate data for 96 compounds in one week. The 384-well format assay utilizes a Thermo Multidrop Combi and an optimized LC-MS/MS method. The previously reported LCMS/ MS method reduced the analytical run time by 3-fold, down to 1.2 min injection-to-injection. The Multidrop was able to deliver hepatocytes to 384-well plates with minimal viability loss. Comparison of results from the new 384-well and historical 24-well assays yielded a correlation of 0.95. In addition, results obtained for 25 marketed drugs with various metabolism pathways had a correlation of 0.75 when compared with literature values. Precision was maintained in the new format as 8 compounds tested in ≥39 independent experiments had coefficients of variation ≤21%. The ability to predict in vivo clearances using the new stability assay format was also investigated using 22 marketed drugs and 26 AbbVie compounds. Correction of intrinsic clearance values with binding to hepatocytes (in vitro data) and plasma (in vivo data) resulted in a higher in vitro to in vivo correlation when comparing 22 marketed compounds in human (0.80 vs 0.35) and 26 AbbVie Discovery compounds in rat (0.56 vs 0.17), demonstrating the importance of correcting for binding in clearance studies. This newly developed high throughput, semi-automated clearance assay allows for rapid screening of Discovery compounds to enable Structure Activity Relationship (SAR) analysis based on high quality hepatocyte stability data in sufficient quantity and quality to drive the next round of compound synthesis.

  1. Combinatorial Strategies and High Throughput Screening in Drug Discovery Targeted to the Channel of Botulinum Neurotoxin

    National Research Council Canada - National Science Library

    Montal, Mauricio

    2006-01-01

    .... The major focus thus far has been the implementation of a reliable and robust high-throughput screen for blockers specific for BoNT using Neuro 2A cells in which BoNTA forms channels with similar properties to those previously characterized in lipid bilayers. The immediate task during the present reporting period involved the detailed characterization of the channel and chaperone activity of BoNTA on Neuro2A cells.

  2. High Throughput Screening in Duchenne Muscular Dystrophy: From Drug Discovery to Functional Genomics

    OpenAIRE

    Thomas J.J. Gintjee; Alvin S.H. Magh; Carmen Bertoni

    2014-01-01

    Centers for the screening of biologically active compounds and genomic libraries are becoming common in the academic setting and have enabled researchers devoted to developing strategies for the treatment of diseases or interested in studying a biological phenomenon to have unprecedented access to libraries that, until few years ago, were accessible only by pharmaceutical companies. As a result, new drugs and genetic targets have now been identified for the treatment of Duchenne muscular dyst...

  3. Upscaling and automation of electrophysiology: toward high throughput screening in ion channel drug discovery

    DEFF Research Database (Denmark)

    Asmild, Margit; Oswald, Nicholas; Krzywkowski, Karen M

    2003-01-01

    by developing two lines of automated patch clamp products, a traditional pipette-based system called Apatchi-1, and a silicon chip-based system QPatch. The degree of automation spans from semi-automation (Apatchi-1) where a trained technician interacts with the system in a limited way, to a complete automation...... (QPatch 96) where the system works continuously and unattended until screening of a full compound library is completed. The performance of the systems range from medium to high throughputs....

  4. Using label-free screening technology to improve efficiency in drug discovery.

    Science.gov (United States)

    Halai, Reena; Cooper, Matthew A

    2012-02-01

    Screening assays have traditionally utilized reporter labels to quantify biological responses relevant to the disease state of interest. However, there are limitations associated with the use of labels that may be overcome with temporal measurements possible with label-free. This review comprises general and system-specific information from literature searches using PubMed, published books and the authors' personal experience. This review highlights the label-free approaches in the context of various applications. The authors also note technical issues relevant to the development of label-free assays and their application to HTS. The limitations associated with the use of transfected cell lines and the use of label-based assays are gradually being realized. As such, greater emphasis is being placed on label-free biophysical techniques using native cell lines. The introduction of 96- and 384-well plate label-free systems is helping to broker a wider acceptance of these approaches in high-throughput screening. However, potential users of the technologies remain skeptical, primarily because the physical basis of the signals generated, and their contextual relevance to cell biology and signal transduction, has not been fully elucidated. Until this is done, these new technology platforms are more likely to complement, rather than replace, traditional screening platforms.

  5. Visibility of microcalcifications in computed and screen-film mammography

    International Nuclear Information System (INIS)

    Cowen, Arnold R.; Launders, Jason H.; Jadav, Mark; Brettle, David S.

    1997-01-01

    Due to the clinically and technically demanding nature of breast x-ray imaging, mammography still remains one of the few essentially film-based radiological imaging techniques in modern medical imaging. There are a range of possible benefits available if a practical and economical direct digital imaging technique can be introduced to routine clinical practice. There has been much debate regarding the minimum specification required for direct digital acquisition. One such direct digital system available is computed radiography (CR), which has a modest specification when compared with modern screen-film mammography (SFM) systems. This paper details two psychophysical studies in which the detection of simulated microcalcifications with CR has been directly compared to that with SFM. The first study found that under scatter-free conditions the minimum detectable size of micro calcification was approximately 130 μm for both SFM and CR. The second study found that SFM had a 4.6% higher probability of observers being able to correctly identify the shape of 350 μm diameter test details; there was no significant difference for either larger or smaller test details. From the results of these studies it has been demonstrated that the modest specification of CR, in terms of limiting resolution, does not translate into a dramatic difference in the perception of details at the limit of detectability. When judging the imaging performance of a system it is more important to compare the signal-to-noise ratio transfer spectrum characteristics, rather than simply the modulation transfer function. (author)

  6. A review of human pluripotent stem cell-derived cardiomyocytes for high-throughput drug discovery, cardiotoxicity screening, and publication standards.

    Science.gov (United States)

    Mordwinkin, Nicholas M; Burridge, Paul W; Wu, Joseph C

    2013-02-01

    Drug attrition rates have increased in past years, resulting in growing costs for the pharmaceutical industry and consumers. The reasons for this include the lack of in vitro models that correlate with clinical results and poor preclinical toxicity screening assays. The in vitro production of human cardiac progenitor cells and cardiomyocytes from human pluripotent stem cells provides an amenable source of cells for applications in drug discovery, disease modeling, regenerative medicine, and cardiotoxicity screening. In addition, the ability to derive human-induced pluripotent stem cells from somatic tissues, combined with current high-throughput screening and pharmacogenomics, may help realize the use of these cells to fulfill the potential of personalized medicine. In this review, we discuss the use of pluripotent stem cell-derived cardiomyocytes for drug discovery and cardiotoxicity screening, as well as current hurdles that must be overcome for wider clinical applications of this promising approach.

  7. Volatility Discovery

    DEFF Research Database (Denmark)

    Dias, Gustavo Fruet; Scherrer, Cristina; Papailias, Fotis

    The price discovery literature investigates how homogenous securities traded on different markets incorporate information into prices. We take this literature one step further and investigate how these markets contribute to stochastic volatility (volatility discovery). We formally show...... that the realized measures from homogenous securities share a fractional stochastic trend, which is a combination of the price and volatility discovery measures. Furthermore, we show that volatility discovery is associated with the way that market participants process information arrival (market sensitivity......). Finally, we compute volatility discovery for 30 actively traded stocks in the U.S. and report that Nyse and Arca dominate Nasdaq....

  8. From computational discovery to experimental characterization of a high hole mobility organic crystal.

    KAUST Repository

    Sokolov, Anatoliy N

    2011-08-16

    For organic semiconductors to find ubiquitous electronics applications, the development of new materials with high mobility and air stability is critical. Despite the versatility of carbon, exploratory chemical synthesis in the vast chemical space can be hindered by synthetic and characterization difficulties. Here we show that in silico screening of novel derivatives of the dinaphtho[2,3-b:2\\',3\\'-f]thieno[3,2-b]thiophene semiconductor with high hole mobility and air stability can lead to the discovery of a new high-performance semiconductor. On the basis of estimates from the Marcus theory of charge transfer rates, we identified a novel compound expected to demonstrate a theoretic twofold improvement in mobility over the parent molecule. Synthetic and electrical characterization of the compound is reported with single-crystal field-effect transistors, showing a remarkable saturation and linear mobility of 12.3 and 16 cm(2) V(-1) s(-1), respectively. This is one of the very few organic semiconductors with mobility greater than 10 cm(2) V(-1) s(-1) reported to date.

  9. Improved Soluble ScFv ELISA Screening Approach for Antibody Discovery Using Phage Display Technology.

    Science.gov (United States)

    Tohidkia, Mohammad R; Sepehri, Maryam; Khajeh, Shirin; Barar, Jaleh; Omidi, Yadollah

    2017-09-01

    Phage display technology (PDT) is a powerful tool for the isolation of recombinant antibody (Ab) fragments. Using PDT, target molecule-specific phage-Ab clones are enriched through the "biopanning" process. The individual specific binders are screened by the monoclonal scFv enzyme-linked immunosorbent assay (ELISA) that may associate with inevitable false-negative results. Thus, in this study, three strategies were investigated for optimization of the scFvs screening using Tomlinson I and J libraries, including (1) optimizing the expression of functional scFvs, (2) improving the sensitivity of ELISA, and (3) preparing different samples containing scFvs. The expression of all scFv Abs was significantly enhanced when scFv clones were cultivated in the terrific broth (TB) medium at the optimum temperature of 30 °C. The protein A-conjugated with horseradish peroxidase (HRP) was found to be a well-suited reagent for the detection of Ag-bound scFvs in comparison with either anti-c-myc Ab or the mixing procedure. Based on our findings, it seems there is no universal media supplement for an improved expression of all scFvs derived from both Tomlinson I and J libraries. We thus propose that expression of scFv fragments in a microplate scale is largely dependent on a variety of parameters, in particular the scFv clones and relevant sequences.

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

    Science.gov (United States)

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

    2018-04-01

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

  11. The In Situ Enzymatic Screening (ISES) Approach to Reaction Discovery and Catalyst Identification.

    Science.gov (United States)

    Swyka, Robert A; Berkowitz, David B

    2017-12-14

    The importance of discovering new chemical transformations and/or optimizing catalytic combinations has led to a flurry of activity in reaction screening. The in situ enzymatic screening (ISES) approach described here utilizes biological tools (enzymes/cofactors) to advance chemistry. The protocol interfaces an organic reaction layer with an adjacent aqueous layer containing reporting enzymes that act upon the organic reaction product, giving rise to a spectroscopic signal. ISES allows the experimentalist to rapidly glean information on the relative rates of a set of parallel organic/organometallic reactions under investigation, without the need to quench the reactions or draw aliquots. In certain cases, the real-time enzymatic readout also provides information on sense and magnitude of enantioselectivity and substrate specificity. This article contains protocols for single-well (relative rate) and double-well (relative rate/enantiomeric excess) ISES, in addition to a colorimetric ISES protocol and a miniaturized double-well procedure. © 2017 by John Wiley & Sons, Inc. Copyright © 2017 John Wiley & Sons, Inc.

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

    Directory of Open Access Journals (Sweden)

    Liansheng Qiao

    2016-12-01

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

  13. Discovery and annotation of small proteins using genomics, proteomics and computational approaches

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Xiaohan; Tschaplinski, Timothy J.; Hurst, Gregory B.; Jawdy, Sara; Abraham, Paul E.; Lankford, Patricia K.; Adams, Rachel M.; Shah, Manesh B.; Hettich, Robert L.; Lindquist, Erika; Kalluri, Udaya C.; Gunter, Lee E.; Pennacchio, Christa; Tuskan, Gerald A.

    2011-03-02

    Small proteins (10 200 amino acids aa in length) encoded by short open reading frames (sORF) play important regulatory roles in various biological processes, including tumor progression, stress response, flowering, and hormone signaling. However, ab initio discovery of small proteins has been relatively overlooked. Recent advances in deep transcriptome sequencing make it possible to efficiently identify sORFs at the genome level. In this study, we obtained 2.6 million expressed sequence tag (EST) reads from Populus deltoides leaf transcriptome and reconstructed full-length transcripts from the EST sequences. We identified an initial set of 12,852 sORFs encoding proteins of 10 200 aa in length. Three computational approaches were then used to enrich for bona fide protein-coding sORFs from the initial sORF set: (1) codingpotential prediction, (2) evolutionary conservation between P. deltoides and other plant species, and (3) gene family clustering within P. deltoides. As a result, a high-confidence sORF candidate set containing 1469 genes was obtained. Analysis of the protein domains, non-protein-coding RNA motifs, sequence length distribution, and protein mass spectrometry data supported this high-confidence sORF set. In the high-confidence sORF candidate set, known protein domains were identified in 1282 genes (higher-confidence sORF candidate set), out of which 611 genes, designated as highest-confidence candidate sORF set, were supported by proteomics data. Of the 611 highest-confidence candidate sORF genes, 56 were new to the current Populus genome annotation. This study not only demonstrates that there are potential sORF candidates to be annotated in sequenced genomes, but also presents an efficient strategy for discovery of sORFs in species with no genome annotation yet available.

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

    Science.gov (United States)

    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.

  15. The Goal Specificity Effect on Strategy Use and Instructional Efficiency during Computer-Based Scientific Discovery Learning

    Science.gov (United States)

    Kunsting, Josef; Wirth, Joachim; Paas, Fred

    2011-01-01

    Using a computer-based scientific discovery learning environment on buoyancy in fluids we investigated the "effects of goal specificity" (nonspecific goals vs. specific goals) for two goal types (problem solving goals vs. learning goals) on "strategy use" and "instructional efficiency". Our empirical findings close an important research gap,…

  16. Wnt Drug Discovery: Weaving Through the Screens, Patents and Clinical Trials

    Directory of Open Access Journals (Sweden)

    Benjamin Lu

    2016-09-01

    Full Text Available The Wnt signaling pathway is intricately involved in many aspects of development and is the root cause of an increasing number of diseases. For example, colorectal cancer is the second leading cause of death in the industrialized world and aberration of Wnt signaling within the colonic stem cell is the cause of more than 90% of these cancers. Despite our advances in successfully targeting other pathways, such as Human Epidermal Growth Factor Receptor 2 (HER2, there are no clinically relevant therapies available for Wnt-related diseases. Here, we investigated where research activities are focused with respect to Wnt signaling modulators by searching the United States Patent and Trade Office (USPTO for patents and patent applications related to Wnt modulators and compared this to clinical trials focusing on Wnt modulation. We found that while the transition of intellectual property surrounding the Wnt ligand-receptor interface to clinical trials is robust, this is not true for specific inhibitors of β-catenin, which is constitutively active in many cancers. Considering the ubiquitous use of the synthetic T-cell Factor/Lymphoid Enhancer Factor (TCF/Lef reporter system and its success in identifying novel modulators in vitro, we speculate that this model of drug discovery does not capture the complexity of in vivo Wnt signaling that may be required if we are to successfully target the Wnt pathway in the clinic. Notwithstanding, increasingly more complex models are being developed, which may not be high throughput, but more pragmatic in our pursuit to control Wnt signaling.

  17. Estimation of radiation exposure from lung cancer screening program with low-dose computed tomography

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Su Yeon; Jun, Jae Kwan [Graduate School of Cancer Science and Policy, National Cancer Center, Seoul (Korea, Republic of)

    2016-12-15

    The National Lung Screening Trial (NLST) demonstrated that screening with Low-dose Computed Tomography (LDCT) screening reduced lung cancer mortality in a high-risk population. Recently, the United States Preventive Services Task Force (USPSTF) gave a B recommendation for annual LDCT screening for individuals at high-risk. With the promising results, Korea developed lung cancer screening guideline and is planning a pilot study for implementation of national lung cancer screening. With widespread adoption of lung cancer screening with LDCT, there are concerns about harms of screening, including high false-positive rates and radiation exposure. Over the 3 rounds of screening in the NLST, 96.4% of positive results were false-positives. Although the initial screening is performed at low dose, subsequent diagnostic examinations following positive results additively contribute to patient's lifetime exposure. As with implementing a large-scale screening program, there is a lack of established risk assessment about the effect of radiation exposure from long-term screening program. Thus, the purpose of this study was to estimate cumulative radiation exposure of annual LDCT lung cancer screening program over 20-year period.

  18. Heuristic lipophilicity potential for computer-aided rational drug design: Optimizations of screening functions and parameters

    Science.gov (United States)

    Du, Qishi; Mezey, Paul G.

    1998-09-01

    In this research we test and compare three possible atom-basedscreening functions used in the heuristic molecular lipophilicity potential(HMLP). Screening function 1 is a power distance-dependent function, b_{{i}} /| {R_{{i}}- r} |^γ, screening function 2is an exponential distance-dependent function, biexp(-| {R_i- r} |/d_0 , and screening function 3 is aweighted distance-dependent function, {{sign}}( {b_i } ){{exp}}ξ ( {| {R_i- r} |/| {b_i } |} )For every screening function, the parameters (γ ,d0, and ξ are optimized using 41 common organic molecules of 4 types of compounds:aliphatic alcohols, aliphatic carboxylic acids, aliphatic amines, andaliphatic alkanes. The results of calculations show that screening function3 cannot give chemically reasonable results, however, both the powerscreening function and the exponential screening function give chemicallysatisfactory results. There are two notable differences between screeningfunctions 1 and 2. First, the exponential screening function has largervalues in the short distance than the power screening function, thereforemore influence from the nearest neighbors is involved using screeningfunction 2 than screening function 1. Second, the power screening functionhas larger values in the long distance than the exponential screeningfunction, therefore screening function 1 is effected by atoms at longdistance more than screening function 2. For screening function 1, thesuitable range of parameter d0 is 1.5 < d0 < 3.0, and d0 = 2.0 is recommended. HMLP developed in this researchprovides a potential tool for computer-aided three-dimensional drugdesign.

  19. Computational and Biochemical Discovery of RSK2 as a Novel Target for Epigallocatechin Gallate (EGCG.

    Directory of Open Access Journals (Sweden)

    Hanyong Chen

    Full Text Available The most active anticancer component in green tea is epigallocatechin-3-gallate (EGCG. Protein interaction with EGCG is a critical step for mediating the effects of EGCG on the regulation of various key molecules involved in signal transduction. By using computational docking screening methods for protein identification, we identified a serine/threonine kinase, 90-kDa ribosomal S6 kinase (RSK2, as a novel molecular target of EGCG. RSK2 includes two kinase catalytic domains in the N-terminal (NTD and the C-terminal (CTD and RSK2 full activation requires phosphorylation of both terminals. The computer prediction was confirmed by an in vitro kinase assay in which EGCG inhibited RSK2 activity in a dose-dependent manner. Pull-down assay results showed that EGCG could bind with RSK2 at both kinase catalytic domains in vitro and ex vivo. Furthermore, results of an ATP competition assay and a computer-docking model showed that EGCG binds with RSK2 in an ATP-dependent manner. In RSK2+/+ and RSK2-/- murine embryonic fibroblasts, EGCG decreased viability only in the presence of RSK2. EGCG also suppressed epidermal growth factor-induced neoplastic cell transformation by inhibiting phosphorylation of histone H3 at Ser10. Overall, these results indicate that RSK2 is a novel molecular target of EGCG.

  20. Materials Screening for the Discovery of New Half-Heuslers: Machine Learning versus ab Initio Methods.

    Science.gov (United States)

    Legrain, Fleur; Carrete, Jesús; van Roekeghem, Ambroise; Madsen, Georg K H; Mingo, Natalio

    2018-01-18

    Machine learning (ML) is increasingly becoming a helpful tool in the search for novel functional compounds. Here we use classification via random forests to predict the stability of half-Heusler (HH) compounds, using only experimentally reported compounds as a training set. Cross-validation yields an excellent agreement between the fraction of compounds classified as stable and the actual fraction of truly stable compounds in the ICSD. The ML model is then employed to screen 71 178 different 1:1:1 compositions, yielding 481 likely stable candidates. The predicted stability of HH compounds from three previous high-throughput ab initio studies is critically analyzed from the perspective of the alternative ML approach. The incomplete consistency among the three separate ab initio studies and between them and the ML predictions suggests that additional factors beyond those considered by ab initio phase stability calculations might be determinant to the stability of the compounds. Such factors can include configurational entropies and quasiharmonic contributions.

  1. In Silico-Based High-Throughput Screen for Discovery of Novel Combinations for Tuberculosis Treatment

    Science.gov (United States)

    Singh, Ragini; Ramachandran, Vasanthi; Shandil, Radha; Sharma, Sreevalli; Khandelwal, Swati; Karmarkar, Malancha; Kumar, Naveen; Solapure, Suresh; Saralaya, Ramanatha; Nanduri, Robert; Panduga, Vijender; Reddy, Jitendar; Prabhakar, K. R.; Rajagopalan, Swaminathan; Rao, Narasimha; Narayanan, Shridhar; Anandkumar, Anand; Datta, Santanu

    2015-01-01

    There are currently 18 drug classes for the treatment of tuberculosis, including those in the development pipeline. An in silico simulation enabled combing the innumerably large search space to derive multidrug combinations. Through the use of ordinary differential equations (ODE), we constructed an in silico kinetic platform in which the major metabolic pathways in Mycobacterium tuberculosis and the mechanisms of the antituberculosis drugs were integrated into a virtual proteome. The optimized model was used to evaluate 816 triplets from the set of 18 drugs. The experimentally derived cumulative fractional inhibitory concentration (∑FIC) value was within twofold of the model prediction. Bacterial enumeration revealed that a significant number of combinations that were synergistic for growth inhibition were also synergistic for bactericidal effect. The in silico-based screen provided new starting points for testing in a mouse model of tuberculosis, in which two novel triplets and five novel quartets were significantly superior to the reference drug triplet of isoniazid, rifampin, and ethambutol (HRE) or the quartet of HRE plus pyrazinamide (HREZ). PMID:26149995

  2. Post processing of protein-compound docking for fragment-based drug discovery (FBDD): in-silico structure-based drug screening and ligand-binding pose prediction.

    Science.gov (United States)

    Fukunishi, Yoshifumi

    2010-01-01

    For fragment-based drug development, both hit (active) compound prediction and docking-pose (protein-ligand complex structure) prediction of the hit compound are important, since chemical modification (fragment linking, fragment evolution) subsequent to the hit discovery must be performed based on the protein-ligand complex structure. However, the naïve protein-compound docking calculation shows poor accuracy in terms of docking-pose prediction. Thus, post-processing of the protein-compound docking is necessary. Recently, several methods for the post-processing of protein-compound docking have been proposed. In FBDD, the compounds are smaller than those for conventional drug screening. This makes it difficult to perform the protein-compound docking calculation. A method to avoid this problem has been reported. Protein-ligand binding free energy estimation is useful to reduce the procedures involved in the chemical modification of the hit fragment. Several prediction methods have been proposed for high-accuracy estimation of protein-ligand binding free energy. This paper summarizes the various computational methods proposed for docking-pose prediction and their usefulness in FBDD.

  3. Discovery of a Dipeptide Epimerase Enzymatic Function Guided by Homology Modeling and Virtual Screening

    Energy Technology Data Exchange (ETDEWEB)

    Kalyanaraman, C.; Imker, H; Fedorov, A; Fedorov, E; Glasner, M; Babbitt, P; Almo, S; Gerlt, J; Jacobson, M

    2008-01-01

    We have developed a computational approach to aid the assignment of enzymatic function for uncharacterized proteins that uses homology modeling to predict the structure of the binding site and in silico docking to identify potential substrates. We apply this method to proteins in the functionally diverse enolase superfamily that are homologous to the characterized L-Ala-D/L-Glu epimerase from Bacillus subtilis. In particular, a protein from Thermotoga martima was predicted to have different substrate specificity, which suggests that it has a different, but as yet unknown, biological function. This prediction was experimentally confirmed, resulting in the assignment of epimerase activity for L-Ala-D/L-Phe, L-Ala-D/L-Tyr, and L-Ala-D/L-His, whereas the enzyme is annotated incorrectly in GenBank as muconate cycloisomerase. Subsequently, crystal structures of the enzyme were determined in complex with three substrates, showing close agreement with the computational models and revealing the structural basis for the observed substrate selectivity.

  4. MRM screening/biomarker discovery with linear ion trap MS: a library of human cancer-specific peptides

    International Nuclear Information System (INIS)

    Yang, Xu; Lazar, Iulia M

    2009-01-01

    The discovery of novel protein biomarkers is essential in the clinical setting to enable early disease diagnosis and increase survivability rates. To facilitate differential expression analysis and biomarker discovery, a variety of tandem mass spectrometry (MS/MS)-based protein profiling techniques have been developed. For achieving sensitive detection and accurate quantitation, targeted MS screening approaches, such as multiple reaction monitoring (MRM), have been implemented. MCF-7 breast cancer protein cellular extracts were analyzed by 2D-strong cation exchange (SCX)/reversed phase liquid chromatography (RPLC) separations interfaced to linear ion trap MS detection. MS data were interpreted with the Sequest-based Bioworks software (Thermo Electron). In-house developed Perl-scripts were used to calculate the spectral counts and the representative fragment ions for each peptide. In this work, we report on the generation of a library of 9,677 peptides (p < 0.001), representing ~1,572 proteins from human breast cancer cells, that can be used for MRM/MS-based biomarker screening studies. For each protein, the library provides the number and sequence of detectable peptides, the charge state, the spectral count, the molecular weight, the parameters that characterize the quality of the tandem mass spectrum (p-value, DeltaM, Xcorr, DeltaCn, Sp, no. of matching a, b, y ions in the spectrum), the retention time, and the top 10 most intense product ions that correspond to a given peptide. Only proteins identified by at least two spectral counts are listed. The experimental distribution of protein frequencies, as a function of molecular weight, closely matched the theoretical distribution of proteins in the human proteome, as provided in the SwissProt database. The amino acid sequence coverage of the identified proteins ranged from 0.04% to 98.3%. The highest-abundance proteins in the cellular extract had a molecular weight (MW)<50,000. Preliminary experiments have

  5. Cost-effectiveness of computed tomographic colonography screening for colorectal cancer in the medicare population

    NARCIS (Netherlands)

    A.B. Knudsen (Amy); I. Lansdorp-Vogelaar (Iris); C.M. Rutter (Carolyn); J.E. Savarino (James); M. van Ballegooijen (Marjolein); K.M. Kuntz (Karen); A. Zauber (Ann)

    2010-01-01

    textabstractBackground The Centers for Medicare and Medicaid Services (CMS) considered whether to reimburse computed tomographic colonography (CTC) for colorectal cancer screening of Medicare enrollees. To help inform its decision, we evaluated the reimbursement rate at which CTC screening could be

  6. International Association for the Study of Lung Cancer Computed Tomography Screening Workshop 2011 Report

    NARCIS (Netherlands)

    Field, John K.; Smith, Robert A.; Aberle, Denise R.; Oudkerk, Matthijs; Baldwin, David R.; Yankelevitz, David; Pedersen, Jesper Holst; Swanson, Scott James; Travis, William D.; Wisbuba, Ignacio I.; Noguchi, Masayuki; Mulshine, Jim L.

    The International Association for the Study of Lung Cancer (IASLC) Board of Directors convened a computed tomography (CT) Screening Task Force to develop an IASLC position statement, after the National Cancer Institute press statement from the National Lung Screening Trial showed that lung cancer

  7. Discovery of DPP IV inhibitors by pharmacophore modeling and QSAR analysis followed by in silico screening.

    Science.gov (United States)

    Al-Masri, Ihab M; Mohammad, Mohammad K; Taha, Mutasem O

    2008-11-01

    Dipeptidyl peptidase IV (DPP IV) deactivates the natural hypoglycemic incretin hormones. Inhibition of this enzyme should restore glucose homeostasis in diabetic patients making it an attractive target for the development of new antidiabetic drugs. With this in mind, the pharmacophoric space of DPP IV was explored using a set of 358 known inhibitors. Thereafter, genetic algorithm and multiple linear regression analysis were employed to select an optimal combination of pharmacophoric models and physicochemical descriptors that yield selfconsistent and predictive quantitative structure-activity relationships (QSAR) (r(2) (287)=0.74, F-statistic=44.5, r(2) (BS)=0.74, r(2) (LOO)=0.69, r(2) (PRESS) against 71 external testing inhibitors=0.51). Two orthogonal pharmacophores (of cross-correlation r(2)=0.23) emerged in the QSAR equation suggesting the existence of at least two distinct binding modes accessible to ligands within the DPP IV binding pocket. Docking experiments supported the binding modes suggested by QSAR/pharmacophore analyses. The validity of the QSAR equation and the associated pharmacophore models were established by the identification of new low-micromolar anti-DPP IV leads retrieved by in silico screening. One of our interesting potent anti-DPP IV hits is the fluoroquinolone gemifloxacin (IC(50)=1.12 muM). The fact that gemifloxacin was recently reported to potently inhibit the prodiabetic target glycogen synthase kinase 3beta (GSK-3beta) suggests that gemifloxacin is an excellent lead for the development of novel dual antidiabetic inhibitors against DPP IV and GSK-3beta.

  8. Difficulties encountered managing nodules detected during a computed tomography lung cancer screening program.

    Science.gov (United States)

    Veronesi, Giulia; Bellomi, Massimo; Scanagatta, Paolo; Preda, Lorenzo; Rampinelli, Cristiano; Guarize, Juliana; Pelosi, Giuseppe; Maisonneuve, Patrick; Leo, Francesco; Solli, Piergiorgio; Masullo, Michele; Spaggiari, Lorenzo

    2008-09-01

    The main challenge of screening a healthy population with low-dose computed tomography is to balance the excessive use of diagnostic procedures with the risk of delayed cancer detection. We evaluated the pitfalls, difficulties, and sources of mistakes in the management of lung nodules detected in volunteers in the Cosmos single-center screening trial. A total of 5201 asymptomatic high-risk volunteers underwent screening with multidetector low-dose computed tomography. Nodules detected at baseline or new nodules at annual screening received repeat low-dose computed tomography at 1 year if less than 5 mm, repeat low-dose computed tomography 3 to 6 months later if between 5 and 8 mm, and fluorodeoxyglucose positron emission tomography if more than 8 mm. Growing nodules at the annual screening received low-dose computed tomography at 6 months and computed tomography-positron emission tomography or surgical biopsy according to doubling time, type, and size. During the first year of screening, 106 patients underwent lung biopsy and 91 lung cancers were identified (70% were stage I). Diagnosis was delayed (false-negative) in 6 patients (stage IIB in 1 patient, stage IIIA in 3 patients, and stage IV in 2 patients), including 2 small cell cancers and 1 central lesion. Surgical biopsy revealed benign disease (false-positives) in 15 cases (14%). Positron emission tomography sensitivity was 88% for prevalent cancers and 70% for cancers diagnosed after first annual screening. No needle biopsy procedures were performed in this cohort of patients. Low-dose computed tomography screening is effective for the early detection of lung cancers, but nodule management remains a challenge. Computed tomography-positron emission tomography is useful at baseline, but its sensitivity decreases significantly the subsequent year. Multidisciplinary management and experience are crucial for minimizing misdiagnoses.

  9. High throughput screening for small molecule enhancers of the interferon signaling pathway to drive next-generation antiviral drug discovery.

    Directory of Open Access Journals (Sweden)

    Dhara A Patel

    Full Text Available Most of current strategies for antiviral therapeutics target the virus specifically and directly, but an alternative approach to drug discovery might be to enhance the immune response to a broad range of viruses. Based on clinical observation in humans and successful genetic strategies in experimental models, we reasoned that an improved interferon (IFN signaling system might better protect against viral infection. Here we aimed to identify small molecular weight compounds that might mimic this beneficial effect and improve antiviral defense. Accordingly, we developed a cell-based high-throughput screening (HTS assay to identify small molecules that enhance the IFN signaling pathway components. The assay is based on a phenotypic screen for increased IFN-stimulated response element (ISRE activity in a fully automated and robust format (Z'>0.7. Application of this assay system to a library of 2240 compounds (including 2160 already approved or approvable drugs led to the identification of 64 compounds with significant ISRE activity. From these, we chose the anthracycline antibiotic, idarubicin, for further validation and mechanism based on activity in the sub-µM range. We found that idarubicin action to increase ISRE activity was manifest by other members of this drug class and was independent of cytotoxic or topoisomerase inhibitory effects as well as endogenous IFN signaling or production. We also observed that this compound conferred a consequent increase in IFN-stimulated gene (ISG expression and a significant antiviral effect using a similar dose-range in a cell-culture system inoculated with encephalomyocarditis virus (EMCV. The antiviral effect was also found at compound concentrations below the ones observed for cytotoxicity. Taken together, our results provide proof of concept for using activators of components of the IFN signaling pathway to improve IFN efficacy and antiviral immune defense as well as a validated HTS approach to identify

  10. Hand held control unit for controlling a display screen-oriented computer game, and a display screen-oriented computer game having one or more such control units

    NARCIS (Netherlands)

    2001-01-01

    A hand-held control unit is used to control a display screen-oriented computer game. The unit comprises a housing with a front side, a set of control members lying generally flush with the front side for through actuating thereof controlling actions of in-game display items, and an output for

  11. A High-Throughput Screening Platform of Microbial Natural Products for the Discovery of Molecules with Antibiofilm Properties against Salmonella

    Science.gov (United States)

    Paytubi, Sonia; de La Cruz, Mercedes; Tormo, Jose R.; Martín, Jesús; González, Ignacio; González-Menendez, Victor; Genilloud, Olga; Reyes, Fernando; Vicente, Francisca; Madrid, Cristina; Balsalobre, Carlos

    2017-01-01

    In this report, we describe a High-Throughput Screening (HTS) to identify compounds that inhibit biofilm formation or cause the disintegration of an already formed biofilm using the Salmonella Enteritidis 3934 strain. Initially, we developed a new methodology for growing Salmonella biofilms suitable for HTS platforms. The biomass associated with biofilm at the solid-liquid interface was quantified by staining both with resazurin and crystal violet, to detect living cells and total biofilm mass, respectively. For a pilot project, a subset of 1120 extracts from the Fundación MEDINA's collection was examined to identify molecules with antibiofilm activity. This is the first validated HTS assay of microbial natural product extracts which allows for the detection of four types of activities which are not mutually exclusive: inhibition of biofilm formation, detachment of the preformed biofilm and antimicrobial activity against planktonic cells or biofilm embedded cells. Currently, several extracts have been selected for further fractionation and purification of the active compounds. In one of the natural extracts patulin has been identified as a potent molecule with antimicrobial activity against both, planktonic cells and cells within the biofilm. These findings provide a proof of concept that the developed HTS can lead to the discovery of new natural compounds with antibiofilm activity against Salmonella and its possible use as an alternative to antimicrobial therapies and traditional disinfectants. PMID:28303128

  12. Computational Methods Used in Hit-to-Lead and Lead Optimization Stages of Structure-Based Drug Discovery.

    Science.gov (United States)

    Heifetz, Alexander; Southey, Michelle; Morao, Inaki; Townsend-Nicholson, Andrea; Bodkin, Mike J

    2018-01-01

    GPCR modeling approaches are widely used in the hit-to-lead (H2L) and lead optimization (LO) stages of drug discovery. The aims of these modeling approaches are to predict the 3D structures of the receptor-ligand complexes, to explore the key interactions between the receptor and the ligand and to utilize these insights in the design of new molecules with improved binding, selectivity or other pharmacological properties. In this book chapter, we present a brief survey of key computational approaches integrated with hierarchical GPCR modeling protocol (HGMP) used in hit-to-lead (H2L) and in lead optimization (LO) stages of structure-based drug discovery (SBDD). We outline the differences in modeling strategies used in H2L and LO of SBDD and illustrate how these tools have been applied in three drug discovery projects.

  13. In person versus computer screening for intimate partner violence among pregnant patients.

    Science.gov (United States)

    Chang, Judy C; Dado, Diane; Schussler, Sara; Hawker, Lynn; Holland, Cynthia L; Burke, Jessica G; Cluss, Patricia A

    2012-09-01

    To compare in person versus computerized screening for intimate partner violence (IPV) in a hospital-based prenatal clinic and explore women's assessment of the screening methods. We compared patient IPV disclosures on a computerized questionnaire to audio-taped first obstetric visits with an obstetric care provider and performed semi-structured interviews with patient participants who reported experiencing IPV. Two-hundred and fifty patient participants and 52 provider participants were in the study. Ninety-one (36%) patients disclosed IPV either via computer or in person. Of those who disclosed IPV, 60 (66%) disclosed via both methods, but 31 (34%) disclosed IPV via only one of the two methods. Twenty-three women returned for interviews. They recommended using both types together. While computerized screening was felt to be non-judgmental and more anonymous, in person screening allowed for tailored questioning and more emotional connection with the provider. Computerized screening allowed disclosure without fear of immediate judgment. In person screening allows more flexibility in wording of questions regarding IPV and opportunity for interpersonal rapport. Both computerized or self-completed screening and in person screening is recommended. Providers should address IPV using non-judgmental, descriptive language, include assessments for psychological IPV, and repeat screening in person, even if no patient disclosure occurs via computer. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  14. Visual ergonomic aspects of glare on computer displays: glossy screens and angular dependence

    Science.gov (United States)

    Brunnström, Kjell; Andrén, Börje; Konstantinides, Zacharias; Nordström, Lukas

    2007-02-01

    Recently flat panel computer displays and notebook computer are designed with a so called glare panel i.e. highly glossy screens, have emerged on the market. The shiny look of the display appeals to the costumers, also there are arguments that the contrast, colour saturation etc improves by using a glare panel. LCD displays suffer often from angular dependent picture quality. This has been even more pronounced by the introduction of Prism Light Guide plates into displays for notebook computers. The TCO label is the leading labelling system for computer displays. Currently about 50% of all computer displays on the market are certified according to the TCO requirements. The requirements are periodically updated to keep up with the technical development and the latest research in e.g. visual ergonomics. The gloss level of the screen and the angular dependence has recently been investigated by conducting user studies. A study of the effect of highly glossy screens compared to matt screens has been performed. The results show a slight advantage for the glossy screen when no disturbing reflexes are present, however the difference was not statistically significant. When disturbing reflexes are present the advantage is changed into a larger disadvantage and this difference is statistically significant. Another study of angular dependence has also been performed. The results indicates a linear relationship between the picture quality and the centre luminance of the screen.

  15. Discovery of a small-molecule inhibitor of Dvl-CXXC5 interaction by computational approaches

    Science.gov (United States)

    Ma, Songling; Choi, Jiwon; Jin, Xuemei; Kim, Hyun-Yi; Yun, Ji-Hye; Lee, Weontae; Choi, Kang-Yell; No, Kyoung Tai

    2018-05-01

    The Wnt/β-catenin signaling pathway plays a significant role in the control of osteoblastogenesis and bone formation. CXXC finger protein 5 (CXXC5) has been recently identified as a negative feedback regulator of osteoblast differentiation through a specific interaction with Dishevelled (Dvl) protein. It was reported that targeting the Dvl-CXXC5 interaction could be a novel anabolic therapeutic target for osteoporosis. In this study, complex structure of Dvl PDZ domain and CXXC5 peptide was simulated with molecular dynamics (MD). Based on the structural analysis of binding modes of MD-simulated Dvl PDZ domain with CXXC5 peptide and crystal Dvl PDZ domain with synthetic peptide-ligands, we generated two different pharmacophore models and applied pharmacophore-based virtual screening to discover potent inhibitors of the Dvl-CXXC5 interaction for the anabolic therapy of osteoporosis. Analysis of 16 compounds selected by means of a virtual screening protocol yielded four compounds that effectively disrupted the Dvl-CXXC5 interaction in the fluorescence polarization assay. Potential compounds were validated by fluorescence spectroscopy and nuclear magnetic resonance. We successfully identified a highly potent inhibitor, BMD4722, which directly binds to the Dvl PDZ domain and disrupts the Dvl-CXXC5 interaction. Overall, CXXC5-Dvl PDZ domain complex based pharmacophore combined with various traditional and simple computational methods is a promising approach for the development of modulators targeting the Dvl-CXXC5 interaction, and the potent inhibitor BMD4722 could serve as a starting point to discover or design more potent and specific the Dvl-CXXC5 interaction disruptors.

  16. Discovery of a small-molecule inhibitor of Dvl-CXXC5 interaction by computational approaches.

    Science.gov (United States)

    Ma, Songling; Choi, Jiwon; Jin, Xuemei; Kim, Hyun-Yi; Yun, Ji-Hye; Lee, Weontae; Choi, Kang-Yell; No, Kyoung Tai

    2018-04-07

    The Wnt/β-catenin signaling pathway plays a significant role in the control of osteoblastogenesis and bone formation. CXXC finger protein 5 (CXXC5) has been recently identified as a negative feedback regulator of osteoblast differentiation through a specific interaction with Dishevelled (Dvl) protein. It was reported that targeting the Dvl-CXXC5 interaction could be a novel anabolic therapeutic target for osteoporosis. In this study, complex structure of Dvl PDZ domain and CXXC5 peptide was simulated with molecular dynamics (MD). Based on the structural analysis of binding modes of MD-simulated Dvl PDZ domain with CXXC5 peptide and crystal Dvl PDZ domain with synthetic peptide-ligands, we generated two different pharmacophore models and applied pharmacophore-based virtual screening to discover potent inhibitors of the Dvl-CXXC5 interaction for the anabolic therapy of osteoporosis. Analysis of 16 compounds selected by means of a virtual screening protocol yielded four compounds that effectively disrupted the Dvl-CXXC5 interaction in the fluorescence polarization assay. Potential compounds were validated by fluorescence spectroscopy and nuclear magnetic resonance. We successfully identified a highly potent inhibitor, BMD4722, which directly binds to the Dvl PDZ domain and disrupts the Dvl-CXXC5 interaction. Overall, CXXC5-Dvl PDZ domain complex based pharmacophore combined with various traditional and simple computational methods is a promising approach for the development of modulators targeting the Dvl-CXXC5 interaction, and the potent inhibitor BMD4722 could serve as a starting point to discover or design more potent and specific the Dvl-CXXC5 interaction disruptors.

  17. Practical considerations and effects of metallic screen fluorescence and backscatter control in gamma computed radiography

    International Nuclear Information System (INIS)

    Mango, Steven

    2016-01-01

    It is a fairly common misconception that the role of metallic screens used with computed radiography is primarily that of scatter control, and that any amplification of the image signal is minimal. To the contrary, this paper shows how the physical interaction between gamma rays and front metallic screens can yield a significant boost in signal and whether that increased signal is, in fact, beneficial or detrimental to image quality. For rear metallic screens, this signal boost is differentiated from backscatter, and image quality considerations should be more carefully thought out because of the separation between the screen and the imaging layer provided by the imaging plate support. Various physical interactions are explained, and a series of practical experiments show the various changes in signal level and image quality with various thicknesses of lead and copper screens. Recommendations are made for the configuration of the imaging plate and screens for optimum image quality and for the control and monitoring of scatter.

  18. China National Lung Cancer Screening Guideline with Low-dose Computed 
Tomography (2018 version

    Directory of Open Access Journals (Sweden)

    Qinghua ZHOU

    2018-02-01

    Full Text Available Background and objective Lung cancer is the leading cause of cancer-related death in China. The results from a randomized controlled trial using annual low-dose computed tomography (LDCT in specific high-risk groups demonstrated a 20% reduction in lung cancer mortality. The aim of tihs study is to establish the China National lung cancer screening guidelines for clinical practice. Methods The China lung cancer early detection and treatment expert group (CLCEDTEG established the China National Lung Cancer Screening Guideline with multidisciplinary representation including 4 thoracic surgeons, 4 thoracic radiologists, 2 medical oncologists, 2 pulmonologists, 2 pathologist, and 2 epidemiologist. Members have engaged in interdisciplinary collaborations regarding lung cancer screening and clinical care of patients with at risk for lung cancer. The expert group reviewed the literature, including screening trials in the United States and Europe and China, and discussed local best clinical practices in the China. A consensus-based guidelines, China National Lung Cancer Screening Guideline (CNLCSG, was recommended by CLCEDTEG appointed by the National Health and Family Planning Commission, based on results of the National Lung Screening Trial, systematic review of evidence related to LDCT screening, and protocol of lung cancer screening program conducted in rural China. Results Annual lung cancer screening with LDCT is recommended for high risk individuals aged 50-74 years who have at least a 20 pack-year smoking history and who currently smoke or have quit within the past five years. Individualized decision making should be conducted before LDCT screening. LDCT screening also represents an opportunity to educate patients as to the health risks of smoking; thus, education should be integrated into the screening process in order to assist smoking cessation. Conclusion A lung cancer screening guideline is recommended for the high-risk population in China

  19. [China National Lung Cancer Screening Guideline with Low-dose Computed 
Tomography (2018 version)].

    Science.gov (United States)

    Zhou, Qinghua; Fan, Yaguang; Wang, Ying; Qiao, Youlin; Wang, Guiqi; Huang, Yunchao; Wang, Xinyun; Wu, Ning; Zhang, Guozheng; Zheng, Xiangpeng; Bu, Hong; Li, Yin; Wei, Sen; Chen, Liang'an; Hu, Chengping; Shi, Yuankai; Sun, Yan

    2018-02-20

    Lung cancer is the leading cause of cancer-related death in China. The results from a randomized controlled trial using annual low-dose computed tomography (LDCT) in specific high-risk groups demonstrated a 20% reduction in lung cancer mortality. The aim of tihs study is to establish the China National lung cancer screening guidelines for clinical practice. The China lung cancer early detection and treatment expert group (CLCEDTEG) established the China National Lung Cancer Screening Guideline with multidisciplinary representation including 4 thoracic surgeons, 4 thoracic radiologists, 2 medical oncologists, 2 pulmonologists, 2 pathologist, and 2 epidemiologist. Members have engaged in interdisciplinary collaborations regarding lung cancer screening and clinical care of patients with at risk for lung cancer. The expert group reviewed the literature, including screening trials in the United States and Europe and China, and discussed local best clinical practices in the China. A consensus-based guidelines, China National Lung Cancer Screening Guideline (CNLCSG), was recommended by CLCEDTEG appointed by the National Health and Family Planning Commission, based on results of the National Lung Screening Trial, systematic review of evidence related to LDCT screening, and protocol of lung cancer screening program conducted in rural China. Annual lung cancer screening with LDCT is recommended for high risk individuals aged 50-74 years who have at least a 20 pack-year smoking history and who currently smoke or have quit within the past five years. Individualized decision making should be conducted before LDCT screening. LDCT screening also represents an opportunity to educate patients as to the health risks of smoking; thus, education should be integrated into the screening process in order to assist smoking cessation. A lung cancer screening guideline is recommended for the high-risk population in China. Additional research , including LDCT combined with biomarkers, is

  20. The Application of Computer-Aided Discovery to Spacecraft Site Selection

    Science.gov (United States)

    Pankratius, V.; Blair, D. M.; Gowanlock, M.; Herring, T.

    2015-12-01

    The selection of landing and exploration sites for interplanetary robotic or human missions is a complex task. Historically it has been labor-intensive, with large groups of scientists manually interpreting a planetary surface across a variety of datasets to identify potential sites based on science and engineering constraints. This search process can be lengthy, and excellent sites may get overlooked when the aggregate value of site selection criteria is non-obvious or non-intuitive. As planetary data collection leads to Big Data repositories and a growing set of selection criteria, scientists will face a combinatorial search space explosion that requires scalable, automated assistance. We are currently exploring more general computer-aided discovery techniques in the context of planetary surface deformation phenomena that can lend themselves to application in the landing site search problem. In particular, we are developing a general software framework that addresses key difficulties: characterizing a given phenomenon or site based on data gathered from multiple instruments (e.g. radar interferometry, gravity, thermal maps, or GPS time series), and examining a variety of possible workflows whose individual configurations are optimized to isolate different features. The framework allows algorithmic pipelines and hypothesized models to be perturbed or permuted automatically within well-defined bounds established by the scientist. For example, even simple choices for outlier and noise handling or data interpolation can drastically affect the detectability of certain features. These techniques aim to automate repetitive tasks that scientists routinely perform in exploratory analysis, and make them more efficient and scalable by executing them in parallel in the cloud. We also explore ways in which machine learning can be combined with human feedback to prune the search space and converge to desirable results. Acknowledgements: We acknowledge support from NASA AIST

  1. Computational approaches for discovery of common immunomodulators in fungal infections: towards broad-spectrum immunotherapeutic interventions.

    Science.gov (United States)

    Kidane, Yared H; Lawrence, Christopher; Murali, T M

    2013-10-07

    Fungi are the second most abundant type of human pathogens. Invasive fungal pathogens are leading causes of life-threatening infections in clinical settings. Toxicity to the host and drug-resistance are two major deleterious issues associated with existing antifungal agents. Increasing a host's tolerance and/or immunity to fungal pathogens has potential to alleviate these problems. A host's tolerance may be improved by modulating the immune system such that it responds more rapidly and robustly in all facets, ranging from the recognition of pathogens to their clearance from the host. An understanding of biological processes and genes that are perturbed during attempted fungal exposure, colonization, and/or invasion will help guide the identification of endogenous immunomodulators and/or small molecules that activate host-immune responses such as specialized adjuvants. In this study, we present computational techniques and approaches using publicly available transcriptional data sets, to predict immunomodulators that may act against multiple fungal pathogens. Our study analyzed data sets derived from host cells exposed to five fungal pathogens, namely, Alternaria alternata, Aspergillus fumigatus, Candida albicans, Pneumocystis jirovecii, and Stachybotrys chartarum. We observed statistically significant associations between host responses to A. fumigatus and C. albicans. Our analysis identified biological processes that were consistently perturbed by these two pathogens. These processes contained both immune response-inducing genes such as MALT1, SERPINE1, ICAM1, and IL8, and immune response-repressing genes such as DUSP8, DUSP6, and SPRED2. We hypothesize that these genes belong to a pool of common immunomodulators that can potentially be activated or suppressed (agonized or antagonized) in order to render the host more tolerant to infections caused by A. fumigatus and C. albicans. Our computational approaches and methodologies described here can now be applied to

  2. Comparison of different strategies in prenatal screening for Down's syndrome: cost effectiveness analysis of computer simulation.

    Science.gov (United States)

    Gekas, Jean; Gagné, Geneviève; Bujold, Emmanuel; Douillard, Daniel; Forest, Jean-Claude; Reinharz, Daniel; Rousseau, François

    2009-02-13

    To assess and compare the cost effectiveness of three different strategies for prenatal screening for Down's syndrome (integrated test, sequential screening, and contingent screenings) and to determine the most useful cut-off values for risk. Computer simulations to study integrated, sequential, and contingent screening strategies with various cut-offs leading to 19 potential screening algorithms. The computer simulation was populated with data from the Serum Urine and Ultrasound Screening Study (SURUSS), real unit costs for healthcare interventions, and a population of 110 948 pregnancies from the province of Québec for the year 2001. Cost effectiveness ratios, incremental cost effectiveness ratios, and screening options' outcomes. The contingent screening strategy dominated all other screening options: it had the best cost effectiveness ratio ($C26,833 per case of Down's syndrome) with fewer procedure related euploid miscarriages and unnecessary terminations (respectively, 6 and 16 per 100,000 pregnancies). It also outperformed serum screening at the second trimester. In terms of the incremental cost effectiveness ratio, contingent screening was still dominant: compared with screening based on maternal age alone, the savings were $C30,963 per additional birth with Down's syndrome averted. Contingent screening was the only screening strategy that offered early reassurance to the majority of women (77.81%) in first trimester and minimised costs by limiting retesting during the second trimester (21.05%). For the contingent and sequential screening strategies, the choice of cut-off value for risk in the first trimester test significantly affected the cost effectiveness ratios (respectively, from $C26,833 to $C37,260 and from $C35,215 to $C45,314 per case of Down's syndrome), the number of procedure related euploid miscarriages (from 6 to 46 and from 6 to 45 per 100,000 pregnancies), and the number of unnecessary terminations (from 16 to 26 and from 16 to 25 per 100

  3. A Review of Human Pluripotent Stem Cell-Derived Cardiomyocytes for High-Throughput Drug Discovery, Cardiotoxicity Screening and Publication Standards

    OpenAIRE

    Mordwinkin, Nicholas M.; Burridge, Paul W.; Wu, Joseph C.

    2012-01-01

    Drug attrition rates have increased in past years, resulting in growing costs for the pharmaceutical industry and consumers. The reasons for this include the lack of in vitro models that correlate with clinical results, and poor preclinical toxicity screening assays. The in vitro production of human cardiac progenitor cells and cardiomyocytes from human pluripotent stem cells provides an amenable source of cells for applications in drug discovery, disease modeling, regenerative medicine, and ...

  4. School Students and Computer Games with Screen Violence

    Science.gov (United States)

    Fedorov, A. V.

    2005-01-01

    In this article, the author states how these days, school students from low-income strata of the population in Russia spend hours sitting in computer rooms and Internet clubs, where, for a relatively small fee, they can play interactive video games. And to determine what games they prefer the author conducted a content analysis of eighty-seven…

  5. Pulsar discoveries by volunteer distributed computing and the strongest continuous gravitational wave signal

    Science.gov (United States)

    Knispel, Benjamin

    2011-07-01

    a double neutron star system disrupted by the second supernova. We present discovery and initial characterisation using observations from five of the largest radio telescopes worldwide. Only a dozen similar systems were previously known. The second discovered radio pulsar, PSR J1952+2630, is in a 9.4-hr orbit with most likely a massive white dwarf of at least 0.95 M⊙. We characterise its orbit by analysis of the apparent spin period changes. This pulsar most likely belongs to the very rare class of intermediate-mass binary pulsars, from which only five systems were previously known. It is a promising target for the future measurement of relativistic effects. In the second half of this thesis, the emission of continuous gravitational waves from a Galactic population of neutron stars is studied. For the first time, realistic estimates of the statistical upper limit of the expected gravitational wave signal are obtained, improving previous estimates by about a factor of six. The simulation is used to obtain for the first time detectability predictions for these objects with ground based gravitational wave detectors and realistic blind searches. It is also shown how to improve possible searches by maximising the number of detections for a fixed amount of computation cycles.

  6. Computational Screening of Materials for Water Splitting Applications

    DEFF Research Database (Denmark)

    Castelli, Ivano Eligio

    Design new materials for energy production in a photoelectrochemical cell, where water is split into hydrogen and oxygen by solar light, is one possible solution to the problem of increasing energy demand and storage. A screening procedure based on ab-initio density functional theory calculations...... Project database, which is based on the experimental ICSD database, and the bandgaps were calculated with focus on finding materials with potential as light harvesters. 24 materials have been proposed for the one-photon water splitting and 23 for the two-photon mechanism. Another method to obtain energy...... from Sun is using a photovoltaic cell that converts solar light into electricity. The absorption spectra of 70 experimentally known compounds, that are expected to be useful for light-to-electricity generation, have been calculated. 17 materials have been predicted to be promising for a single...

  7. ATLAS distributed computing operation shift teams experience during the discovery year and beginning of the long shutdown 1

    International Nuclear Information System (INIS)

    Sedov, Alexey; Girolamo, Alessandro Di; Negri, Guidone; Sakamoto, Hiroshi; Schovancová, Jaroslava; Smirnov, Iouri; Vartapetian, Armen; Yu, Jaehoon

    2014-01-01

    ATLAS Distributed Computing Operation Shifts evolve to meet new requirements. New monitoring tools as well as operational changes lead to modifications in organization of shifts. In this paper we describe the structure of shifts, the roles of different shifts in ATLAS computing grid operation, the influence of a Higgs-like particle discovery on shift operation, the achievements in monitoring and automation that allowed extra focus on the experiment priority tasks, and the influence of the Long Shutdown 1 and operational changes related to the no beam period.

  8. Application of Combination High-Throughput Phenotypic Screening and Target Identification Methods for the Discovery of Natural Product-Based Combination Drugs.

    Science.gov (United States)

    Isgut, Monica; Rao, Mukkavilli; Yang, Chunhua; Subrahmanyam, Vangala; Rida, Padmashree C G; Aneja, Ritu

    2018-03-01

    Modern drug discovery efforts have had mediocre success rates with increasing developmental costs, and this has encouraged pharmaceutical scientists to seek innovative approaches. Recently with the rise of the fields of systems biology and metabolomics, network pharmacology (NP) has begun to emerge as a new paradigm in drug discovery, with a focus on multiple targets and drug combinations for treating disease. Studies on the benefits of drug combinations lay the groundwork for a renewed focus on natural products in drug discovery. Natural products consist of a multitude of constituents that can act on a variety of targets in the body to induce pharmacodynamic responses that may together culminate in an additive or synergistic therapeutic effect. Although natural products cannot be patented, they can be used as starting points in the discovery of potent combination therapeutics. The optimal mix of bioactive ingredients in natural products can be determined via phenotypic screening. The targets and molecular mechanisms of action of these active ingredients can then be determined using chemical proteomics, and by implementing a reverse pharmacokinetics approach. This review article provides evidence supporting the potential benefits of natural product-based combination drugs, and summarizes drug discovery methods that can be applied to this class of drugs. © 2017 Wiley Periodicals, Inc.

  9. Low-dose computed tomography for lung cancer screening: comparison of performance between annual and biennial screen

    Energy Technology Data Exchange (ETDEWEB)

    Sverzellati, Nicola; Silva, M. [University of Parma, Radiology, Department of Surgical Sciences, Parma (Italy); Calareso, G.; Marchiano, A. [Fondazione IRCCS Istituto Nazionale dei Tumori, Department of Radiology, Milan (Italy); Galeone, C. [University of Milano-Bicocca, Department of Statistics and Quantitative Methods, Division of Biostatistics, Epidemiology and Public Health, Laboratory of Healthcare Research and Pharmacoepidemiology, Milan (Italy); Sestini, S.; Pastorino, U. [Fondazione IRCCS Istituto Nazionale dei Tumori, Department of Surgery, Section of Thoracic Surgery, Milan (Italy); Sozzi, G. [Fondazione IRCCS Istituto Nazionale dei Tumori, Tumor Genomics Unit, Department of Experimental Oncology and Molecular Medicine, Milan (Italy)

    2016-11-15

    To compare the performance metrics of two different strategies of lung cancer screening by low-dose computed tomography (LDCT), namely, annual (LDCT1) or biennial (LDCT2) screen. Recall rate, detection rate, interval cancers, sensitivity, specificity, positive and negative predictive values (PPV and NPV, respectively) were compared between LDCT1 and LDCT2 arms of the MILD trial over the first seven (T0-T6; median follow-up 7.3 years) and four rounds (T0-T3; median follow-up 7.3 years), respectively. 1152 LDCT1 and 1151 LDCT2 participants underwent a total of 6893 and 4715 LDCT scans, respectively. The overall recall rate was higher in LDCT2 arm (6.97 %) than in LDCT1 arm (5.81 %) (p = 0.01), which was counterbalanced by the overall lower number of LDCT scans. No difference was observed for the overall detection rate (0.56 % in both arms). The two LDCT arms had similar specificity (99.2 % in both arms), sensitivity (73.5 %, in LDCT2 vs. 68.5 % in LDCT1, p = 0.62), PPV (42.4 %, in LDCT2, vs. 40.6 %, in LDCT1, p = 0.83) and NPV (99.8 %, in LDCT2 vs. 99.7 %, in LDCT1, p = 0.71). Biennial screen may save about one third of LDCT scans with similar performance indicators as compared to annual screening. (orig.)

  10. Low-dose computed tomography for lung cancer screening: comparison of performance between annual and biennial screen

    International Nuclear Information System (INIS)

    Sverzellati, Nicola; Silva, M.; Calareso, G.; Marchiano, A.; Galeone, C.; Sestini, S.; Pastorino, U.; Sozzi, G.

    2016-01-01

    To compare the performance metrics of two different strategies of lung cancer screening by low-dose computed tomography (LDCT), namely, annual (LDCT1) or biennial (LDCT2) screen. Recall rate, detection rate, interval cancers, sensitivity, specificity, positive and negative predictive values (PPV and NPV, respectively) were compared between LDCT1 and LDCT2 arms of the MILD trial over the first seven (T0-T6; median follow-up 7.3 years) and four rounds (T0-T3; median follow-up 7.3 years), respectively. 1152 LDCT1 and 1151 LDCT2 participants underwent a total of 6893 and 4715 LDCT scans, respectively. The overall recall rate was higher in LDCT2 arm (6.97 %) than in LDCT1 arm (5.81 %) (p = 0.01), which was counterbalanced by the overall lower number of LDCT scans. No difference was observed for the overall detection rate (0.56 % in both arms). The two LDCT arms had similar specificity (99.2 % in both arms), sensitivity (73.5 %, in LDCT2 vs. 68.5 % in LDCT1, p = 0.62), PPV (42.4 %, in LDCT2, vs. 40.6 %, in LDCT1, p = 0.83) and NPV (99.8 %, in LDCT2 vs. 99.7 %, in LDCT1, p = 0.71). Biennial screen may save about one third of LDCT scans with similar performance indicators as compared to annual screening. (orig.)

  11. A Computational model for compressed sensing RNAi cellular screening

    Directory of Open Access Journals (Sweden)

    Tan Hua

    2012-12-01

    Full Text Available Abstract Background RNA interference (RNAi becomes an increasingly important and effective genetic tool to study the function of target genes by suppressing specific genes of interest. This system approach helps identify signaling pathways and cellular phase types by tracking intensity and/or morphological changes of cells. The traditional RNAi screening scheme, in which one siRNA is designed to knockdown one specific mRNA target, needs a large library of siRNAs and turns out to be time-consuming and expensive. Results In this paper, we propose a conceptual model, called compressed sensing RNAi (csRNAi, which employs a unique combination of group of small interfering RNAs (siRNAs to knockdown a much larger size of genes. This strategy is based on the fact that one gene can be partially bound with several small interfering RNAs (siRNAs and conversely, one siRNA can bind to a few genes with distinct binding affinity. This model constructs a multi-to-multi correspondence between siRNAs and their targets, with siRNAs much fewer than mRNA targets, compared with the conventional scheme. Mathematically this problem involves an underdetermined system of equations (linear or nonlinear, which is ill-posed in general. However, the recently developed compressed sensing (CS theory can solve this problem. We present a mathematical model to describe the csRNAi system based on both CS theory and biological concerns. To build this model, we first search nucleotide motifs in a target gene set. Then we propose a machine learning based method to find the effective siRNAs with novel features, such as image features and speech features to describe an siRNA sequence. Numerical simulations show that we can reduce the siRNA library to one third of that in the conventional scheme. In addition, the features to describe siRNAs outperform the existing ones substantially. Conclusions This csRNAi system is very promising in saving both time and cost for large-scale RNAi

  12. Cost-effectiveness of implementing computed tomography screening for lung cancer in Taiwan.

    Science.gov (United States)

    Yang, Szu-Chun; Lai, Wu-Wei; Lin, Chien-Chung; Su, Wu-Chou; Ku, Li-Jung; Hwang, Jing-Shiang; Wang, Jung-Der

    2017-06-01

    A screening program for lung cancer requires more empirical evidence. Based on the experience of the National Lung Screening Trial (NLST), we developed a method to adjust lead-time bias and quality-of-life changes for estimating the cost-effectiveness of implementing computed tomography (CT) screening in Taiwan. The target population was high-risk (≥30 pack-years) smokers between 55 and 75 years of age. From a nation-wide, 13-year follow-up cohort, we estimated quality-adjusted life expectancy (QALE), loss-of-QALE, and lifetime healthcare expenditures per case of lung cancer stratified by pathology and stage. Cumulative stage distributions for CT-screening and no-screening were assumed equal to those for CT-screening and radiography-screening in the NLST to estimate the savings of loss-of-QALE and additional costs of lifetime healthcare expenditures after CT screening. Costs attributable to screen-negative subjects, false-positive cases and radiation-induced lung cancer were included to obtain the incremental cost-effectiveness ratio from the public payer's perspective. The incremental costs were US$22,755 per person. After dividing this by savings of loss-of-QALE (1.16 quality-adjusted life year (QALY)), the incremental cost-effectiveness ratio was US$19,683 per QALY. This ratio would fall to US$10,947 per QALY if the stage distribution for CT-screening was the same as that of screen-detected cancers in the NELSON trial. Low-dose CT screening for lung cancer among high-risk smokers would be cost-effective in Taiwan. As only about 5% of our women are smokers, future research is necessary to identify the high-risk groups among non-smokers and increase the coverage. Copyright © 2017 The Author(s). Published by Elsevier B.V. All rights reserved.

  13. Computational screening of organic materials towards improved photovoltaic properties

    Science.gov (United States)

    Dai, Shuo; Olivares-Amaya, Roberto; Amador-Bedolla, Carlos; Aspuru-Guzik, Alan; Borunda, Mario

    2015-03-01

    The world today faces an energy crisis that is an obstruction to the development of the human civilization. One of the most promising solutions is solar energy harvested by economical solar cells. Being the third generation of solar cell materials, organic photovoltaic (OPV) materials is now under active development from both theoretical and experimental points of view. In this study, we constructed a parameter to select the desired molecules based on their optical spectra performance. We applied it to investigate a large collection of potential OPV materials, which were from the CEPDB database set up by the Harvard Clean Energy Project. Time dependent density functional theory (TD-DFT) modeling was used to calculate the absorption spectra of the molecules. Then based on the parameter, we screened out the top performing molecules for their potential OPV usage and suggested experimental efforts toward their synthesis. In addition, from those molecules, we summarized the functional groups that provided molecules certain spectrum capability. It is hoped that useful information could be mined out to provide hints to molecular design of OPV materials.

  14. Screens

    OpenAIRE

    2016-01-01

    This Sixth volume in the series The Key Debates. Mutations and Appropriations in European Film Studies investigates the question of screens in the context both of the dematerialization due to digitalization and the multiplication of media screens. Scholars offer various infomations and theories of topics such as the archeology of screen, film and media theories, contemporary art, pragmatics of new ways of screening (from home video to street screening).

  15. Benefits of computer screen-based simulation in learning cardiac arrest procedures.

    Science.gov (United States)

    Bonnetain, Elodie; Boucheix, Jean-Michel; Hamet, Maël; Freysz, Marc

    2010-07-01

    What is the best way to train medical students early so that they acquire basic skills in cardiopulmonary resuscitation as effectively as possible? Studies have shown the benefits of high-fidelity patient simulators, but have also demonstrated their limits. New computer screen-based multimedia simulators have fewer constraints than high-fidelity patient simulators. In this area, as yet, there has been no research on the effectiveness of transfer of learning from a computer screen-based simulator to more realistic situations such as those encountered with high-fidelity patient simulators. We tested the benefits of learning cardiac arrest procedures using a multimedia computer screen-based simulator in 28 Year 2 medical students. Just before the end of the traditional resuscitation course, we compared two groups. An experiment group (EG) was first asked to learn to perform the appropriate procedures in a cardiac arrest scenario (CA1) in the computer screen-based learning environment and was then tested on a high-fidelity patient simulator in another cardiac arrest simulation (CA2). While the EG was learning to perform CA1 procedures in the computer screen-based learning environment, a control group (CG) actively continued to learn cardiac arrest procedures using practical exercises in a traditional class environment. Both groups were given the same amount of practice, exercises and trials. The CG was then also tested on the high-fidelity patient simulator for CA2, after which it was asked to perform CA1 using the computer screen-based simulator. Performances with both simulators were scored on a precise 23-point scale. On the test on a high-fidelity patient simulator, the EG trained with a multimedia computer screen-based simulator performed significantly better than the CG trained with traditional exercises and practice (16.21 versus 11.13 of 23 possible points, respectively; p<0.001). Computer screen-based simulation appears to be effective in preparing learners to

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

    Science.gov (United States)

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

    2009-03-01

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

  17. Rationality in discovery : a study of logic, cognition, computation and neuropharmacology

    NARCIS (Netherlands)

    Bosch, Alexander Petrus Maria van den

    2001-01-01

    Part I Introduction The specific problem adressed in this thesis is: what is the rational use of theory and experiment in the process of scientific discovery, in theory and in the practice of drug research for Parkinson’s disease? The thesis aims to answer the following specific questions: what is:

  18. Television viewing, computer use and total screen time in Canadian youth.

    Science.gov (United States)

    Mark, Amy E; Boyce, William F; Janssen, Ian

    2006-11-01

    Research has linked excessive television viewing and computer use in children and adolescents to a variety of health and social problems. Current recommendations are that screen time in children and adolescents should be limited to no more than 2 h per day. To determine the percentage of Canadian youth meeting the screen time guideline recommendations. The representative study sample consisted of 6942 Canadian youth in grades 6 to 10 who participated in the 2001/2002 World Health Organization Health Behaviour in School-Aged Children survey. Only 41% of girls and 34% of boys in grades 6 to 10 watched 2 h or less of television per day. Once the time of leisure computer use was included and total daily screen time was examined, only 18% of girls and 14% of boys met the guidelines. The prevalence of those meeting the screen time guidelines was higher in girls than boys. Fewer than 20% of Canadian youth in grades 6 to 10 met the total screen time guidelines, suggesting that increased public health interventions are needed to reduce the number of leisure time hours that Canadian youth spend watching television and using the computer.

  19. Discovery of Novel Inhibitors for Nek6 Protein through Homology Model Assisted Structure Based Virtual Screening and Molecular Docking Approaches

    Directory of Open Access Journals (Sweden)

    P. Srinivasan

    2014-01-01

    Full Text Available Nek6 is a member of the NIMA (never in mitosis, gene A-related serine/threonine kinase family that plays an important role in the initiation of mitotic cell cycle progression. This work is an attempt to emphasize the structural and functional relationship of Nek6 protein based on homology modeling and binding pocket analysis. The three-dimensional structure of Nek6 was constructed by molecular modeling studies and the best model was further assessed by PROCHECK, ProSA, and ERRAT plot in order to analyze the quality and consistency of generated model. The overall quality of computed model showed 87.4% amino acid residues under the favored region. A 3 ns molecular dynamics simulation confirmed that the structure was reliable and stable. Two lead compounds (Binding database ID: 15666, 18602 were retrieved through structure-based virtual screening and induced fit docking approaches as novel Nek6 inhibitors. Hence, we concluded that the potential compounds may act as new leads for Nek6 inhibitors designing.

  20. Radioactivity on the surfaces of computer monitors and television screens due to progeny palatal

    International Nuclear Information System (INIS)

    Abdel-Nady, A.; Morsy, A.A.

    2002-01-01

    Computer monitors and television screens can collect radon progeny. Radon decay forming meta-stable progeny, namely, Po-218, Po-214, and Po-210, which are found mostly in positively, charged aerosol particles. These particles are attract by the large negative field of a video display terminals (VDT) leading to buildup of radioactivity on the VDT screen. The charged aerosol particles might drift in the electric field between the VDT and the operator and be accelerated into the operator's face. The aim of this work is to measure these phenomena set of ultra-sensitive TASTRAK detectors used to measure the plate out of positively charged radioactive radon progeny. The track detectors were fixed on the outer monitor screen. For an occupational computer worker spending 200 days per year for 6 hours a day. It was found that the mean dose equivalent was 1.77 mSv, 0.25 mSv/year for normal CRT and LCD monitors respectively

  1. Computational Screening of Light-absorbing Materials for Photoelectrochemical Water Splitting

    DEFF Research Database (Denmark)

    Castelli, Ivano E.; Kuhar, Korina; Pandey, Mohnish

    2018-01-01

    Efficient conversion of solar energy into electricity or fuels requires the identification of new semiconductors with optimal optical and electronic properties. We discuss the current and future role that computational screening is expected to play in this challenge. We discuss the identification...

  2. Computer Vision Tool and Technician as First Reader of Lung Cancer Screening CT Scans

    NARCIS (Netherlands)

    Ritchie, A.J.; Sanghera, C.; Jacobs, C.; Zhang, W.; Mayo, J.; Schmidt, H.; Gingras, M.; Pasian, S.; Stewart, L.; Tsai, S.; Manos, D.; Seely, J.M.; Burrowes, P.; Bhatia, R.; Atkar-Khattra, S.; Ginneken, B. van; Tammemagi, M.; Tsao, M.S.; Lam, S.; et al.,

    2016-01-01

    To implement a cost-effective low-dose computed tomography (LDCT) lung cancer screening program at the population level, accurate and efficient interpretation of a large volume of LDCT scans is needed. The objective of this study was to evaluate a workflow strategy to identify abnormal LDCT scans in

  3. Computer Decision Support to Improve Autism Screening and Care in Community Pediatric Clinics

    Science.gov (United States)

    Bauer, Nerissa S.; Sturm, Lynne A.; Carroll, Aaron E.; Downs, Stephen M.

    2013-01-01

    An autism module was added to an existing computer decision support system (CDSS) to facilitate adherence to recommended guidelines for screening for autism spectrum disorders in primary care pediatric clinics. User satisfaction was assessed by survey and informal feedback at monthly meetings between clinical staff and the software team. To assess…

  4. The University of Kansas High-Throughput Screening laboratory. Part I: meeting drug-discovery needs in the heartland of America with entrepreneurial flair.

    Science.gov (United States)

    McDonald, Peter R; Roy, Anuradha; Chaguturu, Rathnam

    2011-05-01

    The University of Kansas High-Throughput Screening (KU HTS) core is a state-of-the-art drug-discovery facility with an entrepreneurial open-service policy, which provides centralized resources supporting public- and private-sector research initiatives. The KU HTS core applies pharmaceutical industry project-management principles in an academic setting by bringing together multidisciplinary teams to fill critical scientific and technology gaps, using an experienced team of industry-trained researchers and project managers. The KU HTS proactively engages in supporting grant applications for extramural funding, intellectual-property management and technology transfer. The KU HTS staff further provides educational opportunities for the KU faculty and students to learn cutting-edge technologies in drug-discovery platforms through seminars, workshops, internships and course teaching. This is the first instalment of a two-part contribution from the KU HTS laboratory.

  5. The insulin secretory action of novel polycyclic guanidines: discovery through open innovation phenotypic screening, and exploration of structure-activity relationships.

    Science.gov (United States)

    Shaghafi, Michael B; Barrett, David G; Willard, Francis S; Overman, Larry E

    2014-02-15

    We report the discovery of the glucose-dependent insulin secretogogue activity of a novel class of polycyclic guanidines through phenotypic screening as part of the Lilly Open Innovation Drug Discovery platform. Three compounds from the University of California, Irvine, 1-3, having the 3-arylhexahydropyrrolo[1,2-c]pyrimidin-1-amine scaffold acted as insulin secretagogues under high, but not low, glucose conditions. Exploration of the structure-activity relationship around the scaffold demonstrated the key role of the guanidine moiety, as well as the importance of two lipophilic regions, and led to the identification of 9h, which stimulated insulin secretion in isolated rat pancreatic islets in a glucose-dependent manner. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

  6. Using spatial principles to optimize distributed computing for enabling the physical science discoveries.

    Science.gov (United States)

    Yang, Chaowei; Wu, Huayi; Huang, Qunying; Li, Zhenlong; Li, Jing

    2011-04-05

    Contemporary physical science studies rely on the effective analyses of geographically dispersed spatial data and simulations of physical phenomena. Single computers and generic high-end computing are not sufficient to process the data for complex physical science analysis and simulations, which can be successfully supported only through distributed computing, best optimized through the application of spatial principles. Spatial computing, the computing aspect of a spatial cyberinfrastructure, refers to a computing paradigm that utilizes spatial principles to optimize distributed computers to catalyze advancements in the physical sciences. Spatial principles govern the interactions between scientific parameters across space and time by providing the spatial connections and constraints to drive the progression of the phenomena. Therefore, spatial computing studies could better position us to leverage spatial principles in simulating physical phenomena and, by extension, advance the physical sciences. Using geospatial science as an example, this paper illustrates through three research examples how spatial computing could (i) enable data intensive science with efficient data/services search, access, and utilization, (ii) facilitate physical science studies with enabling high-performance computing capabilities, and (iii) empower scientists with multidimensional visualization tools to understand observations and simulations. The research examples demonstrate that spatial computing is of critical importance to design computing methods to catalyze physical science studies with better data access, phenomena simulation, and analytical visualization. We envision that spatial computing will become a core technology that drives fundamental physical science advancements in the 21st century.

  7. Computer aided drug discovery of highly ligand efficient, low molecular weight imidazopyridine analogs as FLT3 inhibitors.

    Science.gov (United States)

    Frett, Brendan; McConnell, Nick; Smith, Catherine C; Wang, Yuanxiang; Shah, Neil P; Li, Hong-yu

    2015-04-13

    The FLT3 kinase represents an attractive target to effectively treat AML. Unfortunately, no FLT3 targeted therapeutic is currently approved. In line with our continued interests in treating kinase related disease for anti-FLT3 mutant activity, we utilized pioneering synthetic methodology in combination with computer aided drug discovery and identified low molecular weight, highly ligand efficient, FLT3 kinase inhibitors. Compounds were analyzed for biochemical inhibition, their ability to selectively inhibit cell proliferation, for FLT3 mutant activity, and preliminary aqueous solubility. Validated hits were discovered that can serve as starting platforms for lead candidates. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  8. National facility for advanced computational science: A sustainable path to scientific discovery

    Energy Technology Data Exchange (ETDEWEB)

    Simon, Horst; Kramer, William; Saphir, William; Shalf, John; Bailey, David; Oliker, Leonid; Banda, Michael; McCurdy, C. William; Hules, John; Canning, Andrew; Day, Marc; Colella, Philip; Serafini, David; Wehner, Michael; Nugent, Peter

    2004-04-02

    Lawrence Berkeley National Laboratory (Berkeley Lab) proposes to create a National Facility for Advanced Computational Science (NFACS) and to establish a new partnership between the American computer industry and a national consortium of laboratories, universities, and computing facilities. NFACS will provide leadership-class scientific computing capability to scientists and engineers nationwide, independent of their institutional affiliation or source of funding. This partnership will bring into existence a new class of computational capability in the United States that is optimal for science and will create a sustainable path towards petaflops performance.

  9. Screening the Medicines for Malaria Venture Pathogen Box across Multiple Pathogens Reclassifies Starting Points for Open-Source Drug Discovery.

    Science.gov (United States)

    Duffy, Sandra; Sykes, Melissa L; Jones, Amy J; Shelper, Todd B; Simpson, Moana; Lang, Rebecca; Poulsen, Sally-Ann; Sleebs, Brad E; Avery, Vicky M

    2017-09-01

    Open-access drug discovery provides a substantial resource for diseases primarily affecting the poor and disadvantaged. The open-access Pathogen Box collection is comprised of compounds with demonstrated biological activity against specific pathogenic organisms. The supply of this resource by the Medicines for Malaria Venture has the potential to provide new chemical starting points for a number of tropical and neglected diseases, through repurposing of these compounds for use in drug discovery campaigns for these additional pathogens. We tested the Pathogen Box against kinetoplastid parasites and malaria life cycle stages in vitro Consequently, chemical starting points for malaria, human African trypanosomiasis, Chagas disease, and leishmaniasis drug discovery efforts have been identified. Inclusive of this in vitro biological evaluation, outcomes from extensive literature reviews and database searches are provided. This information encompasses commercial availability, literature reference citations, other aliases and ChEMBL number with associated biological activity, where available. The release of this new data for the Pathogen Box collection into the public domain will aid the open-source model of drug discovery. Importantly, this will provide novel chemical starting points for drug discovery and target identification in tropical disease research. Copyright © 2017 Duffy et al.

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

    DEFF Research Database (Denmark)

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

    2013-01-01

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

  11. Using iterative cluster merging with improved gap statistics to perform online phenotype discovery in the context of high-throughput RNAi screens

    Directory of Open Access Journals (Sweden)

    Sun Youxian

    2008-06-01

    Full Text Available Abstract Background The recent emergence of high-throughput automated image acquisition technologies has forever changed how cell biologists collect and analyze data. Historically, the interpretation of cellular phenotypes in different experimental conditions has been dependent upon the expert opinions of well-trained biologists. Such qualitative analysis is particularly effective in detecting subtle, but important, deviations in phenotypes. However, while the rapid and continuing development of automated microscope-based technologies now facilitates the acquisition of trillions of cells in thousands of diverse experimental conditions, such as in the context of RNA interference (RNAi or small-molecule screens, the massive size of these datasets precludes human analysis. Thus, the development of automated methods which aim to identify novel and biological relevant phenotypes online is one of the major challenges in high-throughput image-based screening. Ideally, phenotype discovery methods should be designed to utilize prior/existing information and tackle three challenging tasks, i.e. restoring pre-defined biological meaningful phenotypes, differentiating novel phenotypes from known ones and clarifying novel phenotypes from each other. Arbitrarily extracted information causes biased analysis, while combining the complete existing datasets with each new image is intractable in high-throughput screens. Results Here we present the design and implementation of a novel and robust online phenotype discovery method with broad applicability that can be used in diverse experimental contexts, especially high-throughput RNAi screens. This method features phenotype modelling and iterative cluster merging using improved gap statistics. A Gaussian Mixture Model (GMM is employed to estimate the distribution of each existing phenotype, and then used as reference distribution in gap statistics. This method is broadly applicable to a number of different types of

  12. Optimisation and assessment of three modern touch screen tablet computers for clinical vision testing.

    Directory of Open Access Journals (Sweden)

    Humza J Tahir

    Full Text Available Technological advances have led to the development of powerful yet portable tablet computers whose touch-screen resolutions now permit the presentation of targets small enough to test the limits of normal visual acuity. Such devices have become ubiquitous in daily life and are moving into the clinical space. However, in order to produce clinically valid tests, it is important to identify the limits imposed by the screen characteristics, such as resolution, brightness uniformity, contrast linearity and the effect of viewing angle. Previously we have conducted such tests on the iPad 3. Here we extend our investigations to 2 other devices and outline a protocol for calibrating such screens, using standardised methods to measure the gamma function, warm up time, screen uniformity and the effects of viewing angle and screen reflections. We demonstrate that all three devices manifest typical gamma functions for voltage and luminance with warm up times of approximately 15 minutes. However, there were differences in homogeneity and reflectance among the displays. We suggest practical means to optimise quality of display for vision testing including screen calibration.

  13. Optimisation and assessment of three modern touch screen tablet computers for clinical vision testing.

    Science.gov (United States)

    Tahir, Humza J; Murray, Ian J; Parry, Neil R A; Aslam, Tariq M

    2014-01-01

    Technological advances have led to the development of powerful yet portable tablet computers whose touch-screen resolutions now permit the presentation of targets small enough to test the limits of normal visual acuity. Such devices have become ubiquitous in daily life and are moving into the clinical space. However, in order to produce clinically valid tests, it is important to identify the limits imposed by the screen characteristics, such as resolution, brightness uniformity, contrast linearity and the effect of viewing angle. Previously we have conducted such tests on the iPad 3. Here we extend our investigations to 2 other devices and outline a protocol for calibrating such screens, using standardised methods to measure the gamma function, warm up time, screen uniformity and the effects of viewing angle and screen reflections. We demonstrate that all three devices manifest typical gamma functions for voltage and luminance with warm up times of approximately 15 minutes. However, there were differences in homogeneity and reflectance among the displays. We suggest practical means to optimise quality of display for vision testing including screen calibration.

  14. From computational discovery to experimental characterization of a high hole mobility organic crystal.

    KAUST Repository

    Sokolov, Anatoliy N; Atahan-Evrenk, Sule; Mondal, Rajib; Akkerman, Hylke B; Sá nchez-Carrera, Roel S; Granados-Focil, Sergio; Schrier, Joshua; Mannsfeld, Stefan C B; Zoombelt, Arjan P; Bao, Zhenan; Aspuru-Guzik, Alá n

    2011-01-01

    can be hindered by synthetic and characterization difficulties. Here we show that in silico screening of novel derivatives of the dinaphtho[2,3-b:2',3'-f]thieno[3,2-b]thiophene semiconductor with high hole mobility and air stability can lead

  15. Screening for cognitive impairment in older individuals. Validation study of a computer-based test.

    Science.gov (United States)

    Green, R C; Green, J; Harrison, J M; Kutner, M H

    1994-08-01

    This study examined the validity of a computer-based cognitive test that was recently designed to screen the elderly for cognitive impairment. Criterion-related validity was examined by comparing test scores of impaired patients and normal control subjects. Construct-related validity was computed through correlations between computer-based subtests and related conventional neuropsychological subtests. University center for memory disorders. Fifty-two patients with mild cognitive impairment by strict clinical criteria and 50 unimpaired, age- and education-matched control subjects. Control subjects were rigorously screened by neurological, neuropsychological, imaging, and electrophysiological criteria to identify and exclude individuals with occult abnormalities. Using a cut-off total score of 126, this computer-based instrument had a sensitivity of 0.83 and a specificity of 0.96. Using a prevalence estimate of 10%, predictive values, positive and negative, were 0.70 and 0.96, respectively. Computer-based subtests correlated significantly with conventional neuropsychological tests measuring similar cognitive domains. Thirteen (17.8%) of 73 volunteers with normal medical histories were excluded from the control group, with unsuspected abnormalities on standard neuropsychological tests, electroencephalograms, or magnetic resonance imaging scans. Computer-based testing is a valid screening methodology for the detection of mild cognitive impairment in the elderly, although this particular test has important limitations. Broader applications of computer-based testing will require extensive population-based validation. Future studies should recognize that normal control subjects without a history of disease who are typically used in validation studies may have a high incidence of unsuspected abnormalities on neurodiagnostic studies.

  16. Epistemic Gameplay and Discovery in Computational Model-Based Inquiry Activities

    Science.gov (United States)

    Wilkerson, Michelle Hoda; Shareff, Rebecca; Laina, Vasiliki; Gravel, Brian

    2018-01-01

    In computational modeling activities, learners are expected to discover the inner workings of scientific and mathematical systems: First elaborating their understandings of a given system through constructing a computer model, then "debugging" that knowledge by testing and refining the model. While such activities have been shown to…

  17. Discovery Learning, Representation, and Explanation within a Computer-Based Simulation: Finding the Right Mix

    Science.gov (United States)

    Rieber, Lloyd P.; Tzeng, Shyh-Chii; Tribble, Kelly

    2004-01-01

    The purpose of this research was to explore how adult users interact and learn during an interactive computer-based simulation supplemented with brief multimedia explanations of the content. A total of 52 college students interacted with a computer-based simulation of Newton's laws of motion in which they had control over the motion of a simple…

  18. Mobile Cloud Computing: Resource Discovery, Session Connectivity and Other Open Issues

    NARCIS (Netherlands)

    Schüring, Markus; Karagiannis, Georgios

    2011-01-01

    Abstract—Cloud computing can be considered as a model that provides network access to a shared pool of resources, such as storage and computing power, which can be rapidly provisioned and released with minimal management effort. This paper describes a research activity in the area of mobile cloud

  19. High-throughput screening platform for natural product-based drug discovery against 3 neglected tropical diseases: human African trypanosomiasis, leishmaniasis, and Chagas disease.

    Science.gov (United States)

    Annang, F; Pérez-Moreno, G; García-Hernández, R; Cordon-Obras, C; Martín, J; Tormo, J R; Rodríguez, L; de Pedro, N; Gómez-Pérez, V; Valente, M; Reyes, F; Genilloud, O; Vicente, F; Castanys, S; Ruiz-Pérez, L M; Navarro, M; Gamarro, F; González-Pacanowska, D

    2015-01-01

    African trypanosomiasis, leishmaniasis, and Chagas disease are 3 neglected tropical diseases for which current therapeutic interventions are inadequate or toxic. There is an urgent need to find new lead compounds against these diseases. Most drug discovery strategies rely on high-throughput screening (HTS) of synthetic chemical libraries using phenotypic and target-based approaches. Combinatorial chemistry libraries contain hundreds of thousands of compounds; however, they lack the structural diversity required to find entirely novel chemotypes. Natural products, in contrast, are a highly underexplored pool of unique chemical diversity that can serve as excellent templates for the synthesis of novel, biologically active molecules. We report here a validated HTS platform for the screening of microbial extracts against the 3 diseases. We have used this platform in a pilot project to screen a subset (5976) of microbial extracts from the MEDINA Natural Products library. Tandem liquid chromatography-mass spectrometry showed that 48 extracts contain potentially new compounds that are currently undergoing de-replication for future isolation and characterization. Known active components included actinomycin D, bafilomycin B1, chromomycin A3, echinomycin, hygrolidin, and nonactins, among others. The report here is, to our knowledge, the first HTS of microbial natural product extracts against the above-mentioned kinetoplastid parasites. © 2014 Society for Laboratory Automation and Screening.

  20. Community-Based Multidisciplinary Computed Tomography Screening Program Improves Lung Cancer Survival.

    Science.gov (United States)

    Miller, Daniel L; Mayfield, William R; Luu, Theresa D; Helms, Gerald A; Muster, Alan R; Beckler, Vickie J; Cann, Aaron

    2016-05-01

    Lung cancer is the most common cause of cancer deaths in the United States. Overall survival is less than 20%, with the majority of patients presenting with advanced disease. The National Lung Screening Trial, performed mainly in academic medical centers, showed that cancer mortality can be reduced with computed tomography (CT) screening compared with chest radiography in high-risk patients. To determine whether this survival advantage can be duplicated in a community-based multidisciplinary thoracic oncology program, we initiated a CT scan screening program for lung cancer within an established health care system. In 2008, we launched a lung cancer CT screening program within the WellStar Health System (WHS) consisting of five hospitals, three health parks, 140 outpatient medical offices, and 12 imaging centers that provide care in a five-county area of approximately 1.4 million people in Metro-Atlanta. Screening criteria incorporated were the International Early Lung Cancer Action Program (2008 to 2010) and National Comprehensive Cancer Network guidelines (2011 to 2013) for moderate- and high-risk patients. A total of 1,267 persons underwent CT lung cancer screening in WHS from 2008 through 2013; 53% were men, 87% were 50 years of age or older, and 83% were current or former smokers. Noncalcified indeterminate pulmonary nodules were found in 518 patients (41%). Thirty-six patients (2.8%) underwent a diagnostic procedure for positive findings on their CT scan; 30 proved to have cancer, 28 (2.2%) primary lung cancer and 2 metastatic cancer, and 6 had benign disease. Fourteen patients (50%) had their lung cancer discovered on their initial CT scan, 11 on subsequent scans associated with indeterminate pulmonary nodules growth and 3 patients who had a new indeterminate pulmonary nodules. Only 15 (54%) of these 28 patients would have qualified as a National Lung Screening Trial high-risk patient; 75% had stage I or II disease. Overall 5-year survival was 64% and 5-year

  1. Noninvasive Computed Tomography–based Risk Stratification of Lung Adenocarcinomas in the National Lung Screening Trial

    Science.gov (United States)

    Maldonado, Fabien; Duan, Fenghai; Raghunath, Sushravya M.; Rajagopalan, Srinivasan; Karwoski, Ronald A.; Garg, Kavita; Greco, Erin; Nath, Hrudaya; Robb, Richard A.; Bartholmai, Brian J.

    2015-01-01

    Rationale: Screening for lung cancer using low-dose computed tomography (CT) reduces lung cancer mortality. However, in addition to a high rate of benign nodules, lung cancer screening detects a large number of indolent cancers that generally belong to the adenocarcinoma spectrum. Individualized management of screen-detected adenocarcinomas would be facilitated by noninvasive risk stratification. Objectives: To validate that Computer-Aided Nodule Assessment and Risk Yield (CANARY), a novel image analysis software, successfully risk stratifies screen-detected lung adenocarcinomas based on clinical disease outcomes. Methods: We identified retrospective 294 eligible patients diagnosed with lung adenocarcinoma spectrum lesions in the low-dose CT arm of the National Lung Screening Trial. The last low-dose CT scan before the diagnosis of lung adenocarcinoma was analyzed using CANARY blinded to clinical data. Based on their parametric CANARY signatures, all the lung adenocarcinoma nodules were risk stratified into three groups. CANARY risk groups were compared using survival analysis for progression-free survival. Measurements and Main Results: A total of 294 patients were included in the analysis. Kaplan-Meier analysis of all the 294 adenocarcinoma nodules stratified into the Good, Intermediate, and Poor CANARY risk groups yielded distinct progression-free survival curves (P < 0.0001). This observation was confirmed in the unadjusted and adjusted (age, sex, race, and smoking status) progression-free survival analysis of all stage I cases. Conclusions: CANARY allows the noninvasive risk stratification of lung adenocarcinomas into three groups with distinct post-treatment progression-free survival. Our results suggest that CANARY could ultimately facilitate individualized management of incidentally or screen-detected lung adenocarcinomas. PMID:26052977

  2. Noninvasive Computed Tomography-based Risk Stratification of Lung Adenocarcinomas in the National Lung Screening Trial.

    Science.gov (United States)

    Maldonado, Fabien; Duan, Fenghai; Raghunath, Sushravya M; Rajagopalan, Srinivasan; Karwoski, Ronald A; Garg, Kavita; Greco, Erin; Nath, Hrudaya; Robb, Richard A; Bartholmai, Brian J; Peikert, Tobias

    2015-09-15

    Screening for lung cancer using low-dose computed tomography (CT) reduces lung cancer mortality. However, in addition to a high rate of benign nodules, lung cancer screening detects a large number of indolent cancers that generally belong to the adenocarcinoma spectrum. Individualized management of screen-detected adenocarcinomas would be facilitated by noninvasive risk stratification. To validate that Computer-Aided Nodule Assessment and Risk Yield (CANARY), a novel image analysis software, successfully risk stratifies screen-detected lung adenocarcinomas based on clinical disease outcomes. We identified retrospective 294 eligible patients diagnosed with lung adenocarcinoma spectrum lesions in the low-dose CT arm of the National Lung Screening Trial. The last low-dose CT scan before the diagnosis of lung adenocarcinoma was analyzed using CANARY blinded to clinical data. Based on their parametric CANARY signatures, all the lung adenocarcinoma nodules were risk stratified into three groups. CANARY risk groups were compared using survival analysis for progression-free survival. A total of 294 patients were included in the analysis. Kaplan-Meier analysis of all the 294 adenocarcinoma nodules stratified into the Good, Intermediate, and Poor CANARY risk groups yielded distinct progression-free survival curves (P < 0.0001). This observation was confirmed in the unadjusted and adjusted (age, sex, race, and smoking status) progression-free survival analysis of all stage I cases. CANARY allows the noninvasive risk stratification of lung adenocarcinomas into three groups with distinct post-treatment progression-free survival. Our results suggest that CANARY could ultimately facilitate individualized management of incidentally or screen-detected lung adenocarcinomas.

  3. Data Linkage Graph: computation, querying and knowledge discovery of life science database networks

    Directory of Open Access Journals (Sweden)

    Lange Matthias

    2007-12-01

    Full Text Available To support the interpretation of measured molecular facts, like gene expression experiments or EST sequencing, the functional or the system biological context has to be considered. Doing so, the relationship to existing biological knowledge has to be discovered. In general, biological knowledge is worldwide represented in a network of databases. In this paper we present a method for knowledge extraction in life science databases, which prevents the scientists from screen scraping and web clicking approaches.

  4. Reduction of the performance of a noise screen due to screen-induced wind-speed gradients: numerical computations and wind-tunnel experiments

    NARCIS (Netherlands)

    Salomons, E.M.

    1999-01-01

    Downwind sound propagation over a noise screen is investigated by numerical computations and scale model experiments in a wind tunnel. For the computations, the parabolic equation method is used, with a range-dependent sound-speed profile based on wind-speed profiles measured in the wind tunnel and

  5. Scientific Discovery through Advanced Computing (SciDAC-3) Partnership Project Annual Report

    Energy Technology Data Exchange (ETDEWEB)

    Hoffman, Forest M. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Bochev, Pavel B. [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Cameron-Smith, Philip J.. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Easter, Richard C [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Elliott, Scott M. [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Ghan, Steven J. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Liu, Xiaohong [Univ. of Wyoming, Laramie, WY (United States); Lowrie, Robert B. [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Lucas, Donald D. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Ma, Po-lun [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Sacks, William J. [National Center for Atmospheric Research (NCAR), Boulder, CO (United States); Shrivastava, Manish [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Singh, Balwinder [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Tautges, Timothy J. [Argonne National Lab. (ANL), Argonne, IL (United States); Taylor, Mark A. [Sandia National Lab. (SNL-CA), Livermore, CA (United States); Vertenstein, Mariana [National Center for Atmospheric Research (NCAR), Boulder, CO (United States); Worley, Patrick H. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)

    2014-01-15

    The Applying Computationally Efficient Schemes for BioGeochemical Cycles ACES4BGC Project is advancing the predictive capabilities of Earth System Models (ESMs) by reducing two of the largest sources of uncertainty, aerosols and biospheric feedbacks, with a highly efficient computational approach. In particular, this project is implementing and optimizing new computationally efficient tracer advection algorithms for large numbers of tracer species; adding important biogeochemical interactions between the atmosphere, land, and ocean models; and applying uncertainty quanti cation (UQ) techniques to constrain process parameters and evaluate uncertainties in feedbacks between biogeochemical cycles and the climate system.

  6. Computational science and re-discovery: open-source implementation of ellipsoidal harmonics for problems in potential theory

    International Nuclear Information System (INIS)

    Bardhan, Jaydeep P; Knepley, Matthew G

    2012-01-01

    We present two open-source (BSD) implementations of ellipsoidal harmonic expansions for solving problems of potential theory using separation of variables. Ellipsoidal harmonics are used surprisingly infrequently, considering their substantial value for problems ranging in scale from molecules to the entire solar system. In this paper, we suggest two possible reasons for the paucity relative to spherical harmonics. The first is essentially historical—ellipsoidal harmonics developed during the late 19th century and early 20th, when it was found that only the lowest-order harmonics are expressible in closed form. Each higher-order term requires the solution of an eigenvalue problem, and tedious manual computation seems to have discouraged applications and theoretical studies. The second explanation is practical: even with modern computers and accurate eigenvalue algorithms, expansions in ellipsoidal harmonics are significantly more challenging to compute than those in Cartesian or spherical coordinates. The present implementations reduce the 'barrier to entry' by providing an easy and free way for the community to begin using ellipsoidal harmonics in actual research. We demonstrate our implementation using the specific and physiologically crucial problem of how charged proteins interact with their environment, and ask: what other analytical tools await re-discovery in an era of inexpensive computation?

  7. An eye movement study for identification of suitable font characters for presentation on a computer screen.

    Science.gov (United States)

    Banerjee, Jayeeta; Majumdar, Dhurjati; Majumdar, Deepti; Pal, Madhu Sudan

    2010-06-01

    We are experiencing a shifting of media: from the printed paper to the computer screen. This transition is modifying the process of how we read and understand a text. It is very difficult to conclude on suitability of font characters based upon subjective evaluation method only. Present study evaluates the effect of font type on human cognitive workload during perception of individual alphabets on a computer screen. Twenty six young subjects volunteered for this study. Here, subjects have been shown individual characters of different font types and their eye movements have been recorded. A binocular eye movement recorder was used for eye movement recording. The results showed that different eye movement parameters such as pupil diameter, number of fixations, fixation duration were less for font type Verdana. The present study recommends the use of font type Verdana for presentation of individual alphabets on various electronic displays in order to reduce cognitive workload.

  8. Modeling nanoscale gas sensors under realistic conditions: Computational screening of metal-doped carbon nanotubes

    DEFF Research Database (Denmark)

    García Lastra, Juan Maria; Mowbray, Duncan; Thygesen, Kristian Sommer

    2010-01-01

    We use computational screening to systematically investigate the use of transition-metal-doped carbon nanotubes for chemical-gas sensing. For a set of relevant target molecules (CO, NH3, and H2S) and the main components of air (N2, O2, and H2O), we calculate the binding energy and change in condu......We use computational screening to systematically investigate the use of transition-metal-doped carbon nanotubes for chemical-gas sensing. For a set of relevant target molecules (CO, NH3, and H2S) and the main components of air (N2, O2, and H2O), we calculate the binding energy and change...... the change in the nanotube resistance per doping site as a function of the target molecule concentration assuming charge transport in the diffusive regime. Our analysis points to Ni-doped nanotubes as candidates for CO sensors working under typical atmospheric conditions....

  9. Binary Decision Trees for Preoperative Periapical Cyst Screening Using Cone-beam Computed Tomography.

    Science.gov (United States)

    Pitcher, Brandon; Alaqla, Ali; Noujeim, Marcel; Wealleans, James A; Kotsakis, Georgios; Chrepa, Vanessa

    2017-03-01

    Cone-beam computed tomographic (CBCT) analysis allows for 3-dimensional assessment of periradicular lesions and may facilitate preoperative periapical cyst screening. The purpose of this study was to develop and assess the predictive validity of a cyst screening method based on CBCT volumetric analysis alone or combined with designated radiologic criteria. Three independent examiners evaluated 118 presurgical CBCT scans from cases that underwent apicoectomies and had an accompanying gold standard histopathological diagnosis of either a cyst or granuloma. Lesion volume, density, and specific radiologic characteristics were assessed using specialized software. Logistic regression models with histopathological diagnosis as the dependent variable were constructed for cyst prediction, and receiver operating characteristic curves were used to assess the predictive validity of the models. A conditional inference binary decision tree based on a recursive partitioning algorithm was constructed to facilitate preoperative screening. Interobserver agreement was excellent for volume and density, but it varied from poor to good for the radiologic criteria. Volume and root displacement were strong predictors for cyst screening in all analyses. The binary decision tree classifier determined that if the volume of the lesion was >247 mm 3 , there was 80% probability of a cyst. If volume was cyst probability was 60% (78% accuracy). The good accuracy and high specificity of the decision tree classifier renders it a useful preoperative cyst screening tool that can aid in clinical decision making but not a substitute for definitive histopathological diagnosis after biopsy. Confirmatory studies are required to validate the present findings. Published by Elsevier Inc.

  10. Feasibility of Tablet Computer Screening for Opioid Abuse in the Emergency Department

    Directory of Open Access Journals (Sweden)

    Weiner, Scott G.

    2014-12-01

    Full Text Available Introduction: Tablet computer-based screening may have the potential for detecting patients at risk for opioid abuse in the emergency department (ED. Study objectives were a to determine if the revised Screener and Opioid Assessment for Patients with Pain (SOAPP®-R, a 24-question previously paper-based screening tool for opioid abuse potential, could be administered on a tablet computer to an ED patient population; b to demonstrate that >90% of patients can complete the electronic screener without assistance in 35 years. One hundred percent of subjects completed the screener. Median time to completion was 148 (interquartile range 117.5-184.3 seconds, and 95% (n=78 completed in <5 minutes. 93% (n=76 rated ease of completion as very easy. Conclusions: It is feasible to administer a screening tool to a cohort of ED patients on a tablet computer. The screener administration time is minimal and patient ease of use with this modality is high. [West J Emerg Med. 2015;16(1:18-23

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

    DEFF Research Database (Denmark)

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

    2008-01-01

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

  12. Psychology of computer use: XXXII. Computer screen-savers as distractors.

    Science.gov (United States)

    Volk, F A; Halcomb, C G

    1994-12-01

    The differences in performance of 16 male and 16 female undergraduates on three cognitive tasks were investigated in the presence of visual distractors (computer-generated dynamic graphic images). These tasks included skilled and unskilled proofreading and listening comprehension. The visually demanding task of proofreading (skilled and unskilled) showed no significant decreases in performance in the distractor conditions. Results showed significant decrements, however, in performance on listening comprehension in at least one of the distractor conditions.

  13. Ubiquitous Computing Services Discovery and Execution Using a Novel Intelligent Web Services Algorithm

    Science.gov (United States)

    Choi, Okkyung; Han, SangYong

    2007-01-01

    Ubiquitous Computing makes it possible to determine in real time the location and situations of service requesters in a web service environment as it enables access to computers at any time and in any place. Though research on various aspects of ubiquitous commerce is progressing at enterprises and research centers, both domestically and overseas, analysis of a customer's personal preferences based on semantic web and rule based services using semantics is not currently being conducted. This paper proposes a Ubiquitous Computing Services System that enables a rule based search as well as semantics based search to support the fact that the electronic space and the physical space can be combined into one and the real time search for web services and the construction of efficient web services thus become possible.

  14. Utility of screening computed tomography of chest, abdomen and pelvis in patients after heart transplantation

    International Nuclear Information System (INIS)

    Dasari, Tarun W.; Pavlovic-Surjancev, Biljana; Dusek, Linda; Patel, Nilamkumar; Heroux, Alain L.

    2011-01-01

    Introduction: Malignancy is a late cause of mortality in heart transplant recipients. It is unknown if screening computed tomography scan would lead to early detection of such malignancies or serious vascular anomalies post heart transplantation. Methods: This is a single center observational study of patients undergoing surveillance computed tomography of chest, abdomen and pelvis atleast 5 years after transplantation. Abnormal findings, included pulmonary nodules, lymphadenopathy and intra-thoracic and intra-abdominal masses and vascular anomalies such as abdominal aortic aneurysm. The clinical follow up of each of these major abnormal findings is summarized. Results: A total of 63 patients underwent computed tomography scan of chest, abdomen and pelvis at least 5 years after transplantation. Of these, 54 (86%) were male and 9 (14%) were female. Mean age was 52 ± 9.2 years. Computed tomography revealed 1 lung cancer (squamous cell) only. Non specific pulmonary nodules were seen in 6 patients (9.5%). The most common incidental finding was abdominal aortic aneurysms (N = 6 (9.5%)), which necessitated follow up computed tomography (N = 5) or surgery (N = 1). Mean time to detection of abdominal aortic aneurysms from transplantation was 14.6 ± 4.2 years. Mean age at the time of detection of abdominal aortic aneurysms was 74.5 ± 3.2 years. Conclusion: Screening computed tomography scan in patients 5 years from transplantation revealed only one malignancy but lead to increased detection of abdominal aortic aneurysms. Thus the utility is low in terms of detection of malignancy. Based on this study we do not recommend routine computed tomography post heart transplantation.

  15. Computational approaches to screen candidate ligands with anti- Parkinson's activity using R programming.

    Science.gov (United States)

    Jayadeepa, R M; Niveditha, M S

    2012-01-01

    It is estimated that by 2050 over 100 million people will be affected by the Parkinson's disease (PD). We propose various computational approaches to screen suitable candidate ligand with anti-Parkinson's activity from phytochemicals. Five different types of dopamine receptors have been identified in the brain, D1-D5. Dopamine receptor D3 was selected as the target receptor. The D3 receptor exists in areas of the brain outside the basal ganglia, such as the limbic system, and thus may play a role in the cognitive and emotional changes noted in Parkinson's disease. A ligand library of 100 molecules with anti-Parkinson's activity was collected from literature survey. Nature is the best combinatorial chemist and possibly has answers to all diseases of mankind. Failure of some synthetic drugs and its side effects have prompted many researches to go back to ancient healing methods which use herbal medicines to give relief. Hence, the candidate ligands with anti-Parkinson's were selected from herbal sources through literature survey. Lipinski rules were applied to screen the suitable molecules for the study, the resulting 88 molecules were energy minimized, and subjected to docking using Autodock Vina. The top eleven molecules were screened according to the docking score generated by Autodock Vina Commercial drug Ropinirole was computed similarly and was compared with the 11 phytochemicals score, the screened molecules were subjected to toxicity analysis and to verify toxic property of phytochemicals. R Programming was applied to remove the bias from the top eleven molecules. Using cluster analysis and Confusion Matrix two phytochemicals were computationally selected namely Rosmarinic acid and Gingkolide A for further studies on the disease Parkinson's.

  16. High-Performance Computing in Neuroscience for Data-Driven Discovery, Integration, and Dissemination

    International Nuclear Information System (INIS)

    Bouchard, Kristofer E.

    2016-01-01

    A lack of coherent plans to analyze, manage, and understand data threatens the various opportunities offered by new neuro-technologies. High-performance computing will allow exploratory analysis of massive datasets stored in standardized formats, hosted in open repositories, and integrated with simulations.

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

    Science.gov (United States)

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

    2011-06-01

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

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

    Science.gov (United States)

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

    2011-06-01

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

  19. A brief measure of Smokers' knowledge of lung cancer screening with low-dose computed tomography

    Directory of Open Access Journals (Sweden)

    Lisa M. Lowenstein

    2016-12-01

    Full Text Available We describe the development and psychometric properties of a new, brief measure of smokers' knowledge of lung cancer screening with low-dose computed tomography (LDCT. Content experts identified key facts smokers should know in making an informed decision about lung cancer screening. Sample questions were drafted and iteratively refined based on feedback from content experts and cognitive testing with ten smokers. The resulting 16-item knowledge measure was completed by 108 heavy smokers in Houston, Texas, recruited from 12/2014 to 09/2015. Item difficulty, item discrimination, internal consistency and test-retest reliability were assessed. Group differences based upon education levels and smoking history were explored. Several items were dropped due to ceiling effects or overlapping constructs, resulting in a 12-item knowledge measure. Additional items with high item uncertainty were retained because of their importance in informed decision making about lung cancer screening. Internal consistency reliability of the final scale was acceptable (KR-20 = 0.66 and test-retest reliability of the overall scale was 0.84 (intraclass correlation. Knowledge scores differed across education levels (F = 3.36, p = 0.04, while no differences were observed between current and former smokers (F = 1.43, p = 0.24 or among participants who met or did not meet the 30-pack-year screening eligibility criterion (F = 0.57, p = 0.45. The new measure provides a brief, valid and reliable indicator of smokers' knowledge of key concepts central to making an informed decision about lung cancer screening with LDCT, and can be part of a broader assessment of the quality of smokers' decision making about lung cancer screening.

  20. Performance of computer-aided detection in false-negative screening mammograms of breast cancers

    International Nuclear Information System (INIS)

    Han, Boo Kyung; Kim, Ji Young; Shin, Jung Hee; Choe, Yeon Hyeon

    2004-01-01

    To analyze retrospectively the abnormalities visible on the false-negative screening mammograms of patients with breast cancer and to determine the performance of computer-aided detection (CAD) in the detection of cancers. Of 108 consecutive cases of breast cancer diagnosed over a period of 6 years, of which previous screening mammograms were available, 32 retrospectively visible abnormalities (at which locations cancer later developed) were found in the previous mammograms, and which were originally reported as negative. These 32 patients ranged in age from 38 to 72 years (mean 52 years). We analyzed their previous mammographic findings, and assessed the ability of CAD to mark cancers in previous mammograms, according to the clinical presentation, the type of abnormalities and the mammographic parenchymal density. In these 32 previous mammograms of breast cancers (20 asymptomatic, 12 symptomatic), the retrospectively visible abnormalities were identified as densities in 22, calcifications in 8, and densities with calcifications in 2. CAD marked abnormalities in 20 (63%) of the 32 cancers with false-negative screening mammograms; 14 (70%) of the 20 subsequent screening-detected cancers, 5 (50%) of the 10 interval cancers, and 1 (50%) of the 2 cancers palpable after the screening interval. CAD marked 12 (50%) of the 24 densities and 9 (90%) of the 10 calcifications. CAD marked abnormalities in 7 (50%) of the 14 predominantly fatty breasts, and 13 (72%) of the 18 dense breasts. CAD-assisted diagnosis could potentially decrease the number of false-negative mammograms caused by the failure to recognize the cancer in the screening program, although its usefulness in the prevention of interval cancers appears to be limited

  1. XMPP for cloud computing in bioinformatics supporting discovery and invocation of asynchronous web services

    Directory of Open Access Journals (Sweden)

    Willighagen Egon L

    2009-09-01

    Full Text Available Abstract Background Life sciences make heavily use of the web for both data provision and analysis. However, the increasing amount of available data and the diversity of analysis tools call for machine accessible interfaces in order to be effective. HTTP-based Web service technologies, like the Simple Object Access Protocol (SOAP and REpresentational State Transfer (REST services, are today the most common technologies for this in bioinformatics. However, these methods have severe drawbacks, including lack of discoverability, and the inability for services to send status notifications. Several complementary workarounds have been proposed, but the results are ad-hoc solutions of varying quality that can be difficult to use. Results We present a novel approach based on the open standard Extensible Messaging and Presence Protocol (XMPP, consisting of an extension (IO Data to comprise discovery, asynchronous invocation, and definition of data types in the service. That XMPP cloud services are capable of asynchronous communication implies that clients do not have to poll repetitively for status, but the service sends the results back to the client upon completion. Implementations for Bioclipse and Taverna are presented, as are various XMPP cloud services in bio- and cheminformatics. Conclusion XMPP with its extensions is a powerful protocol for cloud services that demonstrate several advantages over traditional HTTP-based Web services: 1 services are discoverable without the need of an external registry, 2 asynchronous invocation eliminates the need for ad-hoc solutions like polling, and 3 input and output types defined in the service allows for generation of clients on the fly without the need of an external semantics description. The many advantages over existing technologies make XMPP a highly interesting candidate for next generation online services in bioinformatics.

  2. XMPP for cloud computing in bioinformatics supporting discovery and invocation of asynchronous web services.

    Science.gov (United States)

    Wagener, Johannes; Spjuth, Ola; Willighagen, Egon L; Wikberg, Jarl E S

    2009-09-04

    Life sciences make heavily use of the web for both data provision and analysis. However, the increasing amount of available data and the diversity of analysis tools call for machine accessible interfaces in order to be effective. HTTP-based Web service technologies, like the Simple Object Access Protocol (SOAP) and REpresentational State Transfer (REST) services, are today the most common technologies for this in bioinformatics. However, these methods have severe drawbacks, including lack of discoverability, and the inability for services to send status notifications. Several complementary workarounds have been proposed, but the results are ad-hoc solutions of varying quality that can be difficult to use. We present a novel approach based on the open standard Extensible Messaging and Presence Protocol (XMPP), consisting of an extension (IO Data) to comprise discovery, asynchronous invocation, and definition of data types in the service. That XMPP cloud services are capable of asynchronous communication implies that clients do not have to poll repetitively for status, but the service sends the results back to the client upon completion. Implementations for Bioclipse and Taverna are presented, as are various XMPP cloud services in bio- and cheminformatics. XMPP with its extensions is a powerful protocol for cloud services that demonstrate several advantages over traditional HTTP-based Web services: 1) services are discoverable without the need of an external registry, 2) asynchronous invocation eliminates the need for ad-hoc solutions like polling, and 3) input and output types defined in the service allows for generation of clients on the fly without the need of an external semantics description. The many advantages over existing technologies make XMPP a highly interesting candidate for next generation online services in bioinformatics.

  3. XMPP for cloud computing in bioinformatics supporting discovery and invocation of asynchronous web services

    Science.gov (United States)

    Wagener, Johannes; Spjuth, Ola; Willighagen, Egon L; Wikberg, Jarl ES

    2009-01-01

    Background Life sciences make heavily use of the web for both data provision and analysis. However, the increasing amount of available data and the diversity of analysis tools call for machine accessible interfaces in order to be effective. HTTP-based Web service technologies, like the Simple Object Access Protocol (SOAP) and REpresentational State Transfer (REST) services, are today the most common technologies for this in bioinformatics. However, these methods have severe drawbacks, including lack of discoverability, and the inability for services to send status notifications. Several complementary workarounds have been proposed, but the results are ad-hoc solutions of varying quality that can be difficult to use. Results We present a novel approach based on the open standard Extensible Messaging and Presence Protocol (XMPP), consisting of an extension (IO Data) to comprise discovery, asynchronous invocation, and definition of data types in the service. That XMPP cloud services are capable of asynchronous communication implies that clients do not have to poll repetitively for status, but the service sends the results back to the client upon completion. Implementations for Bioclipse and Taverna are presented, as are various XMPP cloud services in bio- and cheminformatics. Conclusion XMPP with its extensions is a powerful protocol for cloud services that demonstrate several advantages over traditional HTTP-based Web services: 1) services are discoverable without the need of an external registry, 2) asynchronous invocation eliminates the need for ad-hoc solutions like polling, and 3) input and output types defined in the service allows for generation of clients on the fly without the need of an external semantics description. The many advantages over existing technologies make XMPP a highly interesting candidate for next generation online services in bioinformatics. PMID:19732427

  4. Structural variation discovery in the cancer genome using next generation sequencing: Computational solutions and perspectives

    Science.gov (United States)

    Liu, Biao; Conroy, Jeffrey M.; Morrison, Carl D.; Odunsi, Adekunle O.; Qin, Maochun; Wei, Lei; Trump, Donald L.; Johnson, Candace S.; Liu, Song; Wang, Jianmin

    2015-01-01

    Somatic Structural Variations (SVs) are a complex collection of chromosomal mutations that could directly contribute to carcinogenesis. Next Generation Sequencing (NGS) technology has emerged as the primary means of interrogating the SVs of the cancer genome in recent investigations. Sophisticated computational methods are required to accurately identify the SV events and delineate their breakpoints from the massive amounts of reads generated by a NGS experiment. In this review, we provide an overview of current analytic tools used for SV detection in NGS-based cancer studies. We summarize the features of common SV groups and the primary types of NGS signatures that can be used in SV detection methods. We discuss the principles and key similarities and differences of existing computational programs and comment on unresolved issues related to this research field. The aim of this article is to provide a practical guide of relevant concepts, computational methods, software tools and important factors for analyzing and interpreting NGS data for the detection of SVs in the cancer genome. PMID:25849937

  5. Abdominal ultrasound-scanning versus non-contrast computed tomography as screening method for abdominal aortic aneurysm

    DEFF Research Database (Denmark)

    Liisberg, Mads; Diederichsen, Axel C.; Lindholt, Jes S.

    2017-01-01

    Background: Validating non-contrast-enhanced computed tomography (nCT) compared to ultrasound sonography (US) as screening method for abdominal aortic aneurysm (AAA) screening. Methods: Consecutively attending men (n = 566) from the pilot study of the randomized Danish CardioVascular Screening......CT seems superior to US concerning sensitivity, and is able to detect aneurysmal lesions not detectable with US. Finally, the prevalence of AAA in Denmark seems to remain relatively high, in this small pilot study group....

  6. A comparison of symptoms after viewing text on a computer screen and hardcopy.

    Science.gov (United States)

    Chu, Christina; Rosenfield, Mark; Portello, Joan K; Benzoni, Jaclyn A; Collier, Juanita D

    2011-01-01

    Computer vision syndrome (CVS) is a complex of eye and vision problems experienced during or related to computer use. Ocular symptoms may include asthenopia, accommodative and vergence difficulties and dry eye. CVS occurs in up to 90% of computer workers, and given the almost universal use of these devices, it is important to identify whether these symptoms are specific to computer operation, or are simply a manifestation of performing a sustained near-vision task. This study compared ocular symptoms immediately following a sustained near task. 30 young, visually-normal subjects read text aloud either from a desktop computer screen or a printed hardcopy page at a viewing distance of 50 cm for a continuous 20 min period. Identical text was used in the two sessions, which was matched for size and contrast. Target viewing angle and luminance were similar for the two conditions. Immediately following completion of the reading task, subjects completed a written questionnaire asking about their level of ocular discomfort during the task. When comparing the computer and hardcopy conditions, significant differences in median symptom scores were reported with regard to blurred vision during the task (t = 147.0; p = 0.03) and the mean symptom score (t = 102.5; p = 0.04). In both cases, symptoms were higher during computer use. Symptoms following sustained computer use were significantly worse than those reported after hard copy fixation under similar viewing conditions. A better understanding of the physiology underlying CVS is critical to allow more accurate diagnosis and treatment. This will allow practitioners to optimize visual comfort and efficiency during computer operation.

  7. Recommendations from the European Society of Thoracic Surgeons (ESTS) regarding computed tomography screening for lung cancer in Europe

    DEFF Research Database (Denmark)

    Pedersen, Jesper Holst; Rzyman, Witold; Veronesi, Giulia

    2017-01-01

    In order to provide recommendations regarding implementation of computed tomography (CT) screening in Europe the ESTS established a working group with eight experts in the field. On a background of the current situation regarding CT screening in Europe and the available evidence, ten recommendati...

  8. Combinatorial materials synthesis and high-throughput screening: an integrated materials chip approach to mapping phase diagrams and discovery and optimization of functional materials.

    Science.gov (United States)

    Xiang, X D

    Combinatorial materials synthesis methods and high-throughput evaluation techniques have been developed to accelerate the process of materials discovery and optimization and phase-diagram mapping. Analogous to integrated circuit chips, integrated materials chips containing thousands of discrete different compositions or continuous phase diagrams, often in the form of high-quality epitaxial thin films, can be fabricated and screened for interesting properties. Microspot x-ray method, various optical measurement techniques, and a novel evanescent microwave microscope have been used to characterize the structural, optical, magnetic, and electrical properties of samples on the materials chips. These techniques are routinely used to discover/optimize and map phase diagrams of ferroelectric, dielectric, optical, magnetic, and superconducting materials.

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

    Directory of Open Access Journals (Sweden)

    Yunierkis Perez-Castillo

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

  10. Efficient Discovery of Novel Multicomponent Mixtures for Hydrogen Storage: A Combined Computational/Experimental Approach

    Energy Technology Data Exchange (ETDEWEB)

    Wolverton, Christopher [Northwestern Univ., Evanston, IL (United States). Dept. of Materials Science and Engineering; Ozolins, Vidvuds [Univ. of California, Los Angeles, CA (United States). Dept. of Materials Science and Engineering; Kung, Harold H. [Northwestern Univ., Evanston, IL (United States). Dept. of Chemical and Biological Engineering; Yang, Jun [Ford Scientific Research Lab., Dearborn, MI (United States); Hwang, Sonjong [California Inst. of Technology (CalTech), Pasadena, CA (United States). Dept. of Chemistry and Chemical Engineering; Shore, Sheldon [The Ohio State Univ., Columbus, OH (United States). Dept. of Chemistry and Biochemistry

    2016-11-28

    The objective of the proposed program is to discover novel mixed hydrides for hydrogen storage, which enable the DOE 2010 system-level goals. Our goal is to find a material that desorbs 8.5 wt.% H2 or more at temperatures below 85°C. The research program will combine first-principles calculations of reaction thermodynamics and kinetics with material and catalyst synthesis, testing, and characterization. We will combine materials from distinct categories (e.g., chemical and complex hydrides) to form novel multicomponent reactions. Systems to be studied include mixtures of complex hydrides and chemical hydrides [e.g. LiNH2+NH3BH3] and nitrogen-hydrogen based borohydrides [e.g. Al(BH4)3(NH3)3]. The 2010 and 2015 FreedomCAR/DOE targets for hydrogen storage systems are very challenging, and cannot be met with existing materials. The vast majority of the work to date has delineated materials into various classes, e.g., complex and metal hydrides, chemical hydrides, and sorbents. However, very recent studies indicate that mixtures of storage materials, particularly mixtures between various classes, hold promise to achieve technological attributes that materials within an individual class cannot reach. Our project involves a systematic, rational approach to designing novel multicomponent mixtures of materials with fast hydrogenation/dehydrogenation kinetics and favorable thermodynamics using a combination of state-of-the-art scientific computing and experimentation. We will use the accurate predictive power of first-principles modeling to understand the thermodynamic and microscopic kinetic processes involved in hydrogen release and uptake and to design new material/catalyst systems with improved properties. Detailed characterization and atomic-scale catalysis experiments will elucidate the effect of dopants and nanoscale catalysts in achieving fast kinetics and reversibility. And

  11. MLViS: A Web Tool for Machine Learning-Based Virtual Screening in Early-Phase of Drug Discovery and Development.

    Science.gov (United States)

    Korkmaz, Selcuk; Zararsiz, Gokmen; Goksuluk, Dincer

    2015-01-01

    Virtual screening is an important step in early-phase of drug discovery process. Since there are thousands of compounds, this step should be both fast and effective in order to distinguish drug-like and nondrug-like molecules. Statistical machine learning methods are widely used in drug discovery studies for classification purpose. Here, we aim to develop a new tool, which can classify molecules as drug-like and nondrug-like based on various machine learning methods, including discriminant, tree-based, kernel-based, ensemble and other algorithms. To construct this tool, first, performances of twenty-three different machine learning algorithms are compared by ten different measures, then, ten best performing algorithms have been selected based on principal component and hierarchical cluster analysis results. Besides classification, this application has also ability to create heat map and dendrogram for visual inspection of the molecules through hierarchical cluster analysis. Moreover, users can connect the PubChem database to download molecular information and to create two-dimensional structures of compounds. This application is freely available through www.biosoft.hacettepe.edu.tr/MLViS/.

  12. Virtual screening, SAR, and discovery of 5-(indole-3-yl)-2-[(2-nitrophenyl)amino] [1,3,4]-oxadiazole as a novel Bcl-2 inhibitor.

    Science.gov (United States)

    Ziedan, Noha I; Hamdy, Rania; Cavaliere, Alessandra; Kourti, Malamati; Prencipe, Filippo; Brancale, Andrea; Jones, Arwyn T; Westwell, Andrew D

    2017-07-01

    A new series of oxadiazoles were designed to act as inhibitors of the anti-apoptotic Bcl-2 protein. Virtual screening led to the discovery of new hits that interact with Bcl-2 at the BH3 binding pocket. Further study of the structure-activity relationship of the most active compound of the first series, compound 1, led to the discovery of a novel oxadiazole analogue, compound 16j, that was a more potent small-molecule inhibitor of Bcl-2. 16j had good in vitro inhibitory activity with submicromolar IC 50 values in a metastatic human breast cancer cell line (MDA-MB-231) and a human cervical cancer cell line (HeLa). The antitumour effect of 16j is concomitant with its ability to bind to Bcl-2 protein as shown by an enzyme-linked immunosorbent assay (IC 50  = 4.27 μm). Compound 16j has a great potential to develop into highly active anticancer agent. © 2017 John Wiley & Sons A/S.

  13. Drug discovery for hearing loss: Phenotypic screening of chemical compounds on primary cultures of the spiral ganglion.

    Science.gov (United States)

    Whitlon, Donna S

    2017-06-01

    In the United States there are, at present, no drugs that are specifically FDA approved to treat hearing loss. Although several clinical trials are ongoing, including one testing D-methionine that is supported by the US Army, none of these trials directly address the effect of noise exposure on cochlear spiral ganglion neurons. We recently published the first report of a systematic chemical compound screen using primary, mammalian spiral ganglion cultures in which we were able to detect a compound and others in its class that increased neurite elongation, a critical step in restoring cochlear synapses after noise induced hearing loss. Here we discuss the issues, both pro and con, that influenced the development of our approach. These considerations may be useful for future compound screens that target the same or other attributes of cochlear spiral ganglion neurons. Copyright © 2016 Elsevier B.V. All rights reserved.

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

    Science.gov (United States)

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

    2016-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Ye Fang

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

  16. Statistical physics of fracture: scientific discovery through high-performance computing

    International Nuclear Information System (INIS)

    Kumar, Phani; Nukala, V V; Simunovic, Srdan; Mills, Richard T

    2006-01-01

    The paper presents the state-of-the-art algorithmic developments for simulating the fracture of disordered quasi-brittle materials using discrete lattice systems. Large scale simulations are often required to obtain accurate scaling laws; however, due to computational complexity, the simulations using the traditional algorithms were limited to small system sizes. We have developed two algorithms: a multiple sparse Cholesky downdating scheme for simulating 2D random fuse model systems, and a block-circulant preconditioner for simulating 2D random fuse model systems. Using these algorithms, we were able to simulate fracture of largest ever lattice system sizes (L = 1024 in 2D, and L = 64 in 3D) with extensive statistical sampling. Our recent simulations on 1024 processors of Cray-XT3 and IBM Blue-Gene/L have further enabled us to explore fracture of 3D lattice systems of size L = 200, which is a significant computational achievement. These largest ever numerical simulations have enhanced our understanding of physics of fracture; in particular, we analyze damage localization and its deviation from percolation behavior, scaling laws for damage density, universality of fracture strength distribution, size effect on the mean fracture strength, and finally the scaling of crack surface roughness

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

    Directory of Open Access Journals (Sweden)

    Xing Wang

    2016-03-01

    Full Text Available 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.

  18. Automated Cervical Screening and Triage, Based on HPV Testing and Computer-Interpreted Cytology.

    Science.gov (United States)

    Yu, Kai; Hyun, Noorie; Fetterman, Barbara; Lorey, Thomas; Raine-Bennett, Tina R; Zhang, Han; Stamps, Robin E; Poitras, Nancy E; Wheeler, William; Befano, Brian; Gage, Julia C; Castle, Philip E; Wentzensen, Nicolas; Schiffman, Mark

    2018-04-11

    State-of-the-art cervical cancer prevention includes human papillomavirus (HPV) vaccination among adolescents and screening/treatment of cervical precancer (CIN3/AIS and, less strictly, CIN2) among adults. HPV testing provides sensitive detection of precancer but, to reduce overtreatment, secondary "triage" is needed to predict women at highest risk. Those with the highest-risk HPV types or abnormal cytology are commonly referred to colposcopy; however, expert cytology services are critically lacking in many regions. To permit completely automatable cervical screening/triage, we designed and validated a novel triage method, a cytologic risk score algorithm based on computer-scanned liquid-based slide features (FocalPoint, BD, Burlington, NC). We compared it with abnormal cytology in predicting precancer among 1839 women testing HPV positive (HC2, Qiagen, Germantown, MD) in 2010 at Kaiser Permanente Northern California (KPNC). Precancer outcomes were ascertained by record linkage. As additional validation, we compared the algorithm prospectively with cytology results among 243 807 women screened at KPNC (2016-2017). All statistical tests were two-sided. Among HPV-positive women, the algorithm matched the triage performance of abnormal cytology. Combined with HPV16/18/45 typing (Onclarity, BD, Sparks, MD), the automatable strategy referred 91.7% of HPV-positive CIN3/AIS cases to immediate colposcopy while deferring 38.4% of all HPV-positive women to one-year retesting (compared with 89.1% and 37.4%, respectively, for typing and cytology triage). In the 2016-2017 validation, the predicted risk scores strongly correlated with cytology (P < .001). High-quality cervical screening and triage performance is achievable using this completely automated approach. Automated technology could permit extension of high-quality cervical screening/triage coverage to currently underserved regions.

  19. A hybrid computational method for the discovery of novel reproduction-related genes.

    Science.gov (United States)

    Chen, Lei; Chu, Chen; Kong, Xiangyin; Huang, Guohua; Huang, Tao; Cai, Yu-Dong

    2015-01-01

    Uncovering the molecular mechanisms underlying reproduction is of great importance to infertility treatment and to the generation of healthy offspring. In this study, we discovered novel reproduction-related genes with a hybrid computational method, integrating three different types of method, which offered new clues for further reproduction research. This method was first executed on a weighted graph, constructed based on known protein-protein interactions, to search the shortest paths connecting any two known reproduction-related genes. Genes occurring in these paths were deemed to have a special relationship with reproduction. These newly discovered genes were filtered with a randomization test. Then, the remaining genes were further selected according to their associations with known reproduction-related genes measured by protein-protein interaction score and alignment score obtained by BLAST. The in-depth analysis of the high confidence novel reproduction genes revealed hidden mechanisms of reproduction and provided guidelines for further experimental validations.

  20. Discovery and Computational Rationalization of Diminishing Alternation in [n]Dendralenes.

    Science.gov (United States)

    Saglam, Mehmet F; Fallon, Thomas; Paddon-Row, Michael N; Sherburn, Michael S

    2016-01-27

    The [n]dendralenes are a family of acyclic hydrocarbons which, by virtue of their ability to rapidly generate structural complexity, have attracted significant recent synthetic attention. [3]Dendralene through [8]dendralene have been previously prepared but no higher member of the family has been reported to date. Here, we describe the first chemical syntheses of the "higher" dendralenes, [9]dendralene through [12]dendralene. We also report a detailed investigation into the spectroscopic properties and chemical reactivity of the complete family of fundamental hydrocarbons, [3]dendralene to [12]dendralene. These studies reveal the first case of diminishing alternation in behavior in a series of related structures. We also report a comprehensive series of computational studies, which trace this dampening oscillatory effect in both spectroscopic measurements and chemical reactivity to conformational preferences.

  1. Combined use of computational chemistry and chemoinformatics methods for chemical discovery

    Energy Technology Data Exchange (ETDEWEB)

    Sugimoto, Manabu, E-mail: sugimoto@kumamoto-u.ac.jp [Graduate School of Science and Technology, Kumamoto University, 2-39-1, Kurokami, Chuo-ku, Kumamoto 860-8555 (Japan); Institute for Molecular Science, 38 Nishigo-Naka, Myodaiji, Okazaki 444-8585 (Japan); CREST, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012 (Japan); Ideo, Toshihiro; Iwane, Ryo [Graduate School of Science and Technology, Kumamoto University, 2-39-1, Kurokami, Chuo-ku, Kumamoto 860-8555 (Japan)

    2015-12-31

    Data analysis on numerical data by the computational chemistry calculations is carried out to obtain knowledge information of molecules. A molecular database is developed to systematically store chemical, electronic-structure, and knowledge-based information. The database is used to find molecules related to a keyword of “cancer”. Then the electronic-structure calculations are performed to quantitatively evaluate quantum chemical similarity of the molecules. Among the 377 compounds registered in the database, 24 molecules are found to be “cancer”-related. This set of molecules includes both carcinogens and anticancer drugs. The quantum chemical similarity analysis, which is carried out by using numerical results of the density-functional theory calculations, shows that, when some energy spectra are referred to, carcinogens are reasonably distinguished from the anticancer drugs. Therefore these spectral properties are considered of as important measures for classification.

  2. Discovery and computer aided potency optimization of a novel class of small molecule CXCR4 antagonists.

    Directory of Open Access Journals (Sweden)

    Victoria Vinader

    Full Text Available Amongst the chemokine signalling axes involved in cancer, chemokine CXCL12 acting on chemokine receptor CXCR4 is particularly significant since it orchestrates migration of cancer cells in a tissue-specific metastatic process. High CXCR4 tumour expression is associated with poor prognosis of lung, brain, CNS, blood and breast cancers. We have identified a new class of small molecule CXCR4 antagonists based on the use of computational modelling studies in concert with experimental determination of in vitro activity against CXCL12-induced intracellular calcium mobilisation, proliferation and chemotaxis. Molecular modelling proved to be a useful tool in rationalising our observed potencies, as well as informing the direction of the synthetic efforts aimed at producing more potent compounds.

  3. Speeding cis-trans regulation discovery by phylogenomic analyses coupled with screenings of an arrayed library of Arabidopsis transcription factors.

    Directory of Open Access Journals (Sweden)

    Gabriel Castrillo

    Full Text Available Transcriptional regulation is an important mechanism underlying gene expression and has played a crucial role in evolution. The number, position and interactions between cis-elements and transcription factors (TFs determine the expression pattern of a gene. To identify functionally relevant cis-elements in gene promoters, a phylogenetic shadowing approach with a lipase gene (LIP1 was used. As a proof of concept, in silico analyses of several Brassicaceae LIP1 promoters identified a highly conserved sequence (LIP1 element that is sufficient to drive strong expression of a reporter gene in planta. A collection of ca. 1,200 Arabidopsis thaliana TF open reading frames (ORFs was arrayed in a 96-well format (RR library and a convenient mating based yeast one hybrid (Y1H screening procedure was established. We constructed an episomal plasmid (pTUY1H to clone the LIP1 element and used it as bait for Y1H screenings. A novel interaction with an HD-ZIP (AtML1 TF was identified and abolished by a 2 bp mutation in the LIP1 element. A role of this interaction in transcriptional regulation was confirmed in planta. In addition, we validated our strategy by reproducing the previously reported interaction between a MYB-CC (PHR1 TF, a central regulator of phosphate starvation responses, with a conserved promoter fragment (IPS1 element containing its cognate binding sequence. Finally, we established that the LIP1 and IPS1 elements were differentially bound by HD-ZIP and MYB-CC family members in agreement with their genetic redundancy in planta. In conclusion, combining in silico analyses of orthologous gene promoters with Y1H screening of the RR library represents a powerful approach to decipher cis- and trans-regulatory codes.

  4. Progression Analysis and Stage Discovery in Continuous Physiological Processes Using Image Computing

    Directory of Open Access Journals (Sweden)

    Ferrucci Luigi

    2010-01-01

    Full Text Available We propose an image computing-based method for quantitative analysis of continuous physiological processes that can be sensed by medical imaging and demonstrate its application to the analysis of morphological alterations of the bone structure, which correlate with the progression of osteoarthritis (OA. The purpose of the analysis is to quantitatively estimate OA progression in a fashion that can assist in understanding the pathophysiology of the disease. Ultimately, the texture analysis will be able to provide an alternative OA scoring method, which can potentially reflect the progression of the disease in a more direct fashion compared to the existing clinically utilized classification schemes based on radiology. This method can be useful not just for studying the nature of OA, but also for developing and testing the effect of drugs and treatments. While in this paper we demonstrate the application of the method to osteoarthritis, its generality makes it suitable for the analysis of other progressive clinical conditions that can be diagnosed and prognosed by using medical imaging.

  5. Computational Evolutionary Methodology for Knowledge Discovery and Forecasting in Epidemiology and Medicine

    International Nuclear Information System (INIS)

    Rao, Dhananjai M.; Chernyakhovsky, Alexander; Rao, Victoria

    2008-01-01

    Humanity is facing an increasing number of highly virulent and communicable diseases such as avian influenza. Researchers believe that avian influenza has potential to evolve into one of the deadliest pandemics. Combating these diseases requires in-depth knowledge of their epidemiology. An effective methodology for discovering epidemiological knowledge is to utilize a descriptive, evolutionary, ecological model and use bio-simulations to study and analyze it. These types of bio-simulations fall under the category of computational evolutionary methods because the individual entities participating in the simulation are permitted to evolve in a natural manner by reacting to changes in the simulated ecosystem. This work describes the application of the aforementioned methodology to discover epidemiological knowledge about avian influenza using a novel eco-modeling and bio-simulation environment called SEARUMS. The mathematical principles underlying SEARUMS, its design, and the procedure for using SEARUMS are discussed. The bio-simulations and multi-faceted case studies conducted using SEARUMS elucidate its ability to pinpoint timelines, epicenters, and socio-economic impacts of avian influenza. This knowledge is invaluable for proactive deployment of countermeasures in order to minimize negative socioeconomic impacts, combat the disease, and avert a pandemic

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

    Science.gov (United States)

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

    2008-07-24

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

  7. Redesign of a computerized clinical reminder for colorectal cancer screening: a human-computer interaction evaluation

    Directory of Open Access Journals (Sweden)

    Saleem Jason J

    2011-11-01

    Full Text Available Abstract Background Based on barriers to the use of computerized clinical decision support (CDS learned in an earlier field study, we prototyped design enhancements to the Veterans Health Administration's (VHA's colorectal cancer (CRC screening clinical reminder to compare against the VHA's current CRC reminder. Methods In a controlled simulation experiment, 12 primary care providers (PCPs used prototypes of the current and redesigned CRC screening reminder in a within-subject comparison. Quantitative measurements were based on a usability survey, workload assessment instrument, and workflow integration survey. We also collected qualitative data on both designs. Results Design enhancements to the VHA's existing CRC screening clinical reminder positively impacted aspects of usability and workflow integration but not workload. The qualitative analysis revealed broad support across participants for the design enhancements with specific suggestions for improving the reminder further. Conclusions This study demonstrates the value of a human-computer interaction evaluation in informing the redesign of information tools to foster uptake, integration into workflow, and use in clinical practice.

  8. Implementation of depression screening in antenatal clinics through tablet computers: results of a feasibility study.

    Science.gov (United States)

    Marcano-Belisario, José S; Gupta, Ajay K; O'Donoghue, John; Ramchandani, Paul; Morrison, Cecily; Car, Josip

    2017-05-10

    Mobile devices may facilitate depression screening in the waiting area of antenatal clinics. This can present implementation challenges, of which we focused on survey layout and technology deployment. We assessed the feasibility of using tablet computers to administer a socio-demographic survey, the Whooley questions and the Edinburgh Postnatal Depression Scale (EPDS) to 530 pregnant women attending National Health Service (NHS) antenatal clinics across England. We randomised participants to one of two layout versions of these surveys: (i) a scrolling layout where each survey was presented on a single screen; or (ii) a paging layout where only one question appeared on the screen at any given time. Overall, 85.10% of eligible pregnant women agreed to take part. Of these, 90.95% completed the study procedures. Approximately 23% of participants answered Yes to at least one Whooley question, and approximately 13% of them scored 10 points of more on the EPDS. We observed no association between survey layout and the responses given to the Whooley questions, the median EPDS scores, the number of participants at increased risk of self-harm, and the number of participants asking for technical assistance. However, we observed a difference in the number of participants at each EPDS scoring interval (p = 0.008), which provide an indication of a woman's risk of depression. A scrolling layout resulted in faster completion times (median = 4 min 46 s) than a paging layout (median = 5 min 33 s) (p = 0.024). However, the clinical significance of this difference (47.5 s) is yet to be determined. Tablet computers can be used for depression screening in the waiting area of antenatal clinics. This requires the careful consideration of clinical workflows, and technology-related issues such as connectivity and security. An association between survey layout and EPDS scoring intervals needs to be explored further to determine if it corresponds to a survey layout effect

  9. A "genome-to-lead" approach for insecticide discovery: pharmacological characterization and screening of Aedes aegypti D(1-like dopamine receptors.

    Directory of Open Access Journals (Sweden)

    Jason M Meyer

    2012-01-01

    Full Text Available BACKGROUND: Many neglected tropical infectious diseases affecting humans are transmitted by arthropods such as mosquitoes and ticks. New mode-of-action chemistries are urgently sought to enhance vector management practices in countries where arthropod-borne diseases are endemic, especially where vector populations have acquired widespread resistance to insecticides. METHODOLOGY/PRINCIPAL FINDINGS: We describe a "genome-to-lead" approach for insecticide discovery that incorporates the first reported chemical screen of a G protein-coupled receptor (GPCR mined from a mosquito genome. A combination of molecular and pharmacological studies was used to functionally characterize two dopamine receptors (AaDOP1 and AaDOP2 from the yellow fever mosquito, Aedes aegypti. Sequence analyses indicated that these receptors are orthologous to arthropod D(1-like (Gα(s-coupled receptors, but share less than 55% amino acid identity in conserved domains with mammalian dopamine receptors. Heterologous expression of AaDOP1 and AaDOP2 in HEK293 cells revealed dose-dependent responses to dopamine (EC(50: AaDOP1 = 3.1±1.1 nM; AaDOP2 = 240±16 nM. Interestingly, only AaDOP1 exhibited sensitivity to epinephrine (EC(50 = 5.8±1.5 nM and norepinephrine (EC(50 = 760±180 nM, while neither receptor was activated by other biogenic amines tested. Differential responses were observed between these receptors regarding their sensitivity to dopamine agonists and antagonists, level of maximal stimulation, and constitutive activity. Subsequently, a chemical library screen was implemented to discover lead chemistries active at AaDOP2. Fifty-one compounds were identified as "hits," and follow-up validation assays confirmed the antagonistic effect of selected compounds at AaDOP2. In vitro comparison studies between AaDOP2 and the human D(1 dopamine receptor (hD(1 revealed markedly different pharmacological profiles and identified amitriptyline and doxepin as AaDOP2

  10. Initial screening test for blunt cerebrovascular injury: Validity assessment of whole-body computed tomography.

    Science.gov (United States)

    Laser, Adriana; Kufera, Joseph A; Bruns, Brandon R; Sliker, Clint W; Tesoriero, Ronald B; Scalea, Thomas M; Stein, Deborah M

    2015-09-01

    Our whole-body computed tomography protocol (WBCT), used to image patients with polytrauma, consists of a noncontrast head computed tomography (CT) followed by a multidetector computed tomography (40- or 64- slice) that includes an intravenous, contrast-enhanced scan from the face through the pelvis. WBCT is used to screen for blunt cerebrovascular injury (BCVI) during initial CT imaging of the patient with polytrauma and allows for early initiation of therapy with the goal of avoiding stroke. WBCT has not been directly compared with CT angiography (CTA) of the neck as a screening tool for BCVI. We hypothesize that WBCT is a valid modality to diagnose BCVI compared with neck CTA, thus screening patients with polytrauma for BCVI and limiting the need for subsequent CTA. A retrospective review of the trauma registry was conducted for all patients diagnosed with BCVI from June 2009 to June 2013 at our institution. All injuries, identified and graded on initial WBCT, were compared with neck CTA imaging performed within the first 72 hours. Sensitivity was calculated for WBCT by the use of CTA as the reference standard. Proportions of agreement also were calculated between the grades of injury for both imaging modalities. A total of 319 injured vessels were identified in 227 patients. On initial WBCT 80 (25%) of the injuries were grade I, 75 (24%) grade II, 45 (14%) grade III, 41 (13%) grade IV, and 58 (18%) were classified as indeterminate: 27 vertebral and 31 carotid lesions. Twenty (6%) of the 319 injuries were not detected on WBCT but identified on subsequent CTA (9 grade I, 7 grade II, 4 grade III); 6 vertebral and 14 carotid. For each vessel type and for all vessels combined, WBCT demonstrated sensitivity rates of over 90% to detect BCVI among the population of patients with at least one vessel injured. There was concordant grading of injuries between WBCT and initial diagnostic CTA in 154 (48% of all injuries). Lower grade injures were more discordant than higher

  11. Discovery of Novel Bovine Viral Diarrhea Inhibitors Using Structure-Based Virtual Screening on the Envelope Protein E2

    Directory of Open Access Journals (Sweden)

    Mariela Bollini

    2018-03-01

    Full Text Available Bovine viral diarrhea virus (BVDV is a member of the genus Pestivirus within the family Flaviviridae. BVDV causes both acute and persistent infections in cattle, leading to substantial financial losses to the livestock industry each year. The global prevalence of persistent BVDV infection and the lack of a highly effective antiviral therapy have spurred intensive efforts to discover and develop novel anti-BVDV therapies in the pharmaceutical industry. Antiviral targeting of virus envelope proteins is an effective strategy for therapeutic intervention of viral infections. We performed prospective small-molecule high-throughput docking to identify molecules that likely bind to the region delimited by domains I and II of the envelope protein E2 of BVDV. Several structurally different compounds were purchased or synthesized, and assayed for antiviral activity against BVDV. Five of the selected compounds were active displaying IC50 values in the low- to mid-micromolar range. For these compounds, their possible binding determinants were characterized by molecular dynamics simulations. A common pattern of interactions between active molecules and aminoacid residues in the binding site in E2 was observed. These findings could offer a better understanding of the interaction of BVDV E2 with these inhibitors, as well as benefit the discovery of novel and more potent BVDV antivirals.

  12. Colworth prize lecture 2016: exploiting new biological targets from a whole-cell phenotypic screening campaign for TB drug discovery.

    Science.gov (United States)

    Moynihan, Patrick Joseph; Besra, Gurdyal S

    2017-10-01

    Mycobacterium tuberculosis is the aetiological agent of tuberculosis (TB) and is the leading bacterial cause of mortality and morbidity in the world. One third of the world's population is infected with TB, and in conjunction with HIV represents a serious problem that urgently needs addressing. TB is a disease of poverty and mostly affects young adults in their productive years, primarily in the developing world. The most recent report from the World Health Organisation states that 8 million new cases of TB were reported and that ~1.5 million people died from TB. The efficacy of treatment is threatened by the emergence of multi-drug and extensively drug-resistant strains of M. tuberculosis. It can be argued that, globally, M. tuberculosis is the single most important infectious agent affecting mankind. Our research aims to establish an academic-industrial partnership with the goal of discovering new drug targets and hit-to-lead new chemical entities for TB drug discovery.

  13. Discovery of novel bovine viral diarrhea inhibitors using structure-based virtual screening on the envelope protein E2

    Science.gov (United States)

    Bollini, Mariela; Leal, Emilse S.; Adler, Natalia S.; Aucar, María G.; Fernández, Gabriela A.; Pascual, María J.; Merwaiss, Fernando; Alvarez, Diego E.; Cavasotto, Claudio N.

    2018-03-01

    Bovine viral diarrhea virus (BVDV) is a member of the genus Pestivirus within the family Flaviviridae. BVDV causes both acute and persistent infections in cattle, leading to substantial financial losses to the livestock industry each year. The global prevalence of persistent BVDV infection and the lack of a highly effective antiviral therapy have spurred intensive efforts to discover and develop novel anti-BVDV therapies in the pharmaceutical industry. Antiviral targeting of virus envelope proteins is an effective strategy for therapeutic intervention of viral infections. We performed prospective small-molecule high-throughput docking to identify molecules that likely bind to the region delimited by domains I and II of the envelope protein E2 of BVDV. Several structurally different compounds were purchased or synthesized, and assayed for antiviral activity against BVDV. Five of the selected compounds were active displaying IC50 values in the low- to mid-micromolar range. For these compounds, their possible binding determinants were characterized by molecular dynamics simulations. A common pattern of interactions between active molecules and aminoacid residues in the binding site in E2 was observed. These findings could offer a better understanding of the interaction of BVDV E2 with these inhibitors, as well as benefit the discovery of novel and more potent BVDV antivirals.

  14. Computer-aided diagnosis for screening of breast cancer on mammograms. Current status and future potential

    International Nuclear Information System (INIS)

    Doi, Kunio

    2007-01-01

    Described are the history, current status and future potential of computer-aided diagnosis (CAD) with particular emphasis on screening mammography for breast cancer. The systematic basic and clinical studies on CAD started around 20 years before and the significance of CAD has been well recognized to be evident because of human errors occurring in the visual check by doctors of so numerous screening images. Improvement of diagnostic accuracy by CAD has been demonstrated by statistical analysis of ROC (receiver operating characteristic) curves. In mammography, reviewed is detection of the early stage breast cancer like microcalcifications by computer alone, by CAD plus one or more doctors' reading, and by practical clinical CAD diagnosis. For differential diagnosis for malignancy, microcalcifications and masses are given their characteristic image properties and the results are that the Az-value (area under ROC curve) is higher in CAD than in doctor's (0.80 vs 0.61) in the former and, doctor's (0.93) is improved by CAD to 0.96 in the latter masses. In this diagnosis, similar images in the digital database are useful and the database can learn by repeated input of individual data by neural network. Detection of the lesion and especially, its differential diagnosis will be more important in parallel to database development and CAD will be also useful for doctor' carrier as an educational mean. (R.T.)

  15. Computer-assisted static/dynamic renal imaging: a screening test for renovascular hypertension

    International Nuclear Information System (INIS)

    Keim, H.J.; Johnson, P.M.; Vaughan, E.D. Jr.; Beg, K.; Follett, D.A.; Freeman, L.M.; Laragh, J.H.

    1979-01-01

    Computer-assisted static/dynamic renal imaging with [ 197 Hg] chlormerodrin and [/sup 99m/Tc] pertechnetate was evaluated prospectively as a screening test for renovascular hypertension. Results are reported for 51 patients: 33 with benign essential hypertension and 18 with renovascular hypertension, and for 21 normal controls. All patients underwent renal arteriography. Patients with significant obesity, renal insufficiency, or renoparenchymal disease were excluded from this study. Independent visual analyses of renal gamma images and time-activity transit curves identified 17 of the 18 patients with renovascular hypertension; one study was equivocal. There were five equivocal and three false-positive results in the essential hypertension and normal control groups. The sensitivity of the method was 94% and the specificity 85%. Since the prevalence of the renovascular subset of hypertension is approximately 5%, the predictive value is only 25%. Inclusion of computer-generated data did not improve this result. Accordingly, this method is not recommended as a primary screening test for renovascular hypertension

  16. Computer Vision Tool and Technician as First Reader of Lung Cancer Screening CT Scans.

    Science.gov (United States)

    Ritchie, Alexander J; Sanghera, Calvin; Jacobs, Colin; Zhang, Wei; Mayo, John; Schmidt, Heidi; Gingras, Michel; Pasian, Sergio; Stewart, Lori; Tsai, Scott; Manos, Daria; Seely, Jean M; Burrowes, Paul; Bhatia, Rick; Atkar-Khattra, Sukhinder; van Ginneken, Bram; Tammemagi, Martin; Tsao, Ming Sound; Lam, Stephen

    2016-05-01

    To implement a cost-effective low-dose computed tomography (LDCT) lung cancer screening program at the population level, accurate and efficient interpretation of a large volume of LDCT scans is needed. The objective of this study was to evaluate a workflow strategy to identify abnormal LDCT scans in which a technician assisted by computer vision (CV) software acts as a first reader with the aim to improve speed, consistency, and quality of scan interpretation. Without knowledge of the diagnosis, a technician reviewed 828 randomly batched scans (136 with lung cancers, 556 with benign nodules, and 136 without nodules) from the baseline Pan-Canadian Early Detection of Lung Cancer Study that had been annotated by the CV software CIRRUS Lung Screening (Diagnostic Image Analysis Group, Nijmegen, The Netherlands). The scans were classified as either normal (no nodules ≥1 mm or benign nodules) or abnormal (nodules or other abnormality). The results were compared with the diagnostic interpretation by Pan-Canadian Early Detection of Lung Cancer Study radiologists. The overall sensitivity and specificity of the technician in identifying an abnormal scan were 97.8% (95% confidence interval: 96.4-98.8) and 98.0% (95% confidence interval: 89.5-99.7), respectively. Of the 112 prevalent nodules that were found to be malignant in follow-up, 92.9% were correctly identified by the technician plus CV compared with 84.8% by the study radiologists. The average time taken by the technician to review a scan after CV processing was 208 ± 120 seconds. Prescreening CV software and a technician as first reader is a promising strategy for improving the consistency and quality of screening interpretation of LDCT scans. Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

  17. Blunt cerebrovascular injury screening with 64-channel multidetector computed tomography: more slices finally cut it.

    Science.gov (United States)

    Paulus, Elena M; Fabian, Timothy C; Savage, Stephanie A; Zarzaur, Ben L; Botta, Vandana; Dutton, Wesley; Croce, Martin A

    2014-02-01

    Aggressive screening to diagnose blunt cerebrovascular injury (BCVI) results in early treatment, leading to improved outcomes and reduced stroke rates. While computed tomographic angiography (CTA) has been widely adopted for BCVI screening, evidence of its diagnostic sensitivity is marginal. Previous work from our institution using 32-channel multidetector CTA in 684 patients demonstrated an inadequate sensitivity of 51% (Ann Surg. 2011,253: 444-450). Digital subtraction angiography (DSA) continues to be the reference standard of diagnosis but has significant drawbacks of invasiveness and resource demands. There have been continued advances in CT technology, and this is the first report of an extensive experience with 64-channel multidetector CTA. Patients screened for BCVI using CTA and DSA (reference) at a Level 1 trauma center during the 12-month period ending in May 2012 were identified. Results of CTA and DSA, complications, and strokes were retrospectively reviewed and compared. A total of 594 patients met criteria for BCVI screening and underwent both CTA and DSA. One hundred twenty-eight patients (22% of those screened) had 163 injured vessels: 99 (61%) carotid artery injuries and 64 (39%) vertebral artery injuries. Sixty-four-channel CTA demonstrated an overall sensitivity per vessel of 68% and specificity of 92%. The 52 false-negative findings on CTA were composed of 34 carotid artery injuries and 18 vertebral artery injuries; 32 (62%) were Grade I injuries. Overall, positive predictive value was 36.2%, and negative predictive value was 97.5%. Six procedure-related complications (1%) occurred with DSA, including two iatrogenic dissections and one stroke. Sixty-four-channel CTA demonstrated a significantly improved sensitivity of 68% versus the 51% previously reported for the 32-channel CTA (p = 0.0075). Sixty-two percent of the false-negative findings occurred with low-grade injuries. Considering complications, cost, and resource demand associated with

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

    Science.gov (United States)

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

    2018-04-12

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

  19. Rapid, computer vision-enabled murine screening system identifies neuropharmacological potential of two new mechanisms

    Directory of Open Access Journals (Sweden)

    Steven L Roberds

    2011-09-01

    Full Text Available The lack of predictive in vitro models for behavioral phenotypes impedes rapid advancement in neuropharmacology and psychopharmacology. In vivo behavioral assays are more predictive of activity in human disorders, but such assays are often highly resource-intensive. Here we describe the successful application of a computer vision-enabled system to identify potential neuropharmacological activity of two new mechanisms. The analytical system was trained using multiple drugs that are used clinically to treat depression, schizophrenia, anxiety, and other psychiatric or behavioral disorders. During blinded testing the PDE10 inhibitor TP-10 produced a signature of activity suggesting potential antipsychotic activity. This finding is consistent with TP-10’s activity in multiple rodent models that is similar to that of clinically used antipsychotic drugs. The CK1ε inhibitor PF-670462 produced a signature consistent with anxiolytic activity and, at the highest dose tested, behavioral effects similar to that of opiate analgesics. Neither TP-10 nor PF-670462 was included in the training set. Thus, computer vision-based behavioral analysis can facilitate drug discovery by identifying neuropharmacological effects of compounds acting through new mechanisms.

  20. [Artificial Intelligence in Drug Discovery].

    Science.gov (United States)

    Fujiwara, Takeshi; Kamada, Mayumi; Okuno, Yasushi

    2018-04-01

    According to the increase of data generated from analytical instruments, application of artificial intelligence(AI)technology in medical field is indispensable. In particular, practical application of AI technology is strongly required in "genomic medicine" and "genomic drug discovery" that conduct medical practice and novel drug development based on individual genomic information. In our laboratory, we have been developing a database to integrate genome data and clinical information obtained by clinical genome analysis and a computational support system for clinical interpretation of variants using AI. In addition, with the aim of creating new therapeutic targets in genomic drug discovery, we have been also working on the development of a binding affinity prediction system for mutated proteins and drugs by molecular dynamics simulation using supercomputer "Kei". We also have tackled for problems in a drug virtual screening. Our developed AI technology has successfully generated virtual compound library, and deep learning method has enabled us to predict interaction between compound and target protein.

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

    Directory of Open Access Journals (Sweden)

    Lan-Ting Xin

    2017-07-01

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

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

    Directory of Open Access Journals (Sweden)

    Guoqing Zhang

    2018-03-01

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

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

    Science.gov (United States)

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

    2018-01-01

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

  4. Cell-free translational screening of an expression sequence tag library of Clonorchis sinensis for novel antigen discovery.

    Science.gov (United States)

    Kasi, Devi; Catherine, Christy; Lee, Seung-Won; Lee, Kyung-Ho; Kim, Yu Jung; Ro Lee, Myeong; Ju, Jung Won; Kim, Dong-Myung

    2017-05-01

    The rapidly evolving cloning and sequencing technologies have enabled understanding of genomic structure of parasite genomes, opening up new ways of combatting parasite-related diseases. To make the most of the exponentially accumulating genomic data, however, it is crucial to analyze the proteins encoded by these genomic sequences. In this study, we adopted an engineered cell-free protein synthesis system for large-scale expression screening of an expression sequence tag (EST) library of Clonorchis sinensis to identify potential antigens that can be used for diagnosis and treatment of clonorchiasis. To allow high-throughput expression and identification of individual genes comprising the library, a cell-free synthesis reaction was designed such that both the template DNA and the expressed proteins were co-immobilized on the same microbeads, leading to microbead-based linkage of the genotype and phenotype. This reaction configuration allowed streamlined expression, recovery, and analysis of proteins. This approach enabled us to identify 21 antigenic proteins. © 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:832-837, 2017. © 2017 American Institute of Chemical Engineers.

  5. Structural insight into exosite binding and discovery of novel exosite inhibitors of botulinum neurotoxin serotype A through in silico screening

    Science.gov (United States)

    Hu, Xin; Legler, Patricia M.; Southall, Noel; Maloney, David J.; Simeonov, Anton; Jadhav, Ajit

    2014-07-01

    Botulinum neurotoxin serotype A (BoNT/A) is the most lethal toxin among the Tier 1 Select Agents. Development of potent and selective small molecule inhibitors against BoNT/A zinc metalloprotease remains a challenging problem due to its exceptionally large substrate binding surface and conformational plasticity. The exosites of the catalytic domain of BoNT/A are intriguing alternative sites for small molecule intervention, but their suitability for inhibitor design remains largely unexplored. In this study, we employed two recently identified exosite inhibitors, D-chicoric acid and lomofungin, to probe the structural features of the exosites and molecular mechanisms of synergistic inhibition. The results showed that D-chicoric acid favors binding at the α-exosite, whereas lomofungin preferentially binds at the β-exosite by mimicking the substrate β-sheet binding interaction. Molecular dynamics simulations and binding interaction analysis of the exosite inhibitors with BoNT/A revealed key elements and hotspots that likely contribute to the inhibitor binding and synergistic inhibition. Finally, we performed database virtual screening for novel inhibitors of BoNT/A targeting the exosites. Hits C1 and C2 showed non-competitive inhibition and likely target the α- and β-exosites, respectively. The identified exosite inhibitors may provide novel candidates for structure-based development of therapeutics against BoNT/A intoxication.

  6. Virtual screening of compound libraries.

    Science.gov (United States)

    Cerqueira, Nuno M F S A; Sousa, Sérgio F; Fernandes, Pedro A; Ramos, Maria João

    2009-01-01

    During the last decade, Virtual Screening (VS) has definitively established itself as an important part of the drug discovery and development process. VS involves the selection of likely drug candidates from large libraries of chemical structures by using computational methodologies, but the generic definition of VS encompasses many different methodologies. This chapter provides an introduction to the field by reviewing a variety of important aspects, including the different types of virtual screening methods, and the several steps required for a successful virtual screening campaign within a state-of-the-art approach, from target selection to postfilter application. This analysis is further complemented with a small collection important VS success stories.

  7. Discovery of Specific Inhibitors for Intestinal E. coli  β-Glucuronidase through In Silico Virtual Screening

    Directory of Open Access Journals (Sweden)

    Ta-Chun Cheng

    2015-01-01

    Full Text Available Glucuronidation is a major metabolism process of detoxification for carcinogens, 4-(methylnitrosamino-1-(3-pyridy-1-butanone (NNK and 1,2-dimethylhydrazine (DMH, of reactive oxygen species (ROS. However, intestinal E. coli   β-glucuronidase (eβG has been considered pivotal to colorectal carcinogenesis. Specific inhibition of eβG may prevent reactivating the glucuronide-carcinogen and protect the intestine from ROS-mediated carcinogenesis. In order to develop specific eβG inhibitors, we found that 59 candidate compounds obtained from the initial virtual screening had high inhibition specificity against eβG but not human βG. In particular, we found that compounds 7145 and 4041 with naphthalenylidene-benzenesulfonamide (NYBS are highly effective and selective to inhibit eβG activity. Compound 4041  (IC50=2.8 μM shows a higher inhibiting ability than compound 7145  (IC50=31.6 μM against eβG. Furthermore, the molecular docking analysis indicates that compound 4041 has two hydrophobic contacts to residues L361 and I363 in the bacterial loop, but 7145 has one contact to L361. Only compound 4041 can bind to key residue (E413 at active site of eβG via hydrogen-bonding interactions. These novel NYBS-based eβG specific inhibitors may provide as novel candidate compounds, which specifically inhibit eβG to reduce eβG-based carcinogenesis and intestinal injury.

  8. A computer-tailored intervention to promote informed decision making for prostate cancer screening among African American men.

    Science.gov (United States)

    Allen, Jennifer D; Mohllajee, Anshu P; Shelton, Rachel C; Drake, Bettina F; Mars, Dana R

    2009-12-01

    African American men experience a disproportionate burden of prostate cancer (CaP) morbidity and mortality. National screening guidelines advise men to make individualized screening decisions through a process termed informed decision making (IDM). In this pilot study, a computer-tailored decision-aid designed to promote IDM was evaluated using a pre-/posttest design. African American men aged 40 years and older were recruited from a variety of community settings (n = 108). At pretest, 43% of men reported having made a screening decision; at posttest 47% reported this to be the case (p = .39). Significant improvements were observed between pre- and posttest on scores of knowledge, decision self-efficacy, and decisional conflict. Men were also more likely to want an active role in decision making after using the tool. These results suggest that use of a computer-tailored decision aid is a promising strategy to promote IDM for CaP screening among African American men.

  9. Computer-aided diagnostics of screening mammography using content-based image retrieval

    Science.gov (United States)

    Deserno, Thomas M.; Soiron, Michael; de Oliveira, Júlia E. E.; de A. Araújo, Arnaldo

    2012-03-01

    Breast cancer is one of the main causes of death among women in occidental countries. In the last years, screening mammography has been established worldwide for early detection of breast cancer, and computer-aided diagnostics (CAD) is being developed to assist physicians reading mammograms. A promising method for CAD is content-based image retrieval (CBIR). Recently, we have developed a classification scheme of suspicious tissue pattern based on the support vector machine (SVM). In this paper, we continue moving towards automatic CAD of screening mammography. The experiments are based on in total 10,509 radiographs that have been collected from different sources. From this, 3,375 images are provided with one and 430 radiographs with more than one chain code annotation of cancerous regions. In different experiments, this data is divided into 12 and 20 classes, distinguishing between four categories of tissue density, three categories of pathology and in the 20 class problem two categories of different types of lesions. Balancing the number of images in each class yields 233 and 45 images remaining in each of the 12 and 20 classes, respectively. Using a two-dimensional principal component analysis, features are extracted from small patches of 128 x 128 pixels and classified by means of a SVM. Overall, the accuracy of the raw classification was 61.6 % and 52.1 % for the 12 and the 20 class problem, respectively. The confusion matrices are assessed for detailed analysis. Furthermore, an implementation of a SVM-based CBIR system for CADx in screening mammography is presented. In conclusion, with a smarter patch extraction, the CBIR approach might reach precision rates that are helpful for the physicians. This, however, needs more comprehensive evaluation on clinical data.

  10. Computational screening of functionalized zinc porphyrins for dye sensitized solar cells

    DEFF Research Database (Denmark)

    Ørnsø, Kristian Baruël; García Lastra, Juan Maria; Thygesen, Kristian Sommer

    2013-01-01

    separation, and high output voltage. Here we demonstrate an extensive computational screening of zinc porphyrins functionalized with electron donating side groups and electron accepting anchoring groups. The trends in frontier energy levels versus side groups are analyzed and a no-loss DSSC level alignment...... quality is estimated. Out of the initial 1029 molecules, we find around 50 candidates with level alignment qualities within 5% of the optimal limit. We show that the level alignment of five zinc porphyrin dyes which were recently used in DSSCs with high efficiencies can be further improved by simple side......An efficient dye sensitized solar cell (DSSC) is one possible solution to meet the world's rapidly increasing energy demands and associated climate challenges. This requires inexpensive and stable dyes with well-positioned frontier energy levels for maximal solar absorption, efficient charge...

  11. Value of three-dimensional computed tomography in screening cerebral aneurysms

    Energy Technology Data Exchange (ETDEWEB)

    Yamaguchi, Tamaki; Sugiura, Yusuke; Suzuki, Atsushi; Yamagata, Yoshitaka [Hyogo Medical Coll. (Japan)

    1997-10-01

    We performed three-dimensional computed tomography (3D-CT) in 6 patients of cerebral aneurysm. Prior cerebral angiography showed a total of 17 aneurysms. 3D-CT alone detected 10 cerebral aneurysm (59%). It was possible to identify aneurysms larger than 10 mm even when located near the circle of Willis. It was difficult to identify aneurysms when smaller than 7 mm regardless of their location. 3D-CT was of limited value in detecting cerebral aneurysms, particularly when located near the circle of Willis with complex vascular network. As cases of oculomotor palsy may be caused by lesions other than cerebral aneurysm, we advocate that 3D-CT be performed after magnetic resonance imaging (MRI) in screening cases of suspected cerebral aneurysm. (author)

  12. Screening of photosynthetic pigments for herbicidal activity with a new computational molecular approach.

    Science.gov (United States)

    Krishnaraj, R Navanietha; Chandran, Saravanan; Pal, Parimal; Berchmans, Sheela

    2013-12-01

    There is an immense interest among the researchers to identify new herbicides which are effective against the herbs without affecting the environment. In this work, photosynthetic pigments are used as the ligands to predict their herbicidal activity. The enzyme 5-enolpyruvylshikimate-3-phosphate (EPSP) synthase is a good target for the herbicides. Homology modeling of the target enzyme is done using Modeler 9.11 and the model is validated. Docking studies were performed with AutoDock Vina algorithm to predict the binding of the natural pigments such as β-carotene, chlorophyll a, chlorophyll b, phycoerythrin and phycocyanin to the target. β-carotene, phycoerythrin and phycocyanin have higher binding energies indicating the herbicidal activity of the pigments. This work reports a procedure to screen herbicides with computational molecular approach. These pigments will serve as potential bioherbicides in the future.

  13. Computational screening of new inorganic materials for highly efficient solar energy conversion

    DEFF Research Database (Denmark)

    Kuhar, Korina

    2017-01-01

    in solar cells convert solar energy into electricity, and PC uses harvested energy to conduct chemical reactions, such as splitting water into oxygen and, more importantly, hydrogen, also known as the fuel of the future. Further progress in both PV and PC fields is mostly limited by the flaws in materials...... materials. In this work a high-throughput computational search for suitable absorbers for PV and PC applications is presented. A set of descriptors has been developed, such that each descriptor targets an important property or issue of a good solar energy conversion material. The screening study...... that we have access to. Despite the vast amounts of energy at our disposal, we are not able to harvest this solar energy efficiently. Currently, there are a few ways of converting solar power into usable energy, such as photovoltaics (PV) or photoelectrochemical generation of fuels (PC). PV processes...

  14. Temporal analysis of laser beam propagation in the atmosphere using computer-generated long phase screens.

    Science.gov (United States)

    Dios, Federico; Recolons, Jaume; Rodríguez, Alejandro; Batet, Oscar

    2008-02-04

    Temporal analysis of the irradiance at the detector plane is intended as the first step in the study of the mean fade time in a free optical communication system. In the present work this analysis has been performed for a Gaussian laser beam propagating in the atmospheric turbulence by means of computer simulation. To this end, we have adapted a previously known numerical method to the generation of long phase screens. The screens are displaced in a transverse direction as the wave is propagated, in order to simulate the wind effect. The amplitude of the temporal covariance and its power spectrum have been obtained at the optical axis, at the beam centroid and at a certain distance from these two points. Results have been worked out for weak, moderate and strong turbulence regimes and when possible they have been compared with theoretical models. These results show a significant contribution of beam wander to the temporal behaviour of the irradiance, even in the case of weak turbulence. We have also found that the spectral bandwidth of the covariance is hardly dependent on the Rytov variance.

  15. A New Screening Methodology for Improved Oil Recovery Processes Using Soft-Computing Techniques

    Science.gov (United States)

    Parada, Claudia; Ertekin, Turgay

    2010-05-01

    The first stage of production of any oil reservoir involves oil displacement by natural drive mechanisms such as solution gas drive, gas cap drive and gravity drainage. Typically, improved oil recovery (IOR) methods are applied to oil reservoirs that have been depleted naturally. In more recent years, IOR techniques are applied to reservoirs even before their natural energy drive is exhausted by primary depletion. Descriptive screening criteria for IOR methods are used to select the appropriate recovery technique according to the fluid and rock properties. This methodology helps in assessing the most suitable recovery process for field deployment of a candidate reservoir. However, the already published screening guidelines neither provide information about the expected reservoir performance nor suggest a set of project design parameters, which can be used towards the optimization of the process. In this study, artificial neural networks (ANN) are used to build a high-performance neuro-simulation tool for screening different improved oil recovery techniques: miscible injection (CO2 and N2), waterflooding and steam injection processes. The simulation tool consists of proxy models that implement a multilayer cascade feedforward back propagation network algorithm. The tool is intended to narrow the ranges of possible scenarios to be modeled using conventional simulation, reducing the extensive time and energy spent in dynamic reservoir modeling. A commercial reservoir simulator is used to generate the data to train and validate the artificial neural networks. The proxy models are built considering four different well patterns with different well operating conditions as the field design parameters. Different expert systems are developed for each well pattern. The screening networks predict oil production rate and cumulative oil production profiles for a given set of rock and fluid properties, and design parameters. The results of this study show that the networks are

  16. Development and Usability Testing of a Computer-Tailored Decision Support Tool for Lung Cancer Screening: Study Protocol.

    Science.gov (United States)

    Carter-Harris, Lisa; Comer, Robert Skipworth; Goyal, Anurag; Vode, Emilee Christine; Hanna, Nasser; Ceppa, DuyKhanh; Rawl, Susan M

    2017-11-16

    Awareness of lung cancer screening remains low in the screening-eligible population, and when patients visit their clinician never having heard of lung cancer screening, engaging in shared decision making to arrive at an informed decision can be a challenge. Therefore, methods to effectively support both patients and clinicians to engage in these important discussions are essential. To facilitate shared decision making about lung cancer screening, effective methods to prepare patients to have these important discussions with their clinician are needed. Our objective is to develop a computer-tailored decision support tool that meets the certification criteria of the International Patient Decision Aid Standards instrument version 4.0 that will support shared decision making in lung cancer screening decisions. Using a 3-phase process, we will develop and test a prototype of a computer-tailored decision support tool in a sample of lung cancer screening-eligible individuals. In phase I, we assembled a community advisory board comprising 10 screening-eligible individuals to develop the prototype. In phase II, we recruited a sample of 13 screening-eligible individuals to test the prototype for usability, acceptability, and satisfaction. In phase III, we are conducting a pilot randomized controlled trial (RCT) with 60 screening-eligible participants who have never been screened for lung cancer. Outcomes tested include lung cancer and screening knowledge, lung cancer screening health beliefs (perceived risk, perceived benefits, perceived barriers, and self-efficacy), perception of being prepared to engage in a patient-clinician discussion about lung cancer screening, occurrence of a patient-clinician discussion about lung cancer screening, and stage of adoption for lung cancer screening. Phases I and II are complete. Phase III is underway. As of July 15, 2017, 60 participants have been enrolled into the study, and have completed the baseline survey, intervention, and first

  17. International Association for the Study of Lung Cancer Computed Tomography Screening Workshop 2011 report

    DEFF Research Database (Denmark)

    Field, John K; Smith, Robert A; Aberle, Denise R

    2011-01-01

    national screening programs; (iii) develop guidelines for the clinical work-up of "indeterminate nodules" resulting from CT screening programmers; (iv) guidelines for pathology reporting of nodules from lung cancer CT screening programs; (v) recommendations for surgical and therapeutic interventions...... of suspicious nodules identified through lung cancer CT screening programs; and (vi) integration of smoking cessation practices into future national lung cancer CT screening programs....

  18. Image processing algorithm of computer-aided diagnosis in lung cancer screening by CT

    International Nuclear Information System (INIS)

    Yamamoto, Shinji

    2004-01-01

    In this paper, an image processing algorithm for computer-aided diagnosis of lung cancer by X-ray CT is described, which has been developed by my research group for these 10 years or so. CT lung images gathered at the mass screening stage are almost all normal, and lung cancer nodules will be found as the rate of less than 10%. To pick up such a very rare nodules with the high accuracy, a very sensitive detection algorithm is requested which is detectable local and very slight variation of the image. On the contrary, such a sensitive detection algorithm introduces a bad effect that a lot of normal shadows will be detected as abnormal shadows. In this paper I describe how to compromise this complicated subject and realize a practical computer-aided diagnosis tool by the image processing algorithm developed by my research group. Especially, I will mainly focus my description to the principle and characteristics of the Quoit filter which is newly developed as a high sensitive filter by my group. (author)

  19. Toward clinically usable CAD for lung cancer screening with computed tomography

    Energy Technology Data Exchange (ETDEWEB)

    Brown, Matthew S.; Lo, Pechin; Goldin, Jonathan G.; Barnoy, Eran; Kim, Grace Hyun J.; McNitt-Gray, Michael F.; Aberle, Denise R. [David Geffen School of Medicine at UCLA, Center for Computer Vision and Imaging Biomarkers, Department of Radiological Sciences, Los Angeles, CA (United States)

    2014-11-15

    The purpose of this study was to define clinically appropriate, computer-aided lung nodule detection (CAD) requirements and protocols based on recent screening trials. In the following paper, we describe a CAD evaluation methodology based on a publically available, annotated computed tomography (CT) image data set, and demonstrate the evaluation of a new CAD system with the functionality and performance required for adoption in clinical practice. A new automated lung nodule detection and measurement system was developed that incorporates intensity thresholding, a Euclidean Distance Transformation, and segmentation based on watersheds. System performance was evaluated against the Lung Imaging Database Consortium (LIDC) CT reference data set. The test set comprised thin-section CT scans from 108 LIDC subjects. The median (±IQR) sensitivity per subject was 100 (±37.5) for nodules ≥ 4 mm and 100 (±8.33) for nodules ≥ 8 mm. The corresponding false positive rates were 0 (±2.0) and 0 (±1.0), respectively. The concordance correlation coefficient between the CAD nodule diameter and the LIDC reference was 0.91, and for volume it was 0.90. The new CAD system shows high nodule sensitivity with a low false positive rate. Automated volume measurements have strong agreement with the reference standard. Thus, it provides comprehensive, clinically-usable lung nodule detection and assessment functionality. (orig.)

  20. Toward clinically usable CAD for lung cancer screening with computed tomography

    International Nuclear Information System (INIS)

    Brown, Matthew S.; Lo, Pechin; Goldin, Jonathan G.; Barnoy, Eran; Kim, Grace Hyun J.; McNitt-Gray, Michael F.; Aberle, Denise R.

    2014-01-01

    The purpose of this study was to define clinically appropriate, computer-aided lung nodule detection (CAD) requirements and protocols based on recent screening trials. In the following paper, we describe a CAD evaluation methodology based on a publically available, annotated computed tomography (CT) image data set, and demonstrate the evaluation of a new CAD system with the functionality and performance required for adoption in clinical practice. A new automated lung nodule detection and measurement system was developed that incorporates intensity thresholding, a Euclidean Distance Transformation, and segmentation based on watersheds. System performance was evaluated against the Lung Imaging Database Consortium (LIDC) CT reference data set. The test set comprised thin-section CT scans from 108 LIDC subjects. The median (±IQR) sensitivity per subject was 100 (±37.5) for nodules ≥ 4 mm and 100 (±8.33) for nodules ≥ 8 mm. The corresponding false positive rates were 0 (±2.0) and 0 (±1.0), respectively. The concordance correlation coefficient between the CAD nodule diameter and the LIDC reference was 0.91, and for volume it was 0.90. The new CAD system shows high nodule sensitivity with a low false positive rate. Automated volume measurements have strong agreement with the reference standard. Thus, it provides comprehensive, clinically-usable lung nodule detection and assessment functionality. (orig.)

  1. A database for CO2 Separation Performances of MOFs based on Computational Materials Screening.

    Science.gov (United States)

    Altintas, Cigdem; Avci, Gokay; Daglar, Hilal; Nemati Vesali Azar, Ayda; Velioglu, Sadiye; Erucar, Ilknur; Keskin, Seda

    2018-05-03

    Metal organic frameworks (MOFs) have been considered as great candidates for CO2 capture. Considering the very large number of available MOFs, high-throughput computational screening plays a critical role in identifying the top performing materials for target applications in a time-effective manner. In this work, we used molecular simulations to screen the most recent and complete MOF database for identifying the most promising materials for CO2 separation from flue gas (CO2/N2) and landfill gas (CO2/CH4) under realistic operating conditions. We first validated our approach by comparing the results of our molecular simulations for the CO2 uptakes, CO2/N2 and CO2/CH4 selectivities of various types of MOFs with the available experimental data. We then computed binary CO2/N2 and CO2/CH4 mixture adsorption data for the entire MOF database and used these results to calculate several adsorbent selection metrics such as selectivity, working capacity, adsorbent performance score, regenerability, and separation potential. MOFs were ranked based on the combination of these metrics and the top performing MOF adsorbents that can achieve CO2/N2 and CO2/CH4 separations with high performance were identified. Molecular simulations for the adsorption of a ternary CO2/N2/CH4 mixture were performed for these top materials in order to provide a more realistic performance assessment of MOF adsorbents. Structure-performance analysis showed that MOFs with ΔQ>30 kJ/mol, 3.8 A≤PLD≤5 A, 5 A≤LCD≤7.5 A, 0.5≤ϕ≤0.75, SA≤1,000 m2/g, ρ>1 g/cm 3 are the best candidates for selective separation of CO2 from flue gas and landfill gas. This information will be very useful to design novel MOFs with the desired structural features that can lead to high CO2 separation potentials. Finally, an online, freely accessible database https://cosmoserc.ku.edu.tr was established, for the first time in the literature, which reports all computed adsorbent metrics of 3,816 MOFs for CO2/N2, CO2/CH4

  2. Resource utilization and costs during the initial years of lung cancer screening with computed tomography in Canada.

    Science.gov (United States)

    Cressman, Sonya; Lam, Stephen; Tammemagi, Martin C; Evans, William K; Leighl, Natasha B; Regier, Dean A; Bolbocean, Corneliu; Shepherd, Frances A; Tsao, Ming-Sound; Manos, Daria; Liu, Geoffrey; Atkar-Khattra, Sukhinder; Cromwell, Ian; Johnston, Michael R; Mayo, John R; McWilliams, Annette; Couture, Christian; English, John C; Goffin, John; Hwang, David M; Puksa, Serge; Roberts, Heidi; Tremblay, Alain; MacEachern, Paul; Burrowes, Paul; Bhatia, Rick; Finley, Richard J; Goss, Glenwood D; Nicholas, Garth; Seely, Jean M; Sekhon, Harmanjatinder S; Yee, John; Amjadi, Kayvan; Cutz, Jean-Claude; Ionescu, Diana N; Yasufuku, Kazuhiro; Martel, Simon; Soghrati, Kamyar; Sin, Don D; Tan, Wan C; Urbanski, Stefan; Xu, Zhaolin; Peacock, Stuart J

    2014-10-01

    It is estimated that millions of North Americans would qualify for lung cancer screening and that billions of dollars of national health expenditures would be required to support population-based computed tomography lung cancer screening programs. The decision to implement such programs should be informed by data on resource utilization and costs. Resource utilization data were collected prospectively from 2059 participants in the Pan-Canadian Early Detection of Lung Cancer Study using low-dose computed tomography (LDCT). Participants who had 2% or greater lung cancer risk over 3 years using a risk prediction tool were recruited from seven major cities across Canada. A cost analysis was conducted from the Canadian public payer's perspective for resources that were used for the screening and treatment of lung cancer in the initial years of the study. The average per-person cost for screening individuals with LDCT was $453 (95% confidence interval [CI], $400-$505) for the initial 18-months of screening following a baseline scan. The screening costs were highly dependent on the detected lung nodule size, presence of cancer, screening intervention, and the screening center. The mean per-person cost of treating lung cancer with curative surgery was $33,344 (95% CI, $31,553-$34,935) over 2 years. This was lower than the cost of treating advanced-stage lung cancer with chemotherapy, radiotherapy, or supportive care alone, ($47,792; 95% CI, $43,254-$52,200; p = 0.061). In the Pan-Canadian study, the average cost to screen individuals with a high risk for developing lung cancer using LDCT and the average initial cost of curative intent treatment were lower than the average per-person cost of treating advanced stage lung cancer which infrequently results in a cure.

  3. Service Discovery At Home

    NARCIS (Netherlands)

    Sundramoorthy, V.; Scholten, Johan; Jansen, P.G.; Hartel, Pieter H.

    Service discovery is a fady new field that kicked off since the advent of ubiquitous computing and has been found essential in the making of intelligent networks by implementing automated discovery and remote control between deviies. This paper provides an ovewiew and comparison of several prominent

  4. Service discovery at home

    NARCIS (Netherlands)

    Sundramoorthy, V.; Scholten, Johan; Jansen, P.G.; Hartel, Pieter H.

    2003-01-01

    Service discovery is a fairly new field that kicked off since the advent of ubiquitous computing and has been found essential in the making of intelligent networks by implementing automated discovery and remote control between devices. This paper provides an overview and comparison of several

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

    International Nuclear Information System (INIS)

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

    2004-01-01

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

  6. Usability testing of a respiratory interface using computer screen and facial expressions videos.

    Science.gov (United States)

    Oliveira, Ana; Pinho, Cátia; Monteiro, Sandra; Marcos, Ana; Marques, Alda

    2013-12-01

    Computer screen videos (CSVs) and users' facial expressions videos (FEVs) are recommended to evaluate systems performance. However, software combining both methods is often non-accessible in clinical research fields. The Observer-XT software is commonly used for clinical research to assess human behaviours. Thus, this study reports on the combination of CSVs and FEVs, to evaluate a graphical user interface (GUI). Eight physiotherapists entered clinical information in the GUI while CSVs and FEVs were collected. The frequency and duration of a list of behaviours found in FEVs were analysed using the Observer-XT-10.5. Simultaneously, the frequency and duration of usability problems of CSVs were manually registered. CSVs and FEVs timelines were also matched to verify combinations. The analysis of FEVs revealed that the category most frequently observed in users behaviour was the eye contact with the screen (ECS, 32±9) whilst verbal communication achieved the highest duration (14.8±6.9min). Regarding the CSVs, 64 problems, related with the interface (73%) and the user (27%), were found. In total, 135 usability problems were identified by combining both methods. The majority were reported through verbal communication (45.8%) and ECS (40.8%). "False alarms" and "misses" did not cause quantifiable reactions and the facial expressions problems were mainly related with the lack of familiarity (55.4%) felt by users when interacting with the interface. These findings encourage the use of Observer-XT-10.5 to conduct small usability sessions, as it identifies emergent groups of problems by combining methods. However, to validate final versions of systems further validation should be conducted using specialized software. © 2013 Published by Elsevier Ltd.

  7. The Study of Learners' Preference for Visual Complexity on Small Screens of Mobile Computers Using Neural Networks

    Science.gov (United States)

    Wang, Lan-Ting; Lee, Kun-Chou

    2014-01-01

    The vision plays an important role in educational technologies because it can produce and communicate quite important functions in teaching and learning. In this paper, learners' preference for the visual complexity on small screens of mobile computers is studied by neural networks. The visual complexity in this study is divided into five…

  8. Improving computer-aided detection assistance in breast cancer screening by removal of obviously false-positive findings

    NARCIS (Netherlands)

    Mordang, Jan-Jurre; Gubern-Merida, Albert; Bria, Alessandro; Tortorella, Francesco; den Heeten, Gerard; Karssemeijer, Nico

    2017-01-01

    Purpose: Computer-aided detection (CADe) systems for mammography screening still mark many false positives. This can cause radiologists to lose confidence in CADe, especially when many false positives are obviously not suspicious to them. In this study, we focus on obvious false positives generated

  9. Improving computer-aided detection assistance in breast cancer screening by removal of obviously false-positive findings

    NARCIS (Netherlands)

    Mordang, J.J.; Gubern Merida, A.; Bria, A.; Tortorella, F.; Heeten, G.; Karssemeijer, N.

    2017-01-01

    PURPOSE: Computer-aided detection (CADe) systems for mammography screening still mark many false positives. This can cause radiologists to lose confidence in CADe, especially when many false positives are obviously not suspicious to them. In this study, we focus on obvious false positives generated

  10. Density functional theory based screening of ternary alkali-transition metal borohydrides: A computational material design project

    DEFF Research Database (Denmark)

    Hummelshøj, Jens Strabo; Landis, David; Voss, Johannes

    2009-01-01

    We present a computational screening study of ternary metal borohydrides for reversible hydrogen storage based on density functional theory. We investigate the stability and decomposition of alloys containing 1 alkali metal atom, Li, Na, or K (M1); and 1 alkali, alkaline earth or 3d/4d transition...

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

    Science.gov (United States)

    Chakraborty, Sandipan; Ramachandran, Balaji; Basu, Soumalee

    2014-10-01

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

  12. Fighting obesity with a sugar-based library: discovery of novel MCH-1R antagonists by a new computational-VAST approach for exploration of GPCR binding sites.

    Science.gov (United States)

    Heifetz, Alexander; Barker, Oliver; Verquin, Geraldine; Wimmer, Norbert; Meutermans, Wim; Pal, Sandeep; Law, Richard J; Whittaker, Mark

    2013-05-24

    Obesity is an increasingly common disease. While antagonism of the melanin-concentrating hormone-1 receptor (MCH-1R) has been widely reported as a promising therapeutic avenue for obesity treatment, no MCH-1R antagonists have reached the market. Discovery and optimization of new chemical matter targeting MCH-1R is hindered by reduced HTS success rates and a lack of structural information about the MCH-1R binding site. X-ray crystallography and NMR, the major experimental sources of structural information, are very slow processes for membrane proteins and are not currently feasible for every GPCR or GPCR-ligand complex. This situation significantly limits the ability of these methods to impact the drug discovery process for GPCR targets in "real-time", and hence, there is an urgent need for other practical and cost-efficient alternatives. We present here a conceptually pioneering approach that integrates GPCR modeling with design, synthesis, and screening of a diverse library of sugar-based compounds from the VAST technology (versatile assembly on stable templates) to provide structural insights on the MCH-1R binding site. This approach creates a cost-efficient new avenue for structure-based drug discovery (SBDD) against GPCR targets. In our work, a primary VAST hit was used to construct a high-quality MCH-1R model. Following model validation, a structure-based virtual screen yielded a 14% hit rate and 10 novel chemotypes of potent MCH-1R antagonists, including EOAI3367472 (IC50 = 131 nM) and EOAI3367474 (IC50 = 213 nM).

  13. Predicting Structures of Ru-Centered Dyes: A Computational Screening Tool.

    Science.gov (United States)

    Fredin, Lisa A; Allison, Thomas C

    2016-04-07

    Dye-sensitized solar cells (DSCs) represent a means for harvesting solar energy to produce electrical power. Though a number of light harvesting dyes are in use, the search continues for more efficient and effective compounds to make commercially viable DSCs a reality. Computational methods have been increasingly applied to understand the dyes currently in use and to aid in the search for improved light harvesting compounds. Semiempirical quantum chemistry methods have a well-deserved reputation for giving good quality results in a very short amount of computer time. The most recent semiempirical models such as PM6 and PM7 are parametrized for a wide variety of molecule types, including organometallic complexes similar to DSC chromophores. In this article, the performance of PM6 is tested against a set of 20 molecules whose geometries were optimized using a density functional theory (DFT) method. It is found that PM6 gives geometries that are in good agreement with the optimized DFT structures. In order to reduce the differences between geometries optimized using PM6 and geometries optimized using DFT, the PM6 basis set parameters have been optimized for a subset of the molecules. It is found that it is sufficient to optimize the basis set for Ru alone to improve the agreement between the PM6 results and the DFT results. When this optimized Ru basis set is used, the mean unsigned error in Ru-ligand bond lengths is reduced from 0.043 to 0.017 Å in the set of 20 test molecules. Though the magnitude of these differences is small, the effect on the calculated UV/vis spectra is significant. These results clearly demonstrate the value of using PM6 to screen DSC chromophores as well as the value of optimizing PM6 basis set parameters for a specific set of molecules.

  14. A Comparison between Effect of Viewing Text on Computer Screen and iPad® on Visual Symptoms and Functions

    Directory of Open Access Journals (Sweden)

    Pittaya Phamonvaechavan

    2017-07-01

    Full Text Available Objective: To compare the ocular symptoms following sustained near vision between laptop computer and iPad®. Methods: Forty normal subjects read text from a laptop computer screen and an iPad® screen for a continuous 20 min period. Similar text was used in both sessions, which was matched for size and contrast. After finishing viewing text, subjects immediately completed a written questionnaire categorizing symptom scores into three groups: Dry eye, Pain and Blurred vision score. The accommodative amplitude and fusional convergence amplitude at near vision were also assessed before and after reading. Results: In both conditions, mean symptom scores were higher during iPad use. When comparing the computer and iPad conditions, mean scores were statistically significant different in Pain score (6.30 vs 8.70; p=0.025 and Blurred vision score (10.13 vs 12.03; p=0.041 but no statistically significant difference in Dry eye score (6.30 vs 6.60; p=0.71. There were significant change in accommodative amplitude and fusional convergence amplitude with near vision when compared before and after near-vision tasks in both cases. Conclusion: Pain and Blurred vision symptoms following sustained iPad use were significantly worse than those reported after computer use under similar viewing conditions. However, both computer screen and iPad cause ocular symptoms having an impact on quality of life.

  15. Comparison of low contrast detectability of computed tomography and screen/film mammography systems

    International Nuclear Information System (INIS)

    Noriah Jamal; Kwan Hoong Ng; McLean, D.

    2006-01-01

    The objective of this study was to compare low contrast detectability of computed radiography (CR) and screen/film (SF) mammography systems. The Nijimegen contrast detail test object (CDMAM type 3.4) was imaged at 28 kV, in automatic exposure control mode separately. Six medical imaging physicists read each CDMAM phantom image. Contrast detail curves were plotted to compare low contrast detectability of CR (soft copy and hard copy) and SF mammography systems. Effect of varying exposure parameters, namely kV, object position inside the breast phantom, and entrance surface exposure (ESE) on the contrast detail curve were also investigated using soft copy CR. The significant of the difference of contrast between CR and SF, and for each exposure parameter was tested using non-parametric Kruskal-Wallis test. We found that the low contrast detectability of CR (soft copy and hard copy) system is not significantly different to that of SF system (p>0.05, Kruskal-Wallis test). For CR soft copy, no significant relationship (p>0.05, Kruskal-Wallis test) was seen for variation of kV, object position inside the breast phantom and ESE. This indicates that CR is comparable with SF for useful detection and visualization of low contrast objects such as small low contrast areas corresponding to breast pathology

  16. Comparison of low-contrast detectability of computed radiography and screen/ film mammography systems

    International Nuclear Information System (INIS)

    Noriah Jamal; Kwan-Hoong Ng; McLean, D.; McLean, D.

    2008-01-01

    The objective of this study is to compare low-contrast detectability of computed radiography (CR) and screen/ film (SF) mammography systems. The Nijimegen contrast detail test object (CDMAM type 3.4) was imaged at 28 kV, in automatic exposure control mode separately. Six medical imaging physicists read each CDMAM phantom image. Contrast detail curves were plotted to compare low-contrast detectability of CR (soft copy and hard copy) and SF mammography systems. Effect of varying exposure parameters, namely kV, object position inside the breast phantom, and entrance surface exposure (ESE) on the contrast detail curve were also investigated using soft copy CR. The significance of the difference in contrast between CR and SF, and for each exposure parameter, was tested using non-parametric Kruskal-Wallis test. The low-contrast detectability of the CR (soft copy and hard copy) system was found to be not significantly different to that of the SF system (p> 0.05, Kruskal-Wallis test).For CR soft copy, no significant relationship (p>0.05, Kruskal-Wallis test) was seen for variation of kV, object position inside the breast phantom and ESE. This indicates that CR is comparable with SF for useful detection and visualization of low-contrast objects such as small low-contrast areas corresponding to breast pathology. (Author)

  17. Computational Screening of MOF-Based Mixed Matrix Membranes for CO2/N2 Separations

    Directory of Open Access Journals (Sweden)

    Zeynep Sumer

    2016-01-01

    Full Text Available Atomically detailed simulations were used to examine CO2/N2 separation potential of metal organic framework- (MOF- based mixed matrix membranes (MMMs in this study. Gas permeability and selectivity of 700 new MMMs composed of 70 different MOFs and 10 different polymers were calculated for CO2/N2 separation. This is the largest number of MOF-based MMMs for which computational screening is done to date. Selecting the appropriate MOFs as filler particles in polymers resulted in MMMs that have higher CO2/N2 selectivities and higher CO2 permeabilities compared to pure polymer membranes. We showed that, for polymers that have low CO2 permeabilities but high CO2 selectivities, the identity of the MOF used as filler is not important. All MOFs enhanced the CO2 permeabilities of this type of polymers without changing their selectivities. Several MOF-based MMMs were identified to exceed the upper bound established for polymers. The methods we introduced in this study will create many opportunities to select the MOF/polymer combinations with useful properties for CO2 separation applications.

  18. Abdominal computed tomography scan as a screening tool in blunt trauma

    International Nuclear Information System (INIS)

    Brasel, K.J.; Borgstrom, D.C.; Kolewe, K.A.

    1997-01-01

    Background. One of the most difficult problems in blunt trauma is evaluation for potential intraabdominal injury. Admission for serial abdominal exams remains the standard of care after intraabdominal injury has been initially excluded. We hypothesized a normal abdominal computed tomography (CT) scan in a subgroup of minimally injured patients would obviate admission for serial abdominal examinations, allowing safe discharge from the emergency department (ED). Methods. We reviewed our blunt trauma experience with patients admitted solely for serial abdominal examinations after a normal CT. Patients were identified from the trauma registry at a Level 1 trauma center from July 1991 through June 1995. Patients with abnormal CTs, extra-abdominal injuries necessitating admission, hemodynamic abnormalities, a Glasgow Coma Scale less than 13, or injury severity scores (ISSs) greater than 15 were excluded. Records of 238 patients remained; we reviewed them to determine the presence of missed abdominal injury. Results. None of the 238 patients had a missed abdominal injury. Average ISS of these patients was 3.2 (range, 0 to 10). Discharging these patients from the ED would result in a yearly cost savings of $32,874 to our medical system. Conclusions. Abdominal CT scan is a safe and cost-effective screening tool in patients with blunt trauma. A normal CT scan in minimally injured patients allows safe discharge from the ED. (authors)

  19. Opportunistic screening for osteoporosis on routine computed tomography? An external validation study

    Energy Technology Data Exchange (ETDEWEB)

    Buckens, Constantinus F. [University Medical Center Utrecht, Department of Radiology, Utrecht (Netherlands); Universitair Medisch Centrum Utrecht, Department of Radiology, Utrecht (Netherlands); Dijkhuis, Gawein; Jong, Pim A. de [University Medical Center Utrecht, Department of Radiology, Utrecht (Netherlands); Keizer, Bart de [University Medical Center Utrecht, Department of Nuclear Medicine, Utrecht (Netherlands); Verhaar, Harald J. [University Medical Center Utrecht, Department of Geriatric Medicine, Utrecht (Netherlands)

    2015-07-15

    Opportunistic screening for osteoporosis using computed tomography (CT) examinations that happen to visualise the spine can be used to identify patients with osteoporosis. We sought to verify the diagnostic performance of vertebral Hounsfield unit (HU) measurements on routine CT examinations for diagnosing osteoporosis in a separate, external population. Consecutive patients who underwent a CT examination of the chest or abdomen and had also received a dual-energy X-ray absorptiometry (DXA) test were retrospectively included. CTs were evaluated for vertebral fractures and vertebral attenuation (density) values were measured. Diagnostic performance measures and the area under the receiver operator characteristics curve (AUC) for diagnosing osteoporosis were calculated. Three hundred and two patients with a mean age of 57.9 years were included, of which 82 (27 %) had osteoporosis according to DXA and 65 (22 %) had vertebral fractures. The diagnostic performance for vertebral HU measurements was modest, with a maximal AUC of 0.74 (0.68 - 0.80). At that optimal threshold the sensitivity was 62 % (51 - 72 %) and the specificity was 79 % (74 - 84 %). We confirmed that simple trabecular vertebral density measurements on routine CT contain diagnostic information related to bone mineral density as measured by DXA, albeit with substantially lower diagnostic accuracy than previously reported. (orig.)

  20. Opportunistic screening for osteoporosis on routine computed tomography? An external validation study

    International Nuclear Information System (INIS)

    Buckens, Constantinus F.; Dijkhuis, Gawein; Jong, Pim A. de; Keizer, Bart de; Verhaar, Harald J.

    2015-01-01

    Opportunistic screening for osteoporosis using computed tomography (CT) examinations that happen to visualise the spine can be used to identify patients with osteoporosis. We sought to verify the diagnostic performance of vertebral Hounsfield unit (HU) measurements on routine CT examinations for diagnosing osteoporosis in a separate, external population. Consecutive patients who underwent a CT examination of the chest or abdomen and had also received a dual-energy X-ray absorptiometry (DXA) test were retrospectively included. CTs were evaluated for vertebral fractures and vertebral attenuation (density) values were measured. Diagnostic performance measures and the area under the receiver operator characteristics curve (AUC) for diagnosing osteoporosis were calculated. Three hundred and two patients with a mean age of 57.9 years were included, of which 82 (27 %) had osteoporosis according to DXA and 65 (22 %) had vertebral fractures. The diagnostic performance for vertebral HU measurements was modest, with a maximal AUC of 0.74 (0.68 - 0.80). At that optimal threshold the sensitivity was 62 % (51 - 72 %) and the specificity was 79 % (74 - 84 %). We confirmed that simple trabecular vertebral density measurements on routine CT contain diagnostic information related to bone mineral density as measured by DXA, albeit with substantially lower diagnostic accuracy than previously reported. (orig.)

  1. Evaluation of the potential benefit of computer-aided diagnosis (CAD) for lung cancer screening using photofluorography

    International Nuclear Information System (INIS)

    Matsumoto, Tsuneo; Nakamura, Hiroshi; Nakanishi, Takashi; Doi, Kunio; Kano, Akiko.

    1993-01-01

    To evaluate the potential benefit of computer-aided diagnosis (CAD) in lung cancer screenings using photofluorographic films, we performed an observer test with 12 radiologists. We used 60 photofluorographic films obtained from a lung cancer screening program in Yamaguchi Prefecture (30 contained cancerous nodules and 30 had no nodules). In these cases, our current automated detection scheme achieved a sensitivity of 80%, but yielded an average of 11 false-positives per image. The observer study consisted of three viewing conditions: 1) only the original image (single reading), 2) the original image and computer output obtained from the current CAD scheme (CAD 1), 3) the original image and computer output obtained from a simulated improved CAD scheme with the same 80% true-positive rate, but with an average of one false-positive per image (CAD 2). Compared with double reading using independent interpretations, which is based on a higher score between two single readings, CAD 2 was more sensitive in subtle cases. The specificity of CAD was superior to that of double reading. Although CAD 1 (Az=0.805) was inferior to double reading (Az=0.837) in terms of the ROC curve, CAD 2 (Az=0.872) significantly improved the ROC curve and also significantly reduced observation time (p<0.05). If the number of false positives can be reduced, computer-aided diagnosis may play an important role in lung cancer screening programs. (author)

  2. Computer/Mobile Device Screen Time of Children and Their Eye Care Behavior: The Roles of Risk Perception and Parenting.

    Science.gov (United States)

    Chang, Fong-Ching; Chiu, Chiung-Hui; Chen, Ping-Hung; Miao, Nae-Fang; Chiang, Jeng-Tung; Chuang, Hung-Yi

    2018-03-01

    This study assessed the computer/mobile device screen time and eye care behavior of children and examined the roles of risk perception and parental practices. Data were obtained from a sample of 2,454 child-parent dyads recruited from 30 primary schools in Taipei city and New Taipei city, Taiwan, in 2016. Self-administered questionnaires were collected from students and parents. Fifth-grade students spend more time on new media (computer/smartphone/tablet: 16 hours a week) than on traditional media (television: 10 hours a week). The average daily screen time (3.5 hours) for these children exceeded the American Academy of Pediatrics recommendations (≤2 hours). Multivariate analysis results showed that after controlling for demographic factors, the parents with higher levels of risk perception and parental efficacy were more likely to mediate their child's eye care behavior. Children who reported lower academic performance, who were from non-intact families, reported lower levels of risk perception of mobile device use, had parents who spent more time using computers and mobile devices, and had lower levels of parental mediation were more likely to spend more time using computers and mobile devices; whereas children who reported higher academic performance, higher levels of risk perception, and higher levels of parental mediation were more likely to engage in higher levels of eye care behavior. Risk perception by children and parental practices are associated with the amount of screen time that children regularly engage in and their level of eye care behavior.

  3. Development of a computer-based automated pure tone hearing screening device: a preliminary clinical trial.

    Science.gov (United States)

    Gan, Kok Beng; Azeez, Dhifaf; Umat, Cila; Ali, Mohd Alauddin Mohd; Wahab, Noor Alaudin Abdul; Mukari, Siti Zamratol Mai-Sarah

    2012-10-01

    Hearing screening is important for the early detection of hearing loss. The requirements of specialized equipment, skilled personnel, and quiet environments for valid screening results limit its application in schools and health clinics. This study aimed to develop an automated hearing screening kit (auto-kit) with the capability of realtime noise level monitoring to ensure that the screening is performed in an environment that conforms to the standard. The auto-kit consists of a laptop, a 24-bit resolution sound card, headphones, a microphone, and a graphical user interface, which is calibrated according to the American National Standards Institute S3.6-2004 standard. The auto-kit can present four test tones (500, 1000, 2000, and 4000 Hz) at 25 or 40 dB HL screening cut-off level. The clinical results at 40 dB HL screening cut-off level showed that the auto-kit has a sensitivity of 92.5% and a specificity of 75.0%. Because the 500 Hz test tone is not included in the standard hearing screening procedure, it can be excluded from the auto-kit test procedure. The exclusion of 500 Hz test tone improved the specificity of the auto-kit from 75.0% to 92.3%, which suggests that the auto-kit could be a valid hearing screening device. In conclusion, the auto-kit may be a valuable hearing screening tool, especially in countries where resources are limited.

  4. Comparison of digital tomosynthesis and computed tomography for lung nodule detection in SOS screening program.

    Science.gov (United States)

    Grosso, Maurizio; Priotto, Roberto; Ghirardo, Donatella; Talenti, Alberto; Roberto, Emanuele; Bertolaccini, Luca; Terzi, Alberto; Chauvie, Stéphane

    2017-08-01

    To compare the lung nodules' detection of digital tomosynthesis (DTS) and computed tomography (CT) in the context of the SOS (Studio OSservazionale) prospective screening program for lung cancer detection. One hundred and thirty-two of the 1843 subjects enrolled in the SOS study underwent CT because non-calcified nodules with diameters larger than 5 mm and/or multiple nodules were present in DTS. Two expert radiologists reviewed the exams classifying the nodules based on their radiological appearance and their dimension. LUNG-RADS classification was applied to compare receiver operator characteristics curve between CT and DTS with respect to final diagnosis. CT was used as gold standard. DTS and CT detected 208 and 179 nodules in the 132 subjects, respectively. Of these 208 nodules, 189 (91%) were solid, partially solid, and ground glass opacity. CT confirmed 140/189 (74%) of these nodules but found 4 nodules that were not detected by DTS. DTS and CT were concordant in 62% of the cases applying the 5-point LUNG-RADS scale. The concordance rose to 86% on a suspicious/non-suspicious binary scale. The areas under the curve in receiver operator characteristics were 0.89 (95% CI 0.83-0.94) and 0.80 (95% CI 0.72-0.89) for CT and DTS, respectively. The mean effective dose was 0.09 ± 0.04 mSv for DTS and 4.90 ± 1.20 mSv for CT. The use of a common classification for nodule detection in DTS and CT helps in comparing the two technologies. DTS detected and correctly classified 74% of the nodules seen by CT but lost 4 nodules identified by CT. Concordance between DTS and CT rose to 86% of the nodules when considering LUNG-RADS on a binary scale.

  5. The interplay of attention economics and computer-aided detection marks in screening mammography

    Science.gov (United States)

    Schwartz, Tayler M.; Sridharan, Radhika; Wei, Wei; Lukyanchenko, Olga; Geiser, William; Whitman, Gary J.; Haygood, Tamara Miner

    2016-03-01

    Introduction: According to attention economists, overabundant information leads to decreased attention for individual pieces of information. Computer-aided detection (CAD) alerts radiologists to findings potentially associated with breast cancer but is notorious for creating an abundance of false-positive marks. We suspected that increased CAD marks do not lengthen mammogram interpretation time, as radiologists will selectively disregard these marks when present in larger numbers. We explore the relevance of attention economics in mammography by examining how the number of CAD marks affects interpretation time. Methods: We performed a retrospective review of bilateral digital screening mammograms obtained between January 1, 2011 and February 28, 2014, using only weekend interpretations to decrease distractions and the likelihood of trainee participation. We stratified data according to reader and used ANOVA to assess the relationship between number of CAD marks and interpretation time. Results: Ten radiologists, with median experience after residency of 12.5 years (range 6 to 24,) interpreted 1849 mammograms. When accounting for number of images, Breast Imaging Reporting and Data System category, and breast density, increasing numbers of CAD marks was correlated with longer interpretation time only for the three radiologists with the fewest years of experience (median 7 years.) Conclusion: For the 7 most experienced readers, increasing CAD marks did not lengthen interpretation time. We surmise that as CAD marks increase, the attention given to individual marks decreases. Experienced radiologists may rapidly dismiss larger numbers of CAD marks as false-positive, having learned that devoting extra attention to such marks does not improve clinical detection.

  6. Scientific Grand Challenges: Discovery In Basic Energy Sciences: The Role of Computing at the Extreme Scale - August 13-15, 2009, Washington, D.C.

    Energy Technology Data Exchange (ETDEWEB)

    Galli, Giulia [Univ. of California, Davis, CA (United States). Workshop Chair; Dunning, Thom [Univ. of Illinois, Urbana, IL (United States). Workshop Chair

    2009-08-13

    The U.S. Department of Energy’s (DOE) Office of Basic Energy Sciences (BES) and Office of Advanced Scientific Computing Research (ASCR) workshop in August 2009 on extreme-scale computing provided a forum for more than 130 researchers to explore the needs and opportunities that will arise due to expected dramatic advances in computing power over the next decade. This scientific community firmly believes that the development of advanced theoretical tools within chemistry, physics, and materials science—combined with the development of efficient computational techniques and algorithms—has the potential to revolutionize the discovery process for materials and molecules with desirable properties. Doing so is necessary to meet the energy and environmental challenges of the 21st century as described in various DOE BES Basic Research Needs reports. Furthermore, computational modeling and simulation are a crucial complement to experimental studies, particularly when quantum mechanical processes controlling energy production, transformations, and storage are not directly observable and/or controllable. Many processes related to the Earth’s climate and subsurface need better modeling capabilities at the molecular level, which will be enabled by extreme-scale computing.

  7. Computational fragment-based screening using RosettaLigand: the SAMPL3 challenge

    Science.gov (United States)

    Kumar, Ashutosh; Zhang, Kam Y. J.

    2012-05-01

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

  8. Implementing a computer-assisted telephone interview (CATI) system to increase colorectal cancer screening: a process evaluation.

    Science.gov (United States)

    White, Mary Jo; Stark, Jennifer R; Luckmann, Roger; Rosal, Milagros C; Clemow, Lynn; Costanza, Mary E

    2006-06-01

    Computer-assisted telephone interviewing (CATI) systems used by telephone counselors (TCs) may be efficient mechanisms to counsel patients on cancer and recommended preventive screening tests in order to extend a primary care provider's reach to his/her patients. The implementation process of such a system for promoting colorectal (CRC) cancer screening using a computer-assisted telephone interview (CATI) system is reported in this paper. The process evaluation assessed three components of the intervention: message production, program implementation and audience reception. Of 1181 potentially eligible patients, 1025 (87%) patients were reached by the TCs and 725 of those patients (71%) were eligible to receive counseling. Five hundred eighty-two (80%) patients agreed to counseling. It is feasible to design and use CATI systems for prevention counseling of patients in primary care practices. CATI systems have the potential of being used as a referral service by primary care providers and health care organizations for patient education.

  9. A computer-tailored intervention to promote informed decision making for prostate cancer screening among African-American men

    Science.gov (United States)

    Allen, Jennifer D.; Mohllajee, Anshu P.; Shelton, Rachel C.; Drake, Bettina F.; Mars, Dana R.

    2010-01-01

    African-American men experience a disproportionate burden of prostate cancer (CaP) morbidity and mortality. National screening guidelines advise men to make individualized screening decisions through a process termed “informed decision making” (IDM). In this pilot study, a computer-tailored decision-aid designed to promote IDM was evaluated using a pre/post test design. African-American men aged 40+ recruited from a variety of community settings (n=108). At pre-test, 43% of men reported having made a screening decision; at post-test 47% reported this to be the case (p=0.39). Significant improvements were observed on scores (0–100%) of knowledge (54% vs 72%; pMen were also more likely to want an active role in decision-making after using the tool (67% vs 75%; p=0.03). These results suggest that use of a computer-tailored decision-aid is a promising strategy to promote IDM for CaP screening among African-American men. PMID:19477736

  10. Cost-effectiveness of computed tomography colonography in colorectal cancer screening: a systematic review.

    Science.gov (United States)

    Hanly, Paul; Skally, Mairead; Fenlon, Helen; Sharp, Linda

    2012-10-01

    The European Code Against Cancer recommends individuals aged ≥ 50 should participate in colorectal cancer screening. CT-colonography (CTC) is one of several screening tests available. We systematically reviewed evidence on, and identified key factors influencing, cost-effectiveness of CTC screening. PubMed, Medline, and the Cochrane library were searched for cost-effectiveness or cost-utility analyses of CTC-based screening, published in English, January 1999 to July 2010. Data was abstracted on setting, model type and horizon, screening scenario(s), comparator(s), participants, uptake, CTC performance and cost, effectiveness, ICERs, and whether extra-colonic findings and medical complications were considered. Sixteen studies were identified from the United States (n = 11), Canada (n = 2), and France, Italy, and the United Kingdom (1 each). Markov state-transition (n = 14) or microsimulation (n = 2) models were used. Eleven considered direct medical costs only; five included indirect costs. Fourteen compared CTC with no screening; fourteen compared CTC with colonoscopy-based screening; fewer compared CTC with sigmoidoscopy (8) or fecal tests (4). Outcomes assessed were life-years gained/saved (13), QALYs (2), or both (1). Three considered extra-colonic findings; seven considered complications. CTC appeared cost-effective versus no screening and, in general, flexible sigmoidoscopy and fecal occult blood testing. Results were mixed comparing CTC to colonoscopy. Parameters most influencing cost-effectiveness included: CTC costs, screening uptake, threshold for polyp referral, and extra-colonic findings. Evidence on cost-effectiveness of CTC screening is heterogeneous, due largely to between-study differences in comparators and parameter values. Future studies should: compare CTC with currently favored tests, especially fecal immunochemical tests; consider extra-colonic findings; and conduct comprehensive sensitivity analyses.

  11. The UK Lung Cancer Screening Trial: a pilot randomised controlled trial of low-dose computed tomography screening for the early detection of lung cancer.

    Science.gov (United States)

    Field, John K; Duffy, Stephen W; Baldwin, David R; Brain, Kate E; Devaraj, Anand; Eisen, Tim; Green, Beverley A; Holemans, John A; Kavanagh, Terry; Kerr, Keith M; Ledson, Martin; Lifford, Kate J; McRonald, Fiona E; Nair, Arjun; Page, Richard D; Parmar, Mahesh Kb; Rintoul, Robert C; Screaton, Nicholas; Wald, Nicholas J; Weller, David; Whynes, David K; Williamson, Paula R; Yadegarfar, Ghasem; Hansell, David M

    2016-05-01

    Lung cancer kills more people than any other cancer in the UK (5-year survival high-risk UK population, determine optimum recruitment, screening, reading and care pathway strategies; and (2) assess the psychological consequences and the health-economic implications of screening. A pilot randomised controlled trial comparing intervention with usual care. A population-based risk questionnaire identified individuals who were at high risk of developing lung cancer (≥ 5% over 5 years). Thoracic centres with expertise in lung cancer imaging, respiratory medicine, pathology and surgery: Liverpool Heart & Chest Hospital, Merseyside, and Papworth Hospital, Cambridgeshire. Individuals aged 50-75 years, at high risk of lung cancer, in the primary care trusts adjacent to the centres. A thoracic LDCT scan. Follow-up computed tomography (CT) scans as per protocol. Referral to multidisciplinary team clinics was determined by nodule size criteria. Population-based recruitment based on risk stratification; management of the trial through web-based database; optimal characteristics of CT scan readers (radiologists vs. radiographers); characterisation of CT-detected nodules utilising volumetric analysis; prevalence of lung cancer at baseline; sociodemographic factors affecting participation; psychosocial measures (cancer distress, anxiety, depression, decision satisfaction); and cost-effectiveness modelling. A total of 247,354 individuals were approached to take part in the trial; 30.7% responded positively to the screening invitation. Recruitment of participants resulted in 2028 in the CT arm and 2027 in the control arm. A total of 1994 participants underwent CT scanning: 42 participants (2.1%) were diagnosed with lung cancer; 36 out of 42 (85.7%) of the screen-detected cancers were identified as stage 1 or 2, and 35 (83.3%) underwent surgical resection as their primary treatment. Lung cancer was more common in the lowest socioeconomic group. Short-term adverse psychosocial

  12. Quality study of portal images acquired by computed radiography and screen-film system under megavoltage ray

    International Nuclear Information System (INIS)

    Cao Guoquan; Jin Xiance; Wu Shixiu; Xie Congying; Zhang Li; Yu Jianyi; Li Yueqing

    2007-01-01

    Objective: To evaluate the quality of the portal images acquired by computed radiography (CR) system and conventional screen-film system, respectively. Methods: Imaging plates (IP) and X-ray films ora home-devised lead phantom with a leakage of 6.45% were acquired, and modulation transfer function (MTF) curves of the both images were measured using edge method. Portal images of 40 nasopharyngeal cancer patients were acquired by IP and screen-film system respectively. Two doctors with similar experience evaluated the damage degree of petrosal bone, the receiver operating characteristic (ROC) curve of CR images and general images were drawn according to two doctors evaluation results. Results: The identification frequency of CR system and screen-film system were 1.159 and 0.806 Lp/mm respectively. For doctor one, the area under ROC curve of CR images and general images were 0.802 and 0.742 respectively. For doctor two, the area under ROC curve of CR images and general images were 0.751 and 0.600 respectively. The MTF curve and ROC curve of CR are both better than those of screen-film system. Conclusion: The image quality of CR portal imaging is much better than that of screen-film system. The utility of CR in linear accelerator for portal imaging is promising in clinic. (authors)

  13. Denver screening protocol for blunt cerebrovascular injury reduces the use of multi-detector computed tomography angiography.

    Science.gov (United States)

    Beliaev, Andrei M; Barber, P Alan; Marshall, Roger J; Civil, Ian

    2014-06-01

    Blunt cerebrovascular injury (BCVI) occurs in 0.2-2.7% of blunt trauma patients and has up to 30% mortality. Conventional screening does not recognize up to 20% of BCVI patients. To improve diagnosis of BCVI, both an expanded battery of screening criteria and a multi-detector computed tomography angiography (CTA) have been suggested. The aim of this study is to investigate whether the use of CTA restricted to the Denver protocol screen-positive patients would reduce the unnecessary use of CTA as a pre-emptive screening tool. This is a registry-based study of blunt trauma patients admitted to Auckland City Hospital from 1998 to 2012. The diagnosis of BCVI was confirmed or excluded with CTA, magnetic resonance angiography and, if these imaging were non-conclusive, four-vessel digital subtraction angiography. Thirty (61%) BCVI and 19 (39%) non-BCVI patients met eligibility criteria. The Denver protocol applied to our cohort of patients had a sensitivity of 97% (95% confidence interval (CI): 83-100%) and a specificity of 42% (95% CI: 20-67%). With a prevalence of BCVI in blunt trauma patients of 0.2% and 2.7%, post-test odds of a screen-positive test were 0.03 (95% CI: 0.002-0.005) and 0.046 (95% CI: 0.314-0.068), respectively. Application of the CTA to the Denver protocol screen-positive trauma patients can decrease the use of CTA as a pre-emptive screening tool by 95-97% and reduces its hazards. © 2013 Royal Australasian College of Surgeons.

  14. Chest Computed Tomographic Image Screening for Cystic Lung Diseases in Patients with Spontaneous Pneumothorax Is Cost Effective.

    Science.gov (United States)

    Gupta, Nishant; Langenderfer, Dale; McCormack, Francis X; Schauer, Daniel P; Eckman, Mark H

    2017-01-01

    Patients without a known history of lung disease presenting with a spontaneous pneumothorax are generally diagnosed as having primary spontaneous pneumothorax. However, occult diffuse cystic lung diseases such as Birt-Hogg-Dubé syndrome (BHD), lymphangioleiomyomatosis (LAM), and pulmonary Langerhans cell histiocytosis (PLCH) can also first present with a spontaneous pneumothorax, and their early identification by high-resolution computed tomographic (HRCT) chest imaging has implications for subsequent management. The objective of our study was to evaluate the cost-effectiveness of HRCT chest imaging to facilitate early diagnosis of LAM, BHD, and PLCH. We constructed a Markov state-transition model to assess the cost-effectiveness of screening HRCT to facilitate early diagnosis of diffuse cystic lung diseases in patients presenting with an apparent primary spontaneous pneumothorax. Baseline data for prevalence of BHD, LAM, and PLCH and rates of recurrent pneumothoraces in each of these diseases were derived from the literature. Costs were extracted from 2014 Medicare data. We compared a strategy of HRCT screening followed by pleurodesis in patients with LAM, BHD, or PLCH versus conventional management with no HRCT screening. In our base case analysis, screening for the presence of BHD, LAM, or PLCH in patients presenting with a spontaneous pneumothorax was cost effective, with a marginal cost-effectiveness ratio of $1,427 per quality-adjusted life-year gained. Sensitivity analysis showed that screening HRCT remained cost effective for diffuse cystic lung diseases prevalence as low as 0.01%. HRCT image screening for BHD, LAM, and PLCH in patients with apparent primary spontaneous pneumothorax is cost effective. Clinicians should consider performing a screening HRCT in patients presenting with apparent primary spontaneous pneumothorax.

  15. Low-Dose Chest Computed Tomography for Lung Cancer Screening Among Hodgkin Lymphoma Survivors: A Cost-Effectiveness Analysis

    International Nuclear Information System (INIS)

    Wattson, Daniel A.; Hunink, M.G. Myriam; DiPiro, Pamela J.; Das, Prajnan; Hodgson, David C.; Mauch, Peter M.; Ng, Andrea K.

    2014-01-01

    Purpose: Hodgkin lymphoma (HL) survivors face an increased risk of treatment-related lung cancer. Screening with low-dose computed tomography (LDCT) may allow detection of early stage, resectable cancers. We developed a Markov decision-analytic and cost-effectiveness model to estimate the merits of annual LDCT screening among HL survivors. Methods and Materials: Population databases and HL-specific literature informed key model parameters, including lung cancer rates and stage distribution, cause-specific survival estimates, and utilities. Relative risks accounted for radiation therapy (RT) technique, smoking status (>10 pack-years or current smokers vs not), age at HL diagnosis, time from HL treatment, and excess radiation from LDCTs. LDCT assumptions, including expected stage-shift, false-positive rates, and likely additional workup were derived from the National Lung Screening Trial and preliminary results from an internal phase 2 protocol that performed annual LDCTs in 53 HL survivors. We assumed a 3% discount rate and a willingness-to-pay (WTP) threshold of $50,000 per quality-adjusted life year (QALY). Results: Annual LDCT screening was cost effective for all smokers. A male smoker treated with mantle RT at age 25 achieved maximum QALYs by initiating screening 12 years post-HL, with a life expectancy benefit of 2.1 months and an incremental cost of $34,841/QALY. Among nonsmokers, annual screening produced a QALY benefit in some cases, but the incremental cost was not below the WTP threshold for any patient subsets. As age at HL diagnosis increased, earlier initiation of screening improved outcomes. Sensitivity analyses revealed that the model was most sensitive to the lung cancer incidence and mortality rates and expected stage-shift from screening. Conclusions: HL survivors are an important high-risk population that may benefit from screening, especially those treated in the past with large radiation fields including mantle or involved-field RT. Screening

  16. Low-Dose Chest Computed Tomography for Lung Cancer Screening Among Hodgkin Lymphoma Survivors: A Cost-Effectiveness Analysis

    Energy Technology Data Exchange (ETDEWEB)

    Wattson, Daniel A., E-mail: dwattson@partners.org [Harvard Radiation Oncology Program, Boston, Massachusetts (United States); Hunink, M.G. Myriam [Departments of Radiology and Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands and Center for Health Decision Science, Harvard School of Public Health, Boston, Massachusetts (United States); DiPiro, Pamela J. [Department of Imaging, Dana-Farber Cancer Institute, Boston, Massachusetts (United States); Das, Prajnan [Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Hodgson, David C. [Department of Radiation Oncology, University of Toronto, Toronto, Ontario (Canada); Mauch, Peter M.; Ng, Andrea K. [Department of Radiation Oncology, Brigham and Women' s Hospital and Dana-Farber Cancer Institute, Boston, Massachusetts (United States)

    2014-10-01

    Purpose: Hodgkin lymphoma (HL) survivors face an increased risk of treatment-related lung cancer. Screening with low-dose computed tomography (LDCT) may allow detection of early stage, resectable cancers. We developed a Markov decision-analytic and cost-effectiveness model to estimate the merits of annual LDCT screening among HL survivors. Methods and Materials: Population databases and HL-specific literature informed key model parameters, including lung cancer rates and stage distribution, cause-specific survival estimates, and utilities. Relative risks accounted for radiation therapy (RT) technique, smoking status (>10 pack-years or current smokers vs not), age at HL diagnosis, time from HL treatment, and excess radiation from LDCTs. LDCT assumptions, including expected stage-shift, false-positive rates, and likely additional workup were derived from the National Lung Screening Trial and preliminary results from an internal phase 2 protocol that performed annual LDCTs in 53 HL survivors. We assumed a 3% discount rate and a willingness-to-pay (WTP) threshold of $50,000 per quality-adjusted life year (QALY). Results: Annual LDCT screening was cost effective for all smokers. A male smoker treated with mantle RT at age 25 achieved maximum QALYs by initiating screening 12 years post-HL, with a life expectancy benefit of 2.1 months and an incremental cost of $34,841/QALY. Among nonsmokers, annual screening produced a QALY benefit in some cases, but the incremental cost was not below the WTP threshold for any patient subsets. As age at HL diagnosis increased, earlier initiation of screening improved outcomes. Sensitivity analyses revealed that the model was most sensitive to the lung cancer incidence and mortality rates and expected stage-shift from screening. Conclusions: HL survivors are an important high-risk population that may benefit from screening, especially those treated in the past with large radiation fields including mantle or involved-field RT. Screening

  17. Low-dose chest computed tomography for lung cancer screening among Hodgkin lymphoma survivors: a cost-effectiveness analysis.

    Science.gov (United States)

    Wattson, Daniel A; Hunink, M G Myriam; DiPiro, Pamela J; Das, Prajnan; Hodgson, David C; Mauch, Peter M; Ng, Andrea K

    2014-10-01

    Hodgkin lymphoma (HL) survivors face an increased risk of treatment-related lung cancer. Screening with low-dose computed tomography (LDCT) may allow detection of early stage, resectable cancers. We developed a Markov decision-analytic and cost-effectiveness model to estimate the merits of annual LDCT screening among HL survivors. Population databases and HL-specific literature informed key model parameters, including lung cancer rates and stage distribution, cause-specific survival estimates, and utilities. Relative risks accounted for radiation therapy (RT) technique, smoking status (>10 pack-years or current smokers vs not), age at HL diagnosis, time from HL treatment, and excess radiation from LDCTs. LDCT assumptions, including expected stage-shift, false-positive rates, and likely additional workup were derived from the National Lung Screening Trial and preliminary results from an internal phase 2 protocol that performed annual LDCTs in 53 HL survivors. We assumed a 3% discount rate and a willingness-to-pay (WTP) threshold of $50,000 per quality-adjusted life year (QALY). Annual LDCT screening was cost effective for all smokers. A male smoker treated with mantle RT at age 25 achieved maximum QALYs by initiating screening 12 years post-HL, with a life expectancy benefit of 2.1 months and an incremental cost of $34,841/QALY. Among nonsmokers, annual screening produced a QALY benefit in some cases, but the incremental cost was not below the WTP threshold for any patient subsets. As age at HL diagnosis increased, earlier initiation of screening improved outcomes. Sensitivity analyses revealed that the model was most sensitive to the lung cancer incidence and mortality rates and expected stage-shift from screening. HL survivors are an important high-risk population that may benefit from screening, especially those treated in the past with large radiation fields including mantle or involved-field RT. Screening may be cost effective for all smokers but possibly not

  18. Bioinformatics and biomarker discovery "Omic" data analysis for personalized medicine

    CERN Document Server

    Azuaje, Francisco

    2010-01-01

    This book is designed to introduce biologists, clinicians and computational researchers to fundamental data analysis principles, techniques and tools for supporting the discovery of biomarkers and the implementation of diagnostic/prognostic systems. The focus of the book is on how fundamental statistical and data mining approaches can support biomarker discovery and evaluation, emphasising applications based on different types of "omic" data. The book also discusses design factors, requirements and techniques for disease screening, diagnostic and prognostic applications. Readers are provided w

  19. Toxins and drug discovery.

    Science.gov (United States)

    Harvey, Alan L

    2014-12-15

    Components from venoms have stimulated many drug discovery projects, with some notable successes. These are briefly reviewed, from captopril to ziconotide. However, there have been many more disappointments on the road from toxin discovery to approval of a new medicine. Drug discovery and development is an inherently risky business, and the main causes of failure during development programmes are outlined in order to highlight steps that might be taken to increase the chances of success with toxin-based drug discovery. These include having a clear focus on unmet therapeutic needs, concentrating on targets that are well-validated in terms of their relevance to the disease in question, making use of phenotypic screening rather than molecular-based assays, and working with development partners with the resources required for the long and expensive development process. Copyright © 2014 The Author. Published by Elsevier Ltd.. All rights reserved.

  20. Comparison between film-screen and computed radiography systems in Brazilian mammography

    International Nuclear Information System (INIS)

    Vieira, L.A.; Oliveira, J.R.; Carvalho, L.A.P.; César, A.C.Z.; Nogueira, M.S.

    2015-01-01

    Since 2004 the Public Health Office of the State of Minas Gerais in Brazil has established the Image Quality Control Program in Mammography. It evaluates the image quality based on an accredited phantom of the Brazilian College of Radiology (CBR). This phantom follows international standards such as masses, specks, fibers, contrast details and spatial resolution. The contrast index (CI) is accessed through optical density (OD) measurements. Although OD is defined under film-screen (FS) scope, among all accessible mammographic systems under the health office surveillance, almost 80% are computed radiography (CR) based. A necessity to adapt the protocol has emerged to consider OD as a conformity parameter. Objective: To verify the OD accessibility under CR´s printed out films and the feasibility to calculate contrast index, in comparison with FS´s. Results: A total of 56 images were evaluated with three different CBR phantoms. They were equally divided into FS and CR systems and a densitometer was used to read out their OD values. The correlation between their contrast-to-noise ratio (CNR) was found to be in the order of 0.77 (±0.14). The samples were not significantly different (inside 5% incertitude) for every phantom. The CNR correlation coefficient was 0.871. For OD, correlation coefficient was 0.989 and a log-fit function has shown good agreement with detector response. The OD-normalized standard deviation difference between CR and FS for every different phantom was 36.6%, 2.8% and 20.2%. A CI range for CR´s lying between 0.13 and 0.69 was found. Conclusions: Different phantoms were successfully tested in both CR and FS to evaluate the feasibility in use contrast index as a conformity parameter since their correlations are strictly related to calibration curve, as provided by phantom manufacturer. The relative CR-FS OD σ-difference provides a spreading indicator, where the first and last phantoms are considerably out of expectation. Such differences are

  1. Computer-aided detection of breast masses: Four-view strategy for screening mammography

    International Nuclear Information System (INIS)

    Wei Jun; Chan Heangping; Zhou Chuan; Wu Yita; Sahiner, Berkman; Hadjiiski, Lubomir M.; Roubidoux, Marilyn A.; Helvie, Mark A.

    2011-01-01

    Purpose: To improve the performance of a computer-aided detection (CAD) system for mass detection by using four-view information in screening mammography. Methods: The authors developed a four-view CAD system that emulates radiologists' reading by using the craniocaudal and mediolateral oblique views of the ipsilateral breast to reduce false positives (FPs) and the corresponding views of the contralateral breast to detect asymmetry. The CAD system consists of four major components: (1) Initial detection of breast masses on individual views, (2) information fusion of the ipsilateral views of the breast (referred to as two-view analysis), (3) information fusion of the corresponding views of the contralateral breast (referred to as bilateral analysis), and (4) fusion of the four-view information with a decision tree. The authors collected two data sets for training and testing of the CAD system: A mass set containing 389 patients with 389 biopsy-proven masses and a normal set containing 200 normal subjects. All cases had four-view mammograms. The true locations of the masses on the mammograms were identified by an experienced MQSA radiologist. The authors randomly divided the mass set into two independent sets for cross validation training and testing. The overall test performance was assessed by averaging the free response receiver operating characteristic (FROC) curves of the two test subsets. The FP rates during the FROC analysis were estimated by using the normal set only. The jackknife free-response ROC (JAFROC) method was used to estimate the statistical significance of the difference between the test FROC curves obtained with the single-view and the four-view CAD systems. Results: Using the single-view CAD system, the breast-based test sensitivities were 58% and 77% at the FP rates of 0.5 and 1.0 per image, respectively. With the four-view CAD system, the breast-based test sensitivities were improved to 76% and 87% at the corresponding FP rates, respectively

  2. Exploring Natural Products from the Biodiversity of Pakistan for Computational Drug Discovery Studies: Collection, Optimization, Design and Development of A Chemical Database (ChemDP).

    Science.gov (United States)

    Mirza, Shaher Bano; Bokhari, Habib; Fatmi, Muhammad Qaiser

    2015-01-01

    Pakistan possesses a rich and vast source of natural products (NPs). Some of these secondary metabolites have been identified as potent therapeutic agents. However, the medicinal usage of most of these compounds has not yet been fully explored. The discoveries for new scaffolds of NPs as inhibitors of certain enzymes or receptors using advanced computational drug discovery approaches are also limited due to the unavailability of accurate 3D structures of NPs. An organized database incorporating all relevant information, therefore, can facilitate to explore the medicinal importance of the metabolites from Pakistani Biodiversity. The Chemical Database of Pakistan (ChemDP; release 01) is a fully-referenced, evolving, web-based, virtual database which has been designed and developed to introduce natural products (NPs) and their derivatives from the biodiversity of Pakistan to Global scientific communities. The prime aim is to provide quality structures of compounds with relevant information for computer-aided drug discovery studies. For this purpose, over 1000 NPs have been identified from more than 400 published articles, for which 2D and 3D molecular structures have been generated with a special focus on their stereochemistry, where applicable. The PM7 semiempirical quantum chemistry method has been used to energy optimize the 3D structure of NPs. The 2D and 3D structures can be downloaded as .sdf, .mol, .sybyl, .mol2, and .pdb files - readable formats by many chemoinformatics/bioinformatics software packages. Each entry in ChemDP contains over 100 data fields representing various molecular, biological, physico-chemical and pharmacological properties, which have been properly documented in the database for end users. These pieces of information have been either manually extracted from the literatures or computationally calculated using various computational tools. Cross referencing to a major data repository i.e. ChemSpider has been made available for overlapping

  3. The Greatest Mathematical Discovery?

    Energy Technology Data Exchange (ETDEWEB)

    Bailey, David H.; Borwein, Jonathan M.

    2010-05-12

    What mathematical discovery more than 1500 years ago: (1) Is one of the greatest, if not the greatest, single discovery in the field of mathematics? (2) Involved three subtle ideas that eluded the greatest minds of antiquity, even geniuses such as Archimedes? (3) Was fiercely resisted in Europe for hundreds of years after its discovery? (4) Even today, in historical treatments of mathematics, is often dismissed with scant mention, or else is ascribed to the wrong source? Answer: Our modern system of positional decimal notation with zero, together with the basic arithmetic computational schemes, which were discovered in India about 500 CE.

  4. An automated tuberculosis screening strategy combining X-ray-based computer-aided detection and clinical information

    Science.gov (United States)

    Melendez, Jaime; Sánchez, Clara I.; Philipsen, Rick H. H. M.; Maduskar, Pragnya; Dawson, Rodney; Theron, Grant; Dheda, Keertan; van Ginneken, Bram

    2016-04-01

    Lack of human resources and radiological interpretation expertise impair tuberculosis (TB) screening programmes in TB-endemic countries. Computer-aided detection (CAD) constitutes a viable alternative for chest radiograph (CXR) reading. However, no automated techniques that exploit the additional clinical information typically available during screening exist. To address this issue and optimally exploit this information, a machine learning-based combination framework is introduced. We have evaluated this framework on a database containing 392 patient records from suspected TB subjects prospectively recruited in Cape Town, South Africa. Each record comprised a CAD score, automatically computed from a CXR, and 12 clinical features. Comparisons with strategies relying on either CAD scores or clinical information alone were performed. Our results indicate that the combination framework outperforms the individual strategies in terms of the area under the receiving operating characteristic curve (0.84 versus 0.78 and 0.72), specificity at 95% sensitivity (49% versus 24% and 31%) and negative predictive value (98% versus 95% and 96%). Thus, it is believed that combining CAD and clinical information to estimate the risk of active disease is a promising tool for TB screening.

  5. Feasibility of a computer-delivered driver safety behavior screening and intervention program initiated during an emergency department visit.

    Science.gov (United States)

    Murphy, Mary; Smith, Lucia; Palma, Anton; Lounsbury, David; Bijur, Polly; Chambers, Paul; Gallagher, E John

    2013-01-01

    Injuries from motor vehicle crashes are a significant public health problem. The emergency department (ED) provides a setting that may be used to screen for behaviors that increase risk for motor vehicle crashes and provide brief interventions to people who might otherwise not have access to screening and intervention. The purpose of the present study was to (1) assess the feasibility of using a computer-assisted screening program to educate ED patients about risky driving behaviors, (2) evaluate patient acceptance of the computer-based traffic safety educational intervention during an ED visit, and (3) assess postintervention changes in risky driving behaviors. Pre/posteducational intervention involving medically stable adult ED patients in a large urban academic ED serving over 100,000 patients annually. Patients completed a self-administered, computer-based program that queried patients on risky driving behaviors (texting, talking, and other forms of distracted driving) and alcohol use. The computer provided patients with educational information on the dangers of these behaviors and data were collected on patient satisfaction with the program. Staff called patients 1 month post-ED visit for a repeat query. One hundred forty-nine patients participated, and 111 completed 1-month follow up (75%); the mean age was 39 (range: 21-70), 59 percent were Hispanic, and 52 percent were male. Ninety-seven percent of patients reported that the program was easy to use and that they were comfortable receiving this education via computer during their ED visit. All driving behaviors significantly decreased in comparison to baseline with the following reductions reported: talking on the phone, 30 percent; aggressive driving, 30 percent; texting while driving, 19 percent; drowsy driving, 16 percent; driving while multitasking, 12 percent; and drinking and driving, 9 percent. Overall, patients were very satisfied receiving educational information about these behaviors via computer

  6. Is computer aided detection (CAD) cost effective in screening mammography? A model based on the CADET II study

    Science.gov (United States)

    2011-01-01

    Background Single reading with computer aided detection (CAD) is an alternative to double reading for detecting cancer in screening mammograms. The aim of this study is to investigate whether the use of a single reader with CAD is more cost-effective than double reading. Methods Based on data from the CADET II study, the cost-effectiveness of single reading with CAD versus double reading was measured in terms of cost per cancer detected. Cost (Pound (£), year 2007/08) of single reading with CAD versus double reading was estimated assuming a health and social service perspective and a 7 year time horizon. As the equipment cost varies according to the unit size a separate analysis was conducted for high, average and low volume screening units. One-way sensitivity analyses were performed by varying the reading time, equipment and assessment cost, recall rate and reader qualification. Results CAD is cost increasing for all sizes of screening unit. The introduction of CAD is cost-increasing compared to double reading because the cost of CAD equipment, staff training and the higher assessment cost associated with CAD are greater than the saving in reading costs. The introduction of single reading with CAD, in place of double reading, would produce an additional cost of £227 and £253 per 1,000 women screened in high and average volume units respectively. In low volume screening units, the high cost of purchasing the equipment will results in an additional cost of £590 per 1,000 women screened. One-way sensitivity analysis showed that the factors having the greatest effect on the cost-effectiveness of CAD with single reading compared with double reading were the reading time and the reader's professional qualification (radiologist versus advanced practitioner). Conclusions Without improvements in CAD effectiveness (e.g. a decrease in the recall rate) CAD is unlikely to be a cost effective alternative to double reading for mammography screening in UK. This study

  7. The efficacy of using computer-aided detection (CAD) for detection of breast cancer in mammography screening

    DEFF Research Database (Denmark)

    Henriksen, Emilie L; Carlsen, Jonathan F; Vejborg, Ilse Mm

    2018-01-01

    Background Early detection of breast cancer (BC) is crucial in lowering the mortality. Purpose To present an overview of studies concerning computer-aided detection (CAD) in screening mammography for early detection of BC and compare diagnostic accuracy and recall rates (RR) of single reading (SR......) with SR + CAD and double reading (DR) with SR + CAD. Material and Methods PRISMA guidelines were used as a review protocol. Articles on clinical trials concerning CAD for detection of BC in a screening population were included. The literature search resulted in 1522 records. A total of 1491 records were...... excluded by abstract and 18 were excluded by full text reading. A total of 13 articles were included. Results All but two studies from the SR vs. SR + CAD group showed an increased sensitivity and/or cancer detection rate (CDR) when adding CAD. The DR vs. SR + CAD group showed no significant differences...

  8. Discovery of the first dual inhibitor of the 5-lipoxygenase-activating protein and soluble epoxide hydrolase using pharmacophore-based virtual screening

    Czech Academy of Sciences Publication Activity Database

    Temml, V.; Garscha, U.; Romp, E.; Schubert, G.; Gerstmeier, J.; Kutil, Zsófia; Matuszczak, B.; Waltenberger, B.; Stuppner, H.; Werz, O.; Schuster, D.

    2017-01-01

    Roč. 7, FEB 20 (2017), č. článku 42751. ISSN 2045-2322 Institutional support: RVO:61389030 Keywords : activating protein * drug discovery * leukotriene biosynthesis * inflammatory diseases * conformer generation * arachidonic-acid * flap * challenges * asthma * risk Subject RIV: CE - Biochemistry OBOR OECD: Physiology (including cytology) Impact factor: 4.259, year: 2016

  9. Designing Second Generation Anti-Alzheimer Compounds as Inhibitors of Human Acetylcholinesterase: Computational Screening of Synthetic Molecules and Dietary Phytochemicals.

    Science.gov (United States)

    Amat-Ur-Rasool, Hafsa; Ahmed, Mehboob

    2015-01-01

    Alzheimer's disease (AD), a big cause of memory loss, is a progressive neurodegenerative disorder. The disease leads to irreversible loss of neurons that result in reduced level of acetylcholine neurotransmitter (ACh). The reduction of ACh level impairs brain functioning. One aspect of AD therapy is to maintain ACh level up to a safe limit, by blocking acetylcholinesterase (AChE), an enzyme that is naturally responsible for its degradation. This research presents an in-silico screening and designing of hAChE inhibitors as potential anti-Alzheimer drugs. Molecular docking results of the database retrieved (synthetic chemicals and dietary phytochemicals) and self-drawn ligands were compared with Food and Drug Administration (FDA) approved drugs against AD as controls. Furthermore, computational ADME studies were performed on the hits to assess their safety. Human AChE was found to be most approptiate target site as compared to commonly used Torpedo AChE. Among the tested dietry phytochemicals, berberastine, berberine, yohimbine, sanguinarine, elemol and naringenin are the worth mentioning phytochemicals as potential anti-Alzheimer drugs The synthetic leads were mostly dual binding site inhibitors with two binding subunits linked by a carbon chain i.e. second generation AD drugs. Fifteen new heterodimers were designed that were computationally more efficient inhibitors than previously reported compounds. Using computational methods, compounds present in online chemical databases can be screened to design more efficient and safer drugs against cognitive symptoms of AD.

  10. Designing Second Generation Anti-Alzheimer Compounds as Inhibitors of Human Acetylcholinesterase: Computational Screening of Synthetic Molecules and Dietary Phytochemicals.

    Directory of Open Access Journals (Sweden)

    Hafsa Amat-Ur-Rasool

    Full Text Available Alzheimer's disease (AD, a big cause of memory loss, is a progressive neurodegenerative disorder. The disease leads to irreversible loss of neurons that result in reduced level of acetylcholine neurotransmitter (ACh. The reduction of ACh level impairs brain functioning. One aspect of AD therapy is to maintain ACh level up to a safe limit, by blocking acetylcholinesterase (AChE, an enzyme that is naturally responsible for its degradation. This research presents an in-silico screening and designing of hAChE inhibitors as potential anti-Alzheimer drugs. Molecular docking results of the database retrieved (synthetic chemicals and dietary phytochemicals and self-drawn ligands were compared with Food and Drug Administration (FDA approved drugs against AD as controls. Furthermore, computational ADME studies were performed on the hits to assess their safety. Human AChE was found to be most approptiate target site as compared to commonly used Torpedo AChE. Among the tested dietry phytochemicals, berberastine, berberine, yohimbine, sanguinarine, elemol and naringenin are the worth mentioning phytochemicals as potential anti-Alzheimer drugs The synthetic leads were mostly dual binding site inhibitors with two binding subunits linked by a carbon chain i.e. second generation AD drugs. Fifteen new heterodimers were designed that were computationally more efficient inhibitors than previously reported compounds. Using computational methods, compounds present in online chemical databases can be screened to design more efficient and safer drugs against cognitive symptoms of AD.

  11. Project Final Report: Ubiquitous Computing and Monitoring System (UCoMS) for Discovery and Management of Energy Resources

    Energy Technology Data Exchange (ETDEWEB)

    Tzeng, Nian-Feng; White, Christopher D.; Moreman, Douglas

    2012-07-14

    The UCoMS research cluster has spearheaded three research areas since August 2004, including wireless and sensor networks, Grid computing, and petroleum applications. The primary goals of UCoMS research are three-fold: (1) creating new knowledge to push forward the technology forefronts on pertinent research on the computing and monitoring aspects of energy resource management, (2) developing and disseminating software codes and toolkits for the research community and the public, and (3) establishing system prototypes and testbeds for evaluating innovative techniques and methods. Substantial progress and diverse accomplishment have been made by research investigators in their respective areas of expertise cooperatively on such topics as sensors and sensor networks, wireless communication and systems, computational Grids, particularly relevant to petroleum applications.

  12. Computational Identification of the Paralogs and Orthologs of Human Cytochrome P450 Superfamily and the Implication in Drug Discovery

    Directory of Open Access Journals (Sweden)

    Shu-Ting Pan

    2016-06-01

    Full Text Available The human cytochrome P450 (CYP superfamily consisting of 57 functional genes is the most important group of Phase I drug metabolizing enzymes that oxidize a large number of xenobiotics and endogenous compounds, including therapeutic drugs and environmental toxicants. The CYP superfamily has been shown to expand itself through gene duplication, and some of them become pseudogenes due to gene mutations. Orthologs and paralogs are homologous genes resulting from speciation or duplication, respectively. To explore the evolutionary and functional relationships of human CYPs, we conducted this bioinformatic study to identify their corresponding paralogs, homologs, and orthologs. The functional implications and implications in drug discovery and evolutionary biology were then discussed. GeneCards and Ensembl were used to identify the paralogs of human CYPs. We have used a panel of online databases to identify the orthologs of human CYP genes: NCBI, Ensembl Compara, GeneCards, OMA (“Orthologous MAtrix” Browser, PATHER, TreeFam, EggNOG, and Roundup. The results show that each human CYP has various numbers of paralogs and orthologs using GeneCards and Ensembl. For example, the paralogs of CYP2A6 include CYP2A7, 2A13, 2B6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, 2F1, 2J2, 2R1, 2S1, 2U1, and 2W1; CYP11A1 has 6 paralogs including CYP11B1, 11B2, 24A1, 27A1, 27B1, and 27C1; CYP51A1 has only three paralogs: CYP26A1, 26B1, and 26C1; while CYP20A1 has no paralog. The majority of human CYPs are well conserved from plants, amphibians, fishes, or mammals to humans due to their important functions in physiology and xenobiotic disposition. The data from different approaches are also cross-validated and validated when experimental data are available. These findings facilitate our understanding of the evolutionary relationships and functional implications of the human CYP superfamily in drug discovery.

  13. Balancing curability and unnecessary surgery in the context of computed tomography screening for lung cancer.

    Science.gov (United States)

    Flores, Raja; Bauer, Thomas; Aye, Ralph; Andaz, Shahriyour; Kohman, Leslie; Sheppard, Barry; Mayfield, William; Thurer, Richard; Smith, Michael; Korst, Robert; Straznicka, Michaela; Grannis, Fred; Pass, Harvey; Connery, Cliff; Yip, Rowena; Smith, James P; Yankelevitz, David; Henschke, Claudia; Altorki, Nasser

    2014-05-01

    Surgical management is a critical component of computed tomography (CT) screening for lung cancer. We report the results for US sites in a large ongoing screening program, the International Early Lung Cancer Action Program (I-ELCAP). We identified all patients who underwent surgical resection. We compared the results before (1993-2005) and after (2006-2011) termination of the National Lung Screening Trial to identify emerging trends. Among 31,646 baseline and 37,861 annual repeat CT screenings, 492 patients underwent surgical resection; 437 (89%) were diagnosed with lung cancer; 396 (91%) had clinical stage I disease. In the 54 (11%) patients with nonmalignant disease, resection was sublobar in 48 and lobectomy in 6. The estimated cure rate based on the 15-year Kaplan-Meier survival for all 428 patients (excluding 9 typical carcinoids) with lung cancer was 84% (95% confidence interval [CI], 80%-88%) and 88% (95% CI, 83%-92%) for clinical stage I disease resected within 1 month of diagnosis. Video-assisted thoracoscopic surgery and sublobar resection increased significantly, from 10% to 34% (P < .0001) and 22% to 34% (P = .01) respectively; there were no significant differences in the percentage of malignant diagnoses (90% vs 87%, P = .36), clinical stage I (92% vs 89%, P = .33), pathologic stage I (85% vs 82%, P = .44), tumor size (P = .61), or cell type (P = .81). The frequency and extent of surgery for nonmalignant disease can be minimized in a CT screening program and provide a high cure rate for those diagnosed with lung cancer and undergoing surgical resection. Copyright © 2014 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.

  14. Computed tomographic colonography to screen for colorectal cancer, extracolonic cancer, and aortic aneurysm: model simulation with cost-effectiveness analysis.

    Science.gov (United States)

    Hassan, Cesare; Pickhardt, Perry J; Pickhardt, Perry; Laghi, Andrea; Kim, Daniel H; Kim, Daniel; Zullo, Angelo; Iafrate, Franco; Di Giulio, Lorenzo; Morini, Sergio

    2008-04-14

    In addition to detecting colorectal neoplasia, abdominal computed tomography (CT) with colonography technique (CTC) can also detect unsuspected extracolonic cancers and abdominal aortic aneurysms (AAA).The efficacy and cost-effectiveness of this combined abdominal CT screening strategy are unknown. A computerized Markov model was constructed to simulate the occurrence of colorectal neoplasia, extracolonic malignant neoplasm, and AAA in a hypothetical cohort of 100,000 subjects from the United States who were 50 years of age. Simulated screening with CTC, using a 6-mm polyp size threshold for reporting, was compared with a competing model of optical colonoscopy (OC), both without and with abdominal ultrasonography for AAA detection (OC-US strategy). In the simulated population, CTC was the dominant screening strategy, gaining an additional 1458 and 462 life-years compared with the OC and OC-US strategies and being less costly, with a savings of $266 and $449 per person, respectively. The additional gains for CTC were largely due to a decrease in AAA-related deaths, whereas the modeled benefit from extracolonic cancer downstaging was a relatively minor factor. At sensitivity analysis, OC-US became more cost-effective only when the CTC sensitivity for large polyps dropped to 61% or when broad variations of costs were simulated, such as an increase in CTC cost from $814 to $1300 or a decrease in OC cost from $1100 to $500. With the OC-US approach, suboptimal compliance had a strong negative influence on efficacy and cost-effectiveness. The estimated mortality from CT-induced cancer was less than estimated colonoscopy-related mortality (8 vs 22 deaths), both of which were minor compared with the positive benefit from screening. When detection of extracolonic findings such as AAA and extracolonic cancer are considered in addition to colorectal neoplasia in our model simulation, CT colonography is a dominant screening strategy (ie, more clinically effective and more cost

  15. Data management, code deployment, and scientific visualization to enhance scientific discovery in fusion research through advanced computing

    International Nuclear Information System (INIS)

    Schissel, D.P.; Finkelstein, A.; Foster, I.T.; Fredian, T.W.; Greenwald, M.J.; Hansen, C.D.; Johnson, C.R.; Keahey, K.; Klasky, S.A.; Li, K.; McCune, D.C.; Peng, Q.; Stevens, R.; Thompson, M.R.

    2002-01-01

    The long-term vision of the Fusion Collaboratory described in this paper is to transform fusion research and accelerate scientific understanding and innovation so as to revolutionize the design of a fusion energy source. The Collaboratory will create and deploy collaborative software tools that will enable more efficient utilization of existing experimental facilities and more effective integration of experiment, theory, and modeling. The computer science research necessary to create the Collaboratory is centered on three activities: security, remote and distributed computing, and scientific visualization. It is anticipated that the presently envisioned Fusion Collaboratory software tools will require 3 years to complete

  16. Spectroscopic and Computational Investigations of Ligand Binding to IspH: Discovery of Non-diphosphate Inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    O' Dowd, Bing [Department of Chemistry, University of Illinois, 600 South Mathews Avenue Urbana IL 61801 USA; Williams, Sarah [Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla CA 92093 USA; Wang, Hongxin [Department of Chemistry, University of California, 1 Shields Avenue Davis CA 95616 USA; Lawrence Berkeley National Laboratory, 1 Cyclotron Road Berkeley CA 94720 USA; No, Joo Hwan [Center for Biophysics and Computational Biology, Urbana, IL (United States); Rao, Guodong [Department of Chemistry, University of Illinois, 600 South Mathews Avenue Urbana IL 61801 USA; Wang, Weixue [Center for Biophysics and Computational Biology, Urbana, IL (United States); McCammon, J. Andrew [Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla CA 92093 USA; Howard Hughes Medical Institute, University of California at San Diego, La Jolla CA 92093 USA; National Biomedical Computation Resource, University of California at San Diego, La Jolla CA 92093 USA; Cramer, Stephen P. [Department of Chemistry, University of California, 1 Shields Avenue Davis CA 95616 USA; Lawrence Berkeley National Laboratory, 1 Cyclotron Road Berkeley CA 94720 USA; Oldfield, Eric [Department of Chemistry, University of Illinois, 600 South Mathews Avenue Urbana IL 61801 USA

    2017-04-07

    Isoprenoid biosynthesis is an important area for anti-infective drug development. One isoprenoid target described is (E)-1-hydroxy-2-methyl-but-2-enyl 4-diphosphate (HMBPP) reductase (IspH), which forms isopentenyl diphosphate and dimethylallyl diphosphate from HMBPP in a 2H + /2e - reduction. IspH contains a 4 Fe-4 S cluster, and in this work, we first investigated how small molecules bound to the cluster by using HYSCORE and NRVS spectroscopies. The results of these, as well as other structural and spectroscopic investigations, led to the conclusion that, in most cases, ligands bound to IspH 4 Fe-4 S clusters by η 1 coordination, forming tetrahedral geometries at the unique fourth Fe, ligand side chains preventing further ligand (e.g., H 2 O, O 2 ) binding. Based on these ideas, we used in silico methods to find drug-like inhibitors that might occupy the HMBPP substrate binding pocket and bind to Fe, leading to the discovery of a barbituric acid analogue with a K i value of ≈500 nm against Pseudomonas aeruginosa IspH.

  17. Stuck on Screens: Patterns of Computer and Gaming Station Use in Youth Seen in a Psychiatric Clinic

    Science.gov (United States)

    Baer, Susan; Bogusz, Elliot; Green, David A.

    2011-01-01

    Objective: Computer and gaming-station use has become entrenched in the culture of our youth. Parents of children with psychiatric disorders report concerns about overuse, but research in this area is limited. The goal of this study is to evaluate computer/gaming-station use in adolescents in a psychiatric clinic population and to examine the relationship between use and functional impairment. Method: 102 adolescents, ages 11–17, from out-patient psychiatric clinics participated. Amount of computer/gaming-station use, type of use (gaming or non-gaming), and presence of addictive features were ascertained along with emotional/functional impairment. Multivariate linear regression was used to examine correlations between patterns of use and impairment. Results: Mean screen time was 6.7±4.2 hrs/day. Presence of addictive features was positively correlated with emotional/functional impairment. Time spent on computer/gaming-station use was not correlated overall with impairment after controlling for addictive features, but non-gaming time was positively correlated with risky behavior in boys. Conclusions: Youth with psychiatric disorders are spending much of their leisure time on the computer/gaming-station and a substantial subset show addictive features of use which is associated with impairment. Further research to develop measures and to evaluate risk is needed to identify the impact of this problem. PMID:21541096

  18. Creation of Novel Protein Variants with CRISPR/Cas9-Mediated Mutagenesis: Turning a Screening By-Product into a Discovery Tool.

    Directory of Open Access Journals (Sweden)

    Katherine F Donovan

    Full Text Available CRISPR/Cas9 screening has proven to be a versatile tool for genomics research. Based on unexpected results from a genome-wide screen, we developed a CRISPR/Cas9-mediated approach to mutagenesis, exploiting the allelic diversity generated by error-prone non-homologous end-joining (NHEJ to identify novel gain-of-function and drug resistant alleles of the MAPK signaling pathway genes MEK1 and BRAF. We define the parameters of a scalable technique to easily generate cell populations containing thousands of endogenous allelic variants to map gene functions. Further, these results highlight an unexpected but important phenomenon, that Cas9-induced gain-of-function alleles are an inherent by-product of normal Cas9 loss-of-function screens and should be investigated during analysis of data from large-scale positive selection screens.

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

    Science.gov (United States)

    Christofferson, Andrew J; Huang, Niu

    2012-01-01

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

  20. Applications of the NRGsuite and the Molecular Docking Software FlexAID in Computational Drug Discovery and Design.

    Science.gov (United States)

    Morency, Louis-Philippe; Gaudreault, Francis; Najmanovich, Rafael

    2018-01-01

    Docking simulations help us understand molecular interactions. Here we present a hands-on tutorial to utilize FlexAID (Flexible Artificial Intelligence Docking), an open source molecular docking software between ligands such as small molecules or peptides and macromolecules such as proteins and nucleic acids. The tutorial uses the NRGsuite PyMOL plugin graphical user interface to set up and visualize docking simulations in real time as well as detect and refine target cavities. The ease of use of FlexAID and the NRGsuite combined with its superior performance relative to widely used docking software provides nonexperts with an important tool to understand molecular interactions with direct applications in structure-based drug design and virtual high-throughput screening.

  1. A Computable Definition of Sepsis Facilitates Screening and Performance Improvement Tracking.

    Science.gov (United States)

    Alessi, Lauren J; Warmus, Holly R; Schaffner, Erin K; Kantawala, Sajel; Carcillo, Joseph; Rosen, Johanna; Horvat, Christopher M

    2018-03-01

    Sepsis kills almost 5,000 children annually, accounting for 16% of pediatric health care spending in the United States. We sought to identify sepsis within the Electronic Health Record (EHR) of a quaternary children's hospital to characterize disease incidence, improve recognition and response, and track performance metrics. Methods are organized in a plan-do-study-act cycle. During the "plan" phase, electronic definitions of sepsis (blood culture and antibiotic within 24 hours) and septic shock (sepsis plus vasoactive medication) were created to establish benchmark data and track progress with statistical process control. The performance of a screening tool was evaluated in the emergency department. During the "do" phase, a novel inpatient workflow is being piloted, which involves regular sepsis screening by nurses using the tool, and a regimented response to high risk patients. Screening tool use in the emergency department reduced time to antibiotics (Fig. 1). Of the 6,159 admissions, EHR definitions identified 1,433 (23.3%) between July and December 2016 with sepsis, of which 159 (11.1%) had septic shock. Hospital mortality for all sepsis patients was 2.2% and 15.7% for septic shock (Table 1). These findings approximate epidemiologic studies of sepsis and severe sepsis, which report a prevalence range of 0.45-8.2% and mortality range of 8.2-25% (Table 2). 1-5 . Implementation of a sepsis screening tool is associated with improved performance. The prevalence of sepsis conditions identified with electronic definitions approximates the epidemiologic landscape characterized by other point-prevalence and administrative studies, providing face validity to this approach, and proving useful for tracking performance improvement.

  2. Beyond Discovery

    DEFF Research Database (Denmark)

    Korsgaard, Steffen; Sassmannshausen, Sean Patrick

    2017-01-01

    In this chapter we explore four alternatives to the dominant discovery view of entrepreneurship; the development view, the construction view, the evolutionary view, and the Neo-Austrian view. We outline the main critique points of the discovery presented in these four alternatives, as well...

  3. Chemical Discovery

    Science.gov (United States)

    Brown, Herbert C.

    1974-01-01

    The role of discovery in the advance of the science of chemistry and the factors that are currently operating to handicap that function are considered. Examples are drawn from the author's work with boranes. The thesis that exploratory research and discovery should be encouraged is stressed. (DT)

  4. Opportunities for Russian Nuclear Weapons Institute developing computer-aided design programs for pharmaceutical drug discovery. Final report

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1996-09-23

    The goal of this study is to determine whether physicists at the Russian Nuclear Weapons Institute can profitably service the need for computer aided drug design (CADD) programs. The Russian physicists` primary competitive advantage is their ability to write particularly efficient code able to work with limited computing power; a history of working with very large, complex modeling systems; an extensive knowledge of physics and mathematics, and price competitiveness. Their primary competitive disadvantage is their lack of biology, and cultural and geographic issues. The first phase of the study focused on defining the competitive landscape, primarily through interviews with and literature searches on the key providers of CADD software. The second phase focused on users of CADD technology to determine deficiencies in the current product offerings, to understand what product they most desired, and to define the potential demand for such a product.

  5. Interobserver agreement and performance score comparison in quality control using a breast phantom: screen-film mammography vs computed radiography

    International Nuclear Information System (INIS)

    Shimamoto, Kazuhiro; Ikeda, Mitsuru; Satake, Hiroko; Ishigaki, Satoko; Sawaki, Akiko; Ishigaki, Takeo

    2002-01-01

    Our objective was to evaluate interobserver agreement and to compare the performance score in quality control of screen-film mammography and computed radiography (CR) using a breast phantom. Eleven radiologists interpreted a breast phantom image (CIRS model X) by four viewing methods: (a) original screen-film; (b) soft-copy reading of the digitized film image; (c) hard-copy reading of CR using an imaging plate; and (d) soft-copy reading of CR. For the soft-copy reading, a 17-in. CRT monitor (1024 x 1536 x 8 bits) was used. The phantom image was evaluated using a scoring system outlined in the instruction manual, and observers judged each object using a three-point rating scale: (a) clearly seen; (b) barely seen; and (c) not seen. For statistical analysis, the kappa statistic was employed. For ''mass'' depiction, interobserver agreement using CR was significantly lower than when using screen-film (p<0.05). There was no significant difference in the kappa value for detecting ''microcalcification''; however, the performance score of ''microcalcification'' on CR hard-copy was significantly lower than on the other three viewing methods (p<0.05). Viewing methods (film or CR, soft-copy or hard-copy) could affect how the phantom image is judged. Paying special attention to viewing conditions is recommended for quality control of CR mammograms. (orig.)

  6. Viral pathogen discovery

    Science.gov (United States)

    Chiu, Charles Y

    2015-01-01

    Viral pathogen discovery is of critical importance to clinical microbiology, infectious diseases, and public health. Genomic approaches for pathogen discovery, including consensus polymerase chain reaction (PCR), microarrays, and unbiased next-generation sequencing (NGS), have the capacity to comprehensively identify novel microbes present in clinical samples. Although numerous challenges remain to be addressed, including the bioinformatics analysis and interpretation of large datasets, these technologies have been successful in rapidly identifying emerging outbreak threats, screening vaccines and other biological products for microbial contamination, and discovering novel viruses associated with both acute and chronic illnesses. Downstream studies such as genome assembly, epidemiologic screening, and a culture system or animal model of infection are necessary to establish an association of a candidate pathogen with disease. PMID:23725672

  7. Discovery of molecular mechanism of a clinical herbal formula upregulating serum HDL-c levels in treatment of metabolic syndrome by in vivo and computational studies.

    Science.gov (United States)

    Chen, Meimei; Yang, Fafu; Kang, Jie; Gan, Huijuan; Lai, Xinmei; Gao, Yuxing

    2018-01-15

    Decreased HDL cholesterol (HDL-c) is considered as an independent risk factor of cardiovascular disease in metabolic syndrome (Mets). Wendan decoction (WDD), a famous clinical traditional Chinese medicine formula in Mets in China, which can obviously up-regulate serum HDL-c levels in Mets. However, till now, the molecular mechanism of up-regulation still remained unclear. In this study, an integrated approach that combined serum ABCA1 in vivo assay, QSAR modeling and molecular docking was developed to explore the molecular mechanism and chemical substance basis of WDD upregulating HDL-c levels. Compared with Mets model group, serum ABCA1 and HDL-c levels intervened by two different doses of WDD for two weeks were significantly up-regulated. Then, kohonen and LDA were applied to develop QSAR models for ABCA1 up-regulators based flavonoids. The derived QSAR model produced the overall accuracy of 100%, a very powerful tool for screening ABCA1 up-regulators. The QSAR model prediction revealed 67 flavonoids in WDD were ABCA1 up-regulators. Finally, they were subjected to the molecular docking to understand their roles in up-regulating ABCA1 expression, which led to discovery of 23 ABCA1 up-regulators targeting LXR beta. Overall, QSAR modeling and docking studies well accounted for the observed in vivo activities of ABCA1 affected by WDD. Copyright © 2017 Elsevier Ltd. All rights reserved.

  8. ACFIS: a web server for fragment-based drug discovery.

    Science.gov (United States)

    Hao, Ge-Fei; Jiang, Wen; Ye, Yuan-Nong; Wu, Feng-Xu; Zhu, Xiao-Lei; Guo, Feng-Biao; Yang, Guang-Fu

    2016-07-08

    In order to foster innovation and improve the effectiveness of drug discovery, there is a considerable interest in exploring unknown 'chemical space' to identify new bioactive compounds with novel and diverse scaffolds. Hence, fragment-based drug discovery (FBDD) was developed rapidly due to its advanced expansive search for 'chemical space', which can lead to a higher hit rate and ligand efficiency (LE). However, computational screening of fragments is always hampered by the promiscuous binding model. In this study, we developed a new web server Auto Core Fragment in silico Screening (ACFIS). It includes three computational modules, PARA_GEN, CORE_GEN and CAND_GEN. ACFIS can generate core fragment structure from the active molecule using fragment deconstruction analysis and perform in silico screening by growing fragments to the junction of core fragment structure. An integrated energy calculation rapidly identifies which fragments fit the binding site of a protein. We constructed a simple interface to enable users to view top-ranking molecules in 2D and the binding mode in 3D for further experimental exploration. This makes the ACFIS a highly valuable tool for drug discovery. The ACFIS web server is free and open to all users at http://chemyang.ccnu.edu.cn/ccb/server/ACFIS/. © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

  9. ACFIS: a web server for fragment-based drug discovery

    Science.gov (United States)

    Hao, Ge-Fei; Jiang, Wen; Ye, Yuan-Nong; Wu, Feng-Xu; Zhu, Xiao-Lei; Guo, Feng-Biao; Yang, Guang-Fu

    2016-01-01

    In order to foster innovation and improve the effectiveness of drug discovery, there is a considerable interest in exploring unknown ‘chemical space’ to identify new bioactive compounds with novel and diverse scaffolds. Hence, fragment-based drug discovery (FBDD) was developed rapidly due to its advanced expansive search for ‘chemical space’, which can lead to a higher hit rate and ligand efficiency (LE). However, computational screening of fragments is always hampered by the promiscuous binding model. In this study, we developed a new web server Auto Core Fragment in silico Screening (ACFIS). It includes three computational modules, PARA_GEN, CORE_GEN and CAND_GEN. ACFIS can generate core fragment structure from the active molecule using fragment deconstruction analysis and perform in silico screening by growing fragments to the junction of core fragment structure. An integrated energy calculation rapidly identifies which fragments fit the binding site of a protein. We constructed a simple interface to enable users to view top-ranking molecules in 2D and the binding mode in 3D for further experimental exploration. This makes the ACFIS a highly valuable tool for drug discovery. The ACFIS web server is free and open to all users at http://chemyang.ccnu.edu.cn/ccb/server/ACFIS/. PMID:27150808

  10. An integrated approach for the knowledge discovery in computer simulation models with a multi-dimensional parameter space

    Energy Technology Data Exchange (ETDEWEB)

    Khawli, Toufik Al; Eppelt, Urs; Hermanns, Torsten [RWTH Aachen University, Chair for Nonlinear Dynamics, Steinbachstr. 15, 52047 Aachen (Germany); Gebhardt, Sascha [RWTH Aachen University, Virtual Reality Group, IT Center, Seffenter Weg 23, 52074 Aachen (Germany); Kuhlen, Torsten [Forschungszentrum Jülich GmbH, Institute for Advanced Simulation (IAS), Jülich Supercomputing Centre (JSC), Wilhelm-Johnen-Straße, 52425 Jülich (Germany); Schulz, Wolfgang [Fraunhofer, ILT Laser Technology, Steinbachstr. 15, 52047 Aachen (Germany)

    2016-06-08

    In production industries, parameter identification, sensitivity analysis and multi-dimensional visualization are vital steps in the planning process for achieving optimal designs and gaining valuable information. Sensitivity analysis and visualization can help in identifying the most-influential parameters and quantify their contribution to the model output, reduce the model complexity, and enhance the understanding of the model behavior. Typically, this requires a large number of simulations, which can be both very expensive and time consuming when the simulation models are numerically complex and the number of parameter inputs increases. There are three main constituent parts in this work. The first part is to substitute the numerical, physical model by an accurate surrogate model, the so-called metamodel. The second part includes a multi-dimensional visualization approach for the visual exploration of metamodels. In the third part, the metamodel is used to provide the two global sensitivity measures: i) the Elementary Effect for screening the parameters, and ii) the variance decomposition method for calculating the Sobol indices that quantify both the main and interaction effects. The application of the proposed approach is illustrated with an industrial application with the goal of optimizing a drilling process using a Gaussian laser beam.

  11. Advances in fragment-based drug discovery platforms.

    Science.gov (United States)

    Orita, Masaya; Warizaya, Masaichi; Amano, Yasushi; Ohno, Kazuki; Niimi, Tatsuya

    2009-11-01

    Fragment-based drug discovery (FBDD) has been established as a powerful alternative and complement to traditional high-throughput screening techniques for identifying drug leads. At present, this technique is widely used among academic groups as well as small biotech and large pharmaceutical companies. In recent years, > 10 new compounds developed with FBDD have entered clinical development, and more and more attention in the drug discovery field is being focused on this technique. Under the FBDD approach, a fragment library of relatively small compounds (molecular mass = 100 - 300 Da) is screened by various methods and the identified fragment hits which normally weakly bind to the target are used as starting points to generate more potent drug leads. Because FBDD is still a relatively new drug discovery technology, further developments and optimizations in screening platforms and fragment exploitation can be expected. This review summarizes recent advances in FBDD platforms and discusses the factors important for the successful application of this technique. Under the FBDD approach, both identifying the starting fragment hit to be developed and generating the drug lead from that starting fragment hit are important. Integration of various techniques, such as computational technology, X-ray crystallography, NMR, surface plasmon resonance, isothermal titration calorimetry, mass spectrometry and high-concentration screening, must be applied in a situation-appropriate manner.

  12. Functional principles of registry-based service discovery

    NARCIS (Netherlands)

    Sundramoorthy, V.; Tan, C.; Hartel, P.H.; Hartog, den J.I.; Scholten, J.

    2005-01-01

    As Service Discovery Protocols (SDP) are becoming increasingly important for ubiquitous computing, they must behave according to predefined principles. We present the functional Principles of Service Discovery for robust, registry-based service discovery. A methodology to guarantee adherence to

  13. Computer-Aided Evaluation of Screening Mammograms Based on Local Texture Models

    Czech Academy of Sciences Publication Activity Database

    Grim, Jiří; Somol, Petr; Haindl, Michal; Daneš, J.

    2009-01-01

    Roč. 18, č. 4 (2009), s. 765-773 ISSN 1057-7149 R&D Projects: GA ČR GA102/07/1594; GA ČR GA102/08/0593; GA MŠk 1M0572 Grant - others:GA MŠk(CZ) 2C06019 Institutional research plan: CEZ:AV0Z10750506 Keywords : Screening mammography * texture information * local statistical model * Gaussian mixture Subject RIV: BB - Applied Statistics, Operational Research Impact factor: 2.848, year: 2009

  14. Designing and testing computer based screening engine for severe sepsis/septic shock.

    Science.gov (United States)

    Herasevich, V; Afessa, B; Chute, C G; Gajic, O

    2008-11-06

    This study addresses the role of a sepsis "sniffer", an automatic screening tool for the timely identification of patients with severe sepsis/septic shock, based electronic medical records. During the two months prospective implementation in a medical intensive care unit, 37 of 320 consecutive patients developed severe sepsis/septic shock. The sniffer demonstrated a sensitivity of 48% and specificity of 86%, and positive predictive value 32%. Further improvements are needed prior to the implementation of sepsis sniffer in clinical practice and research.

  15. The effects of induced oblique astigmatism on symptoms and reading performance while viewing a computer screen.

    Science.gov (United States)

    Rosenfield, Mark; Hue, Jennifer E; Huang, Rae R; Bababekova, Yuliya

    2012-03-01

    Computer vision syndrome (CVS) is a complex of eye and vision problems related to computer use which has been reported in up to 90% of computer users. Ocular symptoms may include asthenopia, accommodative and vergence difficulties and dry eye. Previous studies have reported that uncorrected astigmatism may have a significant impact on symptoms of CVS. However, its effect on task performance is unclear. This study recorded symptoms after a 10 min period of reading from a computer monitor either through the habitual distance refractive correction or with a supplementary -1.00 or -2.00D oblique cylinder added over these lenses in 12 young, visually-normal subjects. Additionally, the distance correction condition was repeated to assess the repeatability of the symptom questionnaire. Subjects' reading speed and accuracy were monitored during the course of the 10 min trial. There was no significant difference in reading rate or the number of errors between the three astigmatic conditions. However, a significant change in symptoms was reported with the median total symptom scores for the 0, 1 and 2D astigmatic conditions being 2.0, 6.5 and 40.0, respectively (p computer operation. Ophthalmic & Physiological Optics © 2011 The College of Optometrists.

  16. Mass prophylactic screening of the organized female populaton using the Thermograph-Computer System

    International Nuclear Information System (INIS)

    Vepkhvadze, R.Ya.; Khvedelidze, E.Sh.

    1984-01-01

    Organizational aspects of the Thermograph Computer System usage have been analyzed. It has been shown that results of thermodiagnosis completely coincide with clinical conclusion, but roentrenological method permits to reveal a disease only for 19 patients from 36 ones. It is possible to examine 120 women for the aim of early diagnosis of mammary gland diseases during the day operating hours with the use of the Thermograph Computer System. A movable thermodiagnostic room simultaneoUsly served as an inspection room to discover visual forms of tumor diseases including diseases of cervix uteri and may be used for mass preventive examination of the organized female population

  17. DESIGN AND DEVELOP A COMPUTER AIDED DESIGN FOR AUTOMATIC EXUDATES DETECTION FOR DIABETIC RETINOPATHY SCREENING

    Directory of Open Access Journals (Sweden)

    C. A. SATHIYAMOORTHY

    2016-04-01

    Full Text Available Diabetic Retinopathy is a severe and widely spread eye disease which can lead to blindness. One of the main symptoms for vision loss is Exudates and it could be prevented by applying an early screening process. In the Existing systems, a Fuzzy C-Means Clustering technique is used for detecting the exudates for analyzation. The main objective of this paper is, to improve the efficiency of the Exudates detection in diabetic retinopathy images. To do this, a three Stage – [TS] approach is introduced for detecting and extracting the exudates automatically from the retinal images for screening the Diabetic retinopathy. TS functions on the image in three levels such as Pre-processing the image, enhancing the image and detecting the Exudates accurately. After successful detection, the detected exudates are classified using GLCM method for finding the accuracy. The TS approach is experimented using MATLAB software and the performance evaluation can be proved by comparing the results with the existing approach’s result and with the hand-drawn ground truths images from the expert ophthalmologist.

  18. Development of an HTS-Compatible Assay for Discovery of Melanoma-Related Microphthalmia Transcription Factor Disruptors Using AlphaScreen Technology.

    Science.gov (United States)

    Wang, Jing; Fang, Pengfei; Chase, Peter; Tshori, Sagi; Razin, Ehud; Spicer, Timothy P; Scampavia, Louis; Hodder, Peter; Guo, Min

    2017-01-01

    Microphthalmia transcription factor (MITF) is a master transcription factor expressed in melanocytes, essential for melanocyte survival, differentiation, and pigment formation, and is a key oncogenic factor in melanoma initiation, migration, and treatment resistance. Although identified as an important therapeutic target for melanoma, clinical inhibitors directly targeting the MITF protein are not available. Based on the functional state of MITF, we have designed an MITF dimerization-based AlphaScreen (MIDAS) assay that sensitively and specifically mirrors the dimerization of MITF in vitro. This assay is further exploited for identification of the MITF dimer disruptor for high-throughput screening. A pilot screen against a library of 1280 pharmacologically active compounds indicates that the MIDAS assay performance exhibits exceptional results with a Z' factor of 0.81 and a signal-to-background (S/B) ratio of 3.92 while identifying initial hit compounds that yield an ability to disrupt MITF-DNA interaction. The results presented demonstrate that the MIDAS assay is ready to screen large chemical libraries in order to discover novel modulators of MITF for potential melanoma treatment.

  19. Drug discovery for schistosomiasis: hit and lead compounds identified in a library of known drugs by medium-throughput phenotypic screening.

    Directory of Open Access Journals (Sweden)

    Maha-Hamadien Abdulla

    2009-07-01

    Full Text Available Praziquantel (PZQ is the only widely available drug to treat schistosomiasis. Given the potential for drug resistance, it is prudent to search for novel therapeutics. Identification of anti-schistosomal chemicals has traditionally relied on phenotypic (whole organism screening with adult worms in vitro and/or animal models of disease-tools that limit automation and throughput with modern microtiter plate-formatted compound libraries.A partially automated, three-component phenotypic screen workflow is presented that utilizes at its apex the schistosomular stage of the parasite adapted to a 96-well plate format with a throughput of 640 compounds per month. Hits that arise are subsequently screened in vitro against adult parasites and finally for efficacy in a murine model of disease. Two GO/NO GO criteria filters in the workflow prioritize hit compounds for tests in the animal disease model in accordance with a target drug profile that demands short-course oral therapy. The screen workflow was inaugurated with 2,160 chemically diverse natural and synthetic compounds, of which 821 are drugs already approved for human use. This affords a unique starting point to 'reposition' (re-profile drugs as anti-schistosomals with potential savings in development timelines and costs.Multiple and dynamic phenotypes could be categorized for schistosomula and adults in vitro, and a diverse set of 'hit' drugs and chemistries were identified, including anti-schistosomals, anthelmintics, antibiotics, and neuromodulators. Of those hits prioritized for tests in the animal disease model, a number of leads were identified, one of which compares reasonably well with PZQ in significantly decreasing worm and egg burdens, and disease-associated pathology. Data arising from the three components of the screen are posted online as a community resource.To accelerate the identification of novel anti-schistosomals, we have developed a partially automated screen workflow that

  20. Higgs Discovery

    DEFF Research Database (Denmark)

    Sannino, Francesco

    2013-01-01

    has been challenged by the discovery of a not-so-heavy Higgs-like state. I will therefore review the recent discovery \\cite{Foadi:2012bb} that the standard model top-induced radiative corrections naturally reduce the intrinsic non-perturbative mass of the composite Higgs state towards the desired...... via first principle lattice simulations with encouraging results. The new findings show that the recent naive claims made about new strong dynamics at the electroweak scale being disfavoured by the discovery of a not-so-heavy composite Higgs are unwarranted. I will then introduce the more speculative......I discuss the impact of the discovery of a Higgs-like state on composite dynamics starting by critically examining the reasons in favour of either an elementary or composite nature of this state. Accepting the standard model interpretation I re-address the standard model vacuum stability within...

  1. Single reading with computer-aided detection performed by selected radiologists in a breast cancer screening program

    Energy Technology Data Exchange (ETDEWEB)

    Bargalló, Xavier, E-mail: xbarga@clinic.cat [Department of Radiology (CDIC), Hospital Clínic de Barcelona, C/ Villarroel, 170, 08036 Barcelona (Spain); Santamaría, Gorane; Amo, Montse del; Arguis, Pedro [Department of Radiology (CDIC), Hospital Clínic de Barcelona, C/ Villarroel, 170, 08036 Barcelona (Spain); Ríos, José [Biostatistics and Data Management Core Facility, IDIBAPS, (Hospital Clinic) C/ Mallorca, 183. Floor -1. Office #60. 08036 Barcelona (Spain); Grau, Jaume [Preventive Medicine and Epidemiology Unit, Hospital Clínic de Barcelona, C/ Villarroel, 170, 08036 Barcelona (Spain); Burrel, Marta; Cores, Enrique; Velasco, Martín [Department of Radiology (CDIC), Hospital Clínic de Barcelona, C/ Villarroel, 170, 08036 Barcelona (Spain)

    2014-11-15

    Highlights: • 1-The cancer detection rate of the screening program improved using a single reading protocol by experienced radiologists assisted by CAD. • 2-The cancer detection rate improved at the cost of increasing recall rate. • 3-CAD, used by breast radiologists, did not help to detect more cancers. - Abstract: Objectives: To assess the impact of shifting from a standard double reading plus arbitration protocol to a single reading by experienced radiologists assisted by computer-aided detection (CAD) in a breast cancer screening program. Methods: This was a prospective study approved by the ethics committee. Data from 21,321 consecutive screening mammograms in incident rounds (2010–2012) were read following a single reading plus CAD protocol and compared with data from 47,462 consecutive screening mammograms in incident rounds (2004–2010) that were interpreted following a double reading plus arbitration protocol. For the single reading, radiologists were selected on the basis of the appraisement of their previous performance. Results: Period 2010–2012 vs. period 2004–2010: Cancer detection rate (CDR): 6.1‰ (95% confidence interval: 5.1–7.2) vs. 5.25‰; Recall rate (RR): 7.02% (95% confidence interval: 6.7–7.4) vs. 7.24% (selected readers before arbitration) and vs. 3.94 (all readers after arbitration); Predictive positive value of recall: 8.69% vs. 13.32%. Average size of invasive cancers: 14.6 ± 9.5 mm vs. 14.3 ± 9.5 mm. Stage: 0 (22.3/26.1%); I (59.2/50.8%); II (19.2/17.1%); III (3.1/3.3%); IV (0/1.9%). Specialized breast radiologists performed better than general radiologists. Conclusions: The cancer detection rate of the screening program improved using a single reading protocol by experienced radiologists assisted by CAD, at the cost of a moderate increase of the recall rate mainly related to the lack of arbitration.

  2. Computational challenges and human factors influencing the design and use of clinical research participant eligibility pre-screening tools

    Directory of Open Access Journals (Sweden)

    Pressler Taylor R

    2012-05-01

    Full Text Available Abstract Background Clinical trials are the primary mechanism for advancing clinical care and evidenced-based practice, yet challenges with the recruitment of participants for such trials are widely recognized as a major barrier to these types of studies. Data warehouses (DW store large amounts of heterogenous clinical data that can be used to enhance recruitment practices, but multiple challenges exist when using a data warehouse for such activities, due to the manner of collection, management, integration, analysis, and dissemination of the data. A critical step in leveraging the DW for recruitment purposes is being able to match trial eligibility criteria to discrete and semi-structured data types in the data warehouse, though trial eligibility criteria tend to be written without concern for their computability. We present the multi-modal evaluation of a web-based tool that can be used for pre-screening patients for clinical trial eligibility and assess the ability of this tool to be practically used for clinical research pre-screening and recruitment. Methods The study used a validation study, usability testing, and a heuristic evaluation to evaluate and characterize the operational characteristics of the software as well as human factors affecting its use. Results Clinical trials from the Division of Cardiology and the Department of Family Medicine were used for this multi-modal evaluation, which included a validation study, usability study, and a heuristic evaluation. From the results of the validation study, the software demonstrated a positive predictive value (PPV of 54.12% and 0.7%, respectively, and a negative predictive value (NPV of 73.3% and 87.5%, respectively, for two types of clinical trials. Heuristic principles concerning error prevention and documentation were characterized as the major usability issues during the heuristic evaluation. Conclusions This software is intended to provide an initial list of eligible patients to a

  3. A TALE-inspired computational screen for proteins that contain approximate tandem repeats.

    Science.gov (United States)

    Perycz, Malgorzata; Krwawicz, Joanna; Bochtler, Matthias

    2017-01-01

    TAL (transcription activator-like) effectors (TALEs) are bacterial proteins that are secreted from bacteria to plant cells to act as transcriptional activators. TALEs and related proteins (RipTALs, BurrH, MOrTL1 and MOrTL2) contain approximate tandem repeats that differ in conserved positions that define specificity. Using PERL, we screened ~47 million protein sequences for TALE-like architecture characterized by approximate tandem repeats (between 30 and 43 amino acids in length) and sequence variability in conserved positions, without requiring sequence similarity to TALEs. Candidate proteins were scored according to their propensity for nuclear localization, secondary structure, repeat sequence complexity, as well as covariation and predicted structural proximity of variable residues. Biological context was tentatively inferred from co-occurrence of other domains and interactome predictions. Approximate repeats with TALE-like features that merit experimental characterization were found in a protein of chestnut blight fungus, a eukaryotic plant pathogen.

  4. Remote Forensics May Bring the Next Sea Change in E-discovery: Are All Networked Computers Now Readily Accessible Under the Revised Federal Rules of Civil Procedure?

    Directory of Open Access Journals (Sweden)

    AleJoseph J. Schwerha

    2008-09-01

    Full Text Available The recent amendments to Rule 26 of the Federal Rules of Civil Procedure created a two-tiered approach to discovery of electronically stored information (“ESI”. Responding parties must produce ESI that is relevant, not subject to privilege, and reasonably accessible. However, because some methods of storing ESI, such as on magnetic backup tapes and within enormous databases, require substantial cost to access and search their contents, the rules permit parties to designate those repositories as “not reasonably accessible” because of undue burden or cost. But even despite the difficulty in searching for ESI, the party’s duty to preserve potentially responsive evidence remains; it simply gains the option to forgo poring over the material. Further, the court might nevertheless compel production if the requesting party demonstrates good cause.Regardless of whether the responding party believes certain documents to be reasonably accessible or not, courts may still require their production.   In such cases, the court may then choose to order production, but shift the costs of doing so to the requesting party.  Throughout this process, the burden and cost of production are central themes.   Their determination is fluid, varying from case to case and even over time in the same situation.   Nowhere is this more evident than where a responding party has numerous, geographically dispersed computers under its control that may contain responsive ESI to a request for production of documents.  Traditionally, a responding party would be forced to make a decision of whether or not to send out computer forensic experts to all of these locations to make forensically sound copies of all of those computers and then analyze each.   This process is time consuming and costly.  Recently, several companies have put forth substantial solutions that facially allow a responding party to capture and analyze data

  5. Positioning graphical objects on computer screens: a three-phase model.

    Science.gov (United States)

    Pastel, Robert

    2011-02-01

    This experiment identifies and models phases during the positioning of graphical objects (called cursors in this article) on computer displays. The human computer-interaction community has traditionally used Fitts' law to model selection in graphical user interfaces, whereas human factors experiments have found the single-component Fitts' law inadequate to model positioning of real objects. Participants (N=145) repeatedly positioned variably sized square cursors within variably sized rectangular targets using computer mice. The times for the cursor to just touch the target, for the cursor to enter the target, and for participants to indicate positioning completion were observed. The positioning tolerances were varied from very precise and difficult to imprecise and easy. The time for the cursor to touch the target was proportional to the initial cursor-target distance. The time for the cursor to completely enter the target after touching was proportional to the logarithms of cursor size divided by target tolerances. The time for participants to indicate positioning after entering was inversely proportional to the tolerance. A three-phase model defined by regions--distant, proximate, and inside the target--was proposed and could model the positioning tasks. The three-phase model provides a framework for ergonomists to evaluate new positioning techniques and can explain their deficiencies. The model provides a means to analyze tasks and enhance interaction during positioning.

  6. Computation of Resonance-Screened Cross Section by the Dorix-Speng System

    Energy Technology Data Exchange (ETDEWEB)

    Haeggblom, H

    1968-09-15

    The report describes a scheme for computation of group cross sections for fast reactors in energy regions where the resonance structure of the cross sections may be dense. A combination of the programmes Dorix and Speng is then used. Dorix calculates group cross sections for each resonance absorber separately. The interaction between resolved resonances in the same isotope is treated using a method described in a separate report. The interaction between correlated and non-correlated resonances in the unresolved region is also considered. By a Dorix calculation we obtain effective microscopic cross sections which are then read in on a library tape. This library contains both point-by-point data and group cross sections and is used in the Speng programme for computation of spectrum and/or macroscopic cross sections. The resonance interaction between different isotopes is computed in Speng by the same method as was used in the Dorix programme for non-correlated unresolved resonances. Consideration is also given to the width of the resonances compared to the energy loss by a neutron colliding with some of the scattering elements.

  7. Computation of Resonance-Screened Cross Section by the Dorix-Speng System

    International Nuclear Information System (INIS)

    Haeggblom, H.

    1968-09-01

    The report describes a scheme for computation of group cross sections for fast reactors in energy regions where the resonance structure of the cross sections may be dense. A combination of the programmes Dorix and Speng is then used. Dorix calculates group cross sections for each resonance absorber separately. The interaction between resolved resonances in the same isotope is treated using a method described in a separate report. The interaction between correlated and non-correlated resonances in the unresolved region is also considered. By a Dorix calculation we obtain effective microscopic cross sections which are then read in on a library tape. This library contains both point-by-point data and group cross sections and is used in the Speng programme for computation of spectrum and/or macroscopic cross sections. The resonance interaction between different isotopes is computed in Speng by the same method as was used in the Dorix programme for non-correlated unresolved resonances. Consideration is also given to the width of the resonances compared to the energy loss by a neutron colliding with some of the scattering elements

  8. Discovery of potent, novel, non-toxic anti-malarial compounds via quantum modelling, virtual screening and in vitro experimental validation

    Directory of Open Access Journals (Sweden)

    Kaludov Nikola

    2011-09-01

    Full Text Available Abstract Background Developing resistance towards existing anti-malarial therapies emphasize the urgent need for new therapeutic options. Additionally, many malaria drugs in use today have high toxicity and low therapeutic indices. Gradient Biomodeling, LLC has developed a quantum-model search technology that uses quantum similarity and does not depend explicitly on chemical structure, as molecules are rigorously described in fundamental quantum attributes related to individual pharmacological properties. Therapeutic activity, as well as toxicity and other essential properties can be analysed and optimized simultaneously, independently of one another. Such methodology is suitable for a search of novel, non-toxic, active anti-malarial compounds. Methods A set of innovative algorithms is used for the fast calculation and interpretation of electron-density attributes of molecular structures at the quantum level for rapid discovery of prospective pharmaceuticals. Potency and efficacy, as well as additional physicochemical, metabolic, pharmacokinetic, safety, permeability and other properties were characterized by the procedure. Once quantum models are developed and experimentally validated, the methodology provides a straightforward implementation for lead discovery, compound optimizzation and de novo molecular design. Results Starting with a diverse training set of 26 well-known anti-malarial agents combined with 1730 moderately active and inactive molecules, novel compounds that have strong anti-malarial activity, low cytotoxicity and structural dissimilarity from the training set were discovered and experimentally validated. Twelve compounds were identified in silico and tested in vitro; eight of them showed anti-malarial activity (IC50 ≤ 10 μM, with six being very effective (IC50 ≤ 1 μM, and four exhibiting low nanomolar potency. The most active compounds were also tested for mammalian cytotoxicity and found to be non-toxic, with a

  9. The efficacy of using computer-aided detection (CAD) for detection of breast cancer in mammography screening: a systematic review.

    Science.gov (United States)

    Henriksen, Emilie L; Carlsen, Jonathan F; Vejborg, Ilse Mm; Nielsen, Michael B; Lauridsen, Carsten A

    2018-01-01

    Background Early detection of breast cancer (BC) is crucial in lowering the mortality. Purpose To present an overview of studies concerning computer-aided detection (CAD) in screening mammography for early detection of BC and compare diagnostic accuracy and recall rates (RR) of single reading (SR) with SR + CAD and double reading (DR) with SR + CAD. Material and Methods PRISMA guidelines were used as a review protocol. Articles on clinical trials concerning CAD for detection of BC in a screening population were included. The literature search resulted in 1522 records. A total of 1491 records were excluded by abstract and 18 were excluded by full text reading. A total of 13 articles were included. Results All but two studies from the SR vs. SR + CAD group showed an increased sensitivity and/or cancer detection rate (CDR) when adding CAD. The DR vs. SR + CAD group showed no significant differences in sensitivity and CDR. Adding CAD to SR increased the RR and decreased the specificity in all but one study. For the DR vs. SR + CAD group only one study reported a significant difference in RR. Conclusion All but two studies showed an increase in RR, sensitivity and CDR when adding CAD to SR. Compared to DR no statistically significant differences in sensitivity or CDR were reported. Additional studies based on organized population-based screening programs, with longer follow-up time, high-volume readers, and digital mammography are needed to evaluate the efficacy of CAD.

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

    Science.gov (United States)

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

    2008-10-01

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

  11. A Study for Visual Realism of Designed Pictures on Computer Screens by Investigation and Brain-Wave Analyses.

    Science.gov (United States)

    Wang, Lan-Ting; Lee, Kun-Chou

    2016-08-01

    In this article, the visual realism of designed pictures on computer screens is studied by investigation and brain-wave analyses. The practical electroencephalogram (EEG) measurement is always time-varying and fluctuating so that conventional statistical techniques are not adequate for analyses. This study proposes a new scheme based on "fingerprinting" to analyze the EEG. Fingerprinting is a technique of probabilistic pattern recognition used in electrical engineering, very like the identification of human fingerprinting in a criminal investigation. The goal of this study was to assess whether subjective preference for pictures could be manifested physiologically by EEG fingerprinting analyses. The most important advantage of the fingerprinting technique is that it does not require accurate measurement. Instead, it uses probabilistic classification. Participants' preference for pictures can be assessed using fingerprinting analyses of physiological EEG measurements. © The Author(s) 2016.

  12. Osteoporosis markers on low-dose lung cancer screening chest computed tomography scans predict all-cause mortality

    Energy Technology Data Exchange (ETDEWEB)

    Buckens, C.F. [University Medical Center Utrecht, Radiology Department, Utrecht (Netherlands); University Medical Center Utrecht, Julius Center for Health Sciences and Primary Care, Utrecht (Netherlands); Graaf, Y. van der [University Medical Center Utrecht, Julius Center for Health Sciences and Primary Care, Utrecht (Netherlands); Verkooijen, H.M.; Mali, W.P.; Jong, P.A. de [University Medical Center Utrecht, Radiology Department, Utrecht (Netherlands); Isgum, I.; Mol, C.P. [University Medical Center Utrecht, Image Sciences Institute, Utrecht (Netherlands); Verhaar, H.J. [University Medical Center Utrecht, Department of Geriatric Medicine, Utrecht (Netherlands); Vliegenthart, R.; Oudkerk, M. [Medical Center Groningen, Department of Radiology, Utrecht (Netherlands); Aalst, C.M. van; Koning, H.J. de [Erasmus MC Rotterdam, Department of Public Health, Rotterdam (Netherlands)

    2015-01-15

    Further survival benefits may be gained from low-dose chest computed tomography (CT) by assessing vertebral fractures and bone density. We sought to assess the association between CT-measured vertebral fractures and bone density with all-cause mortality in lung cancer screening participants. Following a case-cohort design, lung cancer screening trial participants (N = 3,673) who died (N = 196) during a median follow-up of 6 years (inter-quartile range: 5.7-6.3) were identified and added to a random sample of N = 383 from the trial. We assessed vertebral fractures using Genant and acute;s semiquantative method on sagittal reconstructions and measured bone density (Hounsfield Units (HU)) in vertebrae. Cox proportional hazards modelling was used to determine if vertebral fractures or bone density were independently predictive of mortality. The prevalence of vertebral fractures was 35 % (95 % confidence interval 30-40 %) among survivors and 51 % (44-58 %) amongst cases. After adjusting for age, gender, smoking status, pack years smoked, coronary and aortic calcium volume and pulmonary emphysema, the adjusted hazard ratio (HR) for vertebral fracture was 2.04 (1.43-2.92). For each 10 HU decline in trabecular bone density, the adjusted HR was 1.08 (1.02-1.15). Vertebral fractures and bone density are independently associated with all-cause mortality. (orig.)

  13. Comparison of standard reading and computer aided detection (CAD) on a national proficiency test of screening mammography

    International Nuclear Information System (INIS)

    Ciatto, Stefano; Del Turco, Marco Rosselli; Risso, Gabriella; Catarzi, Sandra; Bonardi, Rita; Viterbo, Valeria; Gnutti, Pierangela; Guglielmoni, Barbara; Pinelli, Lelio; Pandiscia, Anna; Navarra, Francesco; Lauria, Adele; Palmiero, Rosa; Indovina, Pietro Luigi

    2003-01-01

    Objective: To evaluate the role of computer aided detection (CAD) in improving the interpretation of screening mammograms Material and methods: Ten radiologists underwent a proficiency test of screening mammography first by conventional reading and then with the help of CAD. Radiologists were blinded to test results for the whole study duration. Results of conventional and CAD reading were compared in terms of sensitivity and recall rate. Double reading was simulated combining conventional readings of four expert radiologists and compared with CAD reading. Results: Considering all ten readings, cancer was identified in 146 or 153 of 170 cases (85.8 vs. 90.0%; χ 2 =0.99, df=1, P=0.31) and recalls were 106 or 152 of 1330 cases (7.9 vs. 11.4%; χ 2 =8.69, df=1, P=0.003) at conventional or CAD reading, respectively. CAD reading was essentially the same (sensitivity 97.0 vs. 96.0%; χ 2 =7.1, df=1, P=0.93; recall rate 10.7 vs. 10.6%; χ 2 =1.5, df=1, P=0.96) as compared with simulated conventional double reading. Conclusion: CAD reading seems to improve the sensitivity of conventional reading while reducing specificity, both effects being of limited size. CAD reading had almost the same performance of simulated conventional double reading, suggesting a possible use of CAD which needs to be confirmed by further studies inclusive of cost-effective analysis

  14. Osteoporosis markers on low-dose lung cancer screening chest computed tomography scans predict all-cause mortality

    International Nuclear Information System (INIS)

    Buckens, C.F.; Graaf, Y. van der; Verkooijen, H.M.; Mali, W.P.; Jong, P.A. de; Isgum, I.; Mol, C.P.; Verhaar, H.J.; Vliegenthart, R.; Oudkerk, M.; Aalst, C.M. van; Koning, H.J. de

    2015-01-01

    Further survival benefits may be gained from low-dose chest computed tomography (CT) by assessing vertebral fractures and bone density. We sought to assess the association between CT-measured vertebral fractures and bone density with all-cause mortality in lung cancer screening participants. Following a case-cohort design, lung cancer screening trial participants (N = 3,673) who died (N = 196) during a median follow-up of 6 years (inter-quartile range: 5.7-6.3) were identified and added to a random sample of N = 383 from the trial. We assessed vertebral fractures using Genant and acute;s semiquantative method on sagittal reconstructions and measured bone density (Hounsfield Units (HU)) in vertebrae. Cox proportional hazards modelling was used to determine if vertebral fractures or bone density were independently predictive of mortality. The prevalence of vertebral fractures was 35 % (95 % confidence interval 30-40 %) among survivors and 51 % (44-58 %) amongst cases. After adjusting for age, gender, smoking status, pack years smoked, coronary and aortic calcium volume and pulmonary emphysema, the adjusted hazard ratio (HR) for vertebral fracture was 2.04 (1.43-2.92). For each 10 HU decline in trabecular bone density, the adjusted HR was 1.08 (1.02-1.15). Vertebral fractures and bone density are independently associated with all-cause mortality. (orig.)

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

    Science.gov (United States)

    Brylinski, Michal; Waldrop, Grover L

    2014-04-02

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

  16. Computer-delivered indirect screening and brief intervention for drug use in the perinatal period: A randomized trial.

    Science.gov (United States)

    Ondersma, Steven J; Svikis, Dace S; Thacker, Casey; Resnicow, Ken; Beatty, Jessica R; Janisse, James; Puder, Karoline

    2018-04-01

    Under-reporting of drug use in the perinatal period is well-documented, and significantly limits the reach of proactive intervention approaches. The Wayne Indirect Drug Use Screener (WIDUS) focuses on correlates of drug use rather than use itself. This trial tested a computer-delivered, brief intervention designed for use with indirect screen-positive cases, seeking to motivate reductions in drug use without presuming its presence. Randomized clinical trial with 500 WIDUS-positive postpartum women recruited between August 14, 2012 and November 19, 2014. Participants were randomly assigned to either a time control condition or a single-session, tailored, indirect brief intervention. The primary outcome was days of drug use over the 6-month follow-up period; secondary outcomes included urine and hair analyses results at 3- and 6-month follow-up. All outcomes were measured by blinded evaluators. Of the 500 participants (252 intervention and 248 control), 36.1% of participants acknowledged drug use in the 3 months prior to pregnancy, but 89% tested positive at the 6-month follow-up. Participants rated the intervention as easy to use (4.9/5) and helpful (4.4/5). Analyses revealed no between-group differences in drug use (52% in the intervention group, vs. 53% among controls; OR 1.03). Exploratory analyses also showed that intervention effects were not moderated by baseline severity, WIDUS score, or readiness to change. The present trial showed no evidence of efficacy for an indirect, single-session, computer-delivered, brief intervention designed as a complement to indirect screening. More direct approaches that still do not presume active drug use may be possible and appropriate. Copyright © 2018 Elsevier B.V. All rights reserved.

  17. Computational screening and molecular dynamics simulation of disease associated nsSNPs in CENP-E

    Energy Technology Data Exchange (ETDEWEB)

    Kumar, Ambuj [Bioinformatics Division, School of Bio Sciences and Technology, Vellore Institute of Technology University, Vellore 632014, Tamil Nadu (India); Purohit, Rituraj, E-mail: riturajpurohit@gmail.com [Bioinformatics Division, School of Bio Sciences and Technology, Vellore Institute of Technology University, Vellore 632014, Tamil Nadu (India)

    2012-10-15

    Aneuploidy and chromosomal instability (CIN) are hallmarks of most solid tumors. Mutations in centroemere proteins have been observed in promoting aneuploidy and tumorigenesis. Recent studies reported that Centromere-associated protein-E (CENP-E) is involved in inducing cancers. In this study we investigated the pathogenic effect of 132 nsSNPs reported in CENP-E using computational platform. Y63H point mutation found to be associated with cancer using SIFT, Polyphen, PhD-SNP, MutPred, CanPredict and Dr. Cancer tools. Further we investigated the binding affinity of ATP molecule to the CENP-E motor domain. Complementarity scores obtained from docking studies showed significant loss in ATP binding affinity of mutant structure. Molecular dynamics simulation was carried to examine the structural consequences of Y63H mutation. Root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration (R{sub g}), solvent accessibility surface area (SASA), energy value, hydrogen bond (NH Bond), eigenvector projection, trace of covariance matrix and atom density analysis results showed notable loss in stability for mutant structure. Y63H mutation was also shown to disrupt the native conformation of ATP binding region in CENP-E motor domain. Docking studies for remaining 18 mutations at 63rd residue position as well as other two computationally predicted disease associated mutations S22L and P69S were also carried to investigate their affect on ATP binding affinity of CENP-E motor domain. Our study provided a promising computational methodology to study the tumorigenic consequences of nsSNPs that have not been characterized and clear clue to the wet lab scientist.

  18. Computational screening and molecular dynamics simulation of disease associated nsSNPs in CENP-E

    International Nuclear Information System (INIS)

    Kumar, Ambuj; Purohit, Rituraj

    2012-01-01

    Aneuploidy and chromosomal instability (CIN) are hallmarks of most solid tumors. Mutations in centroemere proteins have been observed in promoting aneuploidy and tumorigenesis. Recent studies reported that Centromere-associated protein-E (CENP-E) is involved in inducing cancers. In this study we investigated the pathogenic effect of 132 nsSNPs reported in CENP-E using computational platform. Y63H point mutation found to be associated with cancer using SIFT, Polyphen, PhD-SNP, MutPred, CanPredict and Dr. Cancer tools. Further we investigated the binding affinity of ATP molecule to the CENP-E motor domain. Complementarity scores obtained from docking studies showed significant loss in ATP binding affinity of mutant structure. Molecular dynamics simulation was carried to examine the structural consequences of Y63H mutation. Root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration (R g ), solvent accessibility surface area (SASA), energy value, hydrogen bond (NH Bond), eigenvector projection, trace of covariance matrix and atom density analysis results showed notable loss in stability for mutant structure. Y63H mutation was also shown to disrupt the native conformation of ATP binding region in CENP-E motor domain. Docking studies for remaining 18 mutations at 63rd residue position as well as other two computationally predicted disease associated mutations S22L and P69S were also carried to investigate their affect on ATP binding affinity of CENP-E motor domain. Our study provided a promising computational methodology to study the tumorigenic consequences of nsSNPs that have not been characterized and clear clue to the wet lab scientist.

  19. Value of computed tomography as a screening examination of pancreatic cancer

    International Nuclear Information System (INIS)

    Honda, Hiroshi; Watanabe, Katsushi; Nishikawa, Kiyoshi

    1983-01-01

    The abdominal CT films of 50 patients were reviewed by ten radiologists to evaluate the role of CT examination in the screening of pancreatic cancer. The 50 patients consisted of 10 with pancreatic cancer, 8 with other pancreatic abnormalities, and 32 with normal pancreas. Ten radiologists were divided into two groups according to their experience in evaluating CT examinations, an experienced group and an unexperienced group, respectively. In the detectability of pancreatic abnormality, the experienced group showed a sensitivity of 72.2% and a specificity of 86.2%. The unexperienced group showed a sensitivity of 70.9% and a specificity of 72.0%. In the detectability of pancreatic cancer, the experienced group showed a sensitivity of 62.0% and a specificity of 83.4%. The unexperienced group showed a sensitivity of 66.0% and a specificity of 81.8%. In the localization of the pancreatic cancer, there was no difference between the two groups. Pancreatic abnormality can be detected with high accuracy, but diagnosis of the nature of pancreatic cancer is difficult. Experience in evaluating CT examinations elevates the detectability of pancreatic abnormality but does not elevate the detectability of pancreatic cancer. These results suggest the difficulty in diagnosis of pancreatic cancer. (author)

  20. Development and initial testing of a computer-based patient decision aid to promote colorectal cancer screening for primary care practice

    Directory of Open Access Journals (Sweden)

    Fowler Beth

    2005-11-01

    Full Text Available Abstract Background Although colorectal cancer screening is recommended by major policy-making organizations, rates of screening remain low. Our aim was to develop a patient-directed, computer-based decision aid about colorectal cancer screening and investigate whether it could increase patient interest in screening. Methods We used content from evidence-based literature reviews and our previous decision aid research to develop a prototype. We performed two rounds of usability testing with representative patients to revise the content and format. The final decision aid consisted of an introductory segment, four test-specific segments, and information to allow comparison of the tests across several key parameters. We then conducted a before-after uncontrolled trial of 80 patients 50–75 years old recruited from an academic internal medicine practice. Results Mean viewing time was 19 minutes. The decision aid improved patients' intent to ask providers for screening from a mean score of 2.8 (1 = not at all likely to ask, 4 = very likely to ask before viewing the decision aid to 3.2 afterwards (difference, 0.4; p Conclusion We conclude that a computer-based decision aid can increase patient intent to be screened and increase interest in screening. Practice Implications: This decision aid can be viewed by patients prior to provider appointments to increase motivation to be screened and to help them decide about which modality to use for screening. Further work is required to integrate the decision aid with other practice change strategies to raise screening rates to target levels.

  1. Computationally assisted screening and design of cell-interactive peptides by a cell-based assay using peptide arrays and a fuzzy neural network algorithm.

    Science.gov (United States)

    Kaga, Chiaki; Okochi, Mina; Tomita, Yasuyuki; Kato, Ryuji; Honda, Hiroyuki

    2008-03-01

    We developed a method of effective peptide screening that combines experiments and computational analysis. The method is based on the concept that screening efficiency can be enhanced from even limited data by use of a model derived from computational analysis that serves as a guide to screening and combining the model with subsequent repeated experiments. Here we focus on cell-adhesion peptides as a model application of this peptide-screening strategy. Cell-adhesion peptides were screened by use of a cell-based assay of a peptide array. Starting with the screening data obtained from a limited, random 5-mer library (643 sequences), a rule regarding structural characteristics of cell-adhesion peptides was extracted by fuzzy neural network (FNN) analysis. According to this rule, peptides with unfavored residues in certain positions that led to inefficient binding were eliminated from the random sequences. In the restricted, second random library (273 sequences), the yield of cell-adhesion peptides having an adhesion rate more than 1.5-fold to that of the basal array support was significantly high (31%) compared with the unrestricted random library (20%). In the restricted third library (50 sequences), the yield of cell-adhesion peptides increased to 84%. We conclude that a repeated cycle of experiments screening limited numbers of peptides can be assisted by the rule-extracting feature of FNN.

  2. Computer-aided discovery of debris disk candidates: A case study using the Wide-Field Infrared Survey Explorer (WISE) catalog

    Science.gov (United States)

    Nguyen, T.; Pankratius, V.; Eckman, L.; Seager, S.

    2018-04-01

    Debris disks around stars other than the Sun have received significant attention in studies of exoplanets, specifically exoplanetary system formation. Since debris disks are major sources of infrared emissions, infrared survey data such as the Wide-Field Infrared Survey (WISE) catalog potentially harbors numerous debris disk candidates. However, it is currently challenging to perform disk candidate searches for over 747 million sources in the WISE catalog due to the high probability of false positives caused by interstellar matter, galaxies, and other background artifacts. Crowdsourcing techniques have thus started to harness citizen scientists for debris disk identification since humans can be easily trained to distinguish between desired artifacts and irrelevant noises. With a limited number of citizen scientists, however, increasing data volumes from large surveys will inevitably lead to analysis bottlenecks. To overcome this scalability problem and push the current limits of automated debris disk candidate identification, we present a novel approach that uses citizen science results as a seed to train machine learning based classification. In this paper, we detail a case study with a computer-aided discovery pipeline demonstrating such feasibility based on WISE catalog data and NASA's Disk Detective project. Our approach of debris disk candidates classification was shown to be robust under a wide range of image quality and features. Our hybrid approach of citizen science with algorithmic scalability can facilitate big data processing for future detections as envisioned in future missions such as the Transiting Exoplanet Survey Satellite (TESS) and the Wide-Field Infrared Survey Telescope (WFIRST).

  3. Meta-analysis of two computer-assisted screening methods for diagnosing oral precancer and cancer.

    Science.gov (United States)

    Ye, Xiaojing; Zhang, Jing; Tan, Yaqin; Chen, Guanying; Zhou, Gang

    2015-11-01

    The early diagnosis of oral precancer and cancer is crucial and could have the highest impact on improving survival rates. A meta-analysis was conducted to compare the accuracy between the OralCDx brush biopsy and DNA-image cytometry in diagnosing both conditions. Bibliographic databases were systematically searched for original relevant studies on the early diagnosis of oral precancer and oral cancer. Study characteristics were evaluated to determine the accuracy of the two screening strategies. Thirteen studies (eight of OralCDx brush biopsy and five of DNA-image cytometry) were identified as having reported on 1981 oral mucosa lesions. The meta-analysis found that the area under the summary receiver operating characteristic curves of the OralCDx brush biopsy and DNA-image cytometry were 0.8879 and 0.9885, respectively. The pooled sensitivity, specificity, and diagnostic odds ratio of the OralCDx brush biopsy were 86% (95% CI 81-90), 81% (95% CI 78-85), and 20.36 (95% CI 2.72-152.67), respectively, while these modalities of DNA-image cytometry were 89% (95% CI 83-94), 99% (95% CI 97-100), and 446.08 (95% CI 73.36-2712.43), respectively. Results of a pairwise comparison between each modality demonstrated that specificity, area under the curve (AUC), and Q(∗) index of DNA-image cytometry was significantly higher than that of the OralCDx brush biopsy (Z=2.821, p0.05). In conclusion, the meta-analysis of the published studies indicated that DNA-image cytometry is more accurate than the OralCDx brush biopsy in diagnosing oral precancer and oral cancer. Copyright © 2015 Elsevier Ltd. All rights reserved.

  4. Trialling computer touch-screen technology to assess psychological distress in patients with gynaecological cancer

    Directory of Open Access Journals (Sweden)

    Georgia Halkett

    2010-12-01

    Full Text Available BackgroundCancer impacts on the psychological well-being of many cancer patients. Appropriate tools can be used to assist health professionals in identifying patient needs and psychological distress. Recent research suggests that touchscreen technology can be used to administer surveys. The aim of this study was to evaluate the use of a touchscreen system in comparison to written questionnaires in a large tertiary hospital in Western Australia (WA.Method Patients who were scheduled to commence treatment for gynaecological cancer participated in this study. Patients were assigned to complete either a written questionnaire or the same survey using the touchscreen technology. Both methods of survey contained the same scales. All participants were asked to complete a follow-up patient satisfaction survey. Semi-structured interviews were conducted with health professionals to elicit views about the implementation of the technology and the available referral pathways. Data was analysed using descriptive statistics and content analysis. ResultsThirty patients completed the touchscreen questionnaires and an equal number completed the survey on paper. Participants who used the touchscreens were not significantly more satisfied than other participants. Four themes were noted in the interviews with health professionals: usability of technology, patients’ acceptance of technology, advantages of psychological screening and the value of the instruments included.ConclusionAlthough previous studies report that computerised assessments are a feasible option for assessing cancer patients’ needs, the data collected in this study demonstrates that the technology was not reliable with significant practical problems. The technology did not serve these patients better than pen and paper.

  5. Exploration of the associations of touch-screen tablet computer usage and musculoskeletal discomfort.

    Science.gov (United States)

    Chiang, Hsin-Yu Ariel; Liu, Chien-Hsiou

    2016-03-10

    Tablet users may be at high risk of developing physical discomfort because of their usage behaviors and tablet design. Investigate the usage of tablets, variations in head and neck posture associated with different tablet tilt angles, and the association of tablet use with users' musculoskeletal discomfort. A survey of users' subjective perceptions conducted by questionnaire and measurements of users' postures by a 3D Motion analysis system was used to explore the effects of tablet use. The questionnaire results indicated that over half of the participants reported physical discomfort after using tablets, with the most prevalent discomfort in the neck and shoulders, and more intensity of discomfort for the back although only few participants experienced it. Chi-squared tests indicated that significantly more participants who tended to use tablet computers to play games reported having musculoskeletal discomfort after using a tablet. In addition, preferences for tablet tilt angles varied across tasks (reading and game playing). The results from the 3D motion analysis revealed that head and neck flexion angles were significantly reduced when the tablets were positioned at relatively steep tilt angles. Neck flexion angle was significantly higher in game playing. These data add information regarding to the usage of tablet and its associations with physical discomfort (significantly more participants who tended to use tablet computers to play games reported having musculoskeletal discomfort after using a tablet). Steep tilt angles (such as 60°) may cause tablet users to decrease their head and neck flexion angles, which could lead to a more neutral, effortless, and ergonomically correct posture. Maintaining proper neck posture during active activities such as game playing is recommended to avoid neck discomfort.

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

    Science.gov (United States)

    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.

  7. Computational screen and experimental validation of anti-influenza effects of quercetin and chlorogenic acid from traditional Chinese medicine

    Science.gov (United States)

    Liu, Zekun; Zhao, Junpeng; Li, Weichen; Shen, Li; Huang, Shengbo; Tang, Jingjing; Duan, Jie; Fang, Fang; Huang, Yuelong; Chang, Haiyan; Chen, Ze; Zhang, Ran

    2016-01-01

    The Influenza A virus is a great threat for human health, while various subtypes of the virus made it difficult to develop drugs. With the development of state-of-art computational chemistry, computational molecular docking could serve as a virtual screen of potential leading compound. In this study, we performed molecular docking for influenza A H1N1 (A/PR/8/34) with small molecules such as quercetin and chlorogenic acid, which were derived from traditional Chinese medicine. The results showed that these small molecules have strong binding abilities with neuraminidase from H1N1 (A/PR/8/34). Further details showed that the structural features of the molecules might be helpful for further drug design and development. The experiments in vitro, in vivo have validated the anti-influenza effect of quercetin and chlorogenic acid, which indicating comparable protection effects as zanamivir. Taken together, it was proposed that chlorogenic acid and quercetin could be employed as the effective lead compounds for anti-influenza A H1N1.

  8. IPTV Service Framework Based on Secure Authentication and Lightweight Content Encryption for Screen-Migration in Cloud Computing

    Directory of Open Access Journals (Sweden)

    Aymen Abdullah Alsaffar

    2015-01-01

    Full Text Available These days, the advancing of smart devices (e.g. smart phones, tablets, PC, etc. capabilities and the increase of internet bandwidth enables IPTV service provider to extend their services to smart mobile devices. User can just receive their IPTV service using any smart devices by accessing the internet via wireless network from anywhere anytime in the world which is convenience for users. However, wireless network communication has well a known critical security threats and vulnerabilities to user smart devices and IPTV service such as user identity theft, reply attack, MIM attack, and so forth. A secure authentication for user devices and multimedia protection mechanism is necessary to protect both user devices and IPTV services. As result, we proposed framework of IPTV service based on secure authentication mechanism and lightweight content encryption method for screen-migration in Cloud computing. We used cryptographic nonce combined with user ID and password to authenticate user device in any mobile terminal they passes by. In addition we used Lightweight content encryption to protect and reduce the content decode overload at mobile terminals. Our proposed authentication mechanism reduces the computational processing by 30% comparing to other authentication mechanism and our lightweight content encryption reduces encryption delay to 0.259 second.

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

    Science.gov (United States)

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

    2018-02-01

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

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

    Science.gov (United States)

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

    2016-04-22

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

  11. Online image databases as multi-purpose resources: discovery of a new host ant of Rickia wasmannii Cavara (Ascomycota, Laboulbeniales by screening AntWeb.org

    Directory of Open Access Journals (Sweden)

    Ferenc Báthori

    2017-12-01

    Full Text Available Public awareness has been raised on the importance of natural history and academic collections for science and society in a time when reduced financial support and staff cuts are prevalent. In the field of biology, new species and new interspecies associations are constantly discovered by making use of museum collections, digitalised materials or citizen science programs. In our study, the Myrmica Latreille, 1804 image collection of AntWeb.org was screened for fungal ectoparasites. A total of 397 imaged specimens from 133 species were visually investigated. A single specimen of M. hellenica Finzi, 1926, collected in Greece by U. Sahlberg, showed a conspicuous fungal infection. The parasite was identified using microscopic methods as Rickia wasmannii Cavara, an ectoparasitic fungal species specialised to Myrmica ants. This finding represents a new country record and a new Myrmica species for the host spectrum of R. wasmannii. According to our results, online entomological databases can be screened relatively easily for ectoparasitic fungal infections from new hosts and new regions. However, depending on quality of the insect voucher photos, additional investigation of the material could be needed to confirm the identity of the parasite.

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

    Science.gov (United States)

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

    2017-12-01

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

  13. Computer aided drug design

    Science.gov (United States)

    Jain, A.

    2017-08-01

    Computer based method can help in discovery of leads and can potentially eliminate chemical synthesis and screening of many irrelevant compounds, and in this way, it save time as well as cost. Molecular modeling systems are powerful tools for building, visualizing, analyzing and storing models of complex molecular structure that can help to interpretate structure activity relationship. The use of various techniques of molecular mechanics and dynamics and software in Computer aided drug design along with statistics analysis is powerful tool for the medicinal chemistry to synthesis therapeutic and effective drugs with minimum side effect.

  14. Computer-Aided Drug Design in Epigenetics

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    Wenchao Lu

    2018-03-01

    Full Text Available Epigenetic dysfunction has been widely implicated in several diseases especially cancers thus highlights the therapeutic potential for chemical interventions in this field. With rapid development of computational methodologies and high-performance computational resources, computer-aided drug design has emerged as a promising strategy to speed up epigenetic drug discovery. Herein, we make a brief overview of major computational methods reported in the literature including druggability prediction, virtual screening, homology modeling, scaffold hopping, pharmacophore modeling, molecular dynamics simulations, quantum chemistry calculation, and 3D quantitative structure activity relationship that have been successfully applied in the design and discovery of epi-drugs and epi-probes. Finally, we discuss about major limitations of current virtual drug design strategies in epigenetics drug discovery and future directions in this field.

  15. Computer-Aided Drug Design in Epigenetics

    Science.gov (United States)

    Lu, Wenchao; Zhang, Rukang; Jiang, Hao; Zhang, Huimin; Luo, Cheng

    2018-01-01

    Epigenetic dysfunction has been widely implicated in several diseases especially cancers thus highlights the therapeutic potential for chemical interventions in this field. With rapid development of computational methodologies and high-performance computational resources, computer-aided drug design has emerged as a promising strategy to speed up epigenetic drug discovery. Herein, we make a brief overview of major computational methods reported in the literature including druggability prediction, virtual screening, homology modeling, scaffold hopping, pharmacophore modeling, molecular dynamics simulations, quantum chemistry calculation, and 3D quantitative structure activity relationship that have been successfully applied in the design and discovery of epi-drugs and epi-probes. Finally, we discuss about major limitations of current virtual drug design strategies in epigenetics drug discovery and future directions in this field. PMID:29594101

  16. Computer-Aided Drug Design in Epigenetics

    Science.gov (United States)

    Lu, Wenchao; Zhang, Rukang; Jiang, Hao; Zhang, Huimin; Luo, Cheng

    2018-03-01

    Epigenetic dysfunction has been widely implicated in several diseases especially cancers thus highlights the therapeutic potential for chemical interventions in this field. With rapid development of computational methodologies and high-performance computational resources, computer-aided drug design has emerged as a promising strategy to speed up epigenetic drug discovery. Herein, we make a brief overview of major computational methods reported in the literature including druggability prediction, virtual screening, homology modeling, scaffold hopping, pharmacophore modeling, molecular dynamics simulations, quantum chemistry calculation and 3D quantitative structure activity relationship that have been successfully applied in the design and discovery of epi-drugs and epi-probes. Finally, we discuss about major limitations of current virtual drug design strategies in epigenetics drug discovery and future directions in this field.

  17. Atrial Fibrillation Screening in Nonmetropolitan Areas Using a Telehealth Surveillance System With an Embedded Cloud-Computing Algorithm: Prospective Pilot Study.

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    Chen, Ying-Hsien; Hung, Chi-Sheng; Huang, Ching-Chang; Hung, Yu-Chien; Hwang, Juey-Jen; Ho, Yi-Lwun

    2017-09-26

    Atrial fibrillation (AF) is a common form of arrhythmia that is associated with increased risk of stroke and mortality. Detecting AF before the first complication occurs is a recognized priority. No previous studies have examined the feasibility of undertaking AF screening using a telehealth surveillance system with an embedded cloud-computing algorithm; we address this issue in this study. The objective of this study was to evaluate the feasibility of AF screening in nonmetropolitan areas using a telehealth surveillance system with an embedded cloud-computing algorithm. We conducted a prospective AF screening study in a nonmetropolitan area using a single-lead electrocardiogram (ECG) recorder. All ECG measurements were reviewed on the telehealth surveillance system and interpreted by the cloud-computing algorithm and a cardiologist. The process of AF screening was evaluated with a satisfaction questionnaire. Between March 11, 2016 and August 31, 2016, 967 ECGs were recorded from 922 residents in nonmetropolitan areas. A total of 22 (2.4%, 22/922) residents with AF were identified by the physician's ECG interpretation, and only 0.2% (2/967) of ECGs contained significant artifacts. The novel cloud-computing algorithm for AF detection had a sensitivity of 95.5% (95% CI 77.2%-99.9%) and specificity of 97.7% (95% CI 96.5%-98.5%). The overall satisfaction score for the process of AF screening was 92.1%. AF screening in nonmetropolitan areas using a telehealth surveillance system with an embedded cloud-computing algorithm is feasible. ©Ying-Hsien Chen, Chi-Sheng Hung, Ching-Chang Huang, Yu-Chien Hung, Juey-Jen Hwang, Yi-Lwun Ho. Originally published in JMIR Mhealth and Uhealth (http://mhealth.jmir.org), 26.09.2017.

  18. Atrial Fibrillation Screening in Nonmetropolitan Areas Using a Telehealth Surveillance System With an Embedded Cloud-Computing Algorithm: Prospective Pilot Study

    Science.gov (United States)

    Chen, Ying-Hsien; Hung, Chi-Sheng; Huang, Ching-Chang; Hung, Yu-Chien

    2017-01-01

    Background Atrial fibrillation (AF) is a common form of arrhythmia that is associated with increased risk of stroke and mortality. Detecting AF before the first complication occurs is a recognized priority. No previous studies have examined the feasibility of undertaking AF screening using a telehealth surveillance system with an embedded cloud-computing algorithm; we address this issue in this study. Objective The objective of this study was to evaluate the feasibility of AF screening in nonmetropolitan areas using a telehealth surveillance system with an embedded cloud-computing algorithm. Methods We conducted a prospective AF screening study in a nonmetropolitan area using a single-lead electrocardiogram (ECG) recorder. All ECG measurements were reviewed on the telehealth surveillance system and interpreted by the cloud-computing algorithm and a cardiologist. The process of AF screening was evaluated with a satisfaction questionnaire. Results Between March 11, 2016 and August 31, 2016, 967 ECGs were recorded from 922 residents in nonmetropolitan areas. A total of 22 (2.4%, 22/922) residents with AF were identified by the physician’s ECG interpretation, and only 0.2% (2/967) of ECGs contained significant artifacts. The novel cloud-computing algorithm for AF detection had a sensitivity of 95.5% (95% CI 77.2%-99.9%) and specificity of 97.7% (95% CI 96.5%-98.5%). The overall satisfaction score for the process of AF screening was 92.1%. Conclusions AF screening in nonmetropolitan areas using a telehealth surveillance system with an embedded cloud-computing algorithm is feasible. PMID:28951384

  19. A malaria diagnostic tool based on computer vision screening and visualization of Plasmodium falciparum candidate areas in digitized blood smears.

    Directory of Open Access Journals (Sweden)

    Nina Linder

    Full Text Available INTRODUCTION: Microscopy is the gold standard for diagnosis of malaria, however, manual evaluation of blood films is highly dependent on skilled personnel in a time-consuming, error-prone and repetitive process. In this study we propose a method using computer vision detection and visualization of only the diagnostically most relevant sample regions in digitized blood smears. METHODS: Giemsa-stained thin blood films with P. falciparum ring-stage trophozoites (n = 27 and uninfected controls (n = 20 were digitally scanned with an oil immersion objective (0.1 µm/pixel to capture approximately 50,000 erythrocytes per sample. Parasite candidate regions were identified based on color and object size, followed by extraction of image features (local binary patterns, local contrast and Scale-invariant feature transform descriptors used as input to a support vector machine classifier. The classifier was trained on digital slides from ten patients and validated on six samples. RESULTS: The diagnostic accuracy was tested on 31 samples (19 infected and 12 controls. From each digitized area of a blood smear, a panel with the 128 most probable parasite candidate regions was generated. Two expert microscopists were asked to visually inspect the panel on a tablet computer and to judge whether the patient was infected with P. falciparum. The method achieved a diagnostic sensitivity and specificity of 95% and 100% as well as 90% and 100% for the two readers respectively using the diagnostic tool. Parasitemia was separately calculated by the automated system and the correlation coefficient between manual and automated parasitemia counts was 0.97. CONCLUSION: We developed a decision support system for detecting malaria parasites using a computer vision algorithm combined with visualization of sample areas with the highest probability of malaria infection. The system provides a novel method for blood smear screening with a significantly reduced need for

  20. Screening Belief: The Life of Pi, Computer Generated Imagery, and Religious Imagination

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    Rachel Wagner

    2016-07-01

    Full Text Available Ang Lee’s The Life of Pi is based on Yann Martel’s novel of the same name. The film expands upon the novel’s fantastic story through the integration of new visual metaphors that invite religious reflection, and is reinforced by religious rituals within and beyond the film itself. Martel’s novel invites readers to believe Pi’s story without seeing it. Viewers of the film, by contrast, are invited to believe Pi’s story precisely because they are seeing it so vividly. Ang Lee constructs a filmic world using such elaborately developed CGI (computer-generated imagery that the film exhibits only a vestigial relationship to the real-life animals and locations used in its creation. Indeed, it is impossible to make sense of the film’s extensive use of religious themes and rituals without understanding its use of immersive visual effects. For Ang Lee, the manufacture of a seamless, aesthetically appealing CGI world was a means of visually affirming the broadly conceived notions of interconnectedness and purpose that he borrowed from Christianity, Islam, Hinduism, and Jewish mysticism.

  1. Discovery of peroxisome proliferator-activated receptor α (PPARα) activators with a ligand-screening system using a human PPARα-expressing cell line.

    Science.gov (United States)

    Tachibana, Keisuke; Yuzuriha, Tomohiro; Tabata, Ryotaro; Fukuda, Syohei; Maegawa, Takashi; Takahashi, Rika; Tanimoto, Keiichi; Tsujino, Hirofumi; Nunomura, Kazuto; Lin, Bangzhong; Matsuura, Yoshiharu; Tanaka, Toshiya; Hamakubo, Takao; Sakai, Juro Js; Kodama, Tatsuhiko; Kobayashi, Tadayuki; Ishimoto, Kenji; Miyachi, Hiroyuki; Doi, Takefumi

    2018-05-15

    Peroxisome proliferator-activated receptor alpha (PPARα) is a ligand-activated transcription factor that belongs to the superfamily of nuclear hormone receptors. PPARα is mainly expressed in the liver, where it activates fatty acid oxidation and lipoprotein metabolism and improves plasma lipid profiles. Therefore, PPARα activators are often used to treat patients with dyslipidemia. To discover additional PPARα activators as potential compounds for use in hypolipidemic drugs, here we established human hepatoblastoma cell lines with luciferase reporter expression from the promoters containing peroxisome proliferator responsive elements (PPRE) and tetracycline-regulated expression of full-length human PPARα to quantify the effects of chemical ligands on PPARα activity. Using the established cell-based PPARα-activator screening system to screen a library of > 12,000 chemical compounds, we identified several hit compounds with basic chemical skeletons different from those of known PPARα agonists. One of the hit compounds, a 1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid derivative we termed compound 3, selectively up-regulated PPARα transcriptional activity, leading to PPARα target gene expression both in vitro and in vivo. Of note, the half-maximal effective concentrations of the hit compounds were lower than that of the known PPARα ligand fenofibrate. Finally, fenofibrate or compound 3 treatment of high fructose-fed rats having elevated plasma triglyceride levels for 14 days indicated that compound 3 reduces plasma triglyceride levels with similar efficiency as fenofibrate. These observations raise the possibility that 1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid derivatives might be effective drug candidates for selective targeting of PPARα to manage dyslipidemia. Published under license by The American Society for Biochemistry and Molecular Biology, Inc.

  2. Clinical application of low-dose CT combined with computer-aided detection in lung cancer screening

    International Nuclear Information System (INIS)

    Xu Zushan; Hou Hongjun; Xu Yan; Ma Daqing

    2010-01-01

    Objective: To investigate the clinical value of chest low-dose CT (LDCT) combined with computer-aided detection (CAD) system for lung cancer screening in high risk population. Methods: Two hundred and nineteen healthy candidates underwent 64-slice LDCT scan. All images were reviewed in consensus by two radiologists with 15 years of thoracic CT diagnosis experience. Then the image data were analyzed with CAD alone. Finally images were reviewed by two radiologists with 5 years of CT diagnosis experience with and without CT Viewer software. The sensitivity, false positive rate of CAD for pulmonary nodule detection were calculated. SPSS 11.5 software and Chi-square test were used for the statistics. Results: Of 219 candidates ,104(47.5% ) were detected with lung nodules. There were 366 true nodules confirmed by the senior radiologists. The CAD system detected 271 (74.0%) true nodules and 424 false-positive nodules. The false-positive rate was 1.94/per case. The two junior radiologists indentifid 292 (79.8%), 286(78.1%) nodules without CAD and 336 (91.8%), 333 (91.0%) nodules with CAD respectively. There were significant differences for radiologists in indentifying nodules with or without CAD system (P<0.01). Conclusions: CAD is more sensitive than radiologists for indentifying the nodules in the central area or in the hilar region of the lung. While radiologists are more sensitive for the peripheral and sub-pleural nodules,or ground glass opacity nodules, or nodules smaller than 4 mm. CAD can not be used alone. The detection rate can be improved with the combination of radiologist and CAD in LDCT screen. (authors)

  3. High-Throughput Computational Screening of the Metal Organic Framework Database for CH4/H2 Separations.

    Science.gov (United States)

    Altintas, Cigdem; Erucar, Ilknur; Keskin, Seda

    2018-01-31

    Metal organic frameworks (MOFs) have been considered as one of the most exciting porous materials discovered in the last decade. Large surface areas, high pore volumes, and tailorable pore sizes make MOFs highly promising in a variety of applications, mainly in gas separations. The number of MOFs has been increasing very rapidly, and experimental identification of materials exhibiting high gas separation potential is simply impractical. High-throughput computational screening studies in which thousands of MOFs are evaluated to identify the best candidates for target gas separation is crucial in directing experimental efforts to the most useful materials. In this work, we used molecular simulations to screen the most complete and recent collection of MOFs from the Cambridge Structural Database to unlock their CH 4 /H 2 separation performances. This is the first study in the literature, which examines the potential of all existing MOFs for adsorption-based CH 4 /H 2 separation. MOFs (4350) were ranked based on several adsorbent evaluation metrics including selectivity, working capacity, adsorbent performance score, sorbent selection parameter, and regenerability. A large number of MOFs were identified to have extraordinarily large CH 4 /H 2 selectivities compared to traditional adsorbents such as zeolites and activated carbons. We examined the relations between structural properties of MOFs such as pore sizes, porosities, and surface areas and their selectivities. Correlations between the heat of adsorption, adsorbility, metal type of MOFs, and selectivities were also studied. On the basis of these relations, a simple mathematical model that can predict the CH 4 /H 2 selectivity of MOFs was suggested, which will be very useful in guiding the design and development of new MOFs with extraordinarily high CH 4 /H 2 separation performances.

  4. Features of undiagnosed breast cancers at screening breast MR imaging and potential utility of computer-aided evaluation

    Energy Technology Data Exchange (ETDEWEB)

    Seo, Mirinae; Cho, Nariya; Bea, Min Sun; Koo, Hye Ryoung; Kim, Won Hwa; Lee, Su Hyun; Chu, A Jung [Dept. of Radiology, Seoul National University Hospital, Seoul (Korea, Republic of)

    2016-02-15

    To retrospectively evaluate the features of undiagnosed breast cancers on prior screening breast magnetic resonance (MR) images in patients who were subsequently diagnosed with breast cancer, as well as the potential utility of MR-computer-aided evaluation (CAE). Between March 2004 and May 2013, of the 72 consecutive pairs of prior negative MR images and subsequent MR images with diagnosed cancers (median interval, 32.8 months; range, 5.4-104.6 months), 36 (50%) had visible findings (mean size, 1.0 cm; range, 0.3-5.2 cm). The visible findings were divided into either actionable or under threshold groups by the blinded review by 5 radiologists. MR imaging features, reasons for missed cancer, and MR-CAE features according to actionability were evaluated. Of the 36 visible findings on prior MR images, 33.3% (12 of 36) of the lesions were determined to be actionable and 66.7% (24 of 36) were underthreshold; 85.7% (6 of 7) of masses and 31.6% (6 of 19) of non-mass enhancements were classified as actionable lesions. Mimicking physiologic enhancements (27.8%, 10 of 36) and small lesion size (27.8%, 10 of 36) were the most common reasons for missed cancer. Actionable findings tended to show more washout or plateau kinetic patterns on MR-CAE than underthreshold findings, as the 100% of actionable findings and 46.7% of underthreshold findings showed washout or plateau (p = 0.008). MR-CAE has the potential for reducing the number of undiagnosed breast cancers on screening breast MR images, the majority of which are caused by mimicking physiologic enhancements or small lesion size.

  5. Discovery of Potential Inhibitors of Squalene Synthase from Traditional Chinese Medicine Based on Virtual Screening and In Vitro Evaluation of Lipid-Lowering Effect.

    Science.gov (United States)

    Chen, Yankun; Chen, Xi; Luo, Ganggang; Zhang, Xu; Lu, Fang; Qiao, Liansheng; He, Wenjing; Li, Gongyu; Zhang, Yanling

    2018-04-28

    Squalene synthase (SQS), a key downstream enzyme involved in the cholesterol biosynthetic pathway, plays an important role in treating hyperlipidemia. Compared to statins, SQS inhibitors have shown a very significant lipid-lowering effect and do not cause myotoxicity. Thus, the paper aims to discover potential SQS inhibitors from Traditional Chinese Medicine (TCM) by the combination of molecular modeling methods and biological assays. In this study, cynarin was selected as a potential SQS inhibitor candidate compound based on its pharmacophoric properties, molecular docking studies and molecular dynamics (MD) simulations. Cynarin could form hydrophobic interactions with PHE54, LEU211, LEU183 and PRO292, which are regarded as important interactions for the SQS inhibitors. In addition, the lipid-lowering effect of cynarin was tested in sodium oleate-induced HepG2 cells by decreasing the lipidemic parameter triglyceride (TG) level by 22.50%. Finally. cynarin was reversely screened against other anti-hyperlipidemia targets which existed in HepG2 cells and cynarin was unable to map with the pharmacophore of these targets, which indicated that the lipid-lowering effects of cynarin might be due to the inhibition of SQS. This study discovered cynarin is a potential SQS inhibitor from TCM, which could be further clinically explored for the treatment of hyperlipidemia.

  6. Discovery of novel urokinase plasminogen activator (uPA) inhibitors using ligand-based modeling and virtual screening followed by in vitro analysis.

    Science.gov (United States)

    Al-Sha'er, Mahmoud A; Khanfar, Mohammad A; Taha, Mutasem O

    2014-01-01

    Urokinase plasminogen activator (uPA)-a serine protease-is thought to play a central role in tumor metastasis and angiogenesis and, therefore, inhibition of this enzyme could be beneficial in treating cancer. Toward this end, we explored the pharmacophoric space of 202 uPA inhibitors using seven diverse sets of inhibitors to identify high-quality pharmacophores. Subsequently, we employed genetic algorithm-based quantitative structure-activity relationship (QSAR) analysis as a competition arena to select the best possible combination of pharmacophoric models and physicochemical descriptors that can explain bioactivity variation within the training inhibitors (r (2) 162 = 0.74, F-statistic = 64.30, r (2) LOO = 0.71, r (2) PRESS against 40 test inhibitors = 0.79). Three orthogonal pharmacophores emerged in the QSAR equation suggesting the existence of at least three binding modes accessible to ligands within the uPA binding pocket. This conclusion was supported by receiver operating characteristic (ROC) curve analyses of the QSAR-selected pharmacophores. Moreover, the three pharmacophores were comparable with binding interactions seen in crystallographic structures of bound ligands within the uPA binding pocket. We employed the resulting pharmacophoric models and associated QSAR equation to screen the national cancer institute (NCI) list of compounds. The captured hits were tested in vitro. Overall, our modeling workflow identified new low micromolar anti-uPA hits.

  7. Toward the Discovery of a Novel Class of YAP–TEAD Interaction Inhibitors by Virtual Screening Approach Targeting YAP–TEAD Protein–Protein Interface

    Directory of Open Access Journals (Sweden)

    Floriane Gibault

    2018-05-01

    Full Text Available Intrinsically disordered protein YAP (yes-associated protein interacts with TEADs transcriptional factors family (transcriptional enhancer associated domain creating three interfaces. Interface 3, between the Ω-loop of YAP and a shallow pocket of TEAD was identified as the most important TEAD zone for YAP-TEAD interaction. Using the first X-ray structure of the hYAP50–71-hTEAD1209–426 complex (PDB 3KYS published in 2010, a protein-protein interaction inhibitors-enriched library (175,000 chemical compounds was screened against this hydrophobic pocket of TEAD. Four different chemical families have been identified and evaluated using biophysical techniques (thermal shift assay, microscale thermophoresis and in cellulo assays (luciferase activity in transfected HEK293 cells, RTqPCR in MDA-MB231 cells. A first promising hit with micromolar inhibition in the luciferase gene reporter assay was discovered. This hit also decreased mRNA levels of TEAD target genes.

  8. Harnessing the potential of natural products in drug discovery from a cheminformatics vantage point.

    Science.gov (United States)

    Rodrigues, Tiago

    2017-11-15

    Natural products (NPs) present a privileged source of inspiration for chemical probe and drug design. Despite the biological pre-validation of the underlying molecular architectures and their relevance in drug discovery, the poor accessibility to NPs, complexity of the synthetic routes and scarce knowledge of their macromolecular counterparts in phenotypic screens still hinder their broader exploration. Cheminformatics algorithms now provide a powerful means of circumventing the abovementioned challenges and unlocking the full potential of NPs in a drug discovery context. Herein, I discuss recent advances in the computer-assisted design of NP mimics and how artificial intelligence may accelerate future NP-inspired molecular medicine.

  9. Evaluating Computer Screen Time and Its Possible Link to Psychopathology in the Context of Age: A Cross-Sectional Study of Parents and Children.

    Science.gov (United States)

    Segev, Aviv; Mimouni-Bloch, Aviva; Ross, Sharon; Silman, Zmira; Maoz, Hagai; Bloch, Yuval

    2015-01-01

    Several studies have suggested that high levels of computer use are linked to psychopathology. However, there is ambiguity about what should be considered normal or over-use of computers. Furthermore, the nature of the link between computer usage and psychopathology is controversial. The current study utilized the context of age to address these questions. Our hypothesis was that the context of age will be paramount for differentiating normal from excessive use, and that this context will allow a better understanding of the link to psychopathology. In a cross-sectional study, 185 parents and children aged 3-18 years were recruited in clinical and community settings. They were asked to fill out questionnaires regarding demographics, functional and academic variables, computer use as well as psychiatric screening questionnaires. Using a regression model, we identified 3 groups of normal-use, over-use and under-use and examined known factors as putative differentiators between the over-users and the other groups. After modeling computer screen time according to age, factors linked to over-use were: decreased socialization (OR 3.24, Confidence interval [CI] 1.23-8.55, p = 0.018), difficulty to disengage from the computer (OR 1.56, CI 1.07-2.28, p = 0.022) and age, though borderline-significant (OR 1.1 each year, CI 0.99-1.22, p = 0.058). While psychopathology was not linked to over-use, post-hoc analysis revealed that the link between increased computer screen time and psychopathology was age-dependent and solidified as age progressed (p = 0.007). Unlike computer usage, the use of small-screens and smartphones was not associated with psychopathology. The results suggest that computer screen time follows an age-based course. We conclude that differentiating normal from over-use as well as defining over-use as a possible marker for psychiatric difficulties must be performed within the context of age. If verified by additional studies, future research should integrate

  10. Discovery of ebselen as an inhibitor of Cryptosporidium parvum glucose-6-phosphate isomerase (CpGPI by high-throughput screening of existing drugs

    Directory of Open Access Journals (Sweden)

    Rana Eltahan

    2018-04-01

    Full Text Available Cryptosporidium parvum is a water-borne and food-borne apicomplexan pathogen. It is one of the top four diarrheal-causing pathogens in children under the age of five in developing countries, and an opportunistic pathogen in immunocompromised individuals. Unlike other apicomplexans, C. parvum lacks Kreb's cycle and cytochrome-based respiration, thus relying mainly on glycolysis to produce ATP. In this study, we characterized the primary biochemical features of the C. parvum glucose-6-phosphate isomerase (CpGPI and determined its Michaelis constant towards fructose-6-phosphate (Km = 0.309 mM, Vmax = 31.72 nmol/μg/min. We also discovered that ebselen, an organoselenium drug, was a selective inhibitor of CpGPI by high-throughput screening of 1200 known drugs. Ebselen acted on CpGPI as an allosteric noncompetitive inhibitor (IC50 = 8.33 μM; Ki = 36.33 μM, while complete inhibition of CpGPI activity was not achieved. Ebselen could also inhibit the growth of C. parvum in vitro (EC50 = 165 μM at concentrations nontoxic to host cells, albeit with a relatively small in vitro safety window of 4.2 (cytotoxicity TC50 on HCT-8 cells = 700 μM. Additionally, ebselen might also target other enzymes in the parasite, leading to the parasite growth reduction. Therefore, although ebselen is useful in studying the inhibition of CpGPI enzyme activity, further proof is needed to chemically and/or genetically validate CpGPI as a drug target. Keywords: Apicomplexan, Cryptosporidium parvum, Glucose-6-phosphate isomerase (GPI, Ebselen

  11. Discovery of ebselen as an inhibitor of Cryptosporidium parvum glucose-6-phosphate isomerase (CpGPI) by high-throughput screening of existing drugs.

    Science.gov (United States)

    Eltahan, Rana; Guo, Fengguang; Zhang, Haili; Xiang, Lixin; Zhu, Guan

    2018-04-01

    Cryptosporidium parvum is a water-borne and food-borne apicomplexan pathogen. It is one of the top four diarrheal-causing pathogens in children under the age of five in developing countries, and an opportunistic pathogen in immunocompromised individuals. Unlike other apicomplexans, C. parvum lacks Kreb's cycle and cytochrome-based respiration, thus relying mainly on glycolysis to produce ATP. In this study, we characterized the primary biochemical features of the C. parvum glucose-6-phosphate isomerase (CpGPI) and determined its Michaelis constant towards fructose-6-phosphate (K m  = 0.309 mM, V max  = 31.72 nmol/μg/min). We also discovered that ebselen, an organoselenium drug, was a selective inhibitor of CpGPI by high-throughput screening of 1200 known drugs. Ebselen acted on CpGPI as an allosteric noncompetitive inhibitor (IC 50  = 8.33 μM; K i  = 36.33 μM), while complete inhibition of CpGPI activity was not achieved. Ebselen could also inhibit the growth of C. parvum in vitro (EC 50  = 165 μM) at concentrations nontoxic to host cells, albeit with a relatively small in vitro safety window of 4.2 (cytotoxicity TC 50 on HCT-8 cells = 700 μM). Additionally, ebselen might also target other enzymes in the parasite, leading to the parasite growth reduction. Therefore, although ebselen is useful in studying the inhibition of CpGPI enzyme activity, further proof is needed to chemically and/or genetically validate CpGPI as a drug target. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

  12. Effect of smoking cessation on quantitative computed tomography in smokers at risk in a lung cancer screening population

    Energy Technology Data Exchange (ETDEWEB)

    Jobst, Bertram J.; Eichinger, Monika; Wielpuetz, Mark O. [University Hospital Heidelberg, Department of Diagnostic and Interventional Radiology, Heidelberg (Germany); Translational Lung Research Centre Heidelberg (TLRC), Member of the German Lung Research Centre (DZL), Heidelberg (Germany); Thoraxklinik at the University of Heidelberg, Department of Diagnostic and Interventional Radiology with Nuclear Medicine, Heidelberg (Germany); German Cancer Research Center (DKFZ), Department of Radiology, Heidelberg (Germany); Weinheimer, Oliver; Trauth, Mila; Kauczor, Hans-Ulrich [University Hospital Heidelberg, Department of Diagnostic and Interventional Radiology, Heidelberg (Germany); Translational Lung Research Centre Heidelberg (TLRC), Member of the German Lung Research Centre (DZL), Heidelberg (Germany); Thoraxklinik at the University of Heidelberg, Department of Diagnostic and Interventional Radiology with Nuclear Medicine, Heidelberg (Germany); Becker, Nikolaus; Motsch, Erna; Gross, Marie-Luise; Eigentopf, Anke [German Cancer Research Centre (DKFZ Heidelberg), Division of Cancer Epidemiology, Heidelberg (Germany); Tremper, Jan; Delorme, Stefan [German Cancer Research Center (DKFZ), Department of Radiology, Heidelberg (Germany)

    2018-02-15

    To longitudinally evaluate effects of smoking cessation on quantitative CT in a lung cancer screening cohort of heavy smokers over 4 years. After 4 years, low-dose chest CT was available for 314 long-term ex-smokers (ES), 404 continuous smokers (CS) and 39 recent quitters (RQ) who quitted smoking within 2 years after baseline CT. CT acquired at baseline and after 3 and 4 years was subjected to well-evaluated densitometry software, computing mean lung density (MLD) and 15th percentile of the lung density histogram (15TH). At baseline, active smokers showed significantly higher MLD and 15TH (-822±35 and -936±25 HU, respectively) compared to ES (-831±31 and -947±22 HU, p<0.01-0.001). After 3 years, CS again had significantly higher MLD and 15TH (-801±29 and -896±23 HU) than ES (-808±27 and -906±20 HU, p<0.01-0.001) but also RQ (-813±20 and -909±15 HU, p<0.05-0.001). Quantitative CT parameters did not change significantly after 4 years. Importantly, smoking status independently predicted MLD at baseline and year 3 (p<0.001) in multivariate analysis. On quantitative CT, lung density is higher in active smokers than ex-smokers, and sustainably decreases after smoking cessation, reflecting smoking-induced inflammation. Interpretations of quantitative CT data within clinical trials should consider smoking status. (orig.)

  13. Effect of smoking cessation on quantitative computed tomography in smokers at risk in a lung cancer screening population

    International Nuclear Information System (INIS)

    Jobst, Bertram J.; Eichinger, Monika; Wielpuetz, Mark O.; Weinheimer, Oliver; Trauth, Mila; Kauczor, Hans-Ulrich; Becker, Nikolaus; Motsch, Erna; Gross, Marie-Luise; Eigentopf, Anke; Tremper, Jan; Delorme, Stefan

    2018-01-01

    To longitudinally evaluate effects of smoking cessation on quantitative CT in a lung cancer screening cohort of heavy smokers over 4 years. After 4 years, low-dose chest CT was available for 314 long-term ex-smokers (ES), 404 continuous smokers (CS) and 39 recent quitters (RQ) who quitted smoking within 2 years after baseline CT. CT acquired at baseline and after 3 and 4 years was subjected to well-evaluated densitometry software, computing mean lung density (MLD) and 15th percentile of the lung density histogram (15TH). At baseline, active smokers showed significantly higher MLD and 15TH (-822±35 and -936±25 HU, respectively) compared to ES (-831±31 and -947±22 HU, p<0.01-0.001). After 3 years, CS again had significantly higher MLD and 15TH (-801±29 and -896±23 HU) than ES (-808±27 and -906±20 HU, p<0.01-0.001) but also RQ (-813±20 and -909±15 HU, p<0.05-0.001). Quantitative CT parameters did not change significantly after 4 years. Importantly, smoking status independently predicted MLD at baseline and year 3 (p<0.001) in multivariate analysis. On quantitative CT, lung density is higher in active smokers than ex-smokers, and sustainably decreases after smoking cessation, reflecting smoking-induced inflammation. Interpretations of quantitative CT data within clinical trials should consider smoking status. (orig.)

  14. Computer-aided detection of masses in full-field digital mammography using screen-film mammograms for training

    International Nuclear Information System (INIS)

    Kallenberg, Michiel; Karssemeijer, Nico

    2008-01-01

    It would be of great value when available databases of screen-film mammography (SFM) images can be used to train full-field digital mammography (FFDM) computer-aided detection (CAD) systems, as compilation of new databases is costly. In this paper, we investigate this possibility. Firstly, we develop a method that converts an FFDM image into an SFM-like representation. In this conversion method, we establish a relation between exposure and optical density by simulation of an automatic exposure control unit. Secondly, we investigate the effects of using the SFM images as training samples compared to training with FFDM images. Our FFDM database consisted of 266 cases, of which 102 were biopsy-proven malignant masses and 164 normals. The images were acquired with systems of two different manufacturers. We found that, when we trained our FFDM CAD system with a small number of images, training with FFDM images, using a five-fold crossvalidation procedure, outperformed training with SFM images. However, when the full SFM database, consisting of 348 abnormal cases (including 204 priors) and 810 normal cases, was used for training, SFM training outperformed FFDMA training. These results show that an existing CAD system for detection of masses in SFM can be used for FFDM images without retraining.

  15. Evidence-based investigation of the influence of computer-aided detection of polyps on screening of colon cancer with CT colonography

    International Nuclear Information System (INIS)

    Yoshida, Hiroyuki

    2008-01-01

    Computed tomographic colonography (CTC), also known as virtual colonoscopy, is a CT examination of the colon for colorectal neoplasms. Recent large-scale clinical trials have demonstrated that CTC yields sensitivity comparable to optical colonoscopy in the detection of clinically significant polyps in a screening population, making CTC a promising technique for screening of colon cancer. For CTC to be a clinically practical means of screening, it must reliably and consistently detect polyps with high accuracy. However, high-level expertise is required to interpret the resulting CT images to find polyps, resulting in variable diagnostic accuracy among radiologists in the detection of polyps. A key technology to overcome this problem and to bring CTC to prime time for screening of colorectal cancer is computer-aided detection (CAD) of polyps. CAD automatically detects the locations of suspicious polyps in CTC images and presents them to radiologists. CAD has the potential to increase diagnostic performance in the detection of polyps as well as to reduce variability of the diagnostic accuracy among radiologists. This paper presents an evidence-based investigation of the influence of CAD on screening of colon cancer with CTC by describing the benefits of using CAD in the diagnosis of CTC, the fundamental CAD scheme for the detection of polyps in CTC, its detection performance, the effect on the improvement of detection performance, as well as the current and future challenges in CAD. (author)

  16. Children's accuracy of portion size estimation using digital food images: effects of interface design and size of image on computer screen.

    Science.gov (United States)

    Baranowski, Tom; Baranowski, Janice C; Watson, Kathleen B; Martin, Shelby; Beltran, Alicia; Islam, Noemi; Dadabhoy, Hafza; Adame, Su-heyla; Cullen, Karen; Thompson, Debbe; Buday, Richard; Subar, Amy

    2011-03-01

    To test the effect of image size and presence of size cues on the accuracy of portion size estimation by children. Children were randomly assigned to seeing images with or without food size cues (utensils and checked tablecloth) and were presented with sixteen food models (foods commonly eaten by children) in varying portion sizes, one at a time. They estimated each food model's portion size by selecting a digital food image. The same food images were presented in two ways: (i) as small, graduated portion size images all on one screen or (ii) by scrolling across large, graduated portion size images, one per sequential screen. Laboratory-based with computer and food models. Volunteer multi-ethnic sample of 120 children, equally distributed by gender and ages (8 to 13 years) in 2008-2009. Average percentage of correctly classified foods was 60·3 %. There were no differences in accuracy by any design factor or demographic characteristic. Multiple small pictures on the screen at once took half the time to estimate portion size compared with scrolling through large pictures. Larger pictures had more overestimation of size. Multiple images of successively larger portion sizes of a food on one computer screen facilitated quicker portion size responses with no decrease in accuracy. This is the method of choice for portion size estimation on a computer.

  17. Multimodal lung cancer screening using the ITALUNG biomarker panel and low dose computed tomography. Results of the ITALUNG biomarker study.

    Science.gov (United States)

    Carozzi, Francesca Maria; Bisanzi, Simonetta; Carrozzi, Laura; Falaschi, Fabio; Lopes Pegna, Andrea; Mascalchi, Mario; Picozzi, Giulia; Peluso, Marco; Sani, Cristina; Greco, Luana; Ocello, Cristina; Paci, Eugenio

    2017-07-01

    Asymptomatic high-risk subjects, randomized in the intervention arm of the ITALUNG trial (1,406 screened for lung cancer), were enrolled for the ITALUNG biomarker study (n = 1,356), in which samples of blood and sputum were analyzed for plasma DNA quantification (cut off 5 ng/ml), loss of heterozygosity and microsatellite instability. The ITALUNG biomarker panel (IBP) was considered positive if at least one of the two biomarkers included in the panel was positive. Subjects with and without lung cancer diagnosis at the end of the screening cycle with LDCT (n = 517) were evaluated. Out of 18 baseline screen detected lung cancer cases, 17 were IBP positive (94%). Repeat screen-detected lung cancer cases were 18 and 12 of them positive at baseline IBP test (66%). Interval cancer cases (2-years) and biomarker tests after a suspect Non Calcific Nodule follow-up were investigated. The single test versus multimodal screening measures of accuracy were compared in a simulation within the screened ITALUNG intervention arm, considering screen-detected and interval cancer cases. Sensitivity was 90% at baseline screening. Specificity was 71 and 61% for LDCT and IBP as baseline single test, and improved at 89% with multimodal, combined screening. The positive predictive value was 4.3% for LDCT at baseline and 10.6% for multimodal screening. Multimodal screening could improve the screening efficiency at baseline and strategies for future implementation are discussed. If IBP was used as primary screening test, the LDCT burden might decrease of about 60%. © 2017 UICC.

  18. Assessment of dose to patients undergoing computed radiography and film screen x-ray examinations in some Khartoum Hospitals

    International Nuclear Information System (INIS)

    Mohamed Khair, Haiffa Daffa Allah Mustafa

    2015-12-01

    Medical ionizing radiation sources give by far the largest contribution to the population dose from man made sources and most of the contribution comes from diagnostic x-rays. The optimization principle of radiation protection requires the minimization of radiation dose to patients while acquiring diagnostic quality images in radiology. In radiography, the extent of patient dose reduction is limited by the characteristics of the system used and the quality (or penetrating ability) of the x-ray beam. In this study, the entrance surface air kerma doses (ESA Ks) to patients undergoing 7 selected x-ray examinations were estimated. The study was conducted in eight hospitals in Khartoum State, comprising nine x-ray units and a total of 1200 patients were involved. Four of the hospitals involved in this study use computed radiography (CR) technology while the other four use film screen (FS) technology. The selected examinations were, abdomen (AP), chest (PA), pelvis (AP), skull (AP/PA), skull (LAT), thoracic spine (AP) and thoracic spine (LAT). The entrance surface air kerma was calculated by two methods, utilizing software CAL Dose X-3.5 and a mathematical model. Average ESAK values calculated using the two methods for hospitals using (CR) technology in mGy were 2.99 and 2.98, 0.34 and 0.31, 2.79 and 2.58, 0.76 and 0.71, 0.94 and 0.79, 3.4 and 3,2 and 5.9 and 5.03, for the above mentioned selected investigations respectively. And average ESAK values calculated using two methods for hospital using FS technology in mGy were found 4.98 and 4.19, 0.37 and 0.34, 4.15 and 3.95, 2.2 and 2. 1.3 and 1.1, 3.9 and 3.9, 9.4 and 8.3 for the above mentioned selected investigations respectively. Average ESAK values obtained by two methods for FS were higher values than the obtained by CR by 37 and 29%, 50 and 25%, 8%, 32 and 34%, 65 and 64%, 27 and 28%, 12% and 73% and 39% for the above mentioned selected investigations, respectively. This shows that CR technique allows diagnostically

  19. In-bead screening

    DEFF Research Database (Denmark)

    2013-01-01

    The present invention relates to screening of one-bead-one-compound (OBOC) combinatorial libraries which is useful for the discovery of compounds displaying molecular interactions with a biological or a physicochemical system, such as substrates and inhibitors of enzymes and the like. The invention...... provides a method for screening a library of compounds for their interaction with a physico- chemical or biological system and a corresponding kit for performing the method of screening a one-bead-one-compound library of compounds....

  20. SemaTyP: a knowledge graph based literature mining method for drug discovery.

    Science.gov (United States)

    Sang, Shengtian; Yang, Zhihao; Wang, Lei; Liu, Xiaoxia; Lin, Hongfei; Wang, Jian

    2018-05-30

    Drug discovery is the process through which potential new medicines are identified. High-throughput screening and computer-aided drug discovery/design are the two main drug discovery methods for now, which have successfully discovered a series of drugs. However, development of new drugs is still an extremely time-consuming and expensive process. Biomedical literature contains important clues for the identification of potential treatments. It could support experts in biomedicine on their way towards new discoveries. Here, we propose a biomedical knowledge graph-based drug discovery method called SemaTyP, which discovers candidate drugs for diseases by mining published biomedical literature. We first construct a biomedical knowledge graph with the relations extracted from biomedical abstracts, then a logistic regression model is trained by learning the semantic types of paths of known drug therapies' existing in the biomedical knowledge graph, finally the learned model is used to discover drug therapies for new diseases. The experimental results show that our method could not only effectively discover new drug therapies for new diseases, but also could provide the potential mechanism of action of the candidate drugs. In this paper we propose a novel knowledge graph based literature mining method for drug discovery. It could be a supplementary method for current drug discovery methods.

  1. Twenty years on: the impact of fragments on drug discovery.

    Science.gov (United States)

    Erlanson, Daniel A; Fesik, Stephen W; Hubbard, Roderick E; Jahnke, Wolfgang; Jhoti, Harren

    2016-09-01

    After 20 years of sometimes quiet growth, fragment-based drug discovery (FBDD) has become mainstream. More than 30 drug candidates derived from fragments have entered the clinic, with two approved and several more in advanced trials. FBDD has been widely applied in both academia and industry, as evidenced by the large number of papers from universities, non-profit research institutions, biotechnology companies and pharmaceutical companies. Moreover, FBDD draws on a diverse range of disciplines, from biochemistry and biophysics to computational and medicinal chemistry. As the promise of FBDD strategies becomes increasingly realized, now is an opportune time to draw lessons and point the way to the future. This Review briefly discusses how to design fragment libraries, how to select screening techniques and how to make the most of information gleaned from them. It also shows how concepts from FBDD have permeated and enhanced drug discovery efforts.

  2. Blueprint for antimicrobial hit discovery targeting metabolic networks.

    Science.gov (United States)

    Shen, Y; Liu, J; Estiu, G; Isin, B; Ahn, Y-Y; Lee, D-S; Barabási, A-L; Kapatral, V; Wiest, O; Oltvai, Z N

    2010-01-19

    Advances in genome analysis, network biology, and computational chemistry have the potential to revolutionize drug discovery by combining system-level identification of drug targets with the atomistic modeling of small molecules capable of modulating their activity. To demonstrate the effectiveness of such a discovery pipeline, we deduced common antibiotic targets in Escherichia coli and Staphylococcus aureus by identifying shared tissue-specific or uniformly essential metabolic reactions in their metabolic networks. We then predicted through virtual screening dozens of potential inhibitors for several enzymes of these reactions and showed experimentally that a subset of these inhibited both enzyme activities in vitro and bacterial cell viability. This blueprint is applicable for any sequenced organism with high-quality metabolic reconstruction and suggests a general strategy for strain-specific antiinfective therapy.

  3. Discovery Mondays

    CERN Multimedia

    2003-01-01

    Many people don't realise quite how much is going on at CERN. Would you like to gain first-hand knowledge of CERN's scientific and technological activities and their many applications? Try out some experiments for yourself, or pick the brains of the people in charge? If so, then the «Lundis Découverte» or Discovery Mondays, will be right up your street. Starting on May 5th, on every first Monday of the month you will be introduced to a different facet of the Laboratory. CERN staff, non-scientists, and members of the general public, everyone is welcome. So tell your friends and neighbours and make sure you don't miss this opportunity to satisfy your curiosity and enjoy yourself at the same time. You won't have to listen to a lecture, as the idea is to have open exchange with the expert in question and for each subject to be illustrated with experiments and demonstrations. There's no need to book, as Microcosm, CERN's interactive museum, will be open non-stop from 7.30 p.m. to 9 p.m. On the first Discovery M...

  4. Quantitative pre-clinical screening of therapeutics for joint diseases using contrast enhanced micro-computed tomography.

    Science.gov (United States)

    Willett, N J; Thote, T; Hart, M; Moran, S; Guldberg, R E; Kamath, R V

    2016-09-01

    The development of effective therapies for cartilage protection has been limited by a lack of efficient quantitative cartilage imaging modalities in pre-clinical in vivo models. Our objectives were two-fold: first, to validate a new contrast-enhanced 3D imaging analysis technique, equilibrium partitioning of an ionic contrast agent-micro computed tomography (EPIC-μCT), in a rat medial meniscal transection (MMT) osteoarthritis (OA) model; and second, to quantitatively assess the sensitivity of EPIC-μCT to detect the effects of matrix metalloproteinase inhibitor (MMPi) therapy on cartilage degeneration. Rats underwent MMT surgery and tissues were harvested at 1, 2, and 3 weeks post-surgery or rats received an MMPi or vehicle treatment and tissues harvested 3 weeks post-surgery. Parameters of disease progression were evaluated using histopathology and EPIC-μCT. Correlations and power analyses were performed to compare the techniques. EPIC-μCT was shown to provide simultaneous 3D quantification of multiple parameters, including cartilage degeneration and osteophyte formation. In MMT animals treated with MMPi, OA progression was attenuated, as measured by 3D parameters such as lesion volume and osteophyte size. A post-hoc power analysis showed that 3D parameters for EPIC-μCT were more sensitive than 2D parameters requiring fewer animals to detect a therapeutic effect of MMPi. 2D parameters were comparable between EPIC-μCT and histopathology. This study demonstrated that EPIC-μCT has high sensitivity to provide 3D structural and compositional measurements of cartilage and bone in the joint. EPIC-μCT can be used in combination with histology to provide a comprehensive analysis to screen new potential therapies. Copyright © 2016 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

  5. Spondylolysis and spina bifida occulta in pediatric patients: prevalence study using computed tomography as a screening method.

    Science.gov (United States)

    Urrutia, Julio; Cuellar, Jorge; Zamora, Tomas

    2016-02-01

    The prevalence of spondylolysis reported from radiograph-based studies has been questioned in recent computed tomography (CT)-based studies in adults; however, no new data are available in pediatric patients. Spina bifida occulta (SBO), which has been associated to spondylolysis, may be increasing its prevalence, according to recent studies in adults in the last decades, but without new data in pediatric patients. We aimed to determine the prevalence of spondylolysis and SBO in pediatric patients using abdomen and pelvis CT as a screening tool. We studied 228 patients 4-15 years old (107 males), who were evaluated with abdomen and pelvis CT scans for reasons not related to the spine. The entire lumbo-sacral spine was evaluated to detect the presence of spondylolysis and SBO. We compared the prevalence of spondylolysis in patients with and without SBO. A logistic regression analysis was performed to determine the effect of age and sex as independent predictors of spondylolysis and SBO. The prevalence of spondylolysis was 3.5 % (1.1-5.9 %); 2/8 patients presented with olisthesis, both with grade I slip. The prevalence of SBO was 41.2 % (34.8-59.2 %) (94 patients). Spondylolysis was not more frequent in patients with SBO than in patients without SBO. Male sex and decreasing age independently predicted the presence of SBO, but not of spondylolysis. We observed a 3.5 % prevalence of spondylolysis and a 41.2 % prevalence of SBO. SBO was significantly more frequent in males and younger patients.

  6. Clinically Practical Approach for Screening of Low Muscularity Using Electronic Linear Measures on Computed Tomography Images in Critically Ill Patients.

    Science.gov (United States)

    Avrutin, Egor; Moisey, Lesley L; Zhang, Roselyn; Khattab, Jenna; Todd, Emma; Premji, Tahira; Kozar, Rosemary; Heyland, Daren K; Mourtzakis, Marina

    2017-12-06

    Computed tomography (CT) scans performed during routine hospital care offer the opportunity to quantify skeletal muscle and predict mortality and morbidity in intensive care unit (ICU) patients. Existing methods of muscle cross-sectional area (CSA) quantification require specialized software, training, and time commitment that may not be feasible in a clinical setting. In this article, we explore a new screening method to identify patients with low muscle mass. We analyzed 145 scans of elderly ICU patients (≥65 years old) using a combination of measures obtained with a digital ruler, commonly found on hospital radiological software. The psoas and paraspinal muscle groups at the level of the third lumbar vertebra (L3) were evaluated by using 2 linear measures each and compared with an established method of CT image analysis of total muscle CSA in the L3 region. There was a strong association between linear measures of psoas and paraspinal muscle groups and total L3 muscle CSA (R 2 = 0.745, P < 0.001). Linear measures, age, and sex were included as covariates in a multiple logistic regression to predict those with low muscle mass; receiver operating characteristic (ROC) area under the curve (AUC) of the combined psoas and paraspinal linear index model was 0.920. Intraclass correlation coefficients (ICCs) were used to evaluate intrarater and interrater reliability, resulting in scores of 0.979 (95% CI: 0.940-0.992) and 0.937 (95% CI: 0.828-0.978), respectively. A digital ruler can reliably predict L3 muscle CSA, and these linear measures may be used to identify critically ill patients with low muscularity who are at risk for worse clinical outcomes. © 2017 American Society for Parenteral and Enteral Nutrition.

  7. Performance and Cost-Effectiveness of Computed Tomography Lung Cancer Screening Scenarios in a Population-Based Setting: A Microsimulation Modeling Analysis in Ontario, Canada.

    Directory of Open Access Journals (Sweden)

    Kevin Ten Haaf

    2017-02-01

    Full Text Available The National Lung Screening Trial (NLST results indicate that computed tomography (CT lung cancer screening for current and former smokers with three annual screens can be cost-effective in a trial setting. However, the cost-effectiveness in a population-based setting with >3 screening rounds is uncertain. Therefore, the objective of this study was to estimate the cost-effectiveness of lung cancer screening in a population-based setting in Ontario, Canada, and evaluate the effects of screening eligibility criteria.This study used microsimulation modeling informed by various data sources, including the Ontario Health Insurance Plan (OHIP, Ontario Cancer Registry, smoking behavior surveys, and the NLST. Persons, born between 1940 and 1969, were examined from a third-party health care payer perspective across a lifetime horizon. Starting in 2015, 576 CT screening scenarios were examined, varying by age to start and end screening, smoking eligibility criteria, and screening interval. Among the examined outcome measures were lung cancer deaths averted, life-years gained, percentage ever screened, costs (in 2015 Canadian dollars, and overdiagnosis. The results of the base-case analysis indicated that annual screening was more cost-effective than biennial screening. Scenarios with eligibility criteria that required as few as 20 pack-years were dominated by scenarios that required higher numbers of accumulated pack-years. In general, scenarios that applied stringent smoking eligibility criteria (i.e., requiring higher levels of accumulated smoking exposure were more cost-effective than scenarios with less stringent smoking eligibility criteria, with modest differences in life-years gained. Annual screening between ages 55-75 for persons who smoked ≥40 pack-years and who currently smoke or quit ≤10 y ago yielded an incremental cost-effectiveness ratio of $41,136 Canadian dollars ($33,825 in May 1, 2015, United States dollars per life-year gained

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

    Directory of Open Access Journals (Sweden)

    Qifeng Bai

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

  9. Computer-aided system of evaluation for population-based all-in-one service screening (CASE-PASS): from study design to outcome analysis with bias adjustment.

    Science.gov (United States)

    Chen, Li-Sheng; Yen, Amy Ming-Fang; Duffy, Stephen W; Tabar, Laszlo; Lin, Wen-Chou; Chen, Hsiu-Hsi

    2010-10-01

    Population-based routine service screening has gained popularity following an era of randomized controlled trials. The evaluation of these service screening programs is subject to study design, data availability, and the precise data analysis for adjusting bias. We developed a computer-aided system that allows the evaluation of population-based service screening to unify these aspects and facilitate and guide the program assessor to efficiently perform an evaluation. This system underpins two experimental designs: the posttest-only non-equivalent design and the one-group pretest-posttest design and demonstrates the type of data required at both the population and individual levels. Three major analyses were developed that included a cumulative mortality analysis, survival analysis with lead-time adjustment, and self-selection bias adjustment. We used SAS AF software to develop a graphic interface system with a pull-down menu style. We demonstrate the application of this system with data obtained from a Swedish population-based service screen and a population-based randomized controlled trial for the screening of breast, colorectal, and prostate cancer, and one service screening program for cervical cancer with Pap smears. The system provided automated descriptive results based on the various sources of available data and cumulative mortality curves corresponding to the study designs. The comparison of cumulative survival between clinically and screen-detected cases without a lead-time adjustment are also demonstrated. The intention-to-treat and noncompliance analysis with self-selection bias adjustments are also shown to assess the effectiveness of the population-based service screening program. Model validation was composed of a comparison between our adjusted self-selection bias estimates and the empirical results on effectiveness reported in the literature. We demonstrate a computer-aided system allowing the evaluation of population-based service screening

  10. Binding-site assessment by virtual fragment screening.

    Directory of Open Access Journals (Sweden)

    Niu Huang

    2010-04-01

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

  11. Discovery of new antitumoral and antibacterial drugs from brazilian plant extracts using high throughput screening Descoberta de novos fármacos anti-tumorais e anti-bacterianos de extratos vegetais brasileiros através de screening em larga escala

    Directory of Open Access Journals (Sweden)

    Riad Naim Younes

    2007-01-01

    Full Text Available Plants have played a significant role in the treatment of cancer and infectious diseases for the last four decades. The discovery and introduction to market of paclitaxel, the vinca alkaloids, etoposide, and many antibacterial drugs support drug discovery programs based on natural products. Natural products have been rediscovered as important tools for drug development despite advances in combinatorial chemistry, due to the complex molecular structures able to interact with mammalian cell targets. The Brazilian flora, the most diverse in the world, has become an interesting spot to prospect for new chemical leads or hits due to its species diversity and associated chemical richness. Screening programs have been established in Brazil as a strategy to identify potentially active substances. High throughput screening techniques allow for the analysis of large numbers of extracts in a relatively short period of time, and can be considered one of the most efficient ways of finding new leads from natural products. An updated review of the current status of the biological screening program is presented and recent results from new antitumoral and antibacterial chemical leads are discussed.Plantas são uma importante fonte de novos protótipos há pelo menos quatro décadas. A descoberta e introdução no mercado de paclitaxel, dos alcalóides da vinca, etoposídeo e muitos agentes antibacterianos têm servido de apoio ao desenvolvimento de programas de descobrimento de novos fármacos baseados em produtos naturais. Produtos naturais foram recentemente redescobertos como importante ferramenta na descoberta de novos fármacos devido às estruturas moleculares complexas capazes de interagir com alvos em células de mamíferos. A flora brasileira, a mais rica do mundo, tornou-se um importante sítio para prospecção de novos protótipos em decorrência da riqueza de espécies vegetais relacionada a uma possível diversidade química. Programas de triagem t

  12. Multimedia messages in genetics: design, development, and evaluation of a computer-based instructional resource for secondary school students in a Tay Sachs disease carrier screening program.

    Science.gov (United States)

    Gason, Alexandra A; Aitken, MaryAnne; Delatycki, Martin B; Sheffield, Edith; Metcalfe, Sylvia A

    2004-01-01

    Tay Sachs disease is a recessively inherited neurodegenerative disorder, for which carrier screening programs exist worldwide. Education for those offered a screening test is essential in facilitating informed decision-making. In Melbourne, Australia, we have designed, developed, and evaluated a computer-based instructional resource for use in the Tay Sachs disease carrier screening program for secondary school students attending Jewish schools. The resource entitled "Genetics in the Community: Tay Sachs disease" was designed on a platform of educational learning theory. The development of the resource included formative evaluation using qualitative data analysis supported by descriptive quantitative data. The final resource was evaluated within the screening program and compared with the standard oral presentation using a questionnaire. Knowledge outcomes were measured both before and after either of the educational formats. Data from the formative evaluation were used to refine the content and functionality of the final resource. The questionnaire evaluation of 302 students over two years showed the multimedia resource to be equally effective as an oral educational presentation in facilitating participants' knowledge construction. The resource offers a large number of potential benefits, which are not limited to the Tay Sachs disease carrier screening program setting, such as delivery of a consistent educational message, short delivery time, and minimum financial and resource commitment. This article outlines the value of considering educational theory and describes the process of multimedia development providing a framework that may be of value when designing genetics multimedia resources in general.

  13. Examination of Chronic Smoking Behavior and Eligibility for Low-Dose Computed Tomography for Lung Cancer Screening Among Older Chinese Male Smokers.

    Science.gov (United States)

    Li, Chien-Ching; Matthews, Alicia K; Dong, XinQi

    2017-07-01

    Low-dose computed tomography lung cancer (LDCT) screening is an effective way to decrease lung cancer mortality. Both Medicare and private insurers offer coverage of LDCT screening to beneficiaries who are at high risk of developing lung cancer. In this study, we examined rates and predictors of chronic smoking behavior and eligibility for coverage of LDCT screening among older Chinese men living in the greater Chicago area. Data were obtained from the Population Study of Chinese Elderly in Chicago, a population-based survey of community-dwelling, older Chinese adults in the Chicago metropolitan area. Eligibility criteria according to Centers of Medicare and Medicaid Services (CMS) and U.S. Preventive Services Task Force (USPSTF) for LDCT screening were used. Multivariate logistic regression was conducted to determine predictors of chronic smoking behavior which was operationalized as meeting criteria for LDCT screening. A quarter of the sample were current smokers and 42.5% reported a prior history of smoking. Eighteen percent and 22% of older Chinese men met the eligibility criteria for appropriateness for CMS and USPSTF LDCT screening, respectively. Furthermore, education, marital status, and number of children were significantly associated with chronic smoking behavior. Older Chinese men with chronic smoking behavior are at high risk of developing lung cancer and nearly one in five meet eligibility for LDCT screening. Increased outreach and education regarding early detection of lung cancer and smoking cessation are needed for this vulnerable and high-risk population. © The Author 2017. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  14. Novel high-resolution computed tomography-based radiomic classifier for screen-identified pulmonary nodules in the National Lung Screening Trial.

    Science.gov (United States)

    Peikert, Tobias; Duan, Fenghai; Rajagopalan, Srinivasan; Karwoski, Ronald A; Clay, Ryan; Robb, Richard A; Qin, Ziling; Sicks, JoRean; Bartholmai, Brian J; Maldonado, Fabien

    2018-01-01

    Optimization of the clinical management of screen-detected lung nodules is needed to avoid unnecessary diagnostic interventions. Herein we demonstrate the potential value of a novel radiomics-based approach for the classification of screen-detected indeterminate nodules. Independent quantitative variables assessing various radiologic nodule features such as sphericity, flatness, elongation, spiculation, lobulation and curvature were developed from the NLST dataset using 726 indeterminate nodules (all ≥ 7 mm, benign, n = 318 and malignant, n = 408). Multivariate analysis was performed