Science.gov

Sample records for integrates multiple molecular

  1. Multiple time step integrators in ab initio molecular dynamics

    SciTech Connect

    Luehr, Nathan; Martínez, Todd J.; Markland, Thomas E.

    2014-02-28

    Multiple time-scale algorithms exploit the natural separation of time-scales in chemical systems to greatly accelerate the efficiency of molecular dynamics simulations. Although the utility of these methods in systems where the interactions are described by empirical potentials is now well established, their application to ab initio molecular dynamics calculations has been limited by difficulties associated with splitting the ab initio potential into fast and slowly varying components. Here we present two schemes that enable efficient time-scale separation in ab initio calculations: one based on fragment decomposition and the other on range separation of the Coulomb operator in the electronic Hamiltonian. We demonstrate for both water clusters and a solvated hydroxide ion that multiple time-scale molecular dynamics allows for outer time steps of 2.5 fs, which are as large as those obtained when such schemes are applied to empirical potentials, while still allowing for bonds to be broken and reformed throughout the dynamics. This permits computational speedups of up to 4.4x, compared to standard Born-Oppenheimer ab initio molecular dynamics with a 0.5 fs time step, while maintaining the same energy conservation and accuracy.

  2. A selective sphingosine kinase 1 inhibitor integrates multiple molecular therapeutic targets in human leukemia

    PubMed Central

    Paugh, Steven W.; Paugh, Barbara S.; Rahmani, Mohamed; Kapitonov, Dmitri; Almenara, Jorge A.; Kordula, Tomasz; Milstien, Sheldon; Adams, Jeffrey K.; Zipkin, Robert E.; Grant, Steven

    2008-01-01

    The potent bioactive sphingolipid mediator, sphingosine-1-phosphate (S1P), is produced by 2 sphingosine kinase isoenzymes, SphK1 and SphK2. Expression of SphK1 is up-regulated in cancers, including leukemia, and associated with cancer progression. A screen of sphingosine analogs identified (2R,3S,4E)-N-methyl-5-(4′-pentylphenyl)-2-aminopent-4-ene-1,3-diol, designated SK1-I (BML-258), as a potent, water-soluble, isoenzyme-specific inhibitor of SphK1. In contrast to pan-SphK inhibitors, SK1-I did not inhibit SphK2, PKC, or numerous other protein kinases. SK1-I decreased growth and survival of human leukemia U937 and Jurkat cells, and enhanced apoptosis and cleavage of Bcl-2. Lethality of SK1-I was reversed by caspase inhibitors and by expression of Bcl-2. SK1-I not only decreased S1P levels but concomitantly increased levels of its proapoptotic precursor ceramide. Conversely, S1P protected against SK1-I–induced apoptosis. SK1-I also induced multiple perturbations in activation of signaling and survival-related proteins, including diminished phosphorylation of ERK1/2 and Akt. Expression of constitutively active Akt protected against SK1-I–induced apoptosis. Notably, SK1-I potently induced apoptosis in leukemic blasts isolated from patients with acute myelogenous leukemia but was relatively sparing of normal peripheral blood mononuclear leukocytes. Moreover, SK1-I markedly reduced growth of AML xenograft tumors. Our results suggest that specific inhibitors of SphK1 warrant attention as potential additions to the therapeutic armamentarium in leukemia. PMID:18511810

  3. OVA: integrating molecular and physical phenotype data from multiple biomedical domain ontologies with variant filtering for enhanced variant prioritization

    PubMed Central

    Antanaviciute, Agne; Watson, Christopher M.; Harrison, Sally M.; Lascelles, Carolina; Crinnion, Laura; Markham, Alexander F.; Bonthron, David T.; Carr, Ian M.

    2015-01-01

    Motivation: Exome sequencing has become a de facto standard method for Mendelian disease gene discovery in recent years, yet identifying disease-causing mutations among thousands of candidate variants remains a non-trivial task. Results: Here we describe a new variant prioritization tool, OVA (ontology variant analysis), in which user-provided phenotypic information is exploited to infer deeper biological context. OVA combines a knowledge-based approach with a variant-filtering framework. It reduces the number of candidate variants by considering genotype and predicted effect on protein sequence, and scores the remainder on biological relevance to the query phenotype. We take advantage of several ontologies in order to bridge knowledge across multiple biomedical domains and facilitate computational analysis of annotations pertaining to genes, diseases, phenotypes, tissues and pathways. In this way, OVA combines information regarding molecular and physical phenotypes and integrates both human and model organism data to effectively prioritize variants. By assessing performance on both known and novel disease mutations, we show that OVA performs biologically meaningful candidate variant prioritization and can be more accurate than another recently published candidate variant prioritization tool. Availability and implementation: OVA is freely accessible at http://dna2.leeds.ac.uk:8080/OVA/index.jsp Supplementary information: Supplementary data are available at Bioinformatics online. Contact: umaan@leeds.ac.uk PMID:26272982

  4. A high density consensus genetic map of tetraploid cotton that integrates multiple component maps through molecular marker redundancy check

    Technology Transfer Automated Retrieval System (TEKTRAN)

    An ultra-dense consensus (UDC) genetic map of tetraploid cotton was constructed using six high-density component maps and after the integration of a sequence-based marker redundancy check. Public cotton SSR libraries (17,343 markers) were curated for sequence redundancy using 90% as a similarity cut...

  5. Integrated analysis of microRNAs, transcription factors and target genes expression discloses a specific molecular architecture of hyperdiploid multiple myeloma.

    PubMed

    Di Martino, Maria Teresa; Guzzi, Pietro Hiram; Caracciolo, Daniele; Agnelli, Luca; Neri, Antonino; Walker, Brian A; Morgan, Gareth J; Cannataro, Mario; Tassone, Pierfrancesco; Tagliaferri, Pierosandro

    2015-08-01

    Multiple Myeloma (MM) is a malignancy characterized by the hyperdiploid (HD-MM) and the non-hyperdiploid (nHD-MM) subtypes. To shed light within the molecular architecture of these subtypes, we used a novel integromics approach. By annotated MM patient mRNA/microRNA (miRNA) datasets, we investigated mRNAs and miRNAs profiles with relation to changes in transcriptional regulators expression. We found that HD-MM displays specific gene and miRNA expression profiles, involving the Signal Transducer and Activator of Transcription (STAT)3 pathway as well as the Transforming Growth Factor-beta (TGFβ) and the transcription regulator Nuclear Protein-1 (NUPR1). Our data define specific molecular features of HD-MM that may translate in the identification of novel relevant druggable targets. PMID:26056083

  6. Integrated analysis of microRNAs, transcription factors and target genes expression discloses a specific molecular architecture of hyperdiploid multiple myeloma

    PubMed Central

    Caracciolo, Daniele; Agnelli, Luca; Neri, Antonino; Walker, Brian A.; Morgan, Gareth J.; Cannataro, Mario

    2015-01-01

    Multiple Myeloma (MM) is a malignancy characterized by the hyperdiploid (HD-MM) and the non-hyperdiploid (nHD-MM) subtypes. To shed light within the molecular architecture of these subtypes, we used a novel integromics approach. By annotated MM patient mRNA/microRNA (miRNA) datasets, we investigated mRNAs and miRNAs profiles with relation to changes in transcriptional regulators expression. We found that HD-MM displays specific gene and miRNA expression profiles, involving the Signal Transducer and Activator of Transcription (STAT)3 pathway as well as the Transforming Growth Factor–beta (TGFβ) and the transcription regulator Nuclear Protein-1 (NUPR1). Our data define specific molecular features of HD-MM that may translate in the identification of novel relevant druggable targets. PMID:26056083

  7. Integration methods for molecular dynamics

    SciTech Connect

    Leimkuhler, B.J.; Reich, S.; Skeel, R.D.

    1996-12-31

    Classical molecular dynamics simulation of a macromolecule requires the use of an efficient time-stepping scheme that can faithfully approximate the dynamics over many thousands of timesteps. Because these problems are highly nonlinear, accurate approximation of a particular solution trajectory on meaningful time intervals is neither obtainable nor desired, but some restrictions, such as symplecticness, can be imposed on the discretization which tend to imply good long term behavior. The presence of a variety of types and strengths of interatom potentials in standard molecular models places severe restrictions on the timestep for numerical integration used in explicit integration schemes, so much recent research has concentrated on the search for alternatives that possess (1) proper dynamical properties, and (2) a relative insensitivity to the fastest components of the dynamics. We survey several recent approaches. 48 refs., 2 figs.

  8. Multiple interactions between molecular and supramolecular ordering

    NASA Astrophysics Data System (ADS)

    Manno, M.; Emanuele, A.; Martorana, V.; Bulone, D.; San Biagio, P. L.; Palma-Vittorelli, M. B.; Palma, M. U.

    1999-02-01

    We report studies of the interplay among processes of molecular conformational changes, spinodal demixing of the solution, and molecular crosslinking involved in the physical gelation of a biopolysaccharide-water system. Multiple interactions and kinetic competition among these processes were studied under largely different absolute and relative values of their individual rates by appropriate choices of the quenching temperature at constant polymer concentration. Quenching temperature strongly affects the rate of growth but not the final value of the fractal dimension of the gel. Kinetic competition plays a central role in determining the final conformation of individual molecules and the structure and properties of the final gel. This behavior highlights the frustrated nature of the system, and the need of bringing kinetics sharply into focus in gelation theories. General aspects of the present findings and, specifically, the interplay of molecular conformation changes, solution demixing, and molecular crosslinking extend the relevance of these studies to the fast growing field of amyloid condensation and Prion diseases.

  9. Multiple-stage integrating accelerometer

    DOEpatents

    Devaney, H.F.

    1984-06-27

    An accelerometer assembly is provided for use in activating a switch in response to multiple acceleration pulses in series. The accelerometer includes a housing forming a chamber. An inertial mass or piston is slidably disposed in the chamber and spring biased toward a first or reset position. A damping system is also provided to damp piston movement in response to first and subsequent acceleration pulses. Additionally, a cam, including a Z-shaped slot, and cooperating follower pin slidably received therein are mounted to the piston and the housing. The middle or cross-over leg of the Z-shaped slot cooperates with the follower pin to block or limit piston movement and prevent switch activation in response to a lone acceleration pulse. The switch of the assembly is only activated after two or more separate acceleration pulses are sensed and the piston reaches the end of the chamber opposite the reset position.

  10. Multiple-stage integrating accelerometer

    DOEpatents

    Devaney, Howard F.

    1986-01-01

    An accelerometer assembly is provided for use in activating a switch in response to multiple acceleration pulses in series. The accelerometer includes a housing forming a chamber. An inertial mass or piston is slidably disposed in the chamber and spring biased toward a first or reset position. A damping system is also provided to damp piston movement in response to first and subsequent acceleration pulses. Additionally, a cam, including a Z-shaped slot, and cooperating follower pin slidably received therein are mounted to the piston and the housing. The middle or cross-over leg of the Z-shaped slot cooperates with the follower pin to block or limit piston movement and prevent switch activation in response to a lone acceleration pulse. The switch of the assembly is only activated after two or more separate acceleration pulses are sensed and the piston reaches the end of the chamber opposite the reset position.

  11. Integrating structure- and ligand-based virtual screening: comparison of individual, parallel, and fused molecular docking and similarity search calculations on multiple targets.

    PubMed

    Tan, Lu; Geppert, Hanna; Sisay, Mihiret T; Gütschow, Michael; Bajorath, Jürgen

    2008-10-01

    Similarity searching is often used to preselect compounds for docking, thereby decreasing the size of screening databases. However, integrated structure- and ligand-based screening schemes are rare at present. Docking and similarity search calculations using 2D fingerprints were carried out in a comparative manner on nine target enzymes, for which significant numbers of diverse inhibitors could be obtained. In the absence of knowledge-based docking constraints and target-directed parameter optimisation, fingerprint searching displayed a clear preference over docking calculations. Alternative combinations of docking and similarity search results were investigated and found to further increase compound recall of individual methods in a number of instances. When the results of similarity searching and docking were combined, parallel selection of candidate compounds from individual rankings was generally superior to rank fusion. We suggest that complementary results from docking and similarity searching can be captured by integrated compound selection schemes. PMID:18651695

  12. Molecular mechanisms in multiple myeloma drug resistance

    PubMed Central

    Nikesitch, Nicholas; Ling, Silvia C W

    2016-01-01

    Multiple myeloma (MM) is predominantly an incurable malignancy despite high-dose chemotherapy, autologous stem cell transplant and novel agents. MM is a genetically heterogeneous disease and the complexity increases as the disease progresses to a more aggressive stage. MM arises from a plasma cell, which produces and secretes non-functioning immunoglobulins. Most MM cells are sensitive to proteasome inhibitors (PIs), which have become the main drug in the treatment of newly diagnosed and relapsed MM. However, not all MM is sensitive to PIs. This review summarises the literature regarding molecular biology of MM with a focus on the unfolded protein response and explores how this could affect drug sensitivity and progression of disease. PMID:26598624

  13. Multiple identities and the integration of personality.

    PubMed

    Gregg, G S

    1995-09-01

    Life-history interviews show narrators to shift among multiple, often contradictory self-representations. This article outlines a model that accounts for how a relatively small set of self-symbols and metaphors can form a grammar-like system that simultaneously defines and integrates multiple identities. Drawing on generative theories from linguistics, anthropology, and music, the model proposes that this system provides a unitary deep structure that can be configured in various arrangements to yield multiple surface structures. Each "surface" identity constructs an individual's emotions and social relations--and what he or she accepts as "Me" and rejects as "not-Me"--into a distinct pattern, with identity per se appearing as a dialogic or fugue-like structure of opposed voices. Study-of-lives interviews conducted by the author in urban America and rural Morocco are used to present the model and to demonstrate the pivotal role played by multistable or "structurally ambiguous" symbols in anchoring reversible self-representations which integrate personality as a system of organized contraction. The musical analogy is emphasized in order to build a bridge toward current research in cognitive science and toward efforts to formulate a "state integration" theory of personality development. PMID:7562365

  14. Integral 3D display using multiple LCDs

    NASA Astrophysics Data System (ADS)

    Okaichi, Naoto; Miura, Masato; Arai, Jun; Mishina, Tomoyuki

    2015-03-01

    The quality of the integral 3D images created by a 3D imaging system was improved by combining multiple LCDs to utilize a greater number of pixels than that possible with one LCD. A prototype of the display device was constructed by using four HD LCDs. An integral photography (IP) image displayed by the prototype is four times larger than that reconstructed by a single display. The pixel pitch of the HD display used is 55.5 μm, and the number of elemental lenses is 212 horizontally and 119 vertically. The 3D image pixel count is 25,228, and the viewing angle is 28°. Since this method is extensible, it is possible to display an integral 3D image of higher quality by increasing the number of LCDs. Using this integral 3D display structure makes it possible to make the whole device thinner than a projector-based display system. It is therefore expected to be applied to the home television in the future.

  15. Multiple Sclerosis: Molecular Mechanisms and Therapeutic Opportunities

    PubMed Central

    Miljković, Djordje; Spasojević, Ivan

    2013-01-01

    Abstract The pathophysiology of multiple sclerosis (MS) involves several components: redox, inflammatory/autoimmune, vascular, and neurodegenerative. All of them are supported by the intertwined lines of evidence, and none of them should be written off. However, the exact mechanisms of MS initiation, its development, and progression are still elusive, despite the impressive pace by which the data on MS are accumulating. In this review, we will try to integrate the current facts and concepts, focusing on the role of redox changes and various reactive species in MS. Knowing the schedule of initial changes in pathogenic factors and the key turning points, as well as understanding the redox processes involved in MS pathogenesis is the way to enable MS prevention, early treatment, and the development of therapies that target specific pathophysiological components of the heterogeneous mechanisms of MS, which could alleviate the symptoms and hopefully stop MS. Pertinent to this, we will outline (i) redox processes involved in MS initiation; (ii) the role of reactive species in inflammation; (iii) prooxidative changes responsible for neurodegeneration; and (iv) the potential of antioxidative therapy. Antioxid. Redox Signal. 19, 2286–2334. PMID:23473637

  16. Integrated management of multiple reservoir field developments

    SciTech Connect

    Lyons, S.L.; Chan, H.M.; Harper, J.L.; Boyett, B.A.; Dowson, P.R.; Bette, S.

    1995-10-01

    This paper consists of two sections. The authors first describe the coupling of a pipeline network model to a reservoir simulator and then the application of this new simulator to optimize the production strategy of two Mobil field developments. Mobil`s PEGASUS simulator is an integrated all purpose reservoir simulator that handles black-oil, compositional, faulted and naturally fractured reservoirs. The authors have extended the simulator to simultaneously model multiple reservoirs coupled with surface pipeline networks and processes. This allows them to account for the effects of geology, well placement, and surface production facilities on well deliverability in a fully integrated fashion. They have also developed a gas contract allocation system that takes the user-specified constraints, target rates and swing factors and automatically assigns rates to the individual wells of each reservoir. This algorithm calculates the overall deliverability and automatically reduces the user-specified target rates to meet the deliverability constraints. The algorithm and solution technique are described. This enhanced simulator has been applied to model a Mobil field development in the Southern Gas Basin, offshore United Kingdom, which consists of three separate gas reservoirs connected via a pipeline network. The simulator allowed the authors to accurately determine the impact on individual reservoir and total field performance by varying the development timing of these reservoirs. Several development scenarios are shown to illustrate the capabilities of PEGASUS. Another application of this technology is in the field developments in North Sumatra, Indonesia. Here the objective is to economically optimize the development of multiple fields to feed the PT Arun LNG facility. Consideration of a range of gas compositions, well productivity`s, and facilities constraints in an integrated fashion results in improved management of these assets. Model specifics are discussed.

  17. Quantitative Molecular Thermochemistry Based on Path Integrals

    SciTech Connect

    Glaesemann, K R; Fried, L E

    2005-03-14

    The calculation of thermochemical data requires accurate molecular energies and heat capacities. Traditional methods rely upon the standard harmonic normal mode analysis to calculate the vibrational and rotational contributions. We utilize path integral Monte Carlo (PIMC) for going beyond the harmonic analysis, to calculate the vibrational and rotational contributions to ab initio energies. This is an application and extension of a method previously developed in our group.

  18. Multiple Integrated Complementary Healing Approaches: Energetics & Light for bone.

    PubMed

    Gray, Michael G; Lackey, Brett R; Patrick, Evelyn F; Gray, Sandra L; Hurley, Susan G

    2016-01-01

    A synergistic-healing strategy that combines molecular targeting within a system-wide perspective is presented as the Multiple Integrated Complementary Healing Approaches: Energetics And Light (MICHAEL). The basis of the MICHAEL approach is the realization that environmental, nutritional and electromagnetic factors form a regulatory framework involved in bone and nerve healing. The interactions of light, energy, and nutrition with neural, hormonal and cellular pathways will be presented. Energetic therapies including electrical, low-intensity pulsed ultrasound and light based treatments affect growth, differentiation and proliferation of bone and nerve and can be utilized for their healing benefits. However, the benefits of these therapies can be impaired by the absence of nutritional, hormonal and organismal factors. For example, lack of sleep, disrupted circadian rhythms and vitamin-D deficiency can impair healing. Molecular targets, such as the Wnt pathway, protein kinase B and glucocorticoid signaling systems can be modulated by nutritional components, including quercetin, curcumin and Mg(2+) to enhance the healing process. The importance of water and water-regulation will be presented as an integral component. The effects of exercise and acupuncture on bone healing will also be discussed within the context of the MICHAEL approach. PMID:26804592

  19. Lock-in by molecular multiplication

    NASA Astrophysics Data System (ADS)

    Braun, Dieter; Libchaber, Albert

    2003-12-01

    A lock-in amplifier is physically realized at the level of fluorescent dye molecules. It is based on the general property that the emission of a fluorescent dye is the product of quantum efficiency and illumination intensity. For each pixel of a microscopic image, we measure in amplitude and phase an environment property of the dye, such as conformation, membrane voltage, or temperature. This lock-in implementation is highly parallel and reaches the ultimate photon shot noise limit. Using fast temperature oscillations, we apply it to measure the opening/closing kinetics of a molecular beacon (DNA hairpin) at 5 μs resolution.

  20. Integrating Multiple Intelligences in EFL/ESL Classrooms

    ERIC Educational Resources Information Center

    Bas, Gokhan

    2008-01-01

    This article deals with the integration of the theory of Multiple Intelligences in EFL/ESL classrooms. In this study, after the theory of multiple intelligences was presented shortly, the integration of this theory into English classrooms. Intelligence types in MI Theory were discussed and some possible application ways of these intelligence types…

  1. Complementary and Integrative Medicine - Multiple Languages: MedlinePlus

    MedlinePlus

    ... Are Here: Home → Multiple Languages → All Health Topics → Complementary and Integrative Medicine URL of this page: https://www.nlm.nih. ... V W XYZ List of All Topics All Complementary and Integrative Medicine - Multiple Languages To use the sharing features on ...

  2. Code Division Multiple Access system candidate for integrated modular avionics

    NASA Astrophysics Data System (ADS)

    Mendez, Antonio J.; Gagliardi, Robert M.

    1991-02-01

    There are government and industry trends towards avionics modularity and integrated avionics. Key requirements implicit in these trends are suitable data communication concepts compatible with the integration concept. In this paper we explore the use ofCode Division Multiple Access (CDMA) techniques as an alternative to collision detection and collision avoidance multiple access techniques.

  3. Complementary and Integrative Medicine - Multiple Languages: MedlinePlus

    MedlinePlus

    ... Are Here: Home → Multiple Languages → All Health Topics → Complementary and Integrative Medicine URL of this page: https://medlineplus.gov/languages/ ... V W XYZ List of All Topics All Complementary and Integrative Medicine - Multiple Languages To use the sharing features on ...

  4. Multiple molecular penumbras after focal cerebral ischemia.

    PubMed

    Sharp, F R; Lu, A; Tang, Y; Millhorn, D E

    2000-07-01

    Though the ischemic penumbra has been classically described on the basis of blood flow and physiologic parameters, a variety of ischemic penumbras can be described in molecular terms. Apoptosis-related genes induced after focal ischemia may contribute to cell death in the core and the selective cell death adjacent to an infarct. The HSP70 heat shock protein is induced in glia at the edges of an infarct and in neurons often at some distance from the infarct. HSP70 proteins are induced in cells in response to denatured proteins that occur as a result of temporary energy failure. Hypoxia-inducible factor (HIF) is also induced after focal ischemia in regions that can extend beyond the HSP70 induction. The region of HIF induction is proposed to represent the areas of decreased cerebral blood flow and decreased oxygen delivery. Immediate early genes are induced in cortex, hippocampus, thalamus, and other brain regions. These distant changes in gene expression occur because of ischemia-induced spreading depression or depolarization and could contribute to plastic changes in brain after stroke. PMID:10908035

  5. Molecular biomarkers in cerebrospinal fluid of multiple sclerosis patients.

    PubMed

    Fitzner, Brit; Hecker, Michael; Zettl, Uwe Klaus

    2015-10-01

    Multiple sclerosis (MS) is a chronic immune-mediated disease of the central nervous system, usually occurring in young adults and leading to disability. Despite the progress in technology and intensive research work of the last years, diagnosing MS can still be challenging. A heterogenic and complex pathophysiology with various types of disease courses makes MS unique for each patient. There is an urgent need to identify markers facilitating rapid and accurate diagnosis and prognostic assessments with regard to optimal therapy for each MS patient. Cerebrospinal fluid (CSF) is an outstanding source of specific markers related to MS pathology. Molecules reflecting specific pathological processes, such as inflammation, cellular damage, and loss of blood-brain-barrier integrity, are detectable in CSF. Clinically used biomarkers of CSF are oligoclonal bands, IgG-index, measles-rubella-zoster-reaction, anti-aquaporin 4 antibodies, and antibodies against John Cunningham virus. Many other potential biomarkers have been proposed in recent years. In this review we examine the current scientific knowledge on CSF molecular markers that could guide diagnosis and discrimination of different MS forms, support treatment decisions, or be helpful in monitoring and predicting disease progression, therapy response, and complications such as opportunistic infections. PMID:26071103

  6. Microelectromechanical systems integrating molecular spin crossover actuators

    NASA Astrophysics Data System (ADS)

    Manrique-Juarez, Maria D.; Rat, Sylvain; Mathieu, Fabrice; Saya, Daisuke; Séguy, Isabelle; Leïchlé, Thierry; Nicu, Liviu; Salmon, Lionel; Molnár, Gábor; Bousseksou, Azzedine

    2016-08-01

    Silicon MEMS cantilevers coated with a 200 nm thin layer of the molecular spin crossover complex [Fe(H2B(pz)2)2(phen)] (H2B(pz)2 = dihydrobis(pyrazolyl)borate and phen = 1,10-phenantroline) were actuated using an external magnetic field and their resonance frequency was tracked by means of integrated piezoresistive detection. The light-induced spin-state switching of the molecules from the ground low spin to the metastable high spin state at 10 K led to a well-reproducible shift of the cantilever's resonance frequency (Δfr = -0.52 Hz). Control experiments at different temperatures using coated as well as uncoated devices along with simple calculations support the assignment of this effect to the spin transition. This latter translates into changes in mechanical behavior of the cantilever due to the strong spin-state/lattice coupling. A guideline for the optimization of device parameters is proposed so as to efficiently harness molecular scale movements for large-scale mechanical work, thus paving the road for nanoelectromechanical systems (NEMS) actuators based on molecular materials.

  7. Integrated Instruction: Multiple Intelligences and Technology

    ERIC Educational Resources Information Center

    McCoog, Ian J.

    2007-01-01

    Advancements in technology have changed the day to day operation of society. The ways in which we teach and learn have begun the same process. For this reason, we must reexamine instruction. In this article, the author analyzes the changing environment of educational technology and how to incorporate the theory of multiple intelligences. The…

  8. Integrating Learning Styles and Multiple Intelligences.

    ERIC Educational Resources Information Center

    Silver, Harvey; Strong, Richard; Perini, Matthew

    1997-01-01

    Multiple-intelligences theory (MI) explores how cultures and disciplines shape human potential. Both MI and learning-style theories reject dominant ideologies of intelligence. Whereas learning styles are concerned with differences in the learning process, MI centers on learning content and products. Blending learning styles and MI theories via…

  9. Integrative molecular profiling of routine clinical prostate cancer specimens

    PubMed Central

    Grasso, C. S.; Cani, A. K.; Hovelson, D. H.; Quist, M. J.; Douville, N. J.; Yadati, V.; Amin, A. M.; Nelson, P. S.; Betz, B. L.; Liu, C-J.; Knudsen, K. E.; Cooney, K. A.; Feng, F. Y.; McDaniel, A. S.; Tomlins, S. A.

    2015-01-01

    Background Comprehensive molecular profiling led to the recognition of multiple prostate cancer (PCa) molecular subtypes and driving alterations, but translating these findings to clinical practice is challenging. Patients and methods We developed a formalin-fixed paraffin-embedded (FFPE) tissue compatible integrative assay for PCa molecular subtyping and interrogation of relevant genetic/transcriptomic alterations (MiPC). We applied MiPC, which combines capture-based next generation sequencing and quantitative reverse transcription PCR (qRT-PCR), to 53 FFPE PCa specimens representing cases not well represented in frozen tissue cohorts, including 8 paired primary tumor and lymph node metastases. Results were validated using multiplexed PCR based NGS and Sanger sequencing. Results We identified known and novel potential driving, somatic mutations and copy number alterations, including a novel BRAF T599_V600insHT mutation and CYP11B2 amplification in a patient treated with ketoconazole (a potent CYP11B2 inhibitor). qRT-PCR integration enabled comprehensive molecular subtyping and provided complementary information, such as androgen receptor (AR) target gene module assessment in advanced cases and SPINK1 over-expression. MiPC identified highly concordant profiles for all 8 tumor/lymph node metastasis pairs, consistent with limited heterogeneity amongst driving events. MiPC and exome sequencing were performed on separately isolated conventional acinar PCa and prostatic small cell carcinoma (SCC) components from the same FFPE resection specimen to enable direct comparison of histologically distinct components. While both components showed TMPRSS2:ERG fusions, the SCC component exclusively harbored complete TP53 inactivation (frameshift variant and copy loss) and two CREBBP mutations. Conclusions Our results demonstrate the feasibility of integrative profiling of routine PCa specimens, which may have utility for understanding disease biology and enabling personalized

  10. Building a cognitive map by assembling multiple path integration systems.

    PubMed

    Wang, Ranxiao Frances

    2016-06-01

    Path integration and cognitive mapping are two of the most important mechanisms for navigation. Path integration is a primitive navigation system which computes a homing vector based on an animal's self-motion estimation, while cognitive map is an advanced spatial representation containing richer spatial information about the environment that is persistent and can be used to guide flexible navigation to multiple locations. Most theories of navigation conceptualize them as two distinctive, independent mechanisms, although the path integration system may provide useful information for the integration of cognitive maps. This paper demonstrates a fundamentally different scenario, where a cognitive map is constructed in three simple steps by assembling multiple path integrators and extending their basic features. The fact that a collection of path integration systems can be turned into a cognitive map suggests the possibility that cognitive maps may have evolved directly from the path integration system. PMID:26442503

  11. Nonresonant Multiple-Pulse Control of Molecular Motions in Liquid

    NASA Astrophysics Data System (ADS)

    Nikiforov, V. G.

    2015-09-01

    We propose the implementation of the multiple-pulse excitation for manipulation of the molecular contributions to the optically-heterodyne-detected optical-Kerr-effect. The key parameters controlling the specificity of the multiple-pulse excitation scenarios are the pulses durations, the delays between pulses, the relation between the pump pulses amplitudes and the pulses polarizations. We model the high-order optical responses and consider some principles of the scenarios construction. We show that it is possible to adjust the excitation scenario in such a way that the some responses can be removed from detected signal along with the enhancement of the interested response amplitude. The theoretical analysis and first experimental data reveal that the multiple-pulse excitation technique can be useful for the selective spectroscopy of the molecular vibrations and rotations in liquid.

  12. Integral Methodological Pluralism in Science Education Research: Valuing Multiple Perspectives

    ERIC Educational Resources Information Center

    Davis, Nancy T.; Callihan, Laurie P.

    2013-01-01

    This article examines the multiple methodologies used in educational research and proposes a model that includes all of them as contributing to understanding educational contexts and research from multiple perspectives. The model, based on integral theory (Wilber in a theory of everything. Shambhala, Boston, 2000) values all forms of research as…

  13. Multiple Molecular Pathways in Melanomagenesis: Characterization of Therapeutic Targets

    PubMed Central

    Palmieri, Giuseppe; Ombra, MariaNeve; Colombino, Maria; Casula, Milena; Sini, MariaCristina; Manca, Antonella; Paliogiannis, Panagiotis; Ascierto, Paolo Antonio; Cossu, Antonio

    2015-01-01

    Molecular mechanisms involved in pathogenesis of malignant melanoma have been widely studied and novel therapeutic treatments developed in recent past years. Molecular targets for therapy have mostly been recognized in the RAS–RAF–MEK–ERK and PI3K–AKT signaling pathways; small-molecule inhibitors were drawn to specifically target key kinases. Unfortunately, these targeted drugs may display intrinsic or acquired resistance and various evidences suggest that inhibition of a single effector of the signal transduction cascades involved in melanoma pathogenesis may be ineffective in blocking the tumor growth. In this sense, a wider comprehension of the multiple molecular alterations accounting for either response or resistance to treatments with targeted inhibitors may be helpful in assessing, which is the most effective combination of such therapies. In the present review, we summarize the known molecular mechanisms underlying either intrinsic and acquired drug resistance either alternative roads to melanoma pathogenesis, which may become targets for innovative anticancer approaches. PMID:26322273

  14. New Approaches to Molecular Imaging of Multiple Myeloma.

    PubMed

    Vij, Ravi; Fowler, Kathryn J; Shokeen, Monica

    2016-01-01

    Molecular imaging plays an important role in detection and staging of hematologic malignancies. Multiple myeloma (MM) is an age-related hematologic malignancy of clonal bone marrow plasma cells characterized by destructive bone lesions and is fatal in most patients. Traditional skeletal survey and bone scans have sensitivity limitations for osteolytic lesions manifested in MM. Progressive biomedical imaging technologies such as low-dose CT, molecularly targeted PET, MRI, and the functional-anatomic hybrid versions (PET/CT and PET/MRI) provide incremental advancements in imaging MM. Imaging with PET and MRI using molecularly targeted probes is a promising precision medicine platform that might successfully address the clinical ambiguities of myeloma spectrum diseases. The intent of this focus article is to provide a concise review of the present status and promising developments on the horizon, such as the new molecular imaging biomarkers under investigation that can either complement or potentially supersede existing standards. PMID:26541780

  15. The Effects of Tasks on Integrating Information from Multiple Documents

    ERIC Educational Resources Information Center

    Cerdan, Raquel; Vidal-Abarca, Eduardo

    2008-01-01

    The authors examine 2 issues: (a) how students integrate information from multiple scientific documents to describe and explain a physical phenomenon that represents a subset of the information in the documents; and (b) the role of 2 sorts of tasks to achieve this type of integration, either writing an essay on a question requiring integration…

  16. Applying Quadrature Rules with Multiple Nodes to Solving Integral Equations

    SciTech Connect

    Hashemiparast, S. M.; Avazpour, L.

    2008-09-01

    There are many procedures for the numerical solution of Fredholm integral equations. The main idea in these procedures is accuracy of the solution. In this paper, we use Gaussian quadrature with multiple nodes to improve the solution of these integral equations. The application of this method is illustrated via some examples, the related tables are given at the end.

  17. Interstitial integrals in the multiple-scattering model

    SciTech Connect

    Swanson, J.R.; Dill, D.

    1982-08-15

    We present an efficient method for the evaluation of integrals involving multiple-scattering wave functions over the interstitial region. Transformation of the multicenter interstitial wave functions to a single center representation followed by a geometric projection reduces the integrals to products of analytic angular integrals and numerical radial integrals. The projection function, which has the value 1 in the interstitial region and 0 elsewhere, has a closed-form partial-wave expansion. The method is tested by comparing its results with exact normalization and dipole integrals; the differences are 2% at worst and typically less than 1%. By providing an efficient means of calculating Coulomb integrals, the method allows treatment of electron correlations using a multiple scattering basis set.

  18. Integrated Multiscale Modeling of Molecular Computing Devices

    SciTech Connect

    Jerzy Bernholc

    2011-02-03

    will some day reach a miniaturization limit, forcing designers of Si-based electronics to pursue increased performance by other means. Any other alternative approach would have the unenviable task of matching the ability of Si technology to pack more than a billion interconnected and addressable devices on a chip the size of a thumbnail. Nevertheless, the prospects of developing alternative approaches to fabricate electronic devices have spurred an ever-increasing pace of fundamental research. One of the promising possibilities is molecular electronics (ME), self-assembled molecular-based electronic systems composed of single-molecule devices in ultra dense, ultra fast molecular-sized components. This project focused on developing accurate, reliable theoretical modeling capabilities for describing molecular electronics devices. The participants in the project are given in Table 1. The primary outcomes of this fundamental computational science grant are publications in the open scientific literature. As listed below, 62 papers have been published from this project. In addition, the research has also been the subject of more than 100 invited talks at conferences, including several plenary or keynote lectures. Many of the goals of the original proposal were completed. Specifically, the multi-disciplinary group developed a unique set of capabilities and tools for investigating electron transport in fabricated and self-assembled nanostructures at multiple length and time scales.

  19. Study of correlations in molecular motion by multiple quantum NMR

    SciTech Connect

    Tang, J.H.

    1981-11-01

    Nuclear magnetic resonance is a very useful tool for characterizing molecular configurations through the measurement of transition frequencies and dipolar couplings. The measurement of spectral lineshapes, spin-lattice relaxation times, and transverse relaxation times also provide us with valuable information about correlations in molecular motion. The new technique of multiple quantum nuclear magnetic resonance has numerous advantages over the conventional single quantum NMR techniques in obtaining information about static and dynamic interactions of coupled spin systems. In the first two chapters, the theoretical background of spin Hamiltonians and the density matrix formalism of multiple quantum NMR is discussed. The creation and detection of multiple quantum coherence by multiple pulse sequence are discussed. Prototype multiple quantum spectra of oriented benzene are presented. Redfield relaxation theory and the application of multiple quantum NMR to the study of correlations in fluctuations are presented. A specific example of an oriented methyl group relaxed by paramagnetic impurities is studied in detail. The study of possible correlated motion between two coupled methyl groups by multiple quantum NMR is presented. For a six spin system it is shown that the four-quantum spectrum is sensitive to two-body correlations, and serves a ready test of correlated motion. The study of the spin-lattice dynamics of orienting or tunneling methyl groups (CH/sub 3/ and CD/sub 3/) at low temperatures is presented. The anisotropic spin-lattice relaxation of deuterated hexamethylbenzene, caused by the sixfold reorientation of the molecules, is investigated, and the NMR spectrometers and other experimental details are discussed.

  20. Multiple methods integration for structural mechanics analysis and design

    NASA Technical Reports Server (NTRS)

    Housner, J. M.; Aminpour, M. A.

    1991-01-01

    A new research area of multiple methods integration is proposed for joining diverse methods of structural mechanics analysis which interact with one another. Three categories of multiple methods are defined: those in which a physical interface are well defined; those in which a physical interface is not well-defined, but selected; and those in which the interface is a mathematical transformation. Two fundamental integration procedures are presented that can be extended to integrate various methods (e.g., finite elements, Rayleigh Ritz, Galerkin, and integral methods) with one another. Since the finite element method will likely be the major method to be integrated, its enhanced robustness under element distortion is also examined and a new robust shell element is demonstrated.

  1. From multiple unitarity cuts to the coproduct of Feynman integrals

    NASA Astrophysics Data System (ADS)

    Abreu, Samuel; Britto, Ruth; Duhr, Claude; Gardi, Einan

    2014-10-01

    We develop techniques for computing and analyzing multiple unitarity cuts of Feynman integrals, and reconstructing the integral from these cuts. We study the relations among unitarity cuts of a Feynman integral computed via diagrammatic cutting rules, the discontinuity across the corresponding branch cut, and the coproduct of the integral. For single unitarity cuts, these relations are familiar. Here we show that they can be generalized to sequences of unitarity cuts in different channels. Using concrete one- and two-loop scalar integral examples we demonstrate that it is possible to reconstruct a Feynman integral from either single or double unitarity cuts. Our results offer insight into the analytic structure of Feynman integrals as well as a new approach to computing them.

  2. Symbolic programming language in molecular multicenter integral problem

    NASA Astrophysics Data System (ADS)

    Safouhi, Hassan; Bouferguene, Ahmed

    It is well known that in any ab initio molecular orbital (MO) calculation, the major task involves the computation of molecular integrals, among which the computation of three-center nuclear attraction and Coulomb integrals is the most frequently encountered. As the molecular system becomes larger, computation of these integrals becomes one of the most laborious and time-consuming steps in molecular systems calculation. Improvement of the computational methods of molecular integrals would be indispensable to further development in computational studies of large molecular systems. To develop fast and accurate algorithms for the numerical evaluation of these integrals over B functions, we used nonlinear transformations for improving convergence of highly oscillatory integrals. These methods form the basis of new methods for solving various problems that were unsolvable otherwise and have many applications as well. To apply these nonlinear transformations, the integrands should satisfy linear differential equations with coefficients having asymptotic power series in the sense of Poincaré, which in their turn should satisfy some limit conditions. These differential equations are very difficult to obtain explicitly. In the case of molecular integrals, we used a symbolic programming language (MAPLE) to demonstrate that all the conditions required to apply these nonlinear transformation methods are satisfied. Differential equations are obtained explicitly, allowing us to demonstrate that the limit conditions are also satisfied.

  3. Efficient Molecular Dynamics Simulations of Multiple Radical Center Systems Based on the Fragment Molecular Orbital Method

    SciTech Connect

    Nakata, Hiroya; Schmidt, Michael W; Fedorov, Dmitri G; Kitaura, Kazuo; Nakamura, Shinichiro; Gordon, Mark S

    2014-10-16

    The fully analytic energy gradient has been developed and implemented for the restricted open-shell Hartree–Fock (ROHF) method based on the fragment molecular orbital (FMO) theory for systems that have multiple open-shell molecules. The accuracy of the analytic ROHF energy gradient is compared with the corresponding numerical gradient, illustrating the accuracy of the analytic gradient. The ROHF analytic gradient is used to perform molecular dynamics simulations of an unusual open-shell system, liquid oxygen, and mixtures of oxygen and nitrogen. These molecular dynamics simulations provide some insight about how triplet oxygen molecules interact with each other. Timings reveal that the method can calculate the energy gradient for a system containing 4000 atoms in only 6 h. Therefore, it is concluded that the FMO-ROHF method will be useful for investigating systems with multiple open shells.

  4. Method and system of integrating information from multiple sources

    DOEpatents

    Alford, Francine A.; Brinkerhoff, David L.

    2006-08-15

    A system and method of integrating information from multiple sources in a document centric application system. A plurality of application systems are connected through an object request broker to a central repository. The information may then be posted on a webpage. An example of an implementation of the method and system is an online procurement system.

  5. Integrating Multiple Teaching Methods into a General Chemistry Classroom.

    ERIC Educational Resources Information Center

    Francisco, Joseph S.; Nicoll, Gayle; Trautmann, Marcella

    1998-01-01

    Four different methods of teaching--cooperative learning, class discussions, concept maps, and lectures--were integrated into a freshman-level general chemistry course to compare students' levels of participation. Findings support the idea that multiple modes of learning foster the metacognitive skills necessary for mastering general chemistry.…

  6. Multiple molecular forms of glutamine synthetase in pea seeds.

    PubMed

    Antonyuk, L P; Pushkin, A V; Vorobyeva, L M; Solovjeva, N A; Evstigneeva, Z G; Kretovich, W L

    1982-08-20

    Multiple molecular forms of glutamine synthetase (GS, EC 6.3.1.2) have been studied in pea seeds of different varieties. The number of GS molecular forms in the seeds proved to be related to their colour. Two GS forms in the green seeds have been found and only one of them in the yellow seeds. Green seeds had chlorophyll content amounted to 0.4% of the total pigment content in the leaves. Chloroplasts, somewhat smaller than those in pea leaves of the same variety, have been isolated from green seeds. The presence of the second GS form in the pea green seeds we relate to the chloroplasts. By electrophoretic mobility both forms of GS from the green seeds are not identical to the chloroplast GS and the cytosol GS of leaves. Thus, we believe pea plant to contain, at least, four GS forms. PMID:6127624

  7. Multiple ionization bursts in laser-driven hydrogen molecular ion.

    PubMed

    Takemoto, Norio; Becker, Andreas

    2010-11-12

    Theoretical study on H2(+) in an intense infrared laser field on the attosecond time scale reveals that the molecular ion shows multiple bursts of ionization within a half-cycle of the laser field oscillation, in contrast to the widely accepted tunnel ionization picture for an atom. These bursts are found to be induced by transient localization of the electron at one of the nuclei, and a relation between the time instants of the localization and the vector potential of the laser light is derived. A scheme is proposed to probe the localization dynamics by an extreme ultraviolet laser pulse. PMID:21231228

  8. Hyperspectral molecular imaging of multiple receptors using immunolabeled plasmonic nanoparticles

    PubMed Central

    Seekell, Kevin; Crow, Matthew J.; Marinakos, Stella; Ostrander, Julie; Chilkoti, Ashutosh; Wax, Adam

    2011-01-01

    This work presents simultaneous imaging and detection of three different cell receptors using three types of plasmonic nanoparticles (NPs). The size, shape, and composition-dependent scattering profiles of these NPs allow for a system of multiple distinct molecular markers using a single optical source. With this goal in mind, tags consisting of anti-epidermal growth factor receptor gold nanorods, anti-insulin-like growth factor 1-R silver nanospheres, and human epidermal growth factor receptor 2Ab gold nanospheres were developed to monitor the expression of receptors commonly overexpressed by cancer cells. These labels were chosen because they scatter strongly in distinct spectral windows. A hyperspectral darkfield microspectroscopy system was developed to record the scattering spectra of cells labeled with these molecular tags. Simultaneous monitoring of multiple tags may lead to applications such as profiling of cell line immunophenotype and investigation of receptor signaling pathways. Single, dual, and triple tag experiments were performed to analyze NP tag specificity as well as their interactions. Distinct resonance peaks were observed in these studies, showing the ability to characterize cell lines using conjugated NPs. However, interpreting shifts in these peaks due to changes in a cellular dielectric environment may be complicated by plasmon coupling between NPs bound to proximal receptors and other coupling mechanisms due to the receptors themselves. PMID:22112108

  9. Multiple cellular origins and molecular evolution of intrahepatic cholangiocarcinoma.

    PubMed

    Wei, Miaoyan; Lü, Lisheng; Lin, Peiyi; Chen, Zhisheng; Quan, Zhiwei; Tang, Zhaohui

    2016-09-01

    Intrahepatic cholangiocarcinoma (ICC) is an aggressive malignancy associated with unfavorable prognosis and for which no effective treatments are available. Its molecular pathogenesis is poorly understood. Genome-wide sequencing and high-throughput technologies have provided critical insights into the molecular basis of ICC while sparking a heated debate on the cellular origin. Cancer exhibits variabilities in origin, progression and cell biology. Recent evidence suggests that ICC has multiple cellular origins, including differentiated hepatocytes; intrahepatic biliary epithelial cells (IBECs)/cholangiocytes; pluripotent stem cells, such as hepatic stem/progenitor cells (HPCs) and biliary tree stem/progenitor cells (BTSCs); and peribiliary gland (PBG). However, both somatic mutagenesis and epigenomic features are highly cell type-specific. Multiple cellular origins may have profoundly different genomic landscapes and key signaling pathways, driving phenotypic variation and thereby posing significant challenges to personalized medicine in terms of achieving the optimal drug response and patient outcome. Considering this information, we have summarized the latest experimental evidence and relevant literature to provide an up-to-date view of the cellular origin of ICC, which will contribute to establishment of a hierarchical model of carcinogenesis and allow for improvement of the anatomical-based classification of ICC. These new insights have important implications for both the diagnosis and treatment of ICC patients. PMID:26940139

  10. Hyperspectral molecular imaging of multiple receptors using immunolabeled plasmonic nanoparticles

    NASA Astrophysics Data System (ADS)

    Crow, Matthew J.; Seekell, Kevin; Marinakos, Stella; Ostrander, Julie; Chilkoti, Ashutosh; Wax, Adam P.

    2011-03-01

    This work presents simultaneous imaging and detection of three types of cell receptors using three types of plasmonic nanoparticles. The size, shape, and composition-dependent scattering profiles of these particles allow for a system of multiple distinct molecular markers using a single optical source. With this goal in mind, a system of tags consisting of anti-EGFR gold nanorods, anti-IGF1R silver nanospheres, and anti-HER-2 gold nanospheres was developed for monitoring the expression of three commonly overexpressed receptors in cancer cells. These labels were chosen because they each scatter strongly in a distinct spectral window. A hyperspectral dark-field microscope was developed to record the scattering spectra of cells labeled with these molecular tags. The ability to monitor multiple tags simultaneously may lead to applications such as profiling the immunophenotype of cell lines and gaining better knowledge of receptor signaling pathways. Single, dual, and triple tag experiments were performed to analyze the specificity of the nanoparticle tags as well as their effect on one another. While distinct resonance peaks in these studies show the ability to characterize cell lines using conjugated nanoparticles, shifts in these peaks also indicate changes in the cellular dielectric environment which may not be distinct from plasmon coupling between nanoparticles bound to proximal receptors.

  11. Hyperspectral molecular imaging of multiple receptors using immunolabeled plasmonic nanoparticles

    NASA Astrophysics Data System (ADS)

    Seekell, Kevin; Crow, Matthew J.; Marinakos, Stella; Ostrander, Julie; Chilkoti, Ashutosh; Wax, Adam

    2011-11-01

    This work presents simultaneous imaging and detection of three different cell receptors using three types of plasmonic nanoparticles (NPs). The size, shape, and composition-dependent scattering profiles of these NPs allow for a system of multiple distinct molecular markers using a single optical source. With this goal in mind, tags consisting of anti-epidermal growth factor receptor gold nanorods, anti-insulin-like growth factor 1-R silver nanospheres, and human epidermal growth factor receptor 2Ab gold nanospheres were developed to monitor the expression of receptors commonly overexpressed by cancer cells. These labels were chosen because they scatter strongly in distinct spectral windows. A hyperspectral darkfield microspectroscopy system was developed to record the scattering spectra of cells labeled with these molecular tags. Simultaneous monitoring of multiple tags may lead to applications such as profiling of cell line immunophenotype and investigation of receptor signaling pathways. Single, dual, and triple tag experiments were performed to analyze NP tag specificity as well as their interactions. Distinct resonance peaks were observed in these studies, showing the ability to characterize cell lines using conjugated NPs. However, interpreting shifts in these peaks due to changes in a cellular dielectric environment may be complicated by plasmon coupling between NPs bound to proximal receptors and other coupling mechanisms due to the receptors themselves.

  12. Modeling Stochastic Kinetics of Molecular Machines at Multiple Levels: From Molecules to Modules

    PubMed Central

    Chowdhury, Debashish

    2013-01-01

    A molecular machine is either a single macromolecule or a macromolecular complex. In spite of the striking superficial similarities between these natural nanomachines and their man-made macroscopic counterparts, there are crucial differences. Molecular machines in a living cell operate stochastically in an isothermal environment far from thermodynamic equilibrium. In this mini-review we present a catalog of the molecular machines and an inventory of the essential toolbox for theoretically modeling these machines. The tool kits include 1), nonequilibrium statistical-physics techniques for modeling machines and machine-driven processes; and 2), statistical-inference methods for reverse engineering a functional machine from the empirical data. The cell is often likened to a microfactory in which the machineries are organized in modular fashion; each module consists of strongly coupled multiple machines, but different modules interact weakly with each other. This microfactory has its own automated supply chain and delivery system. Buoyed by the success achieved in modeling individual molecular machines, we advocate integration of these models in the near future to develop models of functional modules. A system-level description of the cell from the perspective of molecular machinery (the mechanome) is likely to emerge from further integrations that we envisage here. PMID:23746505

  13. Multiple proviral integration events after virological synapse-mediated HIV-1 spread

    SciTech Connect

    Russell, Rebecca A.; Martin, Nicola; Mitar, Ivonne; Jones, Emma; Sattentau, Quentin J.

    2013-08-15

    HIV-1 can move directly between T cells via virological synapses (VS). Although aspects of the molecular and cellular mechanisms underlying this mode of spread have been elucidated, the outcomes for infection of the target cell remain incompletely understood. We set out to determine whether HIV-1 transfer via VS results in productive, high-multiplicity HIV-1 infection. We found that HIV-1 cell-to-cell spread resulted in nuclear import of multiple proviruses into target cells as seen by fluorescence in-situ hybridization. Proviral integration into the target cell genome was significantly higher than that seen in a cell-free infection system, and consequent de novo viral DNA and RNA production in the target cell detected by quantitative PCR increased over time. Our data show efficient proviral integration across VS, implying the probability of multiple integration events in target cells that drive productive T cell infection. - Highlights: • Cell-to-cell HIV-1 infection delivers multiple vRNA copies to the target cell. • Cell-to-cell infection results in productive infection of the target cell. • Cell-to-cell transmission is more efficient than cell-free HIV-1 infection. • Suggests a mechanism for recombination in cells infected with multiple viral genomes.

  14. An Integrated Biochemistry Laboratory, Including Molecular Modeling

    NASA Astrophysics Data System (ADS)

    Hall, Adele J. Wolfson Mona L.; Branham, Thomas R.

    1996-11-01

    ) experience with methods of protein purification; (iii) incorporation of appropriate controls into experiments; (iv) use of basic statistics in data analysis; (v) writing papers and grant proposals in accepted scientific style; (vi) peer review; (vii) oral presentation of results and proposals; and (viii) introduction to molecular modeling. Figure 1 illustrates the modular nature of the lab curriculum. Elements from each of the exercises can be separated and treated as stand-alone exercises, or combined into short or long projects. We have been able to offer the opportunity to use sophisticated molecular modeling in the final module through funding from an NSF-ILI grant. However, many of the benefits of the research proposal can be achieved with other computer programs, or even by literature survey alone. Figure 1.Design of project-based biochemistry laboratory. Modules (projects, or portions of projects) are indicated as boxes. Each of these can be treated independently, or used as part of a larger project. Solid lines indicate some suggested paths from one module to the next. The skills and knowledge required for protein purification and design are developed in three units: (i) an introduction to critical assays needed to monitor degree of purification, including an evaluation of assay parameters; (ii) partial purification by ion-exchange techniques; and (iii) preparation of a grant proposal on protein design by mutagenesis. Brief descriptions of each of these units follow, with experimental details of each project at the end of this paper. Assays for Lysozyme Activity and Protein Concentration (4 weeks) The assays mastered during the first unit are a necessary tool for determining the purity of the enzyme during the second unit on purification by ion exchange. These assays allow an introduction to the concept of specific activity (units of enzyme activity per milligram of total protein) as a measure of purity. In this first sequence, students learn a turbidimetric assay

  15. Multiple ray cluster rendering for interactive integral imaging system.

    PubMed

    Jiao, Shaohui; Wang, Xiaoguang; Zhou, Mingcai; Li, Weiming; Hong, Tao; Nam, Dongkyung; Lee, Jin-Ho; Wu, Enhua; Wang, Haitao; Kim, Ji-Yeun

    2013-04-22

    In this paper, we present an efficient Computer Generated Integral Imaging (CGII) method, called multiple ray cluster rendering (MRCR). Based on the MRCR, an interactive integral imaging system is realized, which provides accurate 3D image satisfying the changeable observers' positions in real time. The MRCR method can generate all the elemental image pixels within only one rendering pass by ray reorganization of multiple ray clusters and 3D content duplication. It is compatible with various graphic contents including mesh, point cloud, and medical data. Moreover, multi-sampling method is embedded in MRCR method for acquiring anti-aliased 3D image result. To our best knowledge, the MRCR method outperforms the existing CGII methods in both the speed performance and the display quality. Experimental results show that the proposed CGII method can achieve real-time computational speed for large-scale 3D data with about 50,000 points. PMID:23609712

  16. Downsizing of an integrated tracking unit for multiple applications

    NASA Astrophysics Data System (ADS)

    Steinway, William J.; Thomas, James E.; Nicoloff, Michael J.; Patz, Mark D.

    1997-02-01

    This paper describes the specifications and capabilities of the integrated tracking unit (ITU) and its multiple applications are presented. The original ITU was developed by Coleman Research Corporation (CRC) for several federal law enforcement agencies over a four-year period and it has been used for friendly and unfriendly vehicle and person position tracking. The ITU has been down-sized to reduce its physical size, weight, and power requirements with respect to the first generation unit. The ITU consists of a global positioning system (GPS) receiver for precise position location and a cellular phone to transmit voice and data to a PC base station with a modem interface. This paper describes the down-sizing of the unit introduced in CRC's 'An Integrated Tracking Unit for Multiple Applications' paper presented at the 1995 Counterdrug Technology Assessment Center's symposium in Nashua, NH. This paper provides a description of the ITU and tested applications.

  17. Integration of multiple sensor fusion in controller design.

    PubMed

    Abdelrahman, Mohamed; Kandasamy, Parameshwaran

    2003-04-01

    The main focus of this research is to reduce the risk of a catastrophic response of a feedback control system when some of the feedback data from the system sensors are not reliable, while maintaining a reasonable performance of the control system. In this paper a methodology for integrating multiple sensor fusion into the controller design is presented. The multiple sensor fusion algorithm produces, in addition to the estimate of the measurand, a parameter that measures the confidence in the estimated value. This confidence is integrated as a parameter into the controller to produce fast system response when the confidence in the estimate is high, and a slow response when the confidence in the estimate is low. Conditions for the stability of the system with the developed controller are discussed. This methodology is demonstrated on a cupola furnace model. The simulations illustrate the advantages of the new methodology. PMID:12708539

  18. Integrated multiple-input multiple-output visible light communications systems: recent progress and results

    NASA Astrophysics Data System (ADS)

    O'Brien, Dominic; Haas, Harald; Rajbhandari, Sujan; Chun, Hyunchae; Faulkner, Grahame; Cameron, Katherine; Jalajakumari, Aravind V. N.; Henderson, Robert; Tsonev, Dobroslav; Ijaz, Muhammad; Chen, Zhe; Xie, Enyuan; McKendry, Jonathan J. D.; Herrnsdorf, Johannes; Gu, Erdan; Dawson, Martin D.

    2015-01-01

    Solid state lighting systems typically use multiple Light Emitting Diode (LED) die within a single lamp, and multiple lamps within a coverage space. This infrastructure forms the transmitters for Visible Light Communications (VLC), and the availability of low-cost detector arrays offers the possibility of building Multiple Input Multiple Output (MIMO) transmission systems. Different approaches to optical MIMO are being investigated as part of a UK government funded research programme, `Ultra-Parallel Visible Light Communications' (UPVLC). In this paper we present a brief review of the area and report results from systems that use integrated subsystems developed as part of the project. The scalability of these approaches and future directions will also be discussed.

  19. Multiple coherent states for first-principles semiclassical initial value representation molecular dynamics.

    PubMed

    Ceotto, Michele; Atahan, Sule; Tantardini, Gian Franco; Aspuru-Guzik, Alán

    2009-06-21

    A multiple coherent states implementation of the semiclassical approximation is introduced and employed to obtain the power spectra with a few classical trajectories. The method is integrated with the time-averaging semiclassical initial value representation to successfully reproduce anharmonicity and Fermi resonance splittings at a level of accuracy comparable to semiclassical simulations of thousands of trajectories. The method is tested on two different model systems with analytical potentials and implemented in conjunction with the first-principles molecular dynamics scheme to obtain the power spectrum for the carbon dioxide molecule. PMID:19548717

  20. No quiet surrender: molecular guardians in multiple sclerosis brain

    PubMed Central

    Steinman, Lawrence

    2015-01-01

    The brain under immunological attack does not surrender quietly. Investigation of brain lesions in multiple sclerosis (MS) reveals a coordinated molecular response involving various proteins and small molecules ranging from heat shock proteins to small lipids, neurotransmitters, and even gases, which provide protection and foster repair. Reduction of inflammation serves as a necessary prerequisite for effective recovery and regeneration. Remarkably, many lesion-resident molecules activate pathways leading to both suppression of inflammation and promotion of repair mechanisms. These guardian molecules and their corresponding physiologic pathways could potentially be exploited to silence inflammation and repair the injured and degenerating brain and spinal cord in both relapsing-remitting and progressive forms of MS and may be beneficial in other neurologic and psychiatric conditions. PMID:25831441

  1. No quiet surrender: molecular guardians in multiple sclerosis brain.

    PubMed

    Steinman, Lawrence

    2015-04-01

    The brain under immunological attack does not surrender quietly. Investigation of brain lesions in multiple sclerosis (MS) reveals a coordinated molecular response involving various proteins and small molecules ranging from heat shock proteins to small lipids, neurotransmitters, and even gases, which provide protection and foster repair. Reduction of inflammation serves as a necessary prerequisite for effective recovery and regeneration. Remarkably, many lesion-resident molecules activate pathways leading to both suppression of inflammation and promotion of repair mechanisms. These guardian molecules and their corresponding physiologic pathways could potentially be exploited to silence inflammation and repair the injured and degenerating brain and spinal cord in both relapsing-remitting and progressive forms of MS and may be beneficial in other neurologic and psychiatric conditions. PMID:25831441

  2. Surveillance systems integrating multiple sensors for enhanced situational awareness

    NASA Astrophysics Data System (ADS)

    Van Anda, J. B.; Van Anda, J. D.

    2005-05-01

    In the modern world of high value security systems a successful installation requires the sensors to produce more than just good IR images, preprocessed data from these images, imagery in multiple bands fused in intelligent ways with each other and with non imaging information such as Laser ranging is required. This paper describes a system where LW uncooled, color TV, low light level TV, and laser ranging information are fused in a integral Pan and Tilt system to provide a sensor suite with exceptional capabilities for seamlessly integration into an advanced security system. Advances integrated in this system includes the advances sensor suite, sensible symbology for situational awareness in case of operator intervention, parallax and focus tracking through zoom and sensor changes to enhance auto tracking and motion detection algorithms.

  3. Molecular sequelae of proteasome inhibition in human multiple myeloma cells

    PubMed Central

    Mitsiades, Nicholas; Mitsiades, Constantine S.; Poulaki, Vassiliki; Chauhan, Dharminder; Fanourakis, Galinos; Gu, Xuesong; Bailey, Charles; Joseph, Marie; Libermann, Towia A.; Treon, Steven P.; Munshi, Nikhil C.; Richardson, Paul G.; Hideshima, Teru; Anderson, Kenneth C.

    2002-01-01

    The proteasome inhibitor PS-341 inhibits IκB degradation, prevents NF-κB activation, and induces apoptosis in several types of cancer cells, including chemoresistant multiple myeloma (MM) cells. PS-341 has marked clinical activity even in the setting of relapsed refractory MM. However, PS-341-induced apoptotic cascade(s) are not yet fully defined. By using gene expression profiling, we characterized the molecular sequelae of PS-341 treatment in MM cells and further focused on molecular pathways responsible for the anticancer actions of this promising agent. The transcriptional profile of PS-341-treated cells involved down-regulation of growth/survival signaling pathways, and up-regulation of molecules implicated in proapoptotic cascades (which are both consistent with the proapoptotic effect of proteasome inhibition), as well as up-regulation of heat-shock proteins and ubiquitin/proteasome pathway members (which can correspond to stress responses against proteasome inhibition). Further studies on these pathways showed that PS-341 decreases the levels of several antiapoptotic proteins and triggers a dual apoptotic pathway of mitochondrial cytochrome c release and caspase-9 activation, as well as activation of Jun kinase and a Fas/caspase-8-dependent apoptotic pathway [which is inhibited by a dominant negative (decoy) Fas construct]. Stimulation with IGF-1, as well as overexpression of Bcl-2 or constitutively active Akt in MM cells also modestly attenuates PS-341-induced cell death, whereas inhibitors of the BH3 domain of Bcl-2 family members or the heat-shock protein 90 enhance tumor cell sensitivity to proteasome inhibition. These data provide both insight into the molecular mechanisms of antitumor activity of PS-341 and the rationale for future clinical trials of PS-341, in combination with conventional and novel therapies, to improve patient outcome in MM. PMID:12391322

  4. Ab initio multiple cloning algorithm for quantum nonadiabatic molecular dynamics

    SciTech Connect

    Makhov, Dmitry V.; Shalashilin, Dmitrii V.; Glover, William J.; Martinez, Todd J.

    2014-08-07

    We present a new algorithm for ab initio quantum nonadiabatic molecular dynamics that combines the best features of ab initio Multiple Spawning (AIMS) and Multiconfigurational Ehrenfest (MCE) methods. In this new method, ab initio multiple cloning (AIMC), the individual trajectory basis functions (TBFs) follow Ehrenfest equations of motion (as in MCE). However, the basis set is expanded (as in AIMS) when these TBFs become sufficiently mixed, preventing prolonged evolution on an averaged potential energy surface. We refer to the expansion of the basis set as “cloning,” in analogy to the “spawning” procedure in AIMS. This synthesis of AIMS and MCE allows us to leverage the benefits of mean-field evolution during periods of strong nonadiabatic coupling while simultaneously avoiding mean-field artifacts in Ehrenfest dynamics. We explore the use of time-displaced basis sets, “trains,” as a means of expanding the basis set for little cost. We also introduce a new bra-ket averaged Taylor expansion (BAT) to approximate the necessary potential energy and nonadiabatic coupling matrix elements. The BAT approximation avoids the necessity of computing electronic structure information at intermediate points between TBFs, as is usually done in saddle-point approximations used in AIMS. The efficiency of AIMC is demonstrated on the nonradiative decay of the first excited state of ethylene. The AIMC method has been implemented within the AIMS-MOLPRO package, which was extended to include Ehrenfest basis functions.

  5. Ab initio multiple cloning algorithm for quantum nonadiabatic molecular dynamics

    NASA Astrophysics Data System (ADS)

    Makhov, Dmitry V.; Glover, William J.; Martinez, Todd J.; Shalashilin, Dmitrii V.

    2014-08-01

    We present a new algorithm for ab initio quantum nonadiabatic molecular dynamics that combines the best features of ab initio Multiple Spawning (AIMS) and Multiconfigurational Ehrenfest (MCE) methods. In this new method, ab initio multiple cloning (AIMC), the individual trajectory basis functions (TBFs) follow Ehrenfest equations of motion (as in MCE). However, the basis set is expanded (as in AIMS) when these TBFs become sufficiently mixed, preventing prolonged evolution on an averaged potential energy surface. We refer to the expansion of the basis set as "cloning," in analogy to the "spawning" procedure in AIMS. This synthesis of AIMS and MCE allows us to leverage the benefits of mean-field evolution during periods of strong nonadiabatic coupling while simultaneously avoiding mean-field artifacts in Ehrenfest dynamics. We explore the use of time-displaced basis sets, "trains," as a means of expanding the basis set for little cost. We also introduce a new bra-ket averaged Taylor expansion (BAT) to approximate the necessary potential energy and nonadiabatic coupling matrix elements. The BAT approximation avoids the necessity of computing electronic structure information at intermediate points between TBFs, as is usually done in saddle-point approximations used in AIMS. The efficiency of AIMC is demonstrated on the nonradiative decay of the first excited state of ethylene. The AIMC method has been implemented within the AIMS-MOLPRO package, which was extended to include Ehrenfest basis functions.

  6. Ab initio multiple cloning algorithm for quantum nonadiabatic molecular dynamics.

    PubMed

    Makhov, Dmitry V; Glover, William J; Martinez, Todd J; Shalashilin, Dmitrii V

    2014-08-01

    We present a new algorithm for ab initio quantum nonadiabatic molecular dynamics that combines the best features of ab initio Multiple Spawning (AIMS) and Multiconfigurational Ehrenfest (MCE) methods. In this new method, ab initio multiple cloning (AIMC), the individual trajectory basis functions (TBFs) follow Ehrenfest equations of motion (as in MCE). However, the basis set is expanded (as in AIMS) when these TBFs become sufficiently mixed, preventing prolonged evolution on an averaged potential energy surface. We refer to the expansion of the basis set as "cloning," in analogy to the "spawning" procedure in AIMS. This synthesis of AIMS and MCE allows us to leverage the benefits of mean-field evolution during periods of strong nonadiabatic coupling while simultaneously avoiding mean-field artifacts in Ehrenfest dynamics. We explore the use of time-displaced basis sets, "trains," as a means of expanding the basis set for little cost. We also introduce a new bra-ket averaged Taylor expansion (BAT) to approximate the necessary potential energy and nonadiabatic coupling matrix elements. The BAT approximation avoids the necessity of computing electronic structure information at intermediate points between TBFs, as is usually done in saddle-point approximations used in AIMS. The efficiency of AIMC is demonstrated on the nonradiative decay of the first excited state of ethylene. The AIMC method has been implemented within the AIMS-MOLPRO package, which was extended to include Ehrenfest basis functions. PMID:25106573

  7. NEXT Propellant Management System Integration With Multiple Ion Thrusters

    NASA Technical Reports Server (NTRS)

    Sovey, James S.; Soulas, George C.; Herman, Daniel A.

    2011-01-01

    As a critical part of the NEXT test validation process, a multiple-string integration test was performed on the NEXT propellant management system and ion thrusters. The objectives of this test were to verify that the PMS is capable of providing stable flow control to multiple thrusters operating over the NEXT system throttling range and to demonstrate to potential users that the NEXT PMS is ready for transition to flight. A test plan was developed for the sub-system integration test for verification of PMS and thruster system performance and functionality requirements. Propellant management system calibrations were checked during the single and multi-thruster testing. The low pressure assembly total flow rates to the thruster(s) were within 1.4 percent of the calibrated support equipment flow rates. The inlet pressures to the main, cathode, and neutralizer ports of Thruster PM1R were measured as the PMS operated in 1-thruster, 2-thruster, and 3-thruster configurations. It was found that the inlet pressures to Thruster PM1R for 2-thruster and 3-thruster operation as well as single thruster operation with the PMS compare very favorably indicating that flow rates to Thruster PM1R were similar in all cases. Characterizations of discharge losses, accelerator grid current, and neutralizer performance were performed as more operating thrusters were added to the PMS. There were no variations in these parameters as thrusters were throttled and single and multiple thruster operations were conducted. The propellant management system power consumption was at a fixed voltage to the DCIU and a fixed thermal throttle temperature of 75 C. The total power consumed by the PMS was 10.0, 17.9, and 25.2 W, respectively, for single, 2-thruster, and 3-thruster operation with the PMS. These sub-system integration tests of the PMS, the DCIU Simulator, and multiple thrusters addressed, in part, the NEXT PMS and propulsion system performance and functionality requirements.

  8. Integrated Multiscale Modeling of Molecular Computing Devices

    SciTech Connect

    Weinan E

    2012-03-29

    The main bottleneck in modeling transport in molecular devices is to develop the correct formulation of the problem and efficient algorithms for analyzing the electronic structure and dynamics using, for example, the time-dependent density functional theory. We have divided this task into several steps. The first step is to developing the right mathematical formulation and numerical algorithms for analyzing the electronic structure using density functional theory. The second step is to study time-dependent density functional theory, particularly the far-field boundary conditions. The third step is to study electronic transport in molecular devices. We are now at the end of the first step. Under DOE support, we have made subtantial progress in developing linear scaling and sub-linear scaling algorithms for electronic structure analysis. Although there has been a huge amount of effort in the past on developing linear scaling algorithms, most of the algorithms developed suffer from the lack of robustness and controllable accuracy. We have made the following progress: (1) We have analyzed thoroughly the localization properties of the wave-functions. We have developed a clear understanding of the physical as well as mathematical origin of the decay properties. One important conclusion is that even for metals, one can choose wavefunctions that decay faster than any algebraic power. (2) We have developed algorithms that make use of these localization properties. Our algorithms are based on non-orthogonal formulations of the density functional theory. Our key contribution is to add a localization step into the algorithm. The addition of this localization step makes the algorithm quite robust and much more accurate. Moreover, we can control the accuracy of these algorithms by changing the numerical parameters. (3) We have considerably improved the Fermi operator expansion (FOE) approach. Through pole expansion, we have developed the optimal scaling FOE algorithm.

  9. Predicting Protein Function via Semantic Integration of Multiple Networks.

    PubMed

    Yu, Guoxian; Fu, Guangyuan; Wang, Jun; Zhu, Hailong

    2016-01-01

    Determining the biological functions of proteins is one of the key challenges in the post-genomic era. The rapidly accumulated large volumes of proteomic and genomic data drives to develop computational models for automatically predicting protein function in large scale. Recent approaches focus on integrating multiple heterogeneous data sources and they often get better results than methods that use single data source alone. In this paper, we investigate how to integrate multiple biological data sources with the biological knowledge, i.e., Gene Ontology (GO), for protein function prediction. We propose a method, called SimNet, to Semantically i ntegrate multiple functional association Networks derived from heterogenous data sources. SimNet firstly utilizes GO annotations of proteins to capture the semantic similarity between proteins and introduces a semantic kernel based on the similarity. Next, SimNet constructs a composite network, obtained as a weighted summation of individual networks, and aligns the network with the kernel to get the weights assigned to individual networks. Then, it applies a network-based classifier on the composite network to predict protein function. Experiment results on heterogenous proteomic data sources of Yeast, Human, Mouse, and Fly show that, SimNet not only achieves better (or comparable) results than other related competitive approaches, but also takes much less time. The Matlab codes of SimNet are available at https://sites.google.com/site/guoxian85/simnet. PMID:26800544

  10. Multiple cue use and integration in pigeons (Columba livia).

    PubMed

    Legge, Eric L G; Madan, Christopher R; Spetch, Marcia L; Ludvig, Elliot A

    2016-05-01

    Encoding multiple cues can improve the accuracy and reliability of navigation and goal localization. Problems may arise, however, if one cue is displaced and provides information which conflicts with other cues. Here we investigated how pigeons cope with cue conflict by training them to locate a goal relative to two landmarks and then varying the amount of conflict between the landmarks. When the amount of conflict was small, pigeons tended to integrate both cues in their search patterns. When the amount of conflict was large, however, pigeons used information from both cues independently. This context-dependent strategy for resolving spatial cue conflict agrees with Bayes optimal calculations for using information from multiple sources. PMID:26908004

  11. Integrating influenza antigenic dynamics with molecular evolution

    PubMed Central

    Bedford, Trevor; Suchard, Marc A; Lemey, Philippe; Dudas, Gytis; Gregory, Victoria; Hay, Alan J; McCauley, John W; Russell, Colin A; Smith, Derek J; Rambaut, Andrew

    2014-01-01

    Influenza viruses undergo continual antigenic evolution allowing mutant viruses to evade host immunity acquired to previous virus strains. Antigenic phenotype is often assessed through pairwise measurement of cross-reactivity between influenza strains using the hemagglutination inhibition (HI) assay. Here, we extend previous approaches to antigenic cartography, and simultaneously characterize antigenic and genetic evolution by modeling the diffusion of antigenic phenotype over a shared virus phylogeny. Using HI data from influenza lineages A/H3N2, A/H1N1, B/Victoria and B/Yamagata, we determine patterns of antigenic drift across viral lineages, showing that A/H3N2 evolves faster and in a more punctuated fashion than other influenza lineages. We also show that year-to-year antigenic drift appears to drive incidence patterns within each influenza lineage. This work makes possible substantial future advances in investigating the dynamics of influenza and other antigenically-variable pathogens by providing a model that intimately combines molecular and antigenic evolution. DOI: http://dx.doi.org/10.7554/eLife.01914.001 PMID:24497547

  12. Accelerating Ab Initio Path Integral Simulations via Imaginary Multiple-Timestepping.

    PubMed

    Cheng, Xiaolu; Herr, Jonathan D; Steele, Ryan P

    2016-04-12

    This work investigates the use of multiple-timestep schemes in imaginary time for computationally efficient ab initio equilibrium path integral simulations of quantum molecular motion. In the simplest formulation, only every n(th) path integral replica is computed at the target level of electronic structure theory, whereas the remaining low-level replicas still account for nuclear motion quantum effects with a more computationally economical theory. Motivated by recent developments for multiple-timestep techniques in real-time classical molecular dynamics, both 1-electron (atomic-orbital basis set) and 2-electron (electron correlation) truncations are shown to be effective. Structural distributions and thermodynamic averages are tested for representative analytic potentials and ab initio molecular examples. Target quantum chemistry methods include density functional theory and second-order Møller-Plesset perturbation theory, although any level of theory is formally amenable to this framework. For a standard two-level splitting, computational speedups of 1.6-4.0x are observed when using a 4-fold reduction in time slices; an 8-fold reduction is feasible in some cases. Multitiered options further reduce computational requirements and suggest that quantum mechanical motion could potentially be obtained at a cost not significantly different from the cost of classical simulations. PMID:26966920

  13. Molecular Approach to Targeted Therapy for Multiple Sclerosis.

    PubMed

    Sherbet, Gajanan V

    2016-01-01

    The development and evolution of targeted therapy to any disease require the identification of targets amenable to treatment of patients. Here the pathogenetic signalling systems involved in multiple sclerosis are scrutinised to locate nodes of deregulation and dysfunction in order to devise strategies of drug development for targeted intervention. Oliogoclonal bands (OCB) are isoelectric focusing profiles of immunoglobulins synthesised in the central nervous system. OCBs enable the diagnosis of multiple sclerosis with high sensitivity and specificity and are related to the course of the disease and progression. The OCB patterns can be linked with the expression of angiogenic molecular species. Angiogenic signalling which has also been implicated in demyelination provides the option of using angiogenesis inhibitors in disease control. The PI3K (phosphoinositide 3-kinase)/Akt axis has emerged with a key role in myelination with its demonstrable links with mTOR mediated transcription of downstream target genes. Inflammatory signals and innate and acquired immunity from the activation of NF-κB (nuclear factor κB) responsive genes are considered. NF-κB signalling could be implicated in myelination. The transcription factor STAT (signal transducers and activators of transcription) and the EBV (Epstein- Barr virus) transcription factor BZLF1 contributing significantly to the disease process are a major environmental factor linked to MS. EBV can activate TGF (transforming growth factor) and VEGF (vascular endothelial growth factor) signalling. EBV microRNAs are reviewed as signalling mediators of pathogenesis. Stem cell transplantation therapy has lately gained much credence, so the current status of mesenchymal and hematopoietic stem cell therapy is reviewed with emphasis on the differential expression immune-related genes and operation of signalling systems. PMID:26560895

  14. An Integrated Biochemistry Laboratory, Including Molecular Modeling

    NASA Astrophysics Data System (ADS)

    Hall, Adele J. Wolfson Mona L.; Branham, Thomas R.

    1996-11-01

    ) experience with methods of protein purification; (iii) incorporation of appropriate controls into experiments; (iv) use of basic statistics in data analysis; (v) writing papers and grant proposals in accepted scientific style; (vi) peer review; (vii) oral presentation of results and proposals; and (viii) introduction to molecular modeling. Figure 1 illustrates the modular nature of the lab curriculum. Elements from each of the exercises can be separated and treated as stand-alone exercises, or combined into short or long projects. We have been able to offer the opportunity to use sophisticated molecular modeling in the final module through funding from an NSF-ILI grant. However, many of the benefits of the research proposal can be achieved with other computer programs, or even by literature survey alone. Figure 1.Design of project-based biochemistry laboratory. Modules (projects, or portions of projects) are indicated as boxes. Each of these can be treated independently, or used as part of a larger project. Solid lines indicate some suggested paths from one module to the next. The skills and knowledge required for protein purification and design are developed in three units: (i) an introduction to critical assays needed to monitor degree of purification, including an evaluation of assay parameters; (ii) partial purification by ion-exchange techniques; and (iii) preparation of a grant proposal on protein design by mutagenesis. Brief descriptions of each of these units follow, with experimental details of each project at the end of this paper. Assays for Lysozyme Activity and Protein Concentration (4 weeks) The assays mastered during the first unit are a necessary tool for determining the purity of the enzyme during the second unit on purification by ion exchange. These assays allow an introduction to the concept of specific activity (units of enzyme activity per milligram of total protein) as a measure of purity. In this first sequence, students learn a turbidimetric assay

  15. Quantum tunneling splittings from path-integral molecular dynamics.

    PubMed

    Mátyus, Edit; Wales, David J; Althorpe, Stuart C

    2016-03-21

    We illustrate how path-integral molecular dynamics can be used to calculate ground-state tunnelling splittings in molecules or clusters. The method obtains the splittings from ratios of density matrix elements between the degenerate wells connected by the tunnelling. We propose a simple thermodynamic integration scheme for evaluating these elements. Numerical tests on fully dimensional malonaldehyde yield tunnelling splittings in good overall agreement with the results of diffusion Monte Carlo calculations. PMID:27004863

  16. Molecular chaperones: multiple functions, pathologies, and potential applications.

    PubMed

    Macario, Alberto J L; Conway de Macario, Everly

    2007-01-01

    Cell stressors are ubiquitous and frequent, challenging cells often, which leads to the stress response with activation of anti-stress mechanisms. These mechanisms involve a variety of molecules, including molecular chaperones also known as heat-shock proteins (Hsp). The chaperones treated in this article are proteins that assist other proteins to fold, refold, travel to their place of residence (cytosol, organelle, membrane, extracellular space), and translocate across membranes. Molecular chaperones participate in a variety of physiological processes and are widespread in organisms, tissues, and cells. It follows that chaperone failure will have an impact, possibly serious, on one or more cellular function, which may lead to disease. Chaperones must recognize and interact with proteins in need of assistance or client polypeptides (e.g., nascent at the ribosome, or partially denatured by stressors), and have to interact with other chaperones because the chaperoning mechanism involves teams of chaperone molecules, i.e., multimolecular assemblies or chaperone machines. Consequently, chaperone molecules have structural domains with distinctive functions: bind the client polypeptide, interact with other chaperone molecules to build a machine, and interact with other complexes that integrate the chaperoning network. Also, various chaperones have ATP-binding and ATPase sites because the chaperoning process requires as, a rule, energy from ATP hydrolysis. Alterations in any one of these domains due to a mutation or an aberrant post-translational modification can disrupt the chaperoning process and cause diseases termed chaperonopathies. This article presents the pathologic concept of chaperonopathy with examples, and discusses the potential of using chaperones (genes or proteins) in treatment (chaperonotherapy). In addition, emerging topics within the field of study of chaperones (chaperonology) are highlighted, e.g., genomics (chaperonomics), systems biology

  17. Neural Plasticity in Multiple Sclerosis: The Functional and Molecular Background

    PubMed Central

    Ksiazek-Winiarek, Dominika Justyna; Szpakowski, Piotr; Glabinski, Andrzej

    2015-01-01

    Multiple sclerosis is an autoimmune neurodegenerative disorder resulting in motor dysfunction and cognitive decline. The inflammatory and neurodegenerative changes seen in the brains of MS patients lead to progressive disability and increasing brain atrophy. The most common type of MS is characterized by episodes of clinical exacerbations and remissions. This suggests the presence of compensating mechanisms for accumulating damage. Apart from the widely known repair mechanisms like remyelination, another important phenomenon is neuronal plasticity. Initially, neuroplasticity was connected with the developmental stages of life; however, there is now growing evidence confirming that structural and functional reorganization occurs throughout our lifetime. Several functional studies, utilizing such techniques as fMRI, TBS, or MRS, have provided valuable data about the presence of neuronal plasticity in MS patients. CNS ability to compensate for neuronal damage is most evident in RR-MS; however it has been shown that brain plasticity is also preserved in patients with substantial brain damage. Regardless of the numerous studies, the molecular background of neuronal plasticity in MS is still not well understood. Several factors, like IL-1β, BDNF, PDGF, or CB1Rs, have been implicated in functional recovery from the acute phase of MS and are thus considered as potential therapeutic targets. PMID:26229689

  18. Integrative Data Analysis: The Simultaneous Analysis of Multiple Data Sets

    PubMed Central

    Curran, Patrick J.; Hussong, Andrea M.

    2009-01-01

    Both quantitative and methodological techniques exist that foster the development and maintenance of a cumulative knowledge base within the psychological sciences. Most noteworthy of these techniques is meta-analysis which allows for the synthesis of summary statistics drawn from multiple studies when the original data are not available. However, when the original data can be obtained from multiple studies, many advantages stem from the statistical analysis of the pooled data. The authors define integrative data analysis (IDA) as the analysis of multiple data sets that have been pooled into one. Although variants of IDA have been incorporated into other scientific disciplines, the use of these techniques are much less evident in psychology. In this paper the authors present an overview of IDA as it may be applied within the psychological sciences; a discussion of the relative advantages and disadvantages of IDA; a description of analytic strategies for analyzing pooled individual data; and offer recommendations for the use of IDA in practice. PMID:19485623

  19. Integral methodological pluralism in science education research: valuing multiple perspectives

    NASA Astrophysics Data System (ADS)

    Davis, Nancy T.; Callihan, Laurie P.

    2013-09-01

    This article examines the multiple methodologies used in educational research and proposes a model that includes all of them as contributing to understanding educational contexts and research from multiple perspectives. The model, based on integral theory (Wilber in a theory of everything. Shambhala, Boston, 2000) values all forms of research as true, but partial. Consideration of objective (exterior) forms of research and data and subjective (interior) forms of research and data are further divided into individual and collective domains. Taking this categorization system one step further reveals eight indigenous perspectives that form a framework for considering research methodologies. Each perspective has unique questions, data sources, methods and quality criteria designed to reveal what is "true" from that view. As science educators who guide our students' research, this framework offers a useful guide to explain differences in types of research, the purpose and validity of each. It allows professional science educators to appreciate multiple forms of research while maintaining rigorous quality criteria. Use of this framework can also help avoid problems of imposing quality criteria of one methodology on research data and questions gathered using another methodology. This model is explored using the second author's dissertation research. Finally a decision chart is provided to use with those who are starting inquiries to guide their thinking and choice of appropriate methodologies to use when conducting research.

  20. Atomic and molecular effects on spherically convergent ion flow. II. Multiple molecular species

    NASA Astrophysics Data System (ADS)

    Emmert, Gilbert A.; Santarius, John F.

    2010-01-01

    A theoretical model for the effect of molecular interactions on the flow of molecular ions in spherically convergent geometry where the inner grid (cathode) is at a large negative potential and the outer grid (anode) is grounded has been developed. The model assumes a weakly ionized deuterium plasma composed of D+, D2+, and D3+ ions that interact with the dominant background gas (D2). The interactions included are charge exchange, ionization, and dissociative processes. The formalism developed includes the bouncing motion of the ions in the electrostatic well and sums over all generations of subsequent ions produced by atomic and molecular processes. This leads to a set of two coupled Volterra integral equations, which are solved numerically. From the solution of the Volterra equations, one can obtain quantities of interest, such as the energy spectra of the ions and fast neutral atoms and molecules, and the fusion reaction rate. To provide an experimental test, the model is applied to inertial electrostatic devices and the calculated neutron production rate is compared to previously reported measurements for one University of Wisconsin inertial electrostatic confinement device [D. C. Donovan et al., Fusion Sci. Technol. 56, 507 (2009)]. The results show general agreement with the experimental results, but significant differences remain to be resolved.

  1. High sensitivity detection of NO2 employing off-axis integrated cavity output spectroscopy coupled with multiple line integrated spectroscopy

    NASA Astrophysics Data System (ADS)

    Rao, Gottipaty N.; Karpf, Andreas

    2011-05-01

    We report on the development of a new sensor for NO2 with ultrahigh sensitivity of detection. This has been accomplished by combining off-axis integrated cavity output spectroscopy (OA-ICOS) (which can provide large path lengths of the order of several km in a small volume cell) with multiple line integrated absorption spectroscopy (MLIAS) (where we integrate the absorption spectra over a large number of rotational-vibrational transitions of the molecular species to further improve the sensitivity). Employing an external cavity tunable quantum cascade laser operating in the 1601 - 1670 cm-1 range and a high-finesse optical cavity, the absorption spectra of NO2 over 100 transitions in the R-band have been recorded. From the observed linear relationship between the integrated absorption vs. concentration of NO2, we report an effective sensitivity of detection of 10 ppt for NO2. To the best of our knowledge, this is among the most sensitive levels of detection of NO2 to date. A sensitive sensor for the detection of NO2 will be helpful to monitor the ambient air quality, combustion emissions from the automobiles, power plants, aircraft and for the detection of nitrate based explosives (which are commonly used in improvised explosives (IEDs)). Additionally such a sensor would be valuable for the study of complex chemical reactions that undergo in the atmosphere resulting in the formation of photochemical smog, tropospheric ozone and acid rain.

  2. Plant aquaporins: membrane channels with multiple integrated functions.

    PubMed

    Maurel, Christophe; Verdoucq, Lionel; Luu, Doan-Trung; Santoni, Véronique

    2008-01-01

    Aquaporins are channel proteins present in the plasma and intracellular membranes of plant cells, where they facilitate the transport of water and/or small neutral solutes (urea, boric acid, silicic acid) or gases (ammonia, carbon dioxide). Recent progress was made in understanding the molecular bases of aquaporin transport selectivity and gating. The present review examines how a wide range of selectivity profiles and regulation properties allows aquaporins to be integrated in numerous functions, throughout plant development, and during adaptations to variable living conditions. Although they play a central role in water relations of roots, leaves, seeds, and flowers, aquaporins have also been linked to plant mineral nutrition and carbon and nitrogen fixation. PMID:18444909

  3. The molecular basis of multiple vector insertion by gene targeting in mammalian cells.

    PubMed Central

    Ng, P; Baker, M D

    1999-01-01

    Gene targeting using sequence insertion vectors generally results in integration of one copy of the targeting vector generating a tandem duplication of the cognate chromosomal region of homology. However, occasionally the target locus is found to contain >1 copy of the integrated vector. The mechanism by which the latter recombinants arise is not known. In the present study, we investigated the molecular basis by which multiple vectors become integrated at the chromosomal immunoglobulin mu locus in a murine hybridoma. To accomplish this, specially designed insertion vectors were constructed that included six diagnostic restriction enzyme markers in the Cmu region of homology to the target chromosomal mu locus. This enabled contributions by the vector-borne and chromosomal Cmu sequences at the recombinant locus to be ascertained. Targeted recombinants were isolated and analyzed to determine the number of vector copies integrated at the chromosomal immunoglobulin mu locus. Targeted recombinants identified as bearing >1 copy of the integrated vector resulted from a Cmu triplication formed by two vector copies in tandem. Examination of the fate of the Cmu region markers suggested that this class of recombinant was generated predominantly, if not exclusively, by two targeted vector integration events, each involving insertion of a single copy of the vector. Both vector insertion events into the chromosomal mu locus were consistent with the double-strand-break repair mechanism of homologous recombination. We interpret our results, taken together, to mean that a proportion of recipient cells is in a predetermined state that is amenable to targeted but not random vector integration. PMID:10049930

  4. Confirming an integrated pathology of diabetes and its complications by molecular biomarker-target network analysis.

    PubMed

    Zhao, Zide; Zhang, Yingying; Gai, Fengchun; Wang, Ying

    2016-09-01

    Despite ongoing research into diabetes and its complications, the underlying molecular associations remain to be elucidated. The systematic identification of molecular interactions in associated diseases may be approached using a network analysis strategy. The biomarker-target interrelated molecules associated with diabetes and its complications were identified via the Comparative Toxicogenomics Database (CTD); the Search Tool for Recurring Instances of Neighboring Genes was utilized for network construction. Functional enrichment analysis was performed with Database for Annotation, Visualization and Integrated Discovery software to investigate connections between diabetes and its complications. A total of 142 (including 122 biomarkers, 10 therapeutic targets and 10 overlapping molecules) biomarker-target interrelated molecules associated with diabetes and its complications were identified via the CTD database, and analysis of the network yielded 1,087 biological processes and fifteen Kyoto Encyclopedia of Genes and Genomes pathways with significant P‑values. Various critical aspects of the networks were examined in the present study: a) Intermolecular horizontal and vertical combinations in biomarkers and therapeutic targets associated with diabetes and its complicationb) network topology properties associated with molecular pathological responsec) contribution of key molecules to integrated regulation; and d) crosstalk between multiple pathways. Based on a multi-dimensional analysis, it was concluded that the integrated molecular pathological development of diabetes and its complications does not proceed randomly, which suggests a requirement for integrated, multi-target intervention. PMID:27430657

  5. A multiple index integrating different levels of organization.

    PubMed

    Cortes, Rui; Hughes, Samantha; Coimbra, Ana; Monteiro, Sandra; Pereira, Vítor; Lopes, Marisa; Pereira, Sandra; Pinto, Ana; Sampaio, Ana; Santos, Cátia; Carrola, João; de Jesus, Joaquim; Varandas, Simone

    2016-10-01

    Many methods in freshwater biomonitoring tend to be restricted to a few levels of biological organization, limiting the potential spectrum of measurable of cause-effect responses to different anthropogenic impacts. We combined distinct organisational levels, covering biological biomarkers (histopathological and biochemical reactions in liver and fish gills), community based bioindicators (fish guilds, invertebrate metrics/traits and chironomid pupal exuviae) and ecosystem functional indicators (decomposition rates) to assess ecological status at designated Water Framework Directive monitoring sites, covering a gradient of human impact across several rivers in northern Portugal. We used Random Forest to rank the variables that contributed more significantly to successfully predict the different classes of ecological status and also to provide specific cut levels to discriminate each WFD class based on reference condition. A total of 59 Biological Quality Elements and functional indicators were determined using this procedure and subsequently applied to develop the integrated Multiple Ecological Level Index (MELI Index), a potentially powerful bioassessment tool. PMID:27344015

  6. Authorizing multiple chemical passwords by a combinatorial molecular keypad lock.

    PubMed

    Rout, Bhimsen; Milko, Petr; Iron, Mark A; Motiei, Leila; Margulies, David

    2013-10-16

    A combinatorial fluorescent molecular sensor operates as a highly efficient molecular security system. The ability of a pattern-generating molecule to process diverse sets of chemical inputs, discriminate among their concentrations, and form multivalent and kinetically stable complexes is demonstrated as a powerful tool for processing a wide range of chemical "passwords" of different lengths. This system thus indicates the potential for obtaining unbreakable combination locks at the molecular scale. PMID:24088016

  7. Tools and Models for Integrating Multiple Cellular Networks

    SciTech Connect

    Gerstein, Mark

    2015-11-06

    In this grant, we have systematically investigated the integrated networks, which are responsible for the coordination of activity between metabolic pathways in prokaryotes. We have developed several computational tools to analyze the topology of the integrated networks consisting of metabolic, regulatory, and physical interaction networks. The tools are all open-source, and they are available to download from Github, and can be incorporated in the Knowledgebase. Here, we summarize our work as follow. Understanding the topology of the integrated networks is the first step toward understanding its dynamics and evolution. For Aim 1 of this grant, we have developed a novel algorithm to determine and measure the hierarchical structure of transcriptional regulatory networks [1]. The hierarchy captures the direction of information flow in the network. The algorithm is generally applicable to regulatory networks in prokaryotes, yeast and higher organisms. Integrated datasets are extremely beneficial in understanding the biology of a system in a compact manner due to the conflation of multiple layers of information. Therefore for Aim 2 of this grant, we have developed several tools and carried out analysis for integrating system-wide genomic information. To make use of the structural data, we have developed DynaSIN for protein-protein interactions networks with various dynamical interfaces [2]. We then examined the association between network topology with phenotypic effects such as gene essentiality. In particular, we have organized E. coli and S. cerevisiae transcriptional regulatory networks into hierarchies. We then correlated gene phenotypic effects by tinkering with different layers to elucidate which layers were more tolerant to perturbations [3]. In the context of evolution, we also developed a workflow to guide the comparison between different types of biological networks across various species using the concept of rewiring [4], and Furthermore, we have developed

  8. Integrity of hypothalamic fibers and cognitive fatigue in multiple sclerosis.

    PubMed

    Hanken, Katrin; Eling, Paul; Kastrup, Andreas; Klein, Jan; Hildebrandt, Helmut

    2015-01-01

    Cognitive fatigue is a common and disabling symptom of multiple sclerosis (MS), but little is known about its pathophysiology. The present study investigated whether the posterior hypothalamus, which is considered as the waking center, is associated with MS-related cognitive fatigue. We analyzed the integrity of posterior hypothalamic fibers in 49 patients with relapsing-remitting MS and 14 healthy controls. Diffusion tensor imaging (DTI) parameters were calculated for fibers between the posterior hypothalamus and, respectively, the mesencephalon, pons and prefrontal cortex. In addition, DTI parameters were computed for fibers between the anterior hypothalamus and these regions and for the corpus callosum. Cognitive fatigue was assessed using the Fatigue Scale for Motor and Cognitive Functions. Analyses of variance with repeated measures were performed to investigate the impact of cognitive fatigue on diffusion parameters. Cognitively fatigued patients (75.5%) showed a significantly lower mean axial and radial diffusivity for fibers between the posterior hypothalamus and the mesencephalon than cognitively non-fatigued patients (Group(⁎)Target area(⁎)Diffusion orientation: F=4.047; p=0.023). For fibers of the corpus callosum, MS patients presented significantly higher axial and radial diffusivity than healthy controls (Group(⁎)Diffusion orientation: F=9.904; p<0.001). Depressive mood, used as covariate, revealed significant interaction effects for anterior hypothalamic fibers (Target area(⁎)Diffusion orientation(⁎)Depression: F=5.882; p=0.021; Hemisphere(⁎)Diffusion orientation(⁎) Depression: F=8.744; p=0.008). Changes in integrity of fibers between the posterior hypothalamus and the mesencephalon appear to be associated with MS-related cognitive fatigue. These changes might cause an altered modulation of hypothalamic centers responsible for wakefulness. Furthermore, integrity of anterior hypothalamic fibers might be related to depression in MS. PMID

  9. Multiple Time-Step Dual-Hamiltonian Hybrid Molecular Dynamics - Monte Carlo Canonical Propagation Algorithm.

    PubMed

    Chen, Yunjie; Kale, Seyit; Weare, Jonathan; Dinner, Aaron R; Roux, Benoît

    2016-04-12

    A multiple time-step integrator based on a dual Hamiltonian and a hybrid method combining molecular dynamics (MD) and Monte Carlo (MC) is proposed to sample systems in the canonical ensemble. The Dual Hamiltonian Multiple Time-Step (DHMTS) algorithm is based on two similar Hamiltonians: a computationally expensive one that serves as a reference and a computationally inexpensive one to which the workload is shifted. The central assumption is that the difference between the two Hamiltonians is slowly varying. Earlier work has shown that such dual Hamiltonian multiple time-step schemes effectively precondition nonlinear differential equations for dynamics by reformulating them into a recursive root finding problem that can be solved by propagating a correction term through an internal loop, analogous to RESPA. Of special interest in the present context, a hybrid MD-MC version of the DHMTS algorithm is introduced to enforce detailed balance via a Metropolis acceptance criterion and ensure consistency with the Boltzmann distribution. The Metropolis criterion suppresses the discretization errors normally associated with the propagation according to the computationally inexpensive Hamiltonian, treating the discretization error as an external work. Illustrative tests are carried out to demonstrate the effectiveness of the method. PMID:26918826

  10. Multiple Time-Step Dual-Hamiltonian Hybrid Molecular Dynamics — Monte Carlo Canonical Propagation Algorithm

    PubMed Central

    Weare, Jonathan; Dinner, Aaron R.; Roux, Benoît

    2016-01-01

    A multiple time-step integrator based on a dual Hamiltonian and a hybrid method combining molecular dynamics (MD) and Monte Carlo (MC) is proposed to sample systems in the canonical ensemble. The Dual Hamiltonian Multiple Time-Step (DHMTS) algorithm is based on two similar Hamiltonians: a computationally expensive one that serves as a reference and a computationally inexpensive one to which the workload is shifted. The central assumption is that the difference between the two Hamiltonians is slowly varying. Earlier work has shown that such dual Hamiltonian multiple time-step schemes effectively precondition nonlinear differential equations for dynamics by reformulating them into a recursive root finding problem that can be solved by propagating a correction term through an internal loop, analogous to RESPA. Of special interest in the present context, a hybrid MD-MC version of the DHMTS algorithm is introduced to enforce detailed balance via a Metropolis acceptance criterion and ensure consistency with the Boltzmann distribution. The Metropolis criterion suppresses the discretization errors normally associated with the propagation according to the computationally inexpensive Hamiltonian, treating the discretization error as an external work. Illustrative tests are carried out to demonstrate the effectiveness of the method. PMID:26918826

  11. jAMVLE, A new integrated molecular visualization learning environment*.

    PubMed

    Bottomley, Steven; Chandler, David; Morgan, Eleanor; Helmerhorst, Erik

    2006-09-01

    A new computer-based molecular visualization tool has been developed for teaching, and learning, molecular structure. This java-based jmol Amalgamated Molecular Visualization Learning Environment (jAMVLE) is platform-independent, integrated, and interactive. It has an overall graphical user interface that is intuitive and easy to use. The application can be downloaded free from the internet at wabri.org.au/jamvle. A cohort of 28 third year undergraduate molecular biotechnology degree students evaluated the new application through an essay-style project. These were analyzed to identify themes expressed by students in the content of their evaluations. Most students were positive about the new jAMVLE learning environment, and five major benefits emerged from the analysis. In particular, the students perceived that jAMVLE has an appealing interface, is interactive, provides a useful integrated environment, is user friendly, and is an excellent learning tool. Overall, students found that the jAMVLE application stimulated their interest, was a more active learning environment, provided better guidance, and made learning fun. PMID:21638712

  12. 77 FR 39735 - Certain Integrated Circuit Packages Provided With Multiple Heat-Conducting Paths and Products...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-07-05

    ... COMMISSION Certain Integrated Circuit Packages Provided With Multiple Heat- Conducting Paths and Products... the sale within the United States after importation of certain integrated circuit packages provided... integrated circuit packages provided with multiple heat-conducting paths and products containing same...

  13. High integrity carrier phase navigation using multiple civil GPS signals

    NASA Astrophysics Data System (ADS)

    Jung, Jaewoo

    2000-11-01

    A navigation system should guide users to their destinations accurately and reliably. Among the many available navigation aids, the Global Positioning System stands out due to its unique capabilities. It is a satellite-based navigation system which covers the entire Earth with horizontal accuracy of 20 meters for stand alone civil users. Today, the GPS provides only one civil signal, but two more signals will be available in the near future. GPS will provide a second signal at 1227.60 MHz (L2) and a third signal at 1176.45 MHz (Lc), in addition to the current signal at 1575.42 MHz (L1). The focus of this thesis is exploring the possibility of using beat frequencies of these signals to provide navigation aid to users with high accuracy and integrity. To achieve high accuracy, the carrier phase differential GPS is used. The integer ambiguity is resolved using the Cascade Integer Resolution (CIR), which is defined in this thesis. The CIR is an instantaneous, geometry-free integer resolution method utilizing beat frequencies of GPS signals. To insure high integrity, the probability of incorrect integer ambiguity resolution using the CIR is analyzed. The CIR can immediately resolve the Lc integer ambiguity up to 2.4 km from the reference receiver, the Widelane (L1-L2) integer ambiguity up to 22 km, and the Extra Widelane (L2-Lc) integer ambiguity from there on, with probability of incorrect integer resolution of 10-4 . The optimal use of algebraic combinations of multiple GPS signals are also investigated in this thesis. Finally, the gradient of residual differential ionospheric error is estimated to stimated to increase performance of the CIR.

  14. Multiple-analyte fluoroimmunoassay using an integrated optical waveguide sensor.

    PubMed

    Plowman, T E; Durstchi, J D; Wang, H K; Christensen, D A; Herron, J N; Reichert, W M

    1999-10-01

    A silicon oxynitride integrated optical waveguide was used to evanescently excite fluorescence from a multianalyte sensor surface in a rapid, sandwich immunoassay format. Multiple analyte immunoassay (MAIA) results for two sets of three different analytes, one employing polyclonal and the other monoclonal capture antibodies, were compared with results for identical analytes performed in a single-analyte immunoassay (SAIA) format. The MAIA protocol was applied in both phosphate-buffered saline and simulated serum solutions. Point-to-point correlation values between the MAIA and SAIA results varied widely for the polyclonal antibodies (R2 = 0.42-0.98) and were acceptable for the monoclonal antibodies (R2 = 0.93-0.99). Differences in calculated receptor affinities were also evident with polyclonal antibodies, but not so with monoclonal antibodies. Polyclonal antibody capture layers tended to demonstrate departure from ideal receptor-ligand binding while monoclonal antibodies generally displayed monovalent binding. A third set of three antibodies, specific for three cardiac proteins routinely used to categorize myocardial infarction, were also evaluated with the two assay protocols. MAIA responses, over clinically significant ranges for creatin kinase MB, cardiac troponin I, and myoglobin agreed well with responses generated with SAIA protocols (R2 = 0.97-0.99). PMID:10517150

  15. Impaired functional integration in multiple sclerosis: a graph theory study.

    PubMed

    Rocca, Maria A; Valsasina, Paola; Meani, Alessandro; Falini, Andrea; Comi, Giancarlo; Filippi, Massimo

    2016-01-01

    Aim of this study was to explore the topological organization of functional brain network connectivity in a large cohort of multiple sclerosis (MS) patients and to assess whether its disruption contributes to disease clinical manifestations. Graph theoretical analysis was applied to resting state fMRI data from 246 MS patients and 55 matched healthy controls (HC). Functional connectivity between 116 cortical and subcortical brain regions was estimated using a bivariate correlation analysis. Global network properties (network degree, global efficiency, hierarchy, path length and assortativity) were abnormal in MS patients vs HC, and contributed to distinguish cognitively impaired MS patients (34%) from HC, but not the main MS clinical phenotypes. Compared to HC, MS patients also showed: (1) a loss of hubs in the superior frontal gyrus, precuneus and anterior cingulum in the left hemisphere; (2) a different lateralization of basal ganglia hubs (mostly located in the left hemisphere in HC, and in the right hemisphere in MS patients); and (3) a formation of hubs, not seen in HC, in the left temporal pole and cerebellum. MS patients also experienced a decreased nodal degree in the bilateral caudate nucleus and right cerebellum. Such a modification of regional network properties contributed to cognitive impairment and phenotypic variability of MS. An impairment of global integration (likely to reflect a reduced competence in information exchange between distant brain areas) occurs in MS and is associated with cognitive deficits. A regional redistribution of network properties contributes to cognitive status and phenotypic variability of these patients. PMID:25257603

  16. A Fuzzy Logic Framework for Integrating Multiple Learned Models

    SciTech Connect

    Bobi Kai Den Hartog

    1999-03-01

    The Artificial Intelligence field of Integrating Multiple Learned Models (IMLM) explores ways to combine results from sets of trained programs. Aroclor Interpretation is an ill-conditioned problem in which trained programs must operate in scenarios outside their training ranges because it is intractable to train them completely. Consequently, they fail in ways related to the scenarios. We developed a general-purpose IMLM solution, the Combiner, and applied it to Aroclor Interpretation. The Combiner's first step, Scenario Identification (M), learns rules from very sparse, synthetic training data consisting of results from a suite of trained programs called Methods. S1 produces fuzzy belief weights for each scenario by approximately matching the rules. The Combiner's second step, Aroclor Presence Detection (AP), classifies each of three Aroclors as present or absent in a sample. The third step, Aroclor Quantification (AQ), produces quantitative values for the concentration of each Aroclor in a sample. AP and AQ use automatically learned empirical biases for each of the Methods in each scenario. Through fuzzy logic, AP and AQ combine scenario weights, automatically learned biases for each of the Methods in each scenario, and Methods' results to determine results for a sample.

  17. Disease-specific molecular events in cortical multiple sclerosis lesions

    PubMed Central

    Wimmer, Isabella; Höftberger, Romana; Gerlach, Susanna; Haider, Lukas; Zrzavy, Tobias; Hametner, Simon; Mahad, Don; Binder, Christoph J.; Krumbholz, Markus; Bauer, Jan; Bradl, Monika

    2013-01-01

    Cortical lesions constitute an important part of multiple sclerosis pathology. Although inflammation appears to play a role in their formation, the mechanisms leading to demyelination and neurodegeneration are poorly understood. We aimed to identify some of these mechanisms by combining gene expression studies with neuropathological analysis. In our study, we showed that the combination of inflammation, plaque-like primary demyelination and neurodegeneration in the cortex is specific for multiple sclerosis and is not seen in other chronic inflammatory diseases mediated by CD8-positive T cells (Rasmussen’s encephalitis), B cells (B cell lymphoma) or complex chronic inflammation (tuberculous meningitis, luetic meningitis or chronic purulent meningitis). In addition, we performed genome-wide microarray analysis comparing micro-dissected active cortical multiple sclerosis lesions with those of tuberculous meningitis (inflammatory control), Alzheimer’s disease (neurodegenerative control) and with cortices of age-matched controls. More than 80% of the identified multiple sclerosis-specific genes were related to T cell-mediated inflammation, microglia activation, oxidative injury, DNA damage and repair, remyelination and regenerative processes. Finally, we confirmed by immunohistochemistry that oxidative damage in cortical multiple sclerosis lesions is associated with oligodendrocyte and neuronal injury, the latter also affecting axons and dendrites. Our study provides new insights into the complex mechanisms of neurodegeneration and regeneration in the cortex of patients with multiple sclerosis. PMID:23687122

  18. Numerical solution of boundary-integral equations for molecular electrostatics.

    PubMed

    Bardhan, Jaydeep P

    2009-03-01

    Numerous molecular processes, such as ion permeation through channel proteins, are governed by relatively small changes in energetics. As a result, theoretical investigations of these processes require accurate numerical methods. In the present paper, we evaluate the accuracy of two approaches to simulating boundary-integral equations for continuum models of the electrostatics of solvation. The analysis emphasizes boundary-element method simulations of the integral-equation formulation known as the apparent-surface-charge (ASC) method or polarizable-continuum model (PCM). In many numerical implementations of the ASC/PCM model, one forces the integral equation to be satisfied exactly at a set of discrete points on the boundary. We demonstrate in this paper that this approach to discretization, known as point collocation, is significantly less accurate than an alternative approach known as qualocation. Furthermore, the qualocation method offers this improvement in accuracy without increasing simulation time. Numerical examples demonstrate that electrostatic part of the solvation free energy, when calculated using the collocation and qualocation methods, can differ significantly; for a polypeptide, the answers can differ by as much as 10 kcal/mol (approximately 4% of the total electrostatic contribution to solvation). The applicability of the qualocation discretization to other integral-equation formulations is also discussed, and two equivalences between integral-equation methods are derived. PMID:19275391

  19. Molecular Assemblies, Genes and Genomics Integrated Efficiently (MAGGIE)

    SciTech Connect

    Baliga, Nitin S

    2011-05-26

    Final report on MAGGIE. We set ambitious goals to model the functions of individual organisms and their community from molecular to systems scale. These scientific goals are driving the development of sophisticated algorithms to analyze large amounts of experimental measurements made using high throughput technologies to explain and predict how the environment influences biological function at multiple scales and how the microbial systems in turn modify the environment. By experimentally evaluating predictions made using these models we will test the degree to which our quantitative multiscale understanding wilt help to rationally steer individual microbes and their communities towards specific tasks. Towards this end we have made substantial progress towards understanding evolution of gene families, transcriptional structures, detailed structures of keystone molecular assemblies (proteins and complexes), protein interactions, biological networks, microbial interactions, and community structure. Using comparative analysis we have tracked the evolutionary history of gene functions to understand how novel functions evolve. One level up, we have used proteomics data, high-resolution genome tiling microarrays, and 5' RNA sequencing to revise genome annotations, discover new genes including ncRNAs, and map dynamically changing operon structures of five model organisms: For Desulfovibrio vulgaris Hildenborough, Pyrococcus furiosis, Sulfolobus solfataricus, Methanococcus maripaludis and Haiobacterium salinarum NROL We have developed machine learning algorithms to accurately identify protein interactions at a near-zero false positive rate from noisy data generated using tagfess complex purification, TAP purification, and analysis of membrane complexes. Combining other genome-scale datasets produced by ENIGMA (in particular, microarray data) and available from literature we have been able to achieve a true positive rate as high as 65% at almost zero false positives when

  20. Prioritizing Cancer Therapeutic Small Molecules by Integrating Multiple OMICS Datasets

    PubMed Central

    Lv, Sali; Xu, Yanjun; Chen, Xin; Li, Yan; Li, Ronghong; Wang, Qianghu

    2012-01-01

    Abstract Drug design is crucial for the effective discovery of anti-cancer drugs. The success or failure of drug design often depends on the leading compounds screened in pre-clinical studies. Many efforts, such as in vivo animal experiments and in vitro drug screening, have improved this process, but these methods are usually expensive and laborious. In the post-genomics era, it is possible to seek leading compounds for large-scale candidate small-molecule screening with multiple OMICS datasets. In the present study, we developed a computational method of prioritizing small molecules as leading compounds by integrating transcriptomics and toxicogenomics data. This method provides priority lists for the selection of leading compounds, thereby reducing the time required for drug design. We found 11 known therapeutic small molecules for breast cancer in the top 100 candidates in our list, 2 of which were in the top 10. Furthermore, another 3 of the top 10 small molecules were recorded as closely related to cancer treatment in the DrugBank database. A comparison of the results of our approach with permutation tests and shared gene methods demonstrated that our OMICS data-based method is quite competitive. In addition, we applied our method to a prostate cancer dataset. The results of this analysis indicated that our method surpasses both the shared gene method and random selection. These analyses suggest that our method may be a valuable tool for directing experimental studies in cancer drug design, and we believe this time- and cost-effective computational strategy will be helpful in future studies in cancer therapy. PMID:22917481

  1. In silico gene prioritization by integrating multiple data sources.

    PubMed

    Chen, Yixuan; Wang, Wenhui; Zhou, Yingyao; Shields, Robert; Chanda, Sumit K; Elston, Robert C; Li, Jing

    2011-01-01

    Identifying disease genes is crucial to the understanding of disease pathogenesis, and to the improvement of disease diagnosis and treatment. In recent years, many researchers have proposed approaches to prioritize candidate genes by considering the relationship of candidate genes and existing known disease genes, reflected in other data sources. In this paper, we propose an expandable framework for gene prioritization that can integrate multiple heterogeneous data sources by taking advantage of a unified graphic representation. Gene-gene relationships and gene-disease relationships are then defined based on the overall topology of each network using a diffusion kernel measure. These relationship measures are in turn normalized to derive an overall measure across all networks, which is utilized to rank all candidate genes. Based on the informativeness of available data sources with respect to each specific disease, we also propose an adaptive threshold score to select a small subset of candidate genes for further validation studies. We performed large scale cross-validation analysis on 110 disease families using three data sources. Results have shown that our approach consistently outperforms other two state of the art programs. A case study using Parkinson disease (PD) has identified four candidate genes (UBB, SEPT5, GPR37 and TH) that ranked higher than our adaptive threshold, all of which are involved in the PD pathway. In particular, a very recent study has observed a deletion of TH in a patient with PD, which supports the importance of the TH gene in PD pathogenesis. A web tool has been implemented to assist scientists in their genetic studies. PMID:21731658

  2. A Simple and Convenient Method of Multiple Linear Regression to Calculate Iodine Molecular Constants

    ERIC Educational Resources Information Center

    Cooper, Paul D.

    2010-01-01

    A new procedure using a student-friendly least-squares multiple linear-regression technique utilizing a function within Microsoft Excel is described that enables students to calculate molecular constants from the vibronic spectrum of iodine. This method is advantageous pedagogically as it calculates molecular constants for ground and excited…

  3. Generating nonlinear FM chirp radar signals by multiple integrations

    DOEpatents

    Doerry, Armin W.

    2011-02-01

    A phase component of a nonlinear frequency modulated (NLFM) chirp radar pulse can be produced by performing digital integration operations over a time interval defined by the pulse width. Each digital integration operation includes applying to a respectively corresponding input parameter value a respectively corresponding number of instances of digital integration.

  4. Molecular mechanisms of apoptosis in cerebral ischemia: multiple neuroprotective opportunities.

    PubMed

    Nakka, Venkata Prasuja; Gusain, Anchal; Mehta, Suresh L; Raghubir, Ram

    2008-02-01

    Cerebral ischemia/reperfusion (I/R) injury triggers multiple and distinct but overlapping cell signaling pathways, which may lead to cell survival or cell damage. There is overwhelming evidence to suggest that besides necrosis, apoptosis do contributes significantly to the cell death subsequent to I/R injury. Both extrinsic and intrinsic apoptotic pathways play a vital role, and upon initiation, these pathways recruit downstream apoptotic molecules to execute cell death. Caspases and Bcl-2 family members appear to be crucial in regulating multiple apoptotic cell death pathways initiated during I/R. Similarly, inhibitor of apoptosis family of proteins (IAPs), mitogen-activated protein kinases, and newly identified apoptogenic molecules, like second mitochondrial-activated factor/direct IAP-binding protein with low pI (Smac/Diablo), omi/high-temperature requirement serine protease A2 (Omi/HtrA2), X-linked mammalian inhibitor of apoptosis protein-associated factor 1, and apoptosis-inducing factor, have emerged as potent regulators of cellular apoptotic/antiapoptotic machinery. All instances of cell survival/death mechanisms triggered during I/R are multifaceted and interlinked, which ultimately decide the fate of brain cells. Moreover, apoptotic cross-talk between major subcellular organelles suggests that therapeutic strategies should be optimally directed at multiple targets/mechanisms for better therapeutic outcome. Based on the current knowledge, this review briefly focuses I/R injury-induced multiple mechanisms of apoptosis, involving key apoptotic regulators and their emerging roles in orchestrating cell death programme. In addition, we have also highlighted the role of autophagy in modulating cell survival/death during cerebral ischemia. Furthermore, an attempt has been made to provide an encouraging outlook on emerging therapeutic approaches for cerebral ischemia. PMID:18066503

  5. Systems Analysis of Immunity to Influenza Vaccination across Multiple Years and in Diverse Populations Reveals Shared Molecular Signatures.

    PubMed

    Nakaya, Helder I; Hagan, Thomas; Duraisingham, Sai S; Lee, Eva K; Kwissa, Marcin; Rouphael, Nadine; Frasca, Daniela; Gersten, Merril; Mehta, Aneesh K; Gaujoux, Renaud; Li, Gui-Mei; Gupta, Shakti; Ahmed, Rafi; Mulligan, Mark J; Shen-Orr, Shai; Blomberg, Bonnie B; Subramaniam, Shankar; Pulendran, Bali

    2015-12-15

    Systems approaches have been used to describe molecular signatures driving immunity to influenza vaccination in humans. Whether such signatures are similar across multiple seasons and in diverse populations is unknown. We applied systems approaches to study immune responses in young, elderly, and diabetic subjects vaccinated with the seasonal influenza vaccine across five consecutive seasons. Signatures of innate immunity and plasmablasts correlated with and predicted influenza antibody titers at 1 month after vaccination with >80% accuracy across multiple seasons but were not associated with the longevity of the response. Baseline signatures of lymphocyte and monocyte inflammation were positively and negatively correlated, respectively, with antibody responses at 1 month. Finally, integrative analysis of microRNAs and transcriptomic profiling revealed potential regulators of vaccine immunity. These results identify shared vaccine-induced signatures across multiple seasons and in diverse populations and might help guide the development of next-generation vaccines that provide persistent immunity against influenza. PMID:26682988

  6. Integrating multiple evidences in taxonomy: species diversity and phylogeny of mustached bats (Mormoopidae: Pteronotus).

    PubMed

    Pavan, Ana Carolina; Marroig, Gabriel

    2016-10-01

    A phylogenetic systematic perspective is instrumental in recovering new species and their evolutionary relationships. The advent of new technologies for molecular and morphological data acquisition and analysis, allied to the integration of knowledge from different areas, such as ecology and population genetics, allows for the emergence of more rigorous, accurate and complete scientific hypothesis on species diversity. Mustached bats (genus Pteronotus) are a good model for the application of this integrative approach. They are a widely distributed and a morphologically homogeneous group, but comprising species with remarkable differences in their echolocation strategy and feeding behavior. The latest systematic review suggested six species with 17 subspecies in Pteronotus. Subsequent studies using discrete morphological characters supported the same arrangement. However, recent papers reported high levels of genetic divergence among conspecific taxa followed by bioacoustic and geographic agreement, suggesting an underestimated diversity in the genus. To date, no study merging genetic evidences and morphometric variation along the entire geographic range of this group has been attempted. Based on a comprehensive sampling including representatives of all current taxonomic units, we attempt to delimit species in Pteronotus through the application of multiple methodologies and hierarchically distinct datasets. The molecular approach includes six molecular markers from three genetic transmission systems; morphological investigations used 41 euclidean distances estimated through three-dimensional landmarks collected from 1628 skulls. The phylogenetic analysis reveals a greater diversity than previously reported, with a high correspondence among the genetic lineages and the currently recognized subspecies in the genus. Discriminant analysis of variables describing size and shape of cranial bones support the rising of the genetic groups to the specific status. Based on

  7. Molecular structure and elastic properties of thermotropic liquid crystals: Integrated molecular dynamics—Statistical mechanical theory vs molecular field approach

    NASA Astrophysics Data System (ADS)

    Capar, M. Ilk; Nar, A.; Ferrarini, A.; Frezza, E.; Greco, C.; Zakharov, A. V.; Vakulenko, A. A.

    2013-03-01

    The connection between the molecular structure of liquid crystals and their elastic properties, which control the director deformations relevant for electro-optic applications, remains a challenging objective for theories and computations. Here, we compare two methods that have been proposed to this purpose, both characterized by a detailed molecular level description. One is an integrated molecular dynamics-statistical mechanical approach, where the bulk elastic constants of nematics are calculated from the direct correlation function (DCFs) and the single molecule orientational distribution function [D. A. McQuarrie, Statistical Mechanics (Harper & Row, New York, 1973)]. The latter is obtained from atomistic molecular dynamics trajectories, together with the radial distribution function, from which the DCF is then determined by solving the Ornstein-Zernike equation. The other approach is based on a molecular field theory, where the potential of mean torque experienced by a mesogen in the liquid crystal phase is parameterized according to its molecular surface. In this case, the calculation of elastic constants is combined with the Monte Carlo sampling of single molecule conformations. Using these different approaches, but the same description, at the level of molecular geometry and torsional potentials, we have investigated the elastic properties of the nematic phase of two typical mesogens, 4'-n-pentyloxy-4-cyanobiphenyl and 4'-n-heptyloxy-4-cyanobiphenyl. Both methods yield K3(bend) >K1 (splay) >K2 (twist), although there are some discrepancies in the average elastic constants and in their anisotropy. These are interpreted in terms of the different approximations and the different ways of accounting for the structural properties of molecules in the two approaches. In general, the results point to the role of the molecular shape, which is modulated by the conformational freedom and cannot be fully accounted for by a single descriptor such as the aspect ratio.

  8. Molecular structure and elastic properties of thermotropic liquid crystals: integrated molecular dynamics--statistical mechanical theory vs molecular field approach.

    PubMed

    Ilk Capar, M; Nar, A; Ferrarini, A; Frezza, E; Greco, C; Zakharov, A V; Vakulenko, A A

    2013-03-21

    The connection between the molecular structure of liquid crystals and their elastic properties, which control the director deformations relevant for electro-optic applications, remains a challenging objective for theories and computations. Here, we compare two methods that have been proposed to this purpose, both characterized by a detailed molecular level description. One is an integrated molecular dynamics-statistical mechanical approach, where the bulk elastic constants of nematics are calculated from the direct correlation function (DCFs) and the single molecule orientational distribution function [D. A. McQuarrie, Statistical Mechanics (Harper & Row, New York, 1973)]. The latter is obtained from atomistic molecular dynamics trajectories, together with the radial distribution function, from which the DCF is then determined by solving the Ornstein-Zernike equation. The other approach is based on a molecular field theory, where the potential of mean torque experienced by a mesogen in the liquid crystal phase is parameterized according to its molecular surface. In this case, the calculation of elastic constants is combined with the Monte Carlo sampling of single molecule conformations. Using these different approaches, but the same description, at the level of molecular geometry and torsional potentials, we have investigated the elastic properties of the nematic phase of two typical mesogens, 4'-n-pentyloxy-4-cyanobiphenyl and 4'-n-heptyloxy-4-cyanobiphenyl. Both methods yield K3(bend) >K1 (splay) >K2 (twist), although there are some discrepancies in the average elastic constants and in their anisotropy. These are interpreted in terms of the different approximations and the different ways of accounting for the structural properties of molecules in the two approaches. In general, the results point to the role of the molecular shape, which is modulated by the conformational freedom and cannot be fully accounted for by a single descriptor such as the aspect ratio

  9. Information Integration in Multiple Cue Judgment: A Division of Labor Hypothesis

    ERIC Educational Resources Information Center

    Juslin, Peter; Karlsson, Linnea; Olsson, Henrik

    2008-01-01

    There is considerable evidence that judgment is constrained to additive integration of information. The authors propose an explanation of why serial and additive cognitive integration can produce accurate multiple cue judgment both in additive and non-additive environments in terms of an adaptive division of labor between multiple representations.…

  10. Multiple Point Dynamic Gas Density Measurements Using Molecular Rayleigh Scattering

    NASA Technical Reports Server (NTRS)

    Seasholtz, Richard; Panda, Jayanta

    1999-01-01

    A nonintrusive technique for measuring dynamic gas density properties is described. Molecular Rayleigh scattering is used to measure the time-history of gas density simultaneously at eight spatial locations at a 50 kHz sampling rate. The data are analyzed using the Welch method of modified periodograms to reduce measurement uncertainty. Cross-correlations, power spectral density functions, cross-spectral density functions, and coherence functions may be obtained from the data. The technique is demonstrated using low speed co-flowing jets with a heated inner jet.

  11. Angular momentum in molecular quantum mechanical integral evaluation

    NASA Astrophysics Data System (ADS)

    Dunlap, Brett I.

    2005-01-01

    Solid-harmonic derivatives of quantum-mechanical integrals over Gaussian transforms of scalar, or radial, atomic basis functions create angular momentum about each center. Generalized Gaunt coefficients limit the amount of cross differentiation for multi-center integrals to ensure that cross differentiation does not affect the total angular momentum. The generalized Gaunt coefficients satisfy a number of other selection rules, which are exploited in a new computer code for computing forces in analytic density-functional theory based on robust and variational fitting of the Kohn-Sham potential. Two-center exponents are defined for four or more solid-harmonic differentiations of matrix elements. Those differentiations can either build up angular momentum about the centers or give forces on molecular potential-energy surfaces, thus generalized Gaunt coefficients of order greater than the number of centers are considered. These 4- j generalized Gaunt coefficients and two-center exponents are used to compute the first derivatives of all integrals involving all the Gaussian exponents on a triplet of centers at once. First all angular factors are contracted with the corresponding part of the linear-combination-of-atomic-orbitals density matrix. This intermediate quantity is then reused for the nuclear attraction integral and the integrals corresponding to each basis function in the analytic fit of the Kohn-Sham potential in the muffin-tin-like, but analytic, Slater-Roothaan method that allows molecules to dissociate into atoms having any desired energy, including the experimental electronic energy. The energy is stationary in all respects and all forces precisely agree with a previous code in tests on small molecules. During geometry optimization of an icosahedral C 720 fullerene computing these angular factors and transforming them via the 4- j generalized Gaunt coefficient takes more than sixty percent of the total computer time. These same angular factors could be used

  12. Notch signaling deregulation in multiple myeloma: A rational molecular target

    PubMed Central

    Garavelli, Silvia; Platonova, Natalia; Paoli, Alessandro; Basile, Andrea; Taiana, Elisa; Neri, Antonino; Chiaramonte, Raffaella

    2015-01-01

    Despite recent therapeutic advances, multiple myeloma (MM) is still an incurable neoplasia due to intrinsic or acquired resistance to therapy. Myeloma cell localization in the bone marrow milieu allows direct interactions between tumor cells and non-tumor bone marrow cells which promote neoplastic cell growth, survival, bone disease, acquisition of drug resistance and consequent relapse. Twenty percent of MM patients are at high-risk of treatment failure as defined by tumor markers or presentation as plasma cell leukemia. Cumulative evidences indicate a key role of Notch signaling in multiple myeloma onset and progression. Unlike other Notch-related malignancies, where the majority of patients carry gain-of-function mutations in Notch pathway members, in MM cell Notch signaling is aberrantly activated due to an increased expression of Notch receptors and ligands; notably, this also results in the activation of Notch signaling in surrounding stromal cells which contributes to myeloma cell proliferation, survival and migration, as well as to bone disease and intrinsic and acquired pharmacological resistance. Here we review the last findings on the mechanisms and the effects of Notch signaling dysregulation in MM and provide a rationale for a therapeutic strategy aiming at inhibiting Notch signaling, along with a complete overview on the currently available Notch-directed approaches. PMID:26308486

  13. 77 FR 33486 - Certain Integrated Circuit Packages Provided With Multiple Heat-Conducting Paths and Products...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-06-06

    ... COMMISSION Certain Integrated Circuit Packages Provided With Multiple Heat- Conducting Paths and Products... With Multiple Heat-Conducting Paths and Products Containing Same, DN 2899; the Commission is soliciting... multiple heat-conducting paths and products containing same. The complaint names as respondents...

  14. i-PI: A Python interface for ab initio path integral molecular dynamics simulations

    NASA Astrophysics Data System (ADS)

    Ceriotti, Michele; More, Joshua; Manolopoulos, David E.

    2014-03-01

    Recent developments in path integral methodology have significantly reduced the computational expense of including quantum mechanical effects in the nuclear motion in ab initio molecular dynamics simulations. However, the implementation of these developments requires a considerable programming effort, which has hindered their adoption. Here we describe i-PI, an interface written in Python that has been designed to minimise the effort required to bring state-of-the-art path integral techniques to an electronic structure program. While it is best suited to first principles calculations and path integral molecular dynamics, i-PI can also be used to perform classical molecular dynamics simulations, and can just as easily be interfaced with an empirical forcefield code. To give just one example of the many potential applications of the interface, we use it in conjunction with the CP2K electronic structure package to showcase the importance of nuclear quantum effects in high-pressure water. Catalogue identifier: AERN_v1_0 Program summary URL: http://cpc.cs.qub.ac.uk/summaries/AERN_v1_0.html Program obtainable from: CPC Program Library, Queen’s University, Belfast, N. Ireland Licensing provisions: GNU General Public License, version 3 No. of lines in distributed program, including test data, etc.: 138626 No. of bytes in distributed program, including test data, etc.: 3128618 Distribution format: tar.gz Programming language: Python. Computer: Multiple architectures. Operating system: Linux, Mac OSX, Windows. RAM: Less than 256 Mb Classification: 7.7. External routines: NumPy Nature of problem: Bringing the latest developments in the modelling of nuclear quantum effects with path integral molecular dynamics to ab initio electronic structure programs with minimal implementational effort. Solution method: State-of-the-art path integral molecular dynamics techniques are implemented in a Python interface. Any electronic structure code can be patched to receive the atomic

  15. Clusters of Multiple Mutations: Incidence and Molecular Mechanisms

    PubMed Central

    Chan, Kin; Gordenin, Dmitry A.

    2016-01-01

    It has been long understood that mutation distribution across genomic space and in time is not completely random. Indeed, recent surprising discoveries identified multiple simultaneous mutations occurring in tiny regions within chromosomes, while the rest of the genome remains relatively mutation-free. Mechanistic elucidation of these phenomena called mutation showers, mutation clusters, or kataegis is ongoing, in parallel with findings of abundant clustered mutagenesis in cancer genomes. So far, the combination of factors most important for clustered mutagenesis is the induction of DNA lesions with unusually long and persistent single-strand DNA intermediates. In addition to being a fascinating phenomenon, clustered mutagenesis also became an indispensable tool for identifying a previously unrecognized major source of mutation in cancer – APOBEC cytidine deaminases. Future research on clustered mutagenesis carries a promise of shedding light onto important mechanistic details of genome maintenance, with potentially profound implications for human health. PMID:26631512

  16. Proteasome inhibitors - molecular basis and current perspectives in multiple myeloma.

    PubMed

    Kubiczkova, Lenka; Pour, Ludek; Sedlarikova, Lenka; Hajek, Roman; Sevcikova, Sabina

    2014-06-01

    Inhibition of proteasome, a proteolytic complex responsible for the degradation of ubiquitinated proteins, has emerged as a powerful strategy for treatment of multiple myeloma (MM), a plasma cell malignancy. First-in-class agent, bortezomib, has demonstrated great positive therapeutic efficacy in MM, both in pre-clinical and in clinical studies. However, despite its high efficiency, a large proportion of patients do not achieve sufficient clinical response. Therefore, the development of a second-generation of proteasome inhibitors (PIs) with improved pharmacological properties was needed. Recently, several of these new agents have been introduced into clinics including carfilzomib, marizomib and ixazomib. Further, new orally administered second-generation PI oprozomib is being investigated. This review provides an overview of main mechanisms of action of PIs in MM, focusing on the ongoing development and progress of novel anti-proteasome therapeutics. PMID:24712303

  17. [Molecular Mechanism and Malignant Clonal Evolution of Multiple Myeloma].

    PubMed

    Ding, Fei; Zhu, Ping; Wu, Xue-Qiang

    2015-10-01

    Almost all patients with multiple myeloma (MM) have chromosomal translocation which can result in genetic variation. There are mainly five types of chromosomal translocations, involving the IGH gene translocation to 11q13 (CCND1), 4p16 (FGFR/MMSET), 16q23 (MAF), 6p21 (CCND3) and 20q11 (MAFB). It is possible that all IGH translocations converge on a common cell cycle signal pathway. Some MM develops through a multistep transformation from monoclonal gammopathy of undetermined significance (MGUS) to smoldering MM (SMM) and eventually to MM and plasma cell leukemia (PCL). Similarly to what Darwin proposed in the mid-19th century-random genetic variation and natural selection in the context of limited resources, MM clonal evolution follow branching and nonlinear mode. The failure of MM treatment is usually related with the minimal subclone which is hardly found at newlydiagnosed. PMID:26524068

  18. Clinical and molecular genetic aspects of hereditary multiple cutaneous leiomyomatosis.

    PubMed

    Badeloe, Sadhanna; Frank, Jorge

    2009-01-01

    Multiple cutaneous and uterine leiomyomatosis syndrome (MCUL; OMIM 150800) is an autosomal dominantly inherited tumor predisposition disorder, characterized by leiomyomas of the skin and uterus. When associated with kidney cancer, this syndrome is known as hereditary leiomyomatosis and renal cell cancer (HLRCC; OMIM 605839). All disease variants result from heterozygous mutations in the fumarate hydratase (FH) gene. Cutaneous leiomyoma can easily be recognized and confirmed by histological examination. Recognition of these benign skin tumors can lead to the diagnosis of MCUL or HLRCC. Timely diagnosis is crucial for offering affected individuals and families potentially life-saving regular prophylactic screening examinations for renal tumors. Here we provide an overview of clinical and genetic features of this complex tumor syndrome and discuss patient management and current therapeutic strategies. PMID:19939761

  19. Growth, modification and integration of carbon nanotubes into molecular electronics

    NASA Astrophysics Data System (ADS)

    Moscatello, Jason P.

    Molecules are the smallest possible elements for electronic devices, with active elements for such devices typically a few Angstroms in footprint area. Owing to the possibility of producing ultra-high density devices, tremendous effort has been invested in producing electronic junctions by using various types of molecules. The major issues for molecular electronics include (1) developing an effective scheme to connect molecules with the present micro- and nano-technology, (2) increasing the lifetime and stabilities of the devices, and (3) increasing their performance in comparison to the state-of-the-art devices. In this work, we attempt to use carbon nanotubes (CNTs) as the interconnecting nanoelectrodes between molecules and microelectrodes. The ultimate goal is to use two individual CNTs to sandwich molecules in a cross-bar configuration while having these CNTs connected with microelectrodes such that the junction displays the electronic character of the molecule chosen. We have successfully developed an effective scheme to connect molecules with CNTs, which is scalable to arrays of molecular electronic devices. To realize this far reaching goal, the following technical topics have been investigated. (1) Synthesis of multi-walled carbon nanotubes (MWCNTs) by thermal chemical vapor deposition (T-CVD) and plasma-enhanced chemical vapor deposition (PECVD) techniques (Chapter 3). We have evaluated the potential use of tubular and bamboo-like MWCNTs grown by T-CVD and PE-CVD in terms of their structural properties. (2) Horizontal dispersion of MWCNTs with and without surfactants, and the integration of MWCNTs to microelectrodes using deposition by dielectrophoresis (DEP) (Chapter 4). We have systematically studied the use of surfactant molecules to disperse and horizontally align MWCNTs on substrates. In addition, DEP is shown to produce impurityfree placement of MWCNTs, forming connections between microelectrodes. We demonstrate the deposition density is tunable by

  20. Integrated molecular portrait of non-small cell lung cancers

    PubMed Central

    2013-01-01

    Background Non-small cell lung cancer (NSCLC), a leading cause of cancer deaths, represents a heterogeneous group of neoplasms, mostly comprising squamous cell carcinoma (SCC), adenocarcinoma (AC) and large-cell carcinoma (LCC). The objectives of this study were to utilize integrated genomic data including copy-number alteration, mRNA, microRNA expression and candidate-gene full sequencing data to characterize the molecular distinctions between AC and SCC. Methods Comparative genomic hybridization followed by mutational analysis, gene expression and miRNA microarray profiling were performed on 123 paired tumor and non-tumor tissue samples from patients with NSCLC. Results At DNA, mRNA and miRNA levels we could identify molecular markers that discriminated significantly between the various histopathological entities of NSCLC. We identified 34 genomic clusters using aCGH data; several genes exhibited a different profile of aberrations between AC and SCC, including PIK3CA, SOX2, THPO, TP63, PDGFB genes. Gene expression profiling analysis identified SPP1, CTHRC1and GREM1 as potential biomarkers for early diagnosis of the cancer, and SPINK1 and BMP7 to distinguish between AC and SCC in small biopsies or in blood samples. Using integrated genomics approach we found in recurrently altered regions a list of three potential driver genes, MRPS22, NDRG1 and RNF7, which were consistently over-expressed in amplified regions, had wide-spread correlation with an average of ~800 genes throughout the genome and highly associated with histological types. Using a network enrichment analysis, the targets of these potential drivers were seen to be involved in DNA replication, cell cycle, mismatch repair, p53 signalling pathway and other lung cancer related signalling pathways, and many immunological pathways. Furthermore, we also identified one potential driver miRNA hsa-miR-944. Conclusions Integrated molecular characterization of AC and SCC helped identify clinically relevant markers

  1. Curriculum Integration in Arts Education: Connecting Multiple Art Forms through the Idea of "Space"

    ERIC Educational Resources Information Center

    Bautista, Alfredo; Tan, Liang See; Ponnusamy, Letchmi Devi; Yau, Xenia

    2016-01-01

    Arts integration research has focused on documenting how the teaching of specific art forms can be integrated with "core" academic subject matters (e.g. science, mathematics and literacy). However, the question of how the teaching of multiple art forms themselves can be integrated in schools remains to be explored by educational…

  2. The Molecular Mechanisms of Vitamin A Deficiency in Multiple Sclerosis.

    PubMed

    Reza Dorosty-Motlagh, Ahmad; Mohammadzadeh Honarvar, Niyaz; Sedighiyan, Mohsen; Abdolahi, Mina

    2016-09-01

    Vitamin A, considered to be an essential nutrient, has important actions in immunological responses and the central nervous system (CNS). Neuroimmunological functions of vitamin A are mediated through its active metabolite, retinoic acid (RA). In the CNS, RA contributes to regeneration and plasticity, while also playing a key role in enhancing tolerance and reducing inflammatory responses by regulating T cell, B cell and dendritic cell populations. However, evidence has indicated lower plasma levels of vitamin A in patients with multiple sclerosis (MS). Vitamin A deficiency leads to dysregulation of immune tolerance and pathogenic immune cell production in this disease. Vitamin A may ameliorate MS pathogenesis through numerous mechanisms including a reduction in inflammatory processes by re-establishing the balance between pathogenic (Th1, Th17, Th9) and immunoprotective cells (Th2, Tregs), modulating B cell and dendritic cell function as well as increasing tolerance of autoimmunity and regeneration in the CNS. Thus, the results from the current review suggest that vitamin A can be considered as a potential treatment in MS disease management. PMID:27356515

  3. Molecular mechanisms of nutlin-induced apoptosis in multiple myeloma

    PubMed Central

    Saha, Manujendra N; Jiang, Hua

    2010-01-01

    Multiple myeloma (MM) is an incurable plasma cell malignancy in which p53 is rarely mutated. Thus, activation of the p53 pathway by a small molecule inhibitor of the p53-MDM2 interaction, nutlin, in MM cells retaining wild type p53 is an attractive therapeutic strategy. Recently we reported that nutlin plus velcade (a proteasome inhibitor) displayed a synergistic response in MM. However, the mechanism of the p53-mediated apoptosis in MM has not been fully understood. Our data show that nutlin-induced apoptosis correlated with reduction in cell viability, upregulation of p53, p21 and MDM2 protein levels with a simultaneous increase in pro-apoptotic targets PUMA, Bax and Bak and downregulation of anti-apoptotic targets Bcl2 and survivin and activation of caspase in MM cells harboring wild type p53. Nutlin-induced apoptosis was inhibited when activation of caspase was blocked by the caspase inhibitor. Nutlin caused mitochondrial translocation of p53 where it binds with Bcl2, leading to cytochrome C release. Moreover, blocking the transcriptional arm of p53 by the p53-specific transcriptional inhibitor, pifithrin-α, not only inhibited nutlin-induced upregulation of p53-transcriptional targets but also augmented apoptosis in MM cells, suggesting an association of transcription-independent pathway of apoptosis. However, inhibitor of mitochondrial translocation of p53, PFT-µ, did not prevent nutlin-induced apoptosis, suggesting that the p53 transcription-dependent pathway was also operational in nutlin-induced apoptosis in MM. Our study provides the evidence that nutlin-induced apoptosis in MM cells is mediated by transcription-dependent and -independent pathways and supports further clinical evaluation of nutlin as a novel therapeutic agent in MM. PMID:20595817

  4. Quantum Thermal Bath for Path Integral Molecular Dynamics Simulation.

    PubMed

    Brieuc, Fabien; Dammak, Hichem; Hayoun, Marc

    2016-03-01

    The quantum thermal bath (QTB) method has been recently developed to account for the quantum nature of the nuclei by using standard molecular dynamics (MD) simulation. QTB-MD is an efficient but approximate method when dealing with strongly anharmonic systems, while path integral molecular dynamics (PIMD) gives exact results but in a huge amount of computation time. The QTB and PIMD methods have been combined in order to improve the PIMD convergence or correct the failures of the QTB-MD technique. Therefore, a new power spectral density of the random force within the QTB has been developed. A modified centroid-virial estimator of the kinetic energy, especially adapted to QTB-PIMD, has also been proposed. The method is applied to selected systems: a one-dimensional double-well system, a ferroelectric phase transition, and the position distribution of an hydrogen atom in a fuel cell material. The advantage of the QTB-PIMD method is its ability to give exact results with a more reasonable computation time for strongly anharmonic systems. PMID:26799437

  5. Drug Repositioning by Kernel-Based Integration of Molecular Structure, Molecular Activity, and Phenotype Data

    PubMed Central

    Wang, Yongcui; Chen, Shilong; Deng, Naiyang; Wang, Yong

    2013-01-01

    Computational inference of novel therapeutic values for existing drugs, i.e., drug repositioning, offers the great prospect for faster and low-risk drug development. Previous researches have indicated that chemical structures, target proteins, and side-effects could provide rich information in drug similarity assessment and further disease similarity. However, each single data source is important in its own way and data integration holds the great promise to reposition drug more accurately. Here, we propose a new method for drug repositioning, PreDR (Predict Drug Repositioning), to integrate molecular structure, molecular activity, and phenotype data. Specifically, we characterize drug by profiling in chemical structure, target protein, and side-effects space, and define a kernel function to correlate drugs with diseases. Then we train a support vector machine (SVM) to computationally predict novel drug-disease interactions. PreDR is validated on a well-established drug-disease network with 1,933 interactions among 593 drugs and 313 diseases. By cross-validation, we find that chemical structure, drug target, and side-effects information are all predictive for drug-disease relationships. More experimentally observed drug-disease interactions can be revealed by integrating these three data sources. Comparison with existing methods demonstrates that PreDR is competitive both in accuracy and coverage. Follow-up database search and pathway analysis indicate that our new predictions are worthy of further experimental validation. Particularly several novel predictions are supported by clinical trials databases and this shows the significant prospects of PreDR in future drug treatment. In conclusion, our new method, PreDR, can serve as a useful tool in drug discovery to efficiently identify novel drug-disease interactions. In addition, our heterogeneous data integration framework can be applied to other problems. PMID:24244318

  6. Integration of Multiple Genomic and Phenotype Data to Infer Novel miRNA-Disease Associations.

    PubMed

    Shi, Hongbo; Zhang, Guangde; Zhou, Meng; Cheng, Liang; Yang, Haixiu; Wang, Jing; Sun, Jie; Wang, Zhenzhen

    2016-01-01

    MicroRNAs (miRNAs) play an important role in the development and progression of human diseases. The identification of disease-associated miRNAs will be helpful for understanding the molecular mechanisms of diseases at the post-transcriptional level. Based on different types of genomic data sources, computational methods for miRNA-disease association prediction have been proposed. However, individual source of genomic data tends to be incomplete and noisy; therefore, the integration of various types of genomic data for inferring reliable miRNA-disease associations is urgently needed. In this study, we present a computational framework, CHNmiRD, for identifying miRNA-disease associations by integrating multiple genomic and phenotype data, including protein-protein interaction data, gene ontology data, experimentally verified miRNA-target relationships, disease phenotype information and known miRNA-disease connections. The performance of CHNmiRD was evaluated by experimentally verified miRNA-disease associations, which achieved an area under the ROC curve (AUC) of 0.834 for 5-fold cross-validation. In particular, CHNmiRD displayed excellent performance for diseases without any known related miRNAs. The results of case studies for three human diseases (glioblastoma, myocardial infarction and type 1 diabetes) showed that all of the top 10 ranked miRNAs having no known associations with these three diseases in existing miRNA-disease databases were directly or indirectly confirmed by our latest literature mining. All these results demonstrated the reliability and efficiency of CHNmiRD, and it is anticipated that CHNmiRD will serve as a powerful bioinformatics method for mining novel disease-related miRNAs and providing a new perspective into molecular mechanisms underlying human diseases at the post-transcriptional level. CHNmiRD is freely available at http://www.bio-bigdata.com/CHNmiRD. PMID:26849207

  7. Integrative Data Analysis: The Simultaneous Analysis of Multiple Data Sets

    ERIC Educational Resources Information Center

    Curran, Patrick J.; Hussong, Andrea M.

    2009-01-01

    There are both quantitative and methodological techniques that foster the development and maintenance of a cumulative knowledge base within the psychological sciences. Most noteworthy of these techniques is meta-analysis, which allows for the synthesis of summary statistics drawn from multiple studies when the original data are not available.…

  8. Noninvasive imaging of multiple myeloma using near infrared fluorescent molecular probe

    NASA Astrophysics Data System (ADS)

    Hathi, Deep; Zhou, Haiying; Bollerman-Nowlis, Alex; Shokeen, Monica; Akers, Walter J.

    2016-03-01

    Multiple myeloma is a plasma cell malignancy characterized by monoclonal gammopathy and osteolytic bone lesions. Multiple myeloma is most commonly diagnosed in late disease stages, presenting with pathologic fracture. Early diagnosis and monitoring of disease status may improve quality of life and long-term survival for multiple myeloma patients from what is now a devastating and fatal disease. We have developed a near-infrared targeted fluorescent molecular probe with high affinity to the α4β1 integrin receptor (VLA-4)overexpressed by a majority of multiple myeloma cells as a non-radioactive analog to PET/CT tracer currently being developed for human diagnostics. A near-infrared dye that emits about 700 nm was conjugated to a high affinity peptidomimmetic. Binding affinity and specificity for multiple myeloma cells was investigated in vitro by tissue staining and flow cytometry. After demonstration of sensitivity and specificity, preclinical optical imaging studies were performed to evaluate tumor specificity in murine subcutaneous and metastatic multiple myeloma models. The VLA-4-targeted molecular probe showed high affinity for subcutaneous MM tumor xenografts. Importantly, tumor cells specific accumulation in the bone marrow of metastatic multiple myeloma correlated with GFP signal from transfected cells. Ex vivo flow cytometry of tumor tissue and bone marrow further corroborated in vivo imaging data, demonstrating the specificity of the novel agent and potential for quantitative imaging of multiple myeloma burden in these models.

  9. Restructuring for Integrative Education: Multiple Perspectives, Multiple Contexts. Critical Studies in Education and Culture Series.

    ERIC Educational Resources Information Center

    Jennings, Todd, Ed.

    Integrative education is defined as education that promotes learning and teaching in nonfragmented ways that embrace notions of holism, complexity, and interconnection. Furthermore, integrative education embraces the links, rather than the divisions, between the academic disciplines (e.g., arts and sciences) and between various subjective and…

  10. Identifying multiple submissions in Internet research: preserving data integrity.

    PubMed

    Bowen, Anne M; Daniel, Candice M; Williams, Mark L; Baird, Grayson L

    2008-11-01

    Internet-based sexuality research with hidden populations has become increasingly popular. Respondent anonymity may encourage participation and lower social desirability, but associated disinhibition may promote multiple submissions, especially when incentives are offered. The goal of this study was to identify the usefulness of different variables for detecting multiple submissions from repeat responders and to explore incentive effects. The data included 1,900 submissions from a three-session Internet intervention with a pretest and three post-test questionnaires. Participants were men who have sex with men and incentives were offered to rural participants for completing each questionnaire. The final number of submissions included 1,273 "unique", 132 first submissions by "repeat responders" and 495 additional submissions by the "repeat responders" (N = 1,900). Four categories of repeat responders were identified: "infrequent" (2-5 submissions), "persistent" (6-10 submissions), "very persistent" (11-30 submissions), and "hackers" (more than 30 submissions). Internet Provider (IP) addresses, user names, and passwords were the most useful for identifying "infrequent" repeat responders. "Hackers" often varied their IP address and identifying information to prevent easy identification, but investigating the data for small variations in IP, using reverse telephone look up, and patterns across usernames and passwords were helpful. Incentives appeared to play a role in stimulating multiple submissions, especially from the more sophisticated "hackers". Finally, the web is ever evolving and it will be necessary to have good programmers and staff who evolve as fast as "hackers". PMID:18240015

  11. Multiple integral representation for the trigonometric SOS model with domain wall boundaries

    NASA Astrophysics Data System (ADS)

    Galleas, W.

    2012-05-01

    Using the dynamical Yang-Baxter algebra we derive a functional equation for the partition function of the trigonometric SOS model with domain wall boundary conditions. The solution of the equation is given in terms of a multiple contour integral.

  12. Two-Dimensional Integral Combustion for Multiple Phase Flow

    Energy Science and Technology Software Center (ESTSC)

    1997-05-05

    This ANL multiphase two-dimensional combustion computer code solves conservation equations for gaseous species and solid particles (or droplets) of various sizes. General conservation laws, expressed by ellipitic-type partial differential equations are used in conjunction with rate equations governing the mass, momentum, enthaply, species, turbulent kinetic energy, and turbulent dissipation for a two-phase reacting flow. Associated submodels include an integral combustion, a two-parameter turbulence, a particle evaporation, and interfacial submodels. A newly-developed integral combustion submodel replacingmore » an Arrhenius-type differential reaction submodel is implemented to improve numerical convergence and enhance numerical stability. The two-parameter turbulence submodel is modified for both gas and solid phases. The evaporation submodel treats size dispersion as well as particle evaporation. Interfacial submodels use correlations to model interfacial momentum and energy transfer.« less

  13. Integration of Multiple Organic Light Emitting Diodes and a Lens for Emission Angle Control

    NASA Astrophysics Data System (ADS)

    Rahadian, Fanny; Masada, Tatsuya; Fujieda, Ichiro

    We propose to integrate a single lens on top of multiple OLEDs. Angular distribution of the light emitted from the lens surface is altered by turning on the OLEDs selectively. We can use such a light source as a backlight for a liquid crystal display to switch its viewing angle range and/or to display multiple images in different directions. Pixel-level integration would allow one to construct an OLED display with a similar emission angle control.

  14. Identifying Multiple Submissions in Internet Research: Preserving Data Integrity

    PubMed Central

    Bowen, Anne M.; Daniel, Candice M.; Williams, Mark L.; Baird, Grayson L.

    2008-01-01

    Internet-based sexuality research with hidden populations has become increasingly popular. Respondent anonymity may encourage participation and lower social desirability, but associated disinhibition may promote multiple submissions, especially when incentives are offered. The goal of this study was to identify the usefulness of different variables for detecting multiple submissions from repeat responders and to explore incentive effects. The data included 1,900 submissions from a three-session Internet intervention with a pretest and three post-test questionnaires. Participants were men who have sex with men and incentives were offered to rural participants for completing each questionnaire. The final number of submissions included 1,273 “unique”, 132 first submissions by “repeat responders” and 495 additional submissions by the “repeat responders” (N = 1,900). Four categories of repeat responders were identified: “infrequent” (2–5 submissions), “persistent” (6–10 submissions), “very persistent” (11–30 submissions), and “hackers” (more than 30 submissions). Internet Provider (IP) addresses, user names, and passwords were the most useful for identifying “infrequent” repeat responders. “Hackers” often varied their IP address and identifying information to prevent easy identification, but investigating the data for small variations in IP, using reverse telephone look up, and patterns across usernames and passwords were helpful. Incentives appeared to play a role in stimulating multiple submissions, especially from the more sophisticated “hackers”. Finally, the web is ever evolving and it will be necessary to have good programmers and staff who evolve as fast as “hackers”. PMID:18240015

  15. Empathetic, Critical Integrations of Multiple Perspectives: A Core Practice for Language Teacher Education?

    ERIC Educational Resources Information Center

    Daniel, Shannon M.

    2015-01-01

    In this self-study, the author reflects on her implementation of empathetic, critical integrations of multiple perspectives (ECI), which she designed to afford preservice teachers the opportunity to discuss and collectively reflect upon the oft-diverging multiple perspectives, values, and practices they experience during their practicum (Daniel,…

  16. Integrated Dataset of Screening Hits against Multiple Neglected Disease Pathogens

    PubMed Central

    Nwaka, Solomon; Besson, Dominique; Ramirez, Bernadette; Maes, Louis; Matheeussen, An; Bickle, Quentin; Mansour, Nuha R.; Yousif, Fouad; Townson, Simon; Gokool, Suzanne; Cho-Ngwa, Fidelis; Samje, Moses; Misra-Bhattacharya, Shailja; Murthy, P. K.; Fakorede, Foluke; Paris, Jean-Marc; Yeates, Clive; Ridley, Robert; Van Voorhis, Wesley C.; Geary, Timothy

    2011-01-01

    New chemical entities are desperately needed that overcome the limitations of existing drugs for neglected diseases. Screening a diverse library of 10,000 drug-like compounds against 7 neglected disease pathogens resulted in an integrated dataset of 744 hits. We discuss the prioritization of these hits for each pathogen and the strong correlation observed between compounds active against more than two pathogens and mammalian cell toxicity. Our work suggests that the efficiency of early drug discovery for neglected diseases can be enhanced through a collaborative, multi-pathogen approach. PMID:22247786

  17. A microfluidic system with integrated molecular imprinting polymer films for surface plasmon resonance detection

    NASA Astrophysics Data System (ADS)

    Huang, Shih-Chiang; Lee, Gwo-Bin; Chien, Fan-Ching; Chen, Shean-Jen; Chen, Wen-Janq; Yang, Ming-Chang

    2006-07-01

    This paper presents a novel microfluidic system with integrated molecular imprinting polymer (MIP) films designed for surface plasmon resonance (SPR) biosensing of multiple nanoscale biomolecules. The innovative microfluidic chip uses pneumatic microvalves and micropumps to transport a precise amount of the biosample through multiple microchannels to sensing regions containing the locally spin-coated MIP films. The signals of SPR biosensing are basically proportional to the number of molecules adsorbed on the MIP films. Hence, a precise control of flow rates inside microchannels is important to determine the adsorption amount of the molecules in the SPR/MIP chips. The integration of micropumps and microvalves can automate the sample introduction process and precisely control the amount of the sample injection to the microfluidic system. The proposed biochip enables the label-free biosensing of biomolecules in an automatic format, and provides a highly sensitive, highly specific and high-throughput detection performance. Three samples, i.e. progesterone, cholesterol and testosterone, are successfully detected using the developed system. The experimental results show that the proposed SPR/MIP microfluidic chip provides a comparable sensitivity to that of large-scale SPR techniques, but with reduced sample consumption and an automatic format. As such, the developed biochip has significant potential for a wide variety of nanoscale biosensing applications. The preliminary results of the current paper were presented at Transducers 2005, Seoul, Korea, 5-9 June 2005.

  18. The Center for Integrated Molecular Brain Imaging (Cimbi) database.

    PubMed

    Knudsen, Gitte M; Jensen, Peter S; Erritzoe, David; Baaré, William F C; Ettrup, Anders; Fisher, Patrick M; Gillings, Nic; Hansen, Hanne D; Hansen, Lars Kai; Hasselbalch, Steen G; Henningsson, Susanne; Herth, Matthias M; Holst, Klaus K; Iversen, Pernille; Kessing, Lars V; Macoveanu, Julian; Madsen, Kathrine Skak; Mortensen, Erik L; Nielsen, Finn Årup; Paulson, Olaf B; Siebner, Hartwig R; Stenbæk, Dea S; Svarer, Claus; Jernigan, Terry L; Strother, Stephen C; Frokjaer, Vibe G

    2016-01-01

    We here describe a multimodality neuroimaging containing data from healthy volunteers and patients, acquired within the Lundbeck Foundation Center for Integrated Molecular Brain Imaging (Cimbi) in Copenhagen, Denmark. The data is of particular relevance for neurobiological research questions related to the serotonergic transmitter system with its normative data on the serotonergic subtype receptors 5-HT1A, 5-HT1B, 5-HT2A, and 5-HT4 and the 5-HT transporter (5-HTT), but can easily serve other purposes. The Cimbi database and Cimbi biobank were formally established in 2008 with the purpose to store the wealth of Cimbi-acquired data in a highly structured and standardized manner in accordance with the regulations issued by the Danish Data Protection Agency as well as to provide a quality-controlled resource for future hypothesis-generating and hypothesis-driven studies. The Cimbi database currently comprises a total of 1100 PET and 1000 structural and functional MRI scans and it holds a multitude of additional data, such as genetic and biochemical data, and scores from 17 self-reported questionnaires and from 11 neuropsychological paper/computer tests. The database associated Cimbi biobank currently contains blood and in some instances saliva samples from about 500 healthy volunteers and 300 patients with e.g., major depression, dementia, substance abuse, obesity, and impulsive aggression. Data continue to be added to the Cimbi database and biobank. PMID:25891375

  19. Students' integration of multiple representations in a titration experiment

    NASA Astrophysics Data System (ADS)

    Kunze, Nicole M.

    A complete understanding of a chemical concept is dependent upon a student's ability to understand the microscopic or particulate nature of the phenomenon and integrate the microscopic, symbolic, and macroscopic representations of the phenomenon. Acid-base chemistry is a general chemistry topic requiring students to understand the topics of chemical reactions, solutions, and equilibrium presented earlier in the course. In this study, twenty-five student volunteers from a second semester general chemistry course completed two interviews. The first interview was completed prior to any classroom instruction on acids and bases. The second interview took place after classroom instruction, a prelab activity consisting of a titration calculation worksheet, a titration computer simulation, or a microscopic level animation of a titration, and two microcomputer-based laboratory (MBL) titration experiments. During the interviews, participants were asked to define and describe acid-base concepts and in the second interview they also drew the microscopic representations of four stages in an acid-base titration. An analysis of the data showed that participants had integrated the three representations of an acid-base titration to varying degrees. While some participants showed complete understanding of acids, bases, titrations, and solution chemistry, other participants showed several alternative conceptions concerning strong acid and base dissociation, the formation of titration products, and the dissociation of soluble salts. Before instruction, participants' definitions of acid, base, and pH were brief and consisted of descriptive terms. After instruction, the definitions were more scientific and reflected the definitions presented during classroom instruction.

  20. Promoting return of function in multiple sclerosis: An integrated approach

    PubMed Central

    Gacias, Mar; Casaccia, Patrizia

    2013-01-01

    Multiple sclerosis is a disease characterized by inflammatory demyelination, axonal degeneration and progressive brain atrophy. Most of the currently available disease modifying agents proved to be very effective in managing the relapse rate, however progressive neuronal damage continues to occur and leads to progressive accumulation of irreversible disability. For this reason, any therapeutic strategy aimed at restoration of function must take into account not only immunomodulation, but also axonal protection and new myelin formation. We further highlight the importance of an holistic approach, which considers the variability of therapeutic responsiveness as the result of the interplay between genetic differences and the epigenome, which is in turn affected by gender, age and differences in life style including diet, exercise, smoking and social interaction. PMID:24363985

  1. Promoting return of function in multiple sclerosis: An integrated approach.

    PubMed

    Gacias, Mar; Casaccia, Patrizia

    2013-10-01

    Multiple sclerosis is a disease characterized by inflammatory demyelination, axonal degeneration and progressive brain atrophy. Most of the currently available disease modifying agents proved to be very effective in managing the relapse rate, however progressive neuronal damage continues to occur and leads to progressive accumulation of irreversible disability. For this reason, any therapeutic strategy aimed at restoration of function must take into account not only immunomodulation, but also axonal protection and new myelin formation. We further highlight the importance of an holistic approach, which considers the variability of therapeutic responsiveness as the result of the interplay between genetic differences and the epigenome, which is in turn affected by gender, age and differences in life style including diet, exercise, smoking and social interaction. PMID:24363985

  2. Exercise in multiple sclerosis -- an integral component of disease management

    PubMed Central

    2012-01-01

    Multiple sclerosis (MS) is the most common chronic inflammatory disorder of the central nervous system (CNS) in young adults. The disease causes a wide range of symptoms depending on the localization and characteristics of the CNS pathology. In addition to drug-based immunomodulatory treatment, both drug-based and non-drug approaches are established as complementary strategies to alleviate existing symptoms and to prevent secondary diseases. In particular, physical therapy like exercise and physiotherapy can be customized to the individual patient's needs and has the potential to improve the individual outcome. However, high quality systematic data on physical therapy in MS are rare. This article summarizes the current knowledge on the influence of physical activity and exercise on disease-related symptoms and physical restrictions in MS patients. Other treatment strategies such as drug treatments or cognitive training were deliberately excluded for the purposes of this article. PMID:22738091

  3. MULTIPLE FAST MOLECULAR OUTFLOWS IN THE PRE-PLANETARY NEBULA CRL 618

    SciTech Connect

    Lee, Chin-Fei; Huang, Po-Sheng; Sahai, Raghvendra; Sánchez Contreras, Carmen; Tay, Jeremy Jian Hao

    2013-11-01

    CRL 618 is a well-studied pre-planetary nebula. It has multiple highly collimated optical lobes, fast molecular outflows along the optical lobes, and an extended molecular envelope that consists of a dense torus in the equator and a tenuous round halo. Here we present our observations of this source in CO J = 3-2 and HCN J = 4-3 obtained with the Submillimeter Array at up to ∼0.''3 resolutions. We spatially resolve the fast molecular outflow region previously detected in CO near the central star and find it to be composed of multiple outflows that have similar dynamical ages and are oriented along the different optical lobes. We also detect fast molecular outflows further away from the central star near the tips of the extended optical lobes and a pair of equatorial outflows inside the dense torus. We find that two episodes of bullet ejections in different directions are needed, one producing the fast molecular outflows near the central star and one producing the fast molecular outflows near the tips of the extended optical lobes. One possibility to launch these bullets is a magneto-rotational explosion of the stellar envelope.

  4. Research on model of combining multiple neural networks by fuzzy integral-MNNF

    NASA Astrophysics Data System (ADS)

    Fu, Yue; Chai, Bianfang

    2013-03-01

    The method of multiple neural network Fusion using Fuzzy Integral (MNNF) presented by this paper is to improve the detection performance of data mining-based intrusion detection system. The basic idea of MNNF is to mine on distinct feature training dataset by neural networks separately, and detect TCP/IP data by different neural networks, and then nonlinearly combine the results from multiple neural networks by fuzzy integral. The experiment results show that this technique is superior to single neural networks for intrusion detection in terms of classification accuracy. Compared with other combination methods such as Majority, Average, Borda count, fuzzy integral is better than one of them.

  5. Integrating regional conservation priorities for multiple objectives into national policy.

    PubMed

    Beger, Maria; McGowan, Jennifer; Treml, Eric A; Green, Alison L; White, Alan T; Wolff, Nicholas H; Klein, Carissa J; Mumby, Peter J; Possingham, Hugh P

    2015-01-01

    Multinational conservation initiatives that prioritize investment across a region invariably navigate trade-offs among multiple objectives. It seems logical to focus where several objectives can be achieved efficiently, but such multi-objective hotspots may be ecologically inappropriate, or politically inequitable. Here we devise a framework to facilitate a regionally cohesive set of marine-protected areas driven by national preferences and supported by quantitative conservation prioritization analyses, and illustrate it using the Coral Triangle Initiative. We identify areas important for achieving six objectives to address ecosystem representation, threatened fauna, connectivity and climate change. We expose trade-offs between areas that contribute substantially to several objectives and those meeting one or two objectives extremely well. Hence there are two strategies to guide countries choosing to implement regional goals nationally: multi-objective hotspots and complementary sets of single-objective priorities. This novel framework is applicable to any multilateral or global initiative seeking to apply quantitative information in decision making. PMID:26364769

  6. Integrating regional conservation priorities for multiple objectives into national policy

    PubMed Central

    Beger, Maria; McGowan, Jennifer; Treml, Eric A.; Green, Alison L.; White, Alan T.; Wolff, Nicholas H.; Klein, Carissa J.; Mumby, Peter J.; Possingham, Hugh P.

    2015-01-01

    Multinational conservation initiatives that prioritize investment across a region invariably navigate trade-offs among multiple objectives. It seems logical to focus where several objectives can be achieved efficiently, but such multi-objective hotspots may be ecologically inappropriate, or politically inequitable. Here we devise a framework to facilitate a regionally cohesive set of marine-protected areas driven by national preferences and supported by quantitative conservation prioritization analyses, and illustrate it using the Coral Triangle Initiative. We identify areas important for achieving six objectives to address ecosystem representation, threatened fauna, connectivity and climate change. We expose trade-offs between areas that contribute substantially to several objectives and those meeting one or two objectives extremely well. Hence there are two strategies to guide countries choosing to implement regional goals nationally: multi-objective hotspots and complementary sets of single-objective priorities. This novel framework is applicable to any multilateral or global initiative seeking to apply quantitative information in decision making. PMID:26364769

  7. Behavioral, molecular and integrative mechanisms of amphibian osmoregulation.

    PubMed

    Hillyard, S D

    1999-06-01

    Amphibian water balance has been studied at many levels of biological order. Terrestrial species must react to environmental cues that relate to water availability while some arboreal species have cutaneous skin secretions that can reduce evaporative water loss. The Indian tree frog. Polypedates maculatus, uses cutaneous secretions and wiping behavior to lower evaporation but also relies on moist microclimates to endure prolonged survival away from water. The related species, P. leucomystax, inhabits wetter forest habitats. Preliminary studies with this species are unable to demonstrate the expression of wiping behavior, indicating that arid habitats may be a powerful selective force for this behavior. Laboratory experiments on rehydrating toads in the genus Bufo indicate that animals are able to detect changes in barometric pressure and humidity that might result in the availability of water under field situations. Experiments with Bufonid species and with spadefoot toads, Scaphiopus couchi, show that the peptide hormone, angiotensin II, stimulates cutaneous drinking in a similar manner seen for oral drinking by other vertebrate classes. Amphibian tissues have long been used as a model for the study of basic physiological principles of epithelial ion and water transport. Recent progress with tissue cultures has provided information on the molecular structure of ion and water channels that can be applied to obtain a better understanding, at the molecular level, of ion and water balance strategies used by the wide variety of amphibian species. Terrestrial amphibians are more tolerant of dehydration than are other vertebrates and are able to store dilute urine in their urinary bladder. Toads appear to be able to detect the presence of water in their bladders in addition to the availability of water in their environment. Dehydrated toads are able to rehydrate very rapidly by the coordination of behavioral and physiological mechanisms to enhance cutaneous water

  8. Integration of molecular and enzymatic catalysts on graphene for biomimetic generation of antithrombotic species

    NASA Astrophysics Data System (ADS)

    Xue, Teng; Peng, Bo; Xue, Min; Zhong, Xing; Chiu, Chin-Yi; Yang, Si; Qu, Yongquan; Ruan, Lingyan; Jiang, Shan; Dubin, Sergey; Kaner, Richard B.; Zink, Jeffrey I.; Meyerhoff, Mark E.; Duan, Xiangfeng; Huang, Yu

    2014-02-01

    The integration of multiple synergistic catalytic systems can enable the creation of biocompatible enzymatic mimics for cascading reactions under physiologically relevant conditions. Here we report the design of a graphene-haemin-glucose oxidase conjugate as a tandem catalyst, in which graphene functions as a unique support to integrate molecular catalyst haemin and enzymatic catalyst glucose oxidase for biomimetic generation of antithrombotic species. Monomeric haemin can be conjugated with graphene through π-π interactions to function as an effective catalyst for the oxidation of endogenous L-arginine by hydrogen peroxide. Furthermore, glucose oxidase can be covalently linked onto graphene for local generation of hydrogen peroxide through the oxidation of blood glucose. Thus, the integrated graphene-haemin-glucose oxidase catalysts can readily enable the continuous generation of nitroxyl, an antithrombotic species, from physiologically abundant glucose and L-arginine. Finally, we demonstrate that the conjugates can be embedded within polyurethane to create a long-lasting antithrombotic coating for blood-contacting biomedical devices.

  9. Integrating different data types by regularized unsupervised multiple kernel learning with application to cancer subtype discovery

    PubMed Central

    Speicher, Nora K.; Pfeifer, Nico

    2015-01-01

    Motivation: Despite ongoing cancer research, available therapies are still limited in quantity and effectiveness, and making treatment decisions for individual patients remains a hard problem. Established subtypes, which help guide these decisions, are mainly based on individual data types. However, the analysis of multidimensional patient data involving the measurements of various molecular features could reveal intrinsic characteristics of the tumor. Large-scale projects accumulate this kind of data for various cancer types, but we still lack the computational methods to reliably integrate this information in a meaningful manner. Therefore, we apply and extend current multiple kernel learning for dimensionality reduction approaches. On the one hand, we add a regularization term to avoid overfitting during the optimization procedure, and on the other hand, we show that one can even use several kernels per data type and thereby alleviate the user from having to choose the best kernel functions and kernel parameters for each data type beforehand. Results: We have identified biologically meaningful subgroups for five different cancer types. Survival analysis has revealed significant differences between the survival times of the identified subtypes, with P values comparable or even better than state-of-the-art methods. Moreover, our resulting subtypes reflect combined patterns from the different data sources, and we demonstrate that input kernel matrices with only little information have less impact on the integrated kernel matrix. Our subtypes show different responses to specific therapies, which could eventually assist in treatment decision making. Availability and implementation: An executable is available upon request. Contact: nora@mpi-inf.mpg.de or npfeifer@mpi-inf.mpg.de PMID:26072491

  10. Integration over Multiple Timescales in Primary Auditory Cortex

    PubMed Central

    Shamma, Shihab A.

    2013-01-01

    Speech and other natural vocalizations are characterized by large modulations in their sound envelope. The timing of these modulations contains critical information for discrimination of important features, such as phonemes. We studied how depression of synaptic inputs, a mechanism frequently reported in cortex, can contribute to the encoding of envelope dynamics. Using a nonlinear stimulus-response model that accounted for synaptic depression, we predicted responses of neurons in ferret primary auditory cortex (A1) to stimuli with natural temporal modulations. The depression model consistently performed better than linear and second-order models previously used to characterize A1 neurons, and it produced more biologically plausible fits. To test how synaptic depression can contribute to temporal stimulus integration, we used nonparametric maximum a posteriori decoding to compare the ability of neurons showing and not showing depression to reconstruct the stimulus envelope. Neurons showing evidence for depression reconstructed stimuli over a longer range of latencies. These findings suggest that variation in depression across the cortical population supports a rich code for representing the temporal dynamics of natural sounds. PMID:24305812

  11. Integrating multiple scientific computing needs via a Private Cloud infrastructure

    NASA Astrophysics Data System (ADS)

    Bagnasco, S.; Berzano, D.; Brunetti, R.; Lusso, S.; Vallero, S.

    2014-06-01

    In a typical scientific computing centre, diverse applications coexist and share a single physical infrastructure. An underlying Private Cloud facility eases the management and maintenance of heterogeneous use cases such as multipurpose or application-specific batch farms, Grid sites catering to different communities, parallel interactive data analysis facilities and others. It allows to dynamically and efficiently allocate resources to any application and to tailor the virtual machines according to the applications' requirements. Furthermore, the maintenance of large deployments of complex and rapidly evolving middleware and application software is eased by the use of virtual images and contextualization techniques; for example, rolling updates can be performed easily and minimizing the downtime. In this contribution we describe the Private Cloud infrastructure at the INFN-Torino Computer Centre, that hosts a full-fledged WLCG Tier-2 site and a dynamically expandable PROOF-based Interactive Analysis Facility for the ALICE experiment at the CERN LHC and several smaller scientific computing applications. The Private Cloud building blocks include the OpenNebula software stack, the GlusterFS filesystem (used in two different configurations for worker- and service-class hypervisors) and the OpenWRT Linux distribution (used for network virtualization). A future integration into a federated higher-level infrastructure is made possible by exposing commonly used APIs like EC2 and by using mainstream contextualization tools like CloudInit.

  12. Integrating the tools for an individualized prognosis in multiple sclerosis.

    PubMed

    Fernández, O

    2013-08-15

    Clinicians treating multiple sclerosis (MS) patients need biomarkers in order to predict an individualized prognosis for every patient, that is, characteristics that can be measured in an objective manner, and that give information over normal or pathological processes, or about the response to a given therapeutic intervention. Pharmacogenetics/Genomics in the fields of MS by now can be considered a promise. In the meanwhile, clinicians should use the information provided by the many clinical epidemiological studies performed by now, telling us that there are some clinical markers of good prognosis (female sex, young age of onset, optic neuritis or isolated sensory symptoms at debut, long interval between initial and second relapse, no accumulation of disability after five years of disease evolution, normal or near normal magnetic resonance imaging (MRI) at onset). Some markers in biological samples are considered as potential prognostic markers like IgM and neurofilaments in CSF or antimyelin and chitinase 3-like 1 in blood (plasma/sera). Baseline MRI lesion number, lesion load and location have been closely associated with a worse evolution, as well as MRI measures related to axonal damage (black holes in T1, brain atrophy, grey matter atrophy (GMA) and white matter atrophy (WMA), magnetization transfer measures and intracortical lesions). Functional measures (OCT, evoked potentials) have a potential role in measuring neurodegeneration in MS and could be very useful tools for prognosis. Several mathematical approaches to estimate the risk of short term use early clinical and paraclinical biomarkers to predict the evolution of the disease. PMID:23692966

  13. Molecular basis of cell integrity and morphogenesis in Saccharomyces cerevisiae.

    PubMed Central

    Cid, V J; Durán, A; del Rey, F; Snyder, M P; Nombela, C; Sánchez, M

    1995-01-01

    In fungi and many other organisms, a thick outer cell wall is responsible for determining the shape of the cell and for maintaining its integrity. The budding yeast Saccharomyces cerevisiae has been a useful model organism for the study of cell wall synthesis, and over the past few decades, many aspects of the composition, structure, and enzymology of the cell wall have been elucidated. The cell wall of budding yeasts is a complex and dynamic structure; its arrangement alters as the cell grows, and its composition changes in response to different environmental conditions and at different times during the yeast life cycle. In the past few years, we have witnessed a profilic genetic and molecular characterization of some key aspects of cell wall polymer synthesis and hydrolysis in the budding yeast. Furthermore, this organism has been the target of numerous recent studies on the topic of morphogenesis, which have had an enormous impact on our understanding of the intracellular events that participate in directed cell wall synthesis. A number of components that direct polarized secretion, including those involved in assembly and organization of the actin cytoskeleton, secretory pathways, and a series of novel signal transduction systems and regulatory components have been identified. Analysis of these different components has suggested pathways by which polarized secretion is directed and controlled. Our aim is to offer an overall view of the current understanding of cell wall dynamics and of the complex network that controls polarized growth at particular stages of the budding yeast cell cycle and life cycle. PMID:7565410

  14. Integration of multiple research disciplines on the International Space Station

    NASA Technical Reports Server (NTRS)

    Penley, N. J.; Uri, J.; Sivils, T.; Bartoe, J. D.

    2000-01-01

    The International Space Station will provide an extremely high-quality, long-duration microgravity environment for the conduct of research. In addition, the ISS offers a platform for performing observations of Earth and Space from a high-inclination orbit, outside of the Earth's atmosphere. This unique environment and observational capability offers the opportunity for advancement in a diverse set of research fields. Many of these disciplines do not relate to one another, and present widely differing approaches to study, as well as different resource and operational requirements. Significant challenges exist to ensure the highest quality research return for each investigation. Requirements from different investigations must be identified, clarified, integrated and communicated to ISS personnel in a consistent manner. Resources such as power, crew time, etc. must be apportioned to allow the conduct of each investigation. Decisions affecting research must be made at the strategic level as well as at a very detailed execution level. The timing of the decisions can range from years before an investigation to real-time operations. The international nature of the Space Station program adds to the complexity. Each participating country must be assured that their interests are represented during the entire planning and operations process. A process for making decisions regarding research planning, operations, and real-time replanning is discussed. This process ensures adequate representation of all research investigators. It provides a means for timely decisions, and it includes a means to ensure that all ISS International Partners have their programmatic interests represented. c 2000 Published by Elsevier Science Ltd. All rights reserved.

  15. Integrating stakeholder values with multiple attributes to quantify watershed performance

    NASA Astrophysics Data System (ADS)

    Shriver, Deborah M.; Randhir, Timothy O.

    2006-08-01

    Integrating stakeholder values into the process of quantifying impairment of ecosystem functions is an important aspect of watershed assessment and planning. This study develops a classification and prioritization model to assess potential impairment in watersheds. A systematic evaluation of a broad set of abiotic, biotic, and human indicators of watershed structure and function was used to identify the level of degradation at a subbasin scale. Agencies and communities can use the method to effectively target and allocate resources to areas of greatest restoration need. The watershed performance measure (WPM) developed in this study is composed of three major components: (1) hydrologic processes (water quantity and quality), (2) biodiversity at a species scale (core and priority habitat for rare and endangered species and species richness) and landscape scale (impacts of fragmentation), and (3) urban impacts as assessed in the built environment (effective impervious area) and population effects (densities and density of toxic waste sites). Simulation modeling using the Soil and Water Assessment Tool (SWAT), monitoring information, and spatial analysis with GIS were used to assess each criterion in developing this model. Weights for attributes of potential impairment were determined through the use of the attribute prioritization procedure with a panel of expert stakeholders. This procedure uses preselected attributes and corresponding stakeholder values and is data intensive. The model was applied to all subbasins of the Chicopee River Watershed of western Massachusetts, an area with a mixture of rural, heavily forested lands, suburban, and urbanized areas. Highly impaired subbasins in one community were identified using this methodology and evaluated for principal forms of degradation and potential restoration policies and BMPs. This attribute-based prioritization method could be used in identifying baselines, prioritization policies, and adaptive community

  16. Final Report for Integrated Multiscale Modeling of Molecular Computing Devices

    SciTech Connect

    Glotzer, Sharon C.

    2013-08-28

    In collaboration with researchers at Vanderbilt University, North Carolina State University, Princeton and Oakridge National Laboratory we developed multiscale modeling and simulation methods capable of modeling the synthesis, assembly, and operation of molecular electronics devices. Our role in this project included the development of coarse-grained molecular and mesoscale models and simulation methods capable of simulating the assembly of millions of organic conducting molecules and other molecular components into nanowires, crossbars, and other organized patterns.

  17. An Integrated Approach for Accessing Multiple Datasets through LANCE

    NASA Astrophysics Data System (ADS)

    Murphy, K. J.; Teague, M.; Conover, H.; Regner, K.; Beaumont, B.; Masuoka, E.; Vollmer, B.; Theobald, M.; Durbin, P.; Michael, K.; Boller, R. A.; Schmaltz, J. E.; Davies, D.; Horricks, K.; Ilavajhala, S.; Thompson, C. K.; Bingham, A.

    2011-12-01

    The NASA/GSFC Land Atmospheres Near-real time Capability for EOS (LANCE) provides imagery for approximately 40 data products from MODIS, AIRS, AMSR-E and OMI to support the applications community in the study of a variety of phenomena. Thirty-six of these products are available within 2.5 hours of observation at the spacecraft. The data set includes the population density data provided by the EOSDIS Socio-Economic Data and Applications Center (SEDAC). The purpose of this paper is to describe the variety of tools that have been developed by LANCE to support user access to the imagery. The long-standing Rapid Response system has been integrated into LANCE and is a major vehicle for the distribution of the imagery to end users. There are presently approximately 10,000 anonymous users per month accessing these imagery. The products are grouped into 14 applications categories such as Smoke Plumes, Pollution, Fires, Agriculture and the selection of any category will make relevant subsets of the 40 products available as possible overlays in an interactive Web Client utilizing Web Mapping Service (WMS) to support user investigations (http://lance2.modaps.eosdis.nasa.gov/wms/). For example, selecting Severe Storms will include 6 products for MODIS, OMI, AIRS, and AMSR-E plus the SEDAC population density data. The client and WMS were developed using open-source technologies such as OpenLayers and MapServer and provides a uniform, browser-based access to data products. All overlays are downloadable in PNG, JPEG, or GeoTiff form up to 200MB per request. The WMS was beta-tested with the user community and substantial performance improvements were made through the use of such techniques as tile-caching. LANCE established a partnership with Physical Oceanography Distributed Active Archive Center (PO DAAC) to develop an alternative presentation for the 40 data products known as the State of the Earth (SOTE). This provides a Google Earth-based interface to the products grouped in

  18. Integration of transcription and flux data reveals molecular paths associated with differences in oxygen-dependent phenotypes of Saccharomyces cerevisiae

    PubMed Central

    2014-01-01

    Background Saccharomyces cerevisiae is able to adapt to a wide range of external oxygen conditions. Previously, oxygen-dependent phenotypes have been studied individually at the transcriptional, metabolite, and flux level. However, the regulation of cell phenotype occurs across the different levels of cell function. Integrative analysis of data from multiple levels of cell function in the context of a network of several known biochemical interaction types could enable identification of active regulatory paths not limited to a single level of cell function. Results The graph theoretical method called Enriched Molecular Path detection (EMPath) was extended to enable integrative utilization of transcription and flux data. The utility of the method was demonstrated by detecting paths associated with phenotype differences of S. cerevisiae under three different conditions of oxygen provision: 20.9%, 2.8% and 0.5%. The detection of molecular paths was performed in an integrated genome-scale metabolic and protein-protein interaction network. Conclusions The molecular paths associated with the phenotype differences of S. cerevisiae under conditions of different oxygen provisions revealed paths of molecular interactions that could potentially mediate information transfer between processes that respond to the particular oxygen availabilities. PMID:24528924

  19. The VLA Nascent Disk and Multiplicity Survey of Perseus Protostars (VANDAM). II. Multiplicity of Protostars in the Perseus Molecular Cloud

    NASA Astrophysics Data System (ADS)

    Tobin, John J.; Looney, Leslie W.; Li, Zhi-Yun; Chandler, Claire J.; Dunham, Michael M.; Segura-Cox, Dominique; Sadavoy, Sarah I.; Melis, Carl; Harris, Robert J.; Kratter, Kaitlin; Perez, Laura

    2016-02-01

    We present a multiplicity study of all known protostars (94) in the Perseus molecular cloud from a Karl G. Jansky Very Large Array survey at Ka-band (8 mm and 1 cm) and C-band (4 and 6.6 cm). The observed sample has a bolometric luminosity range between 0.1 L⊙ and ˜33 L⊙, with a median of 0.7 L⊙. This multiplicity study is based on the Ka-band data, having a best resolution of ˜0.″065 (15 au) and separations out to ˜43″ (10,000 au) can be probed. The overall multiplicity fraction (MF) is found to be 0.40 ± 0.06 and the companion star fraction (CSF) is 0.71 ± 0.06. The MF and CSF of the Class 0 protostars are 0.57 ± 0.09 and 1.2 ± 0.2, and the MF and CSF of Class I protostars are both 0.23 ± 0.08. The distribution of companion separations appears bi-modal, with a peak at ˜75 au and another peak at ˜3000 au. Turbulent fragmentation is likely the dominant mechanism on >1000 au scales and disk fragmentation is likely to be the dominant mechanism on <200 au scales. Toward three Class 0 sources we find companions separated by <30 au. These systems have the smallest separations of currently known Class 0 protostellar binary systems. Moreover, these close systems are embedded within larger (50-400 au) structures and may be candidates for ongoing disk fragmentation.

  20. May Diet and Dietary Supplements Improve the Wellness of Multiple Sclerosis Patients? A Molecular Approach

    PubMed Central

    Riccio, Paolo; Rossano, Rocco; Liuzzi, Grazia Maria

    2010-01-01

    Multiple sclerosis is a complex and multifactorial neurological disease, and nutrition is one of the environmental factors possibly involved in its pathogenesis. At present, the role of nutrition is unclear, and MS therapy is not associated to a particular diet. MS clinical trials based on specific diets or dietary supplements are very few and in some cases controversial. To understand how diet can influence the course of MS and improve the wellness of MS patients, it is necessary to identify the dietary molecules, their targets and the molecular mechanisms involved in the control of the disease. The aim of this paper is to provide a molecular basis for the nutritional intervention in MS by evaluating at molecular level the effect of dietary molecules on the inflammatory and autoimmune processes involved in the disease. PMID:21461338

  1. Multiple-electron removal and molecular fragmentation of CO by fast F4+ impact

    NASA Astrophysics Data System (ADS)

    Ben-Itzhak, I.; Ginther, S. G.; Carnes, K. D.

    1993-04-01

    Multiple-electron removal from and molecular fragmentation of carbon monoxide molecules caused by collisions with 1-MeV/amu F4+ ions were studied using the coincidence time-of-flight technique. In these collisions, multiple-electron removal of the target molecule is a dominant process. Cross sections for the different levels of ionization of the CO molecule during the collision were determined. The relative cross sections of ionization decrease with increasing number of electrons removed in a similar way as seen in atomic targets. This behavior is in agreement with a two-step mechanism, where first the molecule is ionized by a Franck-Condon ionization and then the molecular ion dissociates. Most of the highly charged intermediate states of the molecule dissociate rapidly. Only CO+ and CO2+ molecular ions have been seen to survive long enough to be detected as molecular ions. The relative cross sections for the different breakup channels were evaluated for collisions in which the molecule broke into two charged fragments as well as for collisions where only a single charged molecular ion or fragment were produced. The average charge state of each fragment resulting from COQ+-->Ci++Oj+ breakup increases with the number of electrons removed from the molecule approximately following the relationship i¯=j¯=Q/2 as long as K-shell electrons are not removed. This does not mean that the charge-state distribution is exactly symmetric, as, in general, removing electrons from the carbon fragment is slightly more likely than removing electrons from the oxygen due to the difference in binding energy. The cross sections for molecular breakup into a charged fragment and a neutral fragment drop rapidly with an increasing number of electrons removed.

  2. Unmixing multiple adjacent fluorescent targets with multispectral excited fluorescence molecular tomography.

    PubMed

    Zhou, Yuan; Guang, Huizhi; Pu, Huangsheng; Zhang, Jiulou; Luo, Jianwen

    2016-06-20

    Fluorescence molecular tomography (FMT) can visualize biological activities at cellular and molecular levels in vivo, and has been extensively used in drug delivery and tumor detection research of small animals. The ill-posedness of the FMT inverse problem makes it difficult to reconstruct and unmix multiple adjacent fluorescent targets that have different functional features but are labeled with the same fluorochrome. A method based on independent component analysis for multispectral excited FMT was proposed in our previous study. It showed that double fluorescent targets with certain edge-to-edge distance (EED) could be unmixed by the method. In this study, the situation is promoted to unmix multiple adjacent fluorescent targets (i.e., more than two fluorescent targets and EED=0). Phantom experiments on the resolving ability of the proposed algorithm demonstrate that the algorithm performs well in unmixing multiple adjacent fluorescent targets in both lateral and axial directions. And also, we recovered the locational information of each independent fluorescent target and described the variable trends of the corresponding fluorescent targets under the excitation spectrum. This method is capable of unmixing multiple fluorescent targets with small EED but labeled with the same fluorochrome, and may be used in imaging of nonspecific probe targeting and metabolism of drugs. PMID:27409108

  3. Multispectral excitation based multiple fluorescent targets resolving in fluorescence molecular tomography

    NASA Astrophysics Data System (ADS)

    Zhou, Yuan; Guang, Huizhi; Pu, Huangsheng; Zhang, Jiulou; Bai, Jing; Luo, Jianwen

    2016-04-01

    Fluorescence molecular tomography (FMT) can visualize biological activities at cellular and molecular levels in vivo, and has been extensively used in drug delivery and tumor detection research of small animals. The ill-posedness of the FMT inverse problem makes it difficult to reconstruct and resolve multiple adjacent fluorescent targets that have different functional features but are labeled with the same fluorochrome. An algorithm based on independent component analysis (ICA) for multispectral excited FMT is proposed to resolve multiple fluorescent targets in this study. Fluorescent targets are excited by multispectral excitation, and the three-dimensional distribution of fluorescent yields under the excitation spectrum is reconstructed by an iterative Tikhonov regularization algorithm. Subsequently, multiple fluorescent targets are resolved from mixed fluorescence signals by employing ICA. Simulations were performed and the results demonstrate that multiple adjacent fluorescent targets can be resolved if the number of excitation wavelengths is not smaller than that of fluorescent targets with different concentrations. The algorithm obtains both independent components that provide spatial information of different fluorescent targets and spectral courses that reflect variation trends of fluorescent yields along with the excitation spectrum. By using this method, it is possible to visualize the metabolism status of drugs in different structure organs, and quantitatively depict the variation trends of fluorescent yields of each functional organ under the excitation spectrum. This method may provide a pattern for tumor detection, drug delivery and treatment monitoring in vivo.

  4. Solution of multi-center molecular integrals of Slater-type orbitals

    NASA Technical Reports Server (NTRS)

    Tai, H.

    1989-01-01

    The troublesome multi-center molecular integrals of Slater-type orbitals (STO) in molecular physics calculations can be evaluated by using the Fourier transform and proper coupling of the two center exchange integrals. A numerical integration procedure is then readily rendered to the final expression in which the integrand consists of well known special functions of arguments containing the geometrical arrangement of the nuclear centers and the exponents of the atomic orbitals. A practical procedure was devised for the calculation of a general multi-center molecular integrals coupling arbitrary Slater-type orbitals. Symmetry relations and asymptotic conditions are discussed. Explicit expressions of three-center one-electron nuclear-attraction integrals and four-center two-electron repulsion integrals for STO of principal quantum number n=2 are listed. A few numerical results are given for the purpose of comparison.

  5. Integrated molecular and morphological biogeography of the calanoid copepod family Eucalanidae

    NASA Astrophysics Data System (ADS)

    Goetze, Erica; Ohman, Mark D.

    2010-12-01

    Species range information forms the empirical data of pelagic biogeography. Early descriptions of canonical zooplankton distributions in the Pacific Ocean were based, in part, on distributional data from the planktonic copepod family Eucalanidae. A large-scale molecular survey of this group, covering Atlantic, Pacific, and Indian Oceans (1295 individuals), increased the total diversity from 24 to 39 evolutionarily significant units (ESUs). New biogeographies are presented here for 18 lineages within 10 described species in the genera Subeucalanus, Pareucalanus, and Rhincalanus. Integration of molecular and morphological data on diversity and distribution resulted in three primary outcomes: (1) the morphological species was confirmed to be valid, and the biogeographic distribution remains largely unchanged from prior reports, (2) the species was found to contain multiple ESUs, each of which has a more restricted distribution than the parent taxon, and (3) the species was found to contain multiple ESUs, whose biogeographic distributions remain unclear. Subeucalanus subtenuis, S. mucronatus, S. subcrassus, Pareucalanus attenuatus, P. langae, and P. parki are all valid genetic and morphological species, and prior distribution records from Fleminger (1973) and Lang (1965) are confirmed to be accurate. New records in the western Indian Ocean extend the biogeographic range of S. subtenuis, S. mucronatus, S. subcrassus, and P. langae. Subeucalanus pileatus, P. sewelli, and R. rostrifrons, all species with Indo-Pacific or circumglobal distributions, consist of genetically divergent, allopatric populations that subdivide the original biogeographic range. Subeucalanus crassus and Rhincalanus nasutus are species complexes containing 4-8 genetically divergent lineages, whose distributions are inadequately characterized. Although results suggest more restricted pelagic habitats for some eucalanid species, those habitats have been previously described for other zooplanktonic taxa

  6. Equilibrium fractionation of H and O isotopes in water from path integral molecular dynamics

    NASA Astrophysics Data System (ADS)

    Pinilla, Carlos; Blanchard, Marc; Balan, Etienne; Ferlat, Guillaume; Vuilleumier, Rodolphe; Mauri, Francesco

    2014-06-01

    The equilibrium fractionation factor between two phases is of importance for the understanding of many planetary and environmental processes. Although thermodynamic equilibrium can be achieved between minerals at high temperature, many natural processes involve reactions between liquids or aqueous solutions and solids. For crystals, the fractionation factor α can be theoretically determined using a statistical thermodynamic approach based on the vibrational properties of the phases. These calculations are mostly performed in the harmonic approximation, using empirical or ab-initio force fields. In the case of aperiodic and dynamic systems such as liquids or solutions, similar calculations can be done using finite-size molecular clusters or snapshots obtained from molecular dynamics (MD) runs. It is however difficult to assess the effect of these approximate models on the isotopic fractionation properties. In this work we present a systematic study of the calculation of the D/H and 18O/16O equilibrium fractionation factors in water for the liquid/vapour and ice/vapour phases using several levels of theory within the simulations. Namely, we use a thermodynamic integration approach based on Path Integral MD calculations (PIMD) and an empirical potential model of water. Compared with standard MD, PIMD takes into account quantum effects in the thermodynamic modeling of systems and the exact fractionation factor for a given potential can be obtained. We compare these exact results with those of modeling strategies usually used, which involve the mapping of the quantum system on its harmonic counterpart. The results show the importance of including configurational disorder for the estimation of isotope fractionation in liquid phases. In addition, the convergence of the fractionation factor as a function of parameters such as the size of the simulated system and multiple isotope substitution is analyzed, showing that isotope fractionation is essentially a local effect in

  7. Positional isomers of cyanostilbene: two-component molecular assembly and multiple-stimuli responsive luminescence

    NASA Astrophysics Data System (ADS)

    Fan, Guoling; Yan, Dongpeng

    2014-05-01

    An understanding of the aggregates and properties of positional isomers can not only uncover how a slight difference in molecular structure alter crystal packing and bulk solid-state properties, but also plays an important role in developing new types of molecule-based functional materials. Herein, we report a study of the molecular packing and static/dynamic luminescence properties of three cyanostilbene (CS)-based isomers (CS1, CS2, CS3) within their single- and two-component molecular solids. Changing the positions of the cyano substitutents in the CS isomers has a marked influence on their packing modes and luminescent properties. Moreover, two-component CS-based materials have been constructed, which exhibit tunable conformations and packing fashions, as well as fluorescence properties, which differ from the pristine CS solids. The CS-based two-component molecular materials show solvent-responsive luminescence due to the dynamic disassembly of the samples. Moreover, it was found that the system based on CS2 and octafluoronaphthalene shows reversible photochromic fluorescence upon alternating light illumination and grinding. Such co-assembly procedures provide a facile way to fabricate patterned luminescent film materials. Therefore, this work not only affords new insight into the relationship between isomers and luminescence from molecular and supramolecular perspectives, but provides an effective strategy to develop multiple-stimuli-responsive luminescent materials.

  8. Pervasive pleiotropy between psychiatric disorders and immune disorders revealed by integrative analysis of multiple GWAS.

    PubMed

    Wang, Qian; Yang, Can; Gelernter, Joel; Zhao, Hongyu

    2015-11-01

    Although some existing epidemiological observations and molecular experiments suggested that brain disorders in the realm of psychiatry may be influenced by immune dysregulation, the degree of genetic overlap between psychiatric disorders and immune disorders has not been well established. We investigated this issue by integrative analysis of genome-wide association studies of 18 complex human traits/diseases (five psychiatric disorders, seven immune disorders, and others) and multiple genome-wide annotation resources (central nervous system genes, immune-related expression-quantitative trait loci (eQTL) and DNase I hypertensive sites from 98 cell lines). We detected pleiotropy in 24 of the 35 psychiatric-immune disorder pairs. The strongest pleiotropy was observed for schizophrenia-rheumatoid arthritis with MHC region included in the analysis (p = 3.9 x 10(-285), and schizophrenia-Crohn's disease with MHC region excluded (p = 1.1 x 10(-36). Significant enrichment (> 1.4 fold) of immune-related eQTL was observed in four psychiatric disorders. Genomic regions responsible for pleiotropy between psychiatric disorders and immune disorders were detected. The MHC region on chromosome 6 appears to be the most important with other regions, such as cytoband 1p13.2, also playing significant roles in pleiotropy. We also found that most alleles shared between schizophrenia and Crohn's disease have the same effect direction, with similar trend found for other disorder pairs, such as bipolar-Crohn's disease. Our results offer a novel bird's-eye view of the genetic relationship and demonstrate strong evidence for pervasive pleiotropy between psychiatric disorders and immune disorders. Our findings might open new routes for prevention and treatment strategies for these disorders based on a new appreciation of the importance of immunological mechanisms in mediating risk of many psychiatric diseases. PMID:26340901

  9. Final technical report for DOE Computational Nanoscience Project: Integrated Multiscale Modeling of Molecular Computing Devices

    SciTech Connect

    Cummings, P. T.

    2010-02-08

    This document reports the outcomes of the Computational Nanoscience Project, "Integrated Multiscale Modeling of Molecular Computing Devices". It includes a list of participants and publications arising from the research supported.

  10. Numerical solution of optimal control problems using multiple-interval integral Gegenbauer pseudospectral methods

    NASA Astrophysics Data System (ADS)

    Tang, Xiaojun

    2016-04-01

    The main purpose of this work is to provide multiple-interval integral Gegenbauer pseudospectral methods for solving optimal control problems. The latest developed single-interval integral Gauss/(flipped Radau) pseudospectral methods can be viewed as special cases of the proposed methods. We present an exact and efficient approach to compute the mesh pseudospectral integration matrices for the Gegenbauer-Gauss and flipped Gegenbauer-Gauss-Radau points. Numerical results on benchmark optimal control problems confirm the ability of the proposed methods to obtain highly accurate solutions.

  11. Optimized breeding strategies for multiple trait integration: II. Process efficiency in event pyramiding and trait fixation.

    PubMed

    Peng, Ting; Sun, Xiaochun; Mumm, Rita H

    2014-01-01

    Multiple trait integration (MTI) is a multi-step process of converting an elite variety/hybrid for value-added traits (e.g. transgenic events) through backcross breeding. From a breeding standpoint, MTI involves four steps: single event introgression, event pyramiding, trait fixation, and version testing. This study explores the feasibility of marker-aided backcross conversion of a target maize hybrid for 15 transgenic events in the light of the overall goal of MTI of recovering equivalent performance in the finished hybrid conversion along with reliable expression of the value-added traits. Using the results to optimize single event introgression (Peng et al. Optimized breeding strategies for multiple trait integration: I. Minimizing linkage drag in single event introgression. Mol Breed, 2013) which produced single event conversions of recurrent parents (RPs) with ≤8 cM of residual non-recurrent parent (NRP) germplasm with ~1 cM of NRP germplasm in the 20 cM regions flanking the event, this study focused on optimizing process efficiency in the second and third steps in MTI: event pyramiding and trait fixation. Using computer simulation and probability theory, we aimed to (1) fit an optimal breeding strategy for pyramiding of eight events into the female RP and seven in the male RP, and (2) identify optimal breeding strategies for trait fixation to create a 'finished' conversion of each RP homozygous for all events. In addition, next-generation seed needs were taken into account for a practical approach to process efficiency. Building on work by Ishii and Yonezawa (Optimization of the marker-based procedures for pyramiding genes from multiple donor lines: I. Schedule of crossing between the donor lines. Crop Sci 47:537-546, 2007a), a symmetric crossing schedule for event pyramiding was devised for stacking eight (seven) events in a given RP. Options for trait fixation breeding strategies considered selfing and doubled haploid approaches to achieve homozygosity

  12. The Effect of Sensory Integration Treatment on Children with Multiple Disabilities.

    ERIC Educational Resources Information Center

    Din, Feng S.; Lodato, Donna M.

    Six children with multiple disabilities (ages 5 to 8) participated in this evaluation of the effect of sensory integration treatment on sensorimotor function and academic learning. The children had cognitive abilities ranging from sub-average to significantly sub-average, three were non-ambulatory, one had severe behavioral problems, and each…

  13. Multiplicity and Self-Identity: Trauma and Integration in Shirley Mason's Art

    ERIC Educational Resources Information Center

    Thompson, Geoffrey

    2011-01-01

    This viewpoint appeared in its original form as the catalogue essay that accompanied the exhibition "Multiplicity and Self-Identity: Trauma and Integration in Shirley Mason's Art," curated by the author for Gallery 2110, Sacramento, CA, and the 2010 Annual Conference of the American Art Therapy Association. The exhibition featured 17 artworks by…

  14. Limited-projection-angle hybrid fluorescence molecular tomography of multiple molecules.

    PubMed

    Radrich, Karin; Mohajerani, Pouyan; Bussemer, Johanna; Schwaiger, Markus; Beer, Ambros J; Ntziachristos, Vasilis

    2014-04-01

    An advantage of fluorescence methods over other imaging modalities is the ability to concurrently resolve multiple moieties using fluorochromes emitting at different spectral regions. Simultaneous imaging of spectrally separated agents is helpful in interrogating multiple functions or establishing internal controls for accurate measurements. Herein, we investigated multimoiety imaging in the context of a limited-projection-angle hybrid fluorescence molecular tomography (FMT), and x-ray computed tomography implementation and the further registration with positron emission tomography (PET) data. Multichannel FMT systems may image fluorescent probes of varying distribution patterns. Therefore, it is possible that different channels may require different use of priors and regularization parameters. We examined the performance of automatically estimating regularization factors implementing priors, using data-driven regularization specific for limited-projection-angle schemes. We were particularly interested in identifying the implementation variations between hybrid-FMT channels due to probe distribution variation. For this reason, initial validation of the data-driven algorithm on a phantom was followed by imaging different agent distributions in animals, assuming superficial and deep seated activity. We further demonstrate the benefits of combining hybrid FMT with PET to gain multiple readings on the molecular composition of disease. PMID:24770661

  15. Diversification of Neoaves: integration of molecular sequence data and fossils

    PubMed Central

    Ericson, Per G.P; Anderson, Cajsa L; Britton, Tom; Elzanowski, Andrzej; Johansson, Ulf S; Källersjö, Mari; Ohlson, Jan I; Parsons, Thomas J; Zuccon, Dario; Mayr, Gerald

    2006-01-01

    Patterns of diversification and timing of evolution within Neoaves, which includes almost 95% of all bird species, are virtually unknown. On the other hand, molecular data consistently indicate a Cretaceous origin of many neoavian lineages and the fossil record seems to support an Early Tertiary diversification. Here, we present the first well-resolved molecular phylogeny for Neoaves, together with divergence time estimates calibrated with a large number of stratigraphically and phylogenetically well-documented fossils. Our study defines several well-supported clades within Neoaves. The calibration results suggest that Neoaves, after an initial split from Galloanseres in Mid-Cretaceous, diversified around or soon after the K/T boundary. Our results thus do not contradict palaeontological data and show that there is no solid molecular evidence for an extensive pre-Tertiary radiation of Neoaves. PMID:17148284

  16. Membrane curvature in cell biology: An integration of molecular mechanisms.

    PubMed

    Jarsch, Iris K; Daste, Frederic; Gallop, Jennifer L

    2016-08-15

    Curving biological membranes establishes the complex architecture of the cell and mediates membrane traffic to control flux through subcellular compartments. Common molecular mechanisms for bending membranes are evident in different cell biological contexts across eukaryotic phyla. These mechanisms can be intrinsic to the membrane bilayer (either the lipid or protein components) or can be brought about by extrinsic factors, including the cytoskeleton. Here, we review examples of membrane curvature generation in animals, fungi, and plants. We showcase the molecular mechanisms involved and how they collaborate and go on to highlight contexts of curvature that are exciting areas of future research. Lessons from how membranes are bent in yeast and mammals give hints as to the molecular mechanisms we expect to see used by plants and protists. PMID:27528656

  17. Multiple time step molecular dynamics in the optimized isokinetic ensemble steered with the molecular theory of solvation: Accelerating with advanced extrapolation of effective solvation forces

    SciTech Connect

    Omelyan, Igor E-mail: omelyan@icmp.lviv.ua; Kovalenko, Andriy

    2013-12-28

    We develop efficient handling of solvation forces in the multiscale method of multiple time step molecular dynamics (MTS-MD) of a biomolecule steered by the solvation free energy (effective solvation forces) obtained from the 3D-RISM-KH molecular theory of solvation (three-dimensional reference interaction site model complemented with the Kovalenko-Hirata closure approximation). To reduce the computational expenses, we calculate the effective solvation forces acting on the biomolecule by using advanced solvation force extrapolation (ASFE) at inner time steps while converging the 3D-RISM-KH integral equations only at large outer time steps. The idea of ASFE consists in developing a discrete non-Eckart rotational transformation of atomic coordinates that minimizes the distances between the atomic positions of the biomolecule at different time moments. The effective solvation forces for the biomolecule in a current conformation at an inner time step are then extrapolated in the transformed subspace of those at outer time steps by using a modified least square fit approach applied to a relatively small number of the best force-coordinate pairs. The latter are selected from an extended set collecting the effective solvation forces obtained from 3D-RISM-KH at outer time steps over a broad time interval. The MTS-MD integration with effective solvation forces obtained by converging 3D-RISM-KH at outer time steps and applying ASFE at inner time steps is stabilized by employing the optimized isokinetic Nosé-Hoover chain (OIN) ensemble. Compared to the previous extrapolation schemes used in combination with the Langevin thermostat, the ASFE approach substantially improves the accuracy of evaluation of effective solvation forces and in combination with the OIN thermostat enables a dramatic increase of outer time steps. We demonstrate on a fully flexible model of alanine dipeptide in aqueous solution that the MTS-MD/OIN/ASFE/3D-RISM-KH multiscale method of molecular dynamics

  18. Integrating Multiple Evidence Sources to Predict Adverse Drug Reactions Based on a Systems Pharmacology Model

    PubMed Central

    Cao, D-S; Xiao, N; Li, Y-J; Zeng, W-B; Liang, Y-Z; Lu, A-P; Xu, Q-S; Chen, AF

    2015-01-01

    Identifying potential adverse drug reactions (ADRs) is critically important for drug discovery and public health. Here we developed a multiple evidence fusion (MEF) method for the large-scale prediction of drug ADRs that can handle both approved drugs and novel molecules. MEF is based on the similarity reference by collaborative filtering, and integrates multiple similarity measures from various data types, taking advantage of the complementarity in the data. We used MEF to integrate drug-related and ADR-related data from multiple levels, including the network structural data formed by known drug–ADR relationships for predicting likely unknown ADRs. On cross-validation, it obtains high sensitivity and specificity, substantially outperforming existing methods that utilize single or a few data types. We validated our prediction by their overlap with drug–ADR associations that are known in databases. The proposed computational method could be used for complementary hypothesis generation and rapid analysis of potential drug–ADR interactions. PMID:26451329

  19. Integration of Mitochondrial Targeting for Molecular Cancer Therapeutics

    PubMed Central

    Marchetti, Philippe; Guerreschi, Pierre; Mortier, Laurent; Kluza, Jerome

    2015-01-01

    Mitochondrial metabolism greatly influences cancer cell survival, invasion, metastasis, and resistance to many anticancer drugs. Furthermore, molecular-targeted therapies (e.g., oncogenic kinase inhibitors) create a dependence of surviving cells on mitochondrial metabolism. For these reasons, inhibition of mitochondrial metabolism represents promising therapeutic pathways in cancer. This review provides an overview of mitochondrial metabolism in cancer and discusses the limitations of mitochondrial inhibition for cancer treatment. Finally, we present preclinical evidence that mitochondrial inhibition could be associated with oncogenic “drivers” inhibitors, which may lead to innovative drug combinations for improving the efficacy of molecular-targeted therapy. PMID:26713093

  20. Network integration and graph analysis in mammalian molecular systems biology

    PubMed Central

    Ma'ayan, A.

    2009-01-01

    Abstraction of intracellular biomolecular interactions into networks is useful for data integration and graph analysis. Network analysis tools facilitate predictions of novel functions for proteins, prediction of functional interactions and identification of intracellular modules. These efforts are linked with drug and phenotype data to accelerate drug-target and biomarker discovery. This review highlights the currently available varieties of mammalian biomolecular networks, and surveys methods and tools to construct, compare, integrate, visualise and analyse such networks. PMID:19045817

  1. Integrated Multiscale Modeling of Molecular Computing Devices. Final Report

    SciTech Connect

    Tim Schulze

    2012-11-01

    The general theme of this research has been to expand the capabilities of a simulation technique, Kinetic Monte Carlo (KMC) and apply it to study self-assembled nano-structures on epitaxial thin films. KMC simulates thin film growth and evolution by replacing the detailed dynamics of the system's evolution, which might otherwise be studied using molecular dynamics, with an appropriate stochastic process.

  2. An update on molecular biology and drug resistance mechanisms of multiple myeloma.

    PubMed

    Mutlu, Pelin; Kiraz, Yağmur; Gündüz, Ufuk; Baran, Yusuf

    2015-12-01

    Multiple myeloma (MM), a neoplasm of plasma cells, is the second most common hematological malignancy. Incidance rates increase after age 40. MM is most commonly seen in men and African-American population. There are several factors to this, such as obesity, environmental factors, family history, genetic factors and monoclonal gammopathies of undetermined significance (MGUS) that have been implicated as potentially etiologic. Development of MM involves a series of complex molecular events, including chromosomal abnormalities, oncogene activation and growth factor dysregulation. Chemotherapy is the most commonly used treatment strategy in MM. However, MM is a difficult disease to treat because of its marked resistance to chemotherapy. MM has been shown to be commonly multidrug resistance (MDR)-negative at diagnosis and associated with a high incidence of MDR expression at relapse. This review deals with the molecular aspects of MM, drug resistance mechanisms during treatment and also possible new applications for overcoming drug resistance. PMID:26235594

  3. Multiple exciton generation in quantum dots versus singlet fission in molecular chromophores for solar photon conversion.

    PubMed

    Beard, Matthew C; Johnson, Justin C; Luther, Joseph M; Nozik, Arthur J

    2015-06-28

    Both multiple exciton generation (MEG) in semiconductor nanocrystals and singlet fission (SF) in molecular chromophores have the potential to greatly increase the power conversion efficiency of solar cells for the production of solar electricity (photovoltaics) and solar fuels (artificial photosynthesis) when used in solar photoconverters. MEG creates two or more excitons per absorbed photon, and SF produces two triplet states from a single singlet state. In both cases, multiple charge carriers from a single absorbed photon can be extracted from the cell and used to create higher power conversion efficiencies for a photovoltaic cell or a cell that produces solar fuels, like hydrogen from water splitting or reduced carbon fuels from carbon dioxide and water (analogous to biological photosynthesis). The similarities and differences in the mechanisms and photoconversion cell architectures between MEG and SF are discussed. PMID:25987579

  4. Multiple rescattering processes in high-order harmonic generation from molecular system.

    PubMed

    Zhang, Cai-Ping; Xia, Chang-Long; Jia, Xiang-Fu; Miao, Xiang-Yang

    2016-09-01

    The molecular multiple rescattering processes have been theoretically investigated via solving the time-dependent Schrödinger equation. Not only has the physical model been established, but also the related rescatterings originating from recombination with parent nucleus and with neighboring nucleus have been distinguished. Moreover, it has shown that the rescatterings originating from recombination with parent nucleus are similar with those atomic rescatterings, while those rescatterings from recombination with neighboring nucleus both before and after reversing the direction of the laser field are more sensitive to the internuclear distance. With time-frequency distribution and classical electron dynamics, the underlying mechanisms are revealed. PMID:27607636

  5. Fluorescence molecular tomography on animal model by means of multiple views structured light illumination

    NASA Astrophysics Data System (ADS)

    Ducros, N.; Bassi, A.; Valentini, G.; Canti, G.; Arridge, S.; D'Andrea, C.

    2013-03-01

    Fluorescence molecular tomography (FMT) is quite demanding in terms of acquisition/computational times due to the huge amount of data. Different research groups have proposed compression approaches regarding both illumination (wide field structured light instead of raster point scanning) and detection (compression of the acquired images). The authors have previously proposed a fast FMT reconstruction method based on the combination of a multiple-view approach with a full compression scheme. This method had been successfully tested on a cylindrical phantom and is being generalized in this paper to samples of arbitrary shape. The devised procedure and algorithms have been tested on an ex-vivo mouse.

  6. Hollow fiber integrated microfluidic platforms for in vitro Co-culture of multiple cell types.

    PubMed

    Huang, Jen-Huang; Harris, Jennifer F; Nath, Pulak; Iyer, Rashi

    2016-10-01

    This study demonstrates a rapid prototyping approach for fabricating and integrating porous hollow fibers (HFs) into microfluidic device. Integration of HF can enhance mass transfer and recapitulate tubular shapes for tissue-engineered environments. We demonstrate the integration of single or multiple HFs, which can give the users the flexibility to control the total surface area for tissue development. We also present three microfluidic designs to enable different co-culture conditions such as the ability to co-culture multiple cell types simultaneously on a flat and tubular surface, or inside the lumen of multiple HFs. Additionally, we introduce a pressurized cell seeding process that can allow the cells to uniformly adhere on the inner surface of HFs without losing their viabilities. Co-cultures of lung epithelial cells and microvascular endothelial cells were demonstrated on the different platforms for at least five days. Overall, these platforms provide new opportunities for co-culturing of multiple cell types in a single device to reconstruct native tissue micro-environment for biomedical and tissue engineering research. PMID:27613401

  7. Multicenter molecular integrals for Slater orbitals of higher principal quantum numbers

    NASA Technical Reports Server (NTRS)

    Tai, H.

    1989-01-01

    As was shown earlier by Tai (1979), by using the Fourier-transform technique and properly coupling a pair of two-center exchange integrals, the multicenter molecular integrals can be cast into a simple expression upon which numerical procedures can be directly applied. In this paper, the procedure of Tai is extended to integrals involving orbitals with arbitrarily higher principal quantum number. The derivation is outlined, and the explicit expressions are presented for a three-center nuclear attraction integral and a four-center two-electron Coulomb repulsion integral of arbitrary higher states.

  8. Intermolecular transfer integrals for organic molecular materials: can basis set convergence be achieved?

    NASA Astrophysics Data System (ADS)

    Huang, Jingsong; Kertesz, Miklos

    2004-05-01

    Intermolecular transfer integrals, and associated band-structures of organic molecular materials can be calculated through a dimer approach. Extensive numerical studies are performed on an ethylene π-dimer to investigate the basis sets dependence of transfer integrals. Convergence of calculated transfer integrals is achieved with respect to both Gaussian and plane-wave basis sets, provided the same level of theory is used. Effects of diffuse and polarization Gaussian functions on transfer integrals are identified. Comparison of experimental and theoretical values of transfer integrals of the TTF-TCNQ charge transfer salt is also presented.

  9. Aerobic Fitness is Associated with Gray Matter Volume and White Matter Integrity in Multiple Sclerosis

    PubMed Central

    Prakash, Ruchika Shaurya; Snook, Erin M.; Motl, Robert W.; Kramer, Arthur F.

    2009-01-01

    Alterations in gray and white matter have been well documented in individuals with multiple sclerosis. Severity and extent of such brain tissue damage have been associated with cognitive impairment, disease duration and neurological disability, making quantitative indices of tissue damage important markers of disease progression. In this study, we investigated the association between cardiorespiratory fitness and measures of gray matter atrophy and white matter integrity. Employing a voxel-based approach to analyses of gray matter and white matter, we specifically examined whether higher levels of fitness in multiple sclerosis participants were associated with preserved gray matter volume and integrity of white matter. We found a positive association between cardiorespiratory fitness and regional gray matter volumes and higher focal fractional anisotropy values. Statistical mapping revealed that higher levels of fitness were associated with greater gray matter volume in the midline cortical structures including the medial frontal gyrus, anterior cingulate cortex and the precuneus. Further, we also found increasing levels of fitness were associated with higher fractional anisotropy in the left thalamic radiation and right anterior corona radiata. Both preserved gray matter volume and white-matter tract integrity were associated with better performance on measures of processing speed. Taken together, these results suggest that fitness exerts a prophylactic influence on the cerebral atrophy observed early on preserving neuronal integrity in multiple sclerosis, thereby reducing long-term disability. PMID:19560443

  10. Integrative and regularized principal component analysis of multiple sources of data.

    PubMed

    Liu, Binghui; Shen, Xiaotong; Pan, Wei

    2016-06-15

    Integration of data of disparate types has become increasingly important to enhancing the power for new discoveries by combining complementary strengths of multiple types of data. One application is to uncover tumor subtypes in human cancer research in which multiple types of genomic data are integrated, including gene expression, DNA copy number, and DNA methylation data. In spite of their successes, existing approaches based on joint latent variable models require stringent distributional assumptions and may suffer from unbalanced scales (or units) of different types of data and non-scalability of the corresponding algorithms. In this paper, we propose an alternative based on integrative and regularized principal component analysis, which is distribution-free, computationally efficient, and robust against unbalanced scales. The new method performs dimension reduction simultaneously on multiple types of data, seeking data-adaptive sparsity and scaling. As a result, in addition to feature selection for each type of data, integrative clustering is achieved. Numerically, the proposed method compares favorably against its competitors in terms of accuracy (in identifying hidden clusters), computational efficiency, and robustness against unbalanced scales. In particular, compared with a popular method, the new method was competitive in identifying tumor subtypes associated with distinct patient survival patterns when applied to a combined analysis of DNA copy number, mRNA expression, and DNA methylation data in a glioblastoma multiforme study. Copyright © 2016 John Wiley & Sons, Ltd. PMID:26756854

  11. Aerobic fitness is associated with gray matter volume and white matter integrity in multiple sclerosis.

    PubMed

    Prakash, Ruchika Shaurya; Snook, Erin M; Motl, Robert W; Kramer, Arthur F

    2010-06-23

    Alterations in gray and white matter have been well documented in individuals with multiple sclerosis. Severity and extent of such brain tissue damage have been associated with cognitive impairment, disease duration and neurological disability, making quantitative indices of tissue damage important markers of disease progression. In this study, we investigated the association between cardiorespiratory fitness and measures of gray matter atrophy and white matter integrity. Employing voxel-based approaches to analysis of gray matter and white matter, we specifically examined whether higher levels of fitness in multiple sclerosis participants were associated with preserved gray matter volume and integrity of white matter. We found a positive association between cardiorespiratory fitness and regional gray matter volumes and higher focal fractional anisotropy values. Statistical mapping revealed that higher levels of fitness were associated with greater gray matter volume in the midline cortical structures including the medial frontal gyrus, anterior cingulate cortex and the precuneus. Further, we also found that increasing levels of fitness were associated with higher fractional anisotropy in the left thalamic radiation and right anterior corona radiata. Both preserved gray matter volume and white matter tract integrity were associated with better performance on measures of processing speed. Taken together, these results suggest that fitness exerts a prophylactic influence on the structural decline observed early on, preserving neuronal integrity in multiple sclerosis, thereby reducing long-term disability. PMID:19560443

  12. Soybean knowledge base (SoyKB): a web resource for integration of soybean translational genomics and molecular breeding.

    PubMed

    Joshi, Trupti; Fitzpatrick, Michael R; Chen, Shiyuan; Liu, Yang; Zhang, Hongxin; Endacott, Ryan Z; Gaudiello, Eric C; Stacey, Gary; Nguyen, Henry T; Xu, Dong

    2014-01-01

    Soybean Knowledge Base (http://soykb.org) is a comprehensive web resource developed for bridging soybean translational genomics and molecular breeding research. It provides information for six entities including genes/proteins, microRNAs/sRNAs, metabolites, single nucleotide polymorphisms, plant introduction lines and traits. It also incorporates many multi-omics datasets including transcriptomics, proteomics, metabolomics and molecular breeding data, such as quantitative trait loci, traits and germplasm information. Soybean Knowledge Base has a new suite of tools such as In Silico Breeding Program for soybean breeding, which includes a graphical chromosome visualizer for ease of navigation. It integrates quantitative trait loci, traits and germplasm information along with genomic variation data, such as single nucleotide polymorphisms, insertions, deletions and genome-wide association studies data, from multiple soybean cultivars and Glycine soja. PMID:24136998

  13. Real-time trace gas sensor using a multimode diode laser and multiple-line integrated cavity enhanced absorption spectroscopy.

    PubMed

    Karpf, Andreas; Rao, Gottipaty N

    2015-07-01

    We describe and demonstrate a highly sensitive trace gas sensor based on a simplified design that is capable of measuring sub-ppb concentrations of NO2 in tens of milliseconds. The sensor makes use of a relatively inexpensive Fabry-Perot diode laser to conduct off-axis cavity enhanced spectroscopy. The broad frequency range of a multimode Fabry-Perot diode laser spans a large number of absorption lines, thereby removing the need for a single-frequency tunable laser source. The use of cavity enhanced absorption spectroscopy enhances the sensitivity of the sensor by providing a pathlength on the order of 1 km in a small volume. Off-axis alignment excites a large number of cavity modes simultaneously, thereby reducing the sensor's susceptibility to vibration. Multiple-line integrated absorption spectroscopy (where one integrates the absorption spectra over a large number of rovibronic transitions of the molecular species) further improves the sensitivity of detection. Relatively high laser power (∼400  mW) is used to compensate for the low coupling efficiency of a broad linewidth laser to the optical cavity. The approach was demonstrated using a 407 nm diode laser to detect trace quantities of NO2 in zero air. Sensitivities of 750 ppt, 110 ppt, and 65 ppt were achieved using integration times of 50 ms, 5 s, and 20 s respectively. PMID:26193156

  14. Locally accessible conformations of proteins: multiple molecular dynamics simulations of crambin.

    PubMed Central

    Caves, L. S.; Evanseck, J. D.; Karplus, M.

    1998-01-01

    Multiple molecular dynamics (MD) simulations of crambin with different initial atomic velocities are used to sample conformations in the vicinity of the native structure. Individual trajectories of length up to 5 ns sample only a fraction of the conformational distribution generated by ten independent 120 ps trajectories at 300 K. The backbone atom conformational space distribution is analyzed using principal components analysis (PCA). Four different major conformational regions are found. In general, a trajectory samples only one region and few transitions between the regions are observed. Consequently, the averages of structural and dynamic properties over the ten trajectories differ significantly from those obtained from individual trajectories. The nature of the conformational sampling has important consequences for the utilization of MD simulations for a wide range of problems, such as comparisons with X-ray or NMR data. The overall average structure is significantly closer to the X-ray structure than any of the individual trajectory average structures. The high frequency (less than 10 ps) atomic fluctuations from the ten trajectories tend to be similar, but the lower frequency (100 ps) motions are different. To improve conformational sampling in molecular dynamics simulations of proteins, as in nucleic acids, multiple trajectories with different initial conditions should be used rather than a single long trajectory. PMID:9541397

  15. A Conformational Analysis Study on the Melanocortin 4 Receptor Using Multiple Molecular Dynamics Simulations.

    PubMed

    Shahlaei, Mohsen; Mousavi, Atefeh

    2015-09-01

    Taking into account the uncertainties involved in 3D model of biomolecule developed by homology modeling (HM), it is important to opportunely validate the initial structure before employing for different purposes such as drug design. Extended simulation times and the necessity of correct representation of interactions within the protein and the nearby molecules impose significant limitations on molecular dynamics (MD)-based refinement of structures developed by HM. Consequently, there is a pressing requirement for more efficient methods for HM and subsequent validation of developed structure. Multiple MD simulation runs are well suited for producing ensembles of structures. In this context, a computational investigation was presented to study the structure of melanocortin 4 receptor (MC4R) using molecular dynamics (MD) simulations in explicit phospholipids bilayer. Several MD runs with different initial velocities were employed to sample conformations in the neighborhood of the native structure of receptor, collecting trajectories spanning 0.21 ms. The coherence between the results, different structural analysis, and the convergence of parameters derived by principal component analysis (PCA) shows that an accurate description of the MC4R conformational space around the native state was achieved by multiple MD trajectories. PMID:25487745

  16. Orthogonal matrix factorization enables integrative analysis of multiple RNA binding proteins

    PubMed Central

    Stražar, Martin; Žitnik, Marinka; Zupan, Blaž; Ule, Jernej; Curk, Tomaž

    2016-01-01

    Motivation: RNA binding proteins (RBPs) play important roles in post-transcriptional control of gene expression, including splicing, transport, polyadenylation and RNA stability. To model protein–RNA interactions by considering all available sources of information, it is necessary to integrate the rapidly growing RBP experimental data with the latest genome annotation, gene function, RNA sequence and structure. Such integration is possible by matrix factorization, where current approaches have an undesired tendency to identify only a small number of the strongest patterns with overlapping features. Because protein–RNA interactions are orchestrated by multiple factors, methods that identify discriminative patterns of varying strengths are needed. Results: We have developed an integrative orthogonality-regularized nonnegative matrix factorization (iONMF) to integrate multiple data sources and discover non-overlapping, class-specific RNA binding patterns of varying strengths. The orthogonality constraint halves the effective size of the factor model and outperforms other NMF models in predicting RBP interaction sites on RNA. We have integrated the largest data compendium to date, which includes 31 CLIP experiments on 19 RBPs involved in splicing (such as hnRNPs, U2AF2, ELAVL1, TDP-43 and FUS) and processing of 3’UTR (Ago, IGF2BP). We show that the integration of multiple data sources improves the predictive accuracy of retrieval of RNA binding sites. In our study the key predictive factors of protein–RNA interactions were the position of RNA structure and sequence motifs, RBP co-binding and gene region type. We report on a number of protein-specific patterns, many of which are consistent with experimentally determined properties of RBPs. Availability and implementation: The iONMF implementation and example datasets are available at https://github.com/mstrazar/ionmf. Contact: tomaz.curk@fri.uni-lj.si Supplementary information: Supplementary data are available

  17. Molecular Evidence for High Frequency of Multiple Paternity in a Freshwater Shrimp Species Caridina ensifera

    PubMed Central

    Yue, Gen Hua; Chang, Alex

    2010-01-01

    Background Molecular genetic analyses of parentage provide insights into mating systems. Although there are 22,000 members in Malacostraca, not much has been known about mating systems in Malacostraca. The freshwater shrimp Caridina ensifera blue, is a new species belonging to Malacostraca which was discovered recently in Sulawesi, Indonesia. Due to its small body size and low fecundity, this species is an ideal species to study the occurrence and frequency of multiple paternity and to understand of how the low fecundity species persist and evolve. Methodology/Principal Findings In this study, we developed four polymorphic microsatellites from C. ensifera and applied them to investigate the occurrence and frequency of multiple paternity in 20 C. ensifera broods caught from Lake Matano, Sulawesi. By genotyping the mother and all offspring from each brood we discovered multiple paternity in all 20 broods. In most of the 20 broods, fathers contributed skewed numbers of offspring and there was an apparent inverse correlation between reproductive success of sires and their relatedness to mothers. Conclusions/Significance Our results in combination with recent reports on multiple paternity in crayfish, crab and lobster species suggests that multiple paternity is common in Malacostraca. Skewed contribution of fathers to the numbers of offspring and inverse correlation between reproductive success of sires and their relatedness to mothers suggest that sperm competition occurred and/or pre- and postcopulatory female choice happen, which may be important for avoiding the occurrence of inbreeding and optimize genetic variation in offspring and for persistence and evolution of low fecundity species. PMID:20856862

  18. JINN, an integrated software package for molecular geneticists.

    PubMed Central

    Johnsen, M

    1984-01-01

    I describe JINN, a microcomputer-based system designed to maintain and search a strain collection, to enter, modify and analyze sequences, and to use the EMBL Sequence Data Base. The major objective during development of this program has been integration of individual program modules to ensure a consistent and helpful user interface. The system is running under the CP/M operating system and requires little in the way of particular hardware configuration. PMID:6320101

  19. Critical zone study in Korea: integration of hydrogeology, mineralogy, sedimentology and molecular biogeochemistry

    NASA Astrophysics Data System (ADS)

    Lee, J. Y.; Kwon, K.; Jo, K. N.; Lee, J. S.

    2015-12-01

    Critical Zone (CZ) is the topmost layer of the Earth ranging from the vegetation canopy down to the soil, groundwater, and bedrock that sustains our ecosystem including human life. This CZ is being greatly influenced by the climate change and anthropogenic forces. We introduce the Critical Zone Frontier Research Laboratory (CFRL), a critical zone research lab recently funded by the Korean government for 2015-2020. The objective of CFRL is to unravel the relationships between climate and CZ changes to propose a prediction model for future responses of CZ to climate change. For this ultimate goal, we establish multiple CZ observatories in Kangwon areas and investigate soil, groundwater, and cave environments by integration of hydrogeology, mineralogy, sedimentology and molecular biogeochemistry. This study will enhance our understanding about CZ and local resolution of a climate change model. This research is financially supported by the Basic Research Laboratory Program through the National Research Foundation of Korea funded by the Ministry of Science, ICT and Future Planning.

  20. Integration of Morphological Data into Molecular Phylogenetic Analysis: Toward the Identikit of the Stylasterid Ancestor.

    PubMed

    Puce, Stefania; Pica, Daniela; Schiaparelli, Stefano; Negrisolo, Enrico

    2016-01-01

    Stylasteridae is a hydroid family including 29 worldwide-distributed genera, all provided with a calcareous skeleton. They are abundant in shallow and deep waters and represent an important component of marine communities. In the present paper, we studied the evolution of ten morphological characters, currently used in stylasterid taxonomy, using a phylogenetic approach. Our results indicate that stylasterid morphology is highly plastic and that many events of independent evolution and reversion have occurred. Our analysis also allows sketching a possible identikit of the stylasterid ancestor. It had calcareous skeleton, reticulate-granular coenosteal texture, polyps randomly arranged, gastrostyle, and dactylopore spines, while lacking a gastropore lip and dactylostyles. If the ancestor had single or double/multiple chambered gastropore tube is uncertain. These data suggest that the ancestor was similar to the extant genera Cyclohelia and Stellapora. Our investigation is the first attempt to integrate molecular and morphological information to clarify the stylasterid evolutionary scenario and represents the first step to infer the stylasterid ancestor morphology. PMID:27537333

  1. Integration of Morphological Data into Molecular Phylogenetic Analysis: Toward the Identikit of the Stylasterid Ancestor

    PubMed Central

    Puce, Stefania; Pica, Daniela; Schiaparelli, Stefano; Negrisolo, Enrico

    2016-01-01

    Stylasteridae is a hydroid family including 29 worldwide-distributed genera, all provided with a calcareous skeleton. They are abundant in shallow and deep waters and represent an important component of marine communities. In the present paper, we studied the evolution of ten morphological characters, currently used in stylasterid taxonomy, using a phylogenetic approach. Our results indicate that stylasterid morphology is highly plastic and that many events of independent evolution and reversion have occurred. Our analysis also allows sketching a possible identikit of the stylasterid ancestor. It had calcareous skeleton, reticulate-granular coenosteal texture, polyps randomly arranged, gastrostyle, and dactylopore spines, while lacking a gastropore lip and dactylostyles. If the ancestor had single or double/multiple chambered gastropore tube is uncertain. These data suggest that the ancestor was similar to the extant genera Cyclohelia and Stellapora. Our investigation is the first attempt to integrate molecular and morphological information to clarify the stylasterid evolutionary scenario and represents the first step to infer the stylasterid ancestor morphology. PMID:27537333

  2. Generalized Scalable Multiple Copy Algorithms for Molecular Dynamics Simulations in NAMD.

    PubMed

    Jiang, Wei; Phillips, James C; Huang, Lei; Fajer, Mikolai; Meng, Yilin; Gumbart, James C; Luo, Yun; Schulten, Klaus; Roux, Benoît

    2014-03-01

    Computational methodologies that couple the dynamical evolution of a set of replicated copies of a system of interest offer powerful and flexible approaches to characterize complex molecular processes. Such multiple copy algorithms (MCAs) can be used to enhance sampling, compute reversible work and free energies, as well as refine transition pathways. Widely used examples of MCAs include temperature and Hamiltonian-tempering replica-exchange molecular dynamics (T-REMD and H-REMD), alchemical free energy perturbation with lambda replica-exchange (FEP/λ-REMD), umbrella sampling with Hamiltonian replica exchange (US/H-REMD), and string method with swarms-of-trajectories conformational transition pathways. Here, we report a robust and general implementation of MCAs for molecular dynamics (MD) simulations in the highly scalable program NAMD built upon the parallel programming system Charm++. Multiple concurrent NAMD instances are launched with internal partitions of Charm++ and located continuously within a single communication world. Messages between NAMD instances are passed by low-level point-to-point communication functions, which are accessible through NAMD's Tcl scripting interface. The communication-enabled Tcl scripting provides a sustainable application interface for end users to realize generalized MCAs without modifying the source code. Illustrative applications of MCAs with fine-grained inter-copy communication structure, including global lambda exchange in FEP/λ-REMD, window swapping US/H-REMD in multidimensional order parameter space, and string method with swarms-of-trajectories were carried out on IBM Blue Gene/Q to demonstrate the versatility and massive scalability of the present implementation. PMID:24944348

  3. Evidence for nucleosynthetic enrichment of the protosolar molecular cloud core by multiple supernova events

    PubMed Central

    Schiller, Martin; Paton, Chad; Bizzarro, Martin

    2015-01-01

    The presence of isotope heterogeneity of nucleosynthetic origin amongst meteorites and their components provides a record of the diverse stars that contributed matter to the protosolar molecular cloud core. Understanding how and when the solar system’s nucleosynthetic heterogeneity was established and preserved within the solar protoplanetary disk is critical for unraveling the earliest formative stages of the solar system. Here, we report calcium and magnesium isotope measurements of primitive and differentiated meteorites as well as various types of refractory inclusions, including refractory inclusions (CAIs) formed with the canonical 26Al/27Al of ~5 × 10−5 (26Al decays to 26Mg with a half-life of ~0.73 Ma) and CAIs that show fractionated and unidentified nuclear effects (FUN-CAIs) to understand the origin of the solar system’s nucleosynthetic heterogeneity. Bulk analyses of primitive and differentiated meteorites along with canonical and FUN-CAIs define correlated, mass-independent variations in 43Ca, 46Ca and 48Ca. Moreover, sequential dissolution experiments of the Ivuna carbonaceous chondrite aimed at identifying the nature and number of presolar carriers of isotope anomalies within primitive meteorites have detected the presence of multiple carriers of the short-lived 26Al nuclide as well as carriers of anomalous and uncorrelated 43Ca, 46Ca and 48Ca compositions, which requires input from multiple and recent supernovae sources. We infer that the solar system’s correlated nucleosynthetic variability reflects unmixing of old, galactically-inherited homogeneous dust from a new, supernovae-derived dust component formed shortly prior to or during the evolution of the giant molecular cloud parental to the protosolar molecular cloud core. This implies that similarly to 43Ca, 46Ca and 48Ca, the short-lived 26Al nuclide was heterogeneously distributed in the inner solar system at the time of CAI formation. PMID:25684790

  4. Excited states of ribosome translocation revealed through integrative molecular modeling

    PubMed Central

    Whitford, Paul C.; Ahmed, Aqeel; Yu, Yanan; Hennelly, Scott P.; Tama, Florence; Spahn, Christian M. T.; Onuchic, José N.; Sanbonmatsu, Karissa Y.

    2011-01-01

    The dynamic nature of biomolecules leads to significant challenges when characterizing the structural properties associated with function. While X-ray crystallography and imaging techniques (such as cryo-electron microscopy) can reveal the structural details of stable molecular complexes, strategies must be developed to characterize configurations that exhibit only marginal stability (such as intermediates) or configurations that do not correspond to minima on the energy landscape (such as transition-state ensembles). Here, we present a methodology (MDfit) that utilizes molecular dynamics simulations to generate configurations of excited states that are consistent with available biophysical and biochemical measurements. To demonstrate the approach, we present a sequence of configurations that are suggested to be associated with transfer RNA (tRNA) movement through the ribosome (translocation). The models were constructed by combining information from X-ray crystallography, cryo-electron microscopy, and biochemical data. These models provide a structural framework for translocation that may be further investigated experimentally and theoretically to determine the precise energetic character of each configuration and the transition dynamics between them. PMID:22080606

  5. Excited states of ribosome translocation revealed through integrative molecular modeling.

    PubMed

    Whitford, Paul C; Ahmed, Aqeel; Yu, Yanan; Hennelly, Scott P; Tama, Florence; Spahn, Christian M T; Onuchic, José N; Sanbonmatsu, Karissa Y

    2011-11-22

    The dynamic nature of biomolecules leads to significant challenges when characterizing the structural properties associated with function. While X-ray crystallography and imaging techniques (such as cryo-electron microscopy) can reveal the structural details of stable molecular complexes, strategies must be developed to characterize configurations that exhibit only marginal stability (such as intermediates) or configurations that do not correspond to minima on the energy landscape (such as transition-state ensembles). Here, we present a methodology (MDfit) that utilizes molecular dynamics simulations to generate configurations of excited states that are consistent with available biophysical and biochemical measurements. To demonstrate the approach, we present a sequence of configurations that are suggested to be associated with transfer RNA (tRNA) movement through the ribosome (translocation). The models were constructed by combining information from X-ray crystallography, cryo-electron microscopy, and biochemical data. These models provide a structural framework for translocation that may be further investigated experimentally and theoretically to determine the precise energetic character of each configuration and the transition dynamics between them. PMID:22080606

  6. Clinical value of molecular subtyping multiple myeloma using gene expression profiling.

    PubMed

    Weinhold, N; Heuck, C J; Rosenthal, A; Thanendrarajan, S; Stein, C K; Van Rhee, F; Zangari, M; Hoering, A; Tian, E; Davies, F E; Barlogie, B; Morgan, G J

    2016-02-01

    Using a data set of 1217 patients with multiple myeloma enrolled in Total Therapies, we have examined the impact of novel therapies on molecular and risk subgroups and the clinical value of molecular classification. Bortezomib significantly improved the progression-free survival (PFS) and overall survival (OS) of the MMSET (MS) subgroup. Thalidomide and bortezomib positively impacted the PFS of low-risk (LoR) cases defined by the GEP70 signature, whereas high-risk (HiR) cases showed no significant changes in outcome. We show that molecular classification is important if response rates are to be used to predict outcomes. The t(11;14)-containing CD-1 and CD-2 subgroups showed clear differences in time to response and cumulative response rates but similar PFS and OS. Furthermore, complete remission was not significantly associated with the outcome of the MAF/MAFB (MF) subgroup or HiR cases. HiR cases were enriched in the MF, MS and proliferation subgroups, but the poor outcome of these groups was not linked to subgroup-specific characteristics such as MAF overexpression per se. It is especially important to define risk status if HiR cases are to be managed appropriately because of their aggressive clinical course, high rates of early relapse and the need to maintain therapeutic pressure on the clone. PMID:26526987

  7. Multiple origins of deep-sea Asellota (Crustacea: Isopoda) from shallow waters revealed by molecular data

    PubMed Central

    Raupach, Michael J.; Mayer, Christoph; Malyutina, Marina; Wägele, Johann-Wolfgang

    2008-01-01

    The Asellota are a highly variable group of Isopoda with many species in freshwater and marine shallow-water environments. However, in the deep sea, they show their most impressive radiation with a broad range of astonishing morphological adaptations and bizarre body forms. Nevertheless, the evolution and phylogeny of the deep-sea Asellota are poorly known because of difficulties in scoring morphological characters. In this study, the molecular phylogeny of the Asellota is evaluated for 15 marine shallow-water species and 101 deep-sea species, using complete 18S and partial 28S rDNA gene sequences. Our molecular data support the monophyly of most deep-sea families and give evidence for a multiple colonization of the deep sea by at least four major lineages of asellote isopods. According to our molecular data, one of these lineages indicates an impressive radiation in the deep sea. Furthermore, the present study rejects the monophyly of the family Janiridae, a group of plesiomorphic shallow-water Asellota, and several shallow-water and deep-sea genera (Acanthaspidia, Ianthopsis, Haploniscus, Echinozone, Eurycope, Munnopsurus and Syneurycope). PMID:19033145

  8. Melt rheology and molecular weight degradation of amylopectin during multiple pass extrusion of starch

    SciTech Connect

    Willett, J.L.; Millard, M.M.; Jasberg, B.K.

    1996-12-31

    The degradation of starch during extrusion and the role of specific mechanical energy (SME) in this process have been widely studied for single pass extrusion, Multiple extrusion histories are not uncommon in the plastics industry, but little if any has been reported on their effects on starch. Native waxy maize starch (app. 98% amylopectin) was initially converted to a thermoplastic by twin screw extrusion. This extrudate was equilibrated to either 18% or 23% moisture content, and subsequently re-extruded in a single screw extruder (3:1 compression screw) at 110{degrees}C or 130{degrees}C. Melt viscosity data were calculated using the output-pressure data from the second pass. The melts exhibited shear thinning behavior; the power law index increased with temperature, and slightly with moisture content. Molecular weights of selected second-pass extrudates, as well as the native starch and the first-pass extrudate, were measured by light scattering in dimethyl sulfoxide/water. The initial extrusion pass reduced the molecular weight from 300 million to 50 million. Molecular weight reductions in the second pass increased with increasing SME. A first order expression was shown to fit the MW-SME data with a correlation coefficient of 0.91. Implications of the degradation on extrusion processing of starch and the use of single screw extruders for rheological characterization will be discussed.

  9. Scientific concepts and applications of integrated discrete multiple organ co-culture technology

    PubMed Central

    Gayathri, Loganathan; Dhanasekaran, Dharumadurai; Akbarsha, Mohammad A.

    2015-01-01

    Over several decades, animals have been used as models to investigate the human-specific drug toxicity, but the outcomes are not always reliably extrapolated to the humans in vivo. Appropriate in vitro human-based experimental system that includes in vivo parameters is required for the evaluation of multiple organ interaction, multiple organ/organ-specific toxicity, and metabolism of xenobiotic compounds to avoid the use of animals for toxicity testing. One such versatile in vitro technology in which human primary cells could be used is integrated discrete multiple organ co-culture (IdMOC). IdMOC system adopts wells-within-well concept that facilitates co-culture of cells from different organs in a discrete manner, separately in the respective media in the smaller inner wells which are then interconnected by an overlay of a universal medium in the large containing well. This novel in vitro approach mimics the in vivo situation to a great extent, and employs cells from multiple organs that are physically separated but interconnected by a medium that mimics the systemic circulation and provides for multiple organ interaction. Applications of IdMOC include assessment of multiple organ toxicity, drug distribution, organ-specific toxicity, screening of anticancer drugs, metabolic cytotoxicity, etc. PMID:25969651

  10. Genetic, Epigenetic, and Environmental Factors Influencing Neurovisceral Integration of Cardiovascular Modulation: Focus on Multiple Sclerosis.

    PubMed

    Sternberg, Zohara

    2016-03-01

    Thought to be an autoimmune inflammatory CNS disease, multiple sclerosis (MS) involves multiple pathologies with heterogeneous clinical presentations. An impaired neurovisceral integration of cardiovascular modulation, indicated by sympathetic and parasympathetic autonomic nervous system (ANS) dysfunction, is among common MS clinical presentations. ANS dysfunction could not only enhance MS inflammatory and neurodegenerative processes, but can also lead to clinical symptoms such as depression, fatigue, sleep disorder, migraine, osteoporosis, and cerebral hemodynamic impairments. Therefore, factors influencing ANS functional activities, in one way or another, will have a significant impact on MS disease course. This review describes the genetic and epigenetic factors, and their interactions with a number of environmental factors contributing to the neurovisceral integration of cardiovascular modulation, with a focus on MS. Future studies should investigate the improvement in cardiovascular ANS function, as a strategy for preventing and minimizing MS-related morbidities, and improving patients' quality of life. PMID:26502224

  11. Quadrature rules with multiple nodes for evaluating integrals with strong singularities

    NASA Astrophysics Data System (ADS)

    Milovanovic, Gradimir V.; Spalevic, Miodrag M.

    2006-05-01

    We present a method based on the Chakalov-Popoviciu quadrature formula of Lobatto type, a rather general case of quadrature with multiple nodes, for approximating integrals defined by Cauchy principal values or by Hadamard finite parts. As a starting point we use the results obtained by L. Gori and E. Santi (cf. On the evaluation of Hilbert transforms by means of a particular class of Turan quadrature rules, Numer. Algorithms 10 (1995), 27-39; Quadrature rules based on s-orthogonal polynomials for evaluating integrals with strong singularities, Oberwolfach Proceedings: Applications and Computation of Orthogonal Polynomials, ISNM 131, Birkhauser, Basel, 1999, pp. 109-119). We generalize their results by using some of our numerical procedures for stable calculation of the quadrature formula with multiple nodes of Gaussian type and proposed methods for estimating the remainder term in such type of quadrature formulae. Numerical examples, illustrations and comparisons are also shown.

  12. Integration of molecular pathology, epidemiology and social science for global precision medicine.

    PubMed

    Nishi, Akihiro; Milner, Danny A; Giovannucci, Edward L; Nishihara, Reiko; Tan, Andy S; Kawachi, Ichiro; Ogino, Shuji

    2016-01-01

    The precision medicine concept and the unique disease principle imply that each patient has unique pathogenic processes resulting from heterogeneous cellular genetic and epigenetic alterations and interactions between cells (including immune cells) and exposures, including dietary, environmental, microbial and lifestyle factors. As a core method field in population health science and medicine, epidemiology is a growing scientific discipline that can analyze disease risk factors and develop statistical methodologies to maximize utilization of big data on populations and disease pathology. The evolving transdisciplinary field of molecular pathological epidemiology (MPE) can advance biomedical and health research by linking exposures to molecular pathologic signatures, enhancing causal inference and identifying potential biomarkers for clinical impact. The MPE approach can be applied to any diseases, although it has been most commonly used in neoplastic diseases (including breast, lung and colorectal cancers) because of availability of various molecular diagnostic tests. However, use of state-of-the-art genomic, epigenomic and other omic technologies and expensive drugs in modern healthcare systems increases racial, ethnic and socioeconomic disparities. To address this, we propose to integrate molecular pathology, epidemiology and social science. Social epidemiology integrates the latter two fields. The integrative social MPE model can embrace sociology, economics and precision medicine, address global health disparities and inequalities, and elucidate biological effects of social environments, behaviors and networks. We foresee advancements of molecular medicine, including molecular diagnostics, biomedical imaging and targeted therapeutics, which should benefit individuals in a global population, by means of an interdisciplinary approach of integrative MPE and social health science. PMID:26636627

  13. What Do Effective Treatments for Multiple Sclerosis Tell Us about the Molecular Mechanisms Involved in Pathogenesis?

    PubMed Central

    Buzzard, Katherine A.; Broadley, Simon A.; Butzkueven, Helmut

    2012-01-01

    Multiple sclerosis is a potentially debilitating disease of the central nervous system. A concerted program of research by many centers around the world has consistently demonstrated the importance of the immune system in its pathogenesis. This knowledge has led to the formal testing of a number of therapeutic agents in both animal models and humans. These clinical trials have shed yet further light on the pathogenesis of MS through their sometimes unexpected effects and by their differential effects in terms of impact on relapses, progression of the disease, paraclinical parameters (MRI) and the adverse events that are experienced. Here we review the currently approved medications for the commonest form of multiple sclerosis (relapsing-remitting) and the emerging therapies for which preliminary results from phase II/III clinical trials are available. A detailed analysis of the molecular mechanisms responsible for the efficacy of these medications in multiple sclerosis indicates that blockade or modulation of both T- and B-cell activation and migration pathways in the periphery or CNS can lead to amelioration of the disease. It is hoped that further therapeutic trials will better delineate the pathogenesis of MS, ultimately leading to even better treatments with fewer adverse effects. PMID:23202920

  14. Molecular pharmacodynamics of new oral drugs used in the treatment of multiple sclerosis

    PubMed Central

    di Nuzzo, Luigi; Orlando, Rosamaria; Nasca, Carla; Nicoletti, Ferdinando

    2014-01-01

    New oral drugs have considerably enriched the therapeutic armamentarium for the treatment of multiple sclerosis. This review focuses on the molecular pharmacodynamics of fingolimod, dimethyl fumarate (BG-12), laquinimod, and teriflunomide. We specifically comment on the action of these drugs at three levels: 1) the regulation of the immune system; 2) the permeability of the blood–brain barrier; and 3) the central nervous system. Fingolimod phosphate (the active metabolite of fingolimod) has a unique mechanism of action and represents the first ligand of G-protein-coupled receptors (sphingosine-1-phosphate receptors) active in the treatment of multiple sclerosis. Dimethyl fumarate activates the nuclear factor (erythroid-derived 2)-related factor 2 pathway of cell defense as a result of an initial depletion of reduced glutathione. We discuss how this mechanism lies on the border between cell protection and toxicity. Laquinimod has multiple (but less defined) mechanisms of action, which make the drug slightly more effective on disability progression than on annualized relapse rate in clinical studies. Teriflunomide acts as a specific inhibitor of the de novo pyrimidine biosynthesis. We also discuss new unexpected mechanisms of these drugs, such as the induction of brain-derived neurotrophic factor by fingolimod and the possibility that laquinimod and teriflunomide regulate the kynurenine pathway of tryptophan metabolism. PMID:24876766

  15. Variational path integral molecular dynamics and hybrid Monte Carlo algorithms using a fourth order propagator with applications to molecular systems.

    PubMed

    Kamibayashi, Yuki; Miura, Shinichi

    2016-08-21

    In the present study, variational path integral molecular dynamics and associated hybrid Monte Carlo (HMC) methods have been developed on the basis of a fourth order approximation of a density operator. To reveal various parameter dependence of physical quantities, we analytically solve one dimensional harmonic oscillators by the variational path integral; as a byproduct, we obtain the analytical expression of the discretized density matrix using the fourth order approximation for the oscillators. Then, we apply our methods to realistic systems like a water molecule and a para-hydrogen cluster. In the HMC, we adopt two level description to avoid the time consuming Hessian evaluation. For the systems examined in this paper, the HMC method is found to be about three times more efficient than the molecular dynamics method if appropriate HMC parameters are adopted; the advantage of the HMC method is suggested to be more evident for systems described by many body interaction. PMID:27544094

  16. Integrating genomics, proteomics and bioinformatics in translational studies of molecular medicine.

    PubMed

    Ostrowski, Jerzy; Wyrwicz, Lucjan S

    2009-09-01

    Understanding the molecular mechanisms of disease requires the introduction of molecular diagnostics into medical practice. Current medicine employs only elements of molecular diagnostics, which are usually applied on the scale of single genes. Medicine in the postgenomic era will utilize thousands of disease-associated molecular markers provided by high-throughput sequencing and functional genomic, proteomic and metabolomic studies. Such a spectrum of techniques will link clinical medicine based on molecularly oriented diagnostics with the prediction and prevention of disease. To achieve this task, large-scale and genome-wide biological and medical data must be combined with biostatistical and bioinformatic analyses to model biological systems. Collecting, cataloging and comparing data from molecular studies, and the subsequent development of conclusions, creates the fundamentals of systems biology. This highly complex analytical process reflects a new scientific paradigm known as integrative genomics. PMID:19732006

  17. Integrative genomics--a basic and essential tool for the development of molecular medicine.

    PubMed

    Ostrowski, Jerzy

    2008-01-01

    Understanding the molecular mechanisms of disease requires the introduction of molecular diagnostics into medical practice. Current medicine employs only elements of molecular diagnostics, and usually on the scale of single genes. Medicine in the post-genomic era will utilize thousands of molecular markers associated with disease that are provided by high-throughput sequencing and functional genomic, proteomic and metabolomic studies. Such a spectrum of techniques will link clinical medicine based on molecularly oriented diagnostics with the prediction and prevention of disease. To achieve this task, large-scale and genome-wide biological and medical data must be combined with biostatistical analyses and bioinformatic modeling of biological systems. The collecting, cataloging and comparison of data from molecular studies and the subsequent development of conclusions create the fundamentals of systems biology. This highly complex analytical process reflects a new scientific paradigm called integrative genomics. PMID:19172842

  18. The eye in hand: predicting others' behavior by integrating multiple sources of information

    PubMed Central

    Pezzulo, Giovanni; Costantini, Marcello

    2015-01-01

    The ability to predict the outcome of other beings' actions confers significant adaptive advantages. Experiments have assessed that human action observation can use multiple information sources, but it is currently unknown how they are integrated and how conflicts between them are resolved. To address this issue, we designed an action observation paradigm requiring the integration of multiple, potentially conflicting sources of evidence about the action target: the actor's gaze direction, hand preshape, and arm trajectory, and their availability and relative uncertainty in time. In two experiments, we analyzed participants' action prediction ability by using eye tracking and behavioral measures. The results show that the information provided by the actor's gaze affected participants' explicit predictions. However, results also show that gaze information was disregarded as soon as information on the actor's hand preshape was available, and this latter information source had widespread effects on participants' prediction ability. Furthermore, as the action unfolded in time, participants relied increasingly more on the arm movement source, showing sensitivity to its increasing informativeness. Therefore, the results suggest that the brain forms a robust estimate of the actor's motor intention by integrating multiple sources of information. However, when informative motor cues such as a preshaped hand with a given grip are available and might help in selecting action targets, people tend to capitalize on such motor cues, thus turning out to be more accurate and fast in inferring the object to be manipulated by the other's hand. PMID:25568158

  19. PIF4 Integrates Multiple Environmental and Hormonal Signals for Plant Growth Regulation in Arabidopsis

    PubMed Central

    Choi, Hyunmo; Oh, Eunkyoo

    2016-01-01

    As sessile organisms, plants must be able to adapt to the environment. Plants respond to the environment by adjusting their growth and development, which is mediated by sophisticated signaling networks that integrate multiple environmental and endogenous signals. Recently, increasing evidence has shown that a bHLH transcription factor PIF4 plays a major role in the multiple signal integration for plant growth regulation. PIF4 is a positive regulator in cell elongation and its activity is regulated by various environmental signals, including light and temperature, and hormonal signals, including auxin, gibberellic acid and brassinosteroid, both transcriptionally and post-translationally. Moreover, recent studies have shown that the circadian clock and metabolic status regulate endogenous PIF4 level. The PIF4 transcription factor cooperatively regulates the target genes involved in cell elongation with hormone-regulated transcription factors. Therefore, PIF4 is a key integrator of multiple signaling pathways, which optimizes growth in the environment. This review will discuss our current understanding of the PIF4-mediated signaling networks that control plant growth. PMID:27432188

  20. PIF4 Integrates Multiple Environmental and Hormonal Signals for Plant Growth Regulation in Arabidopsis.

    PubMed

    Choi, Hyunmo; Oh, Eunkyoo

    2016-08-31

    As sessile organisms, plants must be able to adapt to the environment. Plants respond to the environment by adjusting their growth and development, which is mediated by sophisticated signaling networks that integrate multiple environmental and endogenous signals. Recently, increasing evidence has shown that a bHLH transcription factor PIF4 plays a major role in the multiple signal integration for plant growth regulation. PIF4 is a positive regulator in cell elongation and its activity is regulated by various environmental signals, including light and temperature, and hormonal signals, including auxin, gibberellic acid and brassinosteroid, both transcriptionally and post-translationally. Moreover, recent studies have shown that the circadian clock and metabolic status regulate endogenous PIF4 level. The PIF4 transcription factor cooperatively regulates the target genes involved in cell elongation with hormone-regulated transcription factors. Therefore, PIF4 is a key integrator of multiple signaling pathways, which optimizes growth in the environment. This review will discuss our current understanding of the PIF4-mediated signaling networks that control plant growth. PMID:27432188

  1. The eye in hand: predicting others' behavior by integrating multiple sources of information.

    PubMed

    Ambrosini, Ettore; Pezzulo, Giovanni; Costantini, Marcello

    2015-04-01

    The ability to predict the outcome of other beings' actions confers significant adaptive advantages. Experiments have assessed that human action observation can use multiple information sources, but it is currently unknown how they are integrated and how conflicts between them are resolved. To address this issue, we designed an action observation paradigm requiring the integration of multiple, potentially conflicting sources of evidence about the action target: the actor's gaze direction, hand preshape, and arm trajectory, and their availability and relative uncertainty in time. In two experiments, we analyzed participants' action prediction ability by using eye tracking and behavioral measures. The results show that the information provided by the actor's gaze affected participants' explicit predictions. However, results also show that gaze information was disregarded as soon as information on the actor's hand preshape was available, and this latter information source had widespread effects on participants' prediction ability. Furthermore, as the action unfolded in time, participants relied increasingly more on the arm movement source, showing sensitivity to its increasing informativeness. Therefore, the results suggest that the brain forms a robust estimate of the actor's motor intention by integrating multiple sources of information. However, when informative motor cues such as a preshaped hand with a given grip are available and might help in selecting action targets, people tend to capitalize on such motor cues, thus turning out to be more accurate and fast in inferring the object to be manipulated by the other's hand. PMID:25568158

  2. Balancing an accurate representation of the molecular surface in generalized born formalisms with integrator stability in molecular dynamics simulations.

    PubMed

    Chocholousová, Jana; Feig, Michael

    2006-04-30

    Different integrator time steps in NVT and NVE simulations of protein and nucleic acid systems are tested with the GBMV (Generalized Born using Molecular Volume) and GBSW (Generalized Born with simple SWitching) methods. The simulation stability and energy conservation is investigated in relation to the agreement with the Poisson theory. It is found that very close agreement between generalized Born methods and the Poisson theory based on the commonly used sharp molecular surface definition results in energy drift and simulation artifacts in molecular dynamics simulation protocols with standard 2-fs time steps. New parameters are proposed for the GBMV method, which maintains very good agreement with the Poisson theory while providing energy conservation and stable simulations at time steps of 1 to 1.5 fs. PMID:16518883

  3. A Methodology for Multiple Rule System Integration and Resolution Within a Singular Knowledge Base

    NASA Technical Reports Server (NTRS)

    Kautzmann, Frank N., III

    1988-01-01

    Expert Systems which support knowledge representation by qualitative modeling techniques experience problems, when called upon to support integrated views embodying description and explanation, especially when other factors such as multiple causality, competing rule model resolution, and multiple uses of knowledge representation are included. A series of prototypes are being developed to demonstrate the feasibility of automating the process of systems engineering, design and configuration, and diagnosis and fault management. A study involves not only a generic knowledge representation; it must also support multiple views at varying levels of description and interaction between physical elements, systems, and subsystems. Moreover, it will involve models of description and explanation for each level. This multiple model feature requires the development of control methods between rule systems and heuristics on a meta-level for each expert system involved in an integrated and larger class of expert system. The broadest possible category of interacting expert systems is described along with a general methodology for the knowledge representation and control of mutually exclusive rule systems.

  4. Jacobian integration method increases the statistical power to measure gray matter atrophy in multiple sclerosis☆

    PubMed Central

    Nakamura, Kunio; Guizard, Nicolas; Fonov, Vladimir S.; Narayanan, Sridar; Collins, D. Louis; Arnold, Douglas L.

    2013-01-01

    Gray matter atrophy provides important insights into neurodegeneration in multiple sclerosis (MS) and can be used as a marker of neuroprotection in clinical trials. Jacobian integration is a method for measuring volume change that uses integration of the local Jacobian determinants of the nonlinear deformation field registering two images, and is a promising tool for measuring gray matter atrophy. Our main objective was to compare the statistical power of the Jacobian integration method to commonly used methods in terms of the sample size required to detect a treatment effect on gray matter atrophy. We used multi-center longitudinal data from relapsing–remitting MS patients and evaluated combinations of cross-sectional and longitudinal pre-processing with SIENAX/FSL, SPM, and FreeSurfer, as well as the Jacobian integration method. The Jacobian integration method outperformed these other commonly used methods, reducing the required sample size by a factor of 4–5. The results demonstrate the advantage of using the Jacobian integration method to assess neuroprotection in MS clinical trials. PMID:24266007

  5. Modulation of C. elegans touch sensitivity is integrated at multiple levels.

    PubMed

    Chen, Xiaoyin; Chalfie, Martin

    2014-05-01

    Sensory systems can adapt to different environmental signals. Here we identify four conditions that modulate anterior touch sensitivity in Caenorhabditis elegans after several hours and demonstrate that such sensory modulation is integrated at multiple levels to produce a single output. Prolonged vibration involving integrin signaling directly sensitizes the touch receptor neurons (TRNs). In contrast, hypoxia, the dauer state, and high salt reduce touch sensitivity by preventing the release of long-range neuroregulators, including two insulin-like proteins. Integration of these latter inputs occurs at upstream neurohormonal cells and at the insulin signaling cascade within the TRNs. These signals and those from integrin signaling converge to modulate touch sensitivity by regulating AKT kinases and DAF-16/FOXO. Thus, activation of either the integrin or insulin pathways can compensate for defects in the other pathway. This modulatory system integrates conflicting signals from different modalities, and adapts touch sensitivity to both mechanical and non-mechanical conditions. PMID:24806678

  6. Integrative molecular characterization of head and neck cancer cell model genomes

    PubMed Central

    Tsui, Ivy F.L.; Garnis, Cathie

    2010-01-01

    Background Cell lines are invaluable model systems for the investigation of cancer. Knowledge of the molecular alterations that exist within cell models is required to define the mechanisms governing cellular phenotypes. Methods Five tongue squamous cell carcinomas cell lines and one submaxillary salivary gland epidermoid carcinoma cell line were analyzed for copy number and mRNA expression by tiling-path DNA microarrays and Agilent Whole Human Genome Oligoarrays, respectively. Results Integrative analysis of genetic and expression alterations revealed the molecular landscape of each cell line. Molecular results for individual cell lines and across all samples have been summarized and made available for easy reference. Conclusion Our integrative genomic analyses have defined the DNA and RNA alterations for each individual line. These data will be useful to anyone modelling oral cancer behaviour, providing a molecular context that will be useful for deciphering cell phenotypes. PMID:20014447

  7. Molecular clock integration of brown adipose tissue formation and function

    PubMed Central

    Nam, Deokhwa; Yechoor, Vijay K.; Ma, Ke

    2016-01-01

    Abstract The circadian clock is an essential time-keeping mechanism that entrains internal physiology to environmental cues. Despite the well-established link between the molecular clock and metabolic homeostasis, an intimate interplay between the clock machinery and the metabolically active brown adipose tissue (BAT) is only emerging. Recently, we came to appreciate that the formation and metabolic functions of BAT, a key organ for body temperature maintenance, are under an orchestrated circadian clock regulation. Two complementary studies from our group uncover that the cell-intrinsic clock machinery exerts concerted control of brown adipogenesis with consequent impacts on adaptive thermogenesis, which adds a previously unappreciated temporal dimension to the regulatory mechanisms governing BAT development and function. The essential clock transcriptional activator, Bmal1, suppresses adipocyte lineage commitment and differentiation, whereas the clock repressor, Rev-erbα, promotes these processes. This newly discovered temporal mechanism in fine-tuning BAT thermogenic capacity may enable energy utilization and body temperature regulation in accordance with external timing signals during development and functional recruitment. Given the important role of BAT in whole-body metabolic homeostasis, pharmacological interventions targeting the BAT-modulatory activities of the clock circuit may offer new avenues for the prevention and treatment of metabolic disorders, particularly those associated with circadian dysregulation. PMID:27385482

  8. Molecular clock integration of brown adipose tissue formation and function.

    PubMed

    Nam, Deokhwa; Yechoor, Vijay K; Ma, Ke

    2016-01-01

    The circadian clock is an essential time-keeping mechanism that entrains internal physiology to environmental cues. Despite the well-established link between the molecular clock and metabolic homeostasis, an intimate interplay between the clock machinery and the metabolically active brown adipose tissue (BAT) is only emerging. Recently, we came to appreciate that the formation and metabolic functions of BAT, a key organ for body temperature maintenance, are under an orchestrated circadian clock regulation. Two complementary studies from our group uncover that the cell-intrinsic clock machinery exerts concerted control of brown adipogenesis with consequent impacts on adaptive thermogenesis, which adds a previously unappreciated temporal dimension to the regulatory mechanisms governing BAT development and function. The essential clock transcriptional activator, Bmal1, suppresses adipocyte lineage commitment and differentiation, whereas the clock repressor, Rev-erbα, promotes these processes. This newly discovered temporal mechanism in fine-tuning BAT thermogenic capacity may enable energy utilization and body temperature regulation in accordance with external timing signals during development and functional recruitment. Given the important role of BAT in whole-body metabolic homeostasis, pharmacological interventions targeting the BAT-modulatory activities of the clock circuit may offer new avenues for the prevention and treatment of metabolic disorders, particularly those associated with circadian dysregulation. PMID:27385482

  9. Tuning cell migration: contractility as an integrator of intracellular signals from multiple cues

    PubMed Central

    Bordeleau, Francois; Reinhart-King, Cynthia A.

    2016-01-01

    There has been immense progress in our understanding of the factors driving cell migration in both two-dimensional and three-dimensional microenvironments over the years. However, it is becoming increasingly evident that even though most cells share many of the same signaling molecules, they rarely respond in the same way to migration cues. To add to the complexity, cells are generally exposed to multiple cues simultaneously, in the form of growth factors and/or physical cues from the matrix. Understanding the mechanisms that modulate the intracellular signals triggered by multiple cues remains a challenge. Here, we will focus on the molecular mechanism involved in modulating cell migration, with a specific focus on how cell contractility can mediate the crosstalk between signaling initiated at cell-matrix adhesions and growth factor receptors. PMID:27508074

  10. Tuning cell migration: contractility as an integrator of intracellular signals from multiple cues.

    PubMed

    Bordeleau, Francois; Reinhart-King, Cynthia A

    2016-01-01

    There has been immense progress in our understanding of the factors driving cell migration in both two-dimensional and three-dimensional microenvironments over the years. However, it is becoming increasingly evident that even though most cells share many of the same signaling molecules, they rarely respond in the same way to migration cues. To add to the complexity, cells are generally exposed to multiple cues simultaneously, in the form of growth factors and/or physical cues from the matrix. Understanding the mechanisms that modulate the intracellular signals triggered by multiple cues remains a challenge. Here, we will focus on the molecular mechanism involved in modulating cell migration, with a specific focus on how cell contractility can mediate the crosstalk between signaling initiated at cell-matrix adhesions and growth factor receptors. PMID:27508074

  11. Integrating molecular dynamics simulations with chemical probing experiments using SHAPE-FIT.

    PubMed

    Kirmizialtin, Serdal; Hennelly, Scott P; Schug, Alexander; Onuchic, Jose N; Sanbonmatsu, Karissa Y

    2015-01-01

    Integration and calibration of molecular dynamics simulations with experimental data remain a challenging endeavor. We have developed a novel method to integrate chemical probing experiments with molecular simulations of RNA molecules by using a native structure-based model. Selective 2'-hydroxyl acylation by primer extension (SHAPE) characterizes the mobility of each residue in the RNA. Our method, SHAPE-FIT, automatically optimizes the potential parameters of the force field according to measured reactivities from SHAPE. The optimized parameter set allows simulations of dynamics highly consistent with SHAPE probing experiments. Such atomistic simulations, thoroughly grounded in experiment, can open a new window on RNA structure-function relations. PMID:25726467

  12. Integrating molecular dynamics simulations with chemical probing experiments using SHAPE-FIT

    PubMed Central

    Kirmizialtin, Serdal; Hennelly, Scott P.; Schug, Alexander; Onuchic, Jose N.; Sanbonmatsu, Karissa Y.

    2016-01-01

    Integration and calibration of molecular dynamics simulations with experimental data remains a challenging endeavor. We have developed a novel method to integrate chemical probing experiments with molecular simulations of RNA molecules by using a native structure-based model. Selective 2’-hydroxyl acylation by primer extension (SHAPE) characterizes the mobility of each residue in the RNA. Our method, SHAPE-FIT, automatically optimizes the potential parameters of the forcefield according to measured reactivities from SHAPE. The optimized parameter set allows simulations of dynamics highly consistent with SHAPE probing experiments. Such atomistic simulations, thoroughly grounded in experiment, can open a new window on RNA structure-function relations. PMID:25726467

  13. Investigation of optimized wafer sampling with multiple integrated metrology modules within photolithography equipment

    NASA Astrophysics Data System (ADS)

    Taylor, Ted L.; Makimura, Eri

    2007-03-01

    Micron Technology, Inc., explores the challenges of defining specific wafer sampling scenarios for users of multiple integrated metrology modules within a Tokyo Electron Limited (TEL) CLEAN TRACK TM LITHIUS TM. With the introduction of integrated metrology (IM) into the photolithography coater/developer, users are faced with the challenge of determining what type of data is required to collect to adequately monitor the photolithography tools and the manufacturing process. Photolithography coaters/developers have a metrology block that is capable of integrating three metrology modules into the standard wafer flow. Taking into account the complexity of multiple metrology modules and varying across-wafer sampling plans per metrology module, users must optimize the module wafer sampling to obtain their desired goals. Users must also understand the complexity of the coater/developer handling systems to deliver wafers to each module. Coater/developer systems typically process wafers sequentially through each module to ensure consistent processing. In these systems, the first wafer must process through a module before the next wafer can process through a module, and the first wafer must return to the cassette before the second wafer can return to the cassette. IM modules within this type of system can reduce throughput and limit flexible wafer selections. Finally, users must have the ability to select specific wafer samplings for each IM module. This case study explores how to optimize wafer sampling plans and how to identify limitations with the complexity of multiple integrated modules to ensure maximum metrology throughput without impact to the productivity of processing wafers through the photolithography cell (litho cell).

  14. Integrated molecular mechanism directing nucleosome reorganization by human FACT

    PubMed Central

    Tsunaka, Yasuo; Fujiwara, Yoshie; Oyama, Takuji; Hirose, Susumu; Morikawa, Kosuke

    2016-01-01

    Facilitates chromatin transcription (FACT) plays essential roles in chromatin remodeling during DNA transcription, replication, and repair. Our structural and biochemical studies of human FACT–histone interactions present precise views of nucleosome reorganization, conducted by the FACT-SPT16 (suppressor of Ty 16) Mid domain and its adjacent acidic AID segment. AID accesses the H2B N-terminal basic region exposed by partial unwrapping of the nucleosomal DNA, thereby triggering the invasion of FACT into the nucleosome. The crystal structure of the Mid domain complexed with an H3–H4 tetramer exhibits two separate contact sites; the Mid domain forms a novel intermolecular β structure with H4. At the other site, the Mid–H2A steric collision on the H2A-docking surface of the H3–H4 tetramer within the nucleosome induces H2A–H2B displacement. This integrated mechanism results in disrupting the H3 αN helix, which is essential for retaining the nucleosomal DNA ends, and hence facilitates DNA stripping from histone. PMID:26966247

  15. Integrated molecular mechanism directing nucleosome reorganization by human FACT.

    PubMed

    Tsunaka, Yasuo; Fujiwara, Yoshie; Oyama, Takuji; Hirose, Susumu; Morikawa, Kosuke

    2016-03-15

    Facilitates chromatin transcription (FACT) plays essential roles in chromatin remodeling during DNA transcription, replication, and repair. Our structural and biochemical studies of human FACT-histone interactions present precise views of nucleosome reorganization, conducted by the FACT-SPT16 (suppressor of Ty 16) Mid domain and its adjacent acidic AID segment. AID accesses the H2B N-terminal basic region exposed by partial unwrapping of the nucleosomal DNA, thereby triggering the invasion of FACT into the nucleosome. The crystal structure of the Mid domain complexed with an H3-H4 tetramer exhibits two separate contact sites; the Mid domain forms a novel intermolecular β structure with H4. At the other site, the Mid-H2A steric collision on the H2A-docking surface of the H3-H4 tetramer within the nucleosome induces H2A-H2B displacement. This integrated mechanism results in disrupting the H3 αN helix, which is essential for retaining the nucleosomal DNA ends, and hence facilitates DNA stripping from histone. PMID:26966247

  16. Integrative systems medicine approaches to identify molecular targets in lymphoid malignancies.

    PubMed

    Frazzi, Raffaele; Auffray, Charles; Ferrari, Angela; Filippini, Perla; Rutella, Sergio; Cesario, Alfredo

    2016-01-01

    Although survival rates for lymphoproliferative disorders are steadily increasing both in the US and in Europe, there is need for optimizing front-line therapies and developing more effective salvage strategies. Recent advances in molecular genetics have highlighted the biological diversity of lymphoproliferative disorders. In particular, integrative approaches including whole genome sequencing, whole exome sequencing, and transcriptome or RNA sequencing have been instrumental to the identification of molecular targets for treatment. Herein, we will discuss how genomic, epigenomic and proteomic approaches in lymphoproliferative disorders have supported the discovery of molecular lesions and their therapeutic targeting in the clinic. PMID:27580852

  17. Coupled biophysical global ocean model and molecular genetic analyses identify multiple introductions of cryptogenic species.

    PubMed

    Dawson, Michael N; Sen Gupta, Alex; England, Matthew H

    2005-08-23

    The anthropogenic introduction of exotic species is one of the greatest modern threats to marine biodiversity. Yet exotic species introductions remain difficult to predict and are easily misunderstood because knowledge of natural dispersal patterns, species diversity, and biogeography is often insufficient to distinguish between a broadly dispersed natural population and an exotic one. Here we compare a global molecular phylogeny of a representative marine meroplanktonic taxon, the moon-jellyfish Aurelia, with natural dispersion patterns predicted by a global biophysical ocean model. Despite assumed high dispersal ability, the phylogeny reveals many cryptic species and predominantly regional structure with one notable exception: the globally distributed Aurelia sp.1, which, molecular data suggest, may occasionally traverse the Pacific unaided. This possibility is refuted by the ocean model, which shows much more limited dispersion and patterns of distribution broadly consistent with modern biogeographic zones, thus identifying multiple introductions worldwide of this cryptogenic species. This approach also supports existing evidence that (i) the occurrence in Hawaii of Aurelia sp. 4 and other native Indo-West Pacific species with similar life histories is most likely due to anthropogenic translocation, and (ii) there may be a route for rare natural colonization of northeast North America by the European marine snail Littorina littorea, whose status as endemic or exotic is unclear. PMID:16103373

  18. A low molecular weight artificial RNA of unique size with multiple probe target regions

    NASA Technical Reports Server (NTRS)

    Pitulle, C.; Dsouza, L.; Fox, G. E.

    1997-01-01

    Artificial RNAs (aRNAs) containing novel sequence segments embedded in a deletion mutant of Vibrio proteolyticus 5S rRNA have previously been shown to be expressed from a plasmid borne growth rate regulated promoter in E. coli. These aRNAs accumulate to high levels and their detection is a promising tool for studies in molecular microbial ecology and in environmental monitoring. Herein a new construct is described which illustrates the versatility of detection that is possible with aRNAs. This 3xPen aRNA construct carries a 72 nucleotide insert with three copies of a unique 17 base probe target sequence. This aRNA is 160 nucleotides in length and again accumulates to high levels in the E. coli cytoplasm without incorporating into ribosomes. The 3xPen aRNA illustrates two improvements in detection. First, by appropriate selection of insert size, we obtained an aRNA which provides a unique and hence, easily quantifiable peak, on a high resolution gel profile of low molecular weight RNAs. Second, the existence of multiple probe targets results in a nearly commensurate increase in signal when detection is by hybridization. These aRNAs are naturally amplified and carry sequence segments that are not found in known rRNA sequences. It thus may be possible to detect them directly. An experimental step involving RT-PCR or PCR amplification of the gene could therefore be avoided.

  19. The interaction between 4-aminoantipyrine and bovine serum albumin: multiple spectroscopic and molecular docking investigations.

    PubMed

    Teng, Yue; Liu, Rutao; Li, Chao; Xia, Qing; Zhang, Pengjun

    2011-06-15

    4-Aminoantipyrine (AAP) is widely used in the pharmaceutical industry, in biochemical experiments and in environmental monitoring. AAP as an aromatic pollutant in the environment poses a great threat to human health. To evaluate the toxicity of AAP at the protein level, the effects of AAP on bovine serum albumin (BSA) were investigated by multiple spectroscopic techniques and molecular modeling. After the inner filter effect was eliminated, the experimental results showed that AAP effectively quenched the intrinsic fluorescence of BSA via static quenching. The number of binding sites, the binding constant, the thermodynamic parameters and binding subdomain were measured, and indicated that AAP could spontaneously bind with BSA on subdomain IIIA through electrostatic forces. Molecular docking results revealed that AAP interacted with the Glu 488 and Glu 502 residues of BSA. Furthermore, the conformation of BSA was demonstrably changed in the presence of AAP. The skeletal structure of BSA loosened, exposing internal hydrophobic aromatic ring amino acids and peptide strands to the solution. PMID:21497437

  20. Transcriptomic Profile Reveals Gender-Specific Molecular Mechanisms Driving Multiple Sclerosis Progression

    PubMed Central

    Irizar, Haritz; Muñoz-Culla, Maider; Sepúlveda, Lucia; Sáenz-Cuesta, Matías; Prada, Álvaro; Castillo-Triviño, Tamara; Zamora-López, Gorka; de Munain, Adolfo López; Olascoaga, Javier; Otaegui, David

    2014-01-01

    Background Although the most common clinical presentation of multiple sclerosis (MS) is the so called Relapsing-Remitting MS (RRMS), the molecular mechanisms responsible for its progression are currently unknown. To tackle this problem, a whole-genome gene expression analysis has been performed on RRMS patients. Results The comparative analysis of the Affymetrix Human Gene 1.0 ST microarray data from peripheral blood leucocytes obtained from 25 patients in remission and relapse and 25 healthy subjects has revealed 174 genes altered in both remission and relapse, a high proportion of them showing what we have called “mirror pattern”: they are upregulated in remission and downregulated in relapse or vice versa. The coexpression analysis of these genes has shown that they are organized in three female-specific and one male-specific modules. Conclusions The interpretation of the modules of the coexpression network suggests that Epstein-Barr virus (EBV) reactivation of B cells happens in MS relapses; however, qPCR expression data of the viral genes supports that hypothesis only in female patients, reinforcing the notion that different molecular processes drive disease progression in females and males. Besides, we propose that the “primed” state showed by neutrophils in women is an endogenous control mechanism triggered to keep EBV reactivation under control through vitamin B12 physiology. Finally, our results also point towards an important sex-specific role of non-coding RNA in MS. PMID:24587374

  1. Infrared-active quadruple contrast FePt nanoparticles for multiple scale molecular imaging.

    PubMed

    Chou, Shang-Wei; Liu, Chien-Liang; Liu, Tzu-Ming; Shen, Yu-Fang; Kuo, Lun-Chang; Wu, Cheng-Ham; Hsieh, Tsung-Yuan; Wu, Pei-Chun; Tsai, Ming-Rung; Yang, Che-Chang; Chang, Kai-Yao; Lu, Meng-Hua; Li, Pai-Chi; Chen, Shi-Ping; Wang, Yu-Hsin; Lu, Chen-Wen; Chen, Yi-An; Huang, Chih-Chia; Wang, Churng-Ren Chris; Hsiao, Jong-Kai; Li, Meng-Lin; Chou, Pi-Tai

    2016-04-01

    A single nanomaterial with multiple imaging contrasts and functions is highly desired for multiscale theragnosis. Herein, we demonstrate single 1-1.9 μm infrared-active FePt alloy nanoparticles (FePt NPs) offering unprecedented four-contrast-in-one molecular imaging - computed tomography (CT), magnetic resonance imaging (MRI), photoacoustic (PA) imaging, and high-order multiphoton luminescence (HOMPL) microscopy. The PA response of FePt NPs outperforms that of infrared-active gold nanorods by 3- to 5.6-fold under identical excitation fluence and particle concentrations. HOMPL (680 nm) of an isolated FePt NP renders spatial full-width-at-half-maximum values of 432 nm and 300 nm beyond the optical diffraction limit for 1230-nm and 920-nm excitation, respectively. The in vivo targeting function was successfully visualized using HOMPL, PA imaging, CT, and MRI, thereby validating FePt as a single nanomaterial system covering up to four types (Optical/PA/CT/MRI) of molecular imaging contrast, ranging from the microscopic level to whole-body scale investigation. PMID:26854391

  2. Molecular Mechanisms of the Action of Vitamin A in Th17/Treg Axis in Multiple Sclerosis.

    PubMed

    Abdolahi, Mina; Yavari, Parvaneh; Honarvar, Niyaz Mohammadzadeh; Bitarafan, Sama; Mahmoudi, Maryam; Saboor-Yaraghi, Ali Akbar

    2015-12-01

    Multiple sclerosis (MS) is an autoinflammatory disease of the central nervous system (CNS). The immunopathogenesis of this disease involves an impaired balance of T helper (Th) 17 cells and regulatory T (Tregs) cells. MS is an autoinflammatory disease characterized by the degeneration of the CNS. For many years, MS has been considered to be an autoreactive Th1 and Th17 cell-dominated disease. The activity and number of Th17 cells are increased in MS; however, the function and number of Treg cells are reduced. Therefore, in MS, the balance between Th17 cells and Treg cells is impaired. Th17 cells produce pro-inflammatory cytokines, which play a role in experimental autoimmune encephalomyelitis (EAE) and MS. However, Treg cell-mediated production of cytokines maintains immune homeostasis and can ameliorate the progression of MS. These observations, therefore, confirm the pathogenic and protective role of Th17 and Treg cells, respectively, and highlight the importance of maintaining the balance of both of these cell types. Evidence suggests that vitamin A and its active metabolites (all-trans-retinoic acid and 9-cis-retinoic acid) modulate the imbalance of Th17 and Treg cells through multiple molecular pathways and can be considered as a promising target in the prevention and treatment of MS. PMID:26319266

  3. High-precision, automated integration of multiple isothermal titration calorimetric thermograms: new features of NITPIC.

    PubMed

    Scheuermann, Thomas H; Brautigam, Chad A

    2015-04-01

    Isothermal titration calorimetry (ITC) has become a standard and widely available tool to measure the thermodynamic parameters of macromolecular associations. Modern applications of the method, including global analysis and drug screening, require the acquisition of multiple sets of data; sometimes these data sets number in the hundreds. Therefore, there is a need for quick, precise, and automated means to process the data, particularly at the first step of data analysis, which is commonly the integration of the raw data to yield an interpretable isotherm. Herein, we describe enhancements to an algorithm that previously has been shown to provide an automated, unbiased, and high-precision means to integrate ITC data. These improvements allow for the speedy and precise serial integration of an unlimited number of ITC data sets, and they have been implemented in the freeware program NITPIC, version 1.1.0. We present a comprehensive comparison of the performance of this software against an older version of NITPIC and a current version of Origin, which is commonly used for integration. The new methods recapitulate the excellent performance of the previous versions of NITPIC while speeding it up substantially, and their precision is significantly better than that of Origin. This new version of NITPIC is therefore well suited to the serial integration of many ITC data sets. PMID:25524420

  4. A fast and high performance multiple data integration algorithm for identifying human disease genes

    PubMed Central

    2015-01-01

    Background Integrating multiple data sources is indispensable in improving disease gene identification. It is not only due to the fact that disease genes associated with similar genetic diseases tend to lie close with each other in various biological networks, but also due to the fact that gene-disease associations are complex. Although various algorithms have been proposed to identify disease genes, their prediction performances and the computational time still should be further improved. Results In this study, we propose a fast and high performance multiple data integration algorithm for identifying human disease genes. A posterior probability of each candidate gene associated with individual diseases is calculated by using a Bayesian analysis method and a binary logistic regression model. Two prior probability estimation strategies and two feature vector construction methods are developed to test the performance of the proposed algorithm. Conclusions The proposed algorithm is not only generated predictions with high AUC scores, but also runs very fast. When only a single PPI network is employed, the AUC score is 0.769 by using F2 as feature vectors. The average running time for each leave-one-out experiment is only around 1.5 seconds. When three biological networks are integrated, the AUC score using F3 as feature vectors increases to 0.830, and the average running time for each leave-one-out experiment takes only about 12.54 seconds. It is better than many existing algorithms. PMID:26399620

  5. Real object-based 360-degree integral-floating display using multiple depth camera

    NASA Astrophysics Data System (ADS)

    Erdenebat, Munkh-Uchral; Dashdavaa, Erkhembaatar; Kwon, Ki-Chul; Wu, Hui-Ying; Yoo, Kwan-Hee; Kim, Young-Seok; Kim, Nam

    2015-03-01

    A novel 360-degree integral-floating display based on the real object is proposed. The general procedure of the display system is similar with conventional 360-degree integral-floating displays. Unlike previously presented 360-degree displays, the proposed system displays the 3D image generated from the real object in 360-degree viewing zone. In order to display real object in 360-degree viewing zone, multiple depth camera have been utilized to acquire the depth information around the object. Then, the 3D point cloud representations of the real object are reconstructed according to the acquired depth information. By using a special point cloud registration method, the multiple virtual 3D point cloud representations captured by each depth camera are combined as single synthetic 3D point cloud model, and the elemental image arrays are generated for the newly synthesized 3D point cloud model from the given anamorphic optic system's angular step. The theory has been verified experimentally, and it shows that the proposed 360-degree integral-floating display can be an excellent way to display real object in the 360-degree viewing zone.

  6. Identification of Functional Modules by Integration of Multiple Data Sources Using a Bayesian Network Classifier

    PubMed Central

    Wang, Jinlian; Zuo, Yiming; Liu, Lun; Man, Yangao; Tadesse, Mahlet G.; Ressom, Habtom W

    2014-01-01

    Background Prediction of functional modules is indispensable for detecting protein deregulation in human complex diseases such as cancer. Bayesian network (BN) is one of the most commonly used models to integrate heterogeneous data from multiple sources such as protein domain, interactome, functional annotation, genome-wide gene expression, and the literature. Methods and Results In this paper, we present a BN classifier that is customized to: 1) increase the ability to integrate diverse information from different sources, 2) effectively predict protein-protein interactions, 3) infer aberrant networks with scale-free and small world properties, and 4) group molecules into functional modules or pathways based on the primary function and biological features. Application of this model on discovering protein biomarkers of hepatocelluar carcinoma (HCC) leads to the identification of functional modules that provide insights into the mechanism of the development and progression of HCC. These functional modules include cell cycle deregulation, increased angiogenesis (e.g., vascular endothelial growth factor, blood vessel morphogenesis), oxidative metabolic alterations, and aberrant activation of signaling pathways involved in cellular proliferation, survival, and differentiation. Conclusion The discoveries and conclusions derived from our customized BN classifier are consistent with previously published results. The proposed approach for determining BN structure facilitates the integration of heterogeneous data from multiple sources to elucidate the mechanisms of complex diseases. PMID:24736851

  7. MSblender: a probabilistic approach for integrating peptide identifications from multiple database search engines

    PubMed Central

    Kwon, Taejoon; Choi, Hyungwon; Vogel, Christine; Nesvizhskii, Alexey I.; Marcotte, Edward M.

    2011-01-01

    Shotgun proteomics using mass spectrometry is a powerful method for protein identification but suffers limited sensitivity in complex samples. Integrating peptide identifications from multiple database search engines is a promising strategy to increase the number of peptide identifications and reduce the volume of unassigned tandem mass spectra. Existing methods pool statistical significance scores such as p-values or posterior probabilities of peptide-spectrum matches (PSMs) from multiple search engines after high scoring peptides have been assigned to spectra, but these methods lack reliable control of identification error rates as data are integrated from different search engines. We developed a statistically coherent method for integrative analysis, termed MSblender. MSblender converts raw search scores from search engines into a probability score for all possible PSMs and properly accounts for the correlation between search scores. The method reliably estimates false discovery rates and identifies more PSMs than any single search engine at the same false discovery rate. Increased identifications increment spectral counts for all detected proteins and allow quantification of proteins that would not have been quantified by individual search engines. We also demonstrate that enhanced quantification contributes to improve sensitivity in differential expression analyses. PMID:21488652

  8. MSblender: A probabilistic approach for integrating peptide identifications from multiple database search engines.

    PubMed

    Kwon, Taejoon; Choi, Hyungwon; Vogel, Christine; Nesvizhskii, Alexey I; Marcotte, Edward M

    2011-07-01

    Shotgun proteomics using mass spectrometry is a powerful method for protein identification but suffers limited sensitivity in complex samples. Integrating peptide identifications from multiple database search engines is a promising strategy to increase the number of peptide identifications and reduce the volume of unassigned tandem mass spectra. Existing methods pool statistical significance scores such as p-values or posterior probabilities of peptide-spectrum matches (PSMs) from multiple search engines after high scoring peptides have been assigned to spectra, but these methods lack reliable control of identification error rates as data are integrated from different search engines. We developed a statistically coherent method for integrative analysis, termed MSblender. MSblender converts raw search scores from search engines into a probability score for every possible PSM and properly accounts for the correlation between search scores. The method reliably estimates false discovery rates and identifies more PSMs than any single search engine at the same false discovery rate. Increased identifications increment spectral counts for most proteins and allow quantification of proteins that would not have been quantified by individual search engines. We also demonstrate that enhanced quantification contributes to improve sensitivity in differential expression analyses. PMID:21488652

  9. Molecular phylogenetics reveal multiple tertiary vicariance origins of the African rain forest trees

    PubMed Central

    Couvreur, Thomas LP; Chatrou, Lars W; Sosef, Marc SM; Richardson, James E

    2008-01-01

    Background Tropical rain forests are the most diverse terrestrial ecosystems on the planet. How this diversity evolved remains largely unexplained. In Africa, rain forests are situated in two geographically isolated regions: the West-Central Guineo-Congolian region and the coastal and montane regions of East Africa. These regions have strong floristic affinities with each other, suggesting a former connection via an Eocene pan-African rain forest. High levels of endemism observed in both regions have been hypothesized to be the result of either 1) a single break-up followed by a long isolation or 2) multiple fragmentation and reconnection since the Oligocene. To test these hypotheses the evolutionary history of endemic taxa within a rain forest restricted African lineage of the plant family Annonaceae was studied. Molecular phylogenies and divergence dates were estimated using a Bayesian relaxed uncorrelated molecular clock assumption accounting for both calibration and phylogenetic uncertainties. Results Our results provide strong evidence that East African endemic lineages of Annonaceae have multiple origins dated to significantly different times spanning the Oligocene and Miocene epochs. Moreover, these successive origins (c. 33, 16 and 8 million years – Myr) coincide with known periods of aridification and geological activity in Africa that would have recurrently isolated the Guineo-Congolian rain forest from the East African one. All East African taxa were found to have diversified prior to Pleistocene times. Conclusion Molecular phylogenetic dating analyses of this large pan-African clade of Annonaceae unravels an interesting pattern of diversification for rain forest restricted trees co-occurring in West/Central and East African rain forests. Our results suggest that repeated reconnections between the West/Central and East African rain forest blocks allowed for biotic exchange while the break-ups induced speciation via vicariance, enhancing the levels of

  10. The expression pattern of small nucleolar and small Cajal body-specific RNAs characterizes distinct molecular subtypes of multiple myeloma

    PubMed Central

    Ronchetti, D; Todoerti, K; Tuana, G; Agnelli, L; Mosca, L; Lionetti, M; Fabris, S; Colapietro, P; Miozzo, M; Ferrarini, M; Tassone, P; Neri, A

    2012-01-01

    Small nucleolar RNAs (snoRNAs) and small Cajal body-specific RNAs (scaRNAs) are non-coding RNAs involved in the maturation of other RNA molecules and generally located in the introns of host genes. It is now emerging that altered sno/scaRNAs expression may have a pathological role in cancer. This study elucidates the patterns of sno/scaRNAs expression in multiple myeloma (MM) by profiling purified malignant plasma cells from 55 MMs, 8 secondary plasma cell leukemias (sPCLs) and 4 normal controls. Overall, a global sno/scaRNAs downregulation was found in MMs and, even more, in sPCLs compared with normal plasma cells. Whereas SCARNA22 resulted the only sno/scaRNA characterizing the translocation/cyclin D4 (TC4) MM, TC2 group displayed a distinct sno/scaRNA signature overexpressing members of SNORD115 and SNORD116 families located in a region finely regulated by an imprinting center at 15q11, which, however, resulted overall hypomethylated in MMs independently of the SNORD115 and SNORD116 expression levels. Finally, integrative analyses with available gene expression and genome-wide data revealed the occurrence of significant sno/scaRNAs/host genes co-expression and the putative influence of allelic imbalances on specific snoRNAs expression. Our data extend the current view of sno/scaRNAs deregulation in cancer and add novel information to the bio-molecular complexity of plasma cell dyscrasias. PMID:23178508

  11. A unified scheme for the calculation of differentiated and undifferentiated molecular integrals over solid-harmonic Gaussians.

    PubMed

    Reine, Simen; Tellgren, Erik; Helgaker, Trygve

    2007-09-14

    Utilizing the fact that solid-harmonic combinations of Cartesian and Hermite Gaussian atomic orbitals are identical, a new scheme for the evaluation of molecular integrals over solid-harmonic atomic orbitals is presented, where the integration is carried out over Hermite rather than Cartesian atomic orbitals. Since Hermite Gaussians are defined as derivatives of spherical Gaussians, the corresponding molecular integrals become the derivatives of integrals over spherical Gaussians, whose transformation to the solid-harmonic basis is performed in the same manner as for integrals over Cartesian Gaussians, using the same expansion coefficients. The presented solid-harmonic Hermite scheme simplifies the evaluation of derivative molecular integrals, since differentiation by nuclear coordinates merely increments the Hermite quantum numbers, thereby providing a unified scheme for undifferentiated and differentiated four-center molecular integrals. For two- and three-center two-electron integrals, the solid-harmonic Hermite scheme is particularly efficient, significantly reducing the cost relative to the Cartesian scheme. PMID:17712455

  12. Reusable nanostencils for creating multiple biofunctional molecular nanopatterns on polymer substrate.

    PubMed

    Huang, Min; Galarreta, Betty C; Artar, Alp; Adato, Ronen; Aksu, Serap; Altug, Hatice

    2012-09-12

    In this paper, we demonstrate a novel method for high throughput patterning of bioprobes with nanoscale features on biocompatible polymer substrate. Our technique, based on nanostencil lithography, employs high resolution and robust masks integrated with array of reservoirs. We show that the smallest pattern size can reach down to 100 nm. We also show that different types of biomolecules can be patterned on the same substrate simultaneously. Furthermore, the stencil can be reused multiple times to generate a series of identical patterns at low cost. Finally, we demonstrate that biomolecules can be covalently patterned on the surface while retaining their biofunctionalities. By offering the flexibility on the nanopattern design and enabling the reusability of the stencil, our approach significantly simplifies the bionanopatterning process and therefore could have profound implications in diverse biological and medical applications. PMID:22839211

  13. Integration of multiple view plus depth data for free viewpoint 3D display

    NASA Astrophysics Data System (ADS)

    Suzuki, Kazuyoshi; Yoshida, Yuko; Kawamoto, Tetsuya; Fujii, Toshiaki; Mase, Kenji

    2014-03-01

    This paper proposes a method for constructing a reasonable scale of end-to-end free-viewpoint video system that captures multiple view and depth data, reconstructs three-dimensional polygon models of objects, and display them on virtual 3D CG spaces. This system consists of a desktop PC and four Kinect sensors. First, multiple view plus depth data at four viewpoints are captured by Kinect sensors simultaneously. Then, the captured data are integrated to point cloud data by using camera parameters. The obtained point cloud data are sampled to volume data that consists of voxels. Since volume data that are generated from point cloud data are sparse, those data are made dense by using global optimization algorithm. Final step is to reconstruct surfaces on dense volume data by discrete marching cubes method. Since accuracy of depth maps affects to the quality of 3D polygon model, a simple inpainting method for improving depth maps is also presented.

  14. ePRISM: A case study in multiple proxy and mixed temporal resolution integration

    USGS Publications Warehouse

    Robinson, Marci M.; Dowsett, Harry J.

    2010-01-01

    As part of the Pliocene Research, Interpretation and Synoptic Mapping (PRISM) Project, we present the ePRISM experiment designed I) to provide climate modelers with a reconstruction of an early Pliocene warm period that was warmer than the PRISM interval (similar to 3.3 to 3.0 Ma), yet still similar in many ways to modern conditions and 2) to provide an example of how best to integrate multiple-proxy sea surface temperature (SST) data from time series with varying degrees of temporal resolution and age control as we begin to build the next generation of PRISM, the PRISM4 reconstruction, spanning a constricted time interval. While it is possible to tie individual SST estimates to a single light (warm) oxygen isotope event, we find that the warm peak average of SST estimates over a narrowed time interval is preferential for paleoclimate reconstruction as it allows for the inclusion of more records of multiple paleotemperature proxies.

  15. Characterization of multiple-bit errors from single-ion tracks in integrated circuits

    NASA Technical Reports Server (NTRS)

    Zoutendyk, J. A.; Edmonds, L. D.; Smith, L. S.

    1989-01-01

    The spread of charge induced by an ion track in an integrated circuit and its subsequent collection at sensitive nodal junctions can cause multiple-bit errors. The authors have experimentally and analytically investigated this phenomenon using a 256-kb dynamic random-access memory (DRAM). The effects of different charge-transport mechanisms are illustrated, and two classes of ion-track multiple-bit error clusters are identified. It is demonstrated that ion tracks that hit a junction can affect the lateral spread of charge, depending on the nature of the pull-up load on the junction being hit. Ion tracks that do not hit a junction allow the nearly uninhibited lateral spread of charge.

  16. T2D-Db: An integrated platform to study the molecular basis of Type 2 diabetes

    PubMed Central

    Agrawal, Shipra; Dimitrova, Nevenka; Nathan, Prasanthi; Udayakumar, K; Lakshmi, S Sai; Sriram, S; Manjusha, N; Sengupta, Urmi

    2008-01-01

    Background Type 2 Diabetes Mellitus (T2DM) is a non insulin dependent, complex trait disease that develops due to genetic predisposition and environmental factors. The advanced stage in type 2 diabetes mellitus leads to several micro and macro vascular complications like nephropathy, neuropathy, retinopathy, heart related problems etc. Studies performed on the genetics, biochemistry and molecular biology of this disease to understand the pathophysiology of type 2 diabetes mellitus has led to the generation of a surfeit of data on candidate genes and related aspects. The research is highly progressive towards defining the exact etiology of this disease. Results T2D-Db (Type 2 diabetes Database) is a comprehensive web resource, which provides integrated and curated information on almost all known molecular components involved in the pathogenesis of type 2 diabetes mellitus in the three widely studied mammals namely human, mouse and rat. Information on candidate genes, SNPs (Single Nucleotide Polymorphism) in candidate genes or candidate regions, genome wide association studies (GWA), tissue specific gene expression patterns, EST (Expressed Sequence Tag) data, expression information from microarray data, pathways, protein-protein interactions and disease associated risk factors or complications have been structured in this on line resource. Conclusion Information available in T2D-Db provides an integrated platform for the better molecular level understanding of type 2 diabetes mellitus and its pathogenesis. Importantly, the resource facilitates graphical presentation of the gene/genome wide map of SNP markers and protein-protein interaction networks, besides providing the heat map diagram of the selected gene(s) in an organism across microarray expression experiments from either single or multiple studies. These features aid to the data interpretation in an integrative way. T2D-Db is to our knowledge the first publicly available resource that can cater to the needs of

  17. Integrated airborne lidar and multiple endmember spectral mixture analysis (MESMA) for plant species mapping across multiple functional groups

    NASA Astrophysics Data System (ADS)

    Dahlin, K.; Asner, G. P.

    2010-12-01

    The ability to map plant species distributions has long been one of the key goals of terrestrial remote sensing. Achieving this goal has been challenging, however, due to technical constraints and the difficulty in relating remote observations to ground measurements. Advances in both the types of data that can be collected remotely and in available analytical tools like multiple endmember spectral mixture analysis (MESMA) are allowing for rapid improvements in this field. In 2007 the Carnegie Airborne Observatory (CAO) acquired high resolution lidar and hyperspectral imagery of Jasper Ridge Biological Preserve (Woodside, California). The site contains a mosaic of vegetation types, from grassland to chaparral to evergreen forest. To build a spectral library, 415 GPS points were collected in the field, made up of 44 plant species, six plant categories (for nonphotosynthetic vegetation), and four substrate types. Using the lidar data to select the most illuminated pixels as seen from the aircraft (based on canopy shape and viewing angle), we then reduced the spectral library to only the most fully lit pixels. To identify individual plant species in the imagery, first the hyperspectral data was used to calculate the normalized difference vegetation index (NDVI), and then pixels with an NDVI less than 0.15 were removed from further analysis. The remaining image was stratified into five classes based on vegetation height derived from the lidar data. For each class, a suite of possible endmembers was identified and then three endmember selection procedures (endmember average RMS, minimum average spectral angle, and count based endmember selection) were employed to select the most representative endmembers from each species in each class. Two and three endmember models were then applied and each pixel was assigned a species or plant category based on the highest endmember fraction. To validate the approach, an independent set of 200 points was collected throughout the

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

    PubMed Central

    2012-01-01

    Background The virtual screening (VS) of lead compounds using molecular docking and pharmacophore detection is now an important tool in drug discovery. VS tasks typically require a combination of several software tools and a molecular graphics system. Thus, the integration of all the requisite tools in a single operating environment could reduce the complexity of running VS experiments. However, only a few freely available integrated software platforms have been developed. Results A free open-source platform, IVSPlat 1.0, was developed in this study for the management and automation of VS tasks. We integrated several VS-related programs into a molecular graphics system to provide a comprehensive platform for the solution of VS tasks based on molecular docking, pharmacophore detection, and a combination of both methods. This tool can be used to visualize intermediate and final results of the VS execution, while also providing a clustering tool for the analysis of VS results. A case study was conducted to demonstrate the applicability of this platform. Conclusions IVSPlat 1.0 provides a plug-in-based solution for the management, automation, and visualization of VS tasks. IVSPlat 1.0 is an open framework that allows the integration of extra software to extend its functionality and modified versions can be freely distributed. The open source code and documentation are available at http://kyc.nenu.edu.cn/IVSPlat/. PMID:22222098

  19. Noisy Speech Recognition Based on Integration/Selection of Multiple Noise Suppression Methods Using Noise GMMs

    NASA Astrophysics Data System (ADS)

    Kitaoka, Norihide; Hamaguchi, Souta; Nakagawa, Seiichi

    To achieve high recognition performance for a wide variety of noise and for a wide range of signal-to-noise ratio, this paper presents methods for integration of four noise reduction algorithms: spectral subtraction with smoothing of time direction, temporal domain SVD-based speech enhancement, GMM-based speech estimation and KLT-based comb-filtering. In this paper, we proposed two types of combination methods of noise suppression algorithms: selection of front-end processor and combination of results from multiple recognition processes. Recognition results on the CENSREC-1 task showed the effectiveness of our proposed methods.kn-abstract=

  20. Method for Visually Integrating Multiple Data Acquisition Technologies for Real Time and Retrospective Analysis

    NASA Technical Reports Server (NTRS)

    Bogart, Edward H. (Inventor); Pope, Alan T. (Inventor)

    2000-01-01

    A system for display on a single video display terminal of multiple physiological measurements is provided. A subject is monitored by a plurality of instruments which feed data to a computer programmed to receive data, calculate data products such as index of engagement and heart rate, and display the data in a graphical format simultaneously on a single video display terminal. In addition live video representing the view of the subject and the experimental setup may also be integrated into the single data display. The display may be recorded on a standard video tape recorder for retrospective analysis.

  1. Evaluating environmental sustainability: an integration of multiple-criteria decision-making and fuzzy logic.

    PubMed

    Liu, Kevin F R

    2007-05-01

    While pursuing economic development, countries around the world have become aware of the importance of environmental sustainability; therefore, the evaluation of environmental sustainability has become a significant issue. Traditionally, multiple-criteria decision-making (MCDM) was widely used as a way of evaluating environmental sustainability, Recently, several researchers have attempted to implement this evaluation with fuzzy logic since they recognized the assessment of environmental sustainability as a subjective judgment Intuition. This paper outlines a new evaluation-framework of environmental sustainability, which integrates fuzzy logic into MCDM. This evaluation-framework consists of 36 structured and 5 unstructured decision-points, wherein MCDM is used to handle the former and fuzzy logic serves for the latter, With the integrated evaluation-framework, the evaluations of environmental sustainability in 146 countries are calculated, ranked and clustered, and the evaluation results are very helpful to these countries, as they identify their obstacles towards environmental sustainability. PMID:17377731

  2. One-step integration of multiple genes into the oleaginous yeast Yarrowia lipolytica.

    PubMed

    Gao, Shuliang; Han, Linna; Zhu, Li; Ge, Mei; Yang, Sheng; Jiang, Yu; Chen, Daijie

    2014-12-01

    Yarrowia lipolytica is an unconventional yeast, and is generally recognized as safe (GRAS). It provides a versatile fermentation platform that is used commercially to produce many added-value products. Here we report a multiple fragment assembly method that allows one-step integration of an entire β-carotene biosynthesis pathway (~11 kb, consisting of four genes) via in vivo homologous recombination into the rDNA locus of the Y. lipolytica chromosome. The highest efficiency was 21%, and the highest production of β-carotene was 2.2 ± 0.3 mg per g dry cell weight. The total procedure was completed in less than one week, as compared to a previously reported sequential gene integration method that required n weeks for n genes. This time-saving method will facilitate synthetic biology, metabolic engineering and functional genomics studies of Y. lipolytica. PMID:25216641

  3. Pragmatic Metadata Management for Integration into Multiple Spatial Data Infrastructure Systems and Platforms

    NASA Astrophysics Data System (ADS)

    Benedict, K. K.; Scott, S.

    2013-12-01

    While there has been a convergence towards a limited number of standards for representing knowledge (metadata) about geospatial (and other) data objects and collections, there exist a variety of community conventions around the specific use of those standards and within specific data discovery and access systems. This combination of limited (but multiple) standards and conventions creates a challenge for system developers that aspire to participate in multiple data infrastrucutres, each of which may use a different combination of standards and conventions. While Extensible Markup Language (XML) is a shared standard for encoding most metadata, traditional direct XML transformations (XSLT) from one standard to another often result in an imperfect transfer of information due to incomplete mapping from one standard's content model to another. This paper presents the work at the University of New Mexico's Earth Data Analysis Center (EDAC) in which a unified data and metadata management system has been developed in support of the storage, discovery and access of heterogeneous data products. This system, the Geographic Storage, Transformation and Retrieval Engine (GSTORE) platform has adopted a polyglot database model in which a combination of relational and document-based databases are used to store both data and metadata, with some metadata stored in a custom XML schema designed as a superset of the requirements for multiple target metadata standards: ISO 19115-2/19139/19110/19119, FGCD CSDGM (both with and without remote sensing extensions) and Dublin Core. Metadata stored within this schema is complemented by additional service, format and publisher information that is dynamically "injected" into produced metadata documents when they are requested from the system. While mapping from the underlying common metadata schema is relatively straightforward, the generation of valid metadata within each target standard is necessary but not sufficient for integration into

  4. Biomaterial constructs for delivery of multiple therapeutic genes: a spatiotemporal evaluation of efficacy using molecular beacons.

    PubMed

    Alexander, Jennifer C; Browne, Shane; Pandit, Abhay; Rochev, Yury

    2013-01-01

    Gene therapy is emerging as a potential therapeutic approach for cardiovascular pathogenesis. An appropriate therapy may require multiple genes to enhance therapeutic outcome by modulating inflammatory response and angiogenesis in a controlled and time-dependent manner. Thus, the aim of this research was to assess the spatiotemporal efficacy of a dual-gene therapy model based on 3D collagen scaffolds loaded with the therapeutic genes interleukin 10 (IL-10), a potent anti-inflammatory cytokine, and endothelial nitric oxide synthase (eNOS), a promoter of angiogenesis. A collagen-based scaffold loaded with plasmid IL-10 polyplexes and plasmid eNOS polyplexes encapsulated into microspheres was used to transfect HUVECs and HMSCs cells.The therapeutic efficacy of the system was monitored at 2, 7 and 14 days for eNOS and IL-10 mRNA expression using RT-PCR and live cell imaging molecular beacon technology. The dual gene releasing collagen-based scaffold provided both sustained and delayed release of functional polyplexes in vitro over a 14 day period which was corroborated with variation in expression levels seen using RT-PCR and MB imaging. Maximum fold increases in IL-10 mRNA and eNOS mRNA expression levels occurred at day 7 in HMSCs and HUVECs. However, IL-10 mRNA expression levels seemed dependent on frequency of media changes and/or ease of transfection of the cell type. It was demonstrated that molecular beacons are able to monitor changes in mRNA levels at various time points, in the presence of a 3D scaffolding gene carrier system and the results complemented those of RT-PCR. PMID:23755278

  5. Mechanically Untying a Protein Slipknot: Multiple Pathways Revealed by Force Spectroscopy and Steered Molecular Dynamics Simulations

    PubMed Central

    He, Chengzhi; Genchev, Georgi Z.; Lu, Hui; Li, Hongbin

    2013-01-01

    Protein structure is highly diverse when considering a wide range of protein types, helping to give rise to the multitude of functions that proteins perform. In particular, certain proteins are known to adopt a knotted or slipknotted fold. How such proteins undergo mechanical unfolding was investigated utilizing a combination of single molecule atomic force microscopy (AFM), protein engineering and steered molecular dynamics (SMD) simulations to show the mechanical unfolding mechanism of the slipknotted protein AFV3-109. Our results reveal that the mechancial unfolding of AFV3-109 can proceed via multiple parallel unfolding pathways that all cause the protein slipknot to untie, and the polypeptide chain to completely extend. These distinct unfolding pathways proceed either via a two-state or three-state unfolding process involving the formation of a well-defined, stable intermediate state. SMD simulations predict the same contour length increments for different unfolding pathways as single molecule AFM results, thus provding a plausible molecular mechanism for the mechanical unfolding of AFV3-109. These SMD simulations also reveal that two-state unfolding is initiated from both the N- and C-termini, while three-state unfolding is initiated only from the C-terminus. In both pathways, the protein slipknot was untied during unfolding, and no tightened slipknot conformation observed. Detailed analysis revealed that interactions between key structural elements lock the knotting loop in place, preventing it from shrinking and the formation of a tightened slipknot conformation. Our results demonstrate the bifurcation of the mechancial unfolding pathway of AFV3-109, and point to the generality of a kinetic partitioning mechanism for protein folding/unfolding. PMID:22626004

  6. Molecular Evolution of Multiple-Level Control of Heme Biosynthesis Pathway in Animal Kingdom

    PubMed Central

    Tzou, Wen-Shyong; Chu, Ying; Lin, Tzung-Yi; Hu, Chin-Hwa; Pai, Tun-Wen; Liu, Hsin-Fu; Lin, Han-Jia; Cases, Ildeofonso; Rojas, Ana; Sanchez, Mayka; You, Zong-Ye; Hsu, Ming-Wei

    2014-01-01

    Adaptation of enzymes in a metabolic pathway can occur not only through changes in amino acid sequences but also through variations in transcriptional activation, mRNA splicing and mRNA translation. The heme biosynthesis pathway, a linear pathway comprised of eight consecutive enzymes in animals, provides researchers with ample information for multiple types of evolutionary analyses performed with respect to the position of each enzyme in the pathway. Through bioinformatics analysis, we found that the protein-coding sequences of all enzymes in this pathway are under strong purifying selection, from cnidarians to mammals. However, loose evolutionary constraints are observed for enzymes in which self-catalysis occurs. Through comparative genomics, we found that in animals, the first intron of the enzyme-encoding genes has been co-opted for transcriptional activation of the genes in this pathway. Organisms sense the cellular content of iron, and through iron-responsive elements in the 5′ untranslated regions of mRNAs and the intron-exon boundary regions of pathway genes, translational inhibition and exon choice in enzymes may be enabled, respectively. Pathway product (heme)-mediated negative feedback control can affect the transport of pathway enzymes into the mitochondria as well as the ubiquitin-mediated stability of enzymes. Remarkably, the positions of these controls on pathway activity are not ubiquitous but are biased towards the enzymes in the upstream portion of the pathway. We revealed that multiple-level controls on the activity of the heme biosynthesis pathway depend on the linear depth of the enzymes in the pathway, indicating a new strategy for discovering the molecular constraints that shape the evolution of a metabolic pathway. PMID:24489775

  7. A graphical model method for integrating multiple sources of genome-scale data

    PubMed Central

    Dvorkin, Daniel; Biehs, Brian; Kechris, Katerina

    2016-01-01

    Making effective use of multiple data sources is a major challenge in modern bioinformatics. Genome-wide data such as measures of transcription factor binding, gene expression, and sequence conservation, which are used to identify binding regions and genes that are important to major biological processes such as development and disease, can be difficult to use together due to the different biological meanings and statistical distributions of the heterogeneous data types, but each can provide valuable information for understanding the processes under study. Here we present methods for integrating multiple data sources to gain a more complete picture of gene regulation and expression. Our goal is to identify genes and cis-regulatory regions which play specific biological roles. We describe a graphical mixture model approach for data integration, examine the effect of using different model topologies, and discuss methods for evaluating the effectiveness of the models. Model fitting is computationally efficient and produces results which have clear biological and statistical interpretations. The Hedgehog and Dorsal signaling pathways in Drosophila, which are critical in embryonic development, are used as examples. PMID:23934610

  8. Structure of the EGF receptor transactivation circuit integrates multiple signals with cell context

    SciTech Connect

    Joslin, Elizabeth J.; Shankaran, Harish; Opresko, Lee K.; Bollinger, Nikki; Lauffenburger, Douglas A.; Wiley, H. S.

    2010-05-10

    Transactivation of the epidermal growth factor receptor (EGFR) has been proposed to be a mechanism by which a variety of cellular inputs can be integrated into a single signaling pathway, but the regulatory topology of this important system is unclear. To understand the transactivation circuit, we first created a “non-binding” reporter for ligand shedding. We then quantitatively defined how signals from multiple agonists were integrated both upstream and downstream of the EGFR into the extracellular signal regulated kinase (ERK) cascade in human mammary epithelial cells. We found that transactivation is mediated by a recursive autocrine circuit where ligand shedding drives EGFR-stimulated ERK that in turn drives further ligand shedding. The time from shedding to ERK activation is fast (<5 min) whereas the recursive feedback is slow (>15 min). Simulations showed that this delay in positive feedback greatly enhanced system stability and robustness. Our results indicate that the transactivation circuit is constructed so that the magnitude of ERK signaling is governed by the sum of multiple direct inputs, while recursive, autocrine ligand shedding controls signal duration.

  9. Gene expression profiles from discordant monozygotic twins suggest that molecular pathways are shared among multiple systemic autoimmune diseases

    PubMed Central

    2011-01-01

    Introduction The objective of this study is to determine if multiple systemic autoimmune diseases (SAID) share gene expression pathways that could provide insights into pathogenic mechanisms common to these disorders. Methods RNA microarray analyses (Agilent Human 1A(V2) 20K oligo arrays) were used to quantify gene expression in peripheral blood cells from 20 monozygotic (MZ) twin pairs discordant for SAID. Six affected probands with systemic lupus erythematosus (SLE), six with rheumatoid arthritis (RA), eight with idiopathic inflammatory myopathies (IIM), and their same-gendered unaffected twins, were enrolled. Comparisons were made between discordant twin pairs and these were also each compared to 40 unrelated control subjects (matched 2:1 to each twin by age, gender and ethnicity) using statistical and molecular pathway analyses. Relative quantitative PCR was used to verify independently measures of differential gene expression assessed by microarray analysis. Results Probands and unrelated, matched controls differed significantly in gene expression for 104 probes corresponding to 92 identifiable genes (multiple-comparison adjusted P values < 0.1). Differentially expressed genes involved several overlapping pathways including immune responses (16%), signaling pathways (24%), transcription/translation regulators (26%), and metabolic functions (15%). Interferon (IFN)-response genes (IFI27, OASF, PLSCR1, EIF2AK2, TNFAIP6, and TNFSF10) were up-regulated in probands compared to unrelated controls. Many of the abnormally expressed genes played regulatory roles in multiple cellular pathways. We did not detect any probes expressed differentially in comparisons among the three SAID phenotypes. Similarly, we found no significant differences in gene expression when comparing probands to unaffected twins or unaffected twins to unrelated controls. Gene expression levels for unaffected twins appeared intermediate between that of probands and unrelated controls for 6535 probes

  10. Energy Simulation of Integrated Multiple-Zone Variable Refrigerant Flow System

    SciTech Connect

    Shen, Bo; Rice, C Keith; Baxter, Van D

    2013-01-01

    We developed a detailed steady-state system model, to simulate the performance of an integrated five-zone variable refrigerant flow (VRF)heat pump system. The system is multi-functional, capable of space cooling, space heating, combined space cooling and water heating, and dedicated water heating. Methods were developed to map the VRF performance in each mode, based on the abundant data produced by the equipment system model. The performance maps were used in TRNSYS annual energy simulations. Using TRNSYS, we have successfully setup and run cases for a multiple-split, VRF heat pump and dehumidifier combination in 5-zone houses in 5 climates that control indoor dry-bulb temperature and relative humidity. We compared the calculated energy consumptions for the VRF heat pump against that of a baseline central air source heat pump, coupled with electric water heating and the standalone dehumidifiers. In addition, we investigated multiple control scenarios for the VRF heat pump, i.e. on/off control, variable indoor air flow rate, and using different zone temperature setting schedules, etc. The energy savings for the multiple scenarios were assessed.

  11. Cumulative health risk assessment: integrated approaches for multiple contaminants, exposures, and effects

    SciTech Connect

    Rice, Glenn; Teuschler, Linda; MacDonel, Margaret; Butler, Jim; Finster, Molly; Hertzberg, Rick; Harou, Lynne

    2007-07-01

    Available in abstract form only. Full text of publication follows: As information about environmental contamination has increased in recent years, so has public interest in the combined effects of multiple contaminants. This interest has been highlighted by recent tragedies such as the World Trade Center disaster and hurricane Katrina. In fact, assessing multiple contaminants, exposures, and effects has long been an issue for contaminated sites, including U.S. Department of Energy (DOE) legacy waste sites. Local citizens have explicitly asked the federal government to account for cumulative risks, with contaminants moving offsite via groundwater flow, surface runoff, and air dispersal being a common emphasis. Multiple exposures range from ingestion and inhalation to dermal absorption and external gamma irradiation. Three types of concerns can lead to cumulative assessments: (1) specific sources or releases - e.g., industrial facilities or accidental discharges; (2) contaminant levels - in environmental media or human tissues; and (3) elevated rates of disease - e.g., asthma or cancer. The specific initiator frames the assessment strategy, including a determination of appropriate models to be used. Approaches are being developed to better integrate a variety of data, extending from environmental to internal co-location of contaminants and combined effects, to support more practical assessments of cumulative health risks. (authors)

  12. Encrypting three-dimensional information system based on integral imaging and multiple chaotic maps

    NASA Astrophysics Data System (ADS)

    Xing, Yan; Wang, Qiong-Hua; Xiong, Zhao-Long; Deng, Huan

    2016-02-01

    An encrypting three-dimensional (3-D) information system based on integral imaging (II) and multiple chaotic maps is proposed. In the encrypting process, the elemental image array (EIA) which represents spatial and angular information of the real 3-D scene is picked up by a microlens array. Subsequently, R, G, and B color components decomposed by the EIA are encrypted using multiple chaotic maps. Finally, these three encrypted components are interwoven to obtain the cipher information. The decryption process implements the reverse operation of the encryption process for retrieving the high-quality 3-D images. Since the encrypted EIA has the data redundancy property due to II, and all parameters of the pickup part are the secret keys of the encrypting system, the system sensitivity on the changes of the plaintext and secret keys can be significantly improved. Moreover, the algorithm based on multiple chaotic maps can effectively enhance the security. A preliminary experiment is carried out, and the experimental results verify the effectiveness, robustness, and security of the proposed system.

  13. 360 degree viewable floating autostereoscopic display using integral photography and multiple semitransparent mirrors.

    PubMed

    Zhao, Dong; Su, Baiquan; Chen, Guowen; Liao, Hongen

    2015-04-20

    In this paper, we present a polyhedron-shaped floating autostereoscopic display viewable from 360 degrees using integral photography (IP) and multiple semitransparent mirrors. IP combined with polyhedron-shaped multiple semitransparent mirrors is used to achieve a 360 degree viewable floating three-dimensional (3D) autostereoscopic display, having the advantage of being able to be viewed by several observers from various viewpoints simultaneously. IP is adopted to generate a 3D autostereoscopic image with full parallax property. Multiple semitransparent mirrors reflect corresponding IP images, and the reflected IP images are situated around the center of the polyhedron-shaped display device for producing the floating display. The spatial reflected IP images reconstruct a floating autostereoscopic image viewable from 360 degrees. We manufactured two prototypes for producing such displays and performed two sets of experiments to evaluate the feasibility of the method described above. The results of our experiments showed that our approach can achieve a floating autostereoscopic display viewable from surrounding area. Moreover, it is shown the proposed method is feasible to facilitate the continuous viewpoint of a whole 360 degree display without flipping. PMID:25969022

  14. Assessing District Energy Systems Performance Integrated with Multiple Thermal Energy Storages

    NASA Astrophysics Data System (ADS)

    Rezaie, Behnaz

    The goal of this study is to examine various energy resources in district energy (DE) systems and then DE system performance development by means of multiple thermal energy storages (TES) application. This study sheds light on areas not yet investigated precisely in detail. Throughout the research, major components of the heat plant, energy suppliers of the DE systems, and TES characteristics are separately examined; integration of various configurations of the multiple TESs in the DE system is then analysed. In the first part of the study, various sources of energy are compared, in a consistent manner, financially and environmentally. The TES performance is then assessed from various aspects. Then, TES(s) and DE systems with several sources of energy are integrated, and are investigated as a heat process centre. The most efficient configurations of the multiple TESs integrated with the DE system are investigated. Some of the findings of this study are applied on an actual DE system. The outcomes of this study provide insight for researchers and engineers who work in this field, as well as policy makers and project managers who are decision-makers. The accomplishments of the study are original developments TESs and DE systems. As an original development the Enviro-Economic Function, to balance the economic and environmental aspects of energy resources technologies in DE systems, is developed; various configurations of multiple TESs, including series, parallel, and general grid, are developed. The developed related functions are discharge temperature and energy of the TES, and energy and exergy efficiencies of the TES. The TES charging and discharging behavior of TES instantaneously is also investigated to obtain the charging temperature, the maximum charging temperature, the charging energy flow, maximum heat flow capacity, the discharging temperature, the minimum charging temperature, the discharging energy flow, the maximum heat flow capacity, and performance

  15. Molecular mechanisms of multiple toxin–antitoxin systems are coordinated to govern the persister phenotype

    PubMed Central

    Fasani, Rick A.; Savageau, Michael A.

    2013-01-01

    Toxin–antitoxin systems are ubiquitous and have been implicated in persistence, the multidrug tolerance of bacteria, biofilms, and, by extension, most chronic infections. However, their purpose, apparent redundancy, and coordination remain topics of debate. Our model relates molecular mechanisms to population dynamics for a large class of toxin–antitoxin systems and suggests answers to several of the open questions. The generic architecture of toxin–antitoxin systems provides the potential for bistability, and even when the systems do not exhibit bistability alone, they can be coupled to create a strongly bistable, hysteretic switch between normal and toxic states. Stochastic fluctuations can spontaneously switch the system to the toxic state, creating a heterogeneous population of growing and nongrowing cells, or persisters, that exist under normal conditions, rather than as an induced response. Multiple toxin–antitoxin systems can be cooperatively marshaled for greater effect, with the dilution determined by growth rate serving as the coordinating signal. The model predicts and elucidates experimental results that show a characteristic correlation between persister frequency and the number of toxin–antitoxin systems. PMID:23781105

  16. On multiple component detection in molecular plasmas using cw external-cavity quantum cascade infrared lasers

    NASA Astrophysics Data System (ADS)

    Lopatik, Dmitry; Lang, Norbert; Macherius, Uwe; Zimmermann, Henrik; Roepcke, Juergen

    2012-10-01

    Several cw external cavity quantum cascade lasers (EC-QCLs) have been tested as radiation sources for an absorption spectrometer focused on the analysis of molecular plasmas. Based on the wide spectral tunability of EC-QCLs multiple species detection is demonstrated in low pressure Ar/N2 MW plasmas containing CH4 as hydrocarbon precursor. Using the direct absorption technique the evolution of the concentrations of CH4, C2H2, HCN and H2O has been monitored depending on the discharge conditions (p= 0.5 mbar, f= 2.45 GHz) in a planar MW plasma reactor. The concentrations were found to be in the range of 10 ^11 -- 10 ^14 molecules cm-3. Based on the profiles of absorption lines the gas temperature Tg has been calculated in dependence on the discharge power. Changing the discharge power from 0.2 kW to 1 kW leads to an increase of Tg from 400 to 700 K. The typical spectral line width of the EC-QCLs under the study was about 30 MHz. Varying the power values of an EC-QCL for direct absorption measurements at low pressure conditions no saturation effects in determining the concentrations of CH4 and C2H2 could be found under the used conditions.

  17. Mycophenolic Acid Inhibits Migration and Invasion of Gastric Cancer Cells via Multiple Molecular Pathways

    PubMed Central

    Dun, Boying; Sharma, Ashok; Teng, Yong; Liu, Haitao; Purohit, Sharad; Xu, Heng; Zeng, Lingwen; She, Jin-Xiong

    2013-01-01

    Mycophenolic acid (MPA) is the metabolized product and active element of mycophenolate mofetil (MMF) that has been widely used for the prevention of acute graft rejection. MPA potently inhibits inosine monophosphate dehydrogenase (IMPDH) that is up-regulated in many tumors and MPA is known to inhibit cancer cell proliferation as well as fibroblast and endothelial cell migration. In this study, we demonstrated for the first time MPA’s antimigratory and anti-invasion abilities of MPA-sensitive AGS (gastric cancer) cells. Genome-wide expression analyses using Illumina whole genome microarrays identified 50 genes with ≥2 fold changes and 15 genes with > 4 fold alterations and multiple molecular pathways implicated in cell migration. Real-time RT-PCR analyses of selected genes also confirmed the expression differences. Furthermore, targeted proteomic analyses identified several proteins altered by MPA treatment. Our results indicate that MPA modulates gastric cancer cell migration through down-regulation of a large number of genes (PRKCA, DOCK1, INF2, HSPA5, LRP8 and PDGFRA) and proteins (PRKCA, AKT, SRC, CD147 and MMP1) with promigratory functions as well as up-regulation of a number of genes with antimigratory functions (ATF3, SMAD3, CITED2 and CEAMCAM1). However, a few genes that may promote migration (CYR61 and NOS3) were up-regulated. Therefore, MPA’s overall antimigratory role on cancer cells reflects a balance between promigratory and antimigratory signals influenced by MPA treatment. PMID:24260584

  18. Assessment of otocephalan and protacanthopterygian concepts in the light of multiple molecular phylogenies.

    PubMed

    Zaragüeta-Bagils, René; Lavoué, Sébastien; Tillier, Annie; Bonillo, Céline; Lecointre, Guillaume

    2002-12-01

    The rise of cladistics in ichthyology has dramatically improved our knowledge of teleostean basal interrelationships. However, some questions have remained open, among them the reliability of the Otocephala, a clade grouping clupeomorphs and ostariophysans, and the relationships of the Esocoidei. These two questions have been investigated in the light of new DNA sequences (from 28S and rhodopsin genes) and sequences from data banks (cytochrome b, 12-16S, 18S, MLL and RAG1). The ability of each of these markers to resolve basal teleostean interrelationships is assessed, and the cytochrome b was not found appropriate. Practical (i.e. different taxonomic samplings) and epistemological grounds led us to perform multiple separated phylogenetic analyses, in order to estimate the reliability of the above clades from their repeatability among trees from independent sequence data. The Otocephala are found monophyletic from most of the datasets; otherwise, they are not significantly contradicted from the others, which exhibit unresolved relationships. We conclude that the evidence provided here favours the sister-group relationship of clupeomorphs and ostariophysans. Morphological evidence including fossils is discussed, concluding that morphological works have not yet provided sufficient data to support this group. Salmonids and esocoids are found sister-groups from every molecular dataset in which these groups were sampled. Based on these convincing results, the Protacanthopterygii of Johnson and Patterson [1] are redefined, including the Esocoidei. PMID:12520869

  19. [Multiple endocrine neoplasia type 1 and 2. 1997 diagnostic guidelines and molecular pathology].

    PubMed

    Komminoth, P

    1997-07-01

    Multiple endocrine neoplasia syndromes (MEN) encompass autosomal dominantly inherited diseases which are characterized by the syn- or metachrone development of neoplastic and hyperplastic neuroendocrine lesions in several glands of an affected patient. In MEN type 1 the parathyroids, endocrine pancreas and duodenum and the pituitary and in MEN type 2 the thyroid C-cells, adrenal medulla and parathyroids are involved. Due to the recent identification of the mu gene and RET protooncogene as MEN-1 and MEN-2, respectively, and the elucidation of the genetic defects in affected patients, direct mutational analysis of germline DNA allows for the unambiguous identification of gene carriers and therefore the discrimination of MEN-associated and sporadically occurring neuroendocrine tumors. This is especially helpful in the context of the fairly high de novo mutation rates in MEN, since the discrimination of familial and sporadic neuroendocrine lesions by conventional and immunohistochemical analyses is rather unreliable. While the development of neuroendocrine lesions in young patients, bilateral or multicentricer tumors and the combination of hyperplastic and neoplastic lesions are indicative for a MEN syndrome, such constellations may also occur coincidentally or in association with other inherited diseases. In this overview, most recent findings concerning pathogenesis, molecular features, clinics and therapeutic concepts of MEN-1 and 2 are summarized and discussed. PMID:9380604

  20. Macroscopic contraction of a gel induced by the integrated motion of light-driven molecular motors

    NASA Astrophysics Data System (ADS)

    Li, Quan; Fuks, Gad; Moulin, Emilie; Maaloum, Mounir; Rawiso, Michel; Kulic, Igor; Foy, Justin T.; Giuseppone, Nicolas

    2015-02-01

    Making molecular machines that can be useful in the macroscopic world is a challenging long-term goal of nanoscience. Inspired by the protein machinery found in biological systems, and based on the theoretical understanding of the physics of motion at the nanoscale, organic chemists have developed a number of molecules that can produce work by contraction or rotation when triggered by various external chemical or physical stimuli. In particular, basic molecular switches that commute between at least two thermodynamic minima and more advanced molecular motors that behave as dissipative units working far from equilibrium when fuelled with external energy have been reported. However, despite recent progress, the ultimate challenge of coordinating individual molecular motors in a continuous mechanical process that can have a measurable effect at the macroscale has remained elusive. Here, we show that by integrating light-driven unidirectional molecular rotors as reticulating units in a polymer gel, it is possible to amplify their individual motions to achieve macroscopic contraction of the material. Our system uses the incoming light to operate under far-from-equilibrium conditions, and the work produced by the motor in the photostationary state is used to twist the entangled polymer chains up to the collapse of the gel. Our design could be a starting point to integrate nanomotors in metastable materials to store energy and eventually to convert it.

  1. An Integrative Framework for the Analysis of Multiple and Multimodal Representations for Meaning-Making in Science Education

    ERIC Educational Resources Information Center

    Tang, Kok-Sing; Delgado, Cesar; Moje, Elizabeth Birr

    2014-01-01

    This paper presents an integrative framework for analyzing science meaning-making with representations. It integrates the research on multiple representations and multimodal representations by identifying and leveraging the differences in their units of analysis in two dimensions: timescale and compositional grain size. Timescale considers the…

  2. The need for novel informatics tools for integrating and planning research in molecular and cellular cognition.

    PubMed

    Silva, Alcino J; Müller, Klaus-Robert

    2015-09-01

    The sheer volume and complexity of publications in the biological sciences are straining traditional approaches to research planning. Nowhere is this problem more serious than in molecular and cellular cognition, since in this neuroscience field, researchers routinely use approaches and information from a variety of areas in neuroscience and other biology fields. Additionally, the multilevel integration process characteristic of this field involves the establishment of experimental connections between molecular, electrophysiological, behavioral, and even cognitive data. This multidisciplinary integration process requires strategies and approaches that originate in several different fields, which greatly increases the complexity and demands of this process. Although causal assertions, where phenomenon A is thought to contribute or relate to B, are at the center of this integration process and key to research in biology, there are currently no tools to help scientists keep track of the increasingly more complex network of causal connections they use when making research decisions. Here, we propose the development of semiautomated graphical and interactive tools to help neuroscientists and other biologists, including those working in molecular and cellular cognition, to track, map, and weight causal evidence in research papers. There is a great need for a concerted effort by biologists, computer scientists, and funding institutions to develop maps of causal information that would aid in integration of research findings and in experiment planning. PMID:26286658

  3. Integrating multiple lines of evidence into historical biogeography hypothesis testing: a Bison bison case study

    PubMed Central

    Metcalf, Jessica L.; Prost, Stefan; Nogués-Bravo, David; DeChaine, Eric G.; Anderson, Christian; Batra, Persaram; Araújo, Miguel B.; Cooper, Alan; Guralnick, Robert P.

    2014-01-01

    One of the grand goals of historical biogeography is to understand how and why species' population sizes and distributions change over time. Multiple types of data drawn from disparate fields, combined into a single modelling framework, are necessary to document changes in a species's demography and distribution, and to determine the drivers responsible for change. Yet truly integrated approaches are challenging and rarely performed. Here, we discuss a modelling framework that integrates spatio-temporal fossil data, ancient DNA, palaeoclimatological reconstructions, bioclimatic envelope modelling and coalescence models in order to statistically test alternative hypotheses of demographic and potential distributional changes for the iconic American bison (Bison bison). Using different assumptions about the evolution of the bioclimatic niche, we generate hypothetical distributional and demographic histories of the species. We then test these demographic models by comparing the genetic signature predicted by serial coalescence against sequence data derived from subfossils and modern populations. Our results supported demographic models that include both climate and human-associated drivers of population declines. This synthetic approach, integrating palaeoclimatology, bioclimatic envelopes, serial coalescence, spatio-temporal fossil data and heterochronous DNA sequences, improves understanding of species' historical biogeography by allowing consideration of both abiotic and biotic interactions at the population level. PMID:24403338

  4. Integrating syndromic surveillance data across multiple locations: effects on outbreak detection performance.

    PubMed

    Reis, Ben Y; Mandl, Kenneth D

    2003-01-01

    Syndromic surveillance systems are being deployed widely to monitor for signals of covert bioterrorist attacks. Regional systems are being established through the integration of local surveillance data across multiple facilities. We studied how different methods of data integration affect outbreak detection performance. We used a simulation relying on a semi-synthetic dataset, introducing simulated outbreaks of different sizes into historical visit data from two hospitals. In one simulation, we introduced the synthetic outbreak evenly into both hospital datasets (aggregate model). In the second, the outbreak was introduced into only one or the other of the hospital datasets (local model). We found that the aggregate model had a higher sensitivity for detecting outbreaks that were evenly distributed between the hospitals. However, for outbreaks that were localized to one facility, maintaining individual models for each location proved to be better. Given the complementary benefits offered by both approaches, the results suggest building a hybrid system that includes both individual models for each location, and an aggregate model that combines all the data. We also discuss options for multi-level signal integration hierarchies. PMID:14728233

  5. Molecular 'OR' and 'AND' logic gates integrated in a single molecule

    NASA Astrophysics Data System (ADS)

    Ami, S.; Hliwa, M.; Joachim, C.

    2003-01-01

    Based on the N electrodes elastic scattering quantum chemistry (NESQC) technique, an intramolecular circuit simulator is presented for the design of electronic logic functions integrated inside a single molecule interconnected to the N electrodes. Using molecular rectifier groups, a molecule-OR and a molecule-AND are designed, their current-voltage characteristics calculated and their logic response presented. Both the OR and AND molecules have approximatively the targeted function. The running current of the OR gate, 10 fA, is quite low and the AND gate works only in an output voltage mode. This forbids the design of larger logic functions inside a single molecule with molecular rectifiers.

  6. A simple and accurate algorithm for path integral molecular dynamics with the Langevin thermostat.

    PubMed

    Liu, Jian; Li, Dezhang; Liu, Xinzijian

    2016-07-14

    We introduce a novel simple algorithm for thermostatting path integral molecular dynamics (PIMD) with the Langevin equation. The staging transformation of path integral beads is employed for demonstration. The optimum friction coefficients for the staging modes in the free particle limit are used for all systems. In comparison to the path integral Langevin equation thermostat, the new algorithm exploits a different order of splitting for the phase space propagator associated to the Langevin equation. While the error analysis is made for both algorithms, they are also employed in the PIMD simulations of three realistic systems (the H2O molecule, liquid para-hydrogen, and liquid water) for comparison. It is shown that the new thermostat increases the time interval of PIMD by a factor of 4-6 or more for achieving the same accuracy. In addition, the supplementary material shows the error analysis made for the algorithms when the normal-mode transformation of path integral beads is used. PMID:27421393

  7. A simple and accurate algorithm for path integral molecular dynamics with the Langevin thermostat

    NASA Astrophysics Data System (ADS)

    Liu, Jian; Li, Dezhang; Liu, Xinzijian

    2016-07-01

    We introduce a novel simple algorithm for thermostatting path integral molecular dynamics (PIMD) with the Langevin equation. The staging transformation of path integral beads is employed for demonstration. The optimum friction coefficients for the staging modes in the free particle limit are used for all systems. In comparison to the path integral Langevin equation thermostat, the new algorithm exploits a different order of splitting for the phase space propagator associated to the Langevin equation. While the error analysis is made for both algorithms, they are also employed in the PIMD simulations of three realistic systems (the H2O molecule, liquid para-hydrogen, and liquid water) for comparison. It is shown that the new thermostat increases the time interval of PIMD by a factor of 4-6 or more for achieving the same accuracy. In addition, the supplementary material shows the error analysis made for the algorithms when the normal-mode transformation of path integral beads is used.

  8. Integration of C/N-nutrient and multiple environmental signals into the ABA signaling cascade

    PubMed Central

    Lu, Yu; Yamaguchi, Junji; Sato, Takeo

    2015-01-01

    Due to their immobility, plants have developed sophisticated mechanisms to robustly monitor and appropriately respond to dynamic changes in nutrient availability. Carbon (C) and nitrogen (N) are especially important in regulating plant metabolism and development, thereby affecting crop productivity. In addition to their independent utilization, the ratio of C to N metabolites in the cell, referred to as the “C/N balance”, is important for the regulation of plant growth, although molecular mechanisms mediating C/N signaling remain unclear. Recently ABI1, a protein phosphatase type 2C (PP2C), was shown to be a regulator of C/N response in Arabidopsis plants. ABI1 functions as a negative regulator of abscisic acid (ABA) signal transduction. ABA is versatile phytohormone that regulates multiple aspects of plant growth and adaptation to environmental stress. This review highlights the regulation of the C/N response mediated by a non-canonical ABA signaling pathway that is independent of ABA biosynthesis, as well as recent findings on the direct crosstalk between multiple cellular signals and the ABA signaling cascade. PMID:26786013

  9. Strategic approaches to drug design. I. An integrated software framework for molecular modelling.

    PubMed

    Vinter, J G; Davis, A; Saunders, M R

    1987-04-01

    An integrated molecular graphics and computational chemistry framework is described which has been designed primarily to handle small molecules of up to 300 atoms. The system provides a means of integrating software from any source into a single framework. It is split into two functional subsystems. The first subsystem, called COSMIC, runs on low-cost, serial-linked colour graphics terminals and allows the user to prepare and examine structural data and to submit them for extensive computational chemistry. Links also allow access to databases, other modelling systems and user-written modules. Much of the output from COSMIC cannot be examined with low level graphics. A second subsystem, called ASTRAL, has been developed for the high-resolution Evans & Sutherland PS300 colour graphics terminal and is designed to manipulate complex display structures. The COSMIC minimisers, geometry investigators, molecular orbital displays, electrostatic isopotential generators and various interfaces and utilities are described. PMID:3505586

  10. Plasma DNA integrity index as a potential molecular diagnostic marker for breast cancer.

    PubMed

    Kamel, Azza M; Teama, Salwa; Fawzy, Amal; El Deftar, Mervat

    2016-06-01

    Plasma DNA integrity index is increased in various malignancies including breast cancer, the most common cancer in women worldwide; early detection is crucial for successful treatment. Current screening methods fail to detect many cases of breast cancer at an early stage. In this study, we evaluated the level of plasma DNA integrity index in 260 females (95 with breast cancer, 95 with benign breast lesions, and 70 healthy controls) to verify its potential value in discriminating malignant from benign breast lesions. The criteria of the American Joint Committee on Cancer were used for staging of breast cancer patients. DNA integrity index was measured by real-time PCR. DNA integrity index was significantly higher in breast cancer than in benign breast patients and healthy subjects (P = <0.001). DNA integrity index is correlated with TNM stage. Given 100 % specificity, the highest sensitivity achieved in detecting cancer group was 85.3 % at 0.55 DNA integrity index cutoff. In conclusion, the plasma DNA integrity index may be a promising molecular diagnostic marker of malignancy in breast lesions. PMID:26684805

  11. Generalized Additive Mixed-Models for Pharmacology Using Integrated Discrete Multiple Organ Co-Culture.

    PubMed

    Ingersoll, Thomas; Cole, Stephanie; Madren-Whalley, Janna; Booker, Lamont; Dorsey, Russell; Li, Albert; Salem, Harry

    2016-01-01

    Integrated Discrete Multiple Organ Co-culture (IDMOC) is emerging as an in-vitro alternative to in-vivo animal models for pharmacology studies. IDMOC allows dose-response relationships to be investigated at the tissue and organoid levels, yet, these relationships often exhibit responses that are far more complex than the binary responses often measured in whole animals. To accommodate departure from binary endpoints, IDMOC requires an expansion of analytic techniques beyond simple linear probit and logistic models familiar in toxicology. IDMOC dose-responses may be measured at continuous scales, exhibit significant non-linearity such as local maxima or minima, and may include non-independent measures. Generalized additive mixed-modeling (GAMM) provides an alternative description of dose-response that relaxes assumptions of independence and linearity. We compared GAMMs to traditional linear models for describing dose-response in IDMOC pharmacology studies. PMID:27110941

  12. Integrating gender on multiple levels: a conceptual model for teaching gender issues in family therapy.

    PubMed

    Williams, Lee; McBain, Heidi

    2006-07-01

    As the field of family therapy has evolved, there has been growing recognition as to the importance of gender in family therapy. To prepare the next generation of family therapists adequately, it is important that they recognize the many and complex ways in which gender permeates their work. In this article we present an integrative model to help educators teach family therapists about gender issues. The model examines how gender influences clinical work on multiple levels, including contextual levels such as society and the marriage and family therapy field. The model also acknowledges how gender can influence individuals, including clients, therapists, and supervisors. Finally, the model attempts to capture the complexity of how gender can impact the relational dynamics between two or more individuals. PMID:16933441

  13. Generalized Additive Mixed-Models for Pharmacology Using Integrated Discrete Multiple Organ Co-Culture

    PubMed Central

    Ingersoll, Thomas; Cole, Stephanie; Madren-Whalley, Janna; Booker, Lamont; Dorsey, Russell; Li, Albert; Salem, Harry

    2016-01-01

    Integrated Discrete Multiple Organ Co-culture (IDMOC) is emerging as an in-vitro alternative to in-vivo animal models for pharmacology studies. IDMOC allows dose-response relationships to be investigated at the tissue and organoid levels, yet, these relationships often exhibit responses that are far more complex than the binary responses often measured in whole animals. To accommodate departure from binary endpoints, IDMOC requires an expansion of analytic techniques beyond simple linear probit and logistic models familiar in toxicology. IDMOC dose-responses may be measured at continuous scales, exhibit significant non-linearity such as local maxima or minima, and may include non-independent measures. Generalized additive mixed-modeling (GAMM) provides an alternative description of dose-response that relaxes assumptions of independence and linearity. We compared GAMMs to traditional linear models for describing dose-response in IDMOC pharmacology studies. PMID:27110941

  14. System and method for integrating and accessing multiple data sources within a data warehouse architecture

    DOEpatents

    Musick, Charles R.; Critchlow, Terence; Ganesh, Madhaven; Slezak, Tom; Fidelis, Krzysztof

    2006-12-19

    A system and method is disclosed for integrating and accessing multiple data sources within a data warehouse architecture. The metadata formed by the present method provide a way to declaratively present domain specific knowledge, obtained by analyzing data sources, in a consistent and useable way. Four types of information are represented by the metadata: abstract concepts, databases, transformations and mappings. A mediator generator automatically generates data management computer code based on the metadata. The resulting code defines a translation library and a mediator class. The translation library provides a data representation for domain specific knowledge represented in a data warehouse, including "get" and "set" methods for attributes that call transformation methods and derive a value of an attribute if it is missing. The mediator class defines methods that take "distinguished" high-level objects as input and traverse their data structures and enter information into the data warehouse.

  15. The continuous end-state comfort effect: weighted integration of multiple biases.

    PubMed

    Herbort, Oliver; Butz, Martin V

    2012-05-01

    The grasp orientation when grasping an object is frequently aligned in anticipation of the intended rotation of the object (end-state comfort effect). We analyzed grasp orientation selection in a continuous task to determine the mechanisms underlying the end-state comfort effect. Participants had to grasp a box by a circular handle-which allowed for arbitrary grasp orientations-and then had to rotate the box by various angles. Experiments 1 and 2 revealed both that the rotation's direction considerably determined grasp orientations and that end-postures varied considerably. Experiments 3 and 4 further showed that visual stimuli and initial arm postures biased grasp orientations if the intended rotation could be easily achieved. The data show that end-state comfort but also other factors determine grasp orientation selection. A simple mechanism that integrates multiple weighted biases can account for the data. PMID:21499901

  16. Temperature Dependence of NMR Parameters Calculated from Path Integral Molecular Dynamics Simulations.

    PubMed

    Dračínský, Martin; Bouř, Petr; Hodgkinson, Paul

    2016-03-01

    The influence of temperature on NMR chemical shifts and quadrupolar couplings in model molecular organic solids is explored using path integral molecular dynamics (PIMD) and density functional theory (DFT) calculations of shielding and electric field gradient (EFG) tensors. An approach based on convoluting calculated shielding or EFG tensor components with probability distributions of selected bond distances and valence angles obtained from DFT-PIMD simulations at several temperatures is used to calculate the temperature effects. The probability distributions obtained from the quantum PIMD simulations, which includes nuclear quantum effects, are significantly broader and less temperature dependent than those obtained with conventional DFT molecular dynamics or with 1D scans through the potential energy surface. Predicted NMR observables for the model systems were in excellent agreement with experimental data. PMID:26857802

  17. Integrated Operational Taxonomic Units (IOTUs) in Echolocating Bats: A Bridge between Molecular and Traditional Taxonomy

    PubMed Central

    Galimberti, Andrea; Spada, Martina; Russo, Danilo; Mucedda, Mauro; Agnelli, Paolo; Crottini, Angelica; Ferri, Emanuele; Martinoli, Adriano; Casiraghi, Maurizio

    2012-01-01

    Background Nowadays, molecular techniques are widespread tools for the identification of biological entities. However, until very few years ago, their application to taxonomy provoked intense debates between traditional and molecular taxonomists. To prevent every kind of disagreement, it is essential to standardize taxonomic definitions. Along these lines, we introduced the concept of Integrated Operational Taxonomic Unit (IOTU). IOTUs come from the concept of Operational Taxonomic Unit (OTU) and paralleled the Molecular Operational Taxonomic Unit (MOTU). The latter is largely used as a standard in many molecular-based works (even if not always explicitly formalized). However, while MOTUs are assigned solely on molecular variation criteria, IOTUs are identified from patterns of molecular variation that are supported by at least one more taxonomic characteristic. Methodology/Principal Findings We tested the use of IOTUs on the widest DNA barcoding dataset of Italian echolocating bats species ever assembled (i.e. 31 species, 209 samples). We identified 31 molecular entities, 26 of which corresponded to the morphologically assigned species, two MOTUs and three IOTUs. Interestingly, we found three IOTUs in Myotis nattereri, one of which is a newly described lineage found only in central and southern Italy. In addition, we found a level of molecular variability within four vespertilionid species deserving further analyses. According to our scheme two of them (i.e. M. bechsteinii and Plecotus auritus) should be ranked as unconfirmed candidate species (UCS). Conclusions/Significance From a systematic point of view, IOTUs are more informative than the general concept of OTUs and the more recent MOTUs. According to information content, IOTUs are closer to species, although it is important to underline that IOTUs are not species. Overall, the use of a more precise panel of taxonomic entities increases the clarity in the systematic field and has the potential to fill the gaps

  18. The Frontier of Molecular Spintronics Based on Multiple-Decker Phthalocyaninato Tb(III) Single-Molecule Magnets.

    PubMed

    Katoh, Keiichi; Komeda, Tadahiro; Yamashita, Masahiro

    2016-04-01

    Ever since the first example of a double-decker complex (SnPc2) was discovered in 1936, MPc2 complexes with π systems and chemical and physical stabilities have been used as components in molecular electronic devices. More recently, in 2003, TbPc2 complexes were shown to be single-molecule magnets (SMMs), and researchers have utilized their quantum tunneling of the magnetization (QTM) and magnetic relaxation behavior in spintronic devices. Herein, recent developments in Ln(III)-Pc-based multiple-decker SMMs on surfaces for molecular spintronic devices are presented. In this account, we discuss how dinuclear Tb(III)-Pc multiple-decker complexes can be used to elucidate the relationship between magnetic dipole interactions and SMM properties, because these complexes contain two TbPc2 units in one molecule and their intramolecular Tb(III)-Tb(III) distances can be controlled by changing the number of stacks. Next, we focus on the switching of the Kondo signal of Tb(III)-Pc-based multiple-decker SMMs that are adsorbed onto surfaces, their characterization using STM and STS, and the relationship between the molecular structure, the electronic structure, and the Kondo resonance of Tb(III)-Pc multiple-decker complexes. PMID:26991524

  19. Molecular evidence-based medicine: evolution and integration of information in the genomic era.

    PubMed

    Ioannidis, J P A

    2007-05-01

    Evidence-based medicine and molecular medicine have both been influential in biomedical research in the last 15 years. Despite following largely parallel routes to date, the goals and principles of evidence-based and molecular medicine are complementary and they should be converging. I define molecular evidence-based medicine as the study of medical information that makes sense of the advances of molecular biological disciplines and where errors and biases are properly appreciated and placed in context. Biomedical measurement capacity improves very rapidly. The exponentially growing mass of hypotheses being tested requires a new approach to both statistical and biological inference. Multidimensional biology requires careful exact replication of research findings, but indirect corroboration is often all that is achieved at best. Besides random error, bias remains a major threat. It is often difficult to separate bias from the spirit of scientific inquiry to force data into coherent and 'significant' biological stories. Transparency and public availability of protocols, data, analyses and results may be crucial to make sense of the complex biology of human disease and avoid being flooded by spurious research findings. Research efforts should be integrated across teams in an open, sharing environment. Most research in the future may be designed, performed, and integrated in the public cyberspace. PMID:17461979

  20. Cytogenetic and molecular evidence suggest multiple origins and geographical parthenogenesis in Nothoscordum gracile (Alliaceae)

    PubMed Central

    Souza, Luiz Gustavo Rodrigues; Crosa, Orfeo; Speranza, Pablo; Guerra, Marcelo

    2012-01-01

    Background and Aims Nothoscordum gracile is an apomitic tetraploid widely distributed throughout the Americas and naturalized in many temperate regions of other continents. It has been suggested to form a species complex with sexual and apomictic N. nudicaule and N. macrostemon. Tetraploids of these species also share a structurally heterozygous chromosome complement 2n = 19 (13M + 6A). In this work, the origin of N. gracile and its relationships with its related species was investigated based on cytological and molecular data. Methods Cytogenetic analyses were based on meiotic behaviour, CMA bands, localization of 5S and 45S rDNA sites, and genomic in situ hybridization (GISH). Nuclear ITS and plastidial trnL-trnF sequences were also obtained for most individuals. Key Results Proximal CMA bands were observed in the long arms of all acrocentrics of 2x and 4x N. macrostemon but not in diploid and some tetraploid cytotypes of N. nudicaule. Samples of N. gracile showed a variable number of CMA bands in the long arms of acrocentrics. Analysis of ITS sequences, dot-blot, GISH, and 5S and 45S rDNA sites, revealed no differentiation among the three species. The trnL-trnF cpDNA fragment showed variation with a trend to geographical structuring irrespective of morphospecies and fully congruent with karyotype variation. Conclusions The 2n = 19 karyotype was probably formed by a centric fusion event occurring in N. nudicaule and later transmitted to tetraploid cytotypes of N. macrostemon. Diploids of N. nudicaule and N. macrostemon appeared as consistent recently diverged species, whereas tetraploid apomicts seem to constitute an assemblage of polyploid hybrids originating from multiple independent hybridization events between them, part of which are morphologically recognizable as N. gracile. PMID:22362660

  1. Improved detection of differentially expressed genes in microarray experiments through multiple scanning and image integration

    PubMed Central

    Romualdi, Chiara; Trevisan, Silvia; Celegato, Barbara; Costa, Germano; Lanfranchi, Gerolamo

    2003-01-01

    The variability of results in microarray technology is in part due to the fact that independent scans of a single hybridised microarray give spot images that are not quite the same. To solve this problem and turn it to our advantage, we introduced the approach of multiple scanning and of image integration of microarrays. To this end, we have developed specific software that creates a virtual image that statistically summarises a series of consecutive scans of a microarray. We provide evidence that the use of multiple imaging (i) enhances the detection of differentially expressed genes; (ii) increases the image homogeneity; and (iii) reveals false-positive results such as differentially expressed genes that are detected by a single scan but not confirmed by successive scanning replicates. The increase in the final number of differentially expressed genes detected in a microarray experiment with this approach is remarkable; 50% more for microarrays hybridised with targets labelled by reverse transcriptase, and 200% more for microarrays developed with the tyramide signal amplification (TSA) technique. The results have been confirmed by semi-quantitative RT–PCR tests. PMID:14627839

  2. An integrated voice and data multiple-access scheme for a land-mobile satellite system

    NASA Technical Reports Server (NTRS)

    Li, V. O. K.; Yan, T.-Y.

    1984-01-01

    An analytical study is performed of the satellite requirements for a land mobile satellite system (LMSS). The spacecraft (MSAT-X) would be in GEO and would be compatible with multiple access by mobile radios and antennas and fixed stations. The FCC has received a petition from NASA to reserve the 821-825 and 866-870 MHz frequencies for the LMSS, while communications with fixed earth stations would be in the Ku band. MSAT-X transponders would alter the frequencies of signal and do no processing in the original configuration considered. Channel use would be governed by an integrated demand-assigned, multiple access protocol, which would divide channels into reservation and information channels, governed by a network management center. Further analyses will cover tradeoffs between data and voice users, probability of blocking, and the performance impacts of on-board switching and variable bandwidth assignment. Initial calculations indicate that a large traffic volume can be handled with acceptable delays and voice blocking probabilities.

  3. Integration of multiple cues allows threat-sensitive anti-intraguild predator responses in predatory mites

    PubMed Central

    Walzer, Andreas; Schausberger, Peter

    2013-01-01

    Intraguild (IG) prey is commonly confronted with multiple IG predator species. However, the IG predation (IGP) risk for prey is not only dependent on the predator species, but also on inherent (intraspecific) characteristics of a given IG predator such as its life-stage, sex or gravidity and the associated prey needs. Thus, IG prey should have evolved the ability to integrate multiple IG predator cues, which should allow both inter- and intraspecific threat-sensitive anti-predator responses. Using a guild of plant-inhabiting predatory mites sharing spider mites as prey, we evaluated the effects of single and combined cues (eggs and/or chemical traces left by a predator female on the substrate) of the low risk IG predator Neoseiulus californicus and the high risk IG predator Amblyseius andersoni on time, distance and path shape parameters of the larval IG prey Phytoseiulus persimilis. IG prey discriminated between traces of the low and high risk IG predator, with and without additional presence of their eggs, indicating interspecific threat-sensitivity. The behavioural changes were manifest in distance moved, activity and path shape of IG prey. The cue combination of traces and eggs of the IG predators conveyed other information than each cue alone, allowing intraspecific threat-sensitive responses by IG prey apparent in changed velocities and distances moved. We argue that graded responses to single and combined IG predator cues are adaptive due to minimization of acceptance errors in IG prey decision making. PMID:23750040

  4. Pooling data from multiple longitudinal studies: the role of item response theory in integrative data analysis.

    PubMed

    Curran, Patrick J; Hussong, Andrea M; Cai, Li; Huang, Wenjing; Chassin, Laurie; Sher, Kenneth J; Zucker, Robert A

    2008-03-01

    There are a number of significant challenges researchers encounter when studying development over an extended period of time, including subject attrition, the changing of measurement structures across groups and developmental periods, and the need to invest substantial time and money. Integrative data analysis is an emerging set of methodologies that allows researchers to overcome many of the challenges of single-sample designs through the pooling of data drawn from multiple existing developmental studies. This approach is characterized by a host of advantages, but this also introduces several new complexities that must be addressed prior to broad adoption by developmental researchers. In this article, the authors focus on methods for fitting measurement models and creating scale scores using data drawn from multiple longitudinal studies. The authors present findings from the analysis of repeated measures of internalizing symptomatology that were pooled from three existing developmental studies. The authors describe and demonstrate each step in the analysis and conclude with a discussion of potential limitations and directions for future research. PMID:18331129

  5. A quantitative approach for integrating multiple lines of evidence for the evaluation of environmental health risks

    PubMed Central

    Schleier III, Jerome J.; Marshall, Lucy A.; Davis, Ryan S.

    2015-01-01

    Decision analysis often considers multiple lines of evidence during the decision making process. Researchers and government agencies have advocated for quantitative weight-of-evidence approaches in which multiple lines of evidence can be considered when estimating risk. Therefore, we utilized Bayesian Markov Chain Monte Carlo to integrate several human-health risk assessment, biomonitoring, and epidemiology studies that have been conducted for two common insecticides (malathion and permethrin) used for adult mosquito management to generate an overall estimate of risk quotient (RQ). The utility of the Bayesian inference for risk management is that the estimated risk represents a probability distribution from which the probability of exceeding a threshold can be estimated. The mean RQs after all studies were incorporated were 0.4386, with a variance of 0.0163 for malathion and 0.3281 with a variance of 0.0083 for permethrin. After taking into account all of the evidence available on the risks of ULV insecticides, the probability that malathion or permethrin would exceed a level of concern was less than 0.0001. Bayesian estimates can substantially improve decisions by allowing decision makers to estimate the probability that a risk will exceed a level of concern by considering seemingly disparate lines of evidence. PMID:25648367

  6. Multiple-mode Lamb wave scattering simulations using 3D elastodynamic finite integration technique.

    PubMed

    Leckey, Cara A C; Rogge, Matthew D; Miller, Corey A; Hinders, Mark K

    2012-02-01

    We have implemented three-dimensional (3D) elastodynamic finite integration technique (EFIT) simulations to model Lamb wave scattering for two flaw-types in an aircraft-grade aluminum plate, a rounded rectangle flat-bottom hole and a disbond of the same shape. The plate thickness and flaws explored in this work include frequency-thickness regions where several Lamb wave modes exist and sometimes overlap in phase and/or group velocity. For the case of the flat-bottom hole the depth was incrementally increased to explore progressive changes in multiple-mode Lamb wave scattering due to the damage. The flat-bottom hole simulation results have been compared to experimental data and are shown to provide key insight for this well-defined experimental case by explaining unexpected results in experimental waveforms. For the rounded rectangle disbond flaw, which would be difficult to implement experimentally, we found that Lamb wave behavior differed significantly from the flat-bottom hole flaw. Most of the literature in this field is restricted to low frequency-thickness regions due to difficulties in interpreting data when multiple modes exist. We found that benchmarked 3D EFIT simulations can yield an understanding of scattering behavior for these higher frequency-thickness regions and in cases that would be difficult to set up experimentally. Additionally, our results show that 2D simulations would not have been sufficient for modeling the complicated scattering that occurred. PMID:21908011

  7. Multiple sclerosis, an autoimmune inflammatory disease: prospects for its integrative management.

    PubMed

    Kidd, P M

    2001-12-01

    Multiple sclerosis (MS) is aptly named for the many scars it produces in the brain and spinal cord. A sometimes fatal, often debilitating disease, MS features autoimmune inflammatory attack against the myelin insulation of neurons. Thymus derived (T) cells sensitized against myelin self-antigens secrete tumor necrosis factor, cytokines, prostaglandins, and other inflammatory mediators that strip away the myelin and sometimes destroy the axons. Familial and twin inheritance studies indicate MS is mildly heritable. No single MS locus has been identified, but an HLA haplotype has been implicated. Unique geographic distribution of the disease is best attributed to some combination of vitamin D abnormality and dietary patterns. No pharmaceutical or other therapies exist that confer prolonged remission on MS, and obvious interrelationships between toxic, infectious, and dietary factors make a persuasive case for integrative management. The time-proven MS diet meticulously keeps saturated fats low, includes three fish meals per week, and eliminates allergenic foods. Dietary supplementation for MS minimally requires potent vitamin supplementation, along with the thiol antioxidants, the anti-inflammatory omega-3 fatty acids, and adaptogenic phytonutrients. Gut malabsorption and dysbiosis can be corrected using digestive enzymes and probiotics. Long-term hyperbaric oxygen therapy can slow or remit the disease. Transdermal histamine offers promise, and adenosine monophosphate may sometimes benefit. Chronic viruses and other infectious load must be aggressively treated and exercise should maintain muscle tone and balance. Early intervention with integrative modalities has the potential to make MS a truly manageable disease. PMID:11804546

  8. An Integrated Modeling Framework for Assessment of Impacts of Multiple Global Changes on Terrestrial Productivity

    NASA Astrophysics Data System (ADS)

    Wittig, V.; Yang, X.; Jain, A.

    2008-12-01

    Independent changes in atmospheric carbon dioxide, tropospheric ozone, nitrogen deposition and climate change directly impact terrestrial productivity. Less well understood are the interactive effects of these globally changing factors on terrestrial productivity and the resultant impact on rising atmospheric carbon dioxide concentrations. This study uses the Integrated Science Assessment Model (ISAM) to quantify the impacts of these multiple global changes on terrestrial productivity and further, to project how these changes feedback on atmospheric carbon dioxide concentrations via respiratory carbon fluxes. The ISAM is modified to include a mechanistic model of leaf photosynthesis including the sensitivity of leaf photosynthesis to tropospheric ozone. Leaf-level photosynthetic carbon gain is scaled to the canopy with a sun-shade microclimate model to estimate the gross primary productivity of major biomes comprised of representative plant functional types. The modified carbon cycle in ISAM is coupled to a detailed model of the terrestrial nitrogen cycle therefore providing the integrated modeling framework required to assess the interactive effects of rising carbon dioxide, tropospheric ozone, nitrogen deposition and climate change on global productivity.

  9. Optimal Operation System of the Integrated District Heating System with Multiple Regional Branches

    NASA Astrophysics Data System (ADS)

    Kim, Ui Sik; Park, Tae Chang; Kim, Lae-Hyun; Yeo, Yeong Koo

    This paper presents an optimal production and distribution management for structural and operational optimization of the integrated district heating system (DHS) with multiple regional branches. A DHS consists of energy suppliers and consumers, district heating pipelines network and heat storage facilities in the covered region. In the optimal management system, production of heat and electric power, regional heat demand, electric power bidding and sales, transport and storage of heat at each regional DHS are taken into account. The optimal management system is formulated as a mixed integer linear programming (MILP) where the objectives is to minimize the overall cost of the integrated DHS while satisfying the operation constraints of heat units and networks as well as fulfilling heating demands from consumers. Piecewise linear formulation of the production cost function and stairwise formulation of the start-up cost function are used to compute nonlinear cost function approximately. Evaluation of the total overall cost is based on weekly operations at each district heat branches. Numerical simulations show the increase of energy efficiency due to the introduction of the present optimal management system.

  10. Integration of metabolomics and proteomics in multiple sclerosis: From biomarkers discovery to personalized medicine.

    PubMed

    Del Boccio, Piero; Rossi, Claudia; di Ioia, Maria; Cicalini, Ilaria; Sacchetta, Paolo; Pieragostino, Damiana

    2016-04-01

    Personalized medicine is the science of individualized prevention and therapy. In the last decade, advances in high-throughput approaches allowed the development of proteomic and metabolomic studies in evaluating the association of genetic and phenotypic variability with disease sensitivity and analgesic response. These considerations have more value in case of multiple sclerosis (MuS), a multifactorial disease with high heterogeneity in clinical course and treatment response. In this review, we reported and updated about proteomic and metabolomic studies for the research of new candidate biomarkers in MuS, and difficulties in their clinical applications. We focused especially on the description of both "omics" approaches that, once integrated, may synergically describe pathophysiology conditions. To prove this assumption, we rebuilt interaction between proteins and metabolites described in the literature as potential biomarkers for MuS, and a pathway analysis of these molecules was performed. The result of such speculation demonstrated a strong convergence of proteomic and metabolomic results in this field, showing also a poorness of available tools for incorporating "omics" approaches. In conclusion, the integration of Metabolomics and Proteomics may allow a more complete characterization of such a heterogeneous disease, providing further insights into personalized healthcare. PMID:27061322

  11. Integrating multiple scales of hydraulic conductivity measurements in training image-based stochastic models

    NASA Astrophysics Data System (ADS)

    Mahmud, K.; Mariethoz, G.; Baker, A.; Sharma, A.

    2015-01-01

    Hydraulic conductivity is one of the most critical and at the same time one of the most uncertain parameters in many groundwater models. One problem commonly faced is that the data are usually not collected at the same scale as the discretized elements used in a numerical model. Moreover, it is common that different types of hydraulic conductivity measurements, corresponding to different spatial scales, coexist in a studied domain, which have to be integrated simultaneously. Here we address this issue in the context of Image Quilting, one of the recently developed multiple-point geostatistics methods. Based on a training image that represents fine-scale spatial variability, we use the simplified renormalization upscaling method to obtain a series of upscaled training images that correspond to the different scales at which measurements are available. We then apply Image Quilting with such a multiscale training image to be able to incorporate simultaneously conditioning data at several spatial scales of heterogeneity. The realizations obtained satisfy the conditioning data exactly across all scales, but it can come at the expense of a small approximation in the representation of the physical scale relationships. In order to mitigate this approximation, we iteratively apply a kriging-based correction to the finest scale that ensures local conditioning at the coarsest scales. The method is tested on a series of synthetic examples where it gives good results and shows potential for the integration of different measurement methods in real-case hydrogeological models.

  12. The blackboard model - A framework for integrating multiple cooperating expert systems

    NASA Technical Reports Server (NTRS)

    Erickson, W. K.

    1985-01-01

    The use of an artificial intelligence (AI) architecture known as the blackboard model is examined as a framework for designing and building distributed systems requiring the integration of multiple cooperating expert systems (MCXS). Aerospace vehicles provide many examples of potential systems, ranging from commercial and military aircraft to spacecraft such as satellites, the Space Shuttle, and the Space Station. One such system, free-flying, spaceborne telerobots to be used in construction, servicing, inspection, and repair tasks around NASA's Space Station, is examined. The major difficulties found in designing and integrating the individual expert system components necessary to implement such a robot are outlined. The blackboard model, a general expert system architecture which seems to address many of the problems found in designing and building such a system, is discussed. A progress report on a prototype system under development called DBB (Distributed BlackBoard model) is given. The prototype will act as a testbed for investigating the feasibility, utility, and efficiency of MCXS-based designs developed under the blackboard model.

  13. Integrated health messaging for multiple neglected zoonoses: Approaches, challenges and opportunities in Morocco.

    PubMed

    Ducrotoy, M J; Yahyaoui Azami, H; El Berbri, I; Bouslikhane, M; Fassi Fihri, O; Boué, F; Petavy, A F; Dakkak, A; Welburn, S; Bardosh, K L

    2015-12-01

    Integrating the control of multiple neglected zoonoses at the community-level holds great potential, but critical data is missing to inform the design and implementation of different interventions. In this paper we present an evaluation of an integrated health messaging intervention, using powerpoint presentations, for five bacterial (brucellosis and bovine tuberculosis) and dog-associated (rabies, cystic echinococcosis and leishmaniasis) zoonotic diseases in Sidi Kacem Province, northwest Morocco. Conducted by veterinary and epidemiology students between 2013 and 2014, this followed a process-based approach that encouraged sequential adaptation of images, key messages, and delivery strategies using auto-evaluation and end-user feedback. We describe the challenges and opportunities of this approach, reflecting on who was targeted, how education was conducted, and what tools and approaches were used. Our results showed that: (1) replacing words with local pictures and using "hands-on" activities improved receptivity; (2) information "overload" easily occurred when disease transmission pathways did not overlap; (3) access and receptivity at schools was greater than at the community-level; and (4) piggy-backing on high-priority diseases like rabies offered an important avenue to increase knowledge of other zoonoses. We conclude by discussing the merits of incorporating our validated education approach into the school curriculum in order to influence long-term behaviour change. PMID:26299194

  14. Bioinformatics evaluation of the possibility of heat shock proteins as autoantigens in multiple sclerosis based on molecular mimicry hypothesis.

    PubMed

    Ansari Qeshmi, Safa; Dabbagh, Fatemeh; Borhani Haghighi, Afshin; Ghasemi, Younes

    2016-06-15

    Molecular mimicry is the explanatory link between the heat shock proteins (HSPs) of infectious agents and triggering multiple sclerosis. Considering that there are many similarities between self- and bacterial-HSPs, the goal was to investigate a panel of 60- and 70kDa HSPs from a variety of bacteria in order to predict the role of each microorganism in triggering or progression of the disease under the molecular mimicry hypothesis. By clarifying the peptides meeting criteria for cross-reactivity and elucidating the role of each microorganism in MS pathogenesis, it would be easier to suggest more effective treatment and preventive strategies for this disease. PMID:27235356

  15. Accurate path integral molecular dynamics simulation of ab-initio water at near-zero added cost

    NASA Astrophysics Data System (ADS)

    Elton, Daniel; Fritz, Michelle; Soler, José; Fernandez-Serra, Marivi

    It is now established that nuclear quantum motion plays an important role in determining water's structure and dynamics. These effects are important to consider when evaluating DFT functionals and attempting to develop better ones for water. The standard way of treating nuclear quantum effects, path integral molecular dynamics (PIMD), multiplies the number of energy/force calculations by the number of beads, which is typically 32. Here we introduce a method whereby PIMD can be incorporated into a DFT molecular dynamics simulation at virtually zero cost. The method is based on the cluster (many body) expansion of the energy. We first subtract the DFT monomer energies, using a custom DFT-based monomer potential energy surface. The evolution of the PIMD beads is then performed using only the more-accurate Partridge-Schwenke monomer energy surface. The DFT calculations are done using the centroid positions. Various bead thermostats can be employed to speed up the sampling of the quantum ensemble. The method bears some resemblance to multiple timestep algorithms and other schemes used to speed up PIMD with classical force fields. We show that our method correctly captures some of key effects of nuclear quantum motion on both the structure and dynamics of water. We acknowledge support from DOE Award No. DE-FG02-09ER16052 (D.E.) and DOE Early Career Award No. DE-SC0003871 (M.V.F.S.).

  16. Observation of ambipolar switching in a silver nanoparticle single-electron transistor with multiple molecular floating gates

    NASA Astrophysics Data System (ADS)

    Yamamoto, Makoto; Shinohara, Shuhei; Tamada, Kaoru; Ishii, Hisao; Noguchi, Yutaka

    2016-03-01

    Ambipolar switching behavior was observed in a silver nanoparticle (AgNP)-based single-electron transistor (SET) with tetra-tert-butyl copper phthalocyanine (ttbCuPc) as a molecular floating gate. Depending on the wavelength of the incident light, the stability diagram shifted to the negative and positive directions along the gate voltage axis. These results were explained by the photoinduced charging of ttbCuPc molecules in the vicinity of AgNPs. Moreover, multiple device states were induced by the light irradiation at a wavelength of 600 nm, suggesting that multiple ttbCuPc molecules individually worked as a floating gate.

  17. Discovering transnosological molecular basis of human brain diseases using biclustering analysis of integrated gene expression data

    PubMed Central

    2015-01-01

    Background It has been reported that several brain diseases can be treated as transnosological manner implicating possible common molecular basis under those diseases. However, molecular level commonality among those brain diseases has been largely unexplored. Gene expression analyses of human brain have been used to find genes associated with brain diseases but most of those studies were restricted either to an individual disease or to a couple of diseases. In addition, identifying significant genes in such brain diseases mostly failed when it used typical methods depending on differentially expressed genes. Results In this study, we used a correlation-based biclustering approach to find coexpressed gene sets in five neurodegenerative diseases and three psychiatric disorders. By using biclustering analysis, we could efficiently and fairly identified various gene sets expressed specifically in both single and multiple brain diseases. We could find 4,307 gene sets correlatively expressed in multiple brain diseases and 3,409 gene sets exclusively specified in individual brain diseases. The function enrichment analysis of those gene sets showed many new possible functional bases as well as neurological processes that are common or specific for those eight diseases. Conclusions This study introduces possible common molecular bases for several brain diseases, which open the opportunity to clarify the transnosological perspective assumed in brain diseases. It also showed the advantages of correlation-based biclustering analysis and accompanying function enrichment analysis for gene expression data in this type of investigation. PMID:26043779

  18. New methods for accelerating the convergence of molecular electronic integrals over exponential type orbitals

    NASA Astrophysics Data System (ADS)

    Safouhi, Hassan; Hoggan, Philip

    2003-01-01

    This review on molecular integrals for large electronic systems (MILES) places the problem of analytical integration over exponential-type orbitals (ETOs) in a historical context. After reference to the pioneering work, particularly by Barnett, Shavitt and Yoshimine, it focuses on recent progress towards rapid and accurate analytic solutions of MILES over ETOs. Software such as the hydrogenlike wavefunction package Alchemy by Yoshimine and collaborators is described. The review focuses on convergence acceleration of these highly oscillatory integrals and in particular it highlights suitable nonlinear transformations. Work by Levin and Sidi is described and applied to MILES. A step by step description of progress in the use of nonlinear transformation methods to obtain efficient codes is provided. The recent approach developed by Safouhi is also presented. The current state of the art in this field is summarized to show that ab initio analytical work over ETOs is now a viable option.

  19. The semantic metadatabase (SEMEDA): ontology based integration of federated molecular biological data sources.

    PubMed

    Köhler, Jacob; Schulze-Kremer, Steffen

    2002-01-01

    A system for "intelligent" semantic integration and querying of federated databases is being implemented by using three main components: A component which enables SQL access to integrated databases by database federation (MARGBench), an ontology based semantic metadatabase (SEMEDA) and an ontology based query interface (SEMEDA-query). In this publication we explain and demonstrate the principles, architecture and the use of SEMEDA. Since SEMEDA is implemented as 3 tiered web application database providers can enter all relevant semantic and technical information about their databases by themselves via a web browser. SEMEDA' s collaborative ontology editing feature is not restricted to database integration, and might also be useful for ongoing ontology developments, such as the "Gene Ontology" [2]. SEMEDA can be found at http://www-bm.cs.uni-magdeburg.de/semeda/. We explain how this ontologically structured information can be used for semantic database integration. In addition, requirements to ontologies for molecular biological database integration are discussed and relevant existing ontologies are evaluated. We further discuss how ontologies and structured knowledge sources can be used in SEMEDA and whether they can be merged supplemented or updated to meet the requirements for semantic database integration. PMID:12542408

  20. Molecular Profiling of Multiple Human Cancers Defines an Inflammatory Cancer-Associated Molecular Pattern and Uncovers KPNA2 as a Uniform Poor Prognostic Cancer Marker

    PubMed Central

    Rachidi, Saleh M.; Qin, Tingting; Sun, Shaoli; Zheng, W. Jim; Li, Zihai

    2013-01-01

    Background Immune evasion is one of the recognized hallmarks of cancer. Inflammatory responses to cancer can also contribute directly to oncogenesis. Since the immune system is hardwired to protect the host, there is a possibility that cancers, regardless of their histological origins, endow themselves with a common and shared inflammatory cancer-associated molecular pattern (iCAMP) to promote oncoinflammation. However, the definition of iCAMP has not been conceptually and experimentally investigated. Methods and Findings Genome-wide cDNA expression data was analyzed for 221 normal and 324 cancer specimens from 7 cancer types: breast, prostate, lung, colon, gastric, oral and pancreatic. A total of 96 inflammatory genes with consistent dysregulation were identified, including 44 up-regulated and 52 down-regulated genes. Protein expression was confirmed by immunohistochemistry for some of these genes. The iCAMP contains proteins whose roles in cancer have been implicated and others which are yet to be appreciated. The clinical significance of many iCAMP genes was confirmed in multiple independent cohorts of colon and ovarian cancer patients. In both cases, better prognosis correlated strongly with high CXCL13 and low level of GREM1, LOX, TNFAIP6, CD36, and EDNRA. An “Inflammatory Gene Integrated Score” was further developed from the combination of 18 iCAMP genes in ovarian cancer, which predicted overall survival. Noticeably, as a selective nuclear import protein whose immuno-regulatory function just begins to emerge, karyopherin alpha 2 (KPNA2) is uniformly up-regulated across cancer types. For the first time, the cancer-specific up-regulation of KPNA2 and its clinical significance were verified by tissue microarray analysis in colon and head-neck cancers. Conclusion This work defines an inflammatory signature shared by seven epithelial cancer types and KPNA2 as a consistently up-regulated protein in cancer. Identification of iCAMP may not only serve as a novel

  1. Integrating Multiple Autonomous Underwater Vessels, Surface Vessels and Aircraft into Oceanographic Research Vessel Operations

    NASA Astrophysics Data System (ADS)

    McGillivary, P. A.; Borges de Sousa, J.; Martins, R.; Rajan, K.

    2012-12-01

    Autonomous platforms are increasingly used as components of Integrated Ocean Observing Systems and oceanographic research cruises. Systems deployed can include gliders or propeller-driven autonomous underwater vessels (AUVs), autonomous surface vessels (ASVs), and unmanned aircraft systems (UAS). Prior field campaigns have demonstrated successful communication, sensor data fusion and visualization for studies using gliders and AUVs. However, additional requirements exist for incorporating ASVs and UASs into ship operations. For these systems to be optimally integrated into research vessel data management and operational planning systems involves addressing three key issues: real-time field data availability, platform coordination, and data archiving for later analysis. A fleet of AUVs, ASVs and UAS deployed from a research vessel is best operated as a system integrated with the ship, provided communications among them can be sustained. For this purpose, Disruptive Tolerant Networking (DTN) software protocols for operation in communication-challenged environments help ensure reliable high-bandwidth communications. Additionally, system components need to have considerable onboard autonomy, namely adaptive sampling capabilities using their own onboard sensor data stream analysis. We discuss Oceanographic Decision Support System (ODSS) software currently used for situational awareness and planning onshore, and in the near future event detection and response will be coordinated among multiple vehicles. Results from recent field studies from oceanographic research vessels using AUVs, ASVs and UAS, including the Rapid Environmental Picture (REP-12) cruise, are presented describing methods and results for use of multi-vehicle communication and deliberative control networks, adaptive sampling with single and multiple platforms, issues relating to data management and archiving, and finally challenges that remain in addressing these technological issues. Significantly, the

  2. Integrated proteomic, transcriptomic, and biological network analysis of breast carcinoma reveals molecular features of tumorigenesis and clinical relapse.

    PubMed

    Imielinski, Marcin; Cha, Sangwon; Rejtar, Tomas; Richardson, Elizabeth A; Karger, Barry L; Sgroi, Dennis C

    2012-06-01

    Gene and protein expression changes observed with tumorigenesis are often interpreted independently of each other and out of context of biological networks. To address these limitations, this study examined several approaches to integrate transcriptomic and proteomic data with known protein-protein and signaling interactions in estrogen receptor positive (ER+) breast cancer tumors. An approach that built networks from differentially expressed proteins and identified among them networks enriched in differentially expressed genes yielded the greatest success. This method identified a set of genes and proteins linking pathways of cellular stress response, cancer metabolism, and tumor microenvironment. The proposed network underscores several biologically intriguing events not previously studied in the context of ER+ breast cancer, including the overexpression of p38 mitogen-activated protein kinase and the overexpression of poly(ADP-ribose) polymerase 1. A gene-based expression signature biomarker built from this network was significantly predictive of clinical relapse in multiple independent cohorts of ER+ breast cancer patients, even after correcting for standard clinicopathological variables. The results of this study demonstrate the utility and power of an integrated quantitative proteomic, transcriptomic, and network analysis approach to discover robust and clinically meaningful molecular changes in tumors. PMID:22240506

  3. Integrated defense system overlaps as a disease model: with examples for multiple chemical sensitivity.

    PubMed Central

    Rowat, S C

    1998-01-01

    The central nervous, immune, and endocrine systems communicate through multiple common messengers. Over evolutionary time, what may be termed integrated defense system(s) (IDS) have developed to coordinate these communications for specific contexts; these include the stress response, acute-phase response, nonspecific immune response, immune response to antigen, kindling, tolerance, time-dependent sensitization, neurogenic switching, and traumatic dissociation (TD). These IDSs are described and their overlap is examined. Three models of disease production are generated: damage, in which IDSs function incorrectly; inadequate/inappropriate, in which IDS response is outstripped by a changing context; and evolving/learning, in which the IDS learned response to a context is deemed pathologic. Mechanisms of multiple chemical sensitivity (MCS) are developed from several IDS disease models. Model 1A is pesticide damage to the central nervous system, overlapping with body chemical burdens, TD, and chronic zinc deficiency; model 1B is benzene disruption of interleukin-1, overlapping with childhood developmental windows and hapten-antigenic spreading; and model 1C is autoimmunity to immunoglobulin-G (IgG), overlapping with spreading to other IgG-inducers, sudden spreading of inciters, and food-contaminating chemicals. Model 2A is chemical and stress overload, including comparison with the susceptibility/sensitization/triggering/spreading model; model 2B is genetic mercury allergy, overlapping with: heavy metals/zinc displacement and childhood/gestational mercury exposures; and model 3 is MCS as evolution and learning. Remarks are offered on current MCS research. Problems with clinical measurement are suggested on the basis of IDS models. Large-sample patient self-report epidemiology is described as an alternative or addition to clinical biomarker and animal testing. Images Figure 1 Figure 2 Figure 3 Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 PMID:9539008

  4. A multiple hypotheses uncertainty analysis in hydrological modelling: about model structure, landscape parameterization, and numerical integration

    NASA Astrophysics Data System (ADS)

    Pilz, Tobias; Francke, Till; Bronstert, Axel

    2016-04-01

    Until today a large number of competing computer models has been developed to understand hydrological processes and to simulate and predict streamflow dynamics of rivers. This is primarily the result of a lack of a unified theory in catchment hydrology due to insufficient process understanding and uncertainties related to model development and application. Therefore, the goal of this study is to analyze the uncertainty structure of a process-based hydrological catchment model employing a multiple hypotheses approach. The study focuses on three major problems that have received only little attention in previous investigations. First, to estimate the impact of model structural uncertainty by employing several alternative representations for each simulated process. Second, explore the influence of landscape discretization and parameterization from multiple datasets and user decisions. Third, employ several numerical solvers for the integration of the governing ordinary differential equations to study the effect on simulation results. The generated ensemble of model hypotheses is then analyzed and the three sources of uncertainty compared against each other. To ensure consistency and comparability all model structures and numerical solvers are implemented within a single simulation environment. First results suggest that the selection of a sophisticated numerical solver for the differential equations positively affects simulation outcomes. However, already some simple and easy to implement explicit methods perform surprisingly well and need less computational efforts than more advanced but time consuming implicit techniques. There is general evidence that ambiguous and subjective user decisions form a major source of uncertainty and can greatly influence model development and application at all stages.

  5. Validation of intermolecular transfer integral and bandwidth calculations for organic molecular materials.

    PubMed

    Huang, Jingsong; Kertesz, Miklos

    2005-06-15

    We present an interpretation of the intermolecular transfer integral that is independent from the origin of the energy scale allowing convergence studies of this important parameter of organic molecular materials. We present extensive numerical studies by using an ethylene pi dimer to investigate the dependence of transfer integrals on the level of theory and intermolecular packing. Transfer integrals obtained from semiempirical calculations differ substantially from one another and from ab initio results. The ab initio results are consistent across all the levels used including Hartree-Fock, outer valence Green's function, and various forms of density functional theory (DFT). Validation of transfer integrals and bandwidths is performed by comparing the calculated values with the experimental values of tetrathiafulvalene-tetracyanoquinodimethane (TTF-TCNQ), bis[1,2,5]thiadiazolo-p-quinobis(1,3-dithiole), (BTQBT) K-TCNQ, and hexagonal graphite. DFT in one of its presently popular forms, such as Perdew-Wang functionals (PW91), in combination with sufficient basis sets provides reliable transfer integrals, and therefore can serve as a basis for energy band calculations for soft organic materials with van der Waals gaps. PMID:16008473

  6. A multi-disciplinary approach for the integrated assessment of multiple risks in delta areas.

    NASA Astrophysics Data System (ADS)

    Sperotto, Anna; Torresan, Silvia; Critto, Andrea; Marcomini, Antonio

    2016-04-01

    The assessment of climate change related risks is notoriously difficult due to the complex and uncertain combinations of hazardous events that might happen, the multiplicity of physical processes involved, the continuous changes and interactions of environmental and socio-economic systems. One important challenge lies in predicting and modelling cascades of natural and man -made hazard events which can be triggered by climate change, encompassing different spatial and temporal scales. Another regard the potentially difficult integration of environmental, social and economic disciplines in the multi-risk concept. Finally, the effective interaction between scientists and stakeholders is essential to ensure that multi-risk knowledge is translated into efficient adaptation and management strategies. The assessment is even more complex at the scale of deltaic systems which are particularly vulnerable to global environmental changes, due to the fragile equilibrium between the presence of valuable natural ecosystems and relevant economic activities. Improving our capacity to assess the combined effects of multiple hazards (e.g. sea-level rise, storm surges, reduction in sediment load, local subsidence, saltwater intrusion) is therefore essential to identify timely opportunities for adaptation. A holistic multi-risk approach is here proposed to integrate terminology, metrics and methodologies from different research fields (i.e. environmental, social and economic sciences) thus creating shared knowledge areas to advance multi risk assessment and management in delta regions. A first testing of the approach, including the application of Bayesian network analysis for the assessment of impacts of climate change on key natural systems (e.g. wetlands, protected areas, beaches) and socio-economic activities (e.g. agriculture, tourism), is applied in the Po river delta in Northern Italy. The approach is based on a bottom-up process involving local stakeholders early in different

  7. The integration of molecular dynamics simulations with imposed temperature and stress

    NASA Astrophysics Data System (ADS)

    Lill, J. V.

    1994-04-01

    Nonlinear molecular dynamics equations for the simulation of crystals under the conditions of imposed temperature and tensorial pressure are summarized. The physical effects included in these equations, but absent from previous linear and nonlinear theories, is the elastic response of the material being modeled. The physical effect is expressed through satisfaction of the nonlinear tensorial virial theorem. We transform these equations in Hamiltonian form to an equivalent set of Lagrangian equations, and present an algorithm for their numerical integration. The method uses a combination of Verlet and leap-frog algorithms to integrate the atomic positions and velocities as scaled by dynamical lattice vectors of the crystal, the elements of deformation gradient and its velocity, and the Nosé-Hoover time scale and generalized friction. A consistent error analysis is performed for the combined integration of each degree of freedom. A symmetrization procedure to eliminate rigid rotations of the crystal is introduced. Molecular dynamics simulations of a Martensitic tranformation are presented that demonstrate the validity of the nonlinear tensorial virial theorem throughout the transformation; complementary Metropolis Monte Carlo simulations verify that the correct distribution is sampled.

  8. Integrating Multiple Distribution Models to Guide Conservation Efforts of an Endangered Toad

    PubMed Central

    Treglia, Michael L.; Fisher, Robert N.; Fitzgerald, Lee A.

    2015-01-01

    Species distribution models are used for numerous purposes such as predicting changes in species’ ranges and identifying biodiversity hotspots. Although implications of distribution models for conservation are often implicit, few studies use these tools explicitly to inform conservation efforts. Herein, we illustrate how multiple distribution models developed using distinct sets of environmental variables can be integrated to aid in identification sites for use in conservation. We focus on the endangered arroyo toad (Anaxyrus californicus), which relies on open, sandy streams and surrounding floodplains in southern California, USA, and northern Baja California, Mexico. Declines of the species are largely attributed to habitat degradation associated with vegetation encroachment, invasive predators, and altered hydrologic regimes. We had three main goals: 1) develop a model of potential habitat for arroyo toads, based on long-term environmental variables and all available locality data; 2) develop a model of the species’ current habitat by incorporating recent remotely-sensed variables and only using recent locality data; and 3) integrate results of both models to identify sites that may be employed in conservation efforts. We used a machine learning technique, Random Forests, to develop the models, focused on riparian zones in southern California. We identified 14.37% and 10.50% of our study area as potential and current habitat for the arroyo toad, respectively. Generally, inclusion of remotely-sensed variables reduced modeled suitability of sites, thus many areas modeled as potential habitat were not modeled as current habitat. We propose such sites could be made suitable for arroyo toads through active management, increasing current habitat by up to 67.02%. Our general approach can be employed to guide conservation efforts of virtually any species with sufficient data necessary to develop appropriate distribution models. PMID:26125634

  9. Integrating Multiple Distribution Models to Guide Conservation Efforts of an Endangered Toad.

    PubMed

    Treglia, Michael L; Fisher, Robert N; Fitzgerald, Lee A

    2015-01-01

    Species distribution models are used for numerous purposes such as predicting changes in species' ranges and identifying biodiversity hotspots. Although implications of distribution models for conservation are often implicit, few studies use these tools explicitly to inform conservation efforts. Herein, we illustrate how multiple distribution models developed using distinct sets of environmental variables can be integrated to aid in identification sites for use in conservation. We focus on the endangered arroyo toad (Anaxyrus californicus), which relies on open, sandy streams and surrounding floodplains in southern California, USA, and northern Baja California, Mexico. Declines of the species are largely attributed to habitat degradation associated with vegetation encroachment, invasive predators, and altered hydrologic regimes. We had three main goals: 1) develop a model of potential habitat for arroyo toads, based on long-term environmental variables and all available locality data; 2) develop a model of the species' current habitat by incorporating recent remotely-sensed variables and only using recent locality data; and 3) integrate results of both models to identify sites that may be employed in conservation efforts. We used a machine learning technique, Random Forests, to develop the models, focused on riparian zones in southern California. We identified 14.37% and 10.50% of our study area as potential and current habitat for the arroyo toad, respectively. Generally, inclusion of remotely-sensed variables reduced modeled suitability of sites, thus many areas modeled as potential habitat were not modeled as current habitat. We propose such sites could be made suitable for arroyo toads through active management, increasing current habitat by up to 67.02%. Our general approach can be employed to guide conservation efforts of virtually any species with sufficient data necessary to develop appropriate distribution models. PMID:26125634

  10. Integrating multiple distribution models to guide conservation efforts of an endangered toad

    USGS Publications Warehouse

    Treglia, Michael L.; Fisher, Robert N.; Fitzgerald, Lee A.

    2015-01-01

    Species distribution models are used for numerous purposes such as predicting changes in species’ ranges and identifying biodiversity hotspots. Although implications of distribution models for conservation are often implicit, few studies use these tools explicitly to inform conservation efforts. Herein, we illustrate how multiple distribution models developed using distinct sets of environmental variables can be integrated to aid in identification sites for use in conservation. We focus on the endangered arroyo toad (Anaxyrus californicus), which relies on open, sandy streams and surrounding floodplains in southern California, USA, and northern Baja California, Mexico. Declines of the species are largely attributed to habitat degradation associated with vegetation encroachment, invasive predators, and altered hydrologic regimes. We had three main goals: 1) develop a model of potential habitat for arroyo toads, based on long-term environmental variables and all available locality data; 2) develop a model of the species’ current habitat by incorporating recent remotely-sensed variables and only using recent locality data; and 3) integrate results of both models to identify sites that may be employed in conservation efforts. We used a machine learning technique, Random Forests, to develop the models, focused on riparian zones in southern California. We identified 14.37% and 10.50% of our study area as potential and current habitat for the arroyo toad, respectively. Generally, inclusion of remotely-sensed variables reduced modeled suitability of sites, thus many areas modeled as potential habitat were not modeled as current habitat. We propose such sites could be made suitable for arroyo toads through active management, increasing current habitat by up to 67.02%. Our general approach can be employed to guide conservation efforts of virtually any species with sufficient data necessary to develop appropriate distribution models.

  11. Molecular radiotherapy: The NUKFIT software for calculating the time-integrated activity coefficient

    SciTech Connect

    Kletting, P.; Schimmel, S.; Luster, M.; Kestler, H. A.; Hänscheid, H.; Fernández, M.; Lassmann, M.; Bröer, J. H.; Nosske, D.; Glatting, G.

    2013-10-15

    Purpose: Calculation of the time-integrated activity coefficient (residence time) is a crucial step in dosimetry for molecular radiotherapy. However, available software is deficient in that it is either not tailored for the use in molecular radiotherapy and/or does not include all required estimation methods. The aim of this work was therefore the development and programming of an algorithm which allows for an objective and reproducible determination of the time-integrated activity coefficient and its standard error.Methods: The algorithm includes the selection of a set of fitting functions from predefined sums of exponentials and the choice of an error model for the used data. To estimate the values of the adjustable parameters an objective function, depending on the data, the parameters of the error model, the fitting function and (if required and available) Bayesian information, is minimized. To increase reproducibility and user-friendliness the starting values are automatically determined using a combination of curve stripping and random search. Visual inspection, the coefficient of determination, the standard error of the fitted parameters, and the correlation matrix are provided to evaluate the quality of the fit. The functions which are most supported by the data are determined using the corrected Akaike information criterion. The time-integrated activity coefficient is estimated by analytically integrating the fitted functions. Its standard error is determined assuming Gaussian error propagation. The software was implemented using MATLAB.Results: To validate the proper implementation of the objective function and the fit functions, the results of NUKFIT and SAAM numerical, a commercially available software tool, were compared. The automatic search for starting values was successfully tested for reproducibility. The quality criteria applied in conjunction with the Akaike information criterion allowed the selection of suitable functions. Function fit

  12. Revolutionizing our View of Protostellar Multiplicity and Disks: The VLA Nascent Disk and Multiplicity (VANDAM) Survey of the Perseus Molecular Cloud

    NASA Astrophysics Data System (ADS)

    Tobin, J. J.; Looney, L. W.; Li, Z.-Y.; Chandler, C. J.; Dunham, M. M.; Segura-Cox, D.; Cox, E. G.; Harris, R. J.; Melis, C.; Sadavoy, S. I.; Pérez, L.; Kratter, K.

    2016-05-01

    There is substantial evidence for disk formation taking place during the early stages of star formation and for most stars being born in multiple systems; however, protostellar multiplicity and disk searches have been hampered by low resolution, sample bias, and variable sensitivity. We have conducted an unbiased, high-sensitivity Karl G. Jansky Very Large Array (VLA) survey toward all known protostars (n = 94) in the Perseus molecular cloud (d ˜ 230 pc), with a resolution of ˜ 15 AU (0.06'') at λ = 8 mm. We have detected candidate protostellar disks toward 17 sources (with 12 of those in the Class 0 stage) and we have found substructure on < 50 AU scales for three Class 0 disk candidates, possibly evidence for disk fragmentation. We have discovered 16 new multiple systems (or new components) in this survey; the new systems have separations < 500 AU and 3 by < 30 AU. We also found a bi-modal distribution of separations, with peaks at ˜ 75 AU and ˜ 3000 AU, suggestive of formation through two distinct mechanisms: disk and turbulent fragmentation. The results from this survey demonstrate the necessity and utility of uniform, unbiased surveys of protostellar systems at millimeter and centimeter wavelengths.

  13. BioZone Exploting Source-Capability Information for Integrated Access to Multiple Bioinformatics Data Sources

    SciTech Connect

    Liu, L; Buttler, D; Paques, H; Pu, C; Critchlow

    2002-01-28

    Modern Bioinformatics data sources are widely used by molecular biologists for homology searching and new drug discovery. User-friendly and yet responsive access is one of the most desirable properties for integrated access to the rapidly growing, heterogeneous, and distributed collection of data sources. The increasing volume and diversity of digital information related to bioinformatics (such as genomes, protein sequences, protein structures, etc.) have led to a growing problem that conventional data management systems do not have, namely finding which information sources out of many candidate choices are the most relevant and most accessible to answer a given user query. We refer to this problem as the query routing problem. In this paper we introduce the notation and issues of query routing, and present a practical solution for designing a scalable query routing system based on multi-level progressive pruning strategies. The key idea is to create and maintain source-capability profiles independently, and to provide algorithms that can dynamically discover relevant information sources for a given query through the smart use of source profiles. Compared to the keyword-based indexing techniques adopted in most of the search engines and software, our approach offers fine-granularity of interest matching, thus it is more powerful and effective for handling queries with complex conditions.

  14. BioZoom: Exploiting Source-Capability Information for Integrated Access to Multiple Bioinformatics Data Sources

    SciTech Connect

    Liu, L; Buttler, D; Critchlow, T J; Han, W; Paques, H; Pu, C; Rocco, D

    2003-01-09

    Modern Bioinformatics data sources are widely used by molecular biologists for homology searching and new drug discovery. User-friendly and yet responsive access is one of the most desirable properties for integrated access to the rapidly growing, heterogeneous, and distributed collection of data sources. The increasing volume and diversity of digital information related to bioinformatics (such as genomes, protein sequences, protein structures, etc.) have led to a growing problem that conventional data management systems do not have, namely finding which information sources out of many candidate choices are the most relevant and most accessible to answer a given user query. We refer to this problem as the query routing problem. In this paper we introduce the notation and issues of query routing, and present a practical solution for designing a scalable query routing system based on multi-level progressive pruning strategies. The key idea is to create and maintain source-capability profiles independently, and to provide algorithms that can dynamically discover relevant information sources for a given query through the smart use of source profiles. Compared to the keyword-based indexing techniques adopted in most of the search engines and software, our approach offers fine-granularity of interest matching, thus it is more powerful and effective for handling queries with complex conditions.

  15. Evaluation of Kirkwood-Buff integrals via finite size scaling: a large scale molecular dynamics study

    NASA Astrophysics Data System (ADS)

    Dednam, W.; Botha, A. E.

    2015-01-01

    Solvation of bio-molecules in water is severely affected by the presence of co-solvent within the hydration shell of the solute structure. Furthermore, since solute molecules can range from small molecules, such as methane, to very large protein structures, it is imperative to understand the detailed structure-function relationship on the microscopic level. For example, it is useful know the conformational transitions that occur in protein structures. Although such an understanding can be obtained through large-scale molecular dynamic simulations, it is often the case that such simulations would require excessively large simulation times. In this context, Kirkwood-Buff theory, which connects the microscopic pair-wise molecular distributions to global thermodynamic properties, together with the recently developed technique, called finite size scaling, may provide a better method to reduce system sizes, and hence also the computational times. In this paper, we present molecular dynamics trial simulations of biologically relevant low-concentration solvents, solvated by aqueous co-solvent solutions. In particular we compare two different methods of calculating the relevant Kirkwood-Buff integrals. The first (traditional) method computes running integrals over the radial distribution functions, which must be obtained from large system-size NVT or NpT simulations. The second, newer method, employs finite size scaling to obtain the Kirkwood-Buff integrals directly by counting the particle number fluctuations in small, open sub-volumes embedded within a larger reservoir that can be well approximated by a much smaller simulation cell. In agreement with previous studies, which made a similar comparison for aqueous co-solvent solutions, without the additional solvent, we conclude that the finite size scaling method is also applicable to the present case, since it can produce computationally more efficient results which are equivalent to the more costly radial distribution

  16. Drosophila Myc integrates multiple signaling pathways to regulate intestinal stem cell proliferation during midgut regeneration

    PubMed Central

    Ren, Fangfang; Shi, Qing; Chen, Yongbin; Jiang, Alice; Ip, Y Tony; Jiang, Huaqi; Jiang, Jin

    2013-01-01

    Intestinal stem cells (ISCs) in the Drosophila adult midgut are essential for maintaining tissue homeostasis, and their proliferation and differentiation speed up in order to meet the demand for replenishing the lost cells in response to injury. Several signaling pathways including JAK-STAT, EGFR and Hippo (Hpo) pathways have been implicated in damage-induced ISC proliferation, but the mechanisms that integrate these pathways have remained elusive. Here, we demonstrate that the Drosophila homolog of the oncoprotein Myc (dMyc) functions downstream of these signaling pathways to mediate their effects on ISC proliferation. dMyc expression in precursor cells is stimulated in response to tissue damage, and dMyc is essential for accelerated ISC proliferation and midgut regeneration. We show that tissue damage caused by dextran sulfate sodium feeding stimulates dMyc expression via the Hpo pathway, whereas bleomycin feeding activates dMyc through the JAK-STAT and EGFR pathways. We provide evidence that dMyc expression is transcriptionally upregulated by multiple signaling pathways, which is required for optimal ISC proliferation in response to tissue damage. We have also obtained evidence that tissue damage can upregulate dMyc expression post-transcriptionally. Finally, we show that a basal level of dMyc expression is required for ISC maintenance, proliferation and lineage differentiation during normal tissue homeostasis. PMID:23896988

  17. Efficient implicit integration for finite-strain viscoplasticity with a nested multiplicative split

    NASA Astrophysics Data System (ADS)

    Shutov, A. V.

    2016-07-01

    An efficient and reliable stress computation algorithm is presented, which is based on implicit integration of the local evolution equations of multiplicative finite-strain plasticity/viscoplasticity. The algorithm is illustrated by an example involving a combined nonlinear isotropic/kinematic hardening; numerous backstress tensors are employed for a better description of the material behavior. The considered material model exhibits the so-called weak invariance under arbitrary isochoric changes of the reference configuration, and the presented algorithm retains this useful property. Even more: the weak invariance serves as a guide in constructing this algorithm. The constraint of inelastic incompressibility is exactly preserved as well. The proposed method is first-order accurate. Concerning the accuracy of the stress computation, the new algorithm is comparable to the Euler Backward method with a subsequent correction of incompressibility (EBMSC) and the classical exponential method (EM). Regarding the computational efficiency, the new algorithm is superior to the EBMSC and EM. Some accuracy tests are presented using parameters of the aluminum alloy 5754-O and the 42CrMo4 steel. FEM solutions of two boundary value problems using MSC.MARC are presented to show the correctness of the numerical implementation.

  18. Integrity of the Anterior Visual Pathway and Its Association with Ambulatory Performance in Multiple Sclerosis

    PubMed Central

    Sandroff, Brian M.; Pula, John H.; Motl, Robert W.

    2013-01-01

    Background. Retinal nerve fiber layer thickness (RNFLT) and total macular volume (TMV) represent markers of neuroaxonal degeneration within the anterior visual pathway that might correlate with ambulation in persons with multiple sclerosis (MS). Objective. This study examined the associations between RNFLT and TMV with ambulatory parameters in MS. Methods. Fifty-eight MS patients underwent a neurological examination for generation of an expanded disability status scale (EDSS) score and measurement of RNFLT and TMV using optical coherence tomography (OCT). Participants completed the 6-minute walk (6MW) and the timed 25-foot walk (T25FW). The associations were examined using generalized estimating equation models that accounted for within-patient, inter-eye correlations, and controlled for disease duration, EDSS score, and age. Results. RNFLT was not significantly associated with 6MW (P = 0.99) or T25FW (P = 0.57). TMV was significantly associated with 6MW (P = 0.023) and T25FW (P = 0.005). The coefficients indicated that unit differences in 6MW (100 feet) and T25FW (1 second) were associated with 0.040 and −0.048 unit differences in TMV (mm3), respectively. Conclusion. Integrity of the anterior visual pathway, particularly TMV, might represent a noninvasive measure of neuroaxonal degeneration that is correlated with ambulatory function in MS. PMID:23864950

  19. Integrating semantic information into multiple kernels for protein-protein interaction extraction from biomedical literatures.

    PubMed

    Li, Lishuang; Zhang, Panpan; Zheng, Tianfu; Zhang, Hongying; Jiang, Zhenchao; Huang, Degen

    2014-01-01

    Protein-Protein Interaction (PPI) extraction is an important task in the biomedical information extraction. Presently, many machine learning methods for PPI extraction have achieved promising results. However, the performance is still not satisfactory. One reason is that the semantic resources were basically ignored. In this paper, we propose a multiple-kernel learning-based approach to extract PPIs, combining the feature-based kernel, tree kernel and semantic kernel. Particularly, we extend the shortest path-enclosed tree kernel (SPT) by a dynamic extended strategy to retrieve the richer syntactic information. Our semantic kernel calculates the protein-protein pair similarity and the context similarity based on two semantic resources: WordNet and Medical Subject Heading (MeSH). We evaluate our method with Support Vector Machine (SVM) and achieve an F-score of 69.40% and an AUC of 92.00%, which show that our method outperforms most of the state-of-the-art systems by integrating semantic information. PMID:24622773

  20. Modified principal component analysis: an integration of multiple similarity subspace models.

    PubMed

    Fan, Zizhu; Xu, Yong; Zuo, Wangmeng; Yang, Jian; Tang, Jinhui; Lai, Zhihui; Zhang, David

    2014-08-01

    We modify the conventional principal component analysis (PCA) and propose a novel subspace learning framework, modified PCA (MPCA), using multiple similarity measurements. MPCA computes three similarity matrices exploiting the similarity measurements: 1) mutual information; 2) angle information; and 3) Gaussian kernel similarity. We employ the eigenvectors of similarity matrices to produce new subspaces, referred to as similarity subspaces. A new integrated similarity subspace is then generated using a novel feature selection approach. This approach needs to construct a kind of vector set, termed weak machine cell (WMC), which contains an appropriate number of the eigenvectors spanning the similarity subspaces. Combining the wrapper method and the forward selection scheme, MPCA selects a WMC at a time that has a powerful discriminative capability to classify samples. MPCA is very suitable for the application scenarios in which the number of the training samples is less than the data dimensionality. MPCA outperforms the other state-of-the-art PCA-based methods in terms of both classification accuracy and clustering result. In addition, MPCA can be applied to face image reconstruction. MPCA can use other types of similarity measurements. Extensive experiments on many popular real-world data sets, such as face databases, show that MPCA achieves desirable classification results, as well as has a powerful capability to represent data. PMID:25050950

  1. Integrating Semantic Information into Multiple Kernels for Protein-Protein Interaction Extraction from Biomedical Literatures

    PubMed Central

    Li, Lishuang; Zhang, Panpan; Zheng, Tianfu; Zhang, Hongying; Jiang, Zhenchao; Huang, Degen

    2014-01-01

    Protein-Protein Interaction (PPI) extraction is an important task in the biomedical information extraction. Presently, many machine learning methods for PPI extraction have achieved promising results. However, the performance is still not satisfactory. One reason is that the semantic resources were basically ignored. In this paper, we propose a multiple-kernel learning-based approach to extract PPIs, combining the feature-based kernel, tree kernel and semantic kernel. Particularly, we extend the shortest path-enclosed tree kernel (SPT) by a dynamic extended strategy to retrieve the richer syntactic information. Our semantic kernel calculates the protein-protein pair similarity and the context similarity based on two semantic resources: WordNet and Medical Subject Heading (MeSH). We evaluate our method with Support Vector Machine (SVM) and achieve an F-score of 69.40% and an AUC of 92.00%, which show that our method outperforms most of the state-of-the-art systems by integrating semantic information. PMID:24622773

  2. A way to integrate multiple block layers for middle of line contact patterning

    NASA Astrophysics Data System (ADS)

    Kunnen, E.; Demuynck, S.; Brouri, M.; Boemmels, J.; Versluijs, J.; Ryckaert, J.

    2015-03-01

    It is clear today that further scaling towards smaller dimensions and pitches requires a multitude of additional process steps. Within this work we look for solutions to achieve a middle of line 193i based patterning scheme for N7 logic at a contacted poly pitch of 40-45 nm. At these pitches, trenches can still be printed by means of double patterning. However, they need to be blocked at certain positions because of a limited line end control below 90 nm pitch single print. Based on the 193i patterning abilities, the proposed SRAM (Static Random Access Memory) cell requires 5 blocking layers. Integrating 5 blocking layers is a new challenge since down to N10 one blocking layer was usually sufficient. The difficulty with multiple blocking layers is the removal of the masked parts, especially in cases of overlap. As a solution a novel patterning approach is proposed and tried out on relaxed dimensions (patent pending). The proposed solution is expected not to be sensitive to the number of blocking layers used, and tolerates their overlap. The stack is constructed to be compatible with N7 substrates such as SiGe or P:Si. Experimental results of the stack blocking performance on relaxed pitch will be presented and discussed.

  3. An integrated economic model of multiple types and uses of water

    NASA Astrophysics Data System (ADS)

    Luckmann, Jonas; Grethe, Harald; McDonald, Scott; Orlov, Anton; Siddig, Khalid

    2014-05-01

    Water scarcity is an increasing problem in many parts of the world and the management of water has become an important issue on the political economy agenda in many countries. As water is used in most economic activities and the allocation of water is often a complex problem involving different economic agents and sectors, Computable General Equilibrium (CGE) models have been proven useful to analyze water allocation problems, although their adaptation to include water is still relatively undeveloped. This paper provides a description of an integrated water-focused CGE model (STAGE_W) that includes multiple types and uses of water, and for the first time, the reclamation of wastewater as well as the provision of brackish groundwater as separate, independent activities with specific cost structures. The insights provided by the model are illustrated with an application to the Israeli water sector assuming that freshwater resources available to the economy are cut by 50%. We analyze how the Israeli economy copes with this shock if it reduces potable water supply compared with further investments in the desalination sector. The results demonstrate that the effects on the economy are slightly negative under both scenarios. Counter intuitively, the provision of additional potable water to the economy through desalination does not substantively reduce the negative outcomes. This is mainly due to the high costs of desalination, which are currently subsidized, with the distribution of the negative welfare effect over household groups dependent on how these subsidies are financed.

  4. Phase Behavior of Active Swimmers in Depletants: Molecular Dynamics and Integral Equation Theory

    NASA Astrophysics Data System (ADS)

    Das, Subir K.; Egorov, Sergei A.; Trefz, Benjamin; Virnau, Peter; Binder, Kurt

    2014-05-01

    We study the structure and phase behavior of a binary mixture where one of the components is self-propelling in nature. The interparticle interactions in the system are taken from the Asakura-Oosawa model for colloid-polymer mixtures for which the phase diagram is known. In the current model version, the colloid particles are made active using the Vicsek model for self-propelling particles. The resultant active system is studied by molecular dynamics methods and integral equation theory. Both methods produce results consistent with each other and demonstrate that the Vicsek model-based activity facilitates phase separation, thus, broadening the coexistence region.

  5. Phase behavior of active swimmers in depletants: molecular dynamics and integral equation theory.

    PubMed

    Das, Subir K; Egorov, Sergei A; Trefz, Benjamin; Virnau, Peter; Binder, Kurt

    2014-05-16

    We study the structure and phase behavior of a binary mixture where one of the components is self-propelling in nature. The interparticle interactions in the system are taken from the Asakura-Oosawa model for colloid-polymer mixtures for which the phase diagram is known. In the current model version, the colloid particles are made active using the Vicsek model for self-propelling particles. The resultant active system is studied by molecular dynamics methods and integral equation theory. Both methods produce results consistent with each other and demonstrate that the Vicsek model-based activity facilitates phase separation, thus, broadening the coexistence region. PMID:24877969

  6. Site-controlled Ag nanocrystals grown by molecular beam epitaxy-Towards plasmonic integration technology

    SciTech Connect

    Urbanczyk, Adam; Noetzel, Richard

    2012-12-15

    We demonstrate site-controlled growth of epitaxial Ag nanocrystals on patterned GaAs substrates by molecular beam epitaxy with high degree of long-range uniformity. The alignment is based on lithographically defined holes in which position controlled InAs quantum dots are grown. The Ag nanocrystals self-align preferentially on top of the InAs quantum dots. No such ordering is observed in the absence of InAs quantum dots, proving that the ordering is strain-driven. The presented technique facilitates the placement of active plasmonic nanostructures at arbitrarily defined positions enabling their integration into complex devices and plasmonic circuits.

  7. THE MOLECULAR PATHOLOGY OF MELANOMA: AN INTEGRATED TAXONOMY OF MELANOCYTIC NEOPLASIA

    PubMed Central

    Bastian, Boris C.

    2016-01-01

    Melanomas are comprised of multiple biologically distinct categories, which differ in cell of origin, age of onset, clinical and histologic presentation, pattern of metastasis, ethnic distribution, causative role of UV radiation, predisposing germ line alterations, mutational processes, and patterns of somatic mutations. Neoplasms are initiated by gain of function mutations in one of several primary oncogenes, typically leading to benign melanocytic nevi with characteristic histologic features. The progression of nevi is restrained by multiple tumor suppressive mechanisms. Secondary genetic alterations override these barriers and promote intermediate or overtly malignant tumors along distinct progression trajectories. The current knowledge about pathogenesis, clinical, histological and genetic features of primary melanocytic neoplasms is reviewed and integrated into a taxonomic framework. PMID:24460190

  8. Toward Integrated Molecular Diagnostic System (iMDx): Principles and Applications

    PubMed Central

    Park, Seung-min; Sabour, Andrew F.; Son, Jun Ho; Lee, Sang Hun

    2014-01-01

    Integrated molecular diagnostic systems (iMDx), which are automated, sensitive, specific, user-friendly, robust, rapid, easy-to-use, and portable, can revolutionize future medicine. This review will first focus on the components of sample extraction, preservation, and filtration necessary for all point-of-care devices to include for practical use. Subsequently, we will look for low-powered and precise methods for both sample amplification and signal transduction, going in-depth to the details behind their principles. The final field of total device integration and its application to the clinical field will also be addressed to discuss the practicality for future patient care. We envision that microfluidic systems hold the potential to breakthrough the number of problems brought into the field of medical diagnosis today. PMID:24759281

  9. Efficient molecular dynamics using geodesic integration and solvent–solute splitting

    PubMed Central

    Leimkuhler, Benedict

    2016-01-01

    We present an approach to Langevin dynamics in the presence of holonomic constraints based on decomposition of the system into components representing geodesic flow, constrained impulse and constrained diffusion. We show that a particular ordering of the components results in an integrator that is an order of magnitude more accurate for configurational averages than existing alternatives. Moreover, by combining the geodesic integration method with a solvent–solute force splitting, we demonstrate that stepsizes of at least 8 fs can be used for solvated biomolecules with high sampling accuracy and without substantially altering diffusion rates, approximately increasing by a factor of two the efficiency of molecular dynamics sampling for such systems. The methods described in this article are easily implemented using the standard apparatus of modern simulation codes. PMID:27279779

  10. Using Images, Metaphor, and Hypnosis in Integrating Multiple Personality and Dissociative States: A Review of the Literature.

    ERIC Educational Resources Information Center

    Crawford, Carrie L.

    1990-01-01

    Reviews literature on hypnosis, imagery, and metaphor as applied to the treatment and integration of those with multiple personality disorder (MPD) and dissociative states. Considers diagnostic criteria of MPD; explores current theories of etiology and treatment; and suggests specific examples of various clinical methods of treatment using…

  11. Sequencing and beyond: integrating molecular ‘omics for microbial community profiling

    PubMed Central

    Franzosa, Eric A.; Hsu, Tiffany; Sirota-Madi, Alexandra; Shafquat, Afrah; Abu-Ali, Galeb; Morgan, Xochitl C.

    2016-01-01

    High-throughput DNA sequencing has proven invaluable for investigating diverse environmental and host-associated microbial communities. In this Review, we discuss emerging strategies for microbial community analysis that complement and expand traditional metagenomic profiling. These include novel DNA sequencing strategies for identifying strain-level microbial variation and community temporal dynamics; measuring additional multi'omic data types that better capture community functional activity, such as transcriptomics, proteomics, and metabolomics; and combining multiple forms of multi'omic data in an integrated framework. We highlight studies in which the multi'omics approach has led to improved mechanistic models of microbial community structure and function. PMID:25915636

  12. Auxiliary functions for molecular integrals with Slater-type orbitals. II. Gauss transform methods

    NASA Astrophysics Data System (ADS)

    Ema, I.; López, R.; Fernández, J. J.; Ramírez, G.; Rico, J. F.

    The Gauss transform of Slater-type orbitals is used to express several types of molecular integrals involving these functions in terms of simple auxiliary functions. After reviewing this transform and the way it can be combined with the shift operator technique, a master formula for overlap integrals is derived and used to obtain multipolar moments associated to fragments of two-center distributions and overlaps of derivatives of Slater functions. Moreover, it is proved that integrals involving two-center distributions and irregular harmonics placed at arbitrary points (which determine the electrostatic potential, field and field gradient, as well as higher order derivatives of the potential) can be expressed in terms of auxiliary functions of the same type as those appearing in the overlap. The recurrence relations and series expansions of these functions are thoroughly studied, and algorithms for their calculation are presented. The usefulness and efficiency of this procedure are tested by developing two independent codes: one for the derivatives of the overlap integrals with respect to the centers of the functions, and another for derivatives of the potential (electrostatic field, field gradient, and so forth) at arbitrary points.0

  13. Determination of cloud effective particle size from the multiple-scattering effect on lidar integration-method temperature measurements.

    PubMed

    Reichardt, Jens; Reichardt, Susanne

    2006-04-20

    A method is presented that permits the determination of the cloud effective particle size from Raman- or Rayleigh-integration temperature measurements that exploits the dependence of the multiple-scattering contributions to the lidar signals from heights above the cloud on the particle size of the cloud. Independent temperature information is needed for the determination of size. By use of Raman-integration temperatures, the technique is applied to cirrus measurements. The magnitude of the multiple-scattering effect and the above-cloud lidar signal strength limit the method's range of applicability to cirrus optical depths from 0.1 to 0.5. Our work implies that records of stratosphere temperature obtained with lidar may be affected by multiple scattering in clouds up to heights of 30 km and beyond. PMID:16633433

  14. Integration of Multiple Non-Normal Checklist Procedures into a Single Checklist Procedure for Transport Aircraft: A Preliminary Investigation

    NASA Technical Reports Server (NTRS)

    Foernsler, Lynda J.

    1996-01-01

    Checklists are used by the flight crew to properly configure an aircraft for safe flight and to ensure a high level of safety throughout the duration of the flight. In addition, the checklist provides a sequential framework to meet cockpit operational requirements, and it fosters cross-checking of the flight deck configuration among crew members. This study examined the feasibility of integrating multiple checklists for non-normal procedures into a single procedure for a typical transport aircraft. For the purposes of this report, a typical transport aircraft is one that represents a midpoint between early generation aircraft (B-727/737-200 and DC-10) and modern glass cockpit aircraft (B747-400/777 and MD-11). In this report, potential conflicts among non-normal checklist items during multiple failure situations for a transport aircraft are identified and analyzed. The non-normal checklist procedure that would take precedence for each of the identified multiple failure flight conditions is also identified. The rationale behind this research is that potential conflicts among checklist items might exist when integrating multiple checklists for non-normal procedures into a single checklist. As a rule, multiple failures occurring in today's highly automated and redundant system transport aircraft are extremely improbable. In addition, as shown in this analysis, conflicts among checklist items in a multiple failure flight condition are exceedingly unlikely. The possibility of a multiple failure flight condition occurring with a conflict among checklist items is so remote that integration of the non-normal checklists into a single checklist appears to be a plausible option.

  15. Inferring Diversity and Evolution in Fish by Means of Integrative Molecular Cytogenetics

    PubMed Central

    Artoni, Roberto Ferreira; Castro, Jonathan Pena; Jacobina, Uedson Pereira; Lima-Filho, Paulo Augusto; Félix da Costa, Gideão Wagner Werneck; Molina, Wagner Franco

    2015-01-01

    Fish constitute a paraphyletic and profusely diversified group that has historically puzzled ichthyologists. Hard efforts are necessary to better understand this group, due to its extensive diversity. New species are often identified and it leads to questions about their phylogenetic aspects. Cytogenetics is becoming an important biodiversity-detection tool also used to measure biodiversity evolutionary aspects. Molecular cytogenetics by fluorescence in situ hybridization (FISH) allowed integrating quantitative and qualitative data from DNA sequences and their physical location in chromosomes and genomes. Although there is no intention on presenting a broader review, the current study presents some evidences on the need of integrating molecular cytogenetic data to other evolutionary biology tools to more precisely infer cryptic species detection, population structuring in marine environments, intra- and interspecific karyoevolutionary aspects of freshwater groups, evolutionary dynamics of marine fish chromosomes, and the origin and differentiation of sexual and B chromosomes. The new cytogenetic field, called cytogenomics, is spreading due to its capacity to give resolute answers to countless questions that cannot be answered by traditional methodologies. Indeed, the association between chromosomal markers and DNA sequencing as well as between biological diversity analysis methodologies and phylogenetics triggers the will to search for answers about fish evolutionary, taxonomic, and structural features. PMID:26345638

  16. Revealing potential molecular targets bridging colitis and colorectal cancer based on multidimensional integration strategy

    PubMed Central

    Hu, Yongfei; Li, Xiaobo; Wang, Xishan; Fan, Huihui; Wang, Guiyu; Wang, Dong

    2015-01-01

    Chronic inflammation may play a vital role in the pathogenesis of inflammation-associated tumors. However, the underlying mechanisms bridging ulcerative colitis (UC) and colorectal cancer (CRC) remain unclear. Here, we integrated multidimensional interaction resources, including gene expression profiling, protein-protein interactions (PPIs), transcriptional and post-transcriptional regulation data, and virus-host interactions, to tentatively explore potential molecular targets that functionally link UC and CRC at a systematic level. In this work, by deciphering the overlapping genes, crosstalking genes and pivotal regulators of both UC- and CRC-associated functional module pairs, we revealed a variety of genes (including FOS and DUSP1, etc.), transcription factors (including SMAD3 and ETS1, etc.) and miRNAs (including miR-155 and miR-196b, etc.) that may have the potential to complete the connections between UC and CRC. Interestingly, further analyses of the virus-host interaction network demonstrated that several virus proteins (including EBNA-LP of EBV and protein E7 of HPV) frequently inter-connected to UC- and CRC-associated module pairs with their validated targets significantly enriched in both modules of the host. Together, our results suggested that multidimensional integration strategy provides a novel approach to discover potential molecular targets that bridge the connections between UC and CRC, which could also be extensively applied to studies on other inflammation-related cancers. PMID:26461477

  17. Integrating Molecular Testing in the Diagnosis and Management of Children with Thyroid Lesions.

    PubMed

    Ballester, Leomar Y; Sarabia, Stephen F; Sayeed, Hadi; Patel, Nimesh; Baalwa, Joshua; Athanassaki, Ioanna; Hernandez, Jose A; Fang, Erica; Quintanilla, Norma M; Roy, Angshumoy; López-Terrada, Dolores H

    2016-01-01

    Thyroid nodules occur in 1-2% of children, and identifying which nodules are malignant is often challenging. Cytologic evaluation facilitates the diagnosis of thyroid lesions (TLs), but in 10-40% of cases the interpretation is indeterminate. Patients with indeterminate diagnoses are often treated with hemithyroidectomy followed by completion thyroidectomy, if cancer is found in the initial specimen. Exposing patients to multiple surgeries increases costs and morbidity. The American Thyroid Association states that a combination of molecular markers is likely to optimize the management of patients with indeterminate cytology. However, few studies have addressed the molecular alterations present in pediatric TL. Twenty-seven thyroid carcinomas from patients 10 to 19 years of age were tested for alterations common in adult TL, including BRAF V600E mutation, RET fusions, and TERT promoter mutations. Mutation-negative cases were subsequently analyzed with a next-generation sequencing (NGS) mutation panel to search for additional targets. Histologic diagnoses included 12 classic papillary thyroid carcinomas (PTCs), 13 follicular variant PTCs, 1 medullary thyroid carcinoma, and 1 follicular carcinoma. Fourteen cases showed lymph node involvement, and 13 cases demonstrated lymphovascular invasion. The BRAF V600E mutation was detected in 10/27 cases, and RET fusions were detected in 6/27 cases. No TERT promoter mutations were identified in any of the cases. The NGS panel revealed additional RET and CTNNB1 pathogenic missense mutations. Our results demonstrate that molecular abnormalities are common in pediatric TLs and suggest that incorporation of molecular testing will be helpful in optimizing patient management. PMID:26366474

  18. Integrating Nanostructured Artificial Receptors with Whispering Gallery Mode Optical Microresonators via Inorganic Molecular Imprinting Techniques.

    PubMed

    Hammond, G Denise; Vojta, Adam L; Grant, Sheila A; Hunt, Heather K

    2016-01-01

    The creation of label-free biosensors capable of accurately detecting trace contaminants, particularly small organic molecules, is of significant interest for applications in environmental monitoring. This is achieved by pairing a high-sensitivity signal transducer with a biorecognition element that imparts selectivity towards the compound of interest. However, many environmental pollutants do not have corresponding biorecognition elements. Fortunately, biomimetic chemistries, such as molecular imprinting, allow for the design of artificial receptors with very high selectivity for the target. Here, we perform a proof-of-concept study to show how artificial receptors may be created from inorganic silanes using the molecular imprinting technique and paired with high-sensitivity transducers without loss of device performance. Silica microsphere Whispering Gallery Mode optical microresonators are coated with a silica thin film templated by a small fluorescent dye, fluorescein isothiocyanate, which serves as our model target. Oxygen plasma degradation and solvent extraction of the template are compared. Extracted optical devices are interacted with the template molecule to confirm successful sorption of the template. Surface characterization is accomplished via fluorescence and optical microscopy, ellipsometry, optical profilometry, and contact angle measurements. The quality factors of the devices are measured to evaluate the impact of the coating on device sensitivity. The resulting devices show uniform surface coating with no microstructural damage with Q factors above 10⁶. This is the first report demonstrating the integration of these devices with molecular imprinting techniques, and could lead to new routes to biosensor creation for environmental monitoring. PMID:27314397

  19. Integrating Nanostructured Artificial Receptors with Whispering Gallery Mode Optical Microresonators via Inorganic Molecular Imprinting Techniques

    PubMed Central

    Hammond, G. Denise; Vojta, Adam L.; Grant, Sheila A.; Hunt, Heather K.

    2016-01-01

    The creation of label-free biosensors capable of accurately detecting trace contaminants, particularly small organic molecules, is of significant interest for applications in environmental monitoring. This is achieved by pairing a high-sensitivity signal transducer with a biorecognition element that imparts selectivity towards the compound of interest. However, many environmental pollutants do not have corresponding biorecognition elements. Fortunately, biomimetic chemistries, such as molecular imprinting, allow for the design of artificial receptors with very high selectivity for the target. Here, we perform a proof-of-concept study to show how artificial receptors may be created from inorganic silanes using the molecular imprinting technique and paired with high-sensitivity transducers without loss of device performance. Silica microsphere Whispering Gallery Mode optical microresonators are coated with a silica thin film templated by a small fluorescent dye, fluorescein isothiocyanate, which serves as our model target. Oxygen plasma degradation and solvent extraction of the template are compared. Extracted optical devices are interacted with the template molecule to confirm successful sorption of the template. Surface characterization is accomplished via fluorescence and optical microscopy, ellipsometry, optical profilometry, and contact angle measurements. The quality factors of the devices are measured to evaluate the impact of the coating on device sensitivity. The resulting devices show uniform surface coating with no microstructural damage with Q factors above 106. This is the first report demonstrating the integration of these devices with molecular imprinting techniques, and could lead to new routes to biosensor creation for environmental monitoring. PMID:27314397

  20. From molecule to man: integrating molecular biology with whole organ physiology in studying respiratory disease.

    PubMed

    Königshoff, Melanie; Uhl, Franziska; Gosens, Reinoud

    2011-10-01

    Chronic lung diseases such as asthma, chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF) are all characterized by structural changes of the airways and/or lungs that limit airflow and/or gas exchange. Currently, there is no therapy available that adequately targets the structural remodeling of the airways and lungs in these diseases. This underscores the great need for insight into the mechanisms that underpin the development of airway remodeling, fibrosis and emphysema in these diseases, in order to identify suitable drug targets. It is increasingly evident that structural cell-cell communication within the lung is central to the development of remodeling, indicating that a more integrative approach should be considered when studying molecular and cellular mechanisms of remodeling. Therefore, there is a great need to study molecular and cellular physiological and pathophysiological mechanisms in as much detail as possible, but with as little as possible loss of the physiological context. Here, we will review the use of models such as cellular co-culture, tissue culture, and lung slice culture, in which cell-cell communication and tissue architecture are better preserved or mimicked than in cell culture, and zoom in on the usefulness of molecular and cellular biological tools in these complex model systems to read out or control signaling and gene/protein regulation. PMID:21356323

  1. Implicit Time Integration for Multiscale Molecular Dynamics Using Transcendental Padé Approximants.

    PubMed

    Abi Mansour, Andrew; Ortoleva, Peter J

    2016-04-12

    Molecular dynamics systems evolve through the interplay of collective and localized disturbances. As a practical consequence, there is a restriction on the time step imposed by the broad spectrum of time scales involved. To resolve this restriction, multiscale factorization was introduced for molecular dynamics as a method that exploits the separation of time scales by coevolving the coarse-grained and atom-resolved states via Trotter factorization. Developing a stable time-marching scheme for this coevolution, however, is challenging because the coarse-grained dynamical equations depend on the microstate; therefore, these equations cannot be expressed in closed form. The objective of this paper is to develop an implicit time integration scheme for multiscale simulation of large systems over long periods of time and with high accuracy. The scheme uses Padé approximants to account for both the stochastic and deterministic features of the coarse-grained dynamics. The method is demonstrated for a protein either undergoing a conformational change or migrating under the influence of an external force. The method shows promise in accelerating multiscale molecular dynamics without a loss of atomic precision or the need to conjecture the form of coarse-grained governing equations. PMID:26845510

  2. VitisNet: “Omics” Integration through Grapevine Molecular Networks

    PubMed Central

    Grimplet, Jérôme; Cramer, Grant R.; Dickerson, Julie A.; Mathiason, Kathy; Van Hemert, John; Fennell, Anne Y.

    2009-01-01

    Background Genomic data release for the grapevine has increased exponentially in the last five years. The Vitis vinifera genome has been sequenced and Vitis EST, transcriptomic, proteomic, and metabolomic tools and data sets continue to be developed. The next critical challenge is to provide biological meaning to this tremendous amount of data by annotating genes and integrating them within their biological context. We have developed and validated a system of Grapevine Molecular Networks (VitisNet). Methodology/Principal Findings The sequences from the Vitis vinifera (cv. Pinot Noir PN40024) genome sequencing project and ESTs from the Vitis genus have been paired and the 39,424 resulting unique sequences have been manually annotated. Among these, 13,145 genes have been assigned to 219 networks. The pathway sets include 88 “Metabolic”, 15 “Genetic Information Processing”, 12 “Environmental Information Processing”, 3 “Cellular Processes”, 21 “Transport”, and 80 “Transcription Factors”. The quantitative data is loaded onto molecular networks, allowing the simultaneous visualization of changes in the transcriptome, proteome, and metabolome for a given experiment. Conclusions/Significance VitisNet uses manually annotated networks in SBML or XML format, enabling the integration of large datasets, streamlining biological functional processing, and improving the understanding of dynamic processes in systems biology experiments. VitisNet is grounded in the Vitis vinifera genome (currently at 8x coverage) and can be readily updated with subsequent updates of the genome or biochemical discoveries. The molecular network files can be dynamically searched by pathway name or individual genes, proteins, or metabolites through the MetNet Pathway database and web-portal at http://metnet3.vrac.iastate.edu/. All VitisNet files including the manual annotation of the grape genome encompassing pathway names, individual genes, their genome identifier, and

  3. Integrating data from multiple science networks to conduct cross-scale ecohydrological research. (Invited)

    NASA Astrophysics Data System (ADS)

    Tazik, D.; Roehm, C. L.; Atkin, O.; Ayers, E.; Berukoff, S. J.; Fitzgerald, M.; Held, A. A.; Hinckley, E. S.; Kampe, T. U.; Liddell, M.; Phinn, S. R.; Taylor, J. R.; Thibault, K. M.; Thorpe, A.

    2013-12-01

    Distributed standardized sensor networks that collect coordinated airborne- and ground-based observations and are coupled with remotely sensed satellite imagery provide unique insight into complex ecological processes and feedbacks across a range of spatio-temporal scales. Measurements and information transfer at and across scales are key challenges in ecohydrology. A combination of approaches, for example, isotopic signatures of leaves, evapotranspiration using micrometeorological techniques, and water stress from remote sensing imagery, will improve our ability to integrate data across spatial scales. The collaboration among science networks such as the National Ecological Observatory Network (NEON) in the US and Terrestrial Ecosystem Research Network (TERN) in Australia will provide data that enable researchers to address complex questions regarding processes operating within and across systems, at site-to-continental scales and beyond. In this talk, we present several examples demonstrating combinations of remotely sensed and ground-based ecohydrological data collected using standardized methodologies across multiple sensor networks. Examples include: 1) determining ecohydrological controls on plant production at plot to regional scales; 2) interpreting atmospheric chemical and isotopic deposition gradients across geographic domains; 3) using the stable isotope signatures of small mammal tissues to track drought dynamics across space and time; 4) mapping water quality characteristics in optically complex waters using remotely sensed imagery and high temporal frequency ground based sensor calibration data and 5) scaling plot and individual plant level vegetation structure estimates to continental scale maps of vegetation and ground cover dynamics. Australian scientists are using TERN's infrastructure for improving Soil-Vegetation-Atmosphere Transfer (SVAT) modeling for Australian conditions by assessing plant photosynthetic and respiration performance across a

  4. Drug resistance in multiple myeloma: latest findings and new concepts on molecular mechanisms

    PubMed Central

    Abdi, Jahangir; Chen, Guoan; Chang, Hong

    2013-01-01

    In the era of new and mostly effective therapeutic protocols, multiple myeloma still tends to be a hard-to-treat hematologic cancer. This hallmark of the disease is in fact a sequel to drug resistant phenotypes persisting initially or emerging in the course of treatment. Furthermore, the heterogeneous nature of multiple myeloma makes treating patients with the same drug challenging because finding a drugable oncogenic process common to all patients is not yet feasible, while our current knowledge of genetic/epigenetic basis of multiple myeloma pathogenesis is outstanding. Nonetheless, bone marrow microenvironment components are well known as playing critical roles in myeloma tumor cell survival and environment-mediated drug resistance happening most possibly in all myeloma patients. Generally speaking, however; real mechanisms underlying drug resistance in multiple myeloma are not completely understood. The present review will discuss the latest findings and concepts in this regard. It reviews the association of important chromosomal translocations, oncogenes (e.g. TP53) mutations and deranged signaling pathways (e.g. NFκB) with drug response in clinical and experimental investigations. It will also highlight how bone marrow microenvironment signals (Wnt, Notch) and myeloma cancer stem cells could contribute to drug resistance in multiple myeloma. PMID:24327604

  5. H-bond stability in the tRNA(Asp) anticodon hairpin: 3 ns of multiple molecular dynamics simulations.

    PubMed Central

    Auffinger, P; Westhof, E

    1996-01-01

    Multiple molecular dynamics trajectories of the solvated and neutralized 17-residue tRNA(Asp) anticodon hairpin were generated for a total of 3 ns. Explicit treatment of all long-ranged electrostatic interactions by the particle mesh Ewald algorithm, as implemented in the AMBER MD software package, effected a degree of structural stabilization not previously achieved by use of a long 16-A solvent interaction truncation scheme. The increased stability of this multiple molecular dynamics set was appropriate for an in-depth analysis of the six 500-ps-long trajectories and allowed the characterization of a number of key structural interactions. The dynamical behavior of the standard Watson-Crick base pairs, the noncanonical G30-U40 "wobble" base pair, and the psi 32-C38 pseudo-base pair is presented as well as that of two C--H... O hydrogen bonds found to contribute to the array of tertiary interactions that stabilize the seven-nucleotide native loop conformation. The least mobile residue in the loop is U33, which forms the U-turn motif and which participates in several hydrogen-bonding interactions, whereas the most mobile residue is the apical residue G34 at the wobble position, a factor undoubtedly important in its biological function. The set of multiple molecular dynamics trajectories obtained does not converge on a 500-ps time scale to a unique dynamical model but instead describes an ensemble of structural microstates accessible to the system under the present simulation protocol, which is the result of local structural heterogeneity rather than of global conformational changes. PMID:8842234

  6. Molecular basis for multiple sulfatase deficiency and mechanism for formylglycine generation of the human formylglycine-generating enzyme.

    PubMed

    Dierks, Thomas; Dickmanns, Achim; Preusser-Kunze, Andrea; Schmidt, Bernhard; Mariappan, Malaiyalam; von Figura, Kurt; Ficner, Ralf; Rudolph, Markus Georg

    2005-05-20

    Sulfatases are enzymes essential for degradation and remodeling of sulfate esters. Formylglycine (FGly), the key catalytic residue in the active site, is unique to sulfatases. In higher eukaryotes, FGly is generated from a cysteine precursor by the FGly-generating enzyme (FGE). Inactivity of FGE results in multiple sulfatase deficiency (MSD), a fatal autosomal recessive syndrome. Based on the crystal structure, we report that FGE is a single-domain monomer with a surprising paucity of secondary structure and adopts a unique fold. The effect of all 18 missense mutations found in MSD patients is explained by the FGE structure, providing a molecular basis of MSD. The catalytic mechanism of FGly generation was elucidated by six high-resolution structures of FGE in different redox environments. The structures allow formulation of a novel oxygenase mechanism whereby FGE utilizes molecular oxygen to generate FGly via a cysteine sulfenic acid intermediate. PMID:15907468

  7. Multiple Simulated Annealing-Molecular Dynamics (MSA-MD) for Conformational Space Search of Peptide and Miniprotein

    PubMed Central

    Hao, Ge-Fei; Xu, Wei-Fang; Yang, Sheng-Gang; Yang, Guang-Fu

    2015-01-01

    Protein and peptide structure predictions are of paramount importance for understanding their functions, as well as the interactions with other molecules. However, the use of molecular simulation techniques to directly predict the peptide structure from the primary amino acid sequence is always hindered by the rough topology of the conformational space and the limited simulation time scale. We developed here a new strategy, named Multiple Simulated Annealing-Molecular Dynamics (MSA-MD) to identify the native states of a peptide and miniprotein. A cluster of near native structures could be obtained by using the MSA-MD method, which turned out to be significantly more efficient in reaching the native structure compared to continuous MD and conventional SA-MD simulation. PMID:26492886

  8. Integrative taxonomy and molecular phylogeny of genus Aplysina (Demospongiae: Verongida) from Mexican Pacific.

    PubMed

    Cruz-Barraza, José Antonio; Carballo, José Luis; Rocha-Olivares, Axayacatl; Ehrlich, Hermann; Hog, Martin

    2012-01-01

    Integrative taxonomy provides a major approximation to species delimitation based on integration of different perspectives (e.g. morphology, biochemistry and DNA sequences). The aim of this study was to assess the relationships and boundaries among Eastern Pacific Aplysina species using morphological, biochemical and molecular data. For this, a collection of sponges of the genus Aplysina from the Mexican Pacific was studied on the basis of their morphological, chemical (chitin composition), and molecular markers (mitochondrial COI and nuclear ribosomal rDNA: ITS1-5.8-ITS2). Three morphological species were identified, two of which are new to science. A. clathrata sp. nov. is a yellow to yellow-reddish or -brownish sponge, characterized by external clathrate-like morphology; A. revillagigedi sp. nov. is a lemon yellow to green, cushion-shaped sometimes lobate sponge, characterized by conspicuous oscules, which are slightly elevated and usually linearly distributed on rims; and A. gerardogreeni a known species distributed along the Mexican Pacific coast. Chitin was identified as the main structural component within skeletons of the three species using FTIR, confirming that it is shared among Verongida sponges. Morphological differences were confirmed by DNA sequences from nuclear ITS1-5.8-ITS2. Mitochondrial COI sequences showed extremely low but diagnostic variability for Aplysina revillagigedi sp. nov., thus our results corroborate that COI has limited power for DNA-barcoding of sponges and should be complemented with other markers (e.g. rDNA). Phylogenetic analyses of Aplysina sequences from the Eastern Pacific and Caribbean, resolved two allopatric and reciprocally monophyletic groups for each region. Eastern Pacific species were grouped in general accordance with the taxonomic hypothesis based on morphological characters. An identification key of Eastern Pacific Aplysina species is presented. Our results constitute one of the first approximations to integrative

  9. Integrative Taxonomy and Molecular Phylogeny of Genus Aplysina (Demospongiae: Verongida) from Mexican Pacific

    PubMed Central

    Cruz-Barraza, José Antonio; Carballo, José Luis; Rocha-Olivares, Axayacatl; Ehrlich, Hermann; Hog, Martin

    2012-01-01

    Integrative taxonomy provides a major approximation to species delimitation based on integration of different perspectives (e.g. morphology, biochemistry and DNA sequences). The aim of this study was to assess the relationships and boundaries among Eastern Pacific Aplysina species using morphological, biochemical and molecular data. For this, a collection of sponges of the genus Aplysina from the Mexican Pacific was studied on the basis of their morphological, chemical (chitin composition), and molecular markers (mitochondrial COI and nuclear ribosomal rDNA: ITS1-5.8-ITS2). Three morphological species were identified, two of which are new to science. A. clathrata sp. nov. is a yellow to yellow-reddish or -brownish sponge, characterized by external clathrate-like morphology; A. revillagigedi sp. nov. is a lemon yellow to green, cushion-shaped sometimes lobate sponge, characterized by conspicuous oscules, which are slightly elevated and usually linearly distributed on rims; and A. gerardogreeni a known species distributed along the Mexican Pacific coast. Chitin was identified as the main structural component within skeletons of the three species using FTIR, confirming that it is shared among Verongida sponges. Morphological differences were confirmed by DNA sequences from nuclear ITS1-5.8-ITS2. Mitochondrial COI sequences showed extremely low but diagnostic variability for Aplysina revillagigedi sp. nov., thus our results corroborate that COI has limited power for DNA-barcoding of sponges and should be complemented with other markers (e.g. rDNA). Phylogenetic analyses of Aplysina sequences from the Eastern Pacific and Caribbean, resolved two allopatric and reciprocally monophyletic groups for each region. Eastern Pacific species were grouped in general accordance with the taxonomic hypothesis based on morphological characters. An identification key of Eastern Pacific Aplysina species is presented. Our results constitute one of the first approximations to integrative

  10. NKG2D and DNAM-1 Ligands: Molecular Targets for NK Cell-Mediated Immunotherapeutic Intervention in Multiple Myeloma

    PubMed Central

    Fionda, Cinzia; Soriani, Alessandra; Zingoni, Alessandra; Santoni, Angela; Cippitelli, Marco

    2015-01-01

    A pivotal strategy to improve NK cell-mediated antitumor activity involves the upregulation of activating ligands on tumor cells. Enhancement of NK cell-mediated recognition of multiple myeloma cells was reported by us and others showing increased surface expression of NKG2D and DNAM-1 ligands on tumor cells following treatment with a number of chemotherapeutic agents, such as genotoxic drugs or inhibitors of proteasome, histone deacetylases, GSK3, and HSP-90. These compounds have the capability to affect tumor survival but also to activate specific transduction pathways associated with the upregulation of different NK cell activating ligands on the tumor cells. Here, we will summarize and discuss the molecular pathways whereby these drugs can regulate the expression of NK cell activating ligands in multiple myeloma cells. PMID:26161387

  11. Molecular Phylogenies Support Homoplasy of Multiple Morphological Characters Used in the Taxonomy of Heteroscleromorpha (Porifera: Demospongiae)

    PubMed Central

    Morrow, Christine C.; Redmond, Niamh E.; Picton, Bernard E.; Thacker, Robert W.; Collins, Allen G.; Maggs, Christine A.; Sigwart, Julia D.; Allcock, A. Louise

    2013-01-01

    Sponge classification has long been based mainly on morphocladistic analyses but is now being greatly challenged by more than 12 years of accumulated analyses of molecular data analyses. The current study used phylogenetic hypotheses based on sequence data from 18S rRNA, 28S rRNA, and the CO1 barcoding fragment, combined with morphology to justify the resurrection of the order Axinellida Lévi, 1953. Axinellida occupies a key position in different morphologically derived topologies. The abandonment of Axinellida and the establishment of Halichondrida Vosmaer, 1887 sensu lato to contain Halichondriidae Gray, 1867, Axinellidae Carter, 1875, Bubaridae Topsent, 1894, Heteroxyidae Dendy, 1905, and a new family Dictyonellidae van Soest et al., 1990 was based on the conclusion that an axially condensed skeleton evolved independently in separate lineages in preference to the less parsimonious assumption that asters (star-shaped spicules), acanthostyles (club-shaped spicules with spines), and sigmata (C-shaped spicules) each evolved more than once. Our new molecular trees are congruent and contrast with the earlier, morphologically based, trees. The results show that axially condensed skeletons, asters, acanthostyles, and sigmata are all homoplasious characters. The unrecognized homoplasious nature of these characters explains much of the incongruence between molecular-based and morphology-based phylogenies. We use the molecular trees presented here as a basis for re-interpreting the morphological characters within Heteroscleromorpha. The implications for the classification of Heteroscleromorpha are discussed and a new order Biemnida ord. nov. is erected. PMID:23753661

  12. Molecular phylogenies support homoplasy of multiple morphological characters used in the taxonomy of Heteroscleromorpha (Porifera: Demospongiae).

    PubMed

    Morrow, Christine C; Redmond, Niamh E; Picton, Bernard E; Thacker, Robert W; Collins, Allen G; Maggs, Christine A; Sigwart, Julia D; Allcock, A Louise

    2013-09-01

    Sponge classification has long been based mainly on morphocladistic analyses but is now being greatly challenged by more than 12 years of accumulated analyses of molecular data analyses. The current study used phylogenetic hypotheses based on sequence data from 18S rRNA, 28S rRNA, and the CO1 barcoding fragment, combined with morphology to justify the resurrection of the order Axinellida Lévi, 1953. Axinellida occupies a key position in different morphologically derived topologies. The abandonment of Axinellida and the establishment of Halichondrida Vosmaer, 1887 sensu lato to contain Halichondriidae Gray, 1867, Axinellidae Carter, 1875, Bubaridae Topsent, 1894, Heteroxyidae Dendy, 1905, and a new family Dictyonellidae van Soest et al., 1990 was based on the conclusion that an axially condensed skeleton evolved independently in separate lineages in preference to the less parsimonious assumption that asters (star-shaped spicules), acanthostyles (club-shaped spicules with spines), and sigmata (C-shaped spicules) each evolved more than once. Our new molecular trees are congruent and contrast with the earlier, morphologically based, trees. The results show that axially condensed skeletons, asters, acanthostyles, and sigmata are all homoplasious characters. The unrecognized homoplasious nature of these characters explains much of the incongruence between molecular-based and morphology-based phylogenies. We use the molecular trees presented here as a basis for re-interpreting the morphological characters within Heteroscleromorpha. The implications for the classification of Heteroscleromorpha are discussed and a new order Biemnida ord. nov. is erected. PMID:23753661

  13. Investigating the Complex Chemistry of Functional Energy Storage Systems: The Need for an Integrative, Multiscale (Molecular to Mesoscale) Perspective

    PubMed Central

    2016-01-01

    Electric energy storage systems such as batteries can significantly impact society in a variety of ways, including facilitating the widespread deployment of portable electronic devices, enabling the use of renewable energy generation for local off grid situations and providing the basis of highly efficient power grids integrated with energy production, large stationary batteries, and the excess capacity from electric vehicles. A critical challenge for electric energy storage is understanding the basic science associated with the gap between the usable output of energy storage systems and their theoretical energy contents. The goal of overcoming this inefficiency is to achieve more useful work (w) and minimize the generation of waste heat (q). Minimization of inefficiency can be approached at the macro level, where bulk parameters are identified and manipulated, with optimization as an ultimate goal. However, such a strategy may not provide insight toward the complexities of electric energy storage, especially the inherent heterogeneity of ion and electron flux contributing to the local resistances at numerous interfaces found at several scale lengths within a battery. Thus, the ability to predict and ultimately tune these complex systems to specific applications, both current and future, demands not just parametrization at the bulk scale but rather specific experimentation and understanding over multiple length scales within the same battery system, from the molecular scale to the mesoscale. Herein, we provide a case study examining the insights and implications from multiscale investigations of a prospective battery material, Fe3O4. PMID:27413781

  14. Investigating the Complex Chemistry of Functional Energy Storage Systems: The Need for an Integrative, Multiscale (Molecular to Mesoscale) Perspective.

    PubMed

    Abraham, Alyson; Housel, Lisa M; Lininger, Christianna N; Bock, David C; Jou, Jeffrey; Wang, Feng; West, Alan C; Marschilok, Amy C; Takeuchi, Kenneth J; Takeuchi, Esther S

    2016-06-22

    Electric energy storage systems such as batteries can significantly impact society in a variety of ways, including facilitating the widespread deployment of portable electronic devices, enabling the use of renewable energy generation for local off grid situations and providing the basis of highly efficient power grids integrated with energy production, large stationary batteries, and the excess capacity from electric vehicles. A critical challenge for electric energy storage is understanding the basic science associated with the gap between the usable output of energy storage systems and their theoretical energy contents. The goal of overcoming this inefficiency is to achieve more useful work (w) and minimize the generation of waste heat (q). Minimization of inefficiency can be approached at the macro level, where bulk parameters are identified and manipulated, with optimization as an ultimate goal. However, such a strategy may not provide insight toward the complexities of electric energy storage, especially the inherent heterogeneity of ion and electron flux contributing to the local resistances at numerous interfaces found at several scale lengths within a battery. Thus, the ability to predict and ultimately tune these complex systems to specific applications, both current and future, demands not just parametrization at the bulk scale but rather specific experimentation and understanding over multiple length scales within the same battery system, from the molecular scale to the mesoscale. Herein, we provide a case study examining the insights and implications from multiscale investigations of a prospective battery material, Fe3O4. PMID:27413781

  15. MutAid: Sanger and NGS Based Integrated Pipeline for Mutation Identification, Validation and Annotation in Human Molecular Genetics

    PubMed Central

    Pandey, Ram Vinay; Pabinger, Stephan; Kriegner, Albert; Weinhäusel, Andreas

    2016-01-01

    Traditional Sanger sequencing as well as Next-Generation Sequencing have been used for the identification of disease causing mutations in human molecular research. The majority of currently available tools are developed for research and explorative purposes and often do not provide a complete, efficient, one-stop solution. As the focus of currently developed tools is mainly on NGS data analysis, no integrative solution for the analysis of Sanger data is provided and consequently a one-stop solution to analyze reads from both sequencing platforms is not available. We have therefore developed a new pipeline called MutAid to analyze and interpret raw sequencing data produced by Sanger or several NGS sequencing platforms. It performs format conversion, base calling, quality trimming, filtering, read mapping, variant calling, variant annotation and analysis of Sanger and NGS data under a single platform. It is capable of analyzing reads from multiple patients in a single run to create a list of potential disease causing base substitutions as well as insertions and deletions. MutAid has been developed for expert and non-expert users and supports four sequencing platforms including Sanger, Illumina, 454 and Ion Torrent. Furthermore, for NGS data analysis, five read mappers including BWA, TMAP, Bowtie, Bowtie2 and GSNAP and four variant callers including GATK-HaplotypeCaller, SAMTOOLS, Freebayes and VarScan2 pipelines are supported. MutAid is freely available at https://sourceforge.net/projects/mutaid. PMID:26840129

  16. Differential amplicons (ΔAmp)—a new molecular method to assess RNA integrity

    PubMed Central

    Björkman, J.; Švec, D.; Lott, E.; Kubista, M.; Sjöback, R.

    2015-01-01

    Integrity of the mRNA in clinical samples has major impact on the quality of measured expression levels. This is independent of the measurement technique being next generation sequencing (NGS), Quantitative real-time PCR (qPCR) or microarray profiling. If mRNA is highly degraded or damaged, measured data will be very unreliable and the whole study is likely a waste of time and money. It is therefore common strategy to test the quality of RNA in samples before conducting large and costly studies. Most methods today to assess the quality of RNA are ignorant to the nature of the RNA and, therefore, reflect the integrity of ribosomal RNA, which is the dominant species, rather than of mRNAs, microRNAs and long non-coding RNAs, which usually are the species of interest. Here, we present a novel molecular approach to assess the quality of the targeted RNA species by measuring the differential amplification (ΔAmp) of an Endogenous RNase Resistant (ERR) marker relative to a reference gene, optionally combined with the measurement of two amplicons of different lengths. The combination reveals any mRNA degradation caused by ribonucleases as well as physical, chemical or UV damage. ΔAmp has superior sensitivity to common microfluidic electrophoretic methods, senses the integrity of the actual targeted RNA species, and allows for a smoother and more cost efficient workflow. PMID:27077042

  17. Accelerating ab initio path integral molecular dynamics with multilevel sampling of potential surface

    NASA Astrophysics Data System (ADS)

    Geng, Hua Y.

    2015-02-01

    A multilevel approach to sample the potential energy surface in a path integral formalism is proposed. The purpose is to reduce the required number of ab initio evaluations of energy and forces in ab initio path integral molecular dynamics (AI-PIMD) simulation, without compromising the overall accuracy. To validate the method, the internal energy and free energy of an Einstein crystal are calculated and compared with the analytical solutions. As a preliminary application, we assess the performance of the method in a realistic model-the FCC phase of dense atomic hydrogen, in which the calculated result shows that the acceleration rate is about 3 to 4-fold for a two-level implementation, and can be increased up to 10 times if extrapolation is used. With only 16 beads used for the ab initio potential sampling, this method gives a well converged internal energy. The residual error in pressure is just about 3 GPa, whereas it is about 20 GPa for a plain AI-PIMD calculation with the same number of beads. The vibrational free energy of the FCC phase of dense hydrogen at 300 K is also calculated with an AI-PIMD thermodynamic integration method, which gives a result of about 0.51 eV/proton at a density of rs = 0.912.

  18. Accelerating ab initio path integral molecular dynamics with multilevel sampling of potential surface

    SciTech Connect

    Geng, Hua Y.

    2015-02-15

    A multilevel approach to sample the potential energy surface in a path integral formalism is proposed. The purpose is to reduce the required number of ab initio evaluations of energy and forces in ab initio path integral molecular dynamics (AI-PIMD) simulation, without compromising the overall accuracy. To validate the method, the internal energy and free energy of an Einstein crystal are calculated and compared with the analytical solutions. As a preliminary application, we assess the performance of the method in a realistic model—the FCC phase of dense atomic hydrogen, in which the calculated result shows that the acceleration rate is about 3 to 4-fold for a two-level implementation, and can be increased up to 10 times if extrapolation is used. With only 16 beads used for the ab initio potential sampling, this method gives a well converged internal energy. The residual error in pressure is just about 3 GPa, whereas it is about 20 GPa for a plain AI-PIMD calculation with the same number of beads. The vibrational free energy of the FCC phase of dense hydrogen at 300 K is also calculated with an AI-PIMD thermodynamic integration method, which gives a result of about 0.51 eV/proton at a density of r{sub s}=0.912.

  19. Communication: Phase diagram of C36 by atomistic molecular dynamics and thermodynamic integration through coexistence regions

    NASA Astrophysics Data System (ADS)

    Abramo, M. C.; Caccamo, C.; Costa, D.; Munaò, G.

    2014-09-01

    We report an atomistic molecular dynamics determination of the phase diagram of a rigid-cage model of C36. We first show that free energies obtained via thermodynamic integrations along isotherms displaying "van der Waals loops," are fully reproduced by those obtained via isothermal-isochoric integration encompassing only stable states. We find that a similar result also holds for isochoric paths crossing van der Waals regions of the isotherms, and for integrations extending to rather high densities where liquid-solid coexistence can be expected to occur. On such a basis we are able to map the whole phase diagram of C36, with resulting triple point and critical temperatures about 1770 K and 2370 K, respectively. We thus predict a 600 K window of existence of a stable liquid phase. Also, at the triple point density, we find that the structural functions and the diffusion coefficient maintain a liquid-like character down to 1400-1300 K, this indicating a wide region of possible supercooling. We discuss why all these features might render possible the observation of the melting of C36 fullerite and of its liquid state, at variance with what previously experienced for C60.

  20. Repetitive, marker-free, site-specific integration as a novel tool for multiple chromosomal integration of DNA.

    PubMed

    Petersen, Kia Vest; Martinussen, Jan; Jensen, Peter Ruhdal; Solem, Christian

    2013-06-01

    We present a tool for repetitive, marker-free, site-specific integration in Lactococcus lactis, in which a nonreplicating plasmid vector (pKV6) carrying a phage attachment site (attP) can be integrated into a bacterial attachment site (attB). The novelty of the tool described here is the inclusion of a minimal bacterial attachment site (attB(min)), two mutated loxP sequences (lox66 and lox71) allowing for removal of undesirable vector elements (antibiotic resistance marker), and a counterselection marker (oroP) for selection of loxP recombination on the pKV6 vector. When transformed into L. lactis expressing the phage TP901-1 integrase, pKV6 integrates with high frequency into the chromosome, where it is flanked by attL and attR hybrid attachment sites. After expression of Cre recombinase from a plasmid that is not able to replicate in L. lactis, loxP recombinants can be selected for by using 5-fluoroorotic acid. The introduced attB(min) site can subsequently be used for a second round of integration. To examine if attP recombination was specific to the attB site, integration was performed in strains containing the attB, attL, and attR sites or the attL and attR sites only. Only attP-attB recombination was observed when all three sites were present. In the absence of the attB site, a low frequency of attP-attL recombination was observed. To demonstrate the functionality of the system, the xylose utilization genes (xylABR and xylT) from L. lactis strain KF147 were integrated into the chromosome of L. lactis strain MG1363 in two steps. PMID:23542630

  1. Identification and integration of Picorna-like viruses in multiple insect taxa

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Virus infection often leads to incorporation of a piece of the virus genetic code into the genome of the host organism, referred to as integration. Determining if the virus has integrated into the host genome provides valuable information needed to monitor disease spread. Detection of integrated vir...

  2. An ICT infrastructure to integrate clinical and molecular data in oncology research

    PubMed Central

    2012-01-01

    Background The ONCO-i2b2 platform is a bioinformatics tool designed to integrate clinical and research data and support translational research in oncology. It is implemented by the University of Pavia and the IRCCS Fondazione Maugeri hospital (FSM), and grounded on the software developed by the Informatics for Integrating Biology and the Bedside (i2b2) research center. I2b2 has delivered an open source suite based on a data warehouse, which is efficiently interrogated to find sets of interesting patients through a query tool interface. Methods Onco-i2b2 integrates data coming from multiple sources and allows the users to jointly query them. I2b2 data are then stored in a data warehouse, where facts are hierarchically structured as ontologies. Onco-i2b2 gathers data from the FSM pathology unit (PU) database and from the hospital biobank and merges them with the clinical information from the hospital information system. Our main effort was to provide a robust integrated research environment, giving a particular emphasis to the integration process and facing different challenges, consecutively listed: biospecimen samples privacy and anonymization; synchronization of the biobank database with the i2b2 data warehouse through a series of Extract, Transform, Load (ETL) operations; development and integration of a Natural Language Processing (NLP) module, to retrieve coded information, such as SNOMED terms and malignant tumors (TNM) classifications, and clinical tests results from unstructured medical records. Furthermore, we have developed an internal SNOMED ontology rested on the NCBO BioPortal web services. Results Onco-i2b2 manages data of more than 6,500 patients with breast cancer diagnosis collected between 2001 and 2011 (over 390 of them have at least one biological sample in the cancer biobank), more than 47,000 visits and 96,000 observations over 960 medical concepts. Conclusions Onco-i2b2 is a concrete example of how integrated Information and Communication

  3. EasyCloneMulti: A Set of Vectors for Simultaneous and Multiple Genomic Integrations in Saccharomyces cerevisiae

    PubMed Central

    Baallal Jacobsen, Simo Abdessamad; Jensen, Niels B.; Kildegaard, Kanchana R.; Herrgård, Markus J.; Schneider, Konstantin; Koza, Anna; Forster, Jochen; Nielsen, Jens; Borodina, Irina

    2016-01-01

    Saccharomyces cerevisiae is widely used in the biotechnology industry for production of ethanol, recombinant proteins, food ingredients and other chemicals. In order to generate highly producing and stable strains, genome integration of genes encoding metabolic pathway enzymes is the preferred option. However, integration of pathway genes in single or few copies, especially those encoding rate-controlling steps, is often not sufficient to sustain high metabolic fluxes. By exploiting the sequence diversity in the long terminal repeats (LTR) of Ty retrotransposons, we developed a new set of integrative vectors, EasyCloneMulti, that enables multiple and simultaneous integration of genes in S. cerevisiae. By creating vector backbones that combine consensus sequences that aim at targeting subsets of Ty sequences and a quickly degrading selective marker, integrations at multiple genomic loci and a range of expression levels were obtained, as assessed with the green fluorescent protein (GFP) reporter system. The EasyCloneMulti vector set was applied to balance the expression of the rate-controlling step in the β-alanine pathway for biosynthesis of 3-hydroxypropionic acid (3HP). The best 3HP producing clone, with 5.45 g.L-1 of 3HP, produced 11 times more 3HP than the lowest producing clone, which demonstrates the capability of EasyCloneMulti vectors to impact metabolic pathway enzyme activity. PMID:26934490

  4. Formulation of an explicit-multiple-time-step time integration method for use in a global primitive equation grid model

    NASA Technical Reports Server (NTRS)

    Chao, W. C.

    1982-01-01

    With appropriate modifications, a recently proposed explicit-multiple-time-step scheme (EMTSS) is incorporated into the UCLA model. In this scheme, the linearized terms in the governing equations that generate the gravity waves are split into different vertical modes. Each mode is integrated with an optimal time step, and at periodic intervals these modes are recombined. The other terms are integrated with a time step dictated by the CFL condition for low-frequency waves. This large time step requires a special modification of the advective terms in the polar region to maintain stability. Test runs for 72 h show that EMTSS is a stable, efficient and accurate scheme.

  5. Potent Human Telomerase Inhibitors: Molecular Dynamic Simulations, Multiple Pharmacophore-Based Virtual Screening, and Biochemical Assays.

    PubMed

    Shirgahi Talari, Faezeh; Bagherzadeh, Kowsar; Golestanian, Sahand; Jarstfer, Michael; Amanlou, Massoud

    2015-12-28

    Telomere maintenance is a universal cancer hallmark, and small molecules that disrupt telomere maintenance generally have anticancer properties. Since the vast majority of cancer cells utilize telomerase activity for telomere maintenance, the enzyme has been considered as an anticancer drug target. Recently, rational design of telomerase inhibitors was made possible by the determination of high resolution structures of the catalytic telomerase subunit from a beetle and subsequent molecular modeling of the human telomerase complex. A hybrid strategy including docking, pharmacophore-based virtual screening, and molecular dynamics simulations (MDS) were used to identify new human telomerase inhibitors. Docking methodology was applied to investigate the ssDNA telomeric sequence and two well-known human telomerase inhibitors' (BIBR1532 and MST-312) modes of interactions with hTERT TEN domain. Subsequently molecular dynamic simulations were performed to monitor and compare hTERT TEN domain, TEN-ssDNA, TEN-BIBR1532, TEN-MST-312, and TEN-ssDNA-BIBR1532 behavior in a dynamic environment. Pharmacophore models were generated considering the inhibitors manner in the TEN domain anchor site. These exploratory studies identified several new potent inhibitors whose IC50 values were generated experimentally in a low micromolar range with the aid of biochemical assays, including both the direct telomerase and the telomeric repeat amplification protocol (TRAP) assays. The results suggest that the current models of human telomerase are useful templates for rational inhibitor design. PMID:26529120

  6. Network-based integration of molecular and physiological data elucidates regulatory mechanisms underlying adaptation to high-fat diet.

    PubMed

    Derous, Davina; Kelder, Thomas; van Schothorst, Evert M; van Erk, Marjan; Voigt, Anja; Klaus, Susanne; Keijer, Jaap; Radonjic, Marijana

    2015-07-01

    Health is influenced by interplay of molecular, physiological and environmental factors. To effectively maintain health and prevent disease, health-relevant relations need to be understood at multiple levels of biological complexity. Network-based methods provide a powerful platform for integration and mining of data and knowledge characterizing different aspects of health. Previously, we have reported physiological and gene expression changes associated with adaptation of murine epididymal white adipose tissue (eWAT) to 5 days and 12 weeks of high-fat diet (HFD) and low-fat diet feeding (Voigt et al. in Mol Nutr Food Res 57:1423-1434, 2013. doi: 10.1002/mnfr.201200671 ). In the current study, we apply network analysis on this dataset to comprehensively characterize mechanisms driving the short- and long-term adaptation of eWAT to HFD across multiple levels of complexity. We built a three-layered interaction network comprising enriched biological processes, their transcriptional regulators and associated changes in physiological parameters. The multi-layered network model reveals that early eWAT adaptation to HFD feeding involves major changes at a molecular level, including activation of TGF-β signalling pathway, immune and stress response and downregulation of mitochondrial functioning. Upon prolonged HFD intake, initial transcriptional response tails off, mitochondrial functioning is even further diminished, and in turn the relation between eWAT gene expression and physiological changes becomes more prominent. In particular, eWAT weight and total energy intake negatively correlate with cellular respiration process, revealing mitochondrial dysfunction as a hallmark of late eWAT adaptation to HFD. Apart from global understanding of the time-resolved adaptation to HFD, the multi-layered network model allows several novel mechanistic hypotheses to emerge: (1) early activation of TGF-β signalling as a trigger for structural and morphological changes in

  7. Molecular Features of Triple Negative Breast Cancer: Microarray Evidence and Further Integrated Analysis

    PubMed Central

    Chen, Weicai; Wu, Huisheng; Yuan, Zishan; Wang, Kun; Li, Guojin; Sun, Jie; Yu, Limin

    2015-01-01

    Purpose Breast cancer is a heterogeneous disease usually including four molecular subtypes such as luminal A, luminal B, HER2-enriched, and triple-negative breast cancer (TNBC). TNBC is more aggressive than other breast cancer subtypes. Despite major advances in ER-positive or HER2-amplified breast cancer, there is no targeted agent currently available for TNBC, so it is urgent to identify new potential therapeutic targets for TNBC. Methods We first used microarray analysis to compare gene expression profiling between TNBC and non-TNBC. Furthermore an integrated analysis was conducted based on our own and published data, leading to more robust, reproducible and accurate predictions. Additionally, we performed qRT-PCR in breast cancer cell lines to verify the findings in integrated analysis. Results After searching Gene Expression Omnibus database (GEO), two microarray studies were obtained according to the inclusion criteria. The integrated analysis was conducted, including 30 samples of TNBC and 77 samples of non-TNBC. 556 genes were found to be consistently differentially expressed (344 up-regulated genes and 212 down-regulated genes in TNBC). Functional annotation for these differentially expressed genes (DEGs) showed that the most significantly enriched Gene Ontology (GO) term for molecular functions was protein binding (GO: 0005515, P = 6.09E-21), while that for biological processes was signal transduction (GO: 0007165, P = 9.46E-08), and that for cellular component was cytoplasm (GO: 0005737, P = 2.09E-21). The most significant pathway was Pathways in cancer (P = 6.54E-05) based on Kyoto Encyclopedia of Genes and Genomes (KEGG). DUSP1 (Degree = 21), MYEOV2 (Degree = 15) and UQCRQ (Degree = 14) were identified as the significant hub proteins in the protein-protein interaction (PPI) network. Five genes were selected to perform qRT-PCR in seven breast cancer cell lines, and qRT-PCR results showed that the expression pattern of selected genes in TNBC lines and

  8. Molecular prevalence of multiple genetic disorders in Border collies in Japan and recommendations for genetic counselling.

    PubMed

    Mizukami, K; Yabuki, A; Kohyama, M; Kushida, K; Rahman, M M; Uddin, M M; Sawa, M; Yamato, O

    2016-08-01

    Reproductive management is necessary to prevent deleterious genetic disorders in purebred dogs, but comprehensive studies aimed at prevention of multiple underlying genetic disorders in a single breed have not been performed. The aims of this study were to examine mutant allele frequencies associated with multiple genetic disorders, using Border collies as a representative breed, and to make recommendations for prevention of the disorders. Genotyping of known mutations associated with seven recessive genetic disorders was performed using PCR assays. More than half (56%) of the Border collies had no mutant alleles associated with any of the seven disorders, suggesting that these disorders can be removed from the population over several generations. Since frequencies of each mutant allele differed among disorders, reproductive management should be performed after the establishment of prevention schemes that are appropriate for each disorder, the type and specificity of genetic test available, and the effective population size in each breeding colony. PMID:27387721

  9. Multiple integration site of hepatitis B virus DNA in hepatocellular carcinoma and chronic active hepatitis tissues from children.

    PubMed Central

    Yaginuma, K; Kobayashi, H; Kobayashi, M; Morishima, T; Matsuyama, K; Koike, K

    1987-01-01

    Attention was directed to hepatitis B virus (HBV) integration in tissues obtained from an hepatocellular carcinoma (HCC) of an 11-year-old boy and from the liver of his 6-year-old brother, who had chronic active hepatitis. Multiple HBV DNA integration sites were demonstrated in both tissues. Cell population(s) in the HCC and liver from the patient with chronic active hepatitis were assumed to be heterogeneous with regard to HBV integration. The integrated forms in the two tissues showed similar genetic organization without gross rearrangement. The location of one of the virus-chromosomal junctions was restricted to the 5'-end region of the minus-strand DNA of HBV. The experimental results support our previous model for the mechanism of HBV integration, in which minus-strand replicative intermediates integrate into chromosomal DNA. The integrated HBV DNAs were conserved in the same region of the viral genome, spanning from the C gene through the S gene to the X gene, which contains intrinsic promoter-enhancer sequences. Images PMID:3033312

  10. Solubility of KF in water by molecular dynamics using the Kirkwood integration method

    NASA Astrophysics Data System (ADS)

    Ferrario, Mauro; Ciccotti, Giovanni; Spohr, Eckhard; Cartailler, Thierry; Turq, Pierre

    2002-09-01

    We have studied the solubility of potassium fluoride in aqueous solution at near ambient condition, using a simple modeling for the ion and water interactions and computing the values of the chemical potential by molecular dynamics within the framework of Kirkwood generalized thermodynamic integration approach for the evaluation of free energy differences. We report the details of the procedure we used, which is based--at variance with previous attempts--on the individual determination of the chemical potential for the ions in solution. We explore a wide range of salt concentrations up to more than 25 M and determine the solubility. The agreement with the experimental value is reasonable, taking account of the rather crude model used.

  11. A molecular site-site integral equation that yields the dielectric constant

    NASA Astrophysics Data System (ADS)

    Dyer, Kippi M.; Perkyns, John S.; Stell, George; Pettitt, B. Montgomery

    2008-09-01

    Our recent derivation [K. M. Dyer et al., J. Chem. Phys. 127, 194506 (2007)] of a diagrammatically proper, site-site, integral equation theory using molecular angular expansions is extended to polar fluids. With the addition of atomic site charges we take advantage of the formal long-ranged potential field cancellations before renormalization to generate a set of numerically stable equations. Results for calculations in a minimal (spherical) angular basis set are presented for the radial distribution function, the first dipolar (110) projection, and the dielectric constant for two model diatomic systems. All results, when compared to experiment and simulation, are a significant quantitative and qualitative improvement over previous site-site theories. More importantly, the dielectric constant is not trivial and close to simulation and experiment.

  12. Bulk and integrated acousto-optic spectrometers for molecular astronomy with heterodyne spectrometers

    NASA Technical Reports Server (NTRS)

    Chin, G.; Buhl, D.; Florez, J. M.

    1981-01-01

    A survey of acousto-optic spectrometers for molecular astronomy is presented, noting a technique of combining the acoustic bending of a collimated coherent light beam with a Bragg cell followed by an array of sensitive photodetectors. This acousto-optic spectrometer has a large bandwidth, a large number of channels, high resolution, and is energy efficient. Receiver development has concentrated on high-frequency heterodyne systems for the study of the chemical composition of the interstellar medium. RF spectrometers employing acousto-optic diffraction cells are described. Acousto-optic techniques have been suggested for applications to electronic warfare, electronic countermeasures and electronic support systems. Plans to use integrated optics for the further miniaturization of acousto-optic spectrometers are described. Bulk acousto-optic spectrometers with 300 MHz and 1 GHz bandwidths are being developed for use in the back-end of high-frequency heterodyne receivers for astronomical research.

  13. Integrated photonic decoder with complementary code processing and balanced detection for two-dimensional optical code division multiple access.

    PubMed

    Takiguchi, K; Okuno, M; Takahashi, H; Moriwaki, O

    2007-04-01

    We propose a novel integrated photonic decoder for two-dimensional (time spreading, wavelength hopping) optical code division multiple access. The decoder is composed of multiplexers-demultiplexers, variable delay lines, and a coupler, which processes complementary codes and utilizes balanced detection to reduce unwanted cross-correlation interference. We successfully carried out a 10 Gbit/s transmission that demonstrated its effectiveness. PMID:17339936

  14. QwikMD - Integrative Molecular Dynamics Toolkit for Novices and Experts.

    PubMed

    Ribeiro, João V; Bernardi, Rafael C; Rudack, Till; Stone, John E; Phillips, James C; Freddolino, Peter L; Schulten, Klaus

    2016-01-01

    The proper functioning of biomolecules in living cells requires them to assume particular structures and to undergo conformational changes. Both biomolecular structure and motion can be studied using a wide variety of techniques, but none offers the level of detail as do molecular dynamics (MD) simulations. Integrating two widely used modeling programs, namely NAMD and VMD, we have created a robust, user-friendly software, QwikMD, which enables novices and experts alike to address biomedically relevant questions, where often only molecular dynamics simulations can provide answers. Performing both simple and advanced MD simulations interactively, QwikMD automates as many steps as necessary for preparing, carrying out, and analyzing simulations while checking for common errors and enabling reproducibility. QwikMD meets also the needs of experts in the field, increasing the efficiency and quality of their work by carrying out tedious or repetitive tasks while enabling easy control of every step. Whether carrying out simulations within the live view mode on a small laptop or performing complex and large simulations on supercomputers or Cloud computers, QwikMD uses the same steps and user interface. QwikMD is freely available by download on group and personal computers. It is also available on the cloud at Amazon Web Services. PMID:27216779

  15. Molecular classification based on apomorphic amino acids (Arthropoda, Hexapoda): Integrative taxonomy in the era of phylogenomics

    PubMed Central

    Wu, Hao-Yang; Wang, Yan-Hui; Xie, Qiang; Ke, Yun-Ling; Bu, Wen-Jun

    2016-01-01

    With the great development of sequencing technologies and systematic methods, our understanding of evolutionary relationships at deeper levels within the tree of life has greatly improved over the last decade. However, the current taxonomic methodology is insufficient to describe the growing levels of diversity in both a standardised and general way due to the limitations of using only morphological traits to describe clades. Herein, we propose the idea of a molecular classification based on hierarchical and discrete amino acid characters. Clades are classified based on the results of phylogenetic analyses and described using amino acids with group specificity in phylograms. Practices based on the recently published phylogenomic datasets of insects together with 15 de novo sequenced transcriptomes in this study demonstrate that such a methodology can accommodate various higher ranks of taxonomy. Such an approach has the advantage of describing organisms in a standard and discrete way within a phylogenetic framework, thereby facilitating the recognition of clades from the view of the whole lineage, as indicated by PhyloCode. By combining identification keys and phylogenies, the molecular classification based on hierarchical and discrete characters may greatly boost the progress of integrative taxonomy. PMID:27312960

  16. QwikMD — Integrative Molecular Dynamics Toolkit for Novices and Experts

    NASA Astrophysics Data System (ADS)

    Ribeiro, João V.; Bernardi, Rafael C.; Rudack, Till; Stone, John E.; Phillips, James C.; Freddolino, Peter L.; Schulten, Klaus

    2016-05-01

    The proper functioning of biomolecules in living cells requires them to assume particular structures and to undergo conformational changes. Both biomolecular structure and motion can be studied using a wide variety of techniques, but none offers the level of detail as do molecular dynamics (MD) simulations. Integrating two widely used modeling programs, namely NAMD and VMD, we have created a robust, user-friendly software, QwikMD, which enables novices and experts alike to address biomedically relevant questions, where often only molecular dynamics simulations can provide answers. Performing both simple and advanced MD simulations interactively, QwikMD automates as many steps as necessary for preparing, carrying out, and analyzing simulations while checking for common errors and enabling reproducibility. QwikMD meets also the needs of experts in the field, increasing the efficiency and quality of their work by carrying out tedious or repetitive tasks while enabling easy control of every step. Whether carrying out simulations within the live view mode on a small laptop or performing complex and large simulations on supercomputers or Cloud computers, QwikMD uses the same steps and user interface. QwikMD is freely available by download on group and personal computers. It is also available on the cloud at Amazon Web Services.

  17. Molecular classification based on apomorphic amino acids (Arthropoda, Hexapoda): Integrative taxonomy in the era of phylogenomics.

    PubMed

    Wu, Hao-Yang; Wang, Yan-Hui; Xie, Qiang; Ke, Yun-Ling; Bu, Wen-Jun

    2016-01-01

    With the great development of sequencing technologies and systematic methods, our understanding of evolutionary relationships at deeper levels within the tree of life has greatly improved over the last decade. However, the current taxonomic methodology is insufficient to describe the growing levels of diversity in both a standardised and general way due to the limitations of using only morphological traits to describe clades. Herein, we propose the idea of a molecular classification based on hierarchical and discrete amino acid characters. Clades are classified based on the results of phylogenetic analyses and described using amino acids with group specificity in phylograms. Practices based on the recently published phylogenomic datasets of insects together with 15 de novo sequenced transcriptomes in this study demonstrate that such a methodology can accommodate various higher ranks of taxonomy. Such an approach has the advantage of describing organisms in a standard and discrete way within a phylogenetic framework, thereby facilitating the recognition of clades from the view of the whole lineage, as indicated by PhyloCode. By combining identification keys and phylogenies, the molecular classification based on hierarchical and discrete characters may greatly boost the progress of integrative taxonomy. PMID:27312960

  18. Integrating atomistic molecular dynamics simulations, experiments, and network analysis to study protein dynamics: strength in unity

    PubMed Central

    Papaleo, Elena

    2015-01-01

    In the last years, we have been observing remarkable improvements in the field of protein dynamics. Indeed, we can now study protein dynamics in atomistic details over several timescales with a rich portfolio of experimental and computational techniques. On one side, this provides us with the possibility to validate simulation methods and physical models against a broad range of experimental observables. On the other side, it also allows a complementary and comprehensive view on protein structure and dynamics. What is needed now is a better understanding of the link between the dynamic properties that we observe and the functional properties of these important cellular machines. To make progresses in this direction, we need to improve the physical models used to describe proteins and solvent in molecular dynamics, as well as to strengthen the integration of experiments and simulations to overcome their own limitations. Moreover, now that we have the means to study protein dynamics in great details, we need new tools to understand the information embedded in the protein ensembles and in their dynamic signature. With this aim in mind, we should enrich the current tools for analysis of biomolecular simulations with attention to the effects that can be propagated over long distances and are often associated to important biological functions. In this context, approaches inspired by network analysis can make an important contribution to the analysis of molecular dynamics simulations. PMID:26075210

  19. QwikMD — Integrative Molecular Dynamics Toolkit for Novices and Experts

    PubMed Central

    Ribeiro, João V.; Bernardi, Rafael C.; Rudack, Till; Stone, John E.; Phillips, James C.; Freddolino, Peter L.; Schulten, Klaus

    2016-01-01

    The proper functioning of biomolecules in living cells requires them to assume particular structures and to undergo conformational changes. Both biomolecular structure and motion can be studied using a wide variety of techniques, but none offers the level of detail as do molecular dynamics (MD) simulations. Integrating two widely used modeling programs, namely NAMD and VMD, we have created a robust, user-friendly software, QwikMD, which enables novices and experts alike to address biomedically relevant questions, where often only molecular dynamics simulations can provide answers. Performing both simple and advanced MD simulations interactively, QwikMD automates as many steps as necessary for preparing, carrying out, and analyzing simulations while checking for common errors and enabling reproducibility. QwikMD meets also the needs of experts in the field, increasing the efficiency and quality of their work by carrying out tedious or repetitive tasks while enabling easy control of every step. Whether carrying out simulations within the live view mode on a small laptop or performing complex and large simulations on supercomputers or Cloud computers, QwikMD uses the same steps and user interface. QwikMD is freely available by download on group and personal computers. It is also available on the cloud at Amazon Web Services. PMID:27216779

  20. Towards an Integrative Morpho-molecular Classification of the Collodaria (Polycystinea, Radiolaria).

    PubMed

    Biard, Tristan; Pillet, Loïc; Decelle, Johan; Poirier, Camille; Suzuki, Noritoshi; Not, Fabrice

    2015-07-01

    Collodaria are ubiquitous and abundant marine radiolarian (Rhizaria) protists. They occur as either large colonies or solitary specimens, and, unlike most radiolarians, some taxa lack silicified structures. Collodarians are known to play an important role in oceanic food webs as both active predators and hosts of symbiotic microalgae, yet very little is known about their diversity and evolution. Taxonomic delineation of collodarians is challenging and only a few species have been genetically characterized. Here we investigated collodarian diversity using phylogenetic analyses of both nuclear small (18S) and large (28S) subunits of the ribosomal DNA, including 124 new sequences from 75 collodarians sampled worldwide. The resulting molecular phylogeny was compared to morphology-based classification. Our analyses distinguished the monophyletic clade of skeleton-less and spicule-bearing Sphaerozoidae from the sister clades Collosphaeridae (skeleton-bearing) and Collophidiidae (skeleton-less), while the Thalassicollidae was not retrieved as a monophyletic clade. Detailed morphological examination with electron microscopy combined with molecular analyses revealed many discrepancies, such as a mix between solitary and colonial species, co-existence of skeleton-less and skeleton-bearing specimens within the Collosphaeridae, as well as complex intraspecific variability in silicified structures. Such observations challenge a morphology-based classification and highlight the pertinence of an integrative taxonomic approach to study collodarian diversity. PMID:26092634

  1. The use of artificial intelligence techniques to improve the multiple payload integration process

    NASA Technical Reports Server (NTRS)

    Cutts, Dannie E.; Widgren, Brian K.

    1992-01-01

    A maximum return of science and products with a minimum expenditure of time and resources is a major goal of mission payload integration. A critical component then, in successful mission payload integration is the acquisition and analysis of experiment requirements from the principal investigator and payload element developer teams. One effort to use artificial intelligence techniques to improve the acquisition and analysis of experiment requirements within the payload integration process is described.

  2. Analysis of molecular expression patterns and integration with other knowledge bases using probabilistic Bayesian network models

    SciTech Connect

    Moler, Edward J.; Mian, I.S.

    2000-03-01

    How can molecular expression experiments be interpreted with greater than ten to the fourth measurements per chip? How can one get the most quantitative information possible from the experimental data with good confidence? These are important questions whose solutions require an interdisciplinary combination of molecular and cellular biology, computer science, statistics, and complex systems analysis. The explosion of data from microarray techniques present the problem of interpreting the experiments. The availability of large-scale knowledge bases provide the opportunity to maximize the information extracted from these experiments. We have developed new methods of discovering biological function, metabolic pathways, and regulatory networks from these data and knowledge bases. These techniques are applicable to analyses for biomedical engineering, clinical, and fundamental cell and molecular biology studies. Our approach uses probabilistic, computational methods that give quantitative interpretations of data in a biological context. We have selected Bayesian statistical models with graphical network representations as a framework for our methods. As a first step, we use a nave Bayesian classifier to identify statistically significant patterns in gene expression data. We have developed methods which allow us to (a) characterize which genes or experiments distinguish each class from the others, (b) cross-index the resulting classes with other databases to assess biological meaning of the classes, and (c) display a gross overview of cellular dynamics. We have developed a number of visualization tools to convey the results. We report here our methods of classification and our first attempts at integrating the data and other knowledge bases together with new visualization tools. We demonstrate the utility of these methods and tools by analysis of a series of yeast cDNA microarray data and to a set of cancerous/normal sample data from colon cancer patients. We discuss

  3. The use of molecular-based risk stratification and pharmacogenomics for outcome prediction and personalized therapeutic management of multiple myeloma

    PubMed Central

    Johnson, Sarah K.; Heuck, Christoph J.; Albino, Anthony P.; Qu, Pingping; Zhang, Qing; Barlogie, Bart

    2015-01-01

    Despite improvement in therapeutic efficacy, multiple myeloma (MM) remains incurable with a median survival of approximately 10 years. Gene-expression profiling (GEP) can be used to elucidate the molecular basis for resistance to chemotherapy through global assessment of molecular alterations that exist at diagnosis, after therapeutic treatment and that evolve during tumor progression. Unique GEP signatures associated with recurrent chromosomal translocations and ploidy changes have defined molecular classes with differing clinical features and outcomes. When compared to other stratification systems the GEP70 test remained a significant predictor of outcome, reduced the number of patients classified with a poor prognosis, and identified patients at increased risk of relapse despite their standard clinico-pathologic and genetic findings. GEP studies of serial samples showed that risk increases over time, with relapsed disease showing GEP shifts toward a signature of poor outcomes. GEP signatures of myeloma cells after therapy were prognostic for event-free and overall survival and thus may be used to identify novel strategies for overcoming drug resistance. This brief review will focus on the use of GEP of MM to define high-risk myeloma, and elucidate underlying mechanisms that are beginning to change clinical decision-making and inform drug design. PMID:22002477

  4. Molecular mechanism of long-range synergetic color tuning between multiple amino acid residues in conger rhodopsin

    PubMed Central

    Watanabe, Hiroshi C.; Mori, Yoshiharu; Tada, Takashi; Yokoyama, Shozo; Yamato, Takahisa

    2011-01-01

    The synergetic effects of multiple rhodopsin mutations on color tuning need to be completely elucidated. Systematic genetic studies and spectroscopy have demonstrated an interesting example of synergetic color tuning between two amino acid residues in conger rhodopsin's ancestral pigment (p501): —a double mutation at one nearby and one distant residue led to a significant λmax blue shift of 13 nm, whereas neither of the single mutations at these two sites led to meaningful shifts. To analyze the molecular mechanisms of this synergetic color tuning, we performed homology modeling, molecular simulations, and electronic state calculations. For the double mutant, N195A/A292S, in silico mutation analysis demonstrated conspicuous structural changes in the retinal chromophore, whereas that of the single mutant, A292S, was almost unchanged. Using statistical ensembles of QM/MM optimized structures, the excitation energy of retinal chromophore was evaluated for the three visual pigments. As a result, the λmax shift of double mutant (DM) from p501 was –8 nm, while that of single mutant (SM) from p501 was +1 nm. Molecular dynamics simulation for DM demonstrated frequent isomerization between 6-s-cis and 6-s-trans conformers. Unexpectedly, however, the two conformers exhibited almost identical excitation energy, whereas principal component analysis (PCA) identified the retinal-counterion cooperative change of BLA (bond length alternation) and retinal-counterion interaction lead to the shift. PMID:21297892

  5. Shared and unique responses of plants to multiple individual stresses and stress combinations: physiological and molecular mechanisms

    PubMed Central

    Pandey, Prachi; Ramegowda, Venkategowda; Senthil-Kumar, Muthappa

    2015-01-01

    In field conditions, plants are often simultaneously exposed to multiple biotic and abiotic stresses resulting in substantial yield loss. Plants have evolved various physiological and molecular adaptations to protect themselves under stress combinations. Emerging evidences suggest that plant responses to a combination of stresses are unique from individual stress responses. In addition, plants exhibit shared responses which are common to individual stresses and stress combination. In this review, we provide an update on the current understanding of both unique and shared responses. Specific focus of this review is on heat–drought stress as a major abiotic stress combination and, drought–pathogen and heat–pathogen as examples of abiotic–biotic stress combinations. We also comprehend the current understanding of molecular mechanisms of cross talk in relation to shared and unique molecular responses for plant survival under stress combinations. Thus, the knowledge of shared responses of plants from individual stress studies and stress combinations can be utilized to develop varieties with broad spectrum stress tolerance. PMID:26442037

  6. Solution of the structure of Aspergillus niger acid alpha-amylase by combined molecular replacement and multiple isomorphous replacement methods.

    PubMed

    Brady, R L; Brzozowski, A M; Derewenda, Z S; Dodson, E J; Dodson, G G

    1991-08-01

    The crystal structure of Aspergillus niger acid alpha-amylase was solved by a combination of multiple isomorphous replacement and molecular replacement methods. The atomic coordinates of Aspergillus oryzae (TAKA) alpha-amylase (entry 2TAA in the Protein Data Bank) and experimental diffraction data from a new monoclinic crystal form of TAKA alpha-amylase, were used during the procedure. Sequence identity between the two proteins is approximately 80%. The atomic parameters derived from the molecular replacement solution were too inaccurate to initiate least-squares crystallographic refinement. The molecular model was extensively revised against the experimental electron density map calculated at 3 A resolution. Subsequent crystallographic refinement of this model using synchrotron data to 2.1 A resolution led to a conventional R factor of 16.8%. The structure conforms well to expected stereochemistry with bond lengths deviating from target values by 0.031 A, and planar groups showing a root-mean-square deviation from ideal planes of 0.025 A. PMID:1930834

  7. Multiple Strategies for Spatial Integration of 2D Layouts within Working Memory

    PubMed Central

    Meilinger, Tobias; Watanabe, Katsumi

    2016-01-01

    Prior results on the spatial integration of layouts within a room differed regarding the reference frame that participants used for integration. We asked whether these differences also occur when integrating 2D screen views and, if so, what the reasons for this might be. In four experiments we showed that integrating reference frames varied as a function of task familiarity combined with processing time, cues for spatial transformation, and information about action requirements paralleling results in the 3D case. Participants saw part of an object layout in screen 1, another part in screen 2, and reacted on the integrated layout in screen 3. Layout presentations between two screens coincided or differed in orientation. Aligning misaligned screens for integration is known to increase errors/latencies. The error/latency pattern was thus indicative of the reference frame used for integration. We showed that task familiarity combined with self-paced learning, visual updating, and knowing from where to act prioritized the integration within the reference frame of the initial presentation, which was updated later, and from where participants acted respectively. Participants also heavily relied on layout intrinsic frames. The results show how humans flexibly adjust their integration strategy to a wide variety of conditions. PMID:27101011

  8. Multiple Strategies for Spatial Integration of 2D Layouts within Working Memory.

    PubMed

    Meilinger, Tobias; Watanabe, Katsumi

    2016-01-01

    Prior results on the spatial integration of layouts within a room differed regarding the reference frame that participants used for integration. We asked whether these differences also occur when integrating 2D screen views and, if so, what the reasons for this might be. In four experiments we showed that integrating reference frames varied as a function of task familiarity combined with processing time, cues for spatial transformation, and information about action requirements paralleling results in the 3D case. Participants saw part of an object layout in screen 1, another part in screen 2, and reacted on the integrated layout in screen 3. Layout presentations between two screens coincided or differed in orientation. Aligning misaligned screens for integration is known to increase errors/latencies. The error/latency pattern was thus indicative of the reference frame used for integration. We showed that task familiarity combined with self-paced learning, visual updating, and knowing from where to act prioritized the integration within the reference frame of the initial presentation, which was updated later, and from where participants acted respectively. Participants also heavily relied on layout intrinsic frames. The results show how humans flexibly adjust their integration strategy to a wide variety of conditions. PMID:27101011

  9. Multiple outflows in the bipolar planetary nebula M1-16: A molecular line study

    NASA Technical Reports Server (NTRS)

    Sahai, Raghvendra; Wootten, Alwyn; Schwarz, Hugo E.; Wild, W.

    1994-01-01

    Extensive observations of the molecular gas in the young, compact planetary nebula M1-16 have been made, using the Swedish-ESO-Submillimeter Telescope. A map of the CO J = 2-1 emission shows that the molecular envelope contains both a slow and a fast outflow with expansion velocities of 19 km/s and greater than 34 km/s, respectively. The slow outflow is mildly elliptical, while the fast molecular outflow is bipolar. This fast outflow is roughly aligned with the very fast outflows recently found in the optical, while the long axis of the slow elliptical outflow is roughly orthogonal to the optical outflow axis. The kinematic timescales for the CO fast outflow and the optical very fast outflow agree closely, supporting the view that the former represents material in the slow outflow accelerated by the very fast outflow. The kinematic signature of a disk expanding with about 15.5 km/s can also be seen in the CO J = 2-1 data. The mass-loss rate (a) for the slow outflow is greater than or equal to 2.8 x 10(exp -5) solar mass/yr and possibly as large as 9 x 10(exp -5) solar mass/yr, (b) for the fast outflow is greater than or equal to 5 x 10(exp -6) solar mass/yr, and (c) for the very fast optically visible outflow is approximately equal 5 x 10(exp -7) solar mass/yr. The disk mass is approximately equal 6 x 10(exp -3) solar mass. Grain photoelectric heating results in temperatures of 20-70 K in molecular gas of the slow outflow. The (13)C/(12)C abundance ratio in M1-16 is found to be 0.33, quite possibly the highest found for any evolved object. Upper limits for the (18)O/(16)O and (17)O/(16)O ratios were found to be consistent with the values found in AGB stars. A search for other molecular species in M1-16 resulted in the detection of the high-excitation species HCN, CN, (13)CN, HCO(+), and H(13)CO(+) and possibly N2H(+). Both the HCO(+)/HCN and CN/HCN line-intensity ratios are enhanced, the former by a very large factor, over the values found in the envelopes of AGB

  10. Molecular etiology of arthrogryposis in multiple families of mostly Turkish origin

    PubMed Central

    Bayram, Yavuz; Karaca, Ender; Coban Akdemir, Zeynep; Yilmaz, Elif Ozdamar; Tayfun, Gulsen Akay; Aydin, Hatip; Torun, Deniz; Bozdogan, Sevcan Tug; Gezdirici, Alper; Isikay, Sedat; Atik, Mehmed M.; Gambin, Tomasz; Harel, Tamar; El-Hattab, Ayman W.; Charng, Wu-Lin; Pehlivan, Davut; Jhangiani, Shalini N.; Muzny, Donna M.; Karaman, Ali; Celik, Tamer; Yuregir, Ozge Ozalp; Yildirim, Timur; Bayhan, Ilhan A.; Boerwinkle, Eric; Gibbs, Richard A.; Elcioglu, Nursel; Tuysuz, Beyhan; Lupski, James R.

    2016-01-01

    BACKGROUND. Arthrogryposis, defined as congenital joint contractures in 2 or more body areas, is a clinical sign rather than a specific disease diagnosis. To date, more than 400 different disorders have been described that present with arthrogryposis, and variants of more than 220 genes have been associated with these disorders; however, the underlying molecular etiology remains unknown in the considerable majority of these cases. METHODS. We performed whole exome sequencing (WES) of 52 patients with clinical presentation of arthrogryposis from 48 different families. RESULTS. Affected individuals from 17 families (35.4%) had variants in known arthrogryposis-associated genes, including homozygous variants of cholinergic γ nicotinic receptor (CHRNG, 6 subjects) and endothelin converting enzyme–like 1 (ECEL1, 4 subjects). Deleterious variants in candidate arthrogryposis-causing genes (fibrillin 3 [FBN3], myosin IXA [MYO9A], and pleckstrin and Sec7 domain containing 3 [PSD3]) were identified in 3 families (6.2%). Moreover, in 8 families with a homozygous mutation in an arthrogryposis-associated gene, we identified a second locus with either a homozygous or compound heterozygous variant in a candidate gene (myosin binding protein C, fast type [MYBPC2] and vacuolar protein sorting 8 [VPS8], 2 families, 4.2%) or in another disease-associated genes (6 families, 12.5%), indicating a potential mutational burden contributing to disease expression. CONCLUSION. In 58.3% of families, the arthrogryposis manifestation could be explained by a molecular diagnosis; however, the molecular etiology in subjects from 20 families remained unsolved by WES. Only 5 of these 20 unrelated subjects had a clinical presentation consistent with amyoplasia; a phenotype not thought to be of genetic origin. Our results indicate that increased use of genome-wide technologies will provide opportunities to better understand genetic models for diseases and molecular mechanisms of genetically

  11. Ensemble velocity of non-processive molecular motors with multiple chemical states

    PubMed Central

    Vilfan, Andrej

    2014-01-01

    We study the ensemble velocity of non-processive motor proteins, described with multiple chemical states. In particular, we discuss the velocity as a function of ATP concentration. Even a simple model which neglects the strain dependence of transition rates, reverse transition rates and nonlinearities in the elasticity can show interesting functional dependencies, which deviate significantly from the frequently assumed Michaelis–Menten form. We discuss how the order of events in the duty cycle can be inferred from the measured dependence. The model also predicts the possibility of velocity reversal at a certain ATP concentration if the duty cycle contains several conformational changes of opposite directionalities. PMID:25485083

  12. Integrative Molecular Analysis of Intrahepatic Cholangiocarcinoma Reveals 2 Classes That Have Different Outcomes

    PubMed Central

    SIA, DANIELA; HOSHIDA, YUJIN; VILLANUEVA, AUGUSTO; ROAYAIE, SASAN; FERRER, JOANA; TABAK, BARBARA; PEIX, JUDIT; SOLE, MANEL; TOVAR, VICTORIA; ALSINET, CLARA; CORNELLA, HELENA; KLOTZLE, BRANDY; FAN, JIAN–BING; COTSOGLOU, CHRISTIAN; THUNG, SWAN N.; FUSTER, JOSEP; WAXMAN, SAMUEL; GARCIA–VALDECASAS, JUAN CARLOS; BRUIX, JORDI; SCHWARTZ, MYRON E.; BEROUKHIM, RAMEEN; MAZZAFERRO, VINCENZO; LLOVET, JOSEP M.

    2013-01-01

    BACKGROUND & AIMS Cholangiocarcinoma, the second most common liver cancer, can be classified as intra-hepatic cholangiocarcinoma (ICC) or extrahepatic cholangiocarcinoma. We performed an integrative genomic analysis of ICC samples from a large series of patients. METHODS We performed a gene expression profile, high-density single-nucleotide polymorphism array, and mutation analyses using formalin-fixed ICC samples from 149 patients. Associations with clinicopathologic traits and patient outcomes were examined for 119 cases. Class discovery was based on a non-negative matrix factorization algorithm and significant copy number variations were identified by GISTIC analysis. Gene set enrichment analysis was used to identify signaling pathways activated in specific molecular classes of tumors, and to analyze their genomic overlap with hepatocellular carcinoma (HCC). RESULTS We identified 2 main biological classes of ICC. The inflammation class (38% of ICCs) is characterized by activation of inflammatory signaling pathways, overexpression of cytokines, and STAT3 activation. The proliferation class (62%) is characterized by activation of oncogenic signaling pathways (including RAS, mitogen-activated protein kinase, and MET), DNA amplifications at 11q13.2, deletions at 14q22.1, mutations in KRAS and BRAF, and gene expression signatures previously associated with poor outcomes for patients with HCC. Copy number variation– based clustering was able to refine these molecular groups further. We identified high-level amplifications in 5 regions, including 1p13 (9%) and 11q13.2 (4%), and several focal deletions, such as 9p21.3 (18%) and 14q22.1 (12% in coding regions for the SAV1 tumor suppressor). In a complementary approach, we identified a gene expression signature that was associated with reduced survival times of patients with ICC; this signature was enriched in the proliferation class (P < .001). CONCLUSIONS We used an integrative genomic analysis to identify 2 classes

  13. Accurate and efficient integration for molecular dynamics simulations at constant temperature and pressure.

    PubMed

    Lippert, Ross A; Predescu, Cristian; Ierardi, Douglas J; Mackenzie, Kenneth M; Eastwood, Michael P; Dror, Ron O; Shaw, David E

    2013-10-28

    In molecular dynamics simulations, control over temperature and pressure is typically achieved by augmenting the original system with additional dynamical variables to create a thermostat and a barostat, respectively. These variables generally evolve on timescales much longer than those of particle motion, but typical integrator implementations update the additional variables along with the particle positions and momenta at each time step. We present a framework that replaces the traditional integration procedure with separate barostat, thermostat, and Newtonian particle motion updates, allowing thermostat and barostat updates to be applied infrequently. Such infrequent updates provide a particularly substantial performance advantage for simulations parallelized across many computer processors, because thermostat and barostat updates typically require communication among all processors. Infrequent updates can also improve accuracy by alleviating certain sources of error associated with limited-precision arithmetic. In addition, separating the barostat, thermostat, and particle motion update steps reduces certain truncation errors, bringing the time-average pressure closer to its target value. Finally, this framework, which we have implemented on both general-purpose and special-purpose hardware, reduces software complexity and improves software modularity. PMID:24182003

  14. Integrative Molecular Profiling Reveals Asparagine Synthetase Is a Target in Castration-Resistant Prostate Cancer

    PubMed Central

    Sircar, Kanishka; Huang, Heng; Hu, Limei; Cogdell, David; Dhillon, Jasreman; Tzelepi, Vassiliki; Efstathiou, Eleni; Koumakpayi, Ismaël H.; Saad, Fred; Luo, Dijun; Bismar, Tarek A.; Aparicio, Ana; Troncoso, Patricia; Navone, Nora; Zhang, Wei

    2013-01-01

    The identification of new and effective therapeutic targets for the lethal, castration-resistant stage of prostate cancer (CRPC) has been challenging because of both the paucity of adequate frozen tissues and a lack of integrated molecular analysis. Therefore, in this study, we performed a genome-wide analysis of DNA copy number alterations from 34 unique surgical CRPC specimens and 5 xenografts, with matched transcriptomic profiling of 25 specimens. An integrated analysis of these data revealed that the asparagine synthetase (ASNS) gene showed a gain in copy number and was overexpressed at the transcript level. The overexpression of ASNS was validated by analyzing other public CRPC data sets. ASNS protein expression, as detected by reverse-phase protein lysate array, was tightly correlated with gene copy number. In addition, ASNS protein expression, as determined by IHC analysis, was associated with progression to a therapy-resistant disease state in TMAs that included 77 castration-resistant and 40 untreated prostate cancer patient samples. Knockdown of ASNS by small-interfering RNAs in asparagine-deprived media led to growth inhibition in both androgen-responsive (ie, LNCaP) and castration-resistant (ie, C4-2B) prostate cancer cell lines and in cells isolated from a CRPC xenograft (ie, MDA PCa 180-30). Together, our results suggest that ASNS is up-regulated in cases of CRPC and that depletion of asparagine using ASNS inhibitors will be a novel strategy for targeting CRPC cells. PMID:22245216

  15. Ab initio path-integral molecular dynamics and the quantum nature of hydrogen bonds

    NASA Astrophysics Data System (ADS)

    Yexin, Feng; Ji, Chen; Xin-Zheng, Li; Enge, Wang

    2016-01-01

    The hydrogen bond (HB) is an important type of intermolecular interaction, which is generally weak, ubiquitous, and essential to life on earth. The small mass of hydrogen means that many properties of HBs are quantum mechanical in nature. In recent years, because of the development of computer simulation methods and computational power, the influence of nuclear quantum effects (NQEs) on the structural and energetic properties of some hydrogen bonded systems has been intensively studied. Here, we present a review of these studies by focussing on the explanation of the principles underlying the simulation methods, i.e., the ab initio path-integral molecular dynamics. Its extension in combination with the thermodynamic integration method for the calculation of free energies will also be introduced. We use two examples to show how this influence of NQEs in realistic systems is simulated in practice. Project supported by the National Natural Science Foundation of China (Grant Nos. 11275008, 91021007, and 10974012) and the China Postdoctoral Science Foundation (Grant No. 2014M550005).

  16. Molecular dynamics simulation of the interactions between EHD1 EH domain and multiple peptides* #

    PubMed Central

    Yu, Hua; Wang, Mao-Jun; Xuan, Nan-Xia; Shang, Zhi-Cai; Wu, Jun

    2015-01-01

    Objective: To provide essential information for peptide inhibitor design, the interactions of Eps15 homology domain of Eps15 homology domain-containing protein 1 (EHD1 EH domain) with three peptides containing NPF (asparagine-proline-phenylalanine), DPF (aspartic acid-proline-phenylalanine), and GPF (glycine-proline-phenylalanine) motifs were deciphered at the atomic level. The binding affinities and the underlying structure basis were investigated. Methods: Molecular dynamics (MD) simulations were performed on EHD1 EH domain/peptide complexes for 60 ns using the GROMACS package. The binding free energies were calculated and decomposed by molecular mechanics/generalized Born surface area (MM/GBSA) method using the AMBER package. The alanine scanning was performed to evaluate the binding hot spot residues using FoldX software. Results: The different binding affinities for the three peptides were affected dominantly by van der Waals interactions. Intermolecular hydrogen bonds provide the structural basis of contributions of van der Waals interactions of the flanking residues to the binding. Conclusions: van der Waals interactions should be the main consideration when we design peptide inhibitors of EHD1 EH domain with high affinities. The ability to form intermolecular hydrogen bonds with protein residues can be used as the factor for choosing the flanking residues. PMID:26465136

  17. A norepinephrine coated magnetic molecularly imprinted polymer for simultaneous multiple chiral recognition.

    PubMed

    Chen, Juan; Liang, Ru-Ping; Wang, Xiao-Ni; Qiu, Jian-Ding

    2015-08-28

    A newly designed molecularly imprinted polymer (MIP) material was developed and successfully used as recognition element for enantioselective recognition by microchip electrophoresis. In this work, molecularly imprinted polymers were facilely prepared employing Fe3O4 nanoparticles (NPs) as the supporting substrate and norepinephrine as the functional monomer in the presence of template molecule in a weak alkaline solution. After extracting the embedded template molecules, the produced imprinted Fe3O4@polynorepinephrine (MIP-Fe3O4@PNE) NPs have cavities complementary to three dimensional shape of template molecules favoring high binding capacity and magnetism property for easy manipulation. The MIP-Fe3O4@PNE NPs prepared with l-tryptophan, l-valine, l-threonine, Gly-l-Phe, S-(-)-ofloxacin or S-(-)-binaphthol as template molecules were packed in the polydimethylsiloxane microchannel via magnetic field as novel stationary phase to successful enantioseparation of corresponding target analysts. The MIP-Fe3O4@PNE NPs-based microchip electrophoresis system exhibited strong recognition ability, excellent high-performance, admirable reproducibility and stability, which provided a powerful protocol for separation enantiomers within a short analytical time and opened up an avenue for multiplex chiral compound assay in various systems. PMID:26206627

  18. High-Throughput Multiple Dies-to-Wafer Bonding Technology and III/V-on-Si Hybrid Lasers for Heterogeneous Integration of Optoelectronic Integrated Circuits

    NASA Astrophysics Data System (ADS)

    Luo, Xianshu; Cao, Yulian; Song, Junfeng; Hu, Xiaonan; Cheng, Yungbing; Li, Chengming; Liu, Chongyang; Liow, Tsung-Yang; Yu, Mingbin; Wang, Hong; Wang, Qijie; Lo, Patrick Guo-Qiang

    2015-04-01

    Integrated optical light source on silicon is one of the key building blocks for optical interconnect technology. Great research efforts have been devoting worldwide to explore various approaches to integrate optical light source onto the silicon substrate. The achievements so far include the successful demonstration of III/V-on-Si hybrid lasers through III/V-gain material to silicon wafer bonding technology. However, for potential large-scale integration, leveraging on mature silicon complementary metal oxide semiconductor (CMOS) fabrication technology and infrastructure, more effective bonding scheme with high bonding yield is in great demand considering manufacturing needs. In this paper, we propose and demonstrate a high-throughput multiple dies-to-wafer (D2W) bonding technology which is then applied for the demonstration of hybrid silicon lasers. By temporarily bonding III/V dies to a handle silicon wafer for simultaneous batch processing, it is expected to bond unlimited III/V dies to silicon device wafer with high yield. As proof-of-concept, more than 100 III/V dies bonding to 200 mm silicon wafer is demonstrated. The high performance of the bonding interface is examined with various characterization techniques. Repeatable demonstrations of 16-III/V-die bonding to pre-patterned 200 mm silicon wafers have been performed for various hybrid silicon lasers, in which device library including Fabry-Perot (FP) laser, lateral-coupled distributed feedback (LC-DFB) laser with side wall grating, and mode-locked laser (MLL). From these results, the presented multiple D2W bonding technology can be a key enabler towards the large-scale heterogeneous integration of optoelectronic integrated circuits (H-OEIC).

  19. Structure and discrimination in chiral fluids: A molecular dynamics and integral equation study

    NASA Astrophysics Data System (ADS)

    Cann, N. M.; Das, B.

    2000-08-01

    An analysis of structure and discrimination in simple chiral fluids is presented. The chiral molecules consist of a central carbon bonded to four distinct groups. Molecular-dynamics simulations have been performed on a one-component chiral fluid and on two racemic mixtures. For the racemates, discrimination, as measured by differences in pair distribution functions, is present but found to be small. Intermolecular pair interaction energies are found to be good predictors of the magnitude and the sign (mirror-image pairs favored) of the differences observed in site-site distribution functions. For the one-component fluid, the quality of structural predictions from the reference-interaction-site method and Chandler-Silbey-Ladanyi (CSL) integral equation theories, with the hypernetted chain (HNC) and Percus-Yevick closures, has been examined. These theories generally provide a qualitatively correct description of the site-site distributions. Extensions beyond the HNC level have been explored: Two-field-point bridge diagrams have been explicitly evaluated and included in the CSL theory. The inclusion of these diagrams significantly improves the quality of the integral equation theories. Since the CSL theory has not been used extensively, and bridge diagrams have been evaluated in only a few instances, a detailed analysis of their impact is presented. For racemic mixtures, diagram evaluation is shown to be crucial. Specifically, the differences in site-site distributions for sites on identical and mirror-image molecules are found to originate from bridge diagrams which involve interactions between four-site, or larger, clusters. Discrimination cannot be predicted from an integral equation theory which neglects these diagrams.

  20. Multiple Molecular Subtypes of Triple-Negative Breast Cancer Critically Rely on Androgen Receptor and Respond to Enzalutamide In Vivo

    PubMed Central

    Barton, Valerie N.; D’Amato, Nicholas C.; Gordon, Michael A.; Lind, Hanne T.; Spoelstra, Nicole S.; Babbs, Beatrice L.; Heinz, Richard E.; Elias, Anthony; Jedlicka, Paul; Jacobsen, Britta M.; Richer, Jennifer K.

    2015-01-01

    Triple-negative breast cancer (TNBC) has the lowest 5-year survival rate of invasive breast carcinomas, and currently there are no approved targeted therapies for this aggressive form of the disease. The androgen receptor (AR) is expressed in up to one third of TNBC and we find that all AR+ TNBC primary tumors tested display nuclear localization of AR, indicative of transcriptionally active receptors. While AR is most abundant in the “luminal AR (LAR)” molecular subtype of TNBC, here, for the first time, we use both the new-generation anti-androgen enzalutamide and AR knockdown to demonstrate that the other non-LAR molecular subtypes of TNBC are critically dependent on AR protein. Indeed, AR inhibition significantly reduces baseline proliferation, anchorage-independent growth, migration, and invasion and increases apoptosis in four TNBC lines (SUM159PT, HCC1806, BT549, and MDA-MB-231), representing three non-LAR TNBC molecular subtypes (mesenchymal-like, mesenchymal stem–like, and basal-like 2). In vivo, enzalutamide significantly decreases viability of SUM159PT and HCC1806 xenografts. Furthermore, mechanistic analysis reveals that AR activation upregulates secretion of the EGFR ligand amphiregulin (AREG), an effect abrogated by enzalutamide in vitro and in vivo. Exogenous AREG partially rescues the effects of AR knockdown on proliferation, migration, and invasion, demonstrating that upregulation of AREG is one mechanism by which AR influences tumorigenicity. Together, our findings indicate that non-LAR subtypes of TNBC are AR dependent and, moreover, that enzalutamide is a promising targeted therapy for multiple molecular subtypes of AR+ TNBC. PMID:25713333

  1. Integrated p–n junction InGaN/GaN multiple-quantum-well devices with diverse functionalities

    NASA Astrophysics Data System (ADS)

    Cai, Wei; Gao, Xumin; Yuan, Wei; Yang, Yongchao; Yuan, Jialei; Zhu, Hongbo; Wang, Yongjin

    2016-05-01

    We propose, fabricate, and demonstrate integrated p–n junction InGaN/GaN multiple-quantum-well devices with diverse functionalities on a GaN-on-silicon platform. Suspended devices with a common n-contact are realized using a wafer-level process. For the integrated devices, part of the light emitted by a light-emitting diode (LED) is guided in-plane through a suspended waveguide and is sensed by another photodiode. The induced photocurrent is tuned by the LED. The integrated devices can act as two independent LEDs to deliver different signals simultaneously for free-space visible light communication. Furthermore, the suspended devices can be used as two separate photodiodes to detect incident light with a distinct on/off switching performance.

  2. Accurate and efficient Nyström volume integral equation method for the Maxwell equations for multiple 3-D scatterers

    NASA Astrophysics Data System (ADS)

    Chen, Duan; Cai, Wei; Zinser, Brian; Cho, Min Hyung

    2016-09-01

    In this paper, we develop an accurate and efficient Nyström volume integral equation (VIE) method for the Maxwell equations for a large number of 3-D scatterers. The Cauchy Principal Values that arise from the VIE are computed accurately using a finite size exclusion volume together with explicit correction integrals consisting of removable singularities. Also, the hyper-singular integrals are computed using interpolated quadrature formulae with tensor-product quadrature nodes for cubes, spheres and cylinders, that are frequently encountered in the design of meta-materials. The resulting Nyström VIE method is shown to have high accuracy with a small number of collocation points and demonstrates p-convergence for computing the electromagnetic scattering of these objects. Numerical calculations of multiple scatterers of cubic, spherical, and cylindrical shapes validate the efficiency and accuracy of the proposed method.

  3. Evidence for multiple mechanisms for membrane binding and integration via carboxyl-terminal insertion sequences.

    PubMed

    Kim, P K; Janiak-Spens, F; Trimble, W S; Leber, B; Andrews, D W

    1997-07-22

    Subcellular localization of proteins with carboxyl-terminal insertion sequences requires the molecule be both targeted to and integrated into the correct membrane. The mechanism of membrane integration of cytochrome b5 has been shown to be promiscuous, spontaneous, nonsaturable, and independent of membrane proteins. Thus endoplasmic reticulum localization for cytochrome b5 depends primarily on accurate targeting to the appropriate membrane. Here direct comparison of this mechanism with that of three other proteins integrated into membranes via carboxyl-terminal insertion sequences [vesicle-associated membrane protein 1(Vamp1), polyomavirus middle-T antigen, and Bcl-2] revealed that, unlike cytochrome b5, membrane selectivity for these molecules is conferred at least in part by the mechanisms of membrane integration. Bcl-2 membrane integration was similar to that of cytochrome b5 except that insertion into lipid vesicles was inefficient. Unlike cytochrome b5 and Bcl-2, Vamp1 binding to canine pancreatic microsomes was saturable, ATP-dependent, and abolished by mild trypsin treatment of microsomes. Surprisingly, although the insertion sequence of polyomavirus middle-T antigen was sufficient to mediate electrostatic binding to membranes, binding did not lead to integration into the bilayer. Together these results demonstrate that there are at least two different mechanisms for correct membrane integration of proteins with insertion sequences, one mediated primarily by targeting and one relying on factors in the target membrane to mediate selective integration. Our results also demonstrate that, contrary to expectation, hydrophobicity is not sufficient for insertion sequence-mediated membrane integration. We suggest that the structure of the insertion sequence determines whether or not specific membrane-bound receptor proteins are required for membrane integration. PMID:9220974

  4. Supramolecular inclusion-based molecular integral rigidity: a feasible strategy for controlling the structural connectivity of uranyl polyrotaxane networks.

    PubMed

    Mei, Lei; Wang, Lin; Yuan, Li-yong; An, Shu-wen; Zhao, Yu-liang; Chai, Zhi-fang; Burns, Peter C; Shi, Wei-qun

    2015-08-01

    The assembly of two-dimensional (2D) large channel uranyl-organic polyrotaxane networks as well as structural regulation of uranyl-bearing units using jointed cucurbit[6]uril-based pseudorotaxanes with integral rigidity based on supramolecular inclusion is presented for the first time. This construction strategy concerning controlling molecular integral rigidity based on supramolecular inclusion may afford an entirely new methodology for coordination chemistry. PMID:26121567

  5. Multiple Conformational States of Proteins: A Molecular Dynamics Analysis of Myoglobin

    NASA Astrophysics Data System (ADS)

    Elber, R.; Karplus, M.

    1987-01-01

    A molecular dynamics simulation of myoglobin provides the first direct demonstration that the potential energy surface of a protein is characterized by a large number of thermally accessible minima in the neighborhood of the native structure (for example, approximately 2000 minima were sampled in a 300-picosecond trajectory). This is expected to have important consequences for the interpretation of the activity of transport proteins and enzymes. Different minima correspond to changes in the relative orientation of the helices coupled with side-chain rearrangements that preserve the close packing of the protein interior. The conformational space sampled by the simulation is similar to that found in the evolutionary development of the globins. Glasslike behavior is expected at low temperatures. The minima obtained from the trajectory do not satisfy certain criteria for ultrametricity.

  6. HackaMol: An Object-Oriented Modern Perl Library for Molecular Hacking on Multiple Scales.

    PubMed

    Riccardi, Demian; Parks, Jerry M; Johs, Alexander; Smith, Jeremy C

    2015-04-27

    HackaMol is an open source, object-oriented toolkit written in Modern Perl that organizes atoms within molecules and provides chemically intuitive attributes and methods. The library consists of two components: HackaMol, the core that contains classes for storing and manipulating molecular information, and HackaMol::X, the extensions that use the core. The core is well-tested, well-documented, and easy to install across computational platforms. The goal of the extensions is to provide a more flexible space for researchers to develop and share new methods. In this application note, we provide a description of the core classes and two extensions: HackaMol::X::Calculator, an abstract calculator that uses code references to generalize interfaces with external programs, and HackaMol::X::Vina, a structured class that provides an interface with the AutoDock Vina docking program. PMID:25793330

  7. Optimized breeding strategies for multiple trait integration: I. Minimizing linkage drag in single event introgression.

    PubMed

    Peng, Ting; Sun, Xiaochun; Mumm, Rita H

    2014-01-01

    From a breeding standpoint, multiple trait integration (MTI) is a four-step process of converting an elite variety/hybrid for value-added traits (e.g. transgenic events) using backcross breeding, ultimately regaining the performance attributes of the target hybrid along with reliable expression of the value-added traits. In the light of the overarching goal of recovering equivalent performance in the finished conversion, this study focuses on the first step of MTI, single event introgression, exploring the feasibility of marker-aided backcross conversion of a target maize hybrid for 15 transgenic events, incorporating eight events into the female hybrid parent and seven into the male parent. Single event introgression is conducted in parallel streams to convert the recurrent parent (RP) for individual events, with the primary objective of minimizing residual non-recurrent parent (NRP) germplasm, especially in the chromosomal proximity to the event (i.e. linkage drag). In keeping with a defined lower limit of 96.66 % overall RP germplasm recovery (i.e. ≤120 cM NRP germplasm given a genome size of 1,788 cM), a breeding goal for each of the 15 single event conversions was developed: <8 cM of residual NRP germplasm across the genome with ~1 cM in the 20 cM region flanking the event. Using computer simulation, we aimed to identify optimal breeding strategies for single event introgression to achieve this breeding goal, measuring efficiency in terms of number of backcross generations required, marker data points needed, and total population size across generations. Various selection schemes classified as three-stage, modified two-stage, and combined selection conducted from BC1 through BC3, BC4, or BC5 were compared. The breeding goal was achieved with a selection scheme involving five generations of marker-aided backcrossing, with BC1 through BC3 selected for the event of interest and minimal linkage drag at population size of 600, and BC4 and BC5 selected for

  8. Multiple-site replacement analogs of glucagon. A molecular basis for antagonist design.

    PubMed

    Unson, C G; Wu, C R; Fitzpatrick, K J; Merrifield, R B

    1994-04-29

    Extensive structure activity analysis has allowed us to identify specific residues in the glucagon sequence that are responsible for either receptor recognition or signal transduction. For instance, we have demonstrated that aspartic acid 9 and histidine 1 are essential for activation, and that an ionic interaction between the negative carboxylate and the protonated imidazole may contribute to the activation reaction at the molecular level. In the absence of the carboxylic group at position 9, aspartic 21 or aspartic 15 might furnish distal electrostatic effects to maintain partial agonism. Further investigation established that each of the 4 serine residues in the hormone play distinct roles. Serine 8 provides an important determinant of binding. Whereas neither serines 2, 11, nor 16 are required for receptor recognition. We have shown that serine 16 is essential for signal transduction and thus have identified it to be the third residue in glucagon to participate in a putative catalytic triad together with aspartic 9 and histidine 1, in the transduction of the glucagon response. In this work, we utilized insights into the functional significance of particular residues in the peptide appropriated from our structure-function assignments, as the basis of a molecular approach for the design of active-site directed antagonists of glucagon. The importance as well as the accuracy of our findings are confirmed by the synthesis of a series of improved glucagon antagonists based on replacements at positions 1, 9, 11, 16, and 21. The inhibition index, (I/A)50, of our best antagonist des-His1-[Nle9-Ala11-Ala16]glucagon amide, has been improved 10-fold over the previous best glucagon inhibitor. PMID:8175663

  9. Proteasome inhibitors – molecular basis and current perspectives in multiple myeloma

    PubMed Central

    Kubiczkova, Lenka; Pour, Ludek; Sedlarikova, Lenka; Hajek, Roman; Sevcikova, Sabina

    2014-01-01

    Inhibition of proteasome, a proteolytic complex responsible for the degradation of ubiquitinated proteins, has emerged as a powerful strategy for treatment of multiple myeloma (MM), a plasma cell malignancy. First-in-class agent, bortezomib, has demonstrated great positive therapeutic efficacy in MM, both in pre-clinical and in clinical studies. However, despite its high efficiency, a large proportion of patients do not achieve sufficient clinical response. Therefore, the development of a second-generation of proteasome inhibitors (PIs) with improved pharmacological properties was needed. Recently, several of these new agents have been introduced into clinics including carfilzomib, marizomib and ixazomib. Further, new orally administered second-generation PI oprozomib is being investigated. This review provides an overview of main mechanisms of action of PIs in MM, focusing on the ongoing development and progress of novel anti-proteasome therapeutics. PMID:24712303

  10. Controlling the Interference of Multiple Molecular Orbitals in High-Harmonic Generation

    SciTech Connect

    Woerner, H. J.; Bertrand, J. B.; Hockett, P.; Corkum, P. B.; Villeneuve, D. M.

    2010-06-11

    We demonstrate a new method to investigate the origin of spectral structures in high-harmonic generation. We report detailed measurements of high-harmonic spectra in aligned nitrogen and carbon dioxide molecules. Varying the wavelength and intensity of the generating laser field, we show that the minimum in aligned N{sub 2} molecules is nearly unaffected, whereas the minimum in aligned CO{sub 2} molecules shifts over more than 15 eV. Our quantitative analysis shows that both the interference of multiple orbitals and their structural characteristics affect the position of the minimum. Our method provides a simple approach to the investigation of the high-harmonic generation process in more complex molecules.

  11. An electrochemical molecular recognition-based aptasensor for multiple protein detection.

    PubMed

    Cheng, Lin; Zhang, Jie; Lin, Yan; Wang, Qiong; Zhang, XiuXiu; Ding, YanHua; Cui, Hanfeng; Fan, Hao

    2015-12-15

    This article reports a simple electrochemical approach for the detection of multiple proteins (thrombin and lysozyme) using Dabcyl-labeled aptamer modified metal nanoparticles (DLAPs). DLAPs were immobilized on β-cyclodextrins (β-CDs) modified electrode by means of host-guest self-assembly. During the time of detection, the aptamers' structure will change due to the specific binding with corresponding proteins that forced DLAPs far away from the electrode that had been modified by β-CDs. Thus, the capture of target proteins onto DLAPs was translated via the electrochemical current signal offered by metal nanoparticles. Linearity of the aptasensor for quantitative measurements was demonstrated. Determinations of proteins in human real serum samples were also performed to demonstrate detection in real clinical samples. PMID:26344894

  12. Multiple Integration of the Heat-Conduction Equation for a Space Bounded From the Inside

    NASA Astrophysics Data System (ADS)

    Kot, V. A.

    2016-03-01

    An N-fold integration of the heat-conduction equation for a space bounded from the inside has been performed using a system of identical equalities with definition of the temperature function by a power polynomial with an exponential factor. It is shown that, in a number of cases, the approximate solutions obtained can be considered as exact because their errors comprise hundredths and thousandths of a percent. The method proposed for N-fold integration represents an alternative to classical integral transformations.

  13. Molecular cloning in Escherichia coli of Erwinia chrysanthemi genes encoding multiple forms of pectate lyase.

    PubMed Central

    Collmer, A; Schoedel, C; Roeder, D L; Ried, J L; Rissler, J F

    1985-01-01

    The phytopathogenic enterobacterium Erwinia chrysanthemi excretes multiple isozymes of the plant tissue-disintegrating enzyme, pectate lyase (PL). Genes encoding PL were cloned from E. chrysanthemi CUCPB 1237 into Escherichia coli HB101 by inserting Sau3A-generated DNA fragments into the BamHI site of pBR322 and then screening recombinant transformants for the ability to sink into pectate semisolid agar. Restriction mapping of the cloned DNA in eight pectolytic transformants revealed overlapping portions of a 9.8-kilobase region of the E. chrysanthemi genome. Deletion derivatives of these plasmids were used to localize the pectolytic genotype to a 2.5-kilobase region of the cloned DNA. PL gene expression in E. coli was independent of vector promoters, repressed by glucose, and not induced by galacturonan. PL accumulated largely in the periplasmic space of E. coli. An activity stain used in conjunction with ultrathin-layer isoelectric focusing resolved the PL in E. chrysanthemi culture supernatants and shock fluids of E. coli clones into multiple forms. One isozyme with an apparent pI of 7.8 was produced at a far higher level in E. coli and was common to all of the pectolytic clones. Activity staining of renatured PL in sodium dodecyl sulfate-polyacrylamide gels revealed that this isozyme comigrated with the corresponding isozyme produced by E. chrysanthemi. The PL isozyme profiles produced by different clones and deletion derivative subclones suggest that the cloned region contains at least two PL isozyme structural genes. Pectolytic E. coli clones possessed a limited ability to macerate potato tuber tissues. Images PMID:2982794

  14. Integration and Testing Challenges of Small, Multiple Satellite Missions: Experiences from the Space Technology 5 Project

    NASA Technical Reports Server (NTRS)

    Sauerwein, Timothy A.; Gostomski, Thomas

    2008-01-01

    The ST5 technology demonstration mission led by GSFC of NASA's New Millennium Program managed by JPL consisted of three micro satellites (approximately 30 kg each) deployed into orbit from the Pegasus XL launch vehicle. In order to meet the launch date schedule of ST5, a different approach was required rather than the standard I&T approach used for single, room-sized satellites. The three spacecraft were designed, integrated, and tested at NASA Goddard Space Flight Center. It was determined that there was insufficient time in the schedule to perform three spacecraft I&T activities in series using standard approaches. The solution was for spacecraft #1 to undergo integration and test first, followed by spacecraft #2 and #3 simultaneously. This simultaneous integration was successful for several reasons. Each spacecraft had a Lead Test Conductor who planned and coordinated their spacecraft through its integration and test activities. One team of engineers and technicians executed the integration of all three spacecraft, learning and gaining knowledge and efficiency as spacecraft #1 integration and testing progressed. They became acutely familiar with the hardware, operation and processes for I&T, thus had the experience and knowledge to safely execute I&T for spacecraft #2 and #3. The integration team was extremely versatile; each member could perform many different activities or work any spacecraft, when needed. ST5 was successfully integrated, tested and shipped to the launch site per the I&T schedule that was planned three years previously. The I&T campaign was completed with ST5's successful launch on March 22, 2006.

  15. Molecular Evidence for Multiple Origins of the European Spined Loaches (Teleostei, Cobitidae)

    PubMed Central

    Perdices, Anabel; Bohlen, Joerg; Šlechtová, Vendula; Doadrio, Ignacio

    2016-01-01

    We present a phylogenetic investigation of the Northern Clade, the major monophyletic clade within the freshwater fish family Cobitidae, one of the most prominent families of freshwater fishes found in Asian and European waters. Phylogenetic reconstructions based on the cytochrome b and RAG-1 genes show the genera Microcobitis, Sabanejewia, Koreocobitis and Kichulchoia as monophyletic groups. These reconstructions also show a Cobitis sensu lato and a Misgurnus sensu lato group. The Cobitis sensu lato group includes all species of Cobitis, Iksookimia, Niwaella and Kichulchoia, while the Misgurnus sensu lato group includes Misgurnus, Paramisgurnus and Koreocobitis. Although the monophyly of both the Cobitis sensu lato and Misgurnus sensu lato groups is supported, relationships within the groups are incongruent with current generic definitions. The absence of monophyly of most genera included in the Cobitis sensu lato group (Cobitis, Iksookimia and Niwaella) or their low genetic differentiation (Kichuchoia) supports their consideration as synonyms of Cobitis. Molecular phylogenies indicate that the Asian species of Misgurnus experienced a mitochondrial introgression from a lineage of Cobitis. We also find two nuclear haplotypes in the same Cobitis species from the Adriatic area that, in the absence of morphological differentiation, may indicate molecular introgression. Most lineages within the Northern Clade consist of species found in East Asia. However, some lineages also contain species from Europe and Asia Minor. The phylogenetic relationships presented here are consistent with previous studies suggesting an East Asian origin of the Northern Clade. According to the current distributions and phylogenetic relationships of the Misgurnus sensu lato and Cobitis clade lineages, particularly of M. fossilis and C. melanoleuca, the range expansion of East Asian species into Europe was most likely via Siberia into Northern and Central Europe. Phylogenetic analyses also show

  16. Molecular Evidence for Multiple Origins of the European Spined Loaches (Teleostei, Cobitidae).

    PubMed

    Perdices, Anabel; Bohlen, Joerg; Šlechtová, Vendula; Doadrio, Ignacio

    2016-01-01

    We present a phylogenetic investigation of the Northern Clade, the major monophyletic clade within the freshwater fish family Cobitidae, one of the most prominent families of freshwater fishes found in Asian and European waters. Phylogenetic reconstructions based on the cytochrome b and RAG-1 genes show the genera Microcobitis, Sabanejewia, Koreocobitis and Kichulchoia as monophyletic groups. These reconstructions also show a Cobitis sensu lato and a Misgurnus sensu lato group. The Cobitis sensu lato group includes all species of Cobitis, Iksookimia, Niwaella and Kichulchoia, while the Misgurnus sensu lato group includes Misgurnus, Paramisgurnus and Koreocobitis. Although the monophyly of both the Cobitis sensu lato and Misgurnus sensu lato groups is supported, relationships within the groups are incongruent with current generic definitions. The absence of monophyly of most genera included in the Cobitis sensu lato group (Cobitis, Iksookimia and Niwaella) or their low genetic differentiation (Kichuchoia) supports their consideration as synonyms of Cobitis. Molecular phylogenies indicate that the Asian species of Misgurnus experienced a mitochondrial introgression from a lineage of Cobitis. We also find two nuclear haplotypes in the same Cobitis species from the Adriatic area that, in the absence of morphological differentiation, may indicate molecular introgression. Most lineages within the Northern Clade consist of species found in East Asia. However, some lineages also contain species from Europe and Asia Minor. The phylogenetic relationships presented here are consistent with previous studies suggesting an East Asian origin of the Northern Clade. According to the current distributions and phylogenetic relationships of the Misgurnus sensu lato and Cobitis clade lineages, particularly of M. fossilis and C. melanoleuca, the range expansion of East Asian species into Europe was most likely via Siberia into Northern and Central Europe. Phylogenetic analyses also show

  17. Photoluminescence and bowing parameters of InAsSb/InAs multiple quantum wells grown by molecular beam epitaxy

    SciTech Connect

    Liu, P.-W.; Tsai, G.; Lin, H. H.; Krier, A.; Zhuang, Q. D.; Stone, M.

    2006-11-13

    Detailed studies are reported on the photoluminescence of InAsSb/InAs multiple quantum wells grown by molecular beam epitaxy on InAs substrates with the Sb mole fraction ranging from 0.06 to 0.13. From 4 K photoluminescence the band alignment was determined to be staggered type II. By comparing the emission peak energies with a transition energy calculation it was found that both the conduction and valence bands of InAsSb alloy exhibit some bowing. The bowing parameters were determined to be in the ratio of 4:6. For a sample with Sb composition {approx}0.12 in the quantum well the photoluminescence emission band covers the CO{sub 2} absorption peak making it suitable for use in sources for CO{sub 2} detection.

  18. Molecular diagnostics of a single drug-resistant multiple myeloma case using targeted next-generation sequencing

    PubMed Central

    Ikeda, Hiroshi; Ishiguro, Kazuya; Igarashi, Tetsuyuki; Aoki, Yuka; Hayashi, Toshiaki; Ishida, Tadao; Sasaki, Yasushi; Tokino, Takashi; Shinomura, Yasuhisa

    2015-01-01

    A 69-year-old man was diagnosed with IgG λ-type multiple myeloma (MM), Stage II in October 2010. He was treated with one cycle of high-dose dexamethasone. After three cycles of bortezomib, the patient exhibited slow elevations in the free light-chain levels and developed a significant new increase of serum M protein. Bone marrow cytogenetic analysis revealed a complex karyotype characteristic of malignant plasma cells. To better understand the molecular pathogenesis of this patient, we sequenced for mutations in the entire coding regions of 409 cancer-related genes using a semiconductor-based sequencing platform. Sequencing analysis revealed eight nonsynonymous somatic mutations in addition to several copy number variants, including CCND1 and RB1. These alterations may play roles in the pathobiology of this disease. This targeted next-generation sequencing can allow for the prediction of drug resistance and facilitate improvements in the treatment of MM patients. PMID:26491355

  19. Preclinical anatomical, molecular, and functional imaging of the lung with multiple modalities.

    PubMed

    Gammon, Seth T; Foje, Nathan; Brewer, Elizabeth M; Owers, Elizabeth; Downs, Charles A; Budde, Matthew D; Leevy, W Matthew; Helms, My N

    2014-05-15

    In vivo imaging is an important tool for preclinical studies of lung function and disease. The widespread availability of multimodal animal imaging systems and the rapid rate of diagnostic contrast agent development have empowered researchers to noninvasively study lung function and pulmonary disorders. Investigators can identify, track, and quantify biological processes over time. In this review, we highlight the fundamental principles of bioluminescence, fluorescence, planar X-ray, X-ray computed tomography, magnetic resonance imaging, and nuclear imaging modalities (such as positron emission tomography and single photon emission computed tomography) that have been successfully employed for the study of lung function and pulmonary disorders in a preclinical setting. The major principles, benefits, and applications of each imaging modality and technology are reviewed. Limitations and the future prospective of multimodal imaging in pulmonary physiology are also discussed. In vivo imaging bridges molecular biological studies, drug design and discovery, and the imaging field with modern medical practice, and, as such, will continue to be a mainstay in biomedical research. PMID:24658139

  20. Relationships among pest flour beetles of the genus Tribolium (Tenebrionidae) inferred from multiple molecular markers

    PubMed Central

    Angelini, David R.; Jockusch, Elizabeth L.

    2008-01-01

    Model species often provide initial hypotheses and tools for studies of development, genetics, and molecular evolution in closely related species. Flour beetles of the genus Tribolium MacLeay (1825) are one group with potential for such comparative studies. Tribolium castaneum (Herbst 1797) is an increasingly useful developmental genetic system. The convenience with which congeneric and other species of tenebrionid flour beetles can be reared in the laboratory makes this group attractive for comparative studies on a small phylogenetic scale. Here we present the results of phylogenetic analyses of relationships among the major pest species of Tribolium based on two mitochondrial and three nuclear markers (cytochrome oxidase 1, 16S ribosomal DNA, wingless, 28S ribosomal DNA, histone H3). The utility of partitioning the dataset in a manner informed by biological structure and function is demonstrated by comparing various partitioning strategies. In parsimony and partitioned Bayesian analyses of the combined dataset, the castaneum and confusum species groups are supported as monophyletic and as each other’s closest relatives. However, a sister group relationship between this clade and Tribolium brevicornis (Leconte 1859) is not supported. Therefore, we suggest transferring brevicornis group species to the genus Aphanotus Leconte (1862). The inferred phylogeny provides an evolutionary framework for comparative studies using flour beetles. PMID:18024090

  1. Molecularly Imprinted Polymer Integrated with a Surface Acoustic Wave Technique for Detection of Sulfamethizole.

    PubMed

    Ayankojo, Akinrinade George; Tretjakov, Aleksei; Reut, Jekaterina; Boroznjak, Roman; Öpik, Andres; Rappich, Jörg; Furchner, Andreas; Hinrichs, Karsten; Syritski, Vitali

    2016-01-19

    The synergistic effect of combining molecular imprinting and surface acoustic wave (SAW) technologies for the selective and label-free detection of sulfamethizole as a model antibiotic in aqueous environment was demonstrated. A molecularly imprinted polymer (MIP) for sulfamethizole (SMZ) selective recognition was prepared in the form of a homogeneous thin film on the sensing surfaces of SAW chip by oxidative electropolymerization of m-phenylenediamine (mPD) in the presence of SMZ, acting as a template. Special attention was paid to the rational selection of the functional monomer using computational and spectroscopic approaches. SMZ template incorporation and its subsequent release from the polymer was supported by IR microscopic measurements. Precise control of the thicknesses of the SMZ-MIP and respective nonimprinted reference films (NIP) was achieved by correlating the electrical charge dosage during electrodeposition with spectroscopic ellipsometry measurements in order to ensure accurate interpretation of label-free responses originating from the MIP modified sensor. The fabricated SMZ-MIP films were characterized in terms of their binding affinity and selectivity toward the target by analyzing the binding kinetics recorded using the SAW system. The SMZ-MIPs had SMZ binding capacity approximately more than eight times higher than the respective NIP and were able to discriminate among structurally similar molecules, i.e., sulfanilamide and sulfadimethoxine. The presented approach for the facile integration of a sulfonamide antibiotic-sensing layer with SAW technology allowed observing the real-time binding events of the target molecule at nanomolar concentration levels and could be potentially suitable for cost-effective fabrication of a multianalyte chemosensor for analysis of hazardous pollutants in an aqueous environment. PMID:26704414

  2. Proton transport in triflic acid hydrates studied via path integral car-parrinello molecular dynamics.

    PubMed

    Hayes, Robin L; Paddison, Stephen J; Tuckerman, Mark E

    2009-12-31

    The mono-, di-, and tetrahydrates of trifluoromethanesulfonic acid, which contain characteristic H(3)O(+), H(5)O(2)(+), and H(9)O(4)(+) structures, provide model systems for understanding proton transport in materials with high perfluorosulfonic acid density such as perfluorosulfonic acid membranes commonly employed in hydrogen fuel cells. Ab initio molecular dynamics simulations indicate that protons in these solids are predisposed to transfer to the water most strongly bound to sulfonate groups via a Grotthuss-type mechanism, but quickly return to the most solvated defect structure either due to the lack of a nearby species to stabilize the new defect or a preference for the proton to be maximally hydrated. Path integral molecular dynamics of the mono- and dihydrate reveal significant quantum effects that facilitate proton transfer to the "presolvated" water or SO(3)(-) in the first solvation shell and increase the Zundel character of all the defects. These trends are quantified in free energy profiles for each bonding environment. Hydrogen bonding criteria for HOH-OH(2) and HOH-O(3)S are extracted from the two-dimensional potential of mean force. The quantum radial distribution function, radius of gyration, and root-mean-square displacement position correlation function show that the protonic charge is distributed over two or more water molecules. Metastable structural defects with one excess proton shared between two sulfonate groups and another Zundel or Eigen type cation defect are found for the mono- and dihydrate but not for the tetrahydrate crystal. Results for the tetrahydrate native crystal exhibit minor differences at 210 and 250 K. IR spectra are calculated for all native and stable defect structures. Graph theory techniques are used to characterize the chain lengths and ring sizes in the hydrogen bond network. Low conductivities when limited water is present may be attributable to trapping of protons between SO(3)(-) groups and the increased

  3. The molecular spectrum and clinical impact of DIS3 mutations in multiple myeloma.

    PubMed

    Weißbach, Susann; Langer, Christian; Puppe, Bernhard; Nedeva, Theodora; Bach, Elisa; Kull, Miriam; Bargou, Ralf; Einsele, Hermann; Rosenwald, Andreas; Knop, Stefan; Leich, Ellen

    2015-04-01

    Multiple myeloma (MM) is a plasma cell neoplasm that presents with a major biological and clinical heterogeneity. We here investigated the spectrum of clonal and subclonal mutations of DIS3, an active part of the exosome complex, that may play a role in the development or progression of MM. The whole coding sequence of DIS3 was subjected to deep sequencing in 81 uniformly-treated MM patients and 12 MM cell lines and the overall occurrence of DIS3 mutations as well as the presence of DIS3 mutations in minor and major subclones were correlated with cytogenetic alterations and clinical parameters. Our study identified DIS3 mutations in 9/81 patients that were associated with 13q14 deletions and IGH translocations on the cytogenetic level. Specifically, we detected seven novel somatic DIS3 single nucleotide variants (SNVs) and defined three hot spot mutations within the RNB domain. Lastly, we found a trend towards a shorter median overall survival for patients with DIS3 mutations, and patients carrying DIS3 mutations in minor subclones of their tumours showed a significantly worse response to therapy compared to patients with DIS3 mutations in the major subclone. PMID:25521164

  4. Phylogenetic and molecular epidemiological studies reveal evidence of multiple past recombination events between infectious laryngotracheitis viruses.

    PubMed

    Lee, Sang-Won; Devlin, Joanne M; Markham, John F; Noormohammadi, Amir H; Browning, Glenn F; Ficorilli, Nino P; Hartley, Carol A; Markham, Philip F

    2013-01-01

    In contrast to the RNA viruses, the genome of large DNA viruses such as herpesviruses have been considered to be relatively stable. Intra-specific recombination has been proposed as an important, but underestimated, driving force in herpesvirus evolution. Recently, two distinct field strains of infectious laryngotracheitis virus (ILTV) have been shown to have arisen from independent recombination events between different commercial ILTV vaccines. In this study we sequenced the genomes of additional ILTV strains and also utilized other recently updated complete genome sequences of ILTV to confirm the existence of a number of ILTV recombinants in nature. Multiple recombination events were detected in the unique long and repeat regions of the genome, but not in the unique short region. Most recombinants contained a pair of crossover points between two distinct lineages of ILTV, corresponding to the European origin and the Australian origin vaccine strains of ILTV. These results suggest that there are two distinct genotypic lineages of ILTV and that these commonly recombine in the field. PMID:23383306

  5. Phylogenetic and Molecular Epidemiological Studies Reveal Evidence of Multiple Past Recombination Events between Infectious Laryngotracheitis Viruses

    PubMed Central

    Lee, Sang-Won; Devlin, Joanne M.; Markham, John F.; Noormohammadi, Amir H.; Browning, Glenn F.; Ficorilli, Nino P.; Hartley, Carol A.; Markham, Philip F.

    2013-01-01

    In contrast to the RNA viruses, the genome of large DNA viruses such as herpesviruses have been considered to be relatively stable. Intra-specific recombination has been proposed as an important, but underestimated, driving force in herpesvirus evolution. Recently, two distinct field strains of infectious laryngotracheitis virus (ILTV) have been shown to have arisen from independent recombination events between different commercial ILTV vaccines. In this study we sequenced the genomes of additional ILTV strains and also utilized other recently updated complete genome sequences of ILTV to confirm the existence of a number of ILTV recombinants in nature. Multiple recombination events were detected in the unique long and repeat regions of the genome, but not in the unique short region. Most recombinants contained a pair of crossover points between two distinct lineages of ILTV, corresponding to the European origin and the Australian origin vaccine strains of ILTV. These results suggest that there are two distinct genotypic lineages of ILTV and that these commonly recombine in the field. PMID:23383306

  6. A MOLECULAR EXAMINATION OF RELATEDNESS, MULTIPLE PATERNITY, AND COHABITATION OF THE SOUTHERN PLAINS WOODRAT (NEOTOMA MICROPUS)

    PubMed Central

    Baxter, B. Dnate’; Mendez-Harclerode, Francisca M.; Fulhorst, Charles F.; Bradley, Robert D.

    2009-01-01

    Two hundred twenty-two individuals of the southern plains woodrat (Neotoma micropus) were captured from 198 excavated middens at 10 discrete collecting sites from a single population in south-central Texas. Field data, mitochondrial D-loop haplotypes, and polymorphic microsatellite loci (5–7) were used to determine genetic patterns in parentage, relatedness, and mating strategy. Microsatellite loci were highly polymorphic (average observed heterozygosity = 0.859) and were used to construct genotypes that were unique for each individual (probability of identical genotypes: 1 in 2,104,567). Results indicated a high frequency of multiple paternity (6 of 9 litters), evidence of repeat mating between the same 2 individuals, and no indication of male dominance at any collection site. Examination of these data suggested a promiscuous mating system. Within a site, average relatedness between adult females was similar to that between adult males. A higher level of cohabitation from that previously documented was recorded and finer-scale analyses revealed high levels of relatedness between most cohabiting individuals. Taken with results from other studies of mating behaviors of N. micropus, our results suggest that mating and social behavior of this species are likely influenced by population density. PMID:20011670

  7. Impulsive synchronization of Markovian jumping randomly coupled neural networks with partly unknown transition probabilities via multiple integral approach.

    PubMed

    Chandrasekar, A; Rakkiyappan, R; Cao, Jinde

    2015-10-01

    This paper studies the impulsive synchronization of Markovian jumping randomly coupled neural networks with partly unknown transition probabilities via multiple integral approach. The array of neural networks are coupled in a random fashion which is governed by Bernoulli random variable. The aim of this paper is to obtain the synchronization criteria, which is suitable for both exactly known and partly unknown transition probabilities such that the coupled neural network is synchronized with mixed time-delay. The considered impulsive effects can be synchronized at partly unknown transition probabilities. Besides, a multiple integral approach is also proposed to strengthen the Markovian jumping randomly coupled neural networks with partly unknown transition probabilities. By making use of Kronecker product and some useful integral inequalities, a novel Lyapunov-Krasovskii functional was designed for handling the coupled neural network with mixed delay and then impulsive synchronization criteria are solvable in a set of linear matrix inequalities. Finally, numerical examples are presented to illustrate the effectiveness and advantages of the theoretical results. PMID:26210982

  8. A modular cell-based biosensor using engineered genetic logic circuits to detect and integrate multiple environmental signals.

    PubMed

    Wang, Baojun; Barahona, Mauricio; Buck, Martin

    2013-02-15

    Cells perceive a wide variety of cellular and environmental signals, which are often processed combinatorially to generate particular phenotypic responses. Here, we employ both single and mixed cell type populations, pre-programmed with engineered modular cell signalling and sensing circuits, as processing units to detect and integrate multiple environmental signals. Based on an engineered modular genetic AND logic gate, we report the construction of a set of scalable synthetic microbe-based biosensors comprising exchangeable sensory, signal processing and actuation modules. These cellular biosensors were engineered using distinct signalling sensory modules to precisely identify various chemical signals, and combinations thereof, with a quantitative fluorescent output. The genetic logic gate used can function as a biological filter and an amplifier to enhance the sensing selectivity and sensitivity of cell-based biosensors. In particular, an Escherichia coli consortium-based biosensor has been constructed that can detect and integrate three environmental signals (arsenic, mercury and copper ion levels) via either its native two-component signal transduction pathways or synthetic signalling sensors derived from other bacteria in combination with a cell-cell communication module. We demonstrate how a modular cell-based biosensor can be engineered predictably using exchangeable synthetic gene circuit modules to sense and integrate multiple-input signals. This study illustrates some of the key practical design principles required for the future application of these biosensors in broad environmental and healthcare areas. PMID:22981411

  9. Diffusion Weighted Callosal Integrity Reflects Interhemispheric Communication Efficiency in Multiple Sclerosis

    ERIC Educational Resources Information Center

    Warlop, Nele P.; Achten, Eric; Debruyne, Jan; Vingerhoets, Guy

    2008-01-01

    We aimed to investigate the relation between damage in the corpus callosum and the performance on an interhemispheric communication task in patients with multiple sclerosis (MS). Relative callosal lesion load defined as the ratio between callosal area and the total lesion load in the total corpus callosum, and the diffusion tensor imaging (DTI)…

  10. Meaning, Memory, and Multiplication: Integrating Patterns and Properties with Basic Facts

    ERIC Educational Resources Information Center

    Ploger, Don; Hecht, Steven

    2012-01-01

    Although learning mathematics certainly depends upon accurate understanding of the facts of multiplication, it requires much more. This study examines the relationship between a meaningful understanding of arithmetic operations and the mastery of basic facts. The study began with a joke about a mistaken mathematical fact. The children appreciated…

  11. SOUND SURVEY DESIGNS CAN FACILITATE INTEGRATING STREAM MONITORING DATA ACROSS MULTIPLE PROGRAMS

    EPA Science Inventory

    Multiple agencies in the Pacific Northwest monitor the condition of stream networks or their watersheds. Some agencies use a stream "network" perspective to report on the fraction or length of the network that either meets or violates particular criteria. Other agencies use a "wa...

  12. Molecular cytogenetic identification of a wheat-rye 1R addition line with multiple spikelets and resistance to powdery mildew.

    PubMed

    Yang, Wujuan; Wang, Changyou; Chen, Chunhuan; Wang, Yajuan; Zhang, Hong; Liu, Xinlun; Ji, Wanquan

    2016-04-01

    Alien addition lines are important for transferring useful genes from alien species into common wheat. Rye is an important and valuable gene resource for improving wheat disease resistance, yield, and environment adaptation. A new wheat-rye addition line, N9436B, was developed from the progeny of the cross of common wheat (Triticum aestivum L., 2n = 6x = 42, AABBDD) cultivar Shaanmai 611 and rye (Secale cereal L., 2n = 2x = 14, RR) accession Austrian rye. We characterized this new line by cytology, genomic in situ hybridization (GISH), fluorescence in situ hybridization (FISH), molecular markers, and disease resistance screening. N9436B was stable in morphology and cytology, with a chromosome composition of 2n = 42 + 2t = 22II. GISH investigations showed that this line contained two rye chromosomes. GISH, FISH, and molecular maker identification suggested that the introduced R chromosome and the missing wheat chromosome arms were 1R chromosome and 2DL chromosome arm, respectively. N9436B exhibited 30-37 spikelets per spike and a high level of resistance to powdery mildew (Blumeria graminis f. sp. tritici, Bgt) isolate E09 at the seedling stage. N9436B was cytologically stable, had the trait of multiple spikelets, and was resistant to powdery mildew; this line should thus be useful in wheat improvement. PMID:27021228

  13. Investigation of the interaction between quercetin and human serum albumin by multiple spectra, electrochemical impedance spectra and molecular modeling.

    PubMed

    Dai, Jie; Zou, Ting; Wang, Li; Zhang, Yezhong; Liu, Yi

    2014-12-01

    Quercetin (Qu), a flavonoid compound, exists widely in the human diet and exhibits a variety of pharmacological activities. This work is aimed at studying the effect of Qu on the bioactive protein, human serum albumin (HSA) under simulated biophysical conditions. Multiple spectroscopic methods (including fluorescence and circular dichroism), electrochemical impedance spectra (EIS) and molecular modeling were employed to investigate the interaction between Qu and HSA. The fluorescence quenching and EIS experimental results showed that the fluorescence quenching of HSA was caused by formation of a Qu-HSA complex in the ground state, which belonged to the static quenching mechanism. Based on the calculated thermodynamic parameters, it concluded that the interaction was a spontaneous process and hydrogen bonds combined with van der Waal's forces played a major role in stabilizing the Qu-HSA complex. Molecular modeling results demonstrated that several amino acids participated in the binding process and the formed Qu-HSA complex was stabilized by H-bonding network at site I in sub-domain IIA, which was further confirmed by the site marker competitive experiments. The evidence from circular dichroism (CD) indicated that the secondary structure and microenvironment of HSA were changed. Alterations in the conformation of HSA were observed with a reduction in the amount of α helix from 59.9% (free HSA) to 56% (Qu-HSA complex), indicating a slight unfolding of the protein polypeptides. PMID:24801949

  14. Molecular dynamics at the receptor level of immunodominant myelin oligodendrocyte glycoprotein 35-55 epitope implicated in multiple sclerosis.

    PubMed

    Yannakakis, Mary Patricia; Tzoupis, Haralambos; Michailidou, Elena; Mantzourani, Efthimia; Simal, Carmen; Tselios, Theodore

    2016-07-01

    Multiple Sclerosis (MS) is a common autoimmune disease whereby myelin is destroyed by the immune system. The disease is triggered by the stimulation of encephalitogenic T-cells via the formation of a trimolecular complex between the Human Leukocyte Antigen (HLA), an immunodominant epitope of myelin proteins and T-cell Receptor (TCR). Myelin Oligodendrocyte Glycoprotein (MOG) is located on the external surface of myelin and has been implicated in MS induction. The immunodominant 35-55 epitope of MOG is widely used for in vivo biological evaluation and immunological studies that are related with chronic Experimental Autoimmune Encephalomyelitis (EAE, animal model of MS), inflammatory diseases and MS. In this report, Molecular Dynamics (MD) simulations were used to explore the interactions of MOG35-55 at the receptor level. A detailed mapping of the developed interactions during the creation of the trimolecular complex is reported. This is the first attempt to gain an understanding of the molecular recognition of the MOG35-55 epitope by the HLA and TCR receptors. During the formation of the trimolecular complex, the residues Arg(41) and Arg(46) of MOG35-55 have been confirmed to serve as TCR anchors while Tyr(40) interacts with HLA. The present structural findings indicate that the Arg at positions 41 and 46 is a key residue for the stimulation of the encephalitogenic T-cells. PMID:27388119

  15. A transverse aperture-integral equation solution for edge diffraction by multiple layers of homogeneous material

    NASA Astrophysics Data System (ADS)

    Pearson, L. W.; Whitaker, R. A.

    1991-02-01

    The transverse-aperture/integral-equation method provides a means of computation for diffraction coefficients at blunt edges of a broad class of stratified layers, including sheet-anisotropy models for conducting composites. This paper concentrates on the application of the method when the material profile comprises layers of homogeneous, potentially lossy material. The method proceeds from defining an artificial aperture perpendicular to a semiinfinite, planar, stratified region and passing through the terminal edge of the region. An integral equation is formulated over this infinite-extent aperture, and the solution to the integral equation represents the influence of the edge. The kernel in the integral equation is a weighted sum of the Green functions for the respective half spaces lying on either side of the aperture plane. The vector wave equation is separable in each of these half spaces, resulting in Green functions that are expressible analytically. The Green function for the stratified half space is stated in terms of a Sommerfeld-type integral.

  16. On-chip magnetic separation of superparamagnetic beads for integrated molecular analysis

    NASA Astrophysics Data System (ADS)

    Florescu, Octavian; Wang, Kevan; Au, Patrick; Tang, Jimmy; Harris, Eva; Beatty, P. Robert; Boser, Bernhard E.

    2010-03-01

    We have demonstrated a postprocessed complementary metal oxide semiconductor (CMOS) integrated circuit (IC) capable of on-chip magnetic separation, i.e., removing via magnetic forces the nonspecifically bound magnetic beads from the detection area on the surface of the chip. Initially, 4.5 μm wide superparamagnetic beads sedimenting out of solution due to gravity were attracted to the detection area by a magnetic concentration force generated by flowing current through a conductor embedded in the IC. After sedimentation, the magnetic beads that did not bind strongly to the functionalized surface of the IC through a specific biochemical complex were removed by a magnetic separation force generated by flowing current through another conductor placed laterally to the detection area. As the spherical bead pivoted on the surface of the chip, the lateral magnetic force was further amplified by mechanical leveraging, and 50 mA of current flowing through the separation conductor placed 18 μm away from the bead resulted in 7.5 pN of tensile force on the biomolecular tether immobilizing the bead. This force proved high enough to break nonspecific interactions while leaving specific antibody-antigen bonds intact. A sandwich capture immunoassay on purified human immunoglobulin G showed strong correlation with a control enzyme linked immunosorbent assay and a detection limit of 10 ng/ml or 70 pM. The beads bound to the detection area after on-chip magnetic separation were detected optically. To implement a fully integrated molecular diagnostics platform, the on-chip magnetic separation functionality presented in this work can be readily combine with state-of-the art CMOS-based magnetic bead detection technology.

  17. Replica Exchange Molecular Dynamics Study of Dimerization in Prion Protein: Multiple Modes of Interaction and Stabilization.

    PubMed

    Chamachi, Neharika G; Chakrabarty, Suman

    2016-08-01

    The pathological forms of prions are known to be a result of misfolding, oligomerization, and aggregation of the cellular prion. While the mechanism of misfolding and aggregation in prions has been widely studied using both experimental and computational tools, the structural and energetic characterization of the dimer form have not garnered as much attention. On one hand dimerization can be the first step toward a nucleation-like pathway to aggregation, whereas on the other hand it may also increase the conformational stability preventing self-aggregation. In this work, we have used extensive all-atom replica exchange molecular dynamics simulations of both monomer and dimer forms of a mouse prion protein to understand the structural, dynamic, and thermodynamic stability of dimeric prion as compared to the monomeric form. We show that prion proteins can dimerize spontaneously being stabilized by hydrophobic interactions as well as intermolecular hydrogen bonding and salt bridge formation. We have computed the conformational free energy landscapes for both monomer and dimer forms to compare the thermodynamic stability and misfolding pathways. We observe large conformational heterogeneity among the various modes of interactions between the monomers and the strong intermolecular interactions may lead to as high as 20% β-content. The hydrophobic regions in helix-2, surrounding coil regions, terminal regions along with the natively present β-sheet region appear to actively participate in prion-prion intermolecular interactions. Dimerization seems to considerably suppress the inherent dynamic instability observed in monomeric prions, particularly because the regions of structural frustration constitute the dimer interface. Further, we demonstrate an interesting reversible coupling between the Q160-G131 interaction (which leads to inhibition of β-sheet extension) and the G131-V161 H-bond formation. PMID:27390876

  18. International Myeloma Working Group molecular classification of multiple myeloma: spotlight review

    PubMed Central

    Fonseca, R; Bergsagel, PL; Drach, J; Shaughnessy, J.; Gutierrez, N; Stewart, AK; Morgan, G; Van Ness, B; Chesi, M; Minvielle, S; Neri, A; Barlogie, B; Kuehl, WM; Liebisch, P; Davies, F; Chen-Kiang, S; Durie, BGM; Carrasco, R; Sezer, Orhan; Reiman, Tony; Pilarski, Linda; Avet-Loiseau, H

    2010-01-01

    Myeloma is a malignant proliferation of monoclonal plasma cells. Although morphologically similar, several subtypes of the disease have been identified at the genetic and molecular level. These genetic subtypes are associated with unique clinico-pathological features and dissimilar outcome. At the top hierarchical level, myeloma can be divided into hyperdiploid and non-hyperdiploid subtypes. The latter is mainly composed of cases harboring IgH translocations, generally associated with more aggressive clinical features and shorter survival. The three main IgH translocations in myeloma are the t(11;14)(q13;q32), t(4;14)(p16;q32) and t(14;16)(q32;q23). Trisomies and a more indolent form of the disease characterize hyperdiploid myeloma. A number of genetic progression factors have been identified including deletions of chromosomes 13 and 17 and abnormalities of chromosome 1 (1p deletion and 1q amplification). Other key drivers of cell survival and proliferation have also been identified such as nuclear factor- B-activating mutations and other deregulation factors for the cyclin-dependent pathways regulators. Further understanding of the biological subtypes of the disease has come from the application of novel techniques such as gene expression profiling and array-based comparative genomic hybridization. The combination of data arising from these studies and that previously elucidated through other mechanisms allows for most myeloma cases to be classified under one of several genetic subtypes. This paper proposes a framework for the classification of myeloma subtypes and provides recommendations for genetic testing. This group proposes that genetic testing needs to be incorporated into daily clinical practice and also as an essential component of all ongoing and future clinical trials. PMID:19798094

  19. A reappraisal of the evolution of Asian snakehead fishes (Pisces, Channidae) using molecular data from multiple genes and fossil calibration.

    PubMed

    Adamson, Eleanor A S; Hurwood, David A; Mather, Peter B

    2010-08-01

    Freshwater snakehead fishes (Channidae) provide an interesting target for phylogenetic analysis for the following reasons, their unusual biology, potential for cryptic diversity and availability of a good fossil record. Here, a multi-locus molecular phylogeny was constructed and calibrated using two fossil dates to estimate divergence times within the family. Sampling aimed to explore interspecific divergence of Channa species across Southeast Asia and intra-specific variation where species possessed natural geographical ranges that were extensive. Results contradict divergence times estimated previously independently from single locus mitochondrial data or the fossil record and suggest that after divergence from African taxa 40-50 Ma, evolution of Asian snakeheads has been heavily influenced by multiple broad scale dispersal events across India and Southeast Asia. A similar pattern of divergence within multiple clades suggests that west-east dispersal was limited for many taxa during the Miocene. Deep intra-specific divergence was inferred for C. striata, indicating that long historical periods of isolation ( approximately 8Ma) have not resulted in the evolution of reproductive isolation within this species. Results support suggestions that C. marulia like fishes in northern Cambodia may constitute an undescribed species, and that Indian C. diplogramma warrants taxonomic recognition as being distinct from Southeast Asian C. micropeltes, with the two taxa last sharing a common ancestor in the mid- to late-Miocene. PMID:20359539

  20. An integral equation and simulation study of hydrogen inclusions in a molecular crystal of short-capped nanotubes.

    PubMed

    Lomba, Enrique; Bores, Cecilia; Notario, Rafael; Sánchez-Gil, V

    2016-09-01

    In this work we have assessed the ability of a recently proposed three-dimensional integral equation approach to describe the explicit spatial distribution of molecular hydrogen confined in a crystal formed by short-capped nanotubes of C50 H10. To that aim we have resorted to extensive molecular simulation calculations whose results have been compared with our three-dimensional integral equation approximation. We have first tested the ability of a single C50 H10 nanocage for the encapsulation of H2 by means of molecular dynamics simulations, in particular using targeted molecular dynamics to estimate the binding Gibbs energy of a host hydrogen molecule inside the nanocage. Then, we have investigated the adsorption isotherm of the nanocage crystal using grand canonical Monte Carlo simulations in order to evaluate the maximum load of molecular hydrogen. For a packing close to the maximum load explicit hydrogen density maps and density profiles have been determined using molecular dynamics simulations and the three-dimensional Ornstein-Zernike equation with a hypernetted chain closure. In these conditions of extremely tight confinement the theoretical approach has shown to be able to reproduce the three-dimensional structure of the adsorbed fluid with accuracy down to the finest details. PMID:27367179

  1. An integral equation and simulation study of hydrogen inclusions in a molecular crystal of short-capped nanotubes

    NASA Astrophysics Data System (ADS)

    Lomba, Enrique; Bores, Cecilia; Notario, Rafael; Sánchez-Gil, V.

    2016-09-01

    In this work we have assessed the ability of a recently proposed three-dimensional integral equation approach to describe the explicit spatial distribution of molecular hydrogen confined in a crystal formed by short-capped nanotubes of C50 H10. To that aim we have resorted to extensive molecular simulation calculations whose results have been compared with our three-dimensional integral equation approximation. We have first tested the ability of a single C50 H10 nanocage for the encapsulation of H2 by means of molecular dynamics simulations, in particular using targeted molecular dynamics to estimate the binding Gibbs energy of a host hydrogen molecule inside the nanocage. Then, we have investigated the adsorption isotherm of the nanocage crystal using grand canonical Monte Carlo simulations in order to evaluate the maximum load of molecular hydrogen. For a packing close to the maximum load explicit hydrogen density maps and density profiles have been determined using molecular dynamics simulations and the three-dimensional Ornstein–Zernike equation with a hypernetted chain closure. In these conditions of extremely tight confinement the theoretical approach has shown to be able to reproduce the three-dimensional structure of the adsorbed fluid with accuracy down to the finest details.

  2. Constitutive CD40 Signaling Calibrates Differentiation Outcomes in Responding B Cells via Multiple Molecular Pathways.

    PubMed

    Basu, Srijani; Kaw, Sheetal; D'Souza, Lucas; Vaidya, Tushar; Bal, Vineeta; Rath, Satyajit; George, Anna

    2016-08-01

    CD40 signaling during B cell activation is known to inhibit terminal differentiation and promote memory generation. Blimp-1 is essential for efficient plasma cell (PC) generation, and although CD40 signaling is known to inhibit Blimp-1 induction during B cell activation, the mechanisms involved have been unclear. We report that CD40 signaling induces miR-125b that targets Blimp-1 transcripts, and increases amounts of the ubiquitin ligase Hrd1 that targets BLIMP-1 protein for proteasomal degradation. CD40 signaling also inhibits the early unfolded protein response (UPR) of activated B cells that precedes the induction of terminal differentiation, and Hrd1 feeds into this pathway by targeting the core UPR component IRE-1α. Strikingly, CD40 signaling in the absence of BCR- or TLR-ligation also repressed Blimp-1 transcripts, suggesting that noncognate ligation of CD40 via T-B interactions may repress Blimp-1 in vivo. In support of this, we find that naive B cells purified from CD40-CD154 interaction-deficient mice express higher amounts of Blimp-1 and lower amounts of microRNAs and Hrd1. Higher basal amounts of Blimp-1 in naive CD40(-/-) B cells correlate with an increased tendency of the cells to undergo terminal differentiation upon LPS stimulation. Conversely, a 24-h exposure to CD40 ligation during LPS stimulation of wild-type B cells is sufficient to inhibit PC generation. The data show that CD40-mediated inhibition of PC generation is via engagement of multiple pathways that involve repression of Blimp-1 and inhibition of the UPR that prepares cells to become professional secretors. They also show that constitutive CD40 signaling in vivo involving bystander T-B interactions can calibrate B cell differentiation outcomes. PMID:27342845

  3. Comprehensive Multiple Molecular Profile of Epithelial Mesenchymal Transition in Intrahepatic Cholangiocarcinoma Patients

    PubMed Central

    Ke, Ai-Wu; Dong, Zhao-Ru; Zhang, Peng-Fei; Fan, Jia; Peng, Bao-Gang; Zhou, Jian

    2014-01-01

    Background The aim of this study is to investigate the expression profile of multiple epithelial mesenchymal transition (EMT)-related molecules in intrahepatic cholangiocarcinoma (ICC) and the related prognostic significance. Methods Immunohistochemistry was performed to determine the expression of E-cadherin, Vimentin, Snail, slug and β-catenin in a tissue microarray consisting of tumor tissues of 140 ICC patients undergoing curative resection. The correlation between the expression of these molecules and the clinicopathological characteristics of ICC patients was analyzed, and their prognostic implication was evaluated. Results Reduced E-cadherin and increased Vimentin expression, the characteristic changes of EMT, identified in 55.0% and 55.7% of primary ICCs, respectively, were correlated with lymphatic metastasis and poorer overall survival (OS) and disease-free survival (DFS) of ICCs. The overexpression of snail and nonmembranous β-catenin, which are the major regulators of the EMT, were identified in 49.2% and 45.7% of primary ICCs, while little slug expression was detected in ICCs. Cytoplasmic/nuclear β-catenin did not significantly predict worse DFS and was not related with E-cadherin loss. The overexpression of snail predicted worse OS and DFS. Snail overexpression correlated with the down-regulation of E-cadherin and the up-regulation of Vimentin. Inhibition of snail in an ICC cell line decreased the expression of E-cadherin, enhanced the expression of Vimentin and impaired the invasion and migration ability of ICC cells. Conclusions These data support the hypothesis that EMT plays vital roles in ICC progression and suggest that snail but not slug and β-catenin plays a crucial role in the EMT induction of ICC. PMID:24816558

  4. Molecular evolution of the multiple calmodulin-like cal genes in C. elegans and in nematodes.

    PubMed

    Karabinos, Anton

    2016-09-01

    Calmodulin (CaM) is a major EF hand containing intracellular calcium receptor in animals and plants; however, eukaryotes also express a number of related CaM-like proteins. We have previously characterized an embryonic phenotype of the single Caenorhabditis elegans CaM gene cmd-1, reported no visible RNAi phenotype for the four related cal-1 to cal-4 genes and started tissue-specific expression analyses of these proteins. In the present study, we analyzed evolutionary aspects of the previously reported CAL-1 to CAL-4 proteins, along with the four new CAL-5 to CAL-8 sequences retrieved from the worm database. Phylogenetic analyses suggest that all C. elegans CAL proteins arose from a CaM ancestor through repeated gene duplications, fusions and sequence divergence. The same holds, also, for the variable N-terminal extensions of the CAL-1 to CAL-4 proteins, which have evolved from the CaM-like core domain. We found 97 CAL homologs in different nematode clades and also detected two CAL-7-related sequences outside the nematodes. Moreover, the C. elegans-specific cal-6 gene, representing the most CaM-related sequence found in nematodes so far, harbours many deletions, insertions and sequence substitutions and is predicted, therefore, to be non-functional. These analyses provide an insight into a complex and dynamic origin of the multiple CAL genes in C. elegans and in nematodes and represent also a basis for further functional studies of these CaM-related sequences in nematodes. PMID:27558386

  5. Molecular phylogenetics of moray eels (Muraenidae) demonstrates multiple origins of a shell-crushing jaw (Gymnomuraena, Echidna) and multiple colonizations of the Atlantic Ocean.

    PubMed

    Reece, Joshua S; Bowen, Brian W; Smith, David G; Larson, Allan

    2010-11-01

    Moray eels (Muraenidae) are apex predators on coral reefs around the world, but they are not well studied because their cryptic habitats and occasionally aggressive behaviors make them difficult to collect. We provide a molecular phylogeny of moray eels including 44 species representing two subfamilies, eight genera, and all tropical ocean basins. Phylogenetic relationships among these taxa are estimated from portions of mitochondrial loci cytochrome b (632 bp) and cytochrome oxidase subunit 1 (596 bp), and portions of the nuclear loci RAG-1 (421 bp) and RAG-2 (754 bp). We test four sets of contrasting phylogenetic hypotheses using Bayes Factors, Shimodaira-Hasegawa tests, and Templeton tests. First, our results support the subfamily-level taxonomic distinction between true morays (Muraeninae) and snakemorays (Uropterygiinae), statistically rejecting hypotheses of non-monophyly for each subfamily. Second, we reject a monophyletic grouping of the genera Gymnomuraena and Echidna, which share a durophagous (shell-crushing) cranial morphology and dentition, indicating that the durophagous characters are not homologous. Third, we demonstrate that durophagous feeding habits and associated morphological characters have evolved in parallel in an ancestor of Gymnomuraena and at least three additional times within the genus Echidna. Finally, the tree topology indicates multiple invasions of the Atlantic from the Indo-Pacific, one of these occurring immediately prior to formation of the Isthmus of Panama approximately 2.8 MYA (million years ago) and one or two others occurring in the early to mid Miocene. Cladogenesis occurring within the Atlantic during the mid Miocene and Pliocene also contributed to moray species diversity. These data include a pair of sister species separated by the Isthmus of Panama, allowing a time-calibrated tree with an estimated crown age for Muraenidae at between 41 and 60 MYA, consistent with fossil evidence. Most lineage accumulation within morays

  6. Integrating Multiple Types of Data for Signaling Research: Challenges and Opportunities

    SciTech Connect

    Wiley, H. S.

    2011-02-15

    New technologies promise to provide unprecedented amounts of information that can provide a foundation for creating predictive models of cell signaling pathways. To be useful, however, this information must be integrated into a coherent framework. In addition, the sheer volume of data gathered from the new technologies requires computational approaches for its analysis. Unfortunately, there are many barriers to data integration and analysis, mostly because of a lack of adequate data standards and their inconsistent use by scientists. However, solving the fundamental issues of data sharing will enable the investigation of entirely new areas of cell signaling research.

  7. Design and Integration of an All-Magnetic Attitude Control System for FASTSAT-HSV01's Multiple Pointing Objectives

    NASA Technical Reports Server (NTRS)

    DeKock, Brandon; Sanders, Devon; Vanzwieten, Tannen; Capo-Lugo, Pedro

    2011-01-01

    The FASTSAT-HSV01 spacecraft is a microsatellite with magnetic torque rods as it sole attitude control actuator. FASTSAT s multiple payloads and mission functions require the Attitude Control System (ACS) to maintain Local Vertical Local Horizontal (LVLH)-referenced attitudes without spin-stabilization, while the pointing errors for some attitudes be significantly smaller than the previous best-demonstrated for this type of control system. The mission requires the ACS to hold multiple stable, unstable, and non-equilibrium attitudes, as well as eject a 3U CubeSat from an onboard P-POD and recover from the ensuing tumble. This paper describes the Attitude Control System, the reasons for design choices, how the ACS integrates with the rest of the spacecraft, and gives recommendations for potential future applications of the work.

  8. Critical issues of complex, epitaxial oxide growth and integration with silicon by molecular beam epitaxy

    NASA Astrophysics Data System (ADS)

    Lettieri, James

    Molecular beam epitaxy was used to grow epitaxial oxides on silicon substrates. The growth of BaO, SrO, EuO, and SrTiO3 are discussed with a focus on the general theme of integration of functional, epitaxial oxides into a silicon environment. Oxidation studies of various metal systems relevant for oxide on silicon epitaxy and integration are reported. Results demonstrate the catalytic nature of an alkaline earth metal at small concentrations to enable the oxidation of the poorly oxidizing metals at pressures lower than during deposition of the pure metal alone. Results from the deposition of various elements are presented. The aspects of the growth of alkaline earth oxides on silicon are explained. The transition from the silicon to the alkaline earth oxide as described through reflection high energy electron diffraction (RHEED) is presented and used to understand issues related to each stage of the growth. High quality, commensurate alkaline earth oxides are grown on silicon at room temperature and P O2 background ˜ 3 x 10-8 Torr. The growth of alkaline earth and rare earth oxide solid solutions and rare earth oxides (EuO) are described. The first reported epitaxial EuO on silicon is reported, enabled by the use of a thin buffer layer (13 A) of SrO. Using a strategy of transition from simple structures to the more complex, the growth of a perovskite (SrTiO3) on silicon is demonstrated. Growth of a structurally optimized perovskite structure entails the transformation of a thin interfacial alkaline earth oxide layer into the initial perovskite cells. SrTiO3 and La-doped SrTiO3 on silicon are used to integrate a piezoelectric relevant for microelectromechanical systems (MEMS) applications and a ferroelectric relevant for a ferroelectric random access memory (FRAM) architecture. A d33 value of over 400 pm/V under bias is measured for the piezoelectric (Pb(Mn1/3Nb 2/3)O3 -PbTiO3) and a remanent polarization of 25 muC/cm2 and fatigue free behavior (>1012 cycles) for a

  9. Thermodynamic integration to monitor parameter convergence in molecular dynamics: application to liquid water

    NASA Astrophysics Data System (ADS)

    Soler, Jose M.; Fritz, Michelle; Fernandez-Serra, Marivi

    Checking the convergence of accuracy parameters (e.g. basis set), in ab initio molecular dynamics, is complicated and computationally expensive. This is because entire simulations are required for each new parameter set, and comparing two simulations is subject to large statistical errors in structural (pair correlation functions) and thermodynamic (pressure, compressibility) properties. In this work we propose a method to evaluate parameter convergence without these costly simulations. In the spirit of thermodynamic integration approaches, the average change of a given property is computed with different parameters in the same geometries, extracted from a given MD trajectory or set of trajectories. This same approach can be used to explore tendencies for new exchange-correlation functionals, so that only the most promising ones need to be thoroughly evaluated with entire simulations. This work is supported by DOE Grants No. DE-FG02-09ER16052, No. DE-SC0003871 and the Grant FIS2012-37549-C05 from the Spanish Ministry of Economy and Competitiveness.

  10. MSIplus for Integrated Colorectal Cancer Molecular Testing by Next-Generation Sequencing.

    PubMed

    Hempelmann, Jennifer A; Scroggins, Sheena M; Pritchard, Colin C; Salipante, Stephen J

    2015-11-01

    Molecular analysis of colon cancers currently requires multiphasic testing that uses various assays with different performance characteristics, adding cost and time to patient care. We have developed a single, next-generation sequencing assay to simultaneously evaluate colorectal cancers for mutations in relevant cancer genes (KRAS, NRAS, and BRAF) and for tumor microsatellite instability (MSI). In a sample set of 61 cases, the assay demonstrated overall sensitivity of 100% and specificity of 100% for identifying cancer-associated mutations, with a practical limit of detection at 2% mutant allele fraction. MSIplus was 97% sensitive (34 of 35 MSI-positive cases) and 100% specific (42 of 42 MSI-negative cases) for ascertaining MSI phenotype in a cohort of 78 tumor specimens. These performance characteristics were slightly better than for conventional multiplex PCR MSI testing (97% sensitivity and 95% specificity), which is based on comparison of microsatellite loci amplified from tumor and matched normal material, applied to the same specimen cohort. Because the assay uses an amplicon sequencing approach, it is rapid and appropriate for specimens with limited available material or fragmented DNA. This integrated testing strategy offers several advantages over existing methods, including a lack of need for matched normal material, sensitive and unbiased detection of variants in target genes, and an automated analysis pipeline enabling principled and reproducible identification of cancer-associated mutations and MSI status simultaneously. PMID:26322950

  11. Molecular mechanisms associated with breast cancer based on integrated gene expression profiling by bioinformatics analysis.

    PubMed

    Wu, Di; Han, Bing; Guo, Liang; Fan, Zhimin

    2016-07-01

    In this study, we aimed to gain more insights into the underlying molecular mechanisms responsible for breast cancer (BC) progression. Three gene expression profiles of human BC were integrated and used to screen the differentially expressed genes (DEGs) between healthy breast samples and BC samples. Protein-protein interaction (PPI) network of DEGs was constructed by mapping DEGs into the Search Tool for the Retrieval of Interacting Genes (STRING) database; then the subnetworks of PPI were constructed with plug-in, MCODE and DEGs in Subnetwork 1 were analysed based on Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway database ( http://www.genome.jp/kegg /). In addition, co-expression network of DEGs was established using the Cytoscape. Totalally 931 DEGs were selected, including 340 up-regulated genes and 591 down-regulated genes. KEGG pathway analysis for DEGs in Subnetwork 1 showed that the pathogenesis of BC was associated with cell cycle, oocyte meiosis, progesterone-mediated oocyte maturation and p53 signalling pathways. Meanwhile, the most significant-related DEGs were found by co-expression network analysis of DEGs. In conclusion, CCNG1 might be involved in the progression of BC via inhibiting cell proliferation, and ADAMTS1 might play a crucial role in BC development through the regulation of angiogenesis. PMID:26804550

  12. Molecular architecture of the 26S proteasome holocomplex determined by an integrative approach

    PubMed Central

    Lasker, Keren; Förster, Friedrich; Bohn, Stefan; Walzthoeni, Thomas; Villa, Elizabeth; Unverdorben, Pia; Beck, Florian; Aebersold, Ruedi; Sali, Andrej; Baumeister, Wolfgang

    2012-01-01

    The 26S proteasome is at the executive end of the ubiquitin-proteasome pathway for the controlled degradation of intracellular proteins. While the structure of its 20S core particle (CP) has been determined by X-ray crystallography, the structure of the 19S regulatory particle (RP), which recruits substrates, unfolds them, and translocates them to the CP for degradation, has remained elusive. Here, we describe the molecular architecture of the 26S holocomplex determined by an integrative approach based on data from cryoelectron microscopy, X-ray crystallography, residue-specific chemical cross-linking, and several proteomics techniques. The “lid” of the RP (consisting of Rpn3/5/6/7/8/9/11/12) is organized in a modular fashion. Rpn3/5/6/7/9/12 form a horseshoe-shaped heterohexamer, which connects to the CP and roofs the AAA-ATPase module, positioning the Rpn8/Rpn11 heterodimer close to its mouth. Rpn2 is rigid, supporting the lid, while Rpn1 is conformationally variable, positioned at the periphery of the ATPase ring. The ubiquitin receptors Rpn10 and Rpn13 are located in the distal part of the RP, indicating that they were recruited to the complex late in its evolution. The modular structure of the 26S proteasome provides insights into the sequence of events prior to the degradation of ubiquitylated substrates. PMID:22307589

  13. Silicon sample holder for molecular beam epitaxy on pre-fabricated integrated circuits

    NASA Technical Reports Server (NTRS)

    Hoenk, Michael E. (Inventor); Grunthaner, Paula J. (Inventor); Grunthaner, Frank J. (Inventor)

    1994-01-01

    The sample holder of the invention is formed of the same semiconductor crystal as the integrated circuit on which the molecular beam expitaxial process is to be performed. In the preferred embodiment, the sample holder comprises three stacked micro-machined silicon wafers: a silicon base wafer having a square micro-machined center opening corresponding in size and shape to the active area of a CCD imager chip, a silicon center wafer micro-machined as an annulus having radially inwardly pointing fingers whose ends abut the edges of and center the CCD imager chip within the annulus, and a silicon top wafer micro-machined as an annulus having cantilevered membranes which extend over the top of the CCD imager chip. The micro-machined silicon wafers are stacked in the order given above with the CCD imager chip centered in the center wafer and sandwiched between the base and top wafers. The thickness of the center wafer is about 20% less than the thickness of the CCD imager chip. Preferably, four titanium wires, each grasping the edges of the top and base wafers, compress all three wafers together, flexing the cantilever fingers of the top wafer to accommodate the thickness of the CCD imager chip, acting as a spring holding the CCD imager chip in place.

  14. Simultaneous reconstruction of multiple depth images without off-focus points in integral imaging using a graphics processing unit.

    PubMed

    Yi, Faliu; Lee, Jieun; Moon, Inkyu

    2014-05-01

    The reconstruction of multiple depth images with a ray back-propagation algorithm in three-dimensional (3D) computational integral imaging is computationally burdensome. Further, a reconstructed depth image consists of a focus and an off-focus area. Focus areas are 3D points on the surface of an object that are located at the reconstructed depth, while off-focus areas include 3D points in free-space that do not belong to any object surface in 3D space. Generally, without being removed, the presence of an off-focus area would adversely affect the high-level analysis of a 3D object, including its classification, recognition, and tracking. Here, we use a graphics processing unit (GPU) that supports parallel processing with multiple processors to simultaneously reconstruct multiple depth images using a lookup table containing the shifted values along the x and y directions for each elemental image in a given depth range. Moreover, each 3D point on a depth image can be measured by analyzing its statistical variance with its corresponding samples, which are captured by the two-dimensional (2D) elemental images. These statistical variances can be used to classify depth image pixels as either focus or off-focus points. At this stage, the measurement of focus and off-focus points in multiple depth images is also implemented in parallel on a GPU. Our proposed method is conducted based on the assumption that there is no occlusion of the 3D object during the capture stage of the integral imaging process. Experimental results have demonstrated that this method is capable of removing off-focus points in the reconstructed depth image. The results also showed that using a GPU to remove the off-focus points could greatly improve the overall computational speed compared with using a CPU. PMID:24921860

  15. An integrated modeling approach to support management decisions of coupled groundwater-agricultural systems under multiple uncertainties

    NASA Astrophysics Data System (ADS)

    Hagos Subagadis, Yohannes; Schütze, Niels; Grundmann, Jens

    2015-04-01

    The planning and implementation of effective water resources management strategies need an assessment of multiple (physical, environmental, and socio-economic) issues, and often requires new research in which knowledge of diverse disciplines are combined in a unified methodological and operational frameworks. Such integrative research to link different knowledge domains faces several practical challenges. Such complexities are further compounded by multiple actors frequently with conflicting interests and multiple uncertainties about the consequences of potential management decisions. A fuzzy-stochastic multiple criteria decision analysis tool was developed in this study to systematically quantify both probabilistic and fuzzy uncertainties associated with complex hydrosystems management. It integrated physical process-based models, fuzzy logic, expert involvement and stochastic simulation within a general framework. Subsequently, the proposed new approach is applied to a water-scarce coastal arid region water management problem in northern Oman, where saltwater intrusion into a coastal aquifer due to excessive groundwater extraction for irrigated agriculture has affected the aquifer sustainability, endangering associated socio-economic conditions as well as traditional social structure. Results from the developed method have provided key decision alternatives which can serve as a platform for negotiation and further exploration. In addition, this approach has enabled to systematically quantify both probabilistic and fuzzy uncertainties associated with the decision problem. Sensitivity analysis applied within the developed tool has shown that the decision makers' risk aversion and risk taking attitude may yield in different ranking of decision alternatives. The developed approach can be applied to address the complexities and uncertainties inherent in water resources systems to support management decisions, while serving as a platform for stakeholder participation.

  16. Understanding Introductory Students' Application of Integrals in Physics from Multiple Perspectives

    ERIC Educational Resources Information Center

    Hu, Dehui

    2013-01-01

    Calculus is used across many physics topics from introductory to upper-division level college courses. The concepts of differentiation and integration are important tools for solving real world problems. Using calculus or any mathematical tool in physics is much more complex than the straightforward application of the equations and algorithms that…

  17. Integrating Gender on Multiple Levels: A Conceptual Model for Teaching Gender Issues in Family Therapy

    ERIC Educational Resources Information Center

    Williams, Lee; McBain, Heidi

    2006-01-01

    As the field of family therapy has evolved, there has been growing recognition as to the importance of gender in family therapy. To prepare the next generation of family therapists adequately, it is important that they recognize the many and complex ways in which gender permeates their work. In this article we present an integrative model to help…

  18. Multiple Integrated Examinations: An Observational Study of Different Academic Curricula Based on a Business Administration Assessment

    ERIC Educational Resources Information Center

    Ardolino, Piermatteo; Noventa, Stefano; Formicuzzi, Maddalena; Cubico, Serena; Favretto, Giuseppe

    2016-01-01

    An observational study has been carried out to analyse differences in performance between students of different undergraduate curricula in the same written business administration examination, focusing particularly on possible effects of "integrated" or "multi-modular" examinations, a recently widespread format in Italian…

  19. Pooling Data from Multiple Longitudinal Studies: The Role of Item Response Theory in Integrative Data Analysis

    ERIC Educational Resources Information Center

    Curran, Patrick J.; Hussong, Andrea M.; Cai, Li; Huang, Wenjing; Chassin, Laurie; Sher, Kenneth J.; Zucker, Robert A.

    2008-01-01

    There are a number of significant challenges researchers encounter when studying development over an extended period of time, including subject attrition, the changing of measurement structures across groups and developmental periods, and the need to invest substantial time and money. Integrative data analysis is an emerging set of methodologies…

  20. Integration and Testing Challenges of Small, Multiple Satellite Missions: Experiences from the Space Technology 5 Project

    NASA Technical Reports Server (NTRS)

    Sauerwein, Timothy A.; Gostomski, Thomas

    2007-01-01

    The ST5 payload, part of NASA s New Millennium Program headquartered at JPL, consisted of three micro satellites (approx. 30 kg each) deployed into orbit from the Pegasus XL launch. ST5 was a technology demonstration mission, intended to test new technologies for potential use for future missions. In order to meet the launch date schedule of ST 5, a different approach was required rather than the standard I&T approach used for single, room-sized satellites. The I&T phase was planned for spacecraft #1 to undergo integration and test first, followed by spacecraft #2 and #3 in tandem. A team of engineers and technicians planned and executed the integration of all three spacecraft emphasizing versatility and commonality. They increased their knowledge and efficiency through spacecraft #1 integration and testing and utilized their experience and knowledge to safely execute I&T for spacecraft #2 and #3. Each integration team member could perform many different roles and functions and thus better support activities on any of the three spacecraft. The I&T campaign was completed with STS s successful launch on March 22,2006

  1. Multiple abiotic stimuli are integrated in the regulation of rice gene expression under field conditions.

    PubMed

    Plessis, Anne; Hafemeister, Christoph; Wilkins, Olivia; Gonzaga, Zennia Jean; Meyer, Rachel Sarah; Pires, Inês; Müller, Christian; Septiningsih, Endang M; Bonneau, Richard; Purugganan, Michael

    2015-01-01

    Plants rely on transcriptional dynamics to respond to multiple climatic fluctuations and contexts in nature. We analyzed the genome-wide gene expression patterns of rice (Oryza sativa) growing in rainfed and irrigated fields during two distinct tropical seasons and determined simple linear models that relate transcriptomic variation to climatic fluctuations. These models combine multiple environmental parameters to account for patterns of expression in the field of co-expressed gene clusters. We examined the similarities of our environmental models between tropical and temperate field conditions, using previously published data. We found that field type and macroclimate had broad impacts on transcriptional responses to environmental fluctuations, especially for genes involved in photosynthesis and development. Nevertheless, variation in solar radiation and temperature at the timescale of hours had reproducible effects across environmental contexts. These results provide a basis for broad-based predictive modeling of plant gene expression in the field. PMID:26609814

  2. Integrating multiple health behavior theories into program planning: the PER worksheet.

    PubMed

    Langlois, Marietta A; Hallam, Jeffrey S

    2010-03-01

    The foundation of a logic model or any theory-based planning model is the identification of the behavioral antecedents and the relationship of these variables to the target behavior. Applying theoretical concepts to specific behaviors and populations is often challenging for practitioners and program planning students. The challenge comes from the abstract definition of theoretical constructs, the duplication of similar constructs in multiple theories, and the need to combine multiple theories. To simplify the planning process when utilizing logic models and health behavior theory, we recommend the use of the PER Worksheet. The PER Worksheet is a planning tool that provides layman-term prompts for identifying health behavior antecedents. It encompasses five common health behavior theories-health belief model, theory of planned behavior, social cognitive theory, an ecological perspective, and transtheoretical model. The PER Worksheet is organized into three columns: Predisposing, Enabling, and Reinforcing factors, terms of the PRECEDE/PROCEED model. PMID:18552278

  3. Multi-model inference in comparative phylogeography: an integrative approach based on multiple lines of evidence

    PubMed Central

    Collevatti, Rosane G.; Terribile, Levi C.; Diniz-Filho, José A. F.; Lima-Ribeiro, Matheus S.

    2015-01-01

    Comparative phylogeography has its roots in classical biogeography and, historically, relies on a pattern-based approach. Here, we present a model-based framework for comparative phylogeography. Our framework was initially developed for statistical phylogeography based on a multi-model inference approach, by coupling ecological niche modeling, coalescent simulation and direct spatio-temporal reconstruction of lineage diffusion using a relaxed random walk model. This multi-model inference framework is particularly useful to investigate the complex dynamics and current patterns in genetic diversity in response to processes operating on multiple taxonomic levels in comparative phylogeography. In addition, because of the lack, or incompleteness of fossil record, the understanding of the role of biogeographical events (vicariance and dispersal routes) in most regions worldwide is barely known. Thus, we believe that the expansion of that framework for multiple species under a comparative approach may give clues on genetic legacies in response to Quaternary climate changes and other biogeographical processes. PMID:25741360

  4. Unexpected Inheritance: Multiple Integrations of Ancient Bornavirus and Ebolavirus/Marburgvirus Sequences in Vertebrate Genomes

    PubMed Central

    Belyi, Vladimir A.; Levine, Arnold J.; Skalka, Anna Marie

    2010-01-01

    Vertebrate genomes contain numerous copies of retroviral sequences, acquired over the course of evolution. Until recently they were thought to be the only type of RNA viruses to be so represented, because integration of a DNA copy of their genome is required for their replication. In this study, an extensive sequence comparison was conducted in which 5,666 viral genes from all known non-retroviral families with single-stranded RNA genomes were matched against the germline genomes of 48 vertebrate species, to determine if such viruses could also contribute to the vertebrate genetic heritage. In 19 of the tested vertebrate species, we discovered as many as 80 high-confidence examples of genomic DNA sequences that appear to be derived, as long ago as 40 million years, from ancestral members of 4 currently circulating virus families with single strand RNA genomes. Surprisingly, almost all of the sequences are related to only two families in the Order Mononegavirales: the Bornaviruses and the Filoviruses, which cause lethal neurological disease and hemorrhagic fevers, respectively. Based on signature landmarks some, and perhaps all, of the endogenous virus-like DNA sequences appear to be LINE element-facilitated integrations derived from viral mRNAs. The integrations represent genes that encode viral nucleocapsid, RNA-dependent-RNA-polymerase, matrix and, possibly, glycoproteins. Integrations are generally limited to one or very few copies of a related viral gene per species, suggesting that once the initial germline integration was obtained (or selected), later integrations failed or provided little advantage to the host. The conservation of relatively long open reading frames for several of the endogenous sequences, the virus-like protein regions represented, and a potential correlation between their presence and a species' resistance to the diseases caused by these pathogens, are consistent with the notion that their products provide some important biological

  5. Barcoding against a paradox? Combined molecular species delineations reveal multiple cryptic lineages in elusive meiofaunal sea slugs

    PubMed Central

    2012-01-01

    Background Many marine meiofaunal species are reported to have wide distributions, which creates a paradox considering their hypothesized low dispersal abilities. Correlated with this paradox is an especially high taxonomic deficit for meiofauna, partly related to a lower taxonomic effort and partly to a high number of putative cryptic species. Molecular-based species delineation and barcoding approaches have been advocated for meiofaunal biodiversity assessments to speed up description processes and uncover cryptic lineages. However, these approaches show sensitivity to sampling coverage (taxonomic and geographic) and the success rate has never been explored on mesopsammic Mollusca. Results We collected the meiofaunal sea-slug Pontohedyle (Acochlidia, Heterobranchia) from 28 localities worldwide. With a traditional morphological approach, all specimens fall into two morphospecies. However, with a multi-marker genetic approach, we reveal multiple lineages that are reciprocally monophyletic on single and concatenated gene trees in phylogenetic analyses. These lineages are largely concordant with geographical and oceanographic parameters, leading to our primary species hypothesis (PSH). In parallel, we apply four independent methods of molecular based species delineation: General Mixed Yule Coalescent model (GMYC), statistical parsimony, Bayesian Species Delineation (BPP) and Automatic Barcode Gap Discovery (ABGD). The secondary species hypothesis (SSH) is gained by relying only on uncontradicted results of the different approaches (‘minimum consensus approach’), resulting in the discovery of a radiation of (at least) 12 mainly cryptic species, 9 of them new to science, some sympatric and some allopatric with respect to ocean boundaries. However, the meiofaunal paradox still persists in some Pontohedyle species identified here with wide coastal and trans-archipelago distributions. Conclusions Our study confirms extensive, morphologically cryptic diversity among

  6. CRISPR/Cas9: a molecular Swiss army knife for simultaneous introduction of multiple genetic modifications in Saccharomyces cerevisiae

    PubMed Central

    Mans, Robert; van Rossum, Harmen M.; Wijsman, Melanie; Backx, Antoon; Kuijpers, Niels G.A.; van den Broek, Marcel; Daran-Lapujade, Pascale; Pronk, Jack T.; van Maris, Antonius J.A.; Daran, Jean-Marc G.

    2015-01-01

    A variety of techniques for strain engineering in Saccharomyces cerevisiae have recently been developed. However, especially when multiple genetic manipulations are required, strain construction is still a time-consuming process. This study describes new CRISPR/Cas9-based approaches for easy, fast strain construction in yeast and explores their potential for simultaneous introduction of multiple genetic modifications. An open-source tool (http://yeastriction.tnw.tudelft.nl) is presented for identification of suitable Cas9 target sites in S. cerevisiae strains. A transformation strategy, using in vivo assembly of a guideRNA plasmid and subsequent genetic modification, was successfully implemented with high accuracies. An alternative strategy, using in vitro assembled plasmids containing two gRNAs, was used to simultaneously introduce up to six genetic modifications in a single transformation step with high efficiencies. Where previous studies mainly focused on the use of CRISPR/Cas9 for gene inactivation, we demonstrate the versatility of CRISPR/Cas9-based engineering of yeast by achieving simultaneous integration of a multigene construct combined with gene deletion and the simultaneous introduction of two single-nucleotide mutations at different loci. Sets of standardized plasmids, as well as the web-based Yeastriction target-sequence identifier and primer-design tool, are made available to the yeast research community to facilitate fast, standardized and efficient application of the CRISPR/Cas9 system. PMID:25743786

  7. A Case Study in Integrating Multiple E-commerce Standards via Semantic Web Technology

    NASA Astrophysics Data System (ADS)

    Yu, Yang; Hillman, Donald; Setio, Basuki; Heflin, Jeff

    Internet business-to-business transactions present great challenges in merging information from different sources. In this paper we describe a project to integrate four representative commercial classification systems with the Federal Cataloging System (FCS). The FCS is used by the US Defense Logistics Agency to name, describe and classify all items under inventory control by the DoD. Our approach uses the ECCMA Open Technical Dictionary (eOTD) as a common vocabulary to accommodate all different classifications. We create a semantic bridging ontology between each classification and the eOTD to describe their logical relationships in OWL DL. The essential idea is that since each classification has formal definitions in a common vocabulary, we can use subsumption to automatically integrate them, thus mitigating the need for pairwise mappings. Furthermore our system provides an interactive interface to let users choose and browse the results and more importantly it can translate catalogs that commit to these classifications using compiled mapping results.

  8. Integration of multiple components in polystyrene-based microfluidic devices part I: fabrication and characterization.

    PubMed

    Johnson, Alicia S; Anderson, Kari B; Halpin, Stephen T; Kirkpatrick, Douglas C; Spence, Dana M; Martin, R Scott

    2013-01-01

    In Part I of a two-part series, we describe a simple and inexpensive approach to fabricate polystyrene devices that is based upon melting polystyrene (from either a Petri dish or powder form) against PDMS molds or around electrode materials. The ability to incorporate microchannels in polystyrene and integrate the resulting device with standard laboratory equipment such as an optical plate reader for analyte readout and pipets for fluid propulsion is first described. A simple approach for sample and reagent delivery to the device channels using a standard, multi-channel micropipette and a PDMS-based injection block is detailed. Integration of the microfluidic device with these off-chip functions (sample delivery and readout) enables high-throughput screens and analyses. An approach to fabricate polystyrene-based devices with embedded electrodes is also demonstrated, thereby enabling the integration of microchip electrophoresis with electrochemical detection through the use of a palladium electrode (for a decoupler) and carbon-fiber bundle (for detection). The device was sealed against a PDMS-based microchannel and used for the electrophoretic separation and amperometric detection of dopamine, epinephrine, catechol, and 3,4-dihydroxyphenylacetic acid. Finally, these devices were compared against PDMS-based microchips in terms of their optical transparency and absorption of an anti-platelet drug, clopidogrel. Part I of this series lays the foundation for Part II, where these devices were utilized for various on-chip cellular analysis. PMID:23120747

  9. Towards a Better Understanding of CMMI and Agile Integration - Multiple Case Study of Four Companies

    NASA Astrophysics Data System (ADS)

    Pikkarainen, Minna

    The amount of software is increasing in the different domains in Europe. This provides the industries in smaller countries good opportunities to work in the international markets. Success in the global markets however demands the rapid production of high quality, error free software. Both CMMI and agile methods seem to provide a ready solution for quality and lead time improvements. There is not, however, much empirical evidence available either about 1) how the integration of these two aspects can be done in practice or 2) what it actually demands from assessors and software process improvement groups. The goal of this paper is to increase the understanding of CMMI and agile integration, in particular, focusing on the research question: how to use ‘lightweight’ style of CMMI assessments in agile contexts. This is done via four case studies in which assessments were conducted using the goals of CMMI integrated project management and collaboration and coordination with relevant stakeholder process areas and practices from XP and Scrum. The study shows that the use of agile practices may support the fulfilment of the goals of CMMI process areas but there are still many challenges for the agile teams to be solved within the continuous improvement programs. It also identifies practical advices to the assessors and improvement groups to take into consideration when conducting assessment in the context of agile software development.

  10. Multiple-integrating sphere spectrophotometer for measuring absolute spectral reflectance and transmittance.

    PubMed

    Zerlaut, G A; Anderson, T E

    1981-11-01

    A spectroreflectometer/transmissometer is described that permits determination of absolute optical characteristics in the 300-2600-nm wavelength region (which is essentially the complete solar spectrum). The uniqueness of the instrument derives from use of three rapidly interchangeable 20-cm (8-in.) integrating spheres to measure (1) absolute hemispherical spectral reflectance as a function of angles of incidence from -40 to +40 degrees employing an Edwards-type integrating sphere with a center-mounted sample [using small 2.5-cm (1-in.) diam specimens], (2) absolute hemispherical and absolute diffuse spectral reflectance at an angle of incidence of 20 degrees employing a sphere with a wall-mounted sample (for large specimens) and a screened detector, and (3) absolute hemispherical and absolute directional (near-normal exitance) transmittance employing a complete integrating sphere with the only ports being for the sample and reference beams. Data are presented that demonstrate the ability to measure the spectral reflectance of nonmirror surfaces to an absolute accuracy of 0.995 (an uncertainty of +/-0.005 reflectance units) in both reflectance spheres and of highly specular mirrors to an absolute accuracy of 0.993 (an uncertainty of +/-0.007 reflectance units). Spectral transmittance can be measured to an absolute accuracy of better than 0.995 (an uncertainty of +/-0.005 transmittance units). PMID:20372262

  11. MetaTracker: integration and abstraction of 3D motion tracking data from multiple hardware systems

    NASA Astrophysics Data System (ADS)

    Kopecky, Ken; Winer, Eliot

    2014-06-01

    Motion tracking has long been one of the primary challenges in mixed reality (MR), augmented reality (AR), and virtual reality (VR). Military and defense training can provide particularly difficult challenges for motion tracking, such as in the case of Military Operations in Urban Terrain (MOUT) and other dismounted, close quarters simulations. These simulations can take place across multiple rooms, with many fast-moving objects that need to be tracked with a high degree of accuracy and low latency. Many tracking technologies exist, such as optical, inertial, ultrasonic, and magnetic. Some tracking systems even combine these technologies to complement each other. However, there are no systems that provide a high-resolution, flexible, wide-area solution that is resistant to occlusion. While frameworks exist that simplify the use of tracking systems and other input devices, none allow data from multiple tracking systems to be combined, as if from a single system. In this paper, we introduce a method for compensating for the weaknesses of individual tracking systems by combining data from multiple sources and presenting it as a single tracking system. Individual tracked objects are identified by name, and their data is provided to simulation applications through a server program. This allows tracked objects to transition seamlessly from the area of one tracking system to another. Furthermore, it abstracts away the individual drivers, APIs, and data formats for each system, providing a simplified API that can be used to receive data from any of the available tracking systems. Finally, when single-piece tracking systems are used, those systems can themselves be tracked, allowing for real-time adjustment of the trackable area. This allows simulation operators to leverage limited resources in more effective ways, improving the quality of training.

  12. Proton transport in triflic acid pentahydrate studied via ab initio path integral molecular dynamics.

    PubMed

    Hayes, Robin L; Paddison, Stephen J; Tuckerman, Mark E

    2011-06-16

    Trifluoromethanesulfonic acid hydrates provide a well-defined system to study proton dissociation and transport in perfluorosulfonic acid membranes, typically used as the electrolyte in hydrogen fuel cells, in the limit of minimal water. The triflic acid pentahydrate crystal (CF(3)SO(3)H·5H(2)O) is sufficiently aqueous that it contains an extended three-dimensional water network. Despite it being extended, however, long-range proton transport along the network is structurally unfavorable and would require considerable rearrangement. Nevertheless, the triflic acid pentahydrate crystal system can provide a clear picture of the preferred locations of local protonic defects in the water network, which provides insights about related structures in the disordered, low-hydration environment of perfluorosulfonic acid membranes. Ab initio molecular dynamics simulations reveal that the proton defect is most likely to transfer to the closest water that has the expected presolvation and only contains water in its first solvatio