Science.gov

Sample records for integrates multiple molecular

  1. Integrated molecular profiling of SOD2 expression in multiple myeloma.

    PubMed

    Hurt, Elaine M; Thomas, Suneetha B; Peng, Benjamin; Farrar, William L

    2007-05-01

    Reactive oxygen species are known to be involved in several cellular processes, including cell signaling. SOD2 is a key enzyme in the conversion of reactive oxygen species and has been implicated in a host of disease states, including cancer. Using an integrated, whole-cell approach encompassing epigenetics, genomics, and proteomics, we have defined the role of SOD2 in multiple myeloma. We show that the SOD2 promoter is methylated in several cell lines and there is a correlative decrease in expression. Furthermore, myeloma patient samples have decreased SOD2 expression compared with healthy donors. Overexpression of SOD2 results in decreased proliferation and altered sensitivity to 2-methoxyestradiol-induced DNA damage and apoptosis. Genomic profiling revealed regulation of 65 genes, including genes involved in tumorigenesis, and proteomic analysis identified activation of the JAK/STAT pathway. Analysis of nearly 400 activated transcription factors identified 31 transcription factors with altered DNA binding activity, including XBP1, NFAT, forkhead, and GAS binding sites. Integration of data from our gestalt molecular analysis has defined a role for SOD2 in cellular proliferation, JAK/STAT signaling, and regulation of several transcription factors.

  2. 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.

  3. Multiple program/multiple data molecular dynamics method with multiple time step integrator for large biological systems.

    PubMed

    Jung, Jaewoon; Sugita, Yuji

    2017-06-15

    Parallelization of molecular dynamics (MD) simulation is essential for investigating conformational dynamics of large biological systems, such as ribosomes, viruses, and multiple proteins in cellular environments. To improve efficiency in the parallel computation, we have to reduce the amount of data transfer between processors by introducing domain decomposition schemes. Also, it is important to optimize the computational balance between real-space non-bonded interactions and reciprocal-space interactions for long-range electrostatic interactions. Here, we introduce a novel parallelization scheme for large-scale MD simulations on massively parallel supercomputers consisting of only CPUs. We make use of a multiple program/multiple data (MPMD) approach for separating the real-space and reciprocal-space computations on different processors. We also utilize the r-RESPA multiple time step integrator on the framework of the MPMD approach in an efficient way: when the reciprocal-space computations are skipped in r-RESPA, processors assigned for them are utilized for half of the real-space computations. The new scheme allows us to use twice as many as processors that are available in the conventional single program approach. The best performances of all-atom MD simulations for 1 million (STMV), 8.5 million (8_STMV), and 28.8 million (27_STMV) atom systems on K computer are 65, 36, and 24 ns/day, respectively. The MPMD scheme can accelerate 23.4, 10.2, and 9.2 ns/day from the maximum performance of single-program approach for STMV, 8_STMV, and 27_STMV systems, respectively, which correspond to 57%, 39%, and 60% speed up. This suggests significant speedups by increasing the number of processors without losing parallel computational efficiency. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  4. Error and timing analysis of multiple time-step integration methods for molecular dynamics

    NASA Astrophysics Data System (ADS)

    Han, Guowen; Deng, Yuefan; Glimm, James; Martyna, Glenn

    2007-02-01

    Molecular dynamics simulations of biomolecules performed using multiple time-step integration methods are hampered by resonance instabilities. We analyze the properties of a simple 1D linear system integrated with the symplectic reference system propagator MTS (r-RESPA) technique following earlier work by others. A closed form expression for the time step dependent Hamiltonian which corresponds to r-RESPA integration of the model is derived. This permits us to present an analytic formula for the dependence of the integration accuracy on short-range force cutoff range. A detailed analysis of the force decomposition for the standard Ewald summation method is then given as the Ewald method is a good candidate to achieve high scaling on modern massively parallel machines. We test the new analysis on a realistic system, a protein in water. Under Langevin dynamics with a weak friction coefficient ( ζ=1 ps) to maintain temperature control and using the SHAKE algorithm to freeze out high frequency vibrations, we show that the 5 fs resonance barrier present when all degrees of freedom are unconstrained is postponed to ≈12 fs. An iso-error boundary with respect to the short-range cutoff range and multiple time step size agrees well with the analytical results which are valid due to dominance of the high frequency modes in determining integrator accuracy. Using r-RESPA to treat the long range interactions results in a 6× increase in efficiency for the decomposition described in the text.

  5. Multiple-Time Step Ab Initio Molecular Dynamics Based on Two-Electron Integral Screening.

    PubMed

    Fatehi, Shervin; Steele, Ryan P

    2015-03-10

    A multiple-timestep ab initio molecular dynamics scheme based on varying the two-electron integral screening method used in Hartree-Fock or density functional theory calculations is presented. Although screening is motivated by numerical considerations, it is also related to separations in the length- and timescales characterizing forces in a molecular system: Loose thresholds are sufficient to describe fast motions over short distances, while tight thresholds may be employed for larger length scales and longer times, leading to a practical acceleration of ab initio molecular dynamics simulations. Standard screening approaches can lead, however, to significant discontinuities in (and inconsistencies between) the energy and gradient when the screening threshold is loose, making them inappropriate for use in dynamics. To remedy this problem, a consistent window-screening method that smooths these discontinuities is devised. Further algorithmic improvements reuse electronic-structure information within the dynamics step and enhance efficiency relative to a naı̈ve multiple-timestepping protocol. The resulting scheme is shown to realize meaningful reductions in the cost of Hartree-Fock and B3LYP simulations of a moderately large system, the protonated sarcosine/glycine dipeptide embedded in a 19-water cluster.

  6. Integrating multiple molecular sources into a clinical risk prediction signature by extracting complementary information.

    PubMed

    Hieke, Stefanie; Benner, Axel; Schlenl, Richard F; Schumacher, Martin; Bullinger, Lars; Binder, Harald

    2016-08-30

    High-throughput technology allows for genome-wide measurements at different molecular levels for the same patient, e.g. single nucleotide polymorphisms (SNPs) and gene expression. Correspondingly, it might be beneficial to also integrate complementary information from different molecular levels when building multivariable risk prediction models for a clinical endpoint, such as treatment response or survival. Unfortunately, such a high-dimensional modeling task will often be complicated by a limited overlap of molecular measurements at different levels between patients, i.e. measurements from all molecular levels are available only for a smaller proportion of patients. We propose a sequential strategy for building clinical risk prediction models that integrate genome-wide measurements from two molecular levels in a complementary way. To deal with partial overlap, we develop an imputation approach that allows us to use all available data. This approach is investigated in two acute myeloid leukemia applications combining gene expression with either SNP or DNA methylation data. After obtaining a sparse risk prediction signature e.g. from SNP data, an automatically selected set of prognostic SNPs, by componentwise likelihood-based boosting, imputation is performed for the corresponding linear predictor by a linking model that incorporates e.g. gene expression measurements. The imputed linear predictor is then used for adjustment when building a prognostic signature from the gene expression data. For evaluation, we consider stability, as quantified by inclusion frequencies across resampling data sets. Despite an extremely small overlap in the application example with gene expression and SNPs, several genes are seen to be more stably identified when taking the (imputed) linear predictor from the SNP data into account. In the application with gene expression and DNA methylation, prediction performance with respect to survival also indicates that the proposed approach might

  7. CytoSolve: A Scalable Computational Method for Dynamic Integration of Multiple Molecular Pathway Models.

    PubMed

    Ayyadurai, V A Shiva; Dewey, C Forbes

    2011-03-01

    A grand challenge of computational systems biology is to create a molecular pathway model of the whole cell. Current approaches involve merging smaller molecular pathway models' source codes to create a large monolithic model (computer program) that runs on a single computer. Such a larger model is difficult, if not impossible, to maintain given ongoing updates to the source codes of the smaller models. This paper describes a new system called CytoSolve that dynamically integrates computations of smaller models that can run in parallel across different machines without the need to merge the source codes of the individual models. This approach is demonstrated on the classic Epidermal Growth Factor Receptor (EGFR) model of Kholodenko. The EGFR model is split into four smaller models and each smaller model is distributed on a different machine. Results from four smaller models are dynamically integrated to generate identical results to the monolithic EGFR model running on a single machine. The overhead for parallel and dynamic computation is approximately twice that of a monolithic model running on a single machine. The CytoSolve approach provides a scalable method since smaller models may reside on any computer worldwide, where the source code of each model can be independently maintained and updated.

  8. Acceleration of canonical molecular dynamics simulations using macroscopic expansion of the fast multipole method combined with the multiple timestep integrator algorithm

    NASA Astrophysics Data System (ADS)

    Kawata, Masaaki; Mikami, Masuhiro

    A canonical molecular dynamics (MD) simulation was accelerated by using an efficient implementation of the multiple timestep integrator algorithm combined with the periodic fast multiple method (MEFMM) for both Coulombic and van der Waals interactions. Although a significant reduction in computational cost has been obtained previously by using the integrated method, in which the MEFMM was used only to calculate Coulombic interactions (Kawata, M., and Mikami, M., 2000, J. Comput. Chem., in press), the extension of this method to include van der Waals interactions yielded further acceleration of the overall MD calculation by a factor of about two. Compared with conventional methods, such as the velocity-Verlet algorithm combined with the Ewald method (timestep of 0.25fs), the speedup by using the extended integrated method amounted to a factor of 500 for a 100 ps simulation. Therefore, the extended method reduces substantially the computational effort of large scale MD simulations.

  9. Multiple integral computations

    NASA Astrophysics Data System (ADS)

    Chaloupka, Jan; Kocina, Filip; Veigend, Petr; Nečasová, Gabriela; Kunovský, Jiří; Šátek, Václav

    2017-07-01

    Extending standard numeric integration methods to multi-integrals is possible, however, the numeric effort grows significantly for a given accuracy. In this paper the Modern Taylor Series Method (MTSM) is extended to multi-integrals with the benefit of (theoretically) arbitrary accuracy while being highly parallelizable.

  10. Multiple analyte response and molecular logic operations by excited-state charge-transfer modulation in a bipyridine integrated fluorophore.

    PubMed

    Sreejith, Sivaramapanicker; Divya, Kizhumuri P; Manojkumar, T K; Ajayaghosh, Ayyappanpillai

    2011-02-01

    The tunable excited-state properties of a new donor-π-acceptor-π-donor-type fluorophore 1 with a bipyridyl moiety and its ability to respond to different analytes in solution and on paper microchannels are described. Furthermore, the multiple analyte response of fluorophore 1 has been exploited to perform multiple logic operations. Molecule 1, by virtue of its excited-state charge transfer, exhibits solvatochromism and reversible modulation of its emission in response to multiple chemical inputs, thus resulting in different fluorescent signals. The intraligand charge-transfer (ILCT) emission of 1 at 574 nm has been modulated to three emission outputs by using different chemical inputs, such as Zn(2+), H(+), and ethylenediaminetetraacetic acid (EDTA). Thus, different logic operations such as AND, 2-input-INH, 3-input-INH, IMP, and a combination of these logic operations could be achieved.

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

    USDA-ARS?s Scientific Manuscript database

    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...

  12. A High Density Consensus Genetic Map of Tetraploid Cotton That Integrates Multiple Component Maps through Molecular Marker Redundancy Check

    PubMed Central

    Blenda, Anna; Fang, David D.; Rami, Jean-François; Garsmeur, Olivier; Luo, Feng; Lacape, Jean-Marc

    2012-01-01

    A consensus genetic map of tetraploid cotton was constructed using six high-density 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 cutoff. As a result, 20% of the markers (3,410) could be considered as redundant with some other markers. The marker redundancy information had been a crucial part of the map integration process, in which the six most informative interspecific Gossypium hirsutum×G. barbadense genetic maps were used for assembling a high density consensus (HDC) map for tetraploid cotton. With redundant markers being removed, the HDC map could be constructed thanks to the sufficient number of collinear non-redundant markers in common between the component maps. The HDC map consists of 8,254 loci, originating from 6,669 markers, and spans 4,070 cM, with an average of 2 loci per cM. The HDC map presents a high rate of locus duplications, as 1,292 markers among the 6,669 were mapped in more than one locus. Two thirds of the duplications are bridging homoeologous AT and DT chromosomes constitutive of allopolyploid cotton genome, with an average of 64 duplications per AT/DT chromosome pair. Sequences of 4,744 mapped markers were used for a mutual blast alignment (BBMH) with the 13 major scaffolds of the recently released Gossypium raimondii genome indicating high level of homology between the diploid D genome and the tetraploid cotton genetic map, with only a few minor possible structural rearrangements. Overall, the HDC map will serve as a valuable resource for trait QTL comparative mapping, map-based cloning of important genes, and better understanding of the genome structure and evolution of tetraploid cotton. PMID:23029214

  13. 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.

  14. 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.

  15. 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.

  16. The endogenous and reactive depression subtypes revisited: integrative animal and human studies implicate multiple distinct molecular mechanisms underlying major depressive disorder.

    PubMed

    Malki, Karim; Keers, Robert; Tosto, Maria Grazia; Lourdusamy, Anbarasu; Carboni, Lucia; Domenici, Enrico; Uher, Rudolf; McGuffin, Peter; Schalkwyk, Leonard C

    2014-05-07

    Traditional diagnoses of major depressive disorder (MDD) suggested that the presence or absence of stress prior to onset results in either 'reactive' or 'endogenous' subtypes of the disorder, respectively. Several lines of research suggest that the biological underpinnings of 'reactive' or 'endogenous' subtypes may also differ, resulting in differential response to treatment. We investigated this hypothesis by comparing the gene-expression profiles of three animal models of 'reactive' and 'endogenous' depression. We then translated these findings to clinical samples using a human post-mortem mRNA study. Affymetrix mouse whole-genome oligonucleotide arrays were used to measure gene expression from hippocampal tissues of 144 mice from the Genome-based Therapeutic Drugs for Depression (GENDEP) project. The study used four inbred mouse strains and two depressogenic 'stress' protocols (maternal separation and Unpredictable Chronic Mild Stress) to model 'reactive' depression. Stress-related mRNA differences in mouse were compared with a parallel mRNA study using Flinders Sensitive and Resistant rat lines as a model of 'endogenous' depression. Convergent genes differentially expressed across the animal studies were used to inform candidate gene selection in a human mRNA post-mortem case control study from the Stanley Brain Consortium. In the mouse 'reactive' model, the expression of 350 genes changed in response to early stresses and 370 in response to late stresses. A minimal genetic overlap (less than 8.8%) was detected in response to both stress protocols, but 30% of these genes (21) were also differentially regulated in the 'endogenous' rat study. This overlap is significantly greater than expected by chance. The VAMP-2 gene, differentially expressed across the rodent studies, was also significantly altered in the human study after correcting for multiple testing. Our results suggest that 'endogenous' and 'reactive' subtypes of depression are associated with largely

  17. The endogenous and reactive depression subtypes revisited: integrative animal and human studies implicate multiple distinct molecular mechanisms underlying major depressive disorder

    PubMed Central

    2014-01-01

    Background Traditional diagnoses of major depressive disorder (MDD) suggested that the presence or absence of stress prior to onset results in either ‘reactive’ or ‘endogenous’ subtypes of the disorder, respectively. Several lines of research suggest that the biological underpinnings of ‘reactive’ or ‘endogenous’ subtypes may also differ, resulting in differential response to treatment. We investigated this hypothesis by comparing the gene-expression profiles of three animal models of ‘reactive’ and ‘endogenous’ depression. We then translated these findings to clinical samples using a human post-mortem mRNA study. Methods Affymetrix mouse whole-genome oligonucleotide arrays were used to measure gene expression from hippocampal tissues of 144 mice from the Genome-based Therapeutic Drugs for Depression (GENDEP) project. The study used four inbred mouse strains and two depressogenic ‘stress’ protocols (maternal separation and Unpredictable Chronic Mild Stress) to model ‘reactive’ depression. Stress-related mRNA differences in mouse were compared with a parallel mRNA study using Flinders Sensitive and Resistant rat lines as a model of ‘endogenous’ depression. Convergent genes differentially expressed across the animal studies were used to inform candidate gene selection in a human mRNA post-mortem case control study from the Stanley Brain Consortium. Results In the mouse ‘reactive’ model, the expression of 350 genes changed in response to early stresses and 370 in response to late stresses. A minimal genetic overlap (less than 8.8%) was detected in response to both stress protocols, but 30% of these genes (21) were also differentially regulated in the ‘endogenous’ rat study. This overlap is significantly greater than expected by chance. The VAMP-2 gene, differentially expressed across the rodent studies, was also significantly altered in the human study after correcting for multiple testing. Conclusions Our results suggest

  18. Bayesian correlated clustering to integrate multiple datasets

    PubMed Central

    Kirk, Paul; Griffin, Jim E.; Savage, Richard S.; Ghahramani, Zoubin; Wild, David L.

    2012-01-01

    Motivation: The integration of multiple datasets remains a key challenge in systems biology and genomic medicine. Modern high-throughput technologies generate a broad array of different data types, providing distinct—but often complementary—information. We present a Bayesian method for the unsupervised integrative modelling of multiple datasets, which we refer to as MDI (Multiple Dataset Integration). MDI can integrate information from a wide range of different datasets and data types simultaneously (including the ability to model time series data explicitly using Gaussian processes). Each dataset is modelled using a Dirichlet-multinomial allocation (DMA) mixture model, with dependencies between these models captured through parameters that describe the agreement among the datasets. Results: Using a set of six artificially constructed time series datasets, we show that MDI is able to integrate a significant number of datasets simultaneously, and that it successfully captures the underlying structural similarity between the datasets. We also analyse a variety of real Saccharomyces cerevisiae datasets. In the two-dataset case, we show that MDI’s performance is comparable with the present state-of-the-art. We then move beyond the capabilities of current approaches and integrate gene expression, chromatin immunoprecipitation–chip and protein–protein interaction data, to identify a set of protein complexes for which genes are co-regulated during the cell cycle. Comparisons to other unsupervised data integration techniques—as well as to non-integrative approaches—demonstrate that MDI is competitive, while also providing information that would be difficult or impossible to extract using other methods. Availability: A Matlab implementation of MDI is available from http://www2.warwick.ac.uk/fac/sci/systemsbiology/research/software/. Contact: D.L.Wild@warwick.ac.uk Supplementary information: Supplementary data are available at Bioinformatics online. PMID

  19. Integrated Spectrophotometric Properties of Multiple Stellar Populations

    NASA Astrophysics Data System (ADS)

    Lee, Hyun-chul; Cartwright, Charles

    2016-01-01

    There is mounting evidence that almost all the Milky Way globular clusters (MWGCs) are of multiple stellar populations. Several earlier works have revealed that the color-magnitude diagrams of MWGCs are best reproduced by the combination of stellar populations with different ages and metallicities. However, their integrated spectrophotometric properties have not yet been validated. In this work, we employ the most up-to-dated stellar evolutionary tracks and isochrones from several different groups and calculate the integrated broadband colors and spectral indices for the Milky Way globular clusters and compare the theoretical predictions to the observations.

  20. Vertically Integrated Multiple Nanowire Field Effect Transistor.

    PubMed

    Lee, Byung-Hyun; Kang, Min-Ho; Ahn, Dae-Chul; Park, Jun-Young; Bang, Tewook; Jeon, Seung-Bae; Hur, Jae; Lee, Dongil; Choi, Yang-Kyu

    2015-12-09

    A vertically integrated multiple channel-based field-effect transistor (FET) with the highest number of nanowires reported ever is demonstrated on a bulk silicon substrate without use of wet etching. The driving current is increased by 5-fold due to the inherent vertically stacked five-level nanowires, thus showing good feasibility of three-dimensional integration-based high performance transistor. The developed fabrication process, which is simple and reproducible, is used to create multiple stiction-free and uniformly sized nanowires with the aid of the one-route all-dry etching process (ORADEP). Furthermore, the proposed FET is revamped to create nonvolatile memory with the adoption of a charge trapping layer for enhanced practicality. Thus, this research suggests an ultimate design for the end-of-the-roadmap devices to overcome the limits of scaling.

  1. Integrative genomics identifies distinct molecular classes of neuroblastoma and shows that multiple genes are targeted by regional alterations in DNA copy number.

    PubMed

    Wang, Qun; Diskin, Sharon; Rappaport, Eric; Attiyeh, Edward; Mosse, Yael; Shue, Daniel; Seiser, Eric; Jagannathan, Jayanti; Shusterman, Suzanne; Bansal, Manisha; Khazi, Deepa; Winter, Cynthia; Okawa, Erin; Grant, Gregory; Cnaan, Avital; Zhao, Huaqing; Cheung, Nai-Kong; Gerald, William; London, Wendy; Matthay, Katherine K; Brodeur, Garrett M; Maris, John M

    2006-06-15

    Neuroblastoma is remarkable for its clinical heterogeneity and is characterized by genomic alterations that are strongly correlated with tumor behavior. The specific genes that influence neuroblastoma biology and are targeted by genomic alterations remain largely unknown. We quantified mRNA expression in a highly annotated series of 101 prospectively collected diagnostic neuroblastoma primary tumors using an oligonucleotide-based microarray. Genomic copy number status at the prognostically relevant loci 1p36, 2p24 (MYCN), 11q23, and 17q23 was determined by PCR and was aberrant in 26, 20, 40, and 38 cases, respectively. In addition, 72 diagnostic neuroblastoma primary tumors assayed in a different laboratory were used as an independent validation set. Unsupervised hierarchical clustering showed that gene expression was highly correlated with genomic alterations and clinical markers of tumor behavior. The vast majority of samples with MYCN amplification and 1p36 loss of heterozygosity (LOH) clustered together on a terminal node of the sample dendrogram, whereas the majority of samples with 11q deletion clustered separately and both of these were largely distinct from the copy number neutral group of tumors. Genes involved in neurodevelopment were broadly overrepresented in the more benign tumors, whereas genes involved in RNA processing and cellular proliferation were highly represented in the most malignant cases. By combining transcriptomic and genomic data, we showed that LOH at 1p and 11q was associated with significantly decreased expression of 122 (61%) and 88 (27%) of the genes mapping to 1p35-36 and all of 11q, respectively, suggesting that multiple genes may be targeted by LOH events. A total of 71 of the 1p35-36 genes were also differentially expressed in the independent validation data set, providing a prioritized list of candidate neuroblastoma suppressor genes. Taken together, these data are consistent with the hypotheses that the neuroblastoma

  2. Molecularly Targeted Therapies in Multiple Myeloma

    PubMed Central

    Azab, Feda

    2014-01-01

    Multiple myeloma (MM) is a hematological malignancy that remains incurable because most patients will eventually relapse or become refractory to the treatments. Although the treatments have improved, the major problem in MM is the resistance to therapy. Novel agents are currently in development for the treatment of relapsed/refractory MM, including immunomodulatory drugs, proteasome inhibitors, monoclonal antibodies, cell signaling targeted therapies, and strategies targeting the tumor microenvironment. We have previously reviewed in detail the contemporary immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies therapies for MM. Therefore, in this review, we focused on the role of molecular targeted therapies in the treatment of relapsed/refractory multiple myeloma, including cell signaling targeted therapies (HDAC, PI3K/AKT/mTOR, p38 MAPK, Hsp90, Wnt, Notch, Hedgehog, and cell cycle) and strategies targeting the tumor microenvironment (hypoxia, angiogenesis, integrins, CD44, CXCR4, and selectins). Although these novel agents have improved the therapeutic outcomes for MM patients, further development of new therapeutic agents is warranted. PMID:24829804

  3. Molecularly targeted therapies in multiple myeloma.

    PubMed

    de la Puente, Pilar; Muz, Barbara; Azab, Feda; Luderer, Micah; Azab, Abdel Kareem

    2014-01-01

    Multiple myeloma (MM) is a hematological malignancy that remains incurable because most patients will eventually relapse or become refractory to the treatments. Although the treatments have improved, the major problem in MM is the resistance to therapy. Novel agents are currently in development for the treatment of relapsed/refractory MM, including immunomodulatory drugs, proteasome inhibitors, monoclonal antibodies, cell signaling targeted therapies, and strategies targeting the tumor microenvironment. We have previously reviewed in detail the contemporary immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies therapies for MM. Therefore, in this review, we focused on the role of molecular targeted therapies in the treatment of relapsed/refractory multiple myeloma, including cell signaling targeted therapies (HDAC, PI3K/AKT/mTOR, p38 MAPK, Hsp90, Wnt, Notch, Hedgehog, and cell cycle) and strategies targeting the tumor microenvironment (hypoxia, angiogenesis, integrins, CD44, CXCR4, and selectins). Although these novel agents have improved the therapeutic outcomes for MM patients, further development of new therapeutic agents is warranted.

  4. Optical multiple sample vacuum integrating sphere

    NASA Technical Reports Server (NTRS)

    Butner, C. L. (Inventor)

    1986-01-01

    An integrating sphere comprised of a uniform difusely reflecting spherical cavity, having mutually transverse input and output ports, and a linear sample transport mechanism is described. The sample transport mechanism is secured so that the multiple samples can be brought into registration with the input port, one at a time, without having to open or disassemble the apparatus when a change of sample is desired. A vacuum tight seal is provided between the cavity and the transport mechanism. This maintains the integrity of a vacuum generated with the sphere when attached to the source of optical energy. The device is utilized to test emissive characteristics such as the relative fluorescence quantum efficiency of a dye sample placed in the path of a monochromatic optical energy source coupled to the input port while having a light detector coupled to the output port.

  5. Functional integral approach for multiplicative stochastic processes.

    PubMed

    Arenas, Zochil González; Barci, Daniel G

    2010-05-01

    We present a functional formalism to derive a generating functional for correlation functions of a multiplicative stochastic process represented by a Langevin equation. We deduce a path integral over a set of fermionic and bosonic variables without performing any time discretization. The usual prescriptions to define the Wiener integral appear in our formalism in the definition of Green's functions in the Grassman sector of the theory. We also study nonperturbative constraints imposed by Becchi, Rouet and Stora symmetry (BRS) and supersymmetry on correlation functions. We show that the specific prescription to define the stochastic process is wholly contained in tadpole diagrams. Therefore, in a supersymmetric theory, the stochastic process is uniquely defined since tadpole contributions cancels at all order of perturbation theory.

  6. 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.

  7. Integrating molecular biology into the veterinary curriculum.

    PubMed

    Ryan, Marion T; Sweeney, Torres

    2007-01-01

    The modern discipline of molecular biology is gaining increasing relevance in the field of veterinary medicine. This trend must be reflected in the curriculum if veterinarians are to capitalize on opportunities arising from this field and direct its development toward their own goals as a profession. This review outlines current applications of molecular-based technologies that are relevant to the veterinary profession. In addition, the current techniques and technologies employed within the field of molecular biology are discussed. Difficulties associated with teaching a subject such as molecular biology within a veterinary curriculum can be alleviated by effectively integrating molecular topics throughout the curriculum, pitching the subject at an appropriate depth, and employing varied teaching methods throughout.

  8. 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

  9. Molecular Slater Integrals for Electronic Energy Calculations

    DTIC Science & Technology

    2010-10-15

    Facultad de Ciencias . Departamento de Quı́mica Fı́sica Aplicada. C-XIV. Abstract The algorithms for computing molecular integrals with Slater functions...and propulsion sciences research programs. This extension requires a thorough revision on the performance of the algorithms currently available and

  10. Quantitative molecular thermochemistry based on path integrals.

    PubMed

    Glaesemann, Kurt R; Fried, Laurence E

    2005-07-15

    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 for going beyond the harmonic analysis and to calculate the vibrational and rotational contributions to ab initio energies. This is an application and an extension of a method previously developed in our group [J. Chem. Phys. 118, 1596 (2003)].

  11. 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.

  12. Bead-Fourier path integral molecular dynamics.

    PubMed

    Ivanov, Sergei D; Lyubartsev, Alexander P; Laaksonen, Aatto

    2003-06-01

    Molecular dynamics formulation of Bead-Fourier path integral method for simulation of quantum systems at finite temperatures is presented. Within this scheme, both the bead coordinates and Fourier coefficients, defining the path representing the quantum particle, are treated as generalized coordinates with corresponding generalized momenta and masses. Introduction of the Fourier harmonics together with the center-of-mass thermostating scheme is shown to remove the ergodicity problem, known to pose serious difficulties in standard path integral molecular dynamics simulations. The method is tested for quantum harmonic oscillator and hydrogen atom (Coulombic potential). The simulation results are compared with the exact analytical solutions available for both these systems. Convergence of the results with respect to the number of beads and Fourier harmonics is analyzed. It was shown that addition of a few Fourier harmonics already improves the simulation results substantially, even for a relatively small number of beads. The proposed Bead-Fourier path integral molecular dynamics is a reliable and efficient alternative to simulations of quantum systems.

  13. Bead-Fourier path integral molecular dynamics

    NASA Astrophysics Data System (ADS)

    Ivanov, Sergei D.; Lyubartsev, Alexander P.; Laaksonen, Aatto

    2003-06-01

    Molecular dynamics formulation of Bead-Fourier path integral method for simulation of quantum systems at finite temperatures is presented. Within this scheme, both the bead coordinates and Fourier coefficients, defining the path representing the quantum particle, are treated as generalized coordinates with corresponding generalized momenta and masses. Introduction of the Fourier harmonics together with the center-of-mass thermostating scheme is shown to remove the ergodicity problem, known to pose serious difficulties in standard path integral molecular dynamics simulations. The method is tested for quantum harmonic oscillator and hydrogen atom (Coulombic potential). The simulation results are compared with the exact analytical solutions available for both these systems. Convergence of the results with respect to the number of beads and Fourier harmonics is analyzed. It was shown that addition of a few Fourier harmonics already improves the simulation results substantially, even for a relatively small number of beads. The proposed Bead-Fourier path integral molecular dynamics is a reliable and efficient alternative to simulations of quantum systems.

  14. 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.

  15. An integrative characterization of recurrent molecular aberrations in glioblastoma genomes.

    PubMed

    Sintupisut, Nardnisa; Liu, Pei-Ling; Yeang, Chen-Hsiang

    2013-10-01

    Glioblastoma multiforme (GBM) is the most common and malignant primary brain tumor in adults. Decades of investigations and the recent effort of the Cancer Genome Atlas (TCGA) project have mapped many molecular alterations in GBM cells. Alterations on DNAs may dysregulate gene expressions and drive malignancy of tumors. It is thus important to uncover causal and statistical dependency between 'effector' molecular aberrations and 'target' gene expressions in GBMs. A rich collection of prior studies attempted to combine copy number variation (CNV) and mRNA expression data. However, systematic methods to integrate multiple types of cancer genomic data-gene mutations, single nucleotide polymorphisms, CNVs, DNA methylations, mRNA and microRNA expressions and clinical information-are relatively scarce. We proposed an algorithm to build 'association modules' linking effector molecular aberrations and target gene expressions and applied the module-finding algorithm to the integrated TCGA GBM data sets. The inferred association modules were validated by six tests using external information and datasets of central nervous system tumors: (i) indication of prognostic effects among patients; (ii) coherence of target gene expressions; (iii) retention of effector-target associations in external data sets; (iv) recurrence of effector molecular aberrations in GBM; (v) functional enrichment of target genes; and (vi) co-citations between effectors and targets. Modules associated with well-known molecular aberrations of GBM-such as chromosome 7 amplifications, chromosome 10 deletions, EGFR and NF1 mutations-passed the majority of the validation tests. Furthermore, several modules associated with less well-reported molecular aberrations-such as chromosome 11 CNVs, CD40, PLXNB1 and GSTM1 methylations, and mir-21 expressions-were also validated by external information. In particular, modules constituting trans-acting effects with chromosome 11 CNVs and cis-acting effects with chromosome

  16. Integrating evolutionary and molecular genetics of aging.

    PubMed

    Flatt, Thomas; Schmidt, Paul S

    2009-10-01

    Aging or senescence is an age-dependent decline in physiological function, demographically manifest as decreased survival and fecundity with increasing age. Since aging is disadvantageous it should not evolve by natural selection. So why do organisms age and die? In the 1940s and 1950s evolutionary geneticists resolved this paradox by positing that aging evolves because selection is inefficient at maintaining function late in life. By the 1980s and 1990s this evolutionary theory of aging had received firm empirical support, but little was known about the mechanisms of aging. Around the same time biologists began to apply the tools of molecular genetics to aging and successfully identified mutations that affect longevity. Today, the molecular genetics of aging is a burgeoning field, but progress in evolutionary genetics of aging has largely stalled. Here we argue that some of the most exciting and unresolved questions about aging require an integration of molecular and evolutionary approaches. Is aging a universal process? Why do species age at different rates? Are the mechanisms of aging conserved or lineage-specific? Are longevity genes identified in the laboratory under selection in natural populations? What is the genetic basis of plasticity in aging in response to environmental cues and is this plasticity adaptive? What are the mechanisms underlying trade-offs between early fitness traits and life span? To answer these questions evolutionary biologists must adopt the tools of molecular biology, while molecular biologists must put their experiments into an evolutionary framework. The time is ripe for a synthesis of molecular biogerontology and the evolutionary biology of aging.

  17. 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…

  18. Integrating Advanced Molecular Technologies into Public Health.

    PubMed

    Gwinn, Marta; MacCannell, Duncan R; Khabbaz, Rima F

    2017-03-01

    Advances in laboratory and information technologies are transforming public health microbiology. High-throughput genome sequencing and bioinformatics are enhancing our ability to investigate and control outbreaks, detect emerging infectious diseases, develop vaccines, and combat antimicrobial resistance, all with increased accuracy, timeliness, and efficiency. The Advanced Molecular Detection (AMD) initiative has allowed the Centers for Disease Control and Prevention (CDC) to provide leadership and coordination in integrating new technologies into routine practice throughout the U.S. public health laboratory system. Collaboration and partnerships are the key to navigating this transition and to leveraging the next generation of methods and tools most effectively for public health.

  19. Geometric integrators for multiple time-scale simulation

    NASA Astrophysics Data System (ADS)

    Jia, Zhidong; Leimkuhler, Ben

    2006-05-01

    In this paper, we review and extend recent research on averaging integrators for multiple time-scale simulation such as are needed for physical N-body problems including molecular dynamics, materials modelling and celestial mechanics. A number of methods have been proposed for direct numerical integration of multiscale problems with special structure, such as the mollified impulse method (Garcia-Archilla, Sanz-Serna and Skeel 1999 SIAM J. Sci. Comput. 20 930-63) and the reversible averaging method (Leimkuhler and Reich 2001 J. Comput. Phys. 171 95-114). Features of problems of interest, such as thermostatted coarse-grained molecular dynamics, require extension of the standard framework. At the same time, in some applications the computation of averages plays a crucial role, but the available methods have deficiencies in this regard. We demonstrate that a new approach based on the introduction of shadow variables, which mirror physical variables, has promised for broadening the usefulness of multiscale methods and enhancing accuracy of or simplifying computation of averages. The shadow variables must be computed from an auxiliary equation. While a geometric integrator in the extended space is possible, in practice we observe enhanced long-term energy behaviour only through use of a variant of the method which controls drift of the shadow variables using dissipation and sacrifices the formal geometric properties such as time-reversibility and volume preservation in the enlarged phase space, stabilizing the corresponding properties in the physical variables. The method is applied to a gravitational three-body problem as well as a partially thermostatted model problem for a dilute gas of diatomic molecules.

  20. 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.

  1. Integration of molecular network data reconstructs Gene Ontology

    PubMed Central

    Gligorijević, Vladimir; Janjić, Vuk; Pržulj, Nataša

    2014-01-01

    Motivation: Recently, a shift was made from using Gene Ontology (GO) to evaluate molecular network data to using these data to construct and evaluate GO. Dutkowski et al. provide the first evidence that a large part of GO can be reconstructed solely from topologies of molecular networks. Motivated by this work, we develop a novel data integration framework that integrates multiple types of molecular network data to reconstruct and update GO. We ask how much of GO can be recovered by integrating various molecular interaction data. Results: We introduce a computational framework for integration of various biological networks using penalized non-negative matrix tri-factorization (PNMTF). It takes all network data in a matrix form and performs simultaneous clustering of genes and GO terms, inducing new relations between genes and GO terms (annotations) and between GO terms themselves. To improve the accuracy of our predicted relations, we extend the integration methodology to include additional topological information represented as the similarity in wiring around non-interacting genes. Surprisingly, by integrating topologies of bakers’ yeasts protein–protein interaction, genetic interaction (GI) and co-expression networks, our method reports as related 96% of GO terms that are directly related in GO. The inclusion of the wiring similarity of non-interacting genes contributes 6% to this large GO term association capture. Furthermore, we use our method to infer new relationships between GO terms solely from the topologies of these networks and validate 44% of our predictions in the literature. In addition, our integration method reproduces 48% of cellular component, 41% of molecular function and 41% of biological process GO terms, outperforming the previous method in the former two domains of GO. Finally, we predict new GO annotations of yeast genes and validate our predictions through GIs profiling. Availability and implementation: Supplementary Tables of new GO

  2. Integration of molecular network data reconstructs Gene Ontology.

    PubMed

    Gligorijević, Vladimir; Janjić, Vuk; Pržulj, Nataša

    2014-09-01

    Recently, a shift was made from using Gene Ontology (GO) to evaluate molecular network data to using these data to construct and evaluate GO. Dutkowski et al. provide the first evidence that a large part of GO can be reconstructed solely from topologies of molecular networks. Motivated by this work, we develop a novel data integration framework that integrates multiple types of molecular network data to reconstruct and update GO. We ask how much of GO can be recovered by integrating various molecular interaction data. We introduce a computational framework for integration of various biological networks using penalized non-negative matrix tri-factorization (PNMTF). It takes all network data in a matrix form and performs simultaneous clustering of genes and GO terms, inducing new relations between genes and GO terms (annotations) and between GO terms themselves. To improve the accuracy of our predicted relations, we extend the integration methodology to include additional topological information represented as the similarity in wiring around non-interacting genes. Surprisingly, by integrating topologies of bakers' yeasts protein-protein interaction, genetic interaction (GI) and co-expression networks, our method reports as related 96% of GO terms that are directly related in GO. The inclusion of the wiring similarity of non-interacting genes contributes 6% to this large GO term association capture. Furthermore, we use our method to infer new relationships between GO terms solely from the topologies of these networks and validate 44% of our predictions in the literature. In addition, our integration method reproduces 48% of cellular component, 41% of molecular function and 41% of biological process GO terms, outperforming the previous method in the former two domains of GO. Finally, we predict new GO annotations of yeast genes and validate our predictions through GIs profiling. Supplementary Tables of new GO term associations and predicted gene annotations are

  3. 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.

  4. Microelectromechanical systems integrating molecular spin crossover actuators

    SciTech Connect

    Manrique-Juarez, Maria D.; Rat, Sylvain; Salmon, Lionel; Molnár, Gábor; Bousseksou, Azzedine E-mail: azzedine.bousseksou@lcc-toulouse.fr; Mathieu, Fabrice; Saya, Daisuke; Séguy, Isabelle; Leïchlé, Thierry; Nicu, Liviu E-mail: azzedine.bousseksou@lcc-toulouse.fr

    2016-08-08

    Silicon MEMS cantilevers coated with a 200 nm thin layer of the molecular spin crossover complex [Fe(H{sub 2}B(pz){sub 2}){sub 2}(phen)] (H{sub 2}B(pz){sub 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 (Δf{sub r} = −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.

  5. Using Multiple Ontologies to Integrate Complex Biological Data

    PubMed Central

    Petri, Victoria; Pasko, Dean; Bromberg, Susan; Wu, Wenhua; Chen, Jiali; Nenasheva, Nataliya; Kwitek, Anne; Twigger, Simon; Jacob, Howard

    2005-01-01

    The strength of the rat as a model organism lies in its utility in pharmacology, biochemistry and physiology research. Data resulting from such studies is difficult to represent in databases and the creation of user-friendly data mining tools has proved difficult. The Rat Genome Database has developed a comprehensive ontology-based data structure and annotation system to integrate physiological data along with environmental and experimental factors, as well as genetic and genomic information. RGD uses multiple ontologies to integrate complex biological information from the molecular level to the whole organism, and to develop data mining and presentation tools. This approach allows RGD to indicate not only the phenotypes seen in a strain but also the specific values under each diet and atmospheric condition, as well as gender differences. Harnessing the power of ontologies in this way allows the user to gather and filter data in a customized fashion, so that a researcher can retrieve all phenotype readings for which a high hypoxia is a factor. Utilizing the same data structure for expression data, pathways and biological processes, RGD will provide a comprehensive research platform which allows users to investigate the conditions under which biological processes are altered and to elucidate the mechanisms of disease. PMID:18629202

  6. 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…

  7. 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. Copyright © 2015 Elsevier B.V. All rights reserved.

  8. 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.

  9. 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…

  10. Multiple crossbar network: Integrated supercomputing framework

    SciTech Connect

    Hoebelheinrich, R. )

    1989-01-01

    At Los Alamos National Laboratory, site of one of the world's most powerful scientific supercomputing facilities, a prototype network for an environment that links supercomputers and workstations is being developed. Driven by a need to provide graphics data at movie rates across a network from a Cray supercomputer to a Sun scientific workstation, the network is called the Multiple Crossbar Network (MCN). It is intended to be coarsely grained, loosely coupled, general-purpose interconnection network that will vastly increase the speed at which supercomputers communicate with each other in large networks. The components of the network are described, as well as work done in collaboration with vendors who are interested in providing commercial products. 9 refs.

  11. 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.

  12. 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.

  13. jAMVLE, a New Integrated Molecular Visualization Learning Environment

    ERIC Educational Resources Information Center

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

    2006-01-01

    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…

  14. Shared mental models of integrated care: aligning multiple stakeholder perspectives.

    PubMed

    Evans, Jenna M; Baker, G Ross

    2012-01-01

    Health service organizations and professionals are under increasing pressure to work together to deliver integrated patient care. A common understanding of integration strategies may facilitate the delivery of integrated care across inter-organizational and inter-professional boundaries. This paper aims to build a framework for exploring and potentially aligning multiple stakeholder perspectives of systems integration. The authors draw from the literature on shared mental models, strategic management and change, framing, stakeholder management, and systems theory to develop a new construct, Mental Models of Integrated Care (MMIC), which consists of three types of mental models, i.e. integration-task, system-role, and integration-belief. The MMIC construct encompasses many of the known barriers and enablers to integrating care while also providing a comprehensive, theory-based framework of psychological factors that may influence inter-organizational and inter-professional relations. While the existing literature on integration focuses on optimizing structures and processes, the MMIC construct emphasizes the convergence and divergence of stakeholders' knowledge and beliefs, and how these underlying cognitions influence interactions (or lack thereof) across the continuum of care. MMIC may help to: explain what differentiates effective from ineffective integration initiatives; determine system readiness to integrate; diagnose integration problems; and develop interventions for enhancing integrative processes and ultimately the delivery of integrated care. Global interest and ongoing challenges in integrating care underline the need for research on the mental models that characterize the behaviors of actors within health systems; the proposed framework offers a starting point for applying a cognitive perspective to health systems integration.

  15. 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.

  16. 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.

  17. So Each May Learn: Integrating Learning Styles and Multiple Intelligences.

    ERIC Educational Resources Information Center

    Silver, Harvey F.; Strong, Richard W.; Perini, Matthew J.

    This book shows educators at all grade levels and in all content areas how to implement a holistic learning program that seamlessly integrates learning styles and multiple intelligences into instruction, curriculum, and assessment. It is designed to assist teachers in helping students become more reflective, self-aware learners. The book includes:…

  18. 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.

  19. Content Integration across Multiple Documents Reduces Memory for Sources

    ERIC Educational Resources Information Center

    Braasch, Jason L. G.; McCabe, Rebecca M.; Daniel, Frances

    2016-01-01

    The current experiments systematically examined semantic content integration as a mechanism for explaining source inattention and forgetting when reading-to-remember multiple texts. For all 3 experiments, degree of semantic overlap was manipulated amongst messages provided by various information sources. In Experiment 1, readers' source…

  20. Content Integration across Multiple Documents Reduces Memory for Sources

    ERIC Educational Resources Information Center

    Braasch, Jason L. G.; McCabe, Rebecca M.; Daniel, Frances

    2016-01-01

    The current experiments systematically examined semantic content integration as a mechanism for explaining source inattention and forgetting when reading-to-remember multiple texts. For all 3 experiments, degree of semantic overlap was manipulated amongst messages provided by various information sources. In Experiment 1, readers' source…

  1. 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.…

  2. Non-linear molecular pattern classification using molecular beacons with multiple targets.

    PubMed

    Lee, In-Hee; Lee, Seung Hwan; Park, Tai Hyun; Zhang, Byoung-Tak

    2013-12-01

    In vitro pattern classification has been highlighted as an important future application of DNA computing. Previous work has demonstrated the feasibility of linear classifiers using DNA-based molecular computing. However, complex tasks require non-linear classification capability. Here we design a molecular beacon that can interact with multiple targets and experimentally shows that its fluorescent signals form a complex radial-basis function, enabling it to be used as a building block for non-linear molecular classification in vitro. The proposed method was successfully applied to solving artificial and real-world classification problems: XOR and microRNA expression patterns. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  3. Molecular mechanisms of retroviral integration site selection

    PubMed Central

    Kvaratskhelia, Mamuka; Sharma, Amit; Larue, Ross C.; Serrao, Erik; Engelman, Alan

    2014-01-01

    Retroviral replication proceeds through an obligate integrated DNA provirus, making retroviral vectors attractive vehicles for human gene-therapy. Though most of the host cell genome is available for integration, the process of integration site selection is not random. Retroviruses differ in their choice of chromatin-associated features and also prefer particular nucleotide sequences at the point of insertion. Lentiviruses including HIV-1 preferentially integrate within the bodies of active genes, whereas the prototypical gammaretrovirus Moloney murine leukemia virus (MoMLV) favors strong enhancers and active gene promoter regions. Integration is catalyzed by the viral integrase protein, and recent research has demonstrated that HIV-1 and MoMLV targeting preferences are in large part guided by integrase-interacting host factors (LEDGF/p75 for HIV-1 and BET proteins for MoMLV) that tether viral intasomes to chromatin. In each case, the selectivity of epigenetic marks on histones recognized by the protein tether helps to determine the integration distribution. In contrast, nucleotide preferences at integration sites seem to be governed by the ability for the integrase protein to locally bend the DNA duplex for pairwise insertion of the viral DNA ends. We discuss approaches to alter integration site selection that could potentially improve the safety of retroviral vectors in the clinic. PMID:25147212

  4. 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.

  5. Efficient molecular dynamics simulations of multiple radical center systems based on the fragment molecular orbital method.

    PubMed

    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.

  6. Hypodiploid multiple myeloma is characterized by more aggressive molecular markers than non-hyperdiploid multiple myeloma

    PubMed Central

    Van Wier, Scott; Braggio, Esteban; Baker, Angela; Ahmann, Gregory; Levy, Joan; Carpten, John D.; Fonseca, Rafael

    2013-01-01

    Multiple myeloma can be categorized into hyperdiploid or non-hyperdiploid myeloma based on the number of chromosomes found in the tumor clone. Among the non-hyperdiploid myelomas, the hypodiploid subtype has the most aggressive clinical phenotype, but the genetic differences between groups are not completely defined. In order to understand the genetic background of hypodiploid multiple myeloma better, we compared the genomic (array-based comparative genomic hybridization) and transcriptomic (gene expression profiling) background of 49 patients with hypodiploid myeloma with 50 other non-hyperdiploid and 125 hyperdiploid myeloma patients. There were significant chromosomal and gene expression differences between hyperdiploid patients and non-hyperdiploid and hypodiploid patients. Non-hyperdiploid and hypodiploid patients shared most of the chromosomal abnormalities; nevertheless a subset of these abnormalities, such as monosomies 13, 14 and 22, was markedly increased in hypodiploid patients. Furthermore, deletions of 1p, 12p, 16q and 17p, all associated with poor outcome or progression in multiple myeloma, were significantly enriched in hypodiploid patients. Molecular risk-stratification indices reinforce the worse prognosis associated with hypodiploid multiple myeloma compared with non-hyperdiploid multiple myeloma. Gene expression profiling clustered hypodiploid and non-hyperdiploid subgroups closer than hyperdiploid myeloma but also highlighted the up-regulation of CCND2, WHSC1/MMSET and FGFR3 in the hypodiploid subtype. In summary, hypodiploid multiple myeloma is genetically similar to non-hyperdiploid multiple myeloma but characterized by a higher prevalence of genetic alterations associated with poor outcome and disease progression. It is provocative to hypothesize that hypodiploid multiple myeloma is an advanced stage of non-hyperdiploid multiple myeloma. PMID:23716545

  7. Medium scale integration of molecular logic gates in an automaton.

    PubMed

    Macdonald, Joanne; Li, Yang; Sutovic, Marko; Lederman, Harvey; Pendri, Kiran; Lu, Wanhong; Andrews, Benjamin L; Stefanovic, Darko; Stojanovic, Milan N

    2006-11-01

    The assembly of molecular automata that perform increasingly complex tasks, such as game playing, presents an unbiased test of molecular computation. We now report a second-generation deoxyribozyme-based automaton, MAYA-II, which plays a complete game of tic-tac-toe according to a perfect strategy. In silicon terminology, MAYA-II represents the first "medium-scale integrated molecular circuit", integrating 128 deoxyribozyme-based logic gates, 32 input DNA molecules, and 8 two-channel fluorescent outputs across 8 wells.

  8. HMC algorithm with multiple time scale integration and mass preconditioning

    NASA Astrophysics Data System (ADS)

    Urbach, C.; Jansen, K.; Shindler, A.; Wenger, U.

    2006-01-01

    We present a variant of the HMC algorithm with mass preconditioning (Hasenbusch acceleration) and multiple time scale integration. We have tested this variant for standard Wilson fermions at β=5.6 and at pion masses ranging from 380 to 680 MeV. We show that in this situation its performance is comparable to the recently proposed HMC variant with domain decomposition as preconditioner. We give an update of the "Berlin Wall" figure, comparing the performance of our variant of the HMC algorithm to other published performance data. Advantages of the HMC algorithm with mass preconditioning and multiple time scale integration are that it is straightforward to implement and can be used in combination with a wide variety of lattice Dirac operators.

  9. 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

  10. Symplectic integrator for molecular dynamics of a protein in water

    NASA Astrophysics Data System (ADS)

    Ishida, Hisashi; Nagai, Yoshinori; Kidera, Akinori

    1998-01-01

    The symplectic integrator is an algorithm for solving equations of motion, preserving the volume in phase space and ensuring a stable simulation. We carried out molecular dynamics simulations of liquid water and a protein in water using several variations of symplectic integrators. It was found that a fourth-order symplectic integrator of Calvo and Sanz-Serna generated a trajectory of much higher accuracy than the conventional Verlet and Gear methods with the same requirements for CPU time.

  11. 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

  12. Modeling stochastic kinetics of molecular machines at multiple levels: from molecules to modules.

    PubMed

    Chowdhury, Debashish

    2013-06-04

    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. Copyright © 2013 Biophysical Society. Published by Elsevier Inc. All rights reserved.

  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. 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 integrate 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.

  15. 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.

  16. 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.

  17. Multiple-time-scale motion in molecularly linked nanoparticle arrays.

    PubMed

    George, Christopher; Szleifer, Igal; Ratner, Mark

    2013-01-22

    We explore the transport of electrons between electrodes that encase a two-dimensional array of metallic quantum dots linked by molecular bridges (such as α,ω alkaline dithiols). Because the molecules can move at finite temperatures, the entire transport structure comprising the quantum dots and the molecules is in dynamical motion while the charge is being transported. There are then several physical processes (physical excursions of molecules and quantum dots, electronic migration, ordinary vibrations), all of which influence electronic transport. Each can occur on a different time scale. It is therefore not appropriate to use standard approaches to this sort of electron transfer problem. Instead, we present a treatment in which three different theoretical approaches-kinetic Monte Carlo, classical molecular dynamics, and quantum transport-are all employed. In certain limits, some of the dynamical effects are unimportant. But in general, the transport seems to follow a sort of dynamic bond percolation picture, an approach originally introduced as formal models and later applied to polymer electrolytes. Different rate-determining steps occur in different limits. This approach offers a powerful scheme for dealing with multiple time scale transport problems, as will exist in many situations with several pathways through molecular arrays or even individual molecules that are dynamically disordered.

  18. 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.

  19. Molecular Code Division Multiple Access: Gaussian Mixture Modeling

    NASA Astrophysics Data System (ADS)

    Zamiri-Jafarian, Yeganeh

    Communications between nano-devices is an emerging research field in nanotechnology. Molecular Communication (MC), which is a bio-inspired paradigm, is a promising technique for communication in nano-network. In MC, molecules are administered to exchange information among nano-devices. Due to the nature of molecular signals, traditional communication methods can't be directly applied to the MC framework. The objective of this thesis is to present novel diffusion-based MC methods when multi nano-devices communicate with each other in the same environment. A new channel model and detection technique, along with a molecular-based access method, are proposed in here for communication between asynchronous users. In this work, the received molecular signal is modeled as a Gaussian mixture distribution when the MC system undergoes Brownian noise and inter-symbol interference (ISI). This novel approach demonstrates a suitable modeling for diffusion-based MC system. Using the proposed Gaussian mixture model, a simple receiver is designed by minimizing the error probability. To determine an optimum detection threshold, an iterative algorithm is derived which minimizes a linear approximation of the error probability function. Also, a memory-based receiver is proposed to improve the performance of the MC system by considering previously detected symbols in obtaining the threshold value. Numerical evaluations reveal that theoretical analysis of the bit error rate (BER) performance based on the Gaussian mixture model match simulation results very closely. Furthermore, in this thesis, molecular code division multiple access (MCDMA) is proposed to overcome the inter-user interference (IUI) caused by asynchronous users communicating in a shared propagation environment. Based on the selected molecular codes, a chip detection scheme with an adaptable threshold value is developed for the MCDMA system when the proposed Gaussian mixture model is considered. Results indicate that the

  20. Hybrid CMOS/Molecular Integrated Circuits

    NASA Astrophysics Data System (ADS)

    Stan, M. R.; Rose, G. S.; Ziegler, M. M.

    CMOS silicon technologies are likely to run out of steam in the next 10-15 years despite revolutionary advances in the past few decades. Molecular and other nanoscale technologies show significant promise but it is unlikely that they will completely replace CMOS, at least in the near term. This chapter explores opportunities for using CMOS and nanotechnology to enhance and complement each other in hybrid circuits. As an example of such a hybrid CMOS/nano system, a nanoscale programmable logic array (PLA) based on majority logic is described along with its supplemental CMOS circuitry. It is believed that such systems will be able to sustain the historical advances in the semiconductor industry while addressing manufacturability, yield, power, cost, and performance challenges.

  1. Integrated Molecular Characterization of Uterine Carcinosarcoma.

    PubMed

    Cherniack, Andrew D; Shen, Hui; Walter, Vonn; Stewart, Chip; Murray, Bradley A; Bowlby, Reanne; Hu, Xin; Ling, Shiyun; Soslow, Robert A; Broaddus, Russell R; Zuna, Rosemary E; Robertson, Gordon; Laird, Peter W; Kucherlapati, Raju; Mills, Gordon B; Weinstein, John N; Zhang, Jiashan; Akbani, Rehan; Levine, Douglas A

    2017-03-13

    We performed genomic, epigenomic, transcriptomic, and proteomic characterizations of uterine carcinosarcomas (UCSs). Cohort samples had extensive copy-number alterations and highly recurrent somatic mutations. Frequent mutations were found in TP53, PTEN, PIK3CA, PPP2R1A, FBXW7, and KRAS, similar to endometrioid and serous uterine carcinomas. Transcriptome sequencing identified a strong epithelial-to-mesenchymal transition (EMT) gene signature in a subset of cases that was attributable to epigenetic alterations at microRNA promoters. The range of EMT scores in UCS was the largest among all tumor types studied via The Cancer Genome Atlas. UCSs shared proteomic features with gynecologic carcinomas and sarcomas with intermediate EMT features. Multiple somatic mutations and copy-number alterations in genes that are therapeutic targets were identified.

  2. SPARSE INTEGRATIVE CLUSTERING OF MULTIPLE OMICS DATA SETS

    PubMed Central

    Wang, Sijian; Mo, Qianxing

    2012-01-01

    High resolution microarrays and second-generation sequencing platforms are powerful tools to investigate genome-wide alterations in DNA copy number, methylation, and gene expression associated with a disease. An integrated genomic profiling approach measuring multiple omics data types simultaneously in the same set of biological samples would render an integrated data resolution that would not be available with any single data type. In this study, we use penalized latent variable regression methods for joint modeling of multiple omics data types to identify common latent variables that can be used to cluster patient samples into biologically and clinically relevant disease subtypes. We consider lasso (Tibshirani, 1996), elastic net (Zou and Hastie, 2005), and fused lasso (Tibshirani et al., 2005) methods to induce sparsity in the coefficient vectors, revealing important genomic features that have significant contributions to the latent variables. An iterative ridge regression is used to compute the sparse coefficient vectors. In model selection, a uniform design (Fang and Wang, 1994) is used to seek “experimental” points that scattered uniformly across the search domain for efficient sampling of tuning parameter combinations. We compared our method to sparse singular value decomposition (SVD) and penalized Gaussian mixture model (GMM) using both real and simulated data sets. The proposed method is applied to integrate genomic, epigenomic, and transcriptomic data for subtype analysis in breast and lung cancer data sets. PMID:24587839

  3. Can the meaning of multiple words be integrated unconsciously?

    PubMed Central

    van Gaal, Simon; Naccache, Lionel; Meuwese, Julia D. I.; van Loon, Anouk M.; Leighton, Alexandra H.; Cohen, Laurent; Dehaene, Stanislas

    2014-01-01

    What are the limits of unconscious language processing? Can language circuits process simple grammatical constructions unconsciously and integrate the meaning of several unseen words? Using behavioural priming and electroencephalography (EEG), we studied a specific rule-based linguistic operation traditionally thought to require conscious cognitive control: the negation of valence. In a masked priming paradigm, two masked words were successively (Experiment 1) or simultaneously presented (Experiment 2), a modifier (‘not’/‘very’) and an adjective (e.g. ‘good’/‘bad’), followed by a visible target noun (e.g. ‘peace’/‘murder’). Subjects indicated whether the target noun had a positive or negative valence. The combination of these three words could either be contextually consistent (e.g. ‘very bad - murder’) or inconsistent (e.g. ‘not bad - murder’). EEG recordings revealed that grammatical negations could unfold partly unconsciously, as reflected in similar occipito-parietal N400 effects for conscious and unconscious three-word sequences forming inconsistent combinations. However, only conscious word sequences elicited P600 effects, later in time. Overall, these results suggest that multiple unconscious words can be rapidly integrated and that an unconscious negation can automatically ‘flip the sign’ of an unconscious adjective. These findings not only extend the limits of subliminal combinatorial language processes, but also highlight how consciousness modulates the grammatical integration of multiple words. PMID:24639583

  4. 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

  5. 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

  6. Integrative Analysis of Prognosis Data on Multiple Cancer Subtypes

    PubMed Central

    Liu, Jin; Huang, Jian; Zhang, Yawei; Lan, Qing; Rothman, Nathaniel; Zheng, Tongzhang; Ma, Shuangge

    2014-01-01

    Summary In cancer research, profiling studies have been extensively conducted, searching for genes/SNPs associated with prognosis. Cancer is diverse. Examining the similarity and difference in the genetic basis of multiple subtypes of the same cancer can lead to a better understanding of their connections and distinctions. Classic meta-analysis methods analyze each subtype separately and then compare analysis results across subtypes. Integrative analysis methods, in contrast, analyze the raw data on multiple subtypes simultaneously and can outperform meta-analysis methods. In this study, prognosis data on multiple subtypes of the same cancer are analyzed. An AFT (accelerated failure time) model is adopted to describe survival. The genetic basis of multiple subtypes is described using the heterogeneity model, which allows a gene/SNP to be associated with prognosis of some subtypes but not others. A compound penalization method is developed to identify genes that contain important SNPs associated with prognosis. The proposed method has an intuitive formulation and is realized using an iterative algorithm. Asymptotic properties are rigorously established. Simulation shows that the proposed method has satisfactory performance and outperforms a penalization-based meta-analysis method and a regularized thresholding method. An NHL (non-Hodgkin lymphoma) prognosis study with SNP measurements is analyzed. Genes associated with the three major subtypes, namely DLBCL, FL, and CLL/SLL, are identified. The proposed method identifies genes that are different from alternatives and have important implications and satisfactory prediction performance. PMID:24766212

  7. Valproic acid, a molecular lead to multiple regulatory pathways.

    PubMed

    Kostrouchová, M; Kostrouch, Z; Kostrouchová, M

    2007-01-01

    Valproic acid (2-propyl pentanoic acid) is a drug used for the treatment of epilepsy and bipolar disorder. Although very rare, side effects such as spina bifida and other defects of neural tube closure indicate that valproic acid interferes with developmental regulatory pathways. Recently obtained data show that valproic acid affects cell growth, differentiation, apoptosis and immunogenicity of cultured cancer cells and tumours. Focused studies uncovered the potential of valproic acid to interfere with multiple regulatory mechanisms including histone deacetylases, GSK3 alpha and beta, Akt, the ERK pathway, the phosphoinositol pathway, the tricarboxylic acid cycle, GABA, and the OXPHOS system. Valproic acid is emerging as a potential anticancer drug and may also serve as a molecular lead that can help design drugs with more specific and more potent effects on the one side and drugs with wide additive but weaker effects on the other. Valproic acid is thus a powerful molecular tool for better understanding and therapeutic targeting of pathways that regulate the behaviour of cancer cells.

  8. Multistep tumorigenesis of multiple myeloma: its molecular delineation.

    PubMed

    Iida, Shinsuke; Ueda, Ryuzo

    2003-04-01

    Multiple myeloma (MM) is an incurable malignant neoplasm affecting terminally differentiated B-cells. It derives from post-germinal center B-cells and develops as a result of multistep tumorigenic events, because approximately one third of all MM cases have a history of preceding monoclonal gammopathy of undetermined significance (MGUS) or smoldering myeloma. MM terminates in the formation of extramedullary invasion or in secondary plasma cell leukemia. To account for this clinical experience, investigators have found that intrinsic chromosomal instability followed by complex chromosomal translocations/deletions plays a crucial role in the development from MGUS to MM. Representative aberrations include chromosomal rearrangements involving 14q32 loci and deletion at the long arm of chromosome 13. Contributing to the progression of MM itself are genomic instability and altered methylation of the specific gene promoters. The former results in activation of specific oncogenes such as RAS and FGFR3 or in inactivation of p53, and the latter results in inactivation of tumor suppressor genes, including p16. An accurate understanding of each of these molecular events should help clarify the development of specific molecular targeting therapies based on the differences in dysfunctional signaling pathways found in the cells of all MM patients.

  9. Dissociating conflict adaptation from feature integration: a multiple regression approach.

    PubMed

    Notebaert, Wim; Verguts, Tom

    2007-10-01

    Congruency effects are typically smaller after incongruent than after congruent trials. One explanation is in terms of higher levels of cognitive control after detection of conflict (conflict adaptation; e.g., M. M. Botvinick, T. S. Braver, D. M. Barch, C. S. Carter, & J. D. Cohen, 2001). An alternative explanation for these results is based on feature repetition and/or integration effects (e.g., B. Hommel, R. W. Proctor, & K.-P. Vu, 2004; U. Mayr, E. Awh, & P. Laurey, 2003). Previous attempts to dissociate feature integration from conflict adaptation focused on a particular subset of the data in which feature transitions were held constant (J. G. Kerns et al., 2004) or in which congruency transitions were held constant (C. Akcay & E. Hazeltine, in press), but this has a number of disadvantages. In this article, the authors present a multiple regression solution for this problem and discuss its possibilities and pitfalls.

  10. 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.

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

    PubMed

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

    2014-08-07

    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.

  12. 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.

  13. 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.

  14. Variational path integral molecular dynamics study of a water molecule

    NASA Astrophysics Data System (ADS)

    Miura, Shinichi

    2013-08-01

    In the present study, a variational path integral molecular dynamics method developed by the author [Chem. Phys. Lett. 482, 165 (2009)] is applied to a water molecule on the adiabatic potential energy surface. The method numerically generates an exact wavefunction using a trial wavefunction of the target system. It has been shown that even if a poor trial wavefunction is employed, the exact quantum distribution is numerically extracted, demonstrating the robustness of the variational path integral method.

  15. Quantum tunneling splittings from path-integral molecular dynamics

    NASA Astrophysics Data System (ADS)

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

    2016-03-01

    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.

  16. Evidence for Multiple Outbursts from the Cepheus A Molecular Outflow

    NASA Astrophysics Data System (ADS)

    Narayanan, Gopal; Walker, Christopher K.

    1996-08-01

    We report evidence for multiple episodes of outflow activity in the Cepheus A star-forming region. We present new, high signal-to-noise CSO observations of 12CO J = 3 2, 13CO J = 3 → 2, and CS J = 7 → 6 emission. We also present new, interferometric and single-dish observations of 12CO J = 1 → 0 emission toward the Cepheus A molecular outflow. Using line core velocity centroid maps, we argue that the multiple self-absorption features in the CO J = 3 → 2 line profiles are tracing cool shells of material swept-up by an episodic outflow. We present the results of a flexible three-dimensional LTE outflow model and radiative transfer code that best explain the observations as tracing multiple generations of outflow. The difference in the dynamical timescales between the "old" and "new" swept-up shells gives an estimate of ˜1.6 x 105 yr between the two generations of outbursts. The high-resolution 12CO J = 1 → 0 maps obtained by combining single-dish observations with interferometric data clearly show a shell-like morphology at low velocities. This cool shell appears to encompass the hot, extremely high velocity (EHV) winds seen in the J = 3 → 2 transition. The interferometric observations show that the current generation of outflow is being powered by the object Cepheus A-HW 2. There is also evidence for redirection of the blueshifted lobe of the current generation of outflow, possibly by the extended NH3 structure Cep A-3. We present a model of the outflow geometry that can explain most of the observed structures in Cepheus A. The rotating, dense core traced by the CS observations is ˜0.32 pc in diameter and has an estimated dynamical mass of 330 Msun. The velocity structure of the core suggests that it is being disrupted by the high-velocity winds driving the molecular outflow. This new technique of extracting information from self-absorbed line profiles could be used to study other deeply embedded protostellar systems. Since outflows are believed to be

  17. 77 FR 74027 - Certain Integrated Circuit Packages Provided with Multiple Heat-Conducting Paths and Products...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-12-12

    ... From the Federal Register Online via the Government Publishing Office INTERNATIONAL TRADE COMMISSION Certain Integrated Circuit Packages Provided with Multiple Heat- Conducting Paths and Products... integrated circuit packages provided with multiple heat-conducting paths and products containing same...

  18. On a New Simple Method for Evaluation of Certain Multiple Definite Integrals

    ERIC Educational Resources Information Center

    Sen Gupta, I.; Debnath, L.

    2006-01-01

    This paper deals with a simple method of evaluation of certain multiple definite integrals. This is followed by two main theorems concerning multiple definite integrals. Some examples of applications are given.

  19. On a New Simple Method for Evaluation of Certain Multiple Definite Integrals

    ERIC Educational Resources Information Center

    Sen Gupta, I.; Debnath, L.

    2006-01-01

    This paper deals with a simple method of evaluation of certain multiple definite integrals. This is followed by two main theorems concerning multiple definite integrals. Some examples of applications are given.

  20. Algorithms and novel applications based on the isokinetic ensemble. I. Biophysical and path integral molecular dynamics

    NASA Astrophysics Data System (ADS)

    Minary, Peter; Martyna, Glenn J.; Tuckerman, Mark E.

    2003-02-01

    In this paper (Paper I) and a companion paper (Paper II), novel new algorithms and applications of the isokinetic ensemble as generated by Gauss' principle of least constraint, pioneered for use with molecular dynamics 20 years ago, are presented for biophysical, path integral, and Car-Parrinello based ab initio molecular dynamics. In Paper I, a new "extended system" version of the isokinetic equations of motion that overcomes the ergodicity problems inherent in the standard approach, is developed using a new theory of non-Hamiltonian phase space analysis [M. E. Tuckerman et al., Europhys. Lett. 45, 149 (1999); J. Chem. Phys. 115, 1678 (2001)]. Reversible multiple time step integrations schemes for the isokinetic methods, first presented by Zhang [J. Chem. Phys. 106, 6102 (1997)] are reviewed. Next, holonomic constraints are incorporated into the isokinetic methodology for use in fast efficient biomolecular simulation studies. Model and realistic examples are presented in order to evaluate, critically, the performance of the new isokinetic molecular dynamic schemes. Comparisons are made to the, now standard, canonical dynamics method, Nosé-Hoover chain dynamics [G. J. Martyna et al., J. Chem. Phys. 97, 2635 (1992)]. The new isokinetic techniques are found to yield more efficient sampling than the Nosé-Hoover chain method in both path integral molecular dynamics and biophysical molecular dynamics calculations. In Paper II, the use of isokinetic methods in Car-Parrinello based ab initio molecular dynamics calculations is presented.

  1. Integrated presentation of ecological risk from multiple stressors

    NASA Astrophysics Data System (ADS)

    Goussen, Benoit; Price, Oliver R.; Rendal, Cecilie; Ashauer, Roman

    2016-10-01

    Current environmental risk assessments (ERA) do not account explicitly for ecological factors (e.g. species composition, temperature or food availability) and multiple stressors. Assessing mixtures of chemical and ecological stressors is needed as well as accounting for variability in environmental conditions and uncertainty of data and models. Here we propose a novel probabilistic ERA framework to overcome these limitations, which focusses on visualising assessment outcomes by construct-ing and interpreting prevalence plots as a quantitative prediction of risk. Key components include environmental scenarios that integrate exposure and ecology, and ecological modelling of relevant endpoints to assess the effect of a combination of stressors. Our illustrative results demonstrate the importance of regional differences in environmental conditions and the confounding interactions of stressors. Using this framework and prevalence plots provides a risk-based approach that combines risk assessment and risk management in a meaningful way and presents a truly mechanistic alternative to the threshold approach. Even whilst research continues to improve the underlying models and data, regulators and decision makers can already use the framework and prevalence plots. The integration of multiple stressors, environmental conditions and variability makes ERA more relevant and realistic.

  2. Integrated presentation of ecological risk from multiple stressors.

    PubMed

    Goussen, Benoit; Price, Oliver R; Rendal, Cecilie; Ashauer, Roman

    2016-10-26

    Current environmental risk assessments (ERA) do not account explicitly for ecological factors (e.g. species composition, temperature or food availability) and multiple stressors. Assessing mixtures of chemical and ecological stressors is needed as well as accounting for variability in environmental conditions and uncertainty of data and models. Here we propose a novel probabilistic ERA framework to overcome these limitations, which focusses on visualising assessment outcomes by construct-ing and interpreting prevalence plots as a quantitative prediction of risk. Key components include environmental scenarios that integrate exposure and ecology, and ecological modelling of relevant endpoints to assess the effect of a combination of stressors. Our illustrative results demonstrate the importance of regional differences in environmental conditions and the confounding interactions of stressors. Using this framework and prevalence plots provides a risk-based approach that combines risk assessment and risk management in a meaningful way and presents a truly mechanistic alternative to the threshold approach. Even whilst research continues to improve the underlying models and data, regulators and decision makers can already use the framework and prevalence plots. The integration of multiple stressors, environmental conditions and variability makes ERA more relevant and realistic.

  3. Integrated presentation of ecological risk from multiple stressors

    PubMed Central

    Goussen, Benoit; Price, Oliver R.; Rendal, Cecilie; Ashauer, Roman

    2016-01-01

    Current environmental risk assessments (ERA) do not account explicitly for ecological factors (e.g. species composition, temperature or food availability) and multiple stressors. Assessing mixtures of chemical and ecological stressors is needed as well as accounting for variability in environmental conditions and uncertainty of data and models. Here we propose a novel probabilistic ERA framework to overcome these limitations, which focusses on visualising assessment outcomes by construct-ing and interpreting prevalence plots as a quantitative prediction of risk. Key components include environmental scenarios that integrate exposure and ecology, and ecological modelling of relevant endpoints to assess the effect of a combination of stressors. Our illustrative results demonstrate the importance of regional differences in environmental conditions and the confounding interactions of stressors. Using this framework and prevalence plots provides a risk-based approach that combines risk assessment and risk management in a meaningful way and presents a truly mechanistic alternative to the threshold approach. Even whilst research continues to improve the underlying models and data, regulators and decision makers can already use the framework and prevalence plots. The integration of multiple stressors, environmental conditions and variability makes ERA more relevant and realistic. PMID:27782171

  4. Multiple biomarkers in molecular oncology. I. Molecular diagnostics applications in cervical cancer detection.

    PubMed

    Malinowski, Douglas P

    2007-03-01

    The screening for cervical carcinoma and its malignant precursors (cervical neoplasia) currently employs morphology-based detection methods (Papanicolaou [Pap] smear) in addition to the detection of high-risk human papillomavirus. The combination of the Pap smear with human papillomavirus testing has achieved significant improvements in sensitivity for the detection of cervical disease. Diagnosis of cervical neoplasia is dependent upon histology assessment of cervical biopsy specimens. Attempts to improve the specificity of cervical disease screening have focused on the investigation of molecular biomarkers for adjunctive use in combination with the Pap smear. Active research into the genomic and proteomic alterations that occur during human papillomavirus-induced neoplastic transformation have begun to characterize some of the basic mechanisms inherent to the disease process of cervical cancer development. This research continues to demonstrate the complexity of multiple genomic and proteomic alterations that accumulate during the tumorigenesis process. Despite this diversity, basic patterns of uncontrolled signal transduction, cell cycle deregulation, activation of DNA replication and altered extracellular matrix interactions are beginning to emerge as common features inherent to cervical cancer development. Some of these gene or protein expression alterations have been investigated as potential biomarkers for screening and diagnostics applications. The contribution of multiple gene alterations in the development of cervical cancer suggests that the application of multiple biomarker panels has the potential to develop clinically useful molecular diagnostics. In this review, the application of biomarkers for the improvement of sensitivity and specificity of the detection of cervical neoplasia within cytology specimens will be discussed.

  5. 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.

  6. Application of Molecular Typing Results in Source Attribution Models: The Case of Multiple Locus Variable Number Tandem Repeat Analysis (MLVA) of Salmonella Isolates Obtained from Integrated Surveillance in Denmark.

    PubMed

    de Knegt, Leonardo V; Pires, Sara M; Löfström, Charlotta; Sørensen, Gitte; Pedersen, Karl; Torpdahl, Mia; Nielsen, Eva M; Hald, Tine

    2016-03-01

    Salmonella is an important cause of bacterial foodborne infections in Denmark. To identify the main animal-food sources of human salmonellosis, risk managers have relied on a routine application of a microbial subtyping-based source attribution model since 1995. In 2013, multiple locus variable number tandem repeat analysis (MLVA) substituted phage typing as the subtyping method for surveillance of S. Enteritidis and S. Typhimurium isolated from animals, food, and humans in Denmark. The purpose of this study was to develop a modeling approach applying a combination of serovars, MLVA types, and antibiotic resistance profiles for the Salmonella source attribution, and assess the utility of the results for the food safety decisionmakers. Full and simplified MLVA schemes from surveillance data were tested, and model fit and consistency of results were assessed using statistical measures. We conclude that loci schemes STTR5/STTR10/STTR3 for S. Typhimurium and SE9/SE5/SE2/SE1/SE3 for S. Enteritidis can be used in microbial subtyping-based source attribution models. Based on the results, we discuss that an adjustment of the discriminatory level of the subtyping method applied often will be required to fit the purpose of the study and the available data. The issues discussed are also considered highly relevant when applying, e.g., extended multi-locus sequence typing or next-generation sequencing techniques.

  7. HBV DNA Integration: Molecular Mechanisms and Clinical Implications

    PubMed Central

    Tu, Thomas; Budzinska, Magdalena A.; Shackel, Nicholas A.; Urban, Stephan

    2017-01-01

    Chronic infection with the Hepatitis B Virus (HBV) is a major cause of liver-related morbidity and mortality. One peculiar observation in cells infected with HBV (or with closely‑related animal hepadnaviruses) is the presence of viral DNA integration in the host cell genome, despite this form being a replicative dead-end for the virus. The frequent finding of somatic integration of viral DNA suggests an evolutionary benefit for the virus; however, the mechanism of integration, its functions, and the clinical implications remain unknown. Here we review the current body of knowledge of HBV DNA integration, with particular focus on the molecular mechanisms and its clinical implications (including the possible consequences of replication-independent antigen expression and its possible role in hepatocellular carcinoma). HBV DNA integration is likely to influence HBV replication, persistence, and pathogenesis, and so deserves greater attention in future studies. PMID:28394272

  8. Nonlinear multiplicative dendritic integration in neuron and network models

    PubMed Central

    Zhang, Danke; Li, Yuanqing; Rasch, Malte J.; Wu, Si

    2013-01-01

    Neurons receive inputs from thousands of synapses distributed across dendritic trees of complex morphology. It is known that dendritic integration of excitatory and inhibitory synapses can be highly non-linear in reality and can heavily depend on the exact location and spatial arrangement of inhibitory and excitatory synapses on the dendrite. Despite this known fact, most neuron models used in artificial neural networks today still only describe the voltage potential of a single somatic compartment and assume a simple linear summation of all individual synaptic inputs. We here suggest a new biophysical motivated derivation of a single compartment model that integrates the non-linear effects of shunting inhibition, where an inhibitory input on the route of an excitatory input to the soma cancels or “shunts” the excitatory potential. In particular, our integration of non-linear dendritic processing into the neuron model follows a simple multiplicative rule, suggested recently by experiments, and allows for strict mathematical treatment of network effects. Using our new formulation, we further devised a spiking network model where inhibitory neurons act as global shunting gates, and show that the network exhibits persistent activity in a low firing regime. PMID:23658543

  9. Integrating molecular diagnostics into histopathology training: the Belfast model.

    PubMed

    Flynn, C; James, J; Maxwell, P; McQuaid, S; Ervine, A; Catherwood, M; Loughrey, M B; McGibben, D; Somerville, J; McManus, D T; Gray, M; Herron, B; Salto-Tellez, M

    2014-07-01

    Molecular medicine is transforming modern clinical practice, from diagnostics to therapeutics. Discoveries in research are being incorporated into the clinical setting with increasing rapidity. This transformation is also deeply changing the way we practise pathology. The great advances in cell and molecular biology which have accelerated our understanding of the pathogenesis of solid tumours have been embraced with variable degrees of enthusiasm by diverse medical professional specialties. While histopathologists have not been prompt to adopt molecular diagnostics to date, the need to incorporate molecular pathology into the training of future histopathologists is imperative. Our goal is to create, within an existing 5-year histopathology training curriculum, the structure for formal substantial teaching of molecular diagnostics. This specialist training has two main goals: (1) to equip future practising histopathologists with basic knowledge of molecular diagnostics and (2) to create the option for those interested in a subspecialty experience in tissue molecular diagnostics to pursue this training. It is our belief that this training will help to maintain in future the role of the pathologist at the centre of patient care as the integrator of clinical, morphological and molecular information. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  10. Molecular Surveillance Identifies Multiple Transmissions of Typhoid in West Africa

    PubMed Central

    Wong, Vanessa K.; Holt, Kathryn E.; Okoro, Chinyere; Baker, Stephen; Pickard, Derek J.; Marks, Florian; Page, Andrew J.; Olanipekun, Grace; Munir, Huda; Alter, Roxanne; Fey, Paul D.; Feasey, Nicholas A.; Weill, Francois-Xavier; Le Hello, Simon; Hart, Peter J.; Kariuki, Samuel; Breiman, Robert F.; Gordon, Melita A.; Heyderman, Robert S.; Jacobs, Jan; Lunguya, Octavie; Msefula, Chisomo; MacLennan, Calman A.; Keddy, Karen H.; Smith, Anthony M.; Onsare, Robert S.; De Pinna, Elizabeth; Nair, Satheesh; Amos, Ben; Dougan, Gordon; Obaro, Stephen

    2016-01-01

    Background The burden of typhoid in sub-Saharan African (SSA) countries has been difficult to estimate, in part, due to suboptimal laboratory diagnostics. However, surveillance blood cultures at two sites in Nigeria have identified typhoid associated with Salmonella enterica serovar Typhi (S. Typhi) as an important cause of bacteremia in children. Methods A total of 128 S. Typhi isolates from these studies in Nigeria were whole-genome sequenced, and the resulting data was used to place these Nigerian isolates into a worldwide context based on their phylogeny and carriage of molecular determinants of antibiotic resistance. Results Several distinct S. Typhi genotypes were identified in Nigeria that were related to other clusters of S. Typhi isolates from north, west and central regions of Africa. The rapidly expanding S. Typhi clade 4.3.1 (H58) previously associated with multiple antimicrobial resistances in Asia and in east, central and southern Africa, was not detected in this study. However, antimicrobial resistance was common amongst the Nigerian isolates and was associated with several plasmids, including the IncHI1 plasmid commonly associated with S. Typhi. Conclusions These data indicate that typhoid in Nigeria was established through multiple independent introductions into the country, with evidence of regional spread. MDR typhoid appears to be evolving independently of the haplotype H58 found in other typhoid endemic countries. This study highlights an urgent need for routine surveillance to monitor the epidemiology of typhoid and evolution of antimicrobial resistance within the bacterial population as a means to facilitate public health interventions to reduce the substantial morbidity and mortality of typhoid. PMID:27657909

  11. Molecular Surveillance Identifies Multiple Transmissions of Typhoid in West Africa.

    PubMed

    Wong, Vanessa K; Holt, Kathryn E; Okoro, Chinyere; Baker, Stephen; Pickard, Derek J; Marks, Florian; Page, Andrew J; Olanipekun, Grace; Munir, Huda; Alter, Roxanne; Fey, Paul D; Feasey, Nicholas A; Weill, Francois-Xavier; Le Hello, Simon; Hart, Peter J; Kariuki, Samuel; Breiman, Robert F; Gordon, Melita A; Heyderman, Robert S; Jacobs, Jan; Lunguya, Octavie; Msefula, Chisomo; MacLennan, Calman A; Keddy, Karen H; Smith, Anthony M; Onsare, Robert S; De Pinna, Elizabeth; Nair, Satheesh; Amos, Ben; Dougan, Gordon; Obaro, Stephen

    2016-09-01

    The burden of typhoid in sub-Saharan African (SSA) countries has been difficult to estimate, in part, due to suboptimal laboratory diagnostics. However, surveillance blood cultures at two sites in Nigeria have identified typhoid associated with Salmonella enterica serovar Typhi (S. Typhi) as an important cause of bacteremia in children. A total of 128 S. Typhi isolates from these studies in Nigeria were whole-genome sequenced, and the resulting data was used to place these Nigerian isolates into a worldwide context based on their phylogeny and carriage of molecular determinants of antibiotic resistance. Several distinct S. Typhi genotypes were identified in Nigeria that were related to other clusters of S. Typhi isolates from north, west and central regions of Africa. The rapidly expanding S. Typhi clade 4.3.1 (H58) previously associated with multiple antimicrobial resistances in Asia and in east, central and southern Africa, was not detected in this study. However, antimicrobial resistance was common amongst the Nigerian isolates and was associated with several plasmids, including the IncHI1 plasmid commonly associated with S. Typhi. These data indicate that typhoid in Nigeria was established through multiple independent introductions into the country, with evidence of regional spread. MDR typhoid appears to be evolving independently of the haplotype H58 found in other typhoid endemic countries. This study highlights an urgent need for routine surveillance to monitor the epidemiology of typhoid and evolution of antimicrobial resistance within the bacterial population as a means to facilitate public health interventions to reduce the substantial morbidity and mortality of typhoid.

  12. 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

  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.... International Trade Commission has received a complaint entitled Certain Integrated Circuit Packages Provided... sale within the United States after importation of certain integrated circuit packages provided...

  14. 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.

  15. Evaluation of atomic pressure in the multiple time-step integration algorithm.

    PubMed

    Andoh, Yoshimichi; Yoshii, Noriyuki; Yamada, Atsushi; Okazaki, Susumu

    2017-04-15

    In molecular dynamics (MD) calculations, reduction in calculation time per MD loop is essential. A multiple time-step (MTS) integration algorithm, the RESPA (Tuckerman and Berne, J. Chem. Phys. 1992, 97, 1990-2001), enables reductions in calculation time by decreasing the frequency of time-consuming long-range interaction calculations. However, the RESPA MTS algorithm involves uncertainties in evaluating the atomic interaction-based pressure (i.e., atomic pressure) of systems with and without holonomic constraints. It is not clear which intermediate forces and constraint forces in the MTS integration procedure should be used to calculate the atomic pressure. In this article, we propose a series of equations to evaluate the atomic pressure in the RESPA MTS integration procedure on the basis of its equivalence to the Velocity-Verlet integration procedure with a single time step (STS). The equations guarantee time-reversibility even for the system with holonomic constrants. Furthermore, we generalize the equations to both (i) arbitrary number of inner time steps and (ii) arbitrary number of force components (RESPA levels). The atomic pressure calculated by our equations with the MTS integration shows excellent agreement with the reference value with the STS, whereas pressures calculated using the conventional ad hoc equations deviated from it. Our equations can be extended straightforwardly to the MTS integration algorithm for the isothermal NVT and isothermal-isobaric NPT ensembles. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

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

    PubMed Central

    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

  17. Many Multiple Myelomas: Making More of the Molecular Mayhem

    PubMed Central

    Chesi, Marta; Bergsagel, P. Leif

    2014-01-01

    Multiple myeloma (MM) is malignancy of isotype-switched, BM-localized plasma cells that frequently results in bone destruction, BM failure, and death. Important molecular subgroups are identified by three classes of recurrent immunoglobulin gene translocations and hyperdiploidy, both of which affect disease course. From a clinical standpoint, it is critical to identify MM patients carrying the t(4;14) translocation, which is present in 15% of myelomas and is associated with dysregulation of WHSC1/MMSET and often FGFR3. These patients should all receive bortezomib as part of their initial induction treatment because this has been shown to significantly prolong survival. In contrast, patients with translocations affecting the MAF family of transcription factors, del17p, or gene-expression profiling (GEP)–defined high-risk disease appear to have a worse prognosis that is not dramatically improved by any intervention. These patients should be enrolled in innovative clinical trials. The remaining patients with cyclin D translocations or hyperdiploidy do well with most therapies, and the goal should be to control disease while minimizing toxicity. PMID:22160056

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

    PubMed

    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.

  19. Integrating Multiple Teaching Methods into a General Chemistry Classroom

    NASA Astrophysics Data System (ADS)

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

    1998-02-01

    In addition to the traditional lecture format, three other teaching strategies (class discussions, concept maps, and cooperative learning) were incorporated into a freshman level general chemistry course. Student perceptions of their involvement in each of the teaching methods, as well as their perceptions of the utility of each method were used to assess the effectiveness of the integration of the teaching strategies as received by the students. Results suggest that each strategy serves a unique purpose for the students and increased student involvement in the course. These results indicate that the multiple teaching strategies were well received by the students and that all teaching strategies are necessary for students to get the most out of the course.

  20. An integrated modelling framework for neural circuits with multiple neuromodulators

    PubMed Central

    Vemana, Vinith

    2017-01-01

    Neuromodulators are endogenous neurochemicals that regulate biophysical and biochemical processes, which control brain function and behaviour, and are often the targets of neuropharmacological drugs. Neuromodulator effects are generally complex partly owing to the involvement of broad innervation, co-release of neuromodulators, complex intra- and extrasynaptic mechanism, existence of multiple receptor subtypes and high interconnectivity within the brain. In this work, we propose an efficient yet sufficiently realistic computational neural modelling framework to study some of these complex behaviours. Specifically, we propose a novel dynamical neural circuit model that integrates the effective neuromodulator-induced currents based on various experimental data (e.g. electrophysiology, neuropharmacology and voltammetry). The model can incorporate multiple interacting brain regions, including neuromodulator sources, simulate efficiently and easily extendable to large-scale brain models, e.g. for neuroimaging purposes. As an example, we model a network of mutually interacting neural populations in the lateral hypothalamus, dorsal raphe nucleus and locus coeruleus, which are major sources of neuromodulator orexin/hypocretin, serotonin and norepinephrine/noradrenaline, respectively, and which play significant roles in regulating many physiological functions. We demonstrate that such a model can provide predictions of systemic drug effects of the popular antidepressants (e.g. reuptake inhibitors), neuromodulator antagonists or their combinations. Finally, we developed user-friendly graphical user interface software for model simulation and visualization for both fundamental sciences and pharmacological studies. PMID:28100828

  1. An integrated modelling framework for neural circuits with multiple neuromodulators.

    PubMed

    Joshi, Alok; Youssofzadeh, Vahab; Vemana, Vinith; McGinnity, T M; Prasad, Girijesh; Wong-Lin, KongFatt

    2017-01-01

    Neuromodulators are endogenous neurochemicals that regulate biophysical and biochemical processes, which control brain function and behaviour, and are often the targets of neuropharmacological drugs. Neuromodulator effects are generally complex partly owing to the involvement of broad innervation, co-release of neuromodulators, complex intra- and extrasynaptic mechanism, existence of multiple receptor subtypes and high interconnectivity within the brain. In this work, we propose an efficient yet sufficiently realistic computational neural modelling framework to study some of these complex behaviours. Specifically, we propose a novel dynamical neural circuit model that integrates the effective neuromodulator-induced currents based on various experimental data (e.g. electrophysiology, neuropharmacology and voltammetry). The model can incorporate multiple interacting brain regions, including neuromodulator sources, simulate efficiently and easily extendable to large-scale brain models, e.g. for neuroimaging purposes. As an example, we model a network of mutually interacting neural populations in the lateral hypothalamus, dorsal raphe nucleus and locus coeruleus, which are major sources of neuromodulator orexin/hypocretin, serotonin and norepinephrine/noradrenaline, respectively, and which play significant roles in regulating many physiological functions. We demonstrate that such a model can provide predictions of systemic drug effects of the popular antidepressants (e.g. reuptake inhibitors), neuromodulator antagonists or their combinations. Finally, we developed user-friendly graphical user interface software for model simulation and visualization for both fundamental sciences and pharmacological studies. © 2017 The Authors.

  2. Integrating Multiple Criteria Evaluation and GIS in Ecotourism: a Review

    NASA Astrophysics Data System (ADS)

    Mohd, Z. H.; Ujang, U.

    2016-09-01

    The concept of 'Eco-tourism' is increasingly heard in recent decades. Ecotourism is one adventure that environmentally responsible intended to appreciate the nature experiences and cultures. Ecotourism should have low impact on environment and must contribute to the prosperity of local residents. This article reviews the use of Multiple Criteria Evaluation (MCE) and Geographic Information System (GIS) in ecotourism. Multiple criteria evaluation mostly used to land suitability analysis or fulfill specific objectives based on various attributes that exist in the selected area. To support the process of environmental decision making, the application of GIS is used to display and analysis the data through Analytic Hierarchy Process (AHP). Integration between MCE and GIS tool is important to determine the relative weight for the criteria used objectively. With the MCE method, it can resolve the conflict between recreation and conservation which is to minimize the environmental and human impact. Most studies evidences that the GIS-based AHP as a multi criteria evaluation is a strong and effective in tourism planning which can aid in the development of ecotourism industry effectively.

  3. Multiple Populations in M31 Globular Clusters: Clues from Infrared High Resolution Integrated Light Spectroscopy

    NASA Astrophysics Data System (ADS)

    Sakari, Charli; APOGEE Team

    2017-01-01

    Abundance variations are a common feature of Milky Way globular clusters. The globular clusters in M31 are too distant for detailed abundance studies of their individual stars; however, cluster abundances can be determined through high resolution, integrated light (IL) spectroscopy. In this talk, I discuss how IL abundances can be interpreted in the context of multiple populations. In particular, I will present new infrared abudances of 25 M31 globular clusters, derived from IL spectra from the Apache Point Observatory Galactic Evolution Experiment (APOGEE). These H band spectra allow determinations of C, N, and O from molecular features, and Fe, Na, Mg, Al, Si, Ca, Ti, and K from atomic features. The integrated abundance ratios are then investigated with cluster [Fe/H] and mass.

  4. Data integration and systems biology approaches for biomarker discovery: challenges and opportunities for multiple sclerosis.

    PubMed

    Villoslada, Pablo; Baranzini, Sergio

    2012-07-15

    New "omic" technologies and their application to systems biology approaches offer new opportunities for biomarker discovery in complex disorders, including multiple sclerosis (MS). Recent studies using massive genotyping, DNA arrays, antibody arrays, proteomics, glycomics, and metabolomics from different tissues (blood, cerebrospinal fluid, brain) have identified many molecules associated with MS, defining both susceptibility and functional targets (e.g., biomarkers). Such discoveries involve many different levels in the complex organizational hierarchy of humans (DNA, RNA, protein, etc.), and integrating these datasets into a coherent model with regard to MS pathogenesis would be a significant step forward. Given the dynamic and heterogeneous nature of MS, validating biomarkers is mandatory. To develop accurate markers of disease prognosis or therapeutic response that are clinically useful, combining molecular, clinical, and imaging data is necessary. Such an integrative approach would pave the way towards better patient care and more effective clinical trials that test new therapies, thus bringing the paradigm of personalized medicine in MS one step closer.

  5. Interdisciplinary education to integrate pathology and epidemiology: towards molecular and population-level health science.

    PubMed

    Ogino, Shuji; King, Emily E; Beck, Andrew H; Sherman, Mark E; Milner, Danny A; Giovannucci, Edward

    2012-10-15

    In recent decades, epidemiology, public health, and medical sciences have been increasingly compartmentalized into narrower disciplines. The authors recognize the value of integration of divergent scientific fields in order to create new methods, concepts, paradigms, and knowledge. Herein they describe the recent emergence of molecular pathological epidemiology (MPE), which represents an integration of population and molecular biologic science to gain insights into the etiologies, pathogenesis, evolution, and outcomes of complex multifactorial diseases. Most human diseases, including common cancers (such as breast, lung, prostate, and colorectal cancers, leukemia, and lymphoma) and other chronic diseases (such as diabetes mellitus, cardiovascular diseases, hypertension, autoimmune diseases, psychiatric diseases, and some infectious diseases), are caused by alterations in the genome, epigenome, transcriptome, proteome, metabolome, microbiome, and interactome of all of the above components. In this era of personalized medicine and personalized prevention, we need integrated science (such as MPE) which can decipher diseases at the molecular, genetic, cellular, and population levels simultaneously. The authors believe that convergence and integration of multiple disciplines should be commonplace in research and education. We need to be open-minded and flexible in designing integrated education curricula and training programs for future students, clinicians, practitioners, and investigators.

  6. Interdisciplinary Education to Integrate Pathology and Epidemiology: Towards Molecular and Population-Level Health Science

    PubMed Central

    Ogino, Shuji; King, Emily E.; Beck, Andrew H.; Sherman, Mark E.; Milner, Danny A.; Giovannucci, Edward

    2012-01-01

    In recent decades, epidemiology, public health, and medical sciences have been increasingly compartmentalized into narrower disciplines. The authors recognize the value of integration of divergent scientific fields in order to create new methods, concepts, paradigms, and knowledge. Herein they describe the recent emergence of molecular pathological epidemiology (MPE), which represents an integration of population and molecular biologic science to gain insights into the etiologies, pathogenesis, evolution, and outcomes of complex multifactorial diseases. Most human diseases, including common cancers (such as breast, lung, prostate, and colorectal cancers, leukemia, and lymphoma) and other chronic diseases (such as diabetes mellitus, cardiovascular diseases, hypertension, autoimmune diseases, psychiatric diseases, and some infectious diseases), are caused by alterations in the genome, epigenome, transcriptome, proteome, metabolome, microbiome, and interactome of all of the above components. In this era of personalized medicine and personalized prevention, we need integrated science (such as MPE) which can decipher diseases at the molecular, genetic, cellular, and population levels simultaneously. The authors believe that convergence and integration of multiple disciplines should be commonplace in research and education. We need to be open-minded and flexible in designing integrated education curricula and training programs for future students, clinicians, practitioners, and investigators. PMID:22935517

  7. A Targeted "Capture" and "Removal" Scavenger toward Multiple Pollutants for Water Remediation based on Molecular Recognition.

    PubMed

    Wang, Jie; Shen, Haijing; Hu, Xiaoxia; Li, Yan; Li, Zhihao; Xu, Jinfan; Song, Xiufeng; Zeng, Haibo; Yuan, Quan

    2016-03-01

    For the water remediation techniques based on adsorption, the long-standing contradictories between selectivity and multiple adsorbability, as well as between affinity and recyclability, have put it on weak defense amid more and more severe environment crisis. Here, a pollutant-targeting hydrogel scavenger is reported for water remediation with both high selectivity and multiple adsorbability for several pollutants, and with strong affinity and good recyclability through rationally integrating the advantages of multiple functional materials. In the scavenger, aptamers fold into binding pockets to accommodate the molecular structure of pollutants to afford perfect selectivity, and Janus nanoparticles with antibacterial function as well as anisotropic surfaces to immobilize multiple aptamers allow for simultaneously handling different kinds of pollutants. The scavenger exhibits high efficiencies in removing pollutants from water and it can be easily recycled for many times without significant loss of loading capacities. Moreover, the residual concentrations of each contaminant are well below the drinking water standards. Thermodynamic behavior of the adsorption process is investigated and the rate-controlling process is determined. Furthermore, a point of use device is constructed and it displays high efficiency in removing pollutants from environmental water. The scavenger exhibits great promise to be applied in the next generation of water purification systems.

  8. 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

  9. Integrated Multiple “-omics” Data Reveal Subtypes of Hepatocellular Carcinoma

    PubMed Central

    Liu, Gang; Dong, Chuanpeng; Liu, Lei

    2016-01-01

    Hepatocellular carcinoma is one of the most heterogeneous cancers, as reflected by its multiple grades and difficulty to subtype. In this study, we integrated copy number variation, DNA methylation, mRNA, and miRNA data with the developed “cluster of cluster” method and classified 256 HCC samples from TCGA (The Cancer Genome Atlas) into five major subgroups (S1-S5). We observed that this classification was associated with specific mutations and protein expression, and we detected that each subgroup had distinct molecular signatures. The subclasses were associated not only with survival but also with clinical observations. S1 was characterized by bulk amplification on 8q24, TP53 mutation, low lipid metabolism, highly expressed onco-proteins, attenuated tumor suppressor proteins and a worse survival rate. S2 and S3 were characterized by telomere hypomethylation and a low expression of TERT and DNMT1/3B. Compared to S2, S3 was associated with less copy number variation and some good prognosis biomarkers, including CRP and CYP2E1. In contrast, the mutation rate of CTNNB1 was higher in S3. S4 was associated with bulk amplification and various molecular characteristics at different biological levels. In summary, we classified the HCC samples into five subgroups using multiple “-omics” data. Each subgroup had a distinct survival rate and molecular signature, which may provide information about the pathogenesis of subtypes in HCC. PMID:27806083

  10. Ab initio Path Integral Molecular Dynamics Based on Fragment Molecular Orbital Method

    NASA Astrophysics Data System (ADS)

    Fujita, Takatoshi; Watanabe, Hirofumi; Tanaka, Shigenori

    2009-10-01

    We have developed an ab initio path integral molecular dynamics method based on the fragment molecular orbital method. This “FMO-PIMD” method can treat both nuclei and electrons quantum mechanically, and is useful to simulate large hydrogen-bonded systems with high accuracy. After a benchmark calculation for water monomer, water trimer and glycine pentamer have been studied using the FMO-PIMD method to investigate nuclear quantum effects on structure and molecular interactions. The applicability of the present approach is demonstrated through a number of test calculations.

  11. Diffusion-coupled molecular assembly: structuring of coordination polymers across multiple length scales.

    PubMed

    Hirai, Kenji; Reboul, Julien; Morone, Nobuhiro; Heuser, John E; Furukawa, Shuhei; Kitagawa, Susumu

    2014-10-22

    Porous coordination polymers (PCPs) are an intriguing class of molecular-based materials because of the designability of framework scaffolds, pore sizes and pore surface functionalities. Besides the structural designability at the molecular scale, the structuring of PCPs into mesoscopic/macroscopic morphologies has attracted much attention due to the significance for the practical applications. The structuring of PCPs at the mesoscopic/macroscopic scale has been so far demonstrated by the spatial localization of coordination reactions on the surface of templates or at the phase boundaries. However, these methodologies have never been applied to the fabrication of solid-solution or multivariate metal-organic frameworks (MOFs), in which multiple components are homogeneously mixed. Herein, we demonstrate the structuring of a box-type superstructure comprising of a solid-solution PCP by integrating a bidirectional diffusion of multiple organic ligands into molecular assembly. The parent crystals of [Zn2(ndc)2(bpy)]n were placed in the DMF solution of additional organic component of H2bdc, and the temperature was rapidly elevated up to 80 °C (ndc = 1,4-naphthalenedicarboxylate, bpy = 4,4'-bipyridyl, bdc = 1,4-benzenedicarboxylate). The dissolution of the parent crystals induced the outward diffusion of components; contrariwise, the accumulation of the other organic ligand of H2bdc induced the inward diffusion toward the surface of the parent crystals. This bidirectional diffusion of multiple components spatially localized the recrystallization at the surface of cuboid parent crystals; therefore, the nanocrystals of a solid-solution PCP ([Zn2(bdc)1.5(ndc)0.5(bpy)]n) were organized into a mesoscopic box superstructure. Furthermore, we demonstrated that the box superstructures enhanced the mass transfer kinetics for the separation of hydrocarbons.

  12. Monolithic integration of microelectronics and photonics using molecularly engineered materials

    NASA Astrophysics Data System (ADS)

    Kubacki, Ronald M.

    2005-03-01

    The monolithic integration of CMOS microelectronics with photonics is inevitable and benefits both technologies. Photonic integration to microelectronics provides such solutions as overcoming microprocessor communication roadblocks through the use of optical interconnection. Microelectronic integration can provide benefits to photonic structures by optimizing electronic signals generated by photonic biosensors for example. Photonic integration must complement, build on, and enhance the existing state of CMOS microelectronic technology. Photonic approaches that ignore the realities of CMOS architectures (such as power and thermal limitations), provide little benefit to the CMOS device performance, are incompatible with CMOS silicon manufacturing processes, or are incapable of achieving levels of long term reliability already well demonstrated by microelectronic devices, give little reason for photonic/microelectronic integration. Practical implementation of photonics on chip, monolithically with CMOS type microelectronic devices, remains in the laboratory. This work presents architectures to integrate photonics and microelectronics that address CMOS fabrication realities, increase performance of both the electronic and optical functions, and retain current levels of reliability. Fabricating these structures with the limited CMOS material set and/or typical photonic materials requires materials to be molecularly engineered to provide required properties. Materials have been investigated that enable economic fabrication of photonic structures for monolithic integration. Low loss self assembled silicon nanocomposite VIPIR waveguide structures are combined with long term stable non-linear poled polymers for fabrication of electro-optic active devices. Materials are fabricated using low temperature plasma enhanced chemical vapor deposition (PECVD).

  13. Efficient Calculation of Molecular Integrals over London Atomic Orbitals.

    PubMed

    Irons, Tom J P; Zemen, Jan; Teale, Andrew M

    2017-08-08

    The use of London atomic orbitals (LAOs) in a nonperturbative manner enables the determination of gauge-origin invariant energies and properties for molecular species in arbitrarily strong magnetic fields. Central to the efficient implementation of such calculations for molecular systems is the evaluation of molecular integrals, particularly the electron repulsion integrals (ERIs). We present an implementation of several different algorithms for the evaluation of ERIs over Gaussian-type LAOs at arbitrary magnetic field strengths. The efficiencies of generalized McMurchie-Davidson (MD), Head-Gordon-Pople (HGP), and Rys quadrature schemes are compared. For the Rys quadrature implementation, we avoid the use of high precision arithmetic and interpolation schemes in the computation of the quadrature roots and weights, enabling the application of this algorithm seamlessly to a wide range of magnetic fields. The efficiency of each generalized algorithm is compared by numerical application, classifying the ERIs according to their total angular momenta and evaluating their performance for primitive and contracted basis sets. In common with zero-field integral evaluation, no single algorithm is optimal for all angular momenta; thus, a simple mixed scheme is put forward that selects the most efficient approach to calculate the ERIs for each shell quartet. The mixed approach is significantly more efficient than the exclusive use of any individual algorithm.

  14. Comparison of molecular signatures from multiple skin diseases identifies mechanisms of immunopathogenesis.

    PubMed

    Inkeles, Megan S; Scumpia, Philip O; Swindell, William R; Lopez, David; Teles, Rosane M B; Graeber, Thomas G; Meller, Stephan; Homey, Bernhard; Elder, James T; Gilliet, Michel; Modlin, Robert L; Pellegrini, Matteo

    2015-01-01

    The ability to obtain gene expression profiles from human disease specimens provides an opportunity to identify relevant gene pathways, but is limited by the absence of data sets spanning a broad range of conditions. Here, we analyzed publicly available microarray data from 16 diverse skin conditions in order to gain insight into disease pathogenesis. Unsupervised hierarchical clustering separated samples by disease as well as common cellular and molecular pathways. Disease-specific signatures were leveraged to build a multi-disease classifier, which predicted the diagnosis of publicly and prospectively collected expression profiles with 93% accuracy. In one sample, the molecular classifier differed from the initial clinical diagnosis and correctly predicted the eventual diagnosis as the clinical presentation evolved. Finally, integration of IFN-regulated gene programs with the skin database revealed a significant inverse correlation between IFN-β and IFN-γ programs across all conditions. Our study provides an integrative approach to the study of gene signatures from multiple skin conditions, elucidating mechanisms of disease pathogenesis. In addition, these studies provide a framework for developing tools for personalized medicine toward the precise prediction, prevention, and treatment of disease on an individual level.

  15. 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

    ... Integrated Circuit Packages Provided With Multiple Heat- Conducting Paths and Products Containing Same... within the United States after importation of certain integrated circuit packages provided with multiple... importation, or the sale within the United States after importation of certain integrated circuit...

  16. Enhanced performance for the interacting multiple model estimator with integrated multiple filters

    NASA Astrophysics Data System (ADS)

    Sabordo, Madeleine G.; Aboutanios, Elias

    2015-05-01

    In this paper, we propose a new approach to target visibility for the Interacting Multiple Model (IMM) algorithm. We introduce the IMM Integrated Multiple Filters (IMF) to selectively engage a suitable filter appropriate for gated clutter density at each time step and investigate five model sets that model the dynamic motion of a manoeuvring target. The model sets are incorporated into the IMM-IMF tracker to estimate the behaviour of the target. We employ the Dynamic Error Spectrum (DES) to assess the effectiveness of the tracker with target visibility concept incorporated and to compare the performance of the model sets in enhancing tracking performance. Results show that the new version of target visibility significantly improves the performance of the tracker. Simulation results also demonstrate that the 2CV-CA-2CT model set proves to be the most robust at the cost of computational resource. The CV-CA model is the fastest tracker. However, it is the least robust in terms of performance. These results assist decision makers and researchers in choosing appropriate models for IMMtrackers. Augmenting the capability of the tracker improves the ability of the platform to identify possible threats and consequently, enhance situational awareness.

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

    NASA Astrophysics Data System (ADS)

    Tang, J. H.

    1981-11-01

    The theoretical background of spin Hamiltonians, the density matrix formalism of multiple quantum NMR are discussed as well as creation and detection of multiple quantum coherence by multiple pulse sequence. 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 considered. An oriented methyl group relaxed by paramagnetic impurities is examined and possible correlated motion between two coupled methyl groups is investigated by multiple quantum NMR. 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 spin lattice dynamics of orienting or tunneling methyl groups (CH3 and CD3) at low temperatures and the anisotropic spin lattice relaxation of deuterated hexamethylbenzene, caused by the sixfold reorientation of the molecules are described as well as NMR spectrometers.

  18. A Fuzzy Logic Framework for Integrating Multiple Learned Models

    SciTech Connect

    Hartog, Bobi Kai Den

    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.

  19. 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. Copyright © 2016 Elsevier Inc. All rights reserved.

  20. 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.

  1. Coupling molecular spin centers to microwave planar resonators: towards integration of molecular qubits in quantum circuits.

    PubMed

    Bonizzoni, C; Ghirri, A; Bader, K; van Slageren, J; Perfetti, M; Sorace, L; Lan, Y; Fuhr, O; Ruben, M; Affronte, M

    2016-11-14

    We present spectroscopic measurements looking for the coherent coupling between molecular magnetic centers and microwave photons. The aim is to find the optimal conditions and the best molecular features to achieve the quantum strong coupling regime, for which coherent dynamics of hybrid photon-spin states take place. To this end, we used a high critical temperature YBCO superconducting planar resonator working at 7.7 GHz and at low temperatures to investigate three molecular mononuclear coordination compounds, namely (PPh4)2[Cu(mnt)2] (where mnt(2-) = maleonitriledithiolate), [ErPc2](-)TBA(+) (where pc(2-) is the phtalocyaninato and TBA(+) is the tetra-n-butylammonium cation) and Dy(trensal) (where H3trensal = 2,2',2''-tris(salicylideneimino)triethylamine). Although the strong coupling regime was not achieved in these preliminary experiments, the results provided several hints on how to design molecular magnetic centers to be integrated into hybrid quantum circuits.

  2. 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

  3. Handling missing rows in multi-omics data integration: multiple imputation in multiple factor analysis framework.

    PubMed

    Voillet, Valentin; Besse, Philippe; Liaubet, Laurence; San Cristobal, Magali; González, Ignacio

    2016-10-03

    In omics data integration studies, it is common, for a variety of reasons, for some individuals to not be present in all data tables. Missing row values are challenging to deal with because most statistical methods cannot be directly applied to incomplete datasets. To overcome this issue, we propose a multiple imputation (MI) approach in a multivariate framework. In this study, we focus on multiple factor analysis (MFA) as a tool to compare and integrate multiple layers of information. MI involves filling the missing rows with plausible values, resulting in M completed datasets. MFA is then applied to each completed dataset to produce M different configurations (the matrices of coordinates of individuals). Finally, the M configurations are combined to yield a single consensus solution. We assessed the performance of our method, named MI-MFA, on two real omics datasets. Incomplete artificial datasets with different patterns of missingness were created from these data. The MI-MFA results were compared with two other approaches i.e., regularized iterative MFA (RI-MFA) and mean variable imputation (MVI-MFA). For each configuration resulting from these three strategies, the suitability of the solution was determined against the true MFA configuration obtained from the original data and a comprehensive graphical comparison showing how the MI-, RI- or MVI-MFA configurations diverge from the true configuration was produced. Two approaches i.e., confidence ellipses and convex hulls, to visualize and assess the uncertainty due to missing values were also described. We showed how the areas of ellipses and convex hulls increased with the number of missing individuals. A free and easy-to-use code was proposed to implement the MI-MFA method in the R statistical environment. We believe that MI-MFA provides a useful and attractive method for estimating the coordinates of individuals on the first MFA components despite missing rows. MI-MFA configurations were close to the true

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

    SciTech Connect

    Bardhan, J.; Mathematics and Computer Science; Rush Univ.

    2009-03-07

    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.

  5. 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

  6. High throughput gene expression profiling: a molecular approach to integrative physiology

    PubMed Central

    Liang, Mingyu; Cowley, Allen W; Greene, Andrew S

    2004-01-01

    Integrative physiology emphasizes the importance of understanding multiple pathways with overlapping, complementary, or opposing effects and their interactions in the context of intact organisms. The DNA microarray technology, the most commonly used method for high-throughput gene expression profiling, has been touted as an integrative tool that provides insights into regulatory pathways. However, the physiology community has been slow in acceptance of these techniques because of early failure in generating useful data and the lack of a cohesive theoretical framework in which experiments can be analysed. With recent advances in both technology and analysis, we propose a concept of multidimensional integration of physiology that incorporates data generated by DNA microarray and other functional, genomic, and proteomic approaches to achieve a truly integrative understanding of physiology. Analysis of several studies performed in simpler organisms or in mammalian model animals supports the feasibility of such multidimensional integration and demonstrates the power of DNA microarray as an indispensable molecular tool for such integration. Evaluation of DNA microarray techniques indicates that these techniques, despite limitations, have advanced to a point where the question-driven profiling research has become a feasible complement to the conventional, hypothesis-driven research. With a keen sense of homeostasis, global regulation, and quantitative analysis, integrative physiologists are uniquely positioned to apply these techniques to enhance the understanding of complex physiological functions. PMID:14678487

  7. Integrative network analysis reveals molecular mechanisms of blood pressure regulation

    PubMed Central

    Huan, Tianxiao; Meng, Qingying; Saleh, Mohamed A; Norlander, Allison E; Joehanes, Roby; Zhu, Jun; Chen, Brian H; Zhang, Bin; Johnson, Andrew D; Ying, Saixia; Courchesne, Paul; Raghavachari, Nalini; Wang, Richard; Liu, Poching; O'Donnell, Christopher J; Vasan, Ramachandran; Munson, Peter J; Madhur, Meena S; Harrison, David G; Yang, Xia; Levy, Daniel

    2015-01-01

    Genome-wide association studies (GWAS) have identified numerous loci associated with blood pressure (BP). The molecular mechanisms underlying BP regulation, however, remain unclear. We investigated BP-associated molecular mechanisms by integrating BP GWAS with whole blood mRNA expression profiles in 3,679 individuals, using network approaches. BP transcriptomic signatures at the single-gene and the coexpression network module levels were identified. Four coexpression modules were identified as potentially causal based on genetic inference because expression-related SNPs for their corresponding genes demonstrated enrichment for BP GWAS signals. Genes from the four modules were further projected onto predefined molecular interaction networks, revealing key drivers. Gene subnetworks entailing molecular interactions between key drivers and BP-related genes were uncovered. As proof-of-concept, we validated SH2B3, one of the top key drivers, using Sh2b3−/− mice. We found that a significant number of genes predicted to be regulated by SH2B3 in gene networks are perturbed in Sh2b3−/− mice, which demonstrate an exaggerated pressor response to angiotensin II infusion. Our findings may help to identify novel targets for the prevention or treatment of hypertension. PMID:25882670

  8. Molecular pathology - the value of an integrative approach.

    PubMed

    Salto-Tellez, Manuel; James, Jacqueline A; Hamilton, Peter W

    2014-10-01

    Molecular Pathology (MP) is at the heart of modern diagnostics and translational research, but the controversy on how MP is best developed has not abated. The lack of a proper model or trained pathologists to support the diagnostic and research missions makes MP a rare commodity overall. Here we analyse the scientific and technology areas, in research and diagnostics, which are encompassed by MP of solid tumours; we highlight the broad overlap of technologies and analytical capabilities in tissue research and diagnostics; and we describe an integrated model that rationalizes technical know-how and pathology talent for both. The model is based on a single, accredited laboratory providing a single standard of high-quality for biomarker discovery, biomarker validation and molecular diagnostics.

  9. In Silico Gene Prioritization by Integrating Multiple Data Sources

    PubMed Central

    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

  10. Path integral molecular dynamics at zero thermal temperature

    NASA Astrophysics Data System (ADS)

    Willow, Soohaeng Yoo

    2017-04-01

    Path integral molecular dynamics (PIMD) simulations at the zero thermal temperature still remain inconceivable. Herein, the quantum-mechanical partition function is revised in conjunction with the time-independent Schrödinger equation. The imaginary temperature for the quantum-mechanical partition function is introduced as an independent variable and defined under the guidance of the virial theorem. In the end, computational evidences are provided showing that this revised PIMD simulation at the zero thermal temperature reproduces both the zero-point energy and the probability density obtained from the Schrödinger equation for the harmonic oscillator.

  11. The Eukaryotic Cell Originated in the Integration and Redistribution of Hyperstructures from Communities of Prokaryotic Cells Based on Molecular Complementarity

    PubMed Central

    Norris, Vic; Root-Bernstein, Robert

    2009-01-01

    In the “ecosystems-first” approach to the origins of life, networks of non-covalent assemblies of molecules (composomes), rather than individual protocells, evolved under the constraints of molecular complementarity. Composomes evolved into the hyperstructures of modern bacteria. We extend the ecosystems-first approach to explain the origin of eukaryotic cells through the integration of mixed populations of bacteria. We suggest that mutualism and symbiosis resulted in cellular mergers entailing the loss of redundant hyperstructures, the uncoupling of transcription and translation, and the emergence of introns and multiple chromosomes. Molecular complementarity also facilitated integration of bacterial hyperstructures to perform cytoskeletal and movement functions. PMID:19582221

  12. The eukaryotic cell originated in the integration and redistribution of hyperstructures from communities of prokaryotic cells based on molecular complementarity.

    PubMed

    Norris, Vic; Root-Bernstein, Robert

    2009-06-04

    In the "ecosystems-first" approach to the origins of life, networks of non-covalent assemblies of molecules (composomes), rather than individual protocells, evolved under the constraints of molecular complementarity. Composomes evolved into the hyperstructures of modern bacteria. We extend the ecosystems-first approach to explain the origin of eukaryotic cells through the integration of mixed populations of bacteria. We suggest that mutualism and symbiosis resulted in cellular mergers entailing the loss of redundant hyperstructures, the uncoupling of transcription and translation, and the emergence of introns and multiple chromosomes. Molecular complementarity also facilitated integration of bacterial hyperstructures to perform cytoskeletal and movement functions.

  13. Towards an integrated molecular model of plant-virus interactions.

    PubMed

    Elena, Santiago F; Rodrigo, Guillermo

    2012-12-01

    The application in recent years of network theory methods to the study of host-virus interactions is providing a new perspective to the way viruses manipulate the host to promote their own replication. An integrated molecular model of such pathosystems require three detailed maps describing, firstly, the interactions between viral elements, secondly, the interactions between host elements, and thirdly, the cross-interactions between viral and host elements. Here, we compile available information for Potyvirus infecting Arabidopsis thaliana. With an integrated model, it is possible to analyze the mode of virus action and how the perturbation of the virus targets propagates along the network. These studies suggest that viral pathogenicity results not only from the alteration of individual elements but it is a systemic property. Copyright © 2012 Elsevier B.V. All rights reserved.

  14. A unified scheme for ab initio molecular orbital theory and path integral molecular dynamics

    NASA Astrophysics Data System (ADS)

    Shiga, Motoyuki; Tachikawa, Masanori; Miura, Shinichi

    2001-11-01

    We present a general approach for accurate calculation of chemical substances which treats both nuclei and electrons quantum mechanically, adopting ab initio molecular orbital theory for the electronic structure and path integral molecular dynamics for the nuclei. The present approach enables the evaluation of physical quantities dependent on the nuclear configuration as well as the electronic structure, within the framework of Born-Oppenheimer adiabatic approximation. As an application, we give the path integral formulation of electric response properties—dipole moment and polarizability, which characterize the changes both in electronic structure and nuclear configuration at a given temperature when uniform electrostatic field is present. We also demonstrate the calculation of a water molecule using the present approach and the result of temperature and isotope effects is discussed.

  15. Generating nonlinear FM chirp radar signals by multiple integrations

    DOEpatents

    Doerry, Armin W [Albuquerque, NM

    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.

  16. {sf MBsums} -- a {sf Mathematica} Package for the Representation of Mellin-Barnes Integrals by Multiple Sums

    NASA Astrophysics Data System (ADS)

    Ochman, M.; Riemann, T.

    Feynman integrals may be represented by the Mathematica packages AMBRE and MB as multiple Mellin-Barnes integrals. With the Mathematica package MBsums these Mellin-Barnes integrals are transformed into multiple sums.

  17. Integrated genomic and molecular characterization of cervical cancer.

    PubMed

    2017-03-16

    Cervical cancer remains one of the leading causes of cancer-related deaths worldwide. Here we report the extensive molecular characterization of 228 primary cervical cancers, one of the largest comprehensive genomic studies of cervical cancer to date. We observed notable APOBEC mutagenesis patterns and identified SHKBP1, ERBB3, CASP8, HLA-A and TGFBR2 as novel significantly mutated genes in cervical cancer. We also discovered amplifications in immune targets CD274 (also known as PD-L1) and PDCD1LG2 (also known as PD-L2), and the BCAR4 long non-coding RNA, which has been associated with response to lapatinib. Integration of human papilloma virus (HPV) was observed in all HPV18-related samples and 76% of HPV16-related samples, and was associated with structural aberrations and increased target-gene expression. We identified a unique set of endometrial-like cervical cancers, comprised predominantly of HPV-negative tumours with relatively high frequencies of KRAS, ARID1A and PTEN mutations. Integrative clustering of 178 samples identified keratin-low squamous, keratin-high squamous and adenocarcinoma-rich subgroups. These molecular analyses reveal new potential therapeutic targets for cervical cancers.

  18. Integrating Multiple Data Views for Improved Malware Analysis

    SciTech Connect

    Anderson, Blake H.

    2014-01-31

    Exploiting multiple views of a program makes obfuscating the intended behavior of a program more difficult allowing for better performance in classification, clustering, and phylogenetic reconstruction.

  19. 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.…

  20. Validating Measurement of Knowledge Integration in Science Using Multiple-Choice and Explanation Items

    ERIC Educational Resources Information Center

    Lee, Hee-Sun; Liu, Ou Lydia; Linn, Marcia C.

    2011-01-01

    This study explores measurement of a construct called knowledge integration in science using multiple-choice and explanation items. We use construct and instructional validity evidence to examine the role multiple-choice and explanation items plays in measuring students' knowledge integration ability. For construct validity, we analyze item…

  1. Multiple Integrated Laser Engagement Simulation (MILES) Training and Evaluation Test (TET) Evaluator Guidebook

    DTIC Science & Technology

    1979-09-01

    7:,LEVEVEL$ Research Product 79-11 Multiple Integrated Laser Engagement Simulation -~ (MILES) Training and Evaluation Test (T ET) be Evaluator...COVEREO Multiple Integrated Laser Engagement Simulation (MILES) Training and Evaluation Test (TET) Evaluator Guidebook . 6. PERFORMING ORG. REPORT NUMBER...KEY WORDS (Continue on reverse side If neceaswry and identify by block nwmbsr) Unit Evaluation Engagement Simulation Unit Training Diagnosis

  2. Integration of Multiple Unmanned Systems in an Urban Search and Rescue Environment

    DTIC Science & Technology

    2013-03-01

    NAVAL POSTGRADUATE SCHOOL MONTEREY, CALIFORNIA THESIS Approved for public release; distribution is unlimited INTEGRATION OF...MULTIPLE UNMANNED SYSTEMS IN AN URBAN SEARCH AND RESCUE ENVIRONMENT by Boon Heng Chua March 2013 Thesis Advisor: Oleg Yakimenko Second...AND DATES COVERED Master’s Thesis 4. TITLE AND SUBTITLE INTEGRATION OF MULTIPLE UNMANNED SYSTEMS IN AN URBAN SEARCH AND RESCUE ENVIRONMENT 5

  3. Molecular pathogenesis of multiple myeloma: basic and clinical updates.

    PubMed

    Chesi, Marta; Bergsagel, P Leif

    2013-03-01

    Multiple myeloma is divided into two distinct genetic subtypes based on chromosome content. Hyperdiploid myeloma is characterized by multiple trisomies of chromosomes 3, 5, 7, 9 11, 15, 19 and 21, and lacks recurrent immunoglobulin gene translocations. Non-hyperdiploid myeloma in contrast is characterized by chromosome translocations t(4;14), t(14;16), t(14;20), t(6;14) and t(11;14). A unifying event in the pathogenesis of multiple myeloma is the dysregulated expression of a cyclin D gene, either directly by juxtaposition to an immunoglobulin enhancer, as a result of ectopic expression of a MAF family transcription factor, or indirectly by as yet unidentified mechanisms. Secondary genetic events include rearrangements of MYC, activating mutations of NRAS, KRAS or BRAF, a promiscuous array of mutations that activate NFkB and deletions of 17p. Among the poor-risk genetic features are t(4;14), t(14;16), t(14;20), del 17p and gains of 1q. Available evidence supports the use of a risk-stratified approach to the treatment of patients with multiple myeloma, with the early and prolonged use of bortezomib particularly in patients with t(4;14) and del 17p.

  4. Molecular pathogenesis of multiple myeloma: basic and clinical updates

    PubMed Central

    Chesi, Marta

    2014-01-01

    Multiple myeloma is divided into two distinct genetic subtypes based on chromosome content. Hyperdiploid myeloma is characterized by multiple trisomies of chromosomes 3, 5, 7, 9 11, 15, 19 and 21, and lacks recurrent immunoglobulin gene translocations. Non-hyperdiploid myeloma in contrast is characterized by chromosome translocations t(4;14), t(14;16), t(14;20), t(6;14) and t(11;14). A unifying event in the pathogenesis of multiple myeloma is the dysregulated expression of a cyclin D gene, either directly by juxtaposition to an immunoglobulin enhancer, as a result of ectopic expression of a MAF family transcription factor, or indirectly by as yet unidentified mechanisms. Secondary genetic events include rearrangements of MYC, activating mutations of NRAS, KRAS or BRAF, a promiscuous array of mutations that activate NFkB and deletions of 17p. Among the poor-risk genetic features are t(4;14), t(14;16), t(14;20), del 17p and gains of 1q. Available evidence supports the use of a risk-stratified approach to the treatment of patients with multiple myeloma, with the early and prolonged use of bortezomib particularly in patients with t(4;14) and del 17p. PMID:23456262

  5. 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.

  6. 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.

  7. Efficient stochastic thermostatting of path integral molecular dynamics

    NASA Astrophysics Data System (ADS)

    Ceriotti, Michele; Parrinello, Michele; Markland, Thomas E.; Manolopoulos, David E.

    2010-09-01

    The path integral molecular dynamics (PIMD) method provides a convenient way to compute the quantum mechanical structural and thermodynamic properties of condensed phase systems at the expense of introducing an additional set of high frequency normal modes on top of the physical vibrations of the system. Efficiently sampling such a wide range of frequencies provides a considerable thermostatting challenge. Here we introduce a simple stochastic path integral Langevin equation (PILE) thermostat which exploits an analytic knowledge of the free path integral normal mode frequencies. We also apply a recently developed colored noise thermostat based on a generalized Langevin equation (GLE), which automatically achieves a similar, frequency-optimized sampling. The sampling efficiencies of these thermostats are compared with that of the more conventional Nosé-Hoover chain (NHC) thermostat for a number of physically relevant properties of the liquid water and hydrogen-in-palladium systems. In nearly every case, the new PILE thermostat is found to perform just as well as the NHC thermostat while allowing for a computationally more efficient implementation. The GLE thermostat also proves to be very robust delivering a near-optimum sampling efficiency in all of the cases considered. We suspect that these simple stochastic thermostats will therefore find useful application in many future PIMD simulations.

  8. 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…

  9. 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…

  10. Integration Strategies for Learners with Severe Multiple Disabilities.

    ERIC Educational Resources Information Center

    Eichinger, Joanne; Woltman, Sheila

    1993-01-01

    This article reports the experiences of one school district as it moved from serving students with severe disabilities in segregated programs to a full inclusion model. Year one focused on getting started, planning, and beginning integration efforts and year two on implementation of a structured peer integration program. Applicability of the full…

  11. 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

  12. Integrating open-source software applications to build molecular dynamics systems.

    PubMed

    Allen, Bruce M; Predecki, Paul K; Kumosa, Maciej

    2014-04-05

    Three open-source applications, NanoEngineer-1, packmol, and mis2lmp are integrated using an open-source file format to quickly create molecular dynamics (MD) cells for simulation. The three software applications collectively make up the open-source software (OSS) suite known as MD Studio (MDS). The software is validated through software engineering practices and is verified through simulation of the diglycidyl ether of bisphenol-a and isophorone diamine (DGEBA/IPD) system. Multiple simulations are run using the MDS software to create MD cells, and the data generated are used to calculate density, bulk modulus, and glass transition temperature of the DGEBA/IPD system. Simulation results compare well with published experimental and numerical results. The MDS software prototype confirms that OSS applications can be analyzed against real-world research requirements and integrated to create a new capability. Copyright © 2014 Wiley Periodicals, Inc.

  13. 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

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

    PubMed

    Lazar, Vladimir; Suo, Chen; Orear, Cedric; van den Oord, Joost; Balogh, Zsofia; Guegan, Justine; Job, Bastien; Meurice, Guillaume; Ripoche, Hugues; Calza, Stefano; Hasmats, Johanna; Lundeberg, Joakim; Lacroix, Ludovic; Vielh, Philippe; Dufour, Fabienne; Lehtiö, Janne; Napieralski, Rudolf; Eggermont, Alexander; Schmitt, Manfred; Cadranel, Jacques; Besse, Benjamin; Girard, Philippe; Blackhall, Fiona; Validire, Pierre; Soria, Jean-Charles; Dessen, Philippe; Hansson, Johan; Pawitan, Yudi

    2013-12-03

    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. 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. 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, CTHRC1 and 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. Integrated molecular characterization of AC and SCC helped identify clinically relevant markers and potential drivers, which are

  15. 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.

  16. 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

  17. 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…

  18. 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…

  19. SpectraPlot.com: Integrated spectroscopic modeling of atomic and molecular gases

    NASA Astrophysics Data System (ADS)

    Goldenstein, Christopher S.; Miller, Victor A.; Mitchell Spearrin, R.; Strand, Christopher L.

    2017-10-01

    SpectraPlot is a web-based application for simulating spectra of atomic and molecular gases. At the time this manuscript was written, SpectraPlot consisted of four primary tools for calculating: (1) atomic and molecular absorption spectra, (2) atomic and molecular emission spectra, (3) transition linestrengths, and (4) blackbody emission spectra. These tools currently employ the NIST ASD, HITRAN2012, and HITEMP2010 databases to perform line-by-line simulations of spectra. SpectraPlot employs a modular, integrated architecture, enabling multiple simulations across multiple databases and/or thermodynamic conditions to be visualized in an interactive plot window. The primary objective of this paper is to describe the architecture and spectroscopic models employed by SpectraPlot in order to provide its users with the knowledge required to understand the capabilities and limitations of simulations performed using SpectraPlot. Further, this manuscript discusses the accuracy of several underlying approximations used to decrease computational time, in particular, the use of far-wing cutoff criteria.

  20. 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.

  1. Application of cascaded frequency multiplication to molecular spectroscopy

    NASA Astrophysics Data System (ADS)

    Drouin, Brian J.; Maiwald, Frank W.; Pearson, John C.

    2005-09-01

    Laboratory molecular spectroscopy provides the basis for interpretation of atmospheric, planetary, and astrophysical data gathered by remote sensing. Laboratory studies of atomic and molecular signatures across the electromagnetic spectrum provide high-precision, quantitative data used to interpret the observed environment from remote measurements. Historically, the region of the spectrum above 500 GHz has been relatively unexplored due to atmospheric absorption and technical difficulties generating and detecting radiation. Laboratory spectroscopy at these frequencies has traditionally involved measurement of one or two absorption features and relied on fitting of models to the limited data. We report a new spectrometer built around a computer-controlled commercial synthesizer and millimeter-wave module driving a series of amplifiers followed by a series of wide-bandwidth frequency doublers and triplers. The spectrometer provides the ability to rapidly measure large pieces of frequency space with higher resolution, accuracy, and sensitivity than with Fourier transform infrared techniques. The approach is simple, modular, and requires no custom-built electronics or high voltage and facilitates the use of infrared data analysis techniques on complex submillimeter spectra.

  2. Retrieving and Integrating Data from Multiple Information Sources

    DTIC Science & Technology

    1993-04-30

    part of the report that provides the most NASA - See Handbook NHB 2200.2. meaningful and complete Information. When a NTIS - Leave blank. report is...axioms, but after the axioms.are built _ the domain model is no longer used or needed. In contrast, the domain model in SIMS is an integral part of the...intelligent information systems where, like SIMS, an explicit knowledge model is an integral part of an intelligent information agent. Some additional

  3. 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

  4. Optimized acoustic biochip integrated with microfluidics for biomarkers detection in molecular diagnostics.

    PubMed

    Papadakis, G; Friedt, J M; Eck, M; Rabus, D; Jobst, G; Gizeli, E

    2017-09-01

    The development of integrated platforms incorporating an acoustic device as the detection element requires addressing simultaneously several challenges of technological and scientific nature. The present work was focused on the design of a microfluidic module, which, combined with a dual or array type Love wave acoustic chip could be applied to biomedical applications and molecular diagnostics. Based on a systematic study we optimized the mechanics of the flow cell attachment and the sealing material so that fluidic interfacing/encapsulation would impose minimal losses to the acoustic wave. We have also investigated combinations of operating frequencies with waveguide materials and thicknesses for maximum sensitivity during the detection of protein and DNA biomarkers. Within our investigations neutravidin was used as a model protein biomarker and unpurified PCR amplified Salmonella DNA as the model genetic target. Our results clearly indicate the need for experimental verification of the optimum engineering and analytical parameters, in order to develop commercially viable systems for integrated analysis. The good reproducibility of the signal together with the ability of the array biochip to detect multiple samples hold promise for the future use of the integrated system in a Lab-on-a-Chip platform for application to molecular diagnostics.

  5. Multiple molecular and neuropharmacological effects of MDMA (Ecstasy).

    PubMed

    Simantov, Rabi

    2004-01-02

    3,4-Methylenedioxymethamphetamine (MDMA), commonly referred to as Ecstasy, is a widely abused, psychoactive recreational drug, which induces short- and long-term neuropsychiatric behaviors. This drug is neurotoxic to serotonergic neurons in vivo, and induces programmed cell death in cultured human serotonergic cells and rat neocortical neurons. Over the years it has been shown that MDMA alters the release of several neurotransmitters in the brain, it induces recompartmentation of intracellular serotonin and c-fos, and modifies the expression of a few genes. Recently, we observed changes in gene expression in mice treated with MDMA, and cloned and sequenced 11 cDNAs thus affected (4 correspond to known and 7 to unknown genes). The effect of MDMA on two of these genes, GABA transporter 1 and synaptotagmin IV was studied in detail. Characterization of the relationship between a given gene and certain physiological or behavioral effects of MDMA could shed light on the mechanism of the drug's action. However, establishing such a connection is difficult for several reasons, including that serotonergic neurons are not the only cells affected by MDMA. In this review, molecular and neurochemical events that occur in the brain following exposure to MDMA, and link between the observed molecular changes with known physiological effects of the drug are discussed. It is indicated that MDMA alters the expression of several proteins involved in GABA neurotransmission, thus having critical effect on thermoregulation and MDMA acute toxicity. This analysis should facilitate development of novel approaches to prevent deleterious effects, especially mortality induced by MDMA and other abused psychostimulants.

  6. Integrating fossils with molecular phylogenies improves inference of trait evolution.

    PubMed

    Slater, Graham J; Harmon, Luke J; Alfaro, Michael E

    2012-12-01

    Comparative biologists often attempt to draw inferences about tempo and mode in evolution by comparing the fit of evolutionary models to phylogenetic comparative data consisting of a molecular phylogeny with branch lengths and trait measurements from extant taxa. These kinds of approaches ignore historical evidence for evolutionary pattern and process contained in the fossil record. In this article, we show through simulation that incorporation of fossil information dramatically improves our ability to distinguish among models of quantitative trait evolution using comparative data. We further suggest a novel Bayesian approach that allows fossil information to be integrated even when explicit phylogenetic hypotheses are lacking for extinct representatives of extant clades. By applying this approach to a comparative dataset comprising body sizes for caniform carnivorans, we show that incorporation of fossil information not only improves ancestral state estimates relative to those derived from extant taxa alone, but also results in preference of a model of evolution with trend toward large body size over alternative models such as Brownian motion or Ornstein-Uhlenbeck processes. Our approach highlights the importance of considering fossil information when making macroevolutionary inference, and provides a way to integrate the kind of sparse fossil information that is available to most evolutionary biologists.

  7. Path-integral molecular dynamics simulation of diamond

    NASA Astrophysics Data System (ADS)

    Ramírez, Rafael; Herrero, Carlos P.; Hernández, Eduardo R.

    2006-06-01

    Diamond is studied by path-integral molecular dynamics simulations of the atomic nuclei in combination with a tight-binding Hamiltonian to describe its electronic structure and total energy. This approach allows us to quantify the influence of quantum zero-point vibrations and finite temperatures on both the electronic and vibrational properties of diamond. The electron-phonon coupling mediated by the zero-point vibration reduces the direct electronic gap of diamond by 10%. The calculated decrease of the direct gap with temperature shows good agreement with the experimental data available up to 700K . Anharmonic vibrational frequencies of the crystal have been obtained from a linear-response approach based on the path integral formalism. In particular, the temperature dependence of the zone-center optical phonon has been derived from the simulations. The anharmonicity of the interatomic potential produces a red shift of this phonon frequency. At temperatures above 500K , this shift is overestimated in comparison to available experimental data. The predicted temperature shift of the elastic constant c44 displays reasonable agreement with the available experimental results.

  8. 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

  9. Molecular Genetic and Epigenetic Basis of Multiple Sclerosis.

    PubMed

    Hojati, Zohreh

    2017-01-01

    Multiple Sclerosis (MS) is a chronic immune-mediated disease of spinal cord and brain. The initial event in MS occurs when activated CD4(+) T cells in periphery exacerbates immune responses by stimulating immune cells such as B cells, CD8(+) cells, mast cells, granulocytes and monocytes. These proinflammatory cells pass blood brain barrier by secreting proinflammatory cytokines including TNF-α and INF-γ which activate adhesion factors. APCs (antigen-presenting cells) reactivate CD4(+) T cells after infiltrating the CNS and CD4(+) T cells produce cytokines and chemokines. These proinflammatory cytokines aggravate inflammation by inducing myelin phagocytosis through microglia and astrocytes activation. MS is believed to have a multifactorial origin that includes a combination of multiple genetic, environmental and stochastic factors. Although the exact component of MS risks that can be explained by these factors is difficult to determine, estimates based on genetic and epidemiological studies suggest that up to 60-70 % of the total risk of MS may be contribute to genetic factors. In continue, firstly we provide an overview of the current understanding of epigenetic mechanisms, and so present evidence of how the epigenetic modifications contribute to increased susceptibility of MS. We also explain how specified epigenetic modifications may influence the pathophysiology and key aspects of disease in MS (demyelination, remyelination, inflammation, and neurodegeneration). Finally, we tend to discuss how environmental factors and epigenetic mechanisms may interact to have an effect on MS risk and clinical outcome and recommend new therapeutic interventions that might modulate patients' epigenetic profiles.

  10. Logic integration of mRNA signals by an RNAi-based molecular computer.

    PubMed

    Xie, Zhen; Liu, Siyuan John; Bleris, Leonidas; Benenson, Yaakov

    2010-05-01

    Synthetic in vivo molecular 'computers' could rewire biological processes by establishing programmable, non-native pathways between molecular signals and biological responses. Multiple molecular computer prototypes have been shown to work in simple buffered solutions. Many of those prototypes were made of DNA strands and performed computations using cycles of annealing-digestion or strand displacement. We have previously introduced RNA interference (RNAi)-based computing as a way of implementing complex molecular logic in vivo. Because it also relies on nucleic acids for its operation, RNAi computing could benefit from the tools developed for DNA systems. However, these tools must be harnessed to produce bioactive components and be adapted for harsh operating environments that reflect in vivo conditions. In a step toward this goal, we report the construction and implementation of biosensors that 'transduce' mRNA levels into bioactive, small interfering RNA molecules via RNA strand exchange in a cell-free Drosophila embryo lysate, a step beyond simple buffered environments. We further integrate the sensors with our RNAi 'computational' module to evaluate two-input logic functions on mRNA concentrations. Our results show how RNA strand exchange can expand the utility of RNAi computing and point toward the possibility of using strand exchange in a native biological setting.

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

    PubMed Central

    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

  12. 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.

  13. 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.…

  14. Molecular integrals involving hulthén-type functions ( n = l STO) in relativistic quantum chemistry

    NASA Astrophysics Data System (ADS)

    Malli, Gulzari

    1981-03-01

    Dirac-Fock-Roothaan (DFR) treatment of molecules (with STO as basis) leads to molecular integrals involving n = l STOs which are known in nuclear physics as Hulthén-type functions (HTFs) It is pointed out. that with minor modifications, the existing non-relativistic molecular integral programs which use STO as basis can be used to evaluate molecular integrals involving Hulthén-type functions

  15. On Riemann zeroes, lognormal multiplicative chaos, and Selberg integral

    NASA Astrophysics Data System (ADS)

    Ostrovsky, Dmitry

    2016-02-01

    Rescaled Mellin-type transforms of the exponential functional of the Bourgade-Kuan-Rodgers statistic of Riemann zeroes are conjecturally related to the distribution of the total mass of the limit lognormal stochastic measure of Mandelbrot-Bacry-Muzy. The conjecture implies that a non-trivial, log-infinitely divisible probability distribution is associated with Riemann zeroes. For application, integral moments, covariance structure, multiscaling spectrum, and asymptotics associated with the exponential functional are computed in closed form using the known meromorphic extension of the Selberg integral.

  16. A molecular portrait of microsatellite instability across multiple cancers

    PubMed Central

    Cortes-Ciriano, Isidro; Lee, Sejoon; Park, Woong-Yang; Kim, Tae-Min; Park, Peter J.

    2017-01-01

    Microsatellite instability (MSI) refers to the hypermutability of short repetitive sequences in the genome caused by impaired DNA mismatch repair. Although MSI has been studied for decades, large amounts of sequencing data now available allows us to examine the molecular fingerprints of MSI in greater detail. Here, we analyse ∼8,000 exomes and ∼1,000 whole genomes of cancer patients across 23 cancer types. Our analysis reveals that the frequency of MSI events is highly variable within and across tumour types. We also identify genes in DNA repair and oncogenic pathways recurrently subject to MSI and uncover non-coding loci that frequently display MSI. Finally, we propose a highly accurate exome-based predictive model for the MSI phenotype. These results advance our understanding of the genomic drivers and consequences of MSI, and our comprehensive catalogue of tumour-type-specific MSI loci will enable panel-based MSI testing to identify patients who are likely to benefit from immunotherapy. PMID:28585546

  17. Multiple Quantum Well (MQW) Devices For Monolithic Integrated Optoelectronics

    NASA Astrophysics Data System (ADS)

    Wood, Thomas H.

    1988-05-01

    Semiconductor MQWs represent a new technology for opto-electronics. These MQWs have an electroabsorption effect approximately 50 times larger than conventional semiconductors. They are compatible with existing source and detector material systems and produce devices that are compact and high speed, which makes them useful for monolithic integrated optoelectronic devices.

  18. Multiple Quantum Well(MQW) Devices For Monolithic Integrated Optoelectronics

    NASA Astrophysics Data System (ADS)

    Wood, Thomas H.

    1987-02-01

    A new technology for opto-electronics has been developed, semiconductor MQWs. These MQWs have an electroabsorption effect 30-60 times larger than conventional semiconductors. They are compatible with existing source and detector material systems and produce devices that are compact and high speed, which makes them useful for monolithic integrated optoelectronic devices.

  19. 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…

  20. 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".

  1. 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.

  2. Multiple Distinct Targeting Signals in Integral Peroxisomal Membrane Proteins

    PubMed Central

    Jones, Jacob M.; Morrell, James C.; Gould, Stephen J.

    2001-01-01

    Peroxisomal proteins are synthesized on free polysomes and then transported from the cytoplasm to peroxisomes. This process is mediated by two short well-defined targeting signals in peroxisomal matrix proteins, but a well-defined targeting signal has not yet been described for peroxisomal membrane proteins (PMPs). One assumption in virtually all prior studies of PMP targeting is that a given protein contains one, and only one, distinct targeting signal. Here, we show that the metabolite transporter PMP34, an integral PMP, contains at least two nonoverlapping sets of targeting information, either of which is sufficient for insertion into the peroxisome membrane. We also show that another integral PMP, the peroxin PEX13, also contains two independent sets of peroxisomal targeting information. These results challenge a major assumption of most PMP targeting studies. In addition, we demonstrate that PEX19, a factor required for peroxisomal membrane biogenesis, interacts with the two minimal targeting regions of PMP34. Together, these results raise the interesting possibility that PMP import may require novel mechanisms to ensure the solubility of integral PMPs before their insertion in the peroxisome membrane, and that PEX19 may play a central role in this process. PMID:11402059

  3. 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

  4. Ab initio molecular orbital calculation considering the quantum mechanical effect of nuclei by path integral molecular dynamics

    NASA Astrophysics Data System (ADS)

    Shiga, Motoyuki; Tachikawa, Masanori; Miura, Shinichi

    2000-12-01

    We present an accurate calculational scheme for many-body systems composed of electrons and nuclei, by path integral molecular dynamics technique combined with the ab initio molecular orbital theory. Based upon the scheme, the simulation of a water molecule at room temperature is demonstrated, applying all-electron calculation at the Hartree-Fock level of theory.

  5. inTB - a data integration platform for molecular and clinical epidemiological analysis of tuberculosis

    PubMed Central

    2013-01-01

    Background Tuberculosis is currently the second highest cause of death from infectious diseases worldwide. The emergence of multi and extensive drug resistance is threatening to make tuberculosis incurable. There is growing evidence that the genetic diversity of Mycobacterium tuberculosis may have important clinical consequences. Therefore, combining genetic, clinical and socio-demographic data is critical to understand the epidemiology of this infectious disease, and how virulence and other phenotypic traits evolve over time. This requires dedicated bioinformatics platforms, capable of integrating and enabling analyses of this heterogeneous data. Results We developed inTB, a web-based system for integrated warehousing and analysis of clinical, socio-demographic and molecular data for Mycobacterium sp. isolates. As a database it can organize and display data from any of the standard genotyping methods (SNP, MIRU-VNTR, RFLP and spoligotype), as well as an extensive array of clinical and socio-demographic variables that are used in multiple countries to characterize the disease. Through the inTB interface it is possible to insert and download data, browse the database and search specific parameters. New isolates are automatically classified into strains according to an internal reference, and data uploaded or typed in is checked for internal consistency. As an analysis framework, the system provides simple, point and click analysis tools that allow multiple types of data plotting, as well as simple ways to download data for external analysis. Individual trees for each genotyping method are available, as well as a super tree combining all of them. The integrative nature of inTB grants the user the ability to generate trees for filtered subsets of data crossing molecular and clinical/socio-demografic information. inTB is built on open source software, can be easily installed locally and easily adapted to other diseases. Its design allows for use by research

  6. inTB - a data integration platform for molecular and clinical epidemiological analysis of tuberculosis.

    PubMed

    Soares, Patrícia; Alves, Renato J; Abecasis, Ana B; Penha-Gonçalves, Carlos; Gomes, M Gabriela M; Pereira-Leal, José B

    2013-08-30

    Tuberculosis is currently the second highest cause of death from infectious diseases worldwide. The emergence of multi and extensive drug resistance is threatening to make tuberculosis incurable. There is growing evidence that the genetic diversity of Mycobacterium tuberculosis may have important clinical consequences. Therefore, combining genetic, clinical and socio-demographic data is critical to understand the epidemiology of this infectious disease, and how virulence and other phenotypic traits evolve over time. This requires dedicated bioinformatics platforms, capable of integrating and enabling analyses of this heterogeneous data. We developed inTB, a web-based system for integrated warehousing and analysis of clinical, socio-demographic and molecular data for Mycobacterium sp. isolates. As a database it can organize and display data from any of the standard genotyping methods (SNP, MIRU-VNTR, RFLP and spoligotype), as well as an extensive array of clinical and socio-demographic variables that are used in multiple countries to characterize the disease. Through the inTB interface it is possible to insert and download data, browse the database and search specific parameters. New isolates are automatically classified into strains according to an internal reference, and data uploaded or typed in is checked for internal consistency. As an analysis framework, the system provides simple, point and click analysis tools that allow multiple types of data plotting, as well as simple ways to download data for external analysis. Individual trees for each genotyping method are available, as well as a super tree combining all of them. The integrative nature of inTB grants the user the ability to generate trees for filtered subsets of data crossing molecular and clinical/socio-demografic information. inTB is built on open source software, can be easily installed locally and easily adapted to other diseases. Its design allows for use by research laboratories, hospitals or

  7. 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,…

  8. 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,…

  9. A portable, integrated analyzer for microfluidic - based molecular analysis.

    PubMed

    Qiu, Xianbo; Chen, Dafeng; Liu, Changchun; Mauk, Michael G; Kientz, Terry; Bau, Haim H

    2011-10-01

    A portable, fully automated analyzer that provides actuation and flow control to a disposable, self-contained, microfluidic cassette ("chip") for point-of-care, molecular testing is described. The analyzer provides mechanical actuation to compress pouches that pump liquids in the cassette, to open and close diaphragm valves for flow control, and to induce vibrations that enhance stirring. The analyzer also provides thermal actuation for the temperature cycling needed for polymerase chain reaction (PCR) amplification of nucleic acids and for various drying processes. To improve the temperature uniformity of the PCR chamber, the system utilizes a double-sided heating/cooling scheme with a custom feedforward, variable, structural proportional-integral-derivative (FVSPID) controller. The analyzer includes a programmable central processing unit that directs the sequence and timing of the various operations and that is interfaced with a computer. The disposable cassette receives a sample, and it carries out cell lysis, nucleic acid isolation, concentration, and purification, thermal cycling, and either real time or lateral flow (LF) based detection. The system's operation was demonstrated by processing saliva samples spiked with B. cereus cells. The amplicons were detected with a lateral flow assay using upconverting phosphor reporter particles. This system is particularly suited for use in regions lacking centralized laboratory facilities and skilled personnel.

  10. 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.

  11. 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.

  12. 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.

  13. 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.

  14. 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

  15. 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

    2015-09-14

    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.

  16. Modular multiple sensors information management for computer-integrated surgery.

    PubMed

    Vaccarella, Alberto; Enquobahrie, Andinet; Ferrigno, Giancarlo; Momi, Elena De

    2012-09-01

    In the past 20 years, technological advancements have modified the concept of modern operating rooms (ORs) with the introduction of computer-integrated surgery (CIS) systems, which promise to enhance the outcomes, safety and standardization of surgical procedures. With CIS, different types of sensor (mainly position-sensing devices, force sensors and intra-operative imaging devices) are widely used. Recently, the need for a combined use of different sensors raised issues related to synchronization and spatial consistency of data from different sources of information. In this study, we propose a centralized, multi-sensor management software architecture for a distributed CIS system, which addresses sensor information consistency in both space and time. The software was developed as a data server module in a client-server architecture, using two open-source software libraries: Image-Guided Surgery Toolkit (IGSTK) and OpenCV. The ROBOCAST project (FP7 ICT 215190), which aims at integrating robotic and navigation devices and technologies in order to improve the outcome of the surgical intervention, was used as the benchmark. An experimental protocol was designed in order to prove the feasibility of a centralized module for data acquisition and to test the application latency when dealing with optical and electromagnetic tracking systems and ultrasound (US) imaging devices. Our results show that a centralized approach is suitable for minimizing synchronization errors; latency in the client-server communication was estimated to be 2 ms (median value) for tracking systems and 40 ms (median value) for US images. The proposed centralized approach proved to be adequate for neurosurgery requirements. Latency introduced by the proposed architecture does not affect tracking system performance in terms of frame rate and limits US images frame rate at 25 fps, which is acceptable for providing visual feedback to the surgeon in the OR. Copyright © 2012 John Wiley & Sons, Ltd.

  17. Resolving Multiple Molecular Orbitals Using Two-Dimensional High-Harmonic Spectroscopy

    NASA Astrophysics Data System (ADS)

    Yun, Hyeok; Lee, Kyung-Min; Sung, Jae Hee; Kim, Kyung Taec; Kim, Hyung Taek; Nam, Chang Hee

    2015-04-01

    High-harmonic radiation emitted from molecules in a strong laser field contains information on molecular structure and dynamics. When multiple molecular orbitals participate in high-harmonic generation, resolving the contribution of each orbital is crucial for understanding molecular dynamics and for extending high-harmonic spectroscopy to more complicated molecules. We show that two-dimensional high-harmonic spectroscopy can resolve high-harmonic radiation emitted from the two highest-occupied molecular orbitals, HOMO and HOMO-1, of aligned molecules. By the application of an orthogonally polarized two-color laser field that consists of the fundamental and its second-harmonic fields to aligned CO2 molecules, the characteristics attributed to the two orbitals are found to be separately imprinted in odd and even harmonics. Two-dimensional high-harmonic spectroscopy may open a new route to investigate ultrafast molecular dynamics during chemical processes.

  18. Resolving multiple molecular orbitals using two-dimensional high-harmonic spectroscopy.

    PubMed

    Yun, Hyeok; Lee, Kyung-Min; Sung, Jae Hee; Kim, Kyung Taec; Kim, Hyung Taek; Nam, Chang Hee

    2015-04-17

    High-harmonic radiation emitted from molecules in a strong laser field contains information on molecular structure and dynamics. When multiple molecular orbitals participate in high-harmonic generation, resolving the contribution of each orbital is crucial for understanding molecular dynamics and for extending high-harmonic spectroscopy to more complicated molecules. We show that two-dimensional high-harmonic spectroscopy can resolve high-harmonic radiation emitted from the two highest-occupied molecular orbitals, HOMO and HOMO-1, of aligned molecules. By the application of an orthogonally polarized two-color laser field that consists of the fundamental and its second-harmonic fields to aligned CO2 molecules, the characteristics attributed to the two orbitals are found to be separately imprinted in odd and even harmonics. Two-dimensional high-harmonic spectroscopy may open a new route to investigate ultrafast molecular dynamics during chemical processes.

  19. 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

  20. Extremely sensitive detection of NO₂ employing off-axis integrated cavity output spectroscopy coupled with multiple-line integrated absorption spectroscopy.

    PubMed

    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 kilometers 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 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 versus concentration of NO₂ and the standard deviation of the integrated absorption signal, we report an effective sensitivity of detection of approximately 28 ppt (parts in 10¹²) for NO₂ To the best of our knowledge, this is among the most sensitive levels of detection of NO₂ to date.

  1. 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.

  2. 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

  3. 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.

  4. 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.

  5. 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

  6. The integration of molecular tools into veterinary and spatial epidemiology.

    PubMed

    Muellner, Petra; Zadoks, Ruth N; Perez, Andres M; Spencer, Simon E F; Schukken, Ynte H; French, Nigel P

    2011-09-01

    At the interface of molecular biology and epidemiology, the emerging discipline of molecular epidemiology offers unique opportunities to advance the study of diseases through the investigation of infectious agents at the molecular level. Molecular tools can increase our understanding of the factors that shape the spatial and temporal distribution of pathogens and disease. Both spatial and molecular aspects have always been important to the field of infectious disease epidemiology, but recently news tools have been developed which increase our ability to consider both elements within a common framework. This enables the epidemiologist to make inferences about disease patterns in space and time. This paper introduces some basic concepts of molecular epidemiology in a veterinary context and illustrates the application of molecular tools at a range of spatio-temporal scales. Case studies - a multi-state outbreak of Serratia mastitis, a national control program for campylobacteriosis, and evolution of foot-and-mouth-disease viruses - are used to demonstrate the importance of considering molecular aspects in modern epidemiological studies. The discipline of molecular epidemiology is in its infancy and our contribution aims to promote awareness, understanding and uptake of molecular epidemiology in veterinary science. Copyright © 2011 Elsevier Ltd. All rights reserved.

  7. 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.

  8. 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

  9. 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.

  10. A Targeted “Capture” and “Removal” Scavenger toward Multiple Pollutants for Water Remediation based on Molecular Recognition

    PubMed Central

    Wang, Jie; Shen, Haijing; Hu, Xiaoxia; Li, Yan; Li, Zhihao; Xu, Jinfan; Song, Xiufeng; Zeng, Haibo

    2015-01-01

    For the water remediation techniques based on adsorption, the long‐standing contradictories between selectivity and multiple adsorbability, as well as between affinity and recyclability, have put it on weak defense amid more and more severe environment crisis. Here, a pollutant‐targeting hydrogel scavenger is reported for water remediation with both high selectivity and multiple adsorbability for several pollutants, and with strong affinity and good recyclability through rationally integrating the advantages of multiple functional materials. In the scavenger, aptamers fold into binding pockets to accommodate the molecular structure of pollutants to afford perfect selectivity, and Janus nanoparticles with antibacterial function as well as anisotropic surfaces to immobilize multiple aptamers allow for simultaneously handling different kinds of pollutants. The scavenger exhibits high efficiencies in removing pollutants from water and it can be easily recycled for many times without significant loss of loading capacities. Moreover, the residual concentrations of each contaminant are well below the drinking water standards. Thermodynamic behavior of the adsorption process is investigated and the rate‐controlling process is determined. Furthermore, a point of use device is constructed and it displays high efficiency in removing pollutants from environmental water. The scavenger exhibits great promise to be applied in the next generation of water purification systems. PMID:27774394

  11. Switchable Multiple Spin States in the Kondo description of Doped Molecular Magnets

    PubMed Central

    Ray, Rajyavardhan; Kumar, Sanjeev

    2017-01-01

    We show that introducing electrons in magnetic clusters and molecular magnets lead to rich phase diagrams with a variety of low-spin and high-spin states allowing for multiple switchability. The analysis is carried out for a quantum spin-fermion model using the exact diagonalization, and the cluster mean-field approach. The model is relevant for a number of molecular magnets with triangular motifs consisting of transition metal ions such as Cr, Cu and V. Re-entrant spin-state behavior and chirality on-off transitions exist over a wide parameter regime. A subtle competition among geometrical frustration effects, electron itinerancy, and Kondo coupling at the molecular level is highlighted. Our results demonstrate that electron doping provides a viable mean to tame the magnetic properties of molecular magnets towards potential technological applications. PMID:28176869

  12. Switchable Multiple Spin States in the Kondo description of Doped Molecular Magnets.

    PubMed

    Ray, Rajyavardhan; Kumar, Sanjeev

    2017-02-08

    We show that introducing electrons in magnetic clusters and molecular magnets lead to rich phase diagrams with a variety of low-spin and high-spin states allowing for multiple switchability. The analysis is carried out for a quantum spin-fermion model using the exact diagonalization, and the cluster mean-field approach. The model is relevant for a number of molecular magnets with triangular motifs consisting of transition metal ions such as Cr, Cu and V. Re-entrant spin-state behavior and chirality on-off transitions exist over a wide parameter regime. A subtle competition among geometrical frustration effects, electron itinerancy, and Kondo coupling at the molecular level is highlighted. Our results demonstrate that electron doping provides a viable mean to tame the magnetic properties of molecular magnets towards potential technological applications.

  13. Switchable Multiple Spin States in the Kondo description of Doped Molecular Magnets

    NASA Astrophysics Data System (ADS)

    Ray, Rajyavardhan; Kumar, Sanjeev

    2017-02-01

    We show that introducing electrons in magnetic clusters and molecular magnets lead to rich phase diagrams with a variety of low-spin and high-spin states allowing for multiple switchability. The analysis is carried out for a quantum spin-fermion model using the exact diagonalization, and the cluster mean-field approach. The model is relevant for a number of molecular magnets with triangular motifs consisting of transition metal ions such as Cr, Cu and V. Re-entrant spin-state behavior and chirality on-off transitions exist over a wide parameter regime. A subtle competition among geometrical frustration effects, electron itinerancy, and Kondo coupling at the molecular level is highlighted. Our results demonstrate that electron doping provides a viable mean to tame the magnetic properties of molecular magnets towards potential technological applications.

  14. [Integrated risk evaluation of multiple disasters affecting longyan yield in Fujian Province, East China].

    PubMed

    Chen, Jia-Jin; Wang, Jia-Yi; Li, Li-Chun; Lin, Jing; Yang, Kai; Ma, Zhi-Guo; Xu, Zong-Huan

    2012-03-01

    In this study, an index system for the integrated risk evaluation of multiple disasters on the Longyan production in Fujian Province was constructed, based on the analysis of the major environmental factors affecting the Longyan growth and yield, and from the viewpoints of potential hazard of disaster-causing factors, vulnerability of hazard-affected body, and disaster prevention and mitigation capability of Longyan growth regions in the Province. In addition, an integrated evaluation model of multiple disasters was established to evaluate the risks of the major agro-meteorological disasters affecting the Longyan yield, based on the yearly meteorological data, Longyan planting area and yield, and other socio-economic data in Longyan growth region in Fujian, and by using the integral weight of risk indices determined by AHP and entropy weight coefficient methods. In the Province, the Longyan growth regions with light integrated risk of multiple disasters were distributed in the coastal counties (except Dongshan County) with low elevation south of Changle, the regions with severe and more severe integrated risk were mainly in Zhangping of Longyan, Dongshan, Pinghe, Nanjin, and Hua' an of Zhangzhou, Yongchun and Anxi of Quanzhou, north mountainous areas of Putian and Xianyou, Minqing, Minhou, Luoyuan, and mountainous areas of Fuzhou, and Fuan, Xiapu, and mountainous areas of Ninde, among which, the regions with severe integrated risk were in Dongshan, Zhangping, and other mountainous areas with high altitudes, and the regions with moderate integrated risk were distributed in the other areas of the Province.

  15. Analytic evaluation of two-center molecular integrals

    NASA Technical Reports Server (NTRS)

    Tai, H.

    1986-01-01

    By using the Fourier-transform technique, the explicit expressions for the one-electron - two-center overlap integrals of Slater-type atomic orbitals up to 3d are derived. The final expressions are analytic, simple, and independent of local coordinates. Furthermore, they do not contain the nonclosed-form of exponential integrals which were presented in expressions given in earlier work. It is shown that the two-electron - two-center Coulomb integrals, as well as the hybrid integrals, can simply be expressed in terms of these integrals. The numerical instability arising from the situation in which the exponents of the two orbitals are almost equal is discussed, and a solution for this problem based on a Taylor-series expansion of the integral is suggested.

  16. 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.

  17. Report of the Integrative Molecular Cancer Epidemiology International Symposium, Lyon, France.

    PubMed

    Raimondi, S

    2008-01-01

    An International Symposium on Integrative Molecular Cancer Epidemiology took place in Lyon, France, on 3-5 July 2008. The Symposium focused on aetiological and mechanistic aspects of molecular and genetic cancer epidemiology research and was divided into the following three sections: Molecular epidemiology-application of novel molecular markers to cancer epidemiology.Genomic epidemiology in the era of whole genome scan.INTEGRATIVE MOLECULAR EPIDEMIOLOGY: visions for the future.Participants included epidemiologists, geneticists, biochemical and molecular biologists, pharmacologists, pathologists and all researchers interested in this field. The Symposium provided a complete and clear overview of the present and future programmes in molecular cancer epidemiology. It also served to encourage international scientific collaboration between investigators working in this specific research field, and to stimulate transdisciplinary research with experts of other research areas. Highlights of each of the scientific presentations are summarized below.

  18. Communication: Multiple-timestep ab initio molecular dynamics with electron correlation.

    PubMed

    Steele, Ryan P

    2013-07-07

    A time-reversible, multiple-timestep protocol is presented for ab initio molecular dynamics simulations using correlated, wavefunction-based underlying potentials. The method is motivated by the observation that electron correlation contributions to forces vary on a slower timescale than their Hartree-Fock counterparts. An efficient dynamics algorithm, involving short-timestep Hartree-Fock and long-timestep Moøller-Plesset perturbation theory, is presented and tested. Results indicate stable trajectories and relative speedups comparable to those seen in force field-based multiple-timestep schemes, with the highest efficiency improvement occurring for large systems.

  19. Communication: Multiple-timestep ab initio molecular dynamics with electron correlation

    NASA Astrophysics Data System (ADS)

    Steele, Ryan P.

    2013-07-01

    A time-reversible, multiple-timestep protocol is presented for ab initio molecular dynamics simulations using correlated, wavefunction-based underlying potentials. The method is motivated by the observation that electron correlation contributions to forces vary on a slower timescale than their Hartree-Fock counterparts. An efficient dynamics algorithm, involving short-timestep Hartree-Fock and long-timestep Møller-Plesset perturbation theory, is presented and tested. Results indicate stable trajectories and relative speedups comparable to those seen in force field-based multiple-timestep schemes, with the highest efficiency improvement occurring for large systems.

  20. Molecular Integrative Clustering of Asian Gastric Cell Lines Revealed Two Distinct Chemosensitivity Clusters

    PubMed Central

    Choong, Meng Ling; Tan, Shan Ho; Tan, Tuan Zea; Manesh, Sravanthy; Ngo, Anna; Yong, Jacklyn W. Y.; Yang, Henry He; Lee, May Ann

    2014-01-01

    Cell lines recapitulate cancer heterogeneity without the presence of interfering tissue found in primary tumor. Their heterogeneous characteristics are reflected in their multiple genetic abnormalities and variable responsiveness to drug treatments. In order to understand the heterogeneity observed in Asian gastric cancers, we have performed array comparative genomic hybridization (aCGH) on 18 Asian gastric cell lines. Hierarchical clustering and single-sample Gene Set Enrichment Analysis were performed on the aCGH data together with public gene expression data of the same cell lines obtained from the Cancer Cell Line Encyclopedia. We found a large amount of genetic aberrations, with some cell lines having 13 fold more aberrations than others. Frequently mutated genes and cellular pathways are identified in these Asian gastric cell lines. The combined analyses of aCGH and expression data demonstrate correlation of gene copy number variations and expression profiles in human gastric cancer cells. The gastric cell lines can be grouped into 2 integrative clusters (ICs). Gastric cells in IC1 are enriched with gene associated with mitochondrial activities and oxidative phosphorylation while cells in IC2 are enriched with genes associated with cell signaling and transcription regulations. The two clusters of cell lines were shown to have distinct responsiveness towards several chemotherapeutics agents such as PI3 K and proteosome inhibitors. Our molecular integrative clustering provides insight into critical genes and pathways that may be responsible for the differences in survival in response to chemotherapy. PMID:25343454

  1. Multiple biomarkers in molecular oncology. II. Molecular diagnostics applications in breast cancer management.

    PubMed

    Malinowski, Douglas P

    2007-05-01

    In recent years, the application of genomic and proteomic technologies to the problem of breast cancer prognosis and the prediction of therapy response have begun to yield encouraging results. Independent studies employing transcriptional profiling of primary breast cancer specimens using DNA microarrays have identified gene expression profiles that correlate with clinical outcome in primary breast biopsy specimens. Recent advances in microarray technology have demonstrated reproducibility, making clinical applications more achievable. In this regard, one such DNA microarray device based upon a 70-gene expression signature was recently cleared by the US FDA for application to breast cancer prognosis. These DNA microarrays often employ at least 70 gene targets for transcriptional profiling and prognostic assessment in breast cancer. The use of PCR-based methods utilizing a small subset of genes has recently demonstrated the ability to predict the clinical outcome in early-stage breast cancer. Furthermore, protein-based immunohistochemistry methods have progressed from using gene clusters and gene expression profiling to smaller subsets of expressed proteins to predict prognosis in early-stage breast cancer. Beyond prognostic applications, DNA microarray-based transcriptional profiling has demonstrated the ability to predict response to chemotherapy in early-stage breast cancer patients. In this review, recent advances in the use of multiple markers for prognosis of disease recurrence in early-stage breast cancer and the prediction of therapy response will be discussed.

  2. 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

  3. Plasma proteomic profiles from disease-discordant monozygotic twins suggest that molecular pathways are shared in multiple systemic autoimmune diseases*

    PubMed Central

    2011-01-01

    Introduction Although systemic autoimmune diseases (SAID) share many clinical and laboratory features, whether they also share some common features of pathogenesis remains unclear. We assessed plasma proteomic profiles among different SAID for evidence of common molecular pathways that could provide insights into pathogenic mechanisms shared by these diseases. Methods Differential quantitative proteomic analyses (one-dimensional reverse-phase liquid chromatography-mass spectrometry) were performed to assess patterns of plasma protein expression. Monozygotic twins (four pairs discordant for systemic lupus erythematosus, four pairs discordant for juvenile idiopathic arthritis and two pairs discordant for juvenile dermatomyositis) were studied to minimize polymorphic gene effects. Comparisons were also made to 10 unrelated, matched controls. Results Multiple plasma proteins, including acute phase reactants, structural proteins, immune response proteins, coagulation and transcriptional factors, were differentially expressed similarly among the different SAID studied. Multivariate Random Forest modeling identified seven proteins whose combined altered expression levels effectively segregated affected vs. unaffected twins. Among these seven proteins, four were also identified in univariate analyses of proteomic data (syntaxin 17, α-glucosidase, paraoxonase 1, and the sixth component of complement). Molecular pathway modeling indicated that these factors may be integrated through interactions with a candidate plasma biomarker, PON1 and the pro-inflammatory cytokine IL-6. Conclusions Together, these data suggest that different SAID may share common alterations of plasma protein expression and molecular pathways. An understanding of the mechanisms leading to the altered plasma proteomes common among these SAID may provide useful insights into their pathogeneses. PMID:22044644

  4. 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.

  5. 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.

  6. A variational path integral molecular dynamics study of a solid helium-4

    NASA Astrophysics Data System (ADS)

    Miura, Shinichi

    2011-01-01

    In the present study, a variational path integral molecular dynamics method developed by the author [Chem. Phys. Lett. 482 (2009) 165] is applied to a solid helium-4 in the ground state. The method is a molecular dynamics algorithm for a variational path integral method which can be used to generate the exact ground state numerically. The solid state is shown to successfully be realized by the method, although a poor trial wavefunction that cannot describe the solid state is used.

  7. THE VLA NASCENT DISK AND MULTIPLICITY SURVEY OF PERSEUS PROTOSTARS (VANDAM). II. MULTIPLICITY OF PROTOSTARS IN THE PERSEUS MOLECULAR CLOUD

    SciTech Connect

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

    2016-02-10

    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{sub ⊙} and ∼33 L{sub ⊙}, with a median of 0.7 L{sub ⊙}. 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.

  8. 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.

  9. 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

  10. Genetics and molecular profiling of multiple myeloma: novel tools for clinical management?

    PubMed

    Tassone, Pierfrancesco; Tagliaferri, Pierosandro; Rossi, Marco; Gaspari, Marco; Terracciano, Rosa; Venuta, Salvatore

    2006-07-01

    The understanding of molecular events involved in multiple myeloma (MM) development as well as of mechanisms underlying sensitivity/resistance to anticancer drugs has been dramatically increased by the wide-spread use of modern technologies for genetic analysis, global gene expression and proteomic profiling. Such analytical approaches, which are presently supported by reliable bioinformatic tools, have depicted a new scenario for the development of molecular-based anti-MM agents and for predicting clinical outcome. IgH translocations or a hyperdiploid state are emerging as early genetic signatures of MM which lead to deregulated expression of cyclin D. At present however, the major challenge remains the definition of the potential role of cytogenetic techniques and molecular profiling technologies in individual patient management. Here we will describe the prospective potential and current achievements of such technologies which might produce major advancements in the treatment of this still incurable disease.

  11. A method for integrating multiple components in a decision support system

    Treesearch

    Donald Nute; Walter D. Potter; Zhiyuan Cheng; Mayukh Dass; Astrid Glende; Frederick Maierv; Cy Routh; Hajime Uchiyama; Jin Wang; Sarah Witzig; Mark Twery; Peter Knopp; Scott Thomasma; H. Michael Rauscher

    2005-01-01

    We present a flexible, extensible method for integrating multiple tools into a single large decision support system (DSS) using a forest ecosystem management DSS (NED-2) as an example. In our approach, a rich ontology for the target domain is developed and implemented in the internal data model for the DSS. Semi-autonomous agents control external components and...

  12. 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…

  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. Technology Integration in a One-to-One Laptop Initiative: A Multiple Case Study Analysis

    ERIC Educational Resources Information Center

    Jones, Marsha B.

    2013-01-01

    The purpose of this multiple case study analysis was to examine teachers' experiences and perceptions in order to understand what actions and interactions supported or inhibited technology integration during a one-to-one laptop initiative. This research sought to gain teachers' perspectives on the challenges and successes they faced as classroom…

  15. Technology Integration in a One-to-One Laptop Initiative: A Multiple Case Study Analysis

    ERIC Educational Resources Information Center

    Jones, Marsha B.

    2013-01-01

    The purpose of this multiple case study analysis was to examine teachers' experiences and perceptions in order to understand what actions and interactions supported or inhibited technology integration during a one-to-one laptop initiative. This research sought to gain teachers' perspectives on the challenges and successes they faced as classroom…

  16. Fostering Creativity in Advertising Students: Incorporating the Theories of Multiple Intelligences and Integrative Learning.

    ERIC Educational Resources Information Center

    Rega, Bonney

    Noting that linguistic and mathematical/logical are the two kinds of intelligences the educational system encourages and that the educational system, as well as science in general, tends to neglect the nonverbal form of intellect, this paper describes Howard Gardner's multiple intelligences theory and Peter Kline's theory of integrative learning…

  17. Integration of graphene oxide and DNA as a universal platform for multiple arithmetic logic units.

    PubMed

    Wang, Kun; Ren, Jiangtao; Fan, Daoqing; Liu, Yaqing; Wang, Erkang

    2014-11-28

    By a combination of graphene oxide and DNA, a universal platform was developed for integration of multiple logic gates to implement both half adder and half subtractor functions. A constant undefined threshold range between high and low fluorescence output signals was set for all the developed logic gates.

  18. 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…

  19. STRUCTURE OF THE EGF RECEPTOR TRANSACTIVATION CIRCUIT INTEGRATES MULTIPLE SIGNALS WITH CELL CONTEXT

    PubMed Central

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

    2012-01-01

    Summary Transactivation of the epidermal growth factor receptor (EGFR) is thought to be a process by which a variety of cellular inputs can be integrated into a single signaling pathway through either stimulated proteolysis (shedding) of membrane-anchored EGFR ligands or by modification of the activity of the EGFR. As a first step towards building a predictive model of the EGFR transactivation circuit, we quantitatively defined how signals from multiple agonists were integrated both upstream and downstream of the EGFR to regulate extracellular signal regulated kinase (ERK) activity in human mammary epithelial cells. By using a “non-binding” reporter of ligand shedding, we found that transactivation triggers a positive feedback loop from ERK back to the EGFR such that ligand shedding drives EGFR-stimulated ERK that in turn drives further ligand shedding. Importantly, activated Ras and ERK levels were nearly linear functions of ligand shedding and the effect of multiple, sub-saturating inputs was additive. Simulations showed that ERK-mediated feedback through ligand shedding resulted in a stable steady-state level of activated ERK, but also showed that the extracellular environment can modulate the level of feedback. Our results suggest that the transactivation circuit acts as a context-dependent integrator and amplifier of multiple extracellular signals and that signal integration can effectively occur at multiple points in the EGFR pathway. PMID:20458382

  20. 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

  1. Stochastic, resonance-free multiple time-step algorithm for molecular dynamics with very large time steps

    NASA Astrophysics Data System (ADS)

    Leimkuhler, Ben; Margul, Daniel T.; Tuckerman, Mark E.

    2013-12-01

    Molecular dynamics is one of the most commonly used approaches for studying the dynamics and statistical distributions of physical, chemical, and biological systems using atomistic or coarse-grained models. It is often the case, however, that the interparticle forces drive motion on many time scales, and the efficiency of a calculation is limited by the choice of time step, which must be sufficiently small that the fastest force components are accurately integrated. Multiple time-stepping algorithms partially alleviate this inefficiency by assigning to each time scale an appropriately chosen step-size. As the fast forces are often computationally cheaper to evaluate than the slow forces, this results in a significant gain in efficiency. However, such approaches are limited by resonance phenomena, wherein motion on the fastest time scales limits the step sizes associated with slower time scales. In atomistic models of biomolecular systems, for example, resonances limit the largest time step to around 5-6 fs. Stochastic processes promote mixing and ergodicity in dynamical systems and reduce the impact of resonant modes. In this paper, we introduce a set of stochastic isokinetic equations of motion that are shown to be rigorously ergodic, largely free of resonances, and can be integrated using a multiple time-stepping algorithm which is easily implemented in existing molecular dynamics codes. The technique is applied to a simple, illustrative problem and then to a more realistic system, namely, a flexible water model. Using this approach outer time steps as large as 100 fs are shown to be possible.

  2. 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.

  3. 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.

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

    PubMed Central

    Daste, Frederic

    2016-01-01

    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

  5. 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

  6. Method for detection and identification of multiple chromosomal integration sites in transgenic animals created with lentivirus.

    PubMed

    Bryda, Elizabeth C; Pearson, Michael; Agca, Yuksel; Bauer, Beth A

    2006-12-01

    Transgene delivery systems, particularly those involving retroviruses, often result in the integration of multiple copies of the transgene throughout the host genome. Since site-specific silencing of trangenes can occur; it becomes important to identify the number and chromosomal location of the multiple copies of the transgenes in order to correlate inheritance of the transgene at a particular chromosomal site with a specific and robust phenotype. Using a technique that combines restriction endonuclease digest and several rounds of PCR amplification followed by nucleotide sequencing, it is possible to identify multiple chromosomal integration sites in transgenic founder animals. By designing genotyping assays to detect each individual integration site in the offspring of these founders, the inheritance of transgenes integrated at specific chromosomal locations can be followed efficiently as the transgenes randomly segregate in subsequent generations. Phenotypic characteristics can then be correlated with inheritance of a transgene integrated at a particular chromosomal location to allow rational selection of breeding animals in order to establish the transgenic line.

  7. 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

  8. 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.

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

    PubMed Central

    Fan, Guoling; Yan, Dongpeng

    2014-01-01

    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. PMID:24816686

  10. Identification of multiple low molecular weight placental prolactin-like proteins produced by rat trophoblast cells.

    PubMed

    Soares, M J; De, S K; Foster, B A; Julian, J A; Glasser, S R

    1988-01-01

    Rat trophoblast tissue was found to synthesize a number of low molecular weight proteins possessing prolactin-like characteristics. There appear to be at least three proteins that cross-react with antisera to pituitary prolactin. Two of the proteins had a molecular weight of 25,000, similar to ovine pituitary prolactin, and isoelectric points of 6.8 and 7.0. The third immunoreactive protein had a lower molecular weight (23,500), similar in size to human placental lactogen, and a slightly more acidic isoelectric point of 6.75. The molecular weight variants cross-reacted with an antipeptide serum that was generated to a synthetic peptide representing amino acids 150 to 164 of rat placental lactogen-2 (PL-2). Based on this analysis, we consider these proteins to be related to PL-2. Analysis of trophoblast proteins by gel-filtration chromatography resulted in the identification of another trophoblast prolactin. This material eluted earlier than PL-2-related proteins on a gel-filtration column, possessed prolactin-like activity (determined by competition with ovine pituitary prolactin for rabbit mammary gland or rat liver prolactin receptors) but showed limited cross-reactivity with either the antiserum to pituitary prolactin or the antiserum to the PL-2 peptide. We have thus identified multiple low molecular weight trophoblast prolactins, possessing different biochemical and immunological characteristics.

  11. 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.

  12. Benchmark values for molecular three-center integrals arising in the Dirac equation

    NASA Astrophysics Data System (ADS)

    Baǧcı, A.; Hoggan, P. E.

    2015-10-01

    Previous papers by the authors report that they obtained compact, arbitrarily accurate expressions for two-center, one- and two-electron relativistic molecular integrals expressed over Slater-type orbitals. In the present study, accuracy limits of expressions given are examined for three-center nuclear attraction integrals, which are one-electron, three-center integrals with no analytically closed-form expression. In this work new molecular auxiliary functions are used. They are obtained via Neumann expansion of the Coulomb interaction. The numerical global adaptive method is used to evaluate these integrals for arbitrary values of orbital parameters and quantum numbers. Several methods, such as Laplace expansion of Coulomb interaction, single-center expansion, and the Fourier transformation method, have previously been used to evaluate these integrals considering the values of principal quantum numbers in the set of positive integer numbers. This study of three-center integrals places no restrictions on quantum numbers in all ranges of orbital parameters.

  13. Benchmark values for molecular three-center integrals arising in the Dirac equation.

    PubMed

    Bağcı, A; Hoggan, P E

    2015-10-01

    Previous papers by the authors report that they obtained compact, arbitrarily accurate expressions for two-center, one- and two-electron relativistic molecular integrals expressed over Slater-type orbitals. In the present study, accuracy limits of expressions given are examined for three-center nuclear attraction integrals, which are one-electron, three-center integrals with no analytically closed-form expression. In this work new molecular auxiliary functions are used. They are obtained via Neumann expansion of the Coulomb interaction. The numerical global adaptive method is used to evaluate these integrals for arbitrary values of orbital parameters and quantum numbers. Several methods, such as Laplace expansion of Coulomb interaction, single-center expansion, and the Fourier transformation method, have previously been used to evaluate these integrals considering the values of principal quantum numbers in the set of positive integer numbers. This study of three-center integrals places no restrictions on quantum numbers in all ranges of orbital parameters.

  14. Ab initio path integral ring polymer molecular dynamics: Vibrational spectra of molecules

    NASA Astrophysics Data System (ADS)

    Shiga, Motoyuki; Nakayama, Akira

    2008-01-01

    The path integral ring polymer molecular dynamics method is combined with 'on-the-fly' ab initio electronic structure calculations and applied to vibrational spectra of small molecules, LiH and H 2O, at the room temperature. The results are compared with those of the numerically exact solution and ab initio path integral centroid molecular dynamics calculation. The peak positions in the calculated spectra are found to be reasonable, showing the red-shift due to potential anharmonicity. This unification enables the investigation of real-time quantum dynamics of chemically complex molecular systems on the ab initio Born-Oppenheimer potential energy surface.

  15. 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.

  16. 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.

  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

    NASA Astrophysics Data System (ADS)

    Omelyan, Igor; Kovalenko, Andriy

    2013-12-01

    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. 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

  19. On the applicability of centroid and ring polymer path integral molecular dynamics for vibrational spectroscopy

    NASA Astrophysics Data System (ADS)

    Witt, Alexander; Ivanov, Sergei D.; Shiga, Motoyuki; Forbert, Harald; Marx, Dominik

    2009-05-01

    Centroid molecular dynamics (CMD) and ring polymer molecular dynamics (RPMD) are two conceptually distinct extensions of path integral molecular dynamics that are able to generate approximate quantum dynamics of complex molecular systems. Both methods can be used to compute quasiclassical time correlation functions which have direct application in molecular spectroscopy; in particular, to infrared spectroscopy via dipole autocorrelation functions. The performance of both methods for computing vibrational spectra of several simple but representative molecular model systems is investigated systematically as a function of temperature and isotopic substitution. In this context both CMD and RPMD feature intrinsic problems which are quantified and investigated in detail. Based on the obtained results guidelines for using CMD and RPMD to compute infrared spectra of molecular systems are provided.

  20. A rapid and reliable strategy for chromosomal integration of gene(s) with multiple copies

    PubMed Central

    Gu, Pengfei; Yang, Fan; Su, Tianyuan; Wang, Qian; Liang, Quanfeng; Qi, Qingsheng

    2015-01-01

    Direct optimization of the metabolic pathways on the chromosome requires tools that can fine tune the overexpression of a desired gene or optimize the combination of multiple genes. Although plasmid-dependent overexpression has been used for this task, fundamental issues concerning its genetic stability and operational repeatability have not been addressed. Here, we describe a rapid and reliable strategy for chromosomal integration of gene(s) with multiple copies (CIGMC), which uses the flippase from the yeast 2-μm plasmid. Using green fluorescence protein as a model, we verified that the fluorescent intensity was in accordance with the integration copy number of the target gene. When a narrow-host-range replicon, R6K, was used in the integrative plasmid, the maximum integrated copy number of Escherichia coli reached 15. Applying the CIGMC method to optimize the overexpression of single or multiple genes in amino acid biosynthesis, we successfully improved the product yield and stability of the production. As a flexible strategy, CIGMC can be used in various microorganisms other than E. coli. PMID:25851494

  1. Identification of HBV-MLL4 Integration and Its Molecular Basis in Chinese Hepatocellular Carcinoma

    PubMed Central

    Zhu, Xuehua; Zhu, Guanshan; Chen, Yunqin; Xie, Xiaoying; Ye, Qinghai; Zang, Jie; Ren, Zhenggang; Ji, Qunsheng

    2015-01-01

    To gain molecular insights of HBV integration that may contribute to HCC tumorigenesis, we performed whole transcriptome sequencing and whole genome copy number profiling of hepatocellular carcinoma (HCC) samples from 50 Chinese patients. We identified a total of 33 HBV-human integration sites in 16 of 44 HBV-positive HCC tissues, which were enriched in HBV genotype C-infected patients. In addition, significantly recurrent HBV-MLL4 integration (18%; 8/44) was found in this cohort of patients. Using long-range PCR and Sanger sequencing, we comprehensively characterized gDNA and cDNA sequences that encode for the HBV-MLL4 transcripts, and we revealed that HBV integration into MLL4 exons led to much higher mRNA expression of MLL4 than the integration into MLL4 introns due to an alternative splicing mechanism. Moreover, the HBV-MLL4 integration occurred almost exclusively in CTNNB1 and TP53 wild-type patients. The integration was also associated with a distinct gene expression profile. In conclusion, this is the first report on the molecular basis of the MLL4 integration driving MLL4 over-expression. HBV-MLL4 integration occurred frequently in Chinese HCC patients, representing a unique molecular segment for HCC with HBV infection. PMID:25901726

  2. DNA extraction methods and multiple sampling to improve molecular diagnosis of Sarcocystis spp. in cattle hearts.

    PubMed

    Bräunig, Patrícia; Portella, Luiza Pires; Cezar, Alfredo Skrebsky; Libardoni, Felipe; Sangioni, Luis Antonio; Vogel, Fernanda Silveira Flores; Gonçalves, Paulo Bayard Dias

    2016-10-01

    Molecular detection of Sarcocystis spp. in tissue samples can be useful for experimental and diagnostic purposes. However, the parasite spreads unevenly through tissues, forming tissue cysts, and the cystic wall is an obstacle in DNA extraction protocols. Therefore, adequate sampling and effective disruption of the cysts are essential to improve the accuracy of DNA detection by PCR. The aims of this study were to evaluate the suitability of four protocols for DNA extraction from cysts of Sarcocystis spp. present in bovine myocardium samples or after their harvest in phosphate-buffered saline (PBS) solution as well as determine the effects of single or multiple sampling on the accuracy of molecular diagnosis of sarcocystosis in cattle hearts. Cysts and myocardium samples from nine bovine hearts were randomly distributed to four DNA extraction protocols: kit, kit with modification, DNAzol, and cetyl-trimethyl ammonium bromide (CTAB). Samples were submitted to DNA extraction and PCR as replicates of each heart (simplicate, duplicate, and triplicate), and the probability of a true positive diagnostic was calculated. Among the protocols tested, the kit with modification was determined to be the most suitable for DNA extraction from cysts in PBS solution (92.6 % of DNA detection by PCR); DNAzol resulted in higher DNA detection frequency from bovine myocardium samples (48.1 %). Multiple sampling improved the molecular diagnosis of Sarcocystis spp. infection in cattle hearts, increasing at 22.2 % the rate of true positive diagnostic.

  3. The use of multiple oxygen implants for fabrication of bipolar silicon-on-insulator integrated circuits

    NASA Astrophysics Data System (ADS)

    Platteter, Dale G.; Cheek, Tom F., Jr.

    1988-12-01

    A description is given of the radiation improvements obtained by fabricating bipolar integrated circuits on oxygen-implanted silicon-on-insulator substrates that were manufactured with multiple (low-dose) implants. Bipolar 74ALSOO gates fabricated on these substrates showed an improvement in total dose and dose-rate radiation response over identical circuits fabricated in bulk silicon. Defects in SIMOX material were reduced by over four orders of magnitude. The results demonstrate that bipolar devices, fabricated on multiple-implant SIMOX substrates, can compete with conventional dielectric isolation for many radiation-hardened system applications.

  4. 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

  5. Molecular Integrity of Mitochondria Alters by Potassium Chloride.

    PubMed

    Mishra, Suman; Mishra, Rajnikant

    2015-01-01

    Potassium chloride (KCl) has been commonly used in homogenization buffer and procedures of protein extraction. It is known to facilitate release of membrane-associated molecules but the higher concentration of KCl may affect the integrity of mitochondria by breaching the electrostatic force between the lipids and proteins. Therefore, it has been intended to explore the effect of KCl on mitochondrial proteome. The mitochondria were isolated from the mice liver and sub-fractionated into mitochondrial matrix and outer mitochondrial membrane fraction. The fractions were analysed by denaturing polyacrylamide gel electrophoresis (PAGE) and 2D-PAGE. The analysis of ultrastructure and protein profiles by MALDI-MS and data-mining reveals KCl-associated alterations in the integrity of mitochondria and its proteome. The mitochondrial membrane, cristae, and the matrix proteins appear altered under the influence of KCl.

  6. Multiple trim magnets, or magic fingers,'' for insertion device field integral correction

    SciTech Connect

    Hoyer, E.; Marks, S.; Pipersky, P.; Schlueter, R. )

    1995-02-01

    Multiple trim magnets (MTMs), also known as magic fingers,'' are an arrangement of magnets for reducing integrated magnetic-field errors in insertion devices. The idea is to use transverse arrays of permanent magnets, hence the name multiple trim magnets,'' above and below the midplane, to correct both normal and skew longitudinal magnetic-field integral errors in a device. MTMs are typically installed at the ends of an ID. Adjustments are made by changing either the size, position, or orientation of each trim magnet. Application of the MTMs to the ALS undulators reduced both the normal and skew longitudinal field integral errors, over the entire 20 mm[times]60 mm good field region,'' of the beam aperture by as much as an order of magnitude. The requirements included corrections of field and gradients outside the multipole convergence radius. Additionally, these trim magnet arrays provided correction of the linear component of the integrated field gradients for particles with trajectories not parallel to the nominal beam axis. The MTM concept, design, construction, tests that demonstrated feasibility, and magnetic-field integral reduction of ALS undulators are presented.

  7. 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

  8. Molecular characterization of Neisseria gonorrhoeae on non-cultured specimens from multiple anatomic sites.

    PubMed

    Carannante, Anna; Ghisetti, Valeria; Dal Conte, Ivano; Gregori, Gabriella; Stella, Maria Laura; Vacca, Paola; Del Re, Simonetta; Stefanelli, Paola

    2017-01-01

    The aim of this study was to molecularly characterize Neisseria gonorrhoeae on non-cultured specimens collected from multiple anatomic sites. N. gonorrhoeae multiantigen sequence typing (NG-MAST) together with the gene sequence analysis of antimicrobial resistance (AMR) target genes were used. Seventeen genital and extra-genital samples from eight patients (7 were men who have sex with men, MSM, and 1 women who have sex with men, WSM) with gonorrhoea symptoms were analyzed. For 7, of the 8 patients, conventional culture method has been used to identify gonorrhoea. All the samples were tested with the rapid molecular method CEPHEID. Amplification and sequencing of porB and tbpB, to identify the Sequence Type (ST) by NG-MAST, and penA, mtrR, porB1b, ponA genes were also performed. Antimicrobial susceptibility by Etest, for the available culture positive samples, was carried out. For 7 patients the ST was obtained and for 6 the complete sequence analysis of the AMR target genes was also defined. For the majority of them, samples collected from multiple sites (oropharynx, rectum, vaginal and urethra) confirm the presence of the same gonorrhoea strain. In particular, for 5 patients the same STs and changes in the AMR target genes were identified. Molecular characterization on non-cultured or culture negative specimens for gonorrhoea can successfully be applied directly to genital and extra-genital samples. Thus permit to identify the presence of the same strain in patients with gonorrhoea infection in multiple anatomic sites and to predict the antimicrobial susceptibility pattern.

  9. Molecular Profiling of Glatiramer Acetate Early Treatment Effects in Multiple Sclerosis

    PubMed Central

    Achiron, Anat; Feldman, Anna; Gurevich, Michael

    2009-01-01

    Background: Glatiramer acetate (GA, Copaxone®) has beneficial effects on the clinical course of relapsing-remitting multiple sclerosis (RRMS). However, the exact molecular mechanisms of GA effects are only partially understood. Objective: To characterized GA molecular effects in RRMS patients within 3 months of treatment by microarray profiling of peripheral blood mononuclear cells (PBMC). Methods: Gene-expression profiles were determined in RRMS patients before and at 3 months after initiation of GA treatment using Affimetrix (U133A-2) microarrays containing 14,500 well-characterized human genes. Most informative genes (MIGs) of GA-induced biological convergent pathways operating in RRMS were constructed using gene functional annotation, enrichment analysis and pathway reconstruction bioinformatic softwares. Verification at the mRNA and protein level was performed by qRT-PCR and FACS. Results: GA induced a specific gene expression molecular signature that included altered expression of 480 genes within 3 months of treatment; 262 genes were up-regulated, and 218 genes were down-regulated. The main convergent mechanisms of GA effects were related to antigen-activated apoptosis, inflammation, adhesion, and MHC class-I antigen presentation. Conclusions: Our findings demonstrate that GA treatment induces alternations of immunomodulatory gene expression patterns that are important for suppression of disease activity already at three months of treatment and can be used as molecular markers of GA activity. PMID:19893201

  10. Multiple time scale molecular dynamics for fluids with orientational degrees of freedom. II. Canonical and isokinetic ensembles

    NASA Astrophysics Data System (ADS)

    Omelyan, Igor P.; Kovalenko, Andriy

    2011-12-01

    We have developed several multiple time stepping techniques to overcome the limitations on efficiency of molecular dynamics simulations of complex fluids. They include the modified canonical and isokinetic schemes, as well as the extended isokinetic Nosé-Hoover chain approach. The latter generalizes the method of Minary, Tuckerman, and Martyna for translational motion [Phys. Rev. Lett. 93, 150201 (2004)], 10.1103/PhysRevLett.93.150201 to systems with both translational and orientational degrees of freedom. Although the microcanonical integrators are restricted to relatively small outer time steps of order of 16 fs, we show on the basis of molecular dynamics simulations of ambient water that in the canonical and isokinetic thermostats the size of these steps can be increased to 50 and 75 fs, respectively (at the same inner time step of 4 fs). Within the generalized isokinetic Nosé-Hoover chain algorithm we have derived, huge outer time steps of order of 500 fs can be used without losing numerical stability and affecting equilibrium properties

  11. Benchmark values for molecular two-electron integrals arising from the Dirac equation.

    PubMed

    Bağcı, A; Hoggan, P E

    2015-02-01

    The two-center two-electron Coulomb and hybrid integrals arising in relativistic and nonrelativistic ab initio calculations on molecules are evaluated. Compact, arbitrarily accurate expressions are obtained. They are expressed through molecular auxiliary functions and evaluated with the numerical Global-adaptive method for arbitrary values of parameters in the noninteger Slater-type orbitals. Highly accurate benchmark values are presented for these integrals. The convergence properties of new molecular auxiliary functions are investigated. The comparison for two-center two-electron integrals is made with results obtained from single center expansions by translation of the wave function to a single center with integer principal quantum numbers and results obtained from the Cuba numerical integration algorithm, respectively. The procedures discussed in this work are capable of yielding highly accurate two-center two-electron integrals for all ranges of orbital parameters.

  12. Benchmark values for molecular two-electron integrals arising from the Dirac equation

    NASA Astrophysics Data System (ADS)

    Baǧcı, A.; Hoggan, P. E.

    2015-02-01

    The two-center two-electron Coulomb and hybrid integrals arising in relativistic and nonrelativistic ab initio calculations on molecules are evaluated. Compact, arbitrarily accurate expressions are obtained. They are expressed through molecular auxiliary functions and evaluated with the numerical Global-adaptive method for arbitrary values of parameters in the noninteger Slater-type orbitals. Highly accurate benchmark values are presented for these integrals. The convergence properties of new molecular auxiliary functions are investigated. The comparison for two-center two-electron integrals is made with results obtained from single center expansions by translation of the wave function to a single center with integer principal quantum numbers and results obtained from the Cuba numerical integration algorithm, respectively. The procedures discussed in this work are capable of yielding highly accurate two-center two-electron integrals for all ranges of orbital parameters.

  13. 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.

  14. 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

  15. Molecular Characterization of Pediatric Restrictive Cardiomyopathy from Integrative Genomics

    PubMed Central

    Rindler, Tara N.; Hinton, Robert B.; Salomonis, Nathan; Ware, Stephanie M.

    2017-01-01

    Pediatric restrictive cardiomyopathy (RCM) is a genetically heterogeneous heart disease with limited therapeutic options. RCM cases are largely idiopathic; however, even within families with a known genetic cause for cardiomyopathy, there is striking variability in disease severity. Although accumulating evidence implicates both gene expression and alternative splicing in development of dilated cardiomyopathy (DCM), there have been no detailed molecular characterizations of underlying pathways dysregulated in RCM. RNA-Seq on a cohort of pediatric RCM patients compared to other forms of adult cardiomyopathy and controls identified transcriptional differences highly common to the cardiomyopathies, as well as those unique to RCM. Transcripts selectively induced in RCM include many known and novel G-protein coupled receptors linked to calcium handling and contractile regulation. In-depth comparisons of alternative splicing revealed splicing events shared among cardiomyopathy subtypes, as well as those linked solely to RCM. Genes identified with altered alternative splicing implicate RBM20, a DCM splicing factor, as a potential mediator of alternative splicing in RCM. We present the first comprehensive report on molecular pathways dysregulated in pediatric RCM including unique/shared pathways identified compared to other cardiomyopathy subtypes and demonstrate that disruption of alternative splicing patterns in pediatric RCM occurs in the inverse direction as DCM. PMID:28098235

  16. Molecular Characterization of Pediatric Restrictive Cardiomyopathy from Integrative Genomics.

    PubMed

    Rindler, Tara N; Hinton, Robert B; Salomonis, Nathan; Ware, Stephanie M

    2017-01-18

    Pediatric restrictive cardiomyopathy (RCM) is a genetically heterogeneous heart disease with limited therapeutic options. RCM cases are largely idiopathic; however, even within families with a known genetic cause for cardiomyopathy, there is striking variability in disease severity. Although accumulating evidence implicates both gene expression and alternative splicing in development of dilated cardiomyopathy (DCM), there have been no detailed molecular characterizations of underlying pathways dysregulated in RCM. RNA-Seq on a cohort of pediatric RCM patients compared to other forms of adult cardiomyopathy and controls identified transcriptional differences highly common to the cardiomyopathies, as well as those unique to RCM. Transcripts selectively induced in RCM include many known and novel G-protein coupled receptors linked to calcium handling and contractile regulation. In-depth comparisons of alternative splicing revealed splicing events shared among cardiomyopathy subtypes, as well as those linked solely to RCM. Genes identified with altered alternative splicing implicate RBM20, a DCM splicing factor, as a potential mediator of alternative splicing in RCM. We present the first comprehensive report on molecular pathways dysregulated in pediatric RCM including unique/shared pathways identified compared to other cardiomyopathy subtypes and demonstrate that disruption of alternative splicing patterns in pediatric RCM occurs in the inverse direction as DCM.

  17. 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.

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

    SciTech Connect

    Beard, M. C.; Johnson, J. C.; Luther, J. M.; Nozik, A. J.

    2015-05-18

    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.

  19. Physics Based Protein Structure Refinement through Multiple Molecular Dynamics Trajectories and Structure Averaging

    PubMed Central

    Mirjalili, Vahid; Noyes, Keenan; Feig, Michael

    2014-01-01

    We used molecular dynamics (MD) simulations for structure refinement of CASP10 targets. Refinement was achieved by selecting structures from the MD-based ensembles followed by structural averaging. The overall performance of this method in CASP10 is described and specific aspects are analyzed in detail to provide insight into key components. In particular, the use of different restraint types, sampling from multiple short simulations vs. a single long simulation, the success of a quality assessment criterion, the application of scoring vs. averaging, and the impact of a final refinement step are discussed in detail. PMID:23737254

  20. 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.

  1. Integrity Verification for Multiple Data Copies in Cloud Storage Based on Spatiotemporal Chaos

    NASA Astrophysics Data System (ADS)

    Long, Min; Li, You; Peng, Fei

    Aiming to strike for a balance between the security, efficiency and availability of the data verification in cloud storage, a novel integrity verification scheme based on spatiotemporal chaos is proposed for multiple data copies. Spatiotemporal chaos is implemented for node calculation of the binary tree, and the location of the data in the cloud is verified. Meanwhile, dynamic operation can be made to the data. Furthermore, blind information is used to prevent a third-party auditor (TPA) leakage of the users’ data privacy in a public auditing process. Performance analysis and discussion indicate that it is secure and efficient, and it supports dynamic operation and the integrity verification of multiple copies of data. It has a great potential to be implemented in cloud storage services.

  2. 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.

  3. Modeling of multiple-optical-axis pattern-integrated interference lithography systems.

    PubMed

    Sedivy, Donald E; Gaylord, Thomas K

    2014-06-01

    The image quality and collimation in a multiple-optical-axis pattern-integrated interference lithography system are evaluated for an elementary optical system composed of single-element lenses. Image quality and collimation are individually and jointly optimized for these lenses. Example images for a jointly optimized system are simulated using a combination of ray tracing and Fourier analysis. Even with these nonoptimized components, reasonable fidelity is shown to be possible.

  4. It is time to integrate: the temporal dynamics of object motion and texture motion integration in multiple object tracking.

    PubMed

    Huff, Markus; Papenmeier, Frank

    2013-01-14

    In multiple-object tracking, participants can track several moving objects among identical distractors. It has recently been shown that the human visual system uses motion information in order to keep track of targets (St. Clair et al., Journal of Vision, 10(4), 1-13). Texture on the surface of an object that moved in the opposite direction to the object itself impaired tracking performance. In this study, we examined the temporal interval at which texture motion and object motion is integrated in dynamic scenes. In two multiple-object tracking experiments, we manipulated the texture motion on the objects: The texture either moved in the same direction as the objects, in the opposite direction, or alternated between the same and opposite direction at varying intervals. In Experiment 1, we show that the integration of object motion and texture motion can take place at intervals as short as 100 ms. In Experiment 2, we show that there is a linear relationship between the proportion of opposite texture motion and tracking performance. We suggest that texture motion might cause shifts in perceived object locations, thus influencing tracking performance.

  5. 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

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

    NASA Astrophysics Data System (ADS)

    Kamibayashi, Yuki; Miura, Shinichi

    2016-08-01

    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.

  7. 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.

  8. 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.

  9. 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. Copyright © 2015 the American Physiological Society.

  10. 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

  11. Communication: Kirkwood-Buff integrals in the thermodynamic limit from small-sized molecular dynamics simulations

    NASA Astrophysics Data System (ADS)

    Cortes-Huerto, R.; Kremer, K.; Potestio, R.

    2016-10-01

    We present an accurate and efficient method to obtain Kirkwood-Buff (KB) integrals in the thermodynamic limit from small-sized molecular dynamics simulations. By introducing finite size effects into integral equations of statistical mechanics, we derive an analytical expression connecting the KB integrals of the bulk system with the fluctuations of the number of molecules in the corresponding closed system. We validate the method by calculating the activity coefficients of aqueous urea mixtures and the KB integrals of Lennard-Jones fluids. Moreover, our results demonstrate how to identify simulation conditions under which computer simulations reach the thermodynamic limit.

  12. The integration of occupational therapy into primary care: a multiple case study design

    PubMed Central

    2013-01-01

    Background For over two decades occupational therapists have been encouraged to enhance their roles within primary care and focus on health promotion and prevention activities. While there is a clear fit between occupational therapy and primary care, there have been few practice examples, despite a growing body of evidence to support the role. In 2010, the province of Ontario, Canada provided funding to include occupational therapists as members of Family Health Teams, an interprofessional model of primary care. The integration of occupational therapists into this model of primary care is one of the first large scale initiatives of its kind in North America. The objective of the study was to examine how occupational therapy services are being integrated into primary care teams and understand the structures supporting the integration. Methods A multiple case study design was used to provide an in-depth description of the integration of occupational therapy. Four Family Health Teams with occupational therapists as part of the team were identified. Data collection included in-depth interviews, document analyses, and questionnaires. Results Each Family Health Team had a unique organizational structure that contributed to the integration of occupational therapy. Communication, trust and understanding of occupational therapy were key elements in the integration of occupational therapy into Family Health Teams, and were supported by a number of strategies including co-location, electronic medical records and team meetings. An understanding of occupational therapy was critical for integration into the team and physicians were less likely to understand the occupational therapy role than other health providers. Conclusion With an increased emphasis on interprofessional primary care, new professions will be integrated into primary healthcare teams. The study found that explicit strategies and structures are required to facilitate the integration of a new professional group

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

    PubMed

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

    2014-01-01

    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.

  14. Quantum Chemically Estimated Abraham Solute Parameters Using Multiple Solvent-Water Partition Coefficients and Molecular Polarizability.

    PubMed

    Liang, Yuzhen; Xiong, Ruichang; Sandler, Stanley I; Di Toro, Dominic M

    2017-09-05

    Polyparameter Linear Free Energy Relationships (pp-LFERs), also called Linear Solvation Energy Relationships (LSERs), are used to predict many environmentally significant properties of chemicals. A method is presented for computing the necessary chemical parameters, the Abraham parameters (AP), used by many pp-LFERs. It employs quantum chemical calculations and uses only the chemical's molecular structure. The method computes the Abraham E parameter using density functional theory computed molecular polarizability and the Clausius-Mossotti equation relating the index refraction to the molecular polarizability, estimates the Abraham V as the COSMO calculated molecular volume, and computes the remaining AP S, A, and B jointly with a multiple linear regression using sixty-five solvent-water partition coefficients computed using the quantum mechanical COSMO-SAC solvation model. These solute parameters, referred to as Quantum Chemically estimated Abraham Parameters (QCAP), are further adjusted by fitting to experimentally based APs using QCAP parameters as the independent variables so that they are compatible with existing Abraham pp-LFERs. QCAP and adjusted QCAP for 1827 neutral chemicals are included. For 24 solvent-water systems including octanol-water, predicted log solvent-water partition coefficients using adjusted QCAP have the smallest root-mean-square errors (RMSEs, 0.314-0.602) compared to predictions made using APs estimated using the molecular fragment based method ABSOLV (0.45-0.716). For munition and munition-like compounds, adjusted QCAP has much lower RMSE (0.860) than does ABSOLV (4.45) which essentially fails for these compounds.

  15. A Nonparametric, Multiple Imputation-Based Method for the Retrospective Integration of Data Sets

    PubMed Central

    Carrig, Madeline M.; Manrique-Vallier, Daniel; Ranby, Krista W.; Reiter, Jerome P.; Hoyle, Rick H.

    2015-01-01

    Complex research questions often cannot be addressed adequately with a single data set. One sensible alternative to the high cost and effort associated with the creation of large new data sets is to combine existing data sets containing variables related to the constructs of interest. The goal of the present research was to develop a flexible, broadly applicable approach to the integration of disparate data sets that is based on nonparametric multiple imputation and the collection of data from a convenient, de novo calibration sample. We demonstrate proof of concept for the approach by integrating three existing data sets containing items related to the extent of problematic alcohol use and associations with deviant peers. We discuss both necessary conditions for the approach to work well and potential strengths and weaknesses of the method compared to other data set integration approaches. PMID:26257437

  16. Modulation of C. elegans Touch Sensitivity Is Integrated at Multiple Levels

    PubMed Central

    Chen, Xiaoyin

    2014-01-01

    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

  17. Molecular basis of voltage dependence of connexin channels: an integrative appraisal.

    PubMed

    González, Daniel; Gómez-Hernández, Juan M; Barrio, Luis C

    2007-01-01

    The importance of electrical and molecular signaling through connexin (Cx) channels is now widely recognized. The transfer of ions and other small molecules between adjacent cells is regulated by multiple stimuli, including voltage. Indeed, Cx channels typically exhibit complex voltage sensitivity. Most channels are sensitive to the voltage difference between the cell interiors (or transjunctional voltage, V(j)), while other channels are also sensitive to absolute inside-outside voltage (i.e., the membrane potential, V(m)). The first part of this review is focused on the description of the distinct forms of voltage sensitivity and the gating mechanisms that regulate hemichannel activity, both individually and as components of homotypic and heterotypic gap junctions. We then provide an up to date and precise picture of the molecular and structural aspects of how V(j) and V(m) are sensed, and how they, therefore, control channel opening and closing. Mutagenic strategies coupled with structural, biochemical and electrophysical studies are providing significant insights into how distinct forms of voltage dependence are brought about. The emerging picture indicates that Cx channels can undergo transitions between multiple conductance states driven by distinct voltage-gating mechanisms. Each hemichannel may contain a set of two V(j) gates, one fast and one slow, which mediate the transitions between the main open state to the residual state and to the fully closed state, respectively. Eventually, a V(m) gate regulates channel transitions between the open and closed states. Clusters of charged residues within separate domains of the Cx molecule have been identified as integral parts of the V(j) and V(m) sensors. The charges at the first positions of the amino terminal cytoplasmic domain determine the magnitude and polarity of the sensitivity to fast V(j)-gating, as well as contributing to the V(j)-rectifying properties of ion permeation. Additionally, important advances

  18. Ab initio centroid path integral molecular dynamics: Application to vibrational dynamics of diatomic molecular systems

    NASA Astrophysics Data System (ADS)

    Ohta, Yasuhito; Ohta, Koji; Kinugawa, Kenichi

    2004-01-01

    An ab initio centroid molecular dynamics (CMD) method is developed by combining the CMD method with the ab initio molecular orbital method. The ab initio CMD method is applied to vibrational dynamics of diatomic molecules, H2 and HF. For the H2 molecule, the temperature dependence of the peak frequency of the vibrational spectral density is investigated. The results are compared with those obtained by the ab initio classical molecular dynamics method and exact quantum mechanical treatment. It is shown that the vibrational frequency obtained from the ab initio CMD approaches the exact first excitation frequency as the temperature lowers. For the HF molecule, the position autocorrelation function is also analyzed in detail. The present CMD method is shown to well reproduce the exact quantum result for the information on the vibrational properties of the system.

  19. 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

  20. Three-dimensional molecular mapping of a multiple emulsion by means of CARS microscopy.

    PubMed

    Meyer, Tobias; Akimov, Denis; Tarcea, Nicolae; Chatzipapadopoulos, Susana; Muschiolik, Gerald; Kobow, Jens; Schmitt, Michael; Popp, Jürgen

    2008-02-07

    Multiple emulsions consisting of water droplets dispersed in an oil phase containing emulsifier which is emulsified in an outer water phase (W/O/W) are of great interest in pharmacology for developing new drugs, in the nutrition sciences for designing functional food, and in biology as model systems for cell organelles such as liposomes. In the food industry multiple emulsions with high sugar content in the aqueous phase can be used for the production of sweets, because the high sugar content prevents deterioration. However, for these emulsions the refractive indexes of oil and aqueous phase are very similar. This seriously impedes the analysis of these emulsions, e.g., for process monitoring, because microscopic techniques based on transmission or reflection do not provide sufficient contrast. We have characterized the inner dispersed phase of concentrated W/O/W emulsions with the same refractive index of the three phases by micro Raman spectroscopy and investigated the composition and molecular distribution in water-oil-water emulsions by means of three-dimensional laser scanning CARS (coherent anti-Stokes Raman scattering) microscopy. CARS microscopy has been used to study water droplets dispersed in oil droplets at different Raman resonances to visualize different molecular species. Water droplets with a diameter of about 700 nm could clearly be visualized. The advantages of CARS microscopy for studying this particular system are emphasized by comparing this microscopic technique with conventional confocal reflection and transmission microscopies.

  1. Raman spectroscopy explores molecular structural signatures of hidden materials in depth: Universal Multiple Angle Raman Spectroscopy

    PubMed Central

    Sil, Sanchita; Umapathy, Siva

    2014-01-01

    Non-invasive 3D imaging in materials and medical research involves methodologies such as X-ray imaging, MRI, fluorescence and optical coherence tomography, NIR absorption imaging, etc., providing global morphological/density/absorption changes of the hidden components. However, molecular information of such buried materials has been elusive. In this article we demonstrate observation of molecular structural information of materials hidden/buried in depth using Raman scattering. Typically, Raman spectroscopic observations are made at fixed collection angles, such as, 90°, 135°, and 180°, except in spatially offset Raman scattering (SORS) (only back scattering based collection of photons) and transmission techniques. Such specific collection angles restrict the observations of Raman signals either from or near the surface of the materials. Universal Multiple Angle Raman Spectroscopy (UMARS) presented here employs the principle of (a) penetration depth of photons and then diffuse propagation through non-absorbing media by multiple scattering and (b) detection of signals from all the observable angles. PMID:24930768

  2. DNA-enabled integrated molecular systems for computation and sensing.

    PubMed

    LaBoda, Craig; Duschl, Heather; Dwyer, Chris L

    2014-06-17

    CONSPECTUS: Nucleic acids have become powerful building blocks for creating supramolecular nanostructures with a variety of new and interesting behaviors. The predictable and guided folding of DNA, inspired by nature, allows designs to manipulate molecular-scale processes unlike any other material system. Thus, DNA can be co-opted for engineered and purposeful ends. This Account details a small portion of what can be engineered using DNA within the context of computer architectures and systems. Over a decade of work at the intersection of DNA nanotechnology and computer system design has shown several key elements and properties of how to harness the massive parallelism created by DNA self-assembly. This work is presented, naturally, from the bottom-up beginning with early work on strand sequence design for deterministic, finite DNA nanostructure synthesis. The key features of DNA nanostructures are explored, including how the use of small DNA motifs assembled in a hierarchical manner enables full-addressability of the final nanostructure, an important property for building dense and complicated systems. A full computer system also requires devices that are compatible with DNA self-assembly and cooperate at a higher level as circuits patterned over many, many replicated units. Described here is some work in this area investigating nanowire and nanoparticle devices, as well as chromophore-based circuits called resonance energy transfer (RET) logic. The former is an example of a new way to bring traditional silicon transistor technology to the nanoscale, which is increasingly problematic with current fabrication methods. RET logic, on the other hand, introduces a framework for optical computing at the molecular level. This Account also highlights several architectural system studies that demonstrate that even with low-level devices that are inferior to their silicon counterparts and a substrate that harbors abundant defects, self-assembled systems can still

  3. A DICOM-based 2nd generation Molecular Imaging Data Grid implementing the IHE XDS-i integration profile.

    PubMed

    Lee, Jasper; Zhang, Jianguo; Park, Ryan; Dagliyan, Grant; Liu, Brent; Huang, H K

    2012-07-01

    A Molecular Imaging Data Grid (MIDG) was developed to address current informatics challenges in archival, sharing, search, and distribution of preclinical imaging studies between animal imaging facilities and investigator sites. This manuscript presents a 2nd generation MIDG replacing the Globus Toolkit with a new system architecture that implements the IHE XDS-i integration profile. Implementation and evaluation were conducted using a 3-site interdisciplinary test-bed at the University of Southern California. The 2nd generation MIDG design architecture replaces the initial design's Globus Toolkit with dedicated web services and XML-based messaging for dedicated management and delivery of multi-modality DICOM imaging datasets. The Cross-enterprise Document Sharing for Imaging (XDS-i) integration profile from the field of enterprise radiology informatics was adopted into the MIDG design because streamlined image registration, management, and distribution dataflow are likewise needed in preclinical imaging informatics systems as in enterprise PACS application. Implementation of the MIDG is demonstrated at the University of Southern California Molecular Imaging Center (MIC) and two other sites with specified hardware, software, and network bandwidth. Evaluation of the MIDG involves data upload, download, and fault-tolerance testing scenarios using multi-modality animal imaging datasets collected at the USC Molecular Imaging Center. The upload, download, and fault-tolerance tests of the MIDG were performed multiple times using 12 collected animal study datasets. Upload and download times demonstrated reproducibility and improved real-world performance. Fault-tolerance tests showed that automated failover between Grid Node Servers has minimal impact on normal download times. Building upon the 1st generation concepts and experiences, the 2nd generation MIDG system improves accessibility of disparate animal-model molecular imaging datasets to users outside a molecular

  4. An integrative system biology approach to unravel potential drug candidates for multiple age related disorders.

    PubMed

    Srivastava, Isha; Khurana, Pooja; Yadav, Mohini; Hasija, Yasha

    2017-08-11

    Aging, though an inevitable part of life, is becoming a worldwide social and economic problem. Healthy aging is usually marked by low probability of age related disorders. Good therapeutic approaches are still in need to cure age related disorders. Occurrence of more than one ARD in an individual, expresses the need of discovery of such target proteins, which can affect multiple ARDs. Advanced scientific and medical research technologies throughout last three decades have arrived to the point where lots of key molecular determinants affect human disorders can be examined thoroughly. In this study, we designed and executed an approach to prioritize drugs that may target multiple age related disorders. Our methodology, focused on the analysis of biological pathways and protein protein interaction networks that may contribute to the pharmacology of age related disorders, included various steps such as retrieval and analysis of data, protein-protein interaction network analysis, and statistical and comparative analysis of topological coefficients, pathway, and functional enrichment analysis, and identification of drug-target proteins. We assume that the identified molecular determinants may be prioritized for further screening as novel drug targets to cure multiple ARDs. Based on the analysis, an online tool named as 'ARDnet' has been developed to construct and demonstrate ARD interactions at the level of PPI, ARDs and ARDs protein interaction, ARDs pathway interaction and drug-target interaction. The tool is freely made available at http://genomeinformatics.dtu.ac.in/ARDNet/Index.html. Copyright © 2017. Published by Elsevier B.V.

  5. 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

  6. Optical molecular imaging-guided radiation therapy part 2: Integrated x-ray and fluorescence molecular tomography.

    PubMed

    Shi, Junwei; Udayakumar, Thirupandiyur S; Wang, Zhiqun; Dogan, Nesrin; Pollack, Alan; Yang, Yidong

    2017-09-01

    Differentiating tumor from its surrounding soft tissues is challenging for x-ray computed tomography (CT). Fluorescence molecular tomography (FMT) can directly localize the internal tumors targeted with specific fluorescent probes. A FMT system was developed and integrated onto a CT-guided irradiator to improve tumor localization for image-guided radiation. The FMT system was aligned orthogonal to the cone-beam CT onboard our previously developed image-guided small animal arc radiation treatment system (iSMAART). Through rigorous physical registration, the onboard CT provides accurate surface contour which is used to generate three-dimensional mesh for FMT reconstruction. During FMT experiments, a point laser source perpendicular to the rotating axis was used to excite the internal fluorophores. The normalized optical images from multiple projection angles were adopted for tomographic reconstruction. To investigate the accuracy of the FMT in locating the tumor and recovering its volume, in vivo experiments were conducted on two breast cancer models: MDA-MB-231 cancer xenograft on nude mice and 4T1 cancer xenograft on white mice. Both cancer cell lines overexpress the epidermal growth factor receptor (EGFR). A novel fluorescent poly(lactic-co-glycolic) acid (PLGA) nanoparticle conjugated with anti-EGFR was intravenously injected to specifically target the breast cancer cells. Another ex vivo experiment on a mouse bearing a surgically implanted Indocyanine Green-containing glass tube was conducted, to additionally validate the precision of FMT-guided radiation therapy. The FMT can accurately localize the single-nodule breast tumors actively targeted with fluorescent nanoparticles with localization error < 0.5 mm calculated between the centers of mass of tumors in FMT and CT. The reconstructed tumor volume in FMT was significantly correlated with that in the iodinated contrast-enhanced CT (R(2) = 0.94, P < 0.001). The FMT was able to guide focal radiation delivery

  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. Ixodes ventalloi: morphological and molecular support for species integrity.

    PubMed

    Latrofa, Maria Stefania; Giannelli, Alessio; Persichetti, Maria Flaminia; Pennisi, Maria Grazia; Solano-Gallego, Laia; Brianti, Emanuele; Parisi, Antonio; Wall, Richard; Dantas-Torres, Filipe; Otranto, Domenico

    2017-01-01

    Despite their medical and veterinary importance, some tick species are so poorly studied, that their role within pathogen vector transmission cycles is difficult to assess. The tick Ixodes ventalloi is one such species, and its biology and phylogenetic status remain an issue of debate. In the present study, specimens of adult I. ventalloi (n = 65 females; n = 31 males) infesting cats in the Lipari Island (Aeolian archipelago, Sicily, southern Italy) were characterized morphologically and molecularly, the latter based on mitochondrial 16S rRNA and cytochrome c oxidase subunit 1 (cox1) genes. The genetic data and phylogenetic analyses for both mitochondrial genes suggest the existence of two distinct genogroups. The ecological and epidemiological significance of the genetic structure within the I. ventalloi endemic population remains to be determined. The results highlight the need for further analysis of this tick species, including whole mitochondrial genome sequencing and crossbreeding studies, which will be pivotal to complement features of its status as a vector of pathogens.

  9. Integrated Development of Serum Molecular Markers for Early Diagnosis of Breast Cancer

    DTIC Science & Technology

    2006-09-01

    Molecular Makers for Early Diagnosis of Breast Cancer PRINCIPAL INVESTIGATOR: Anna Lokshin, Ph.D. CONTRACTING ORGANIZATION: University of...NUMBER Integrated Development of Serum Molecular Makers for Early Diagnosis of Breast Cancer 5b. GRANT NUMBER DAMD17-03-1-0696 5c. PROGRAM...Therefore, studies at this stage involve screening people and lead to diagnosis and treatment. The aims of this phase include assessment of (i) the

  10. Cognitive Impairment and Community Integration Outcomes in Individuals Living With Multiple Sclerosis.

    PubMed

    Hughes, Abbey J; Hartoonian, Narineh; Parmenter, Brett; Haselkorn, Jodie K; Lovera, Jesus F; Bourdette, Dennis; Turner, Aaron P

    2015-11-01

    To determine the association between unique domains of cognitive impairment and community integration in individuals with multiple sclerosis (MS), and to determine the contributions of cognitive impairment to community integration beyond the influence of demographic and clinical variables. Cross-sectional analysis of objective neuropsychological assessment and self-report data. Data were collected during baseline assessment of a randomized, multisite controlled trial of ginkgo biloba for cognitive impairment in MS. Hierarchical regression analyses examined the association between subjective and objective measures of cognitive impairment and 3 domains of community integration, adjusting for relevant covariates. Two Veterans Affairs medical center MS clinics. Adults (N=121; ages 24-65y) with a confirmed MS diagnosis. Not applicable. Primary outcomes were scores on the Home Integration (CIQ-H), Social Integration (CIQ-S), and Productivity (CIQ-P) domains of the Community Integration Questionnaire (CIQ). Cognitive impairment was associated with lower scores on the CIQ-H and CIQ-S, but not the CIQ-P. Greater levels of subjective cognitive impairment were associated with lower scores on the CIQ-H and CIQ-S. Greater levels of objective cognitive impairment, specifically slower processing speed and poorer inhibitory control, were related to lower CIQ-S scores. Subjective and objective measures of cognitive impairment were significantly and independently associated with CIQ-S. Objective cognitive impairment may interfere with participation in social activities. Subjective cognitive impairment is also important to assess, because individuals who perceive themselves to be cognitively impaired may be less likely to participate in both home and social activities. Clinical interventions to enhance community integration in individuals with MS may benefit from addressing objective and subjective cognitive impairment by integrating cognitive rehabilitation approaches with self

  11. 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

  12. 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

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

    PubMed Central

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

    2014-01-01

    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

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

    PubMed

    Schiller, Martin; Paton, Chad; Bizzarro, Martin

    2015-01-15

    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 (26)Al/(27)Al of ~5 × 10(-5) ((26)Al decays to (26)Mg 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 (43)Ca, (46)Ca and (48)Ca. 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 (26)Al nuclide as well as carriers of anomalous and uncorrelated (43)Ca, (46)Ca and (48)Ca 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 (43)Ca, (46)Ca and (48)Ca, the short-lived (26)Al nuclide was heterogeneously distributed in the inner solar system at the time of CAI formation.

  15. Multiple pH Regime Molecular Dynamics Simulation for pK Calculations

    PubMed Central

    Nilsson, Lennart; Karshikoff, Andrey

    2011-01-01

    Ionisation equilibria in proteins are influenced by conformational flexibility, which can in principle be accounted for by molecular dynamics simulation. One problem in this method is the bias arising from the fixed protonation state during the simulation. Its effect is mostly exhibited when the ionisation behaviour of the titratable groups is extrapolated to pH regions where the predetermined protonation state of the protein may not be statistically relevant, leading to conformational sampling that is not representative of the true state. In this work we consider a simple approach which can essentially reduce this problem. Three molecular dynamics structure sets are generated, each with a different protonation state of the protein molecule expected to be relevant at three pH regions, and pK calculations from the three sets are combined to predict pK over the entire pH range of interest. This multiple pH molecular dynamics approach was tested on the GCN4 leucine zipper, a protein for which a full data set of experimental data is available. The pK values were predicted with a mean deviation from the experimental data of 0.29 pH units, and with a precision of 0.13 pH units, evaluated on the basis of equivalent sites in the dimeric GCN4 leucine zipper. PMID:21647418

  16. Multiplicity of Mathematical Modeling Strategies to Search for Molecular and Cellular Insights into Bacteria Lung Infection.

    PubMed

    Cantone, Martina; Santos, Guido; Wentker, Pia; Lai, Xin; Vera, Julio

    2017-01-01

    Even today two bacterial lung infections, namely pneumonia and tuberculosis, are among the 10 most frequent causes of death worldwide. These infections still lack effective treatments in many developing countries and in immunocompromised populations like infants, elderly people and transplanted patients. The interaction between bacteria and the host is a complex system of interlinked intercellular and the intracellular processes, enriched in regulatory structures like positive and negative feedback loops. Severe pathological condition can emerge when the immune system of the host fails to neutralize the infection. This failure can result in systemic spreading of pathogens or overwhelming immune response followed by a systemic inflammatory response. Mathematical modeling is a promising tool to dissect the complexity underlying pathogenesis of bacterial lung infection at the molecular, cellular and tissue levels, and also at the interfaces among levels. In this article, we introduce mathematical and computational modeling frameworks that can be used for investigating molecular and cellular mechanisms underlying bacterial lung infection. Then, we compile and discuss published results on the modeling of regulatory pathways and cell populations relevant for lung infection and inflammation. Finally, we discuss how to make use of this multiplicity of modeling approaches to open new avenues in the search of the molecular and cellular mechanisms underlying bacterial infection in the lung.

  17. 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.

  18. The molecular characterization and clinical management of multiple myeloma in the post-genome era

    PubMed Central

    Zhou, Y; Barlogie, B; Shaughnessy, JD

    2013-01-01

    Cancer-causing mutations disrupt coordinated, precise programs of gene expression that govern cell growth and differentiation. Microarray-based gene-expression profiling (GEP) is a powerful tool to globally analyze these changes to study cancer biology and clinical behavior. Despite overwhelming genomic chaos in multiple myeloma (MM), expression patterns within tumor samples are remarkably stable and reproducible. Unique expression patterns associated with recurrent chromosomal translocations and ploidy changes defined molecular classes with differing clinical features and outcomes. Combined molecular techniques also dissected two distinct, reproducible forms of hyperdiploid disease and have molecularly defined MM with high risk for poor clinical outcome. GEP is now used to risk-stratify patients with newly diagnosed MM. Groups with high-risk features are evident in all GEP-defined MM classes, and GEP studies of serial samples showed that risk increases over time, with relapsed disease showing dramatic GEP shifts toward a signature of poor outcomes. This suggests a common mechanism of disease evolution and potentially reflects preferential expansion of therapy-resistant cells. Correlating GEP-defined disease class and risk with outcomes of therapeutic regimens reveals class– specific benefits for individual agents, as well as mechanistic insights into drug sensitivity and resistance. Here, we review modern genomics contributions to understanding MM pathogenesis, prognosis, and therapy. PMID:19657360

  19. 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

  20. Time reversible and symplectic integrators for molecular dynamics simulations of rigid molecules

    NASA Astrophysics Data System (ADS)

    Kamberaj, H.; Low, R. J.; Neal, M. P.

    2005-06-01

    Molecular dynamics integrators are presented for translational and rotational motion of rigid molecules in microcanonical, canonical, and isothermal-isobaric ensembles. The integrators are all time reversible and are also, in some approaches, symplectic for the microcanonical ensembles. They are developed utilizing the quaternion representation on the basis of the Trotter factorization scheme using a Hamiltonian formalism. The structure is similar to that of the velocity Verlet algorithm. Comparison is made with standard integrators in terms of stability and it is found that a larger time step is stable with the new integrators. The canonical and isothermal-isobaric molecular dynamics simulations are defined by using a chain thermostat approach according to generalized Nosé-Hoover and Andersen methods.

  1. Overcoming inherent resistance to histone deacetylase inhibitors in multiple myeloma cells by targeting pathways integral to the actin cytoskeleton.

    PubMed

    Mithraprabhu, S; Khong, T; Spencer, A

    2014-03-20

    Histone deacetylase inhibitors (HDACi) are novel chemotherapeutics undergoing evaluation in clinical trials for the potential treatment of patients with multiple myeloma (MM). Although HDACi have demonstrable synergy when combined with proteasome inhibitors (PIs), recent evidence indicates that combination of HDACi and PI is beneficial only in a subset of patients with advanced MM, clearly indicating that other rational combinations should be explored. In this context we hypothesized that understanding the molecular signature associated with inherent resistance to HDACi would provide a basis for the identification of therapeutic combinations with improved clinical efficacy. Using human myeloma cell lines (HMCL) categorized as sensitive, intermediate or resistant to HDACi, gene expression profiling (GEP) and gene ontology enrichment analyses were performed to determine if a genetic signature associated with inherent resistance to HDACi-resistance could be identified. Correlation of GEP to increasing or decreasing sensitivity to HDACi indicated a unique 35-gene signature that was significantly enriched for two pathways - regulation of actin cytoskeleton and protein processing in endoplasmic reticulum. When HMCL and primary MM samples were treated with a combination of HDACi and agents targeting the signaling pathways integral to the actin cytoskeleton, synergistic cell death was observed in all instances, thus providing a rationale for combining these agents with HDACi for the treatment of MM to overcome resistance. This report validates a molecular approach for the identification of HDACi partner drugs and provides an experimental framework for the identification of novel therapeutic combinations for anti-MM treatment.

  2. 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.

  3. 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

  4. 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

  5. Molecular mechanisms of the co-deposition of multiple pathological proteins in neurodegenerative diseases.

    PubMed

    Nonaka, Takashi; Masuda-Suzukake, Masami; Hasegawa, Masato

    2017-09-25

    Intracellular inclusions composed of abnormal protein aggregates are one of the neuropathological features of neurodegenerative diseases, and the formation of intracellular aggregates is believed to be associated with neurodegeneration leading to the onset of these diseases. In typical or pure cases, characteristic pathologies with one particular protein, such as tau, alpha-synuclein or trans-activation response DNA protein 43 (TDP-43), can be observed in brains of patients. On the other hand, multiple protein pathologies co-exist in many cases, raising the possibility that they may influence each other reciprocally in the pathogenesis and progression of the diseases. However, the molecular mechanisms through which these proteins interact with each other and through which they are co-deposited in brains of patients remain poorly understood. In this review, we focus on the mechanisms of deposition of multiple pathological proteins, such as tau, alpha-synuclein and/or TDP-43, and on co-deposition models of these proteins in vitro and in vivo intended to recapitulate the multiple pathologies found in diseased brains. © 2017 Japanese Society of Neuropathology.

  6. Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro.

    PubMed

    Van den Hof, Wim F P M; Ruiz-Aracama, Ainhoa; Van Summeren, Anke; Jennen, Danyel G J; Gaj, Stan; Coonen, Maarten L J; Brauers, Karen; Wodzig, Will K W H; van Delft, Joost H M; Kleinjans, Jos C S

    2015-04-01

    In order to improve attrition rates of candidate-drugs there is a need for a better understanding of the mechanisms underlying drug-induced hepatotoxicity. We aim to further unravel the toxicological response of hepatocytes to a prototypical cholestatic compound by integrating transcriptomic and metabonomic profiling of HepG2 cells exposed to Cyclosporin A. Cyclosporin A exposure induced intracellular cholesterol accumulation and diminished intracellular bile acid levels. Performing pathway analyses of significant mRNAs and metabolites separately and integrated, resulted in more relevant pathways for the latter. Integrated analyses showed pathways involved in cell cycle and cellular metabolism to be significantly changed. Moreover, pathways involved in protein processing of the endoplasmic reticulum, bile acid biosynthesis and cholesterol metabolism were significantly affected. Our findings indicate that an integrated approach combining metabonomics and transcriptomics data derived from representative in vitro models, with bioinformatics can improve our understanding of the mechanisms of action underlying drug-induced hepatotoxicity. Furthermore, we showed that integrating multiple omics and thereby analyzing genes, microRNAs and metabolites of the opposed model for drug-induced cholestasis can give valuable information about mechanisms of drug-induced cholestasis in vitro and therefore could be used in toxicity screening of new drug candidates at an early stage of drug discovery. Copyright © 2015 Elsevier Ltd. All rights reserved.

  7. 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

  8. 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.

  9. Isotope effects in water as investigated by neutron diffraction and path integral molecular dynamics

    NASA Astrophysics Data System (ADS)

    Zeidler, Anita; Salmon, Philip S.; Fischer, Henry E.; Neuefeind, Jörg C.; Simonson, J. Mike; Markland, Thomas E.

    2012-07-01

    The structures of heavy and light water at 300 K were investigated by using a joint approach in which the method of neutron diffraction with oxygen isotope substitution was complemented by path integral molecular dynamics simulations. The diffraction results, which give intra-molecular O-D and O-H bond distances of 0.985(5) and 0.990(5) Å, were found to be in best agreement with those obtained by using the flexible anharmonic TTM3-F water model. Both techniques show a difference of ≃ 0.5% between the O-D and O-H intra-molecular bond lengths, and the results support a competing quantum effects model for water in which its structural and dynamical properties are governed by an offset between intra-molecular and inter-molecular quantum contributions. Further consideration of the O-O correlations is needed in order to improve agreement with experiment.

  10. Analysis of microRNA and Gene Expression Profiles in Multiple Sclerosis: Integrating Interaction Data to Uncover Regulatory Mechanisms

    PubMed Central

    Freiesleben, Sherry; Hecker, Michael; Zettl, Uwe Klaus; Fuellen, Georg; Taher, Leila

    2016-01-01

    MicroRNAs (miRNAs) have been reported to contribute to the pathophysiology of multiple sclerosis (MS), an inflammatory disorder of the central nervous system. Here, we propose a new consensus-based strategy to analyse and integrate miRNA and gene expression data in MS as well as other publically available data to gain a deeper understanding of the role of miRNAs in MS and to overcome the challenges posed by studies with limited patient sample sizes. We processed and analysed microarray datasets, and compared the expression of genes and miRNAs in the blood of MS patients and controls. We then used our consensus and integration approach to construct two molecular networks dysregulated in MS: a miRNA- and a gene-based network. We identified 18 differentially expressed (DE) miRNAs and 128 DE genes that may contribute to the regulatory alterations behind MS. The miRNAs were linked to immunological and neurological pathways, and we exposed let-7b-5p and miR-345-5p as promising blood-derived disease biomarkers in MS. The results suggest that DE miRNAs are more informative than DE genes in uncovering pathways potentially involved in MS. Our findings provide novel insights into the regulatory mechanisms and networks underlying MS. PMID:27694855

  11. An Integrated Experimental Design for the Assessment of Multiple Toxicological End Points in Rat Bioassays.

    PubMed

    Manservisi, Fabiana; Marquillas, Clara Babot; Buscaroli, Annalisa; Huff, James; Lauriola, Michelina; Mandrioli, Daniele; Manservigi, Marco; Panzacchi, Simona; Silbergeld, Ellen K; Belpoggi, Fiorella

    2017-03-01

    For nearly five decades long-term studies in rodents have been the accepted benchmark for assessing chronic long-term toxic effects, particularly carcinogenicity, of chemicals. The European Food Safety Authority (EFSA) and the World Health Organization (WHO) have pointed out that the current set of internationally utilized test methods capture only some of the potential adverse effects associated with exposures to these agents over the lifetime. In this paper, we propose the adaption of the carcinogenicity bioassay to integrate additional protocols for comprehensive long-term toxicity assessment that includes developmental exposures and long-term outcomes, capable of generating information on a broad spectrum of different end points. An integrated study design based on a stepwise process is described that includes the priority end points of the Economic Co-operation and Development and the National Toxicology Program guidelines on carcinogenicity and chronic toxicity and developmental and reproductive toxicity. Integrating a comprehensive set of relevant toxicological end points in a single protocol represents an opportunity to optimize animal use in accordance with the 3Rs (replacement, reduction and refinement). This strategy has the potential to provide sufficient data on multiple windows of susceptibility of specific interest for risk assessments and public health decision-making by including prenatal, lactational, neonatal exposures and evaluating outcomes over the lifespan. This integrated study design is efficient in that the same generational cohort of rats used for evaluating long-term outcomes can be monitored in satellite parallel experiments to measure biomarkers and other parameters related to system-specific responses including metabolic alterations and endocrine disturbances. Citation: Manservisi F, Babot Marquillas C, Buscaroli A, Huff J, Lauriola M, Mandrioli D, Manservigi M, Panzacchi S, Silbergeld EK, Belpoggi F. 2017. An integrated experimental

  12. An Integrated Experimental Design for the Assessment of Multiple Toxicological End Points in Rat Bioassays

    PubMed Central

    Manservisi, Fabiana; Marquillas, Clara Babot; Buscaroli, Annalisa; Huff, James; Lauriola, Michelina; Mandrioli, Daniele; Manservigi, Marco; Panzacchi, Simona; Silbergeld, Ellen K.; Belpoggi, Fiorella

    2016-01-01

    Background: For nearly five decades long-term studies in rodents have been the accepted benchmark for assessing chronic long-term toxic effects, particularly carcinogenicity, of chemicals. The European Food Safety Authority (EFSA) and the World Health Organization (WHO) have pointed out that the current set of internationally utilized test methods capture only some of the potential adverse effects associated with exposures to these agents over the lifetime. Objectives: In this paper, we propose the adaption of the carcinogenicity bioassay to integrate additional protocols for comprehensive long-term toxicity assessment that includes developmental exposures and long-term outcomes, capable of generating information on a broad spectrum of different end points. Discussion: An integrated study design based on a stepwise process is described that includes the priority end points of the Economic Co-operation and Development and the National Toxicology Program guidelines on carcinogenicity and chronic toxicity and developmental and reproductive toxicity. Integrating a comprehensive set of relevant toxicological end points in a single protocol represents an opportunity to optimize animal use in accordance with the 3Rs (replacement, reduction and refinement). This strategy has the potential to provide sufficient data on multiple windows of susceptibility of specific interest for risk assessments and public health decision-making by including prenatal, lactational, neonatal exposures and evaluating outcomes over the lifespan. Conclusion: This integrated study design is efficient in that the same generational cohort of rats used for evaluating long-term outcomes can be monitored in satellite parallel experiments to measure biomarkers and other parameters related to system-specific responses including metabolic alterations and endocrine disturbances. Citation: Manservisi F, Babot Marquillas C, Buscaroli A, Huff J, Lauriola M, Mandrioli D, Manservigi M, Panzacchi S, Silbergeld

  13. Disease gene prioritization by integrating tissue-specific molecular networks using a robust multi-network model.

    PubMed

    Ni, Jingchao; Koyuturk, Mehmet; Tong, Hanghang; Haines, Jonathan; Xu, Rong; Zhang, Xiang

    2016-11-10

    Accurately prioritizing candidate disease genes is an important and challenging problem. Various network-based methods have been developed to predict potential disease genes by utilizing the disease similarity network and molecular networks such as protein interaction or gene co-expression networks. Although successful, a common limitation of the existing methods is that they assume all diseases share the same molecular network and a single generic molecular network is used to predict candidate genes for all diseases. However, different diseases tend to manifest in different tissues, and the molecular networks in different tissues are usually different. An ideal method should be able to incorporate tissue-specific molecular networks for different diseases. In this paper, we develop a robust and flexible method to integrate tissue-specific molecular networks for disease gene prioritization. Our method allows each disease to have its own tissue-specific network(s). We formulate the problem of candidate gene prioritization as an optimization problem based on network propagation. When there are multiple tissue-specific networks available for a disease, our method can automatically infer the relative importance of each tissue-specific network. Thus it is robust to the noisy and incomplete network data. To solve the optimization problem, we develop fast algorithms which have linear time complexities in the number of nodes in the molecular networks. We also provide rigorous theoretical foundations for our algorithms in terms of their optimality and convergence properties. Extensive experimental results show that our method can significantly improve the accuracy of candidate gene prioritization compared with the state-of-the-art methods. In our experiments, we compare our methods with 7 popular network-based disease gene prioritization algorithms on diseases from Online Mendelian Inheritance in Man (OMIM) database. The experimental results demonstrate that our methods

  14. Integrated argument-based inquiry with multiple representation approach to promote scientific argumentation skill

    NASA Astrophysics Data System (ADS)

    Suminar, Iin; Muslim, Liliawati, Winny

    2017-05-01

    The purpose of this research was to identify student's written argument embedded in scientific inqury investigation and argumentation skill using integrated argument-based inquiry with multiple representation approach. This research was using quasi experimental method with the nonequivalent pretest-posttest control group design. Sample ot this research was 10th grade students at one of High School in Bandung using two classes, they were 26 students of experiment class and 26 students of control class. Experiment class using integrated argument-based inquiry with multiple representation approach, while control class using argument-based inquiry. This study was using argumentation worksheet and argumentation test. Argumentation worksheet encouraged students to formulate research questions, design experiment, observe experiment and explain the data as evidence, construct claim, warrant, embedded multiple modus representation and reflection. Argumentation testinclude problem which asks students to explain evidence, warrants, and backings support of each claim. The result of this research show experiment class students's argumentation skill performed better than control class students that of experiment class was 0.47 and control class was 0.31. The results of unequal variance t-test for independent means show that students'sargumentationskill of experiment class performed better significantly than students'sargumentationskill of control class.

  15. 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.

  16. A model for integrating molecular-based testing in transfusion services

    PubMed Central

    Sandler, S. Gerald; Horn, Trina; Keller, Jessica; Langeberg, Al; Keller, Margaret A.

    2016-01-01

    Background Molecular-based laboratory tests can predict blood group antigens and supplement serological methods, adding a unique technology to assist in resolving discrepant or incomplete blood group typing or antibody identification. Hospital transfusion services have options for integrating molecular-based methods in their routine operations. We describe here the model of a hospital-reference laboratory partnership. Materials and methods Blood samples for compatibility testing were obtained from patients in a 609-bed hospital serving an urban multiethnic and multiracial population. When results of blood group phenotyping by serological methods were inconclusive, samples were referred for molecular-based testing. The reference laboratory used several methods for genotyping, including polymerase chain reaction followed by restriction enzyme-linked polymorphism analysis, sequence-specific primer polymerase chain reaction and array-based approaches. Human erythrocyte antigen, RHCE and RHD single nucleotide polymorphism arrays were integrated into the laboratory as they became commercially available. Results The hospital-reference laboratory model made it possible to integrate blood group genotyping promptly by current technology without the expense of new laboratory equipment or adding personnel with technical expertise. We describe ten cases that illustrate the categories of serological problems that were resolved by molecular methods. Discussion In-hospital molecular testing for transfusion services has logistical advantages, but is financially impractical for most hospitals. Our model demonstrates the advantages of a hospital-reference laboratory partnership. In conclusion, hospital transfusion services can integrate molecular-based testing in their routine services without delay by establishing a partnership with a molecular blood group reference laboratory. The hospital reference-laboratory model promotes genomic medicine without the expense of new equipment and

  17. 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

  18. 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.

  19. 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

  20. Adaptive Estimation of Multiple Fading Factors for GPS/INS Integrated Navigation Systems

    PubMed Central

    Jiang, Chen; Zhang, Shu-Bi; Zhang, Qiu-Zhao

    2017-01-01

    The Kalman filter has been widely applied in the field of dynamic navigation and positioning. However, its performance will be degraded in the presence of significant model errors and uncertain interferences. In the literature, the fading filter was proposed to control the influences of the model errors, and the H-infinity filter can be adopted to address the uncertainties by minimizing the estimation error in the worst case. In this paper, a new multiple fading factor, suitable for the Global Positioning System (GPS) and the Inertial Navigation System (INS) integrated navigation system, is proposed based on the optimization of the filter, and a comprehensive filtering algorithm is constructed by integrating the advantages of the H-infinity filter and the proposed multiple fading filter. Measurement data of the GPS/INS integrated navigation system are collected under actual conditions. Stability and robustness of the proposed filtering algorithm are tested with various experiments and contrastive analysis are performed with the measurement data. Results demonstrate that both the filter divergence and the influences of outliers are restrained effectively with the proposed filtering algorithm, and precision of the filtering results are improved simultaneously. PMID:28587157

  1. Adaptive Estimation of Multiple Fading Factors for GPS/INS Integrated Navigation Systems.

    PubMed

    Jiang, Chen; Zhang, Shu-Bi; Zhang, Qiu-Zhao

    2017-06-01

    The Kalman filter has been widely applied in the field of dynamic navigation and positioning. However, its performance will be degraded in the presence of significant model errors and uncertain interferences. In the literature, the fading filter was proposed to control the influences of the model errors, and the H-infinity filter can be adopted to address the uncertainties by minimizing the estimation error in the worst case. In this paper, a new multiple fading factor, suitable for the Global Positioning System (GPS) and the Inertial Navigation System (INS) integrated navigation system, is proposed based on the optimization of the filter, and a comprehensive filtering algorithm is constructed by integrating the advantages of the H-infinity filter and the proposed multiple fading filter. Measurement data of the GPS/INS integrated navigation system are collected under actual conditions. Stability and robustness of the proposed filtering algorithm are tested with various experiments and contrastive analysis are performed with the measurement data. Results demonstrate that both the filter divergence and the influences of outliers are restrained effectively with the proposed filtering algorithm, and precision of the filtering results are improved simultaneously.

  2. 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

  3. Analytical evaluation of molecular electronic integrals using Poisson's equation: Exponential-type orbitals and atom pairs

    NASA Astrophysics Data System (ADS)

    Absi, Noureddine; Hoggan, Philip

    The integral bottleneck in evaluating molecular energies arises from the two-electron contributions. These are difficult and time-consuming to evaluate, especially over exponential type orbitals, used here to ensure the correct behavior of atomic orbitals. The two-center two-electron integrals are essential to describe atom pairs in molecules and distinguish those that are bound. In this work on analytical integration, it is shown that the two-center Coulomb integrals involved can be expressed as one-electron kinetic energy-like integrals. This is accomplished using the fact that the Coulomb operator is a Green's function of the Laplacian. The ensuing integrals may be further simplified by defining spectral forms for the one-electron potential satisfying Poisson's equation therein. A sum of overlap integrals with the atomic orbital energy eigenvalue as a factor is then obtained to give the Coulomb energy. This is most easily evaluated by direct integration. The orbitals involved in three and four center integrals are translated to two centers. This is discussed very briefly. The evaluation of exchange energy is a straightforward extension of this work. The summation coefficients in spectral forms are evaluated analytically from Gaunt coefficients. The Poisson method may be used to calculate Coulomb energy integrals efficiently. For a single processor, gains of CPU time for a given chemical accuracy exceed a factor of 4. This method lends itself to efficient evaluation on a parallel computer.

  4. The vanilloid receptor family of calcium-permeable channels: molecular integrators of microenvironmental stimuli.

    PubMed

    O'Neil, Roger G; Brown, Rachel C

    2003-12-01

    The TRPV subfamily of calcium-permeable channels is widely distributed in sensory and nonsensory cells from nematodes to mammals. These channels can be variably activated by a diverse range of stimuli (osmotic/mechanical stress, noxious chemicals and heat, endogenous mediators) that often converge on the same channel. Evidence is presented that TRPV channels function as novel "molecular integrators" of diverse microenvironmental stimuli.

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

    PubMed

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

    2012-01-05

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

  6. An integrated molecular cytogenetic map of Cucumis sativus L. chromosome 2

    PubMed Central

    2011-01-01

    Background Integration of molecular, genetic and cytological maps is still a challenge for most plant species. Recent progress in molecular and cytogenetic studies created a basis for developing integrated maps in cucumber (Cucumis sativus L.). Results In this study, eleven fosmid clones and three plasmids containing 45S rDNA, the centromeric satellite repeat Type III and the pericentriomeric repeat CsRP1 sequences respectively were hybridized to cucumber metaphase chromosomes to assign their cytological location on chromosome 2. Moreover, an integrated molecular cytogenetic map of cucumber chromosomes 2 was constructed by fluorescence in situ hybridization (FISH) mapping of 11 fosmid clones together with the cucumber centromere-specific Type III sequence on meiotic pachytene chromosomes. The cytogenetic map was fully integrated with genetic linkage map since each fosmid clone was anchored by a genetically mapped simple sequence repeat marker (SSR). The relationship between the genetic and physical distances along chromosome was analyzed. Conclusions Recombination was not evenly distributed along the physical length of chromosome 2. Suppression of recombination was found in centromeric and pericentromeric regions. Our results also indicated that the molecular markers composing the linkage map for chromosome 2 provided excellent coverage of the chromosome. PMID:21272311

  7. [The academic education in nursing and multiple-victim incidents: an integrative review].

    PubMed

    Salvador, Pétala Tuani Candido de Oliveira; Dantas, Rodrigo Assis Neves; Dantas, Daniele Vieira; Torres, Gilson de Vasconcelos

    2012-06-01

    The objective of this study is to reflect on the knowledge, competencies and skill that must be promoted during the academic education of nurses for an effective professional practice in view of a multiple-victim incident (MVI). This is an integrative literature review regarding academic nursing education. The literature survey was performed on the BDENF, LILACS, SciELO, MEDLINE, Web of Knowledge and HighWire Press databases, using the following descriptors: higher education; nursing education; emergency nursing; and mass casualty incidents. The publications permitted considerations regarding the following themes: particularities; competencies and skills essential in nursing practice in view of multiple-victim incidents; and the professors' strategies to promote those competencies and skills. The literature analysis demonstrated that nursing education should be configured as a space to develop critical thinking skills, which requires professors to have an eclectic educational background.

  8. 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.

  9. A Tri-Factor Model for Integrating Ratings Across Multiple Informants

    PubMed Central

    Bauer, Daniel J.; Howard, Andrea L.; Baldasaro, Ruth E.; Curran, Patrick J.; Hussong, Andrea M.; Chassin, Laurie; Zucker, Robert A.

    2014-01-01

    Psychologists often obtain ratings for target individuals from multiple informants such as parents or peers. In this paper we propose a tri-factor model for multiple informant data that separates target-level variability from informant-level variability and item-level variability. By leveraging item-level data, the tri-factor model allows for examination of a single trait rated on a single target. In contrast to many psychometric models developed for multitrait-multimethod data, the tri-factor model is predominantly a measurement model. It is used to evaluate item quality in scale development, test hypotheses about sources of target variability (e.g., sources of trait differences) versus informant variability (e.g., sources of rater bias), and generate integrative scores that are purged of the subjective biases of single informants. PMID:24079932

  10. 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.

  11. Pooling Data from Multiple Longitudinal Studies: The Role of Item Response Theory in Integrative Data Analysis

    PubMed Central

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

    2010-01-01

    There are a number of significant challenges encountered when studying development over an extended period of time including subject attrition, changing measurement structures across group and developmental period, and the need to invest substantial time and money. Integrative data analysis is an emerging set of methodologies that overcomes 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 paper we focus on methods for fitting measurement models and creating scale scores using data drawn from multiple longitudinal studies. We present findings from the analysis of repeated measures of internalizing symptomatology that were pooled from three existing developmental studies. We describe and demonstrate each step in the analysis and we conclude with a discussion of potential limitations and directions for future research. PMID:18331129

  12. Impaired Neurovisceral Integration of Cardiovascular Modulation Contributes to Multiple Sclerosis Morbidities.

    PubMed

    Sternberg, Zohara

    2017-01-01

    Multiple sclerosis (MS) is an inflammatory demyelinating central nervous system (CNS) disease with an uncertain etiology. MS is heterogeneous, involving multiple clinical pathologies, including neurodegeneration, depression, fatigue and sleep disorders, migraine, osteoporosis and cerebral hemodynamic impairments. The underlying causes of these pathologies remain mostly unknown. Based on the accumulating evidence derived from our studies and those of other investigators, we propose that the dysregulation in the neurovisceral integration of cardiovascular modulation can lead to many MS-related clinical symptoms. We show that MS inflammatory and neurodegenerative processes are intertwined with the aforementioned clinical morbidities and are collectively the manifestations of cardiovascular autonomic nervous system (ANS) dysfunction. The strategies for improving sympathovagal balance would likely prevent and minimize many MS-related clinical symptoms, improving patients' quality of life. Similar strategies could be applied to other autoimmune and neurodegenerative diseases where autonomic imbalance plays a role.

  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. Integration of Symptom Ratings from Multiple Informants in ADHD Diagnosis: A Psychometric Model with Clinical Utility

    PubMed Central

    Martel, Michelle M.; Schimmack, Ulrich; Nikolas, Molly; Nigg, Joel T.

    2015-01-01

    The Diagnostic and Statistical Manual of Mental Disorder—Fifth Edition explicitly requires that Attention-Deficit/Hyperactivity Disorder (ADHD) symptoms should be apparent across settings, taking into account reports from multiple informants. Yet, it provides no guidelines how information from different raters should be combined in ADHD diagnosis. We examined the validity of different approaches using structural equation modeling (SEM) for multiple-informant data. Participants were 725 children, 6 to 17 years old, and their primary caregivers and teachers, recruited from the community and completing a thorough research-based diagnostic assessment, including a clinician-administered diagnostic interview, parent and teacher standardized rating scales and cognitive testing. A best-estimate ADHD diagnosis was generated by a diagnostic team. An SEM model demonstrated convergent validity among raters. We found relatively weak symptom-specific agreement among raters, suggesting that a general average scoring algorithm is preferable to symptom-specific scoring algorithms such as the “or” and “and” algorithms. Finally, to illustrate the validity of this approach, we show that averaging makes it possible to reduce the number of items from 18 items to 8 items without a significant decrease in validity. In conclusion, information from multiple raters increases the validity of ADHD diagnosis, and averaging appears to be the optimal way to integrate information from multiple raters. PMID:25730162

  15. Integration of symptom ratings from multiple informants in ADHD diagnosis: a psychometric model with clinical utility.

    PubMed

    Martel, Michelle M; Schimmack, Ulrich; Nikolas, Molly; Nigg, Joel T

    2015-09-01

    The Diagnostic and Statistical Manual of Mental Disorder-Fifth Edition explicitly requires that attention-deficit/hyperactivity disorder (ADHD) symptoms should be apparent across settings, taking into account reports from multiple informants. Yet, it provides no guidelines how information from different raters should be combined in ADHD diagnosis. We examined the validity of different approaches using structural equation modeling (SEM) for multiple-informant data. Participants were 725 children, 6 to 17 years old, and their primary caregivers and teachers, recruited from the community and completing a thorough research-based diagnostic assessment, including a clinician-administered diagnostic interview, parent and teacher standardized rating scales, and cognitive testing. A best-estimate ADHD diagnosis was generated by a diagnostic team. An SEM model demonstrated convergent validity among raters. We found relatively weak symptom-specific agreement among raters, suggesting that a general average scoring algorithm is preferable to symptom-specific scoring algorithms such as the "or" and "and" algorithms. Finally, to illustrate the validity of this approach, we show that averaging makes it possible to reduce the number of items from 18 items to 8 items without a significant decrease in validity. In conclusion, information from multiple raters increases the validity of ADHD diagnosis, and averaging appears to be the optimal way to integrate information from multiple raters. (c) 2015 APA, all rights reserved.

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

    PubMed

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

    2008-07-07

    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. 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. 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 researchers working on

  17. Parallel higher-order boundary integral electrostatics computation on molecular surfaces with curved triangulation

    NASA Astrophysics Data System (ADS)

    Geng, Weihua

    2013-05-01

    In this paper, we present a parallel higher-order boundary integral method to solve the linear Poisson-Boltzmann (PB) equation. In our method, a well-posed boundary integral formulation is used to ensure the fast convergence of Krylov subspace linear solver such as GMRES. The molecular surfaces are first discretized with flat triangles and then converted to curved triangles with the assistance of normal information at vertices. To maintain the desired accuracy, four-point Gauss-Radau quadratures are used on regular triangles and sixteen-point Gauss-Legendre quadratures together with regularization transformations are applied on singular triangles. To speed up our method, we take advantage of the embarrassingly parallel feature of boundary integral formulation, and parallelize the schemes with the message passing interface (MPI) implementation. Numerical tests show significantly improved accuracy and convergence of the proposed higher-order boundary integral Poisson-Boltzmann (HOBI-PB) solver compared with boundary integral PB solver using often-seen centroid collocation on flat triangles. The higher-order accuracy results achieved by present method are important to sensitive solvation analysis of biomolecules, particularly when accurate electrostatic surface potentials are critical in the molecular simulation. In addition, the higher-order boundary integral schemes presented here and their associated parallelization potentially can be applied to solving boundary integral equations in a general sense.

  18. Improving the convergence of closed and open path integral molecular dynamics via higher order Trotter factorization schemes

    NASA Astrophysics Data System (ADS)

    Pérez, Alejandro; Tuckerman, Mark E.

    2011-08-01

    Higher order factorization schemes are developed for path integral molecular dynamics in order to improve the convergence of estimators for physical observables as a function of the Trotter number. The methods are based on the Takahashi-Imada and Susuki decompositions of the Boltzmann operator. The methods introduced improve the averages of the estimators by using the classical forces needed to carry out the dynamics to construct a posteriori weighting factors for standard path integral molecular dynamics. The new approaches are straightforward to implement in existing path integral codes and carry no significant overhead. The Suzuki higher order factorization was also used to improve the end-to-end distance estimator in open path integral molecular dynamics. The new schemes are tested in various model systems, including an ab initio path integral molecular dynamics calculation on the hydrogen molecule and a quantum water model. The proposed algorithms have potential utility for reducing the cost of path integral molecular dynamics calculations of bulk systems.

  19. Improving the convergence of closed and open path integral molecular dynamics via higher order Trotter factorization schemes.

    PubMed

    Pérez, Alejandro; Tuckerman, Mark E

    2011-08-14

    Higher order factorization schemes are developed for path integral molecular dynamics in order to improve the convergence of estimators for physical observables as a function of the Trotter number. The methods are based on the Takahashi-Imada and Susuki decompositions of the Boltzmann operator. The methods introduced improve the averages of the estimators by using the classical forces needed to carry out the dynamics to construct a posteriori weighting factors for standard path integral molecular dynamics. The new approaches are straightforward to implement in existing path integral codes and carry no significant overhead. The Suzuki higher order factorization was also used to improve the end-to-end distance estimator in open path integral molecular dynamics. The new schemes are tested in various model systems, including an ab initio path integral molecular dynamics calculation on the hydrogen molecule and a quantum water model. The proposed algorithms have potential utility for reducing the cost of path integral molecular dynamics calculations of bulk systems.

  20. Molecular Grafting onto a Stable Framework Yields Novel Cyclic Peptides for the Treatment of Multiple Sclerosis

    PubMed Central

    2013-01-01

    Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) and is characterized by the destruction of myelin and axons leading to progressive disability. Peptide epitopes from CNS proteins, such as myelin oligodendrocyte glycoprotein (MOG), possess promising immunoregulatory potential for treating MS; however, their instability and poor bioavailability is a major impediment for their use clinically. To overcome this problem, we used molecular grafting to incorporate peptide sequences from the MOG35–55 epitope onto a cyclotide, which is a macrocyclic peptide scaffold that has been shown to be intrinsically stable. Using this approach, we designed novel cyclic peptides that retained the structure and stability of the parent scaffold. One of the grafted peptides, MOG3, displayed potent ability to prevent disease development in a mouse model of MS. These results demonstrate the potential of bioengineered cyclic peptides for the treatment of MS. PMID:24147816

  1. Molecular and biologic markers of progression in monoclonal gammopathy of undetermined significance to multiple myeloma.

    PubMed

    Mailankody, Sham; Mena, Esther; Yuan, Constance M; Balakumaran, Arun; Kuehl, W Michael; Landgren, Ola

    2010-12-01

    Multiple myeloma (MM) is a malignant plasma cell dyscrasia localized in the bone marrow. Recent studies have shown that MM is preceded in virtually all cases by a premalignant state called monoclonal gammopathy of undetermined significance (MGUS). This review focuses on non-IgM MGUS and its progression to MM. Although certain clinical markers of MGUS progression have been identified, it currently is not possible to accurately determine individual risk of progression. This review focuses on the various biologic and molecular markers that could be used to determine the risk of MM progression. A better understanding of the pathogenesis will allow us to define the biological high-risk precursor disease and, ultimately, to develop early intervention strategies designed to delay and prevent full-blown MM.

  2. [Molecular diagnosis and prenatal diagnosis in a hereditary multiple osteochondromas family].

    PubMed

    Tang, Ying; Zheng, De-zhu; Guo, Xiao-yan; Liao, Juan; Lan, Feng-hua

    2013-12-18

    To identify the mutation in the disease gene and provide prenatal diagnosis for a hereditary multiple osteochondromas (HMO) family. The exons of EXT1 gene in the proband with HMO and his family members were amplified by PCR. The products were analyzed by direct sequencing. Prenatal genetic diagnosis was performed by amniocentesis sampling after genotyping the proband. In the family, the affected proband was heterozygous of the mutation of 1476_1477delTC in the EXT1 gene, and the proband's father carried the same mutation in part of his somatic cells. No mutation was found in the EXT1 gene of the proband's mother and other 11 siblings of his father. METHODS for molecular diagnosis and prenatal diagnosis of HMO were established and applied to a family of HMO.

  3. Cortical mechanisms for trans-saccadic memory and integration of multiple object features

    PubMed Central

    Prime, Steven L.; Vesia, Michael; Crawford, J. Douglas

    2011-01-01

    Constructing an internal representation of the world from successive visual fixations, i.e. separated by saccadic eye movements, is known as trans-saccadic perception. Research on trans-saccadic perception (TSP) has been traditionally aimed at resolving the problems of memory capacity and visual integration across saccades. In this paper, we review this literature on TSP with a focus on research showing that egocentric measures of the saccadic eye movement can be used to integrate simple object features across saccades, and that the memory capacity for items retained across saccades, like visual working memory, is restricted to about three to four items. We also review recent transcranial magnetic stimulation experiments which suggest that the right parietal eye field and frontal eye fields play a key functional role in spatial updating of objects in TSP. We conclude by speculating on possible cortical mechanisms for governing egocentric spatial updating of multiple objects in TSP. PMID:21242142

  4. 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.

  5. Position synchronised control of multiple robotic manipulators based on integral sliding mode

    NASA Astrophysics Data System (ADS)

    Zhao, Dongya; Zhu, Quanmin

    2014-03-01

    In this study, a new position synchronised control algorithm is developed for multiple robotic manipulator systems. In the merit of system synchronisation and integral sliding mode control, the proposed approach can stabilise position tracking of each robotic manipulator while coordinating its motion with the other manipulators. With the integral sliding mode, the proposed approach has insensitiveness against the lumped system uncertainty within the entire process of operation. Further, a perturbation estimator is proposed to reduce chattering effect. The corresponding stability analysis is presented to lay a foundation for theoretical understanding to the underlying issues as well as safely operating real systems. An illustrative example is bench tested to validate the effectiveness of the proposed approach.

  6. Integrated Microfluidic Platform with Multiple Functions To Probe Tumor-Endothelial Cell Interaction.

    PubMed

    Lin, Ling; Lin, Xuexia; Lin, Luyao; Feng, Qiang; Kitamori, Takehiko; Lin, Jin-Ming; Sun, Jiashu

    2017-09-19

    Interaction between tumor and endothelial cells could affect tumor growth and progression and induce drug resistance during cancer therapy. Investigation of tumor-endothelial cell interaction involves cell coculture, protein detection, and analysis of drug metabolites, which are complicated and time-consuming. In this work, we present an integrated microfluidic device with three individual components (cell coculture component, protein detection component, and pretreatment component for drug metabolites) to probe the interaction between tumor and endothelial cells. Cocultured cervical carcinoma cells (CaSki cells) and human umbilical vein endothelial cells (HUVECs) show higher resistance to chemotherapeutic agents than single-cultured cells, indicated by higher cell viability, increased expression of angiogenic proteins, and elevated level of paclitaxel metabolites under coculture conditions. This integrated microfluidic platform with multiple functions facilitates understanding of the interaction between tumor and endothelial cells, and it may become a promising tool for drug screening within an engineered tumor microenvironment.

  7. Current DOT research on the effect of multiple site damage on structural integrity

    NASA Astrophysics Data System (ADS)

    Tong, P.; Arin, Kemal; Jeong, David Y.; Greif, R.; Brewer, John C.; Bobo, Stephan N.; Sampath, Sam N.

    1992-07-01

    Multiple site damage (MSD) is a type of cracking that may be found in aging airplanes and which may adversely affect their continuing airworthiness. The Volpe National Transportation Systems Center has supported the Federal Aviation Administration Technical Center on structural integrity research for the past two and half years. The work has focused on understanding the behavior of MSD, detection of MSD during airframe inspection, and the avoidance of MSD in future designs. These three elements of the MSD problem are addressed and a summary of the completed work, the current status, and requirements for future research is provided.

  8. 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.

  9. Sarcoptes-World Molecular Network (Sarcoptes-WMN): integrating research on scabies.

    PubMed

    Alasaad, Samer; Walton, Shelley; Rossi, Luca; Bornstein, Set; Abu-Madi, Marawan; Soriguer, Ramón C; Fitzgerald, Scott; Zhu, Xing-Quan; Zimmermann, Werner; Ugbomoiko, Uade Samuel; Pei, Kurtis Jai-Chyi; Heukelbach, Jörg

    2011-05-01

    Parasites threaten human and animal health globally. It is estimated that more than 60% of people on planet Earth carry at least one parasite, many of them several different species. Unfortunately, parasite studies suffer from duplications and inconsistencies between different investigator groups. Hence, groups need to collaborate in an integrated manner in areas including parasite control, improved therapy strategies, diagnostic and surveillance tools, and public awareness. Parasite studies will be better served if there is coordinated management of field data and samples across multidisciplinary approach plans, among academic and non-academic organizations worldwide. In this paper we report the first 'Living organism-World Molecular Network', with the cooperation of 167 parasitologists from 88 countries on all continents. This integrative approach, the 'Sarcoptes-World Molecular Network', seeks to harmonize Sarcoptes epidemiology, diagnosis, treatment, and molecular studies from all over the world, with the aim of decreasing mite infestations in humans and animals.

  10. Simulations of one- and two-electron systems by Bead-Fourier path integral molecular dynamics

    NASA Astrophysics Data System (ADS)

    Ivanov, Sergei D.; Lyubartsev, Alexander P.

    2005-07-01

    The Bead-Fourier path integral molecular dynamics technique introduced earlier [S. D. Ivanov, A. P. Lyubartsev, and A. Laaksonen, Phys. Rev. E 67 066710 (2003)] is applied for simulation of electrons in the simplest molecules: molecular hydrogen, helium atom, and their ions. Special attention is paid to the correct description of electrons in the core region of a nucleus. In an attempt to smooth the Coulomb potential at small distances, a recipe is suggested. The simulation results are in excellent agreement with the analytical solution for the "harmonic helium atom", as well as with the vibrational potential of the H2 molecule and He ionization energies. It is demonstrated, that the Bead-Fourier path integral molecular dynamics technique is able to provide the accuracy required for the description of electron structure and chemical bonds in cases when electron exchange effects need not be taken into account.

  11. 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

  12. XML-based approaches for the integration of heterogeneous bio-molecular data

    PubMed Central

    Mesiti, Marco; Jiménez-Ruiz, Ernesto; Sanz, Ismael; Berlanga-Llavori, Rafael; Perlasca, Paolo; Valentini, Giorgio; Manset, David

    2009-01-01

    Background The today's public database infrastructure spans a very large collection of heterogeneous biological data, opening new opportunities for molecular biology, bio-medical and bioinformatics research, but raising also new problems for their integration and computational processing. Results In this paper we survey the most interesting and novel approaches for the representation, integration and management of different kinds of biological data by exploiting XML and the related recommendations and approaches. Moreover, we present new and interesting cutting edge approaches for the appropriate management of heterogeneous biological data represented through XML. Conclusion XML has succeeded in the integration of heterogeneous biomolecular information, and has established itself as the syntactic glue for biological data sources. Nevertheless, a large variety of XML-based data formats have been proposed, thus resulting in a difficult effective integration of bioinformatics data schemes. The adoption of a few semantic-rich standard formats is urgent to achieve a seamless integration of the current biological resources. PMID:19828083

  13. Integrated clinical and specialty pharmacy practice model for management of patients with multiple sclerosis.

    PubMed

    Hanson, Rebekah L; Habibi, Mitra; Khamo, Nehrin; Abdou, Sherif; Stubbings, JoAnn

    2014-03-15

    An integrated clinical and specialty pharmacy practice model for the management of patients with multiple sclerosis (MS) is described. Specialty medications, such as disease-modifying therapies (DMTs) used to treat MS, are costly and typically require special administration, handling, and storage. DMTs are associated with high rates of nonadherence and may have associated safety risks. The University of Illinois Hospital and Health Sciences System developed an MS pharmacy practice model that sought to address the many challenges of coordinating care with multiple entities outside the health system. Several key features of the integrated model include a dedicated clinical pharmacist on the MS specialty team, an integrated specialty pharmacy service, direct access to the electronic medical record, and face-to-face interaction with patients. Through the active involvement of the neurology clinical pharmacist and an onsite specialty pharmacy service, targeted assessments and medication and disease education are provided to the patient before DMT initiation and maintained throughout therapy. In addition, the regular point of contact and refill coordination encourages improved compliance, appropriate medication use, ongoing safety monitoring, and improved communication with the provider for quicker interventions. This fosters increased accessibility, convenience, and patient confidence. Improving patient outcomes--the priority goal of this service model--will be assessed in future planned studies. Through this new practice model, providers are empowered to incorporate specialty medication management into transitions in care, admission and discharge quality indicators, readmissions, and other core measures. An integrated pharmacy practice model that includes an interdisciplinary team of physicians, nurses, and pharmacists improved patient compliance with MS therapies.

  14. Monolithic integration of multiple-emission-wavelength laser diodes using low-energy ion implantation

    NASA Astrophysics Data System (ADS)

    Aimez, Vincent; Paquette, Michel; Beauvais, Jacques; Beerens, Jean; Poole, Philip J.; Charbonneau, N. Sylvain

    1998-09-01

    A monolithic optoelectronic chip containing multiple emission wavelength laser diodes has been developed. The semiconductor quantum well lasers have Fabry-Perot cavities of 500 micrometers in length. Electrical insulation between individual integrated devices has been achieved by wet etching the top contact layer and by a lift-off of the surface metal contact between the different lasers. The electroluminescence peak emission spectra of the integrated laser diodes has been shifted over a 25 nm range and 74 nm for discrete devices. Blueshifting of the emission wavelength has been achieved by quantum well intermixing using an industrial low energy ion implanter to generate point defects and a rapid thermal annealer to promote interdiffusion of the barrier and quantum well atoms during the recrystallization anneal. Phosphorus ions were implanted with an energy of 360 keV to precisely defined regions of the heterostructure with SiO2 serving as a masking material. Thus reference and intermixed regions were integrated on a single component. Integrated and discrete laser diodes have been assessed in terms of threshold currents and emission wavelengths.

  15. Integration of Molecular Pathology, Epidemiology, and Social Science for Global Precision Medicine

    PubMed Central

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

    2015-01-01

    Summary 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

  16. 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.

  17. Characterization of the molecular mechanism of the bone-anabolic activity of carfilzomib in multiple myeloma.

    PubMed

    Hu, Bo; Chen, Yu; Usmani, Saad Z; Ye, Shiqiao; Qiang, Wei; Papanikolaou, Xenofon; Heuck, Christoph J; Yaccoby, Shmuel; Williams, Bart O; Van Rhee, Frits; Barlogie, Bart; Epstein, Joshua; Qiang, Ya-Wei

    2013-01-01

    Carfilzomib, the next generation of proteasome inhibitor, may increase osteoblast-related markers in patients with multiple myeloma, but the molecular mechanism of its effect on mesenchymal stem cell differentiation to osteoblasts remains unknown. Herein, we demonstrated that carfilzomib significantly promoted mesenchymal stem cell differentiation into osteoblasts. In osteoprogenitor cells and primary mesenchymal stem cells from patients with myeloma, carfilzomib induced increases in alkaline phosphatase activity, matrix mineralization, and calcium deposition via Wnt-independent activation of β-catenin/TCF signaling. Using affinity pull-down assays with immunoblotting analysis and immunofluorescence, we found that carfilzomib induced stabilization of both free and active forms of β-catenin in a time- and dose-dependent manner that was not associated with β-catenin transcriptional regulation. Nuclear translocation of β-catenin protein was associated with TCF transcriptional activity that was independent of the effects of GSK3β-activation and of signaling induced by 19 Wnt ligands, 10 Frizzled receptors, and LRP5/6 co-receptors. Blocking activation of β-catenin/TCF signaling by dominant negative TCF1 or TCF4 attenuated carfilzomib-induced matrix mineralization. Thus, carfilzomib induced osteoblast differentiation via Wnt-independent activation of the β-catenin/TCF pathway. These results provide a novel molecular mechanism critical to understanding the anabolic role of carfilzomib on myeloma-induced bone disease.

  18. Dexamethasone-induced cell death is restricted to specific molecular subgroups of multiple myeloma

    PubMed Central

    Kervoëlen, Charlotte; Ménoret, Emmanuelle; Gomez-Bougie, Patricia; Bataille, Régis; Godon, Catherine; Marionneau-Lambot, Séverine; Moreau, Philippe; Pellat-Deceunynck, Catherine; Amiot, Martine

    2015-01-01

    Due to its cytotoxic effect in lymphoid cells, dexamethasone is widely used in the treatment of multiple myeloma (MM). However, only a subset of myeloma patients responds to high-dose dexamethasone. Despite the undeniable anti-myeloma benefits of dexamethasone, significant adverse effects have been reported. We re-evaluate the anti-tumor effect of dexamethasone according to the molecular heterogeneity of MM. We demonstrated that the pro-death effect of dexamethasone is related to the genetic heterogeneity of MM because sensitive cell lines were restricted to MAF and MMSET signature subgroups, whereas all CCND1 cell lines (n = 10) were resistant to dexamethasone. We demonstrated that the glucocorticoid receptor expression was an important limiting factor for dexamethasone-induced cell death and we found a correlation between glucocorticoid receptor levels and the induction of glucocorticoid-induced leucine zipper (GILZ) under dexamethasone treatment. By silencing GILZ, we next demonstrated that GILZ is necessary for Dex induced apoptosis while triggering an imbalance between anti- and pro-apoptotic Bcl-2 proteins. Finally, the heterogeneity of the dexamethasone response was further confirmed in vivo using myeloma xenograft models. Our findings suggested that the effect of dexamethasone should be re-evaluated within molecular subgroups of myeloma patients to improve its efficacy and reduce its adverse effects. PMID:26323097

  19. Fluorescence detection of adenosine triphosphate through an aptamer-molecular beacon multiple probe.

    PubMed

    Zeng, Xiaodan; Zhang, Xiaoling; Yang, Wen; Jia, Hongying; Li, Yamin

    2012-05-01

    An aptamer-molecular beacon (MB) multiple fluorescent probe for adenosine triphosphate (ATP) assay is proposed in this article. The ATP aptamer was used as a molecular recognition part, and an oligonucleotide (short strand, SS) partially complementary with the aptamer and an MB was used as the other part. In the presence of ATP, the aptamer bound with it, accompanied by the hybridization of MB and SS and the fluorescence recovering. Wherever there is only very weak fluorescence can be measured in the absence of ATP. Based on the relationship of recovering fluorescence and the concentration of ATP, a method for quantifying ATP has been developed. The fluorescence intensity was proportional to the concentration of ATP in the range of 10 to 500 nM with a detection limit of 0.1 nM. Moreover, this method was able to detect ATP with high selectivity in the presence of guanosine triphosphate (GTP), cytidine triphosphate (CTP), and uridine triphosphate (UTP). This method is proved to be simple with high sensitivity, selectivity, and specificity.

  20. 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.

  1. The mitochondrial permeability transition pore (PTP) - an example of multiple molecular exaptation?

    PubMed

    Vianello, Angelo; Casolo, Valentino; Petrussa, Elisa; Peresson, Carlo; Patui, Sonia; Bertolini, Alberto; Passamonti, Sabina; Braidot, Enrico; Zancani, Marco

    2012-11-01

    The mitochondrial permeability transition (PT) is a well-recognized phenomenon that allows mitochondria to undergo a sudden increase of permeability to solutes with molecular mass ≤ 1500Da, leading to organelle swelling and structural modifications. The relevance of PT relies on its master role in the manifestation of programmed cell death (PCD). This function is performed by a mega-channel (in some cases inhibited by cyclosporin A) named permeability transition pore (PTP), whose function could derive from the assembly of different mitochondrial proteins. In this paper we examine the distribution and characteristics of PTP in mitochondria of eukaryotic organisms so far investigated in order to draw a hypothesis on the mechanism of its evolution. As a result, we suggest that PTP may have arisen as a new function linked to a multiple molecular exaptation of different mitochondrial proteins, even though they could nevertheless still play their original role. Furthermore, we suggest that the early appearance of PTP could have had a crucial role in the establishment of endosymbiosis in eukaryotic cells, by the coordinated balancing of ATP production by glycolysis (performed by the primary phagocyte) and oxidative phosphorylation (accomplished by the endosymbiont). Indeed, we argue on the possibility that this new energetic equilibrium could have opened the way to the subsequent evolution toward metazoans. © 2012 Elsevier B.V. All rights reserved.

  2. 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.

  3. 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.

  4. 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

  5. TRIB1 downregulates hepatic lipogenesis and glycogenesis via multiple molecular interactions.

    PubMed

    Ishizuka, Yuumi; Nakayama, Kazuhiro; Ogawa, Ayumi; Makishima, Saho; Boonvisut, Supichaya; Hirao, Atsushi; Iwasaki, Yusaku; Yada, Toshihiko; Yanagisawa, Yoshiko; Miyashita, Hiroshi; Takahashi, Masafumi; Iwamoto, Sadahiko

    2014-04-01

    Mammalian tribbles homolog 1 (TRIB1) regulates hepatic lipogenesis and is genetically associated with plasma triglyceride (TG) levels and cholesterol, but the molecular mechanisms remain obscure. We explored these mechanisms in mouse livers transfected with a TRIB1 overexpression, a shRNA template or a control (LacZ) adenovirus vector. The overexpression of TRIB1 reduced, whereas induction of the shRNA template increased, plasma glucose, TG, and cholesterol and simultaneously hepatic TG and glycogen levels. The involvement of TRIB1 in hepatic lipid accumulation was supported by the findings of a human SNP association study. A TRIB1 SNP, rs6982502, was identified in an enhancer sequence, modulated enhancer activity in reporter gene assays, and was significantly (P=9.39 × 10(-7)) associated with ultrasonographically diagnosed non-alcoholic fatty liver disease in a population of 5570 individuals. Transcriptome analyses of mouse livers revealed significant modulation of the gene sets involved in glycogenolysis and lipogenesis. Enforced TRIB1 expression abolished CCAAT/enhancer binding protein A (CEBPA), CEBPB, and MLXIPL proteins, whereas knockdown increased the protein level. Levels of TRIB1 expression simultaneously affected MKK4 (MAP2K4), MEK1 (MAP2K1), and ERK1/2 (MAPK1/3) protein levels and the phosphorylation of JNK, but not of ERK1/2. Pull-down and mammalian two-hybrid analyses revealed novel molecular interaction between TRIB1 and a hepatic lipogenic master regulator, MLXIPL. Co-expression of TRIB1 and CEBPA or MLXIPL reduced their protein levels and proteasome inhibitors attenuated the reduction. These data suggested that the modulation of TRIB1 expression affects hepatic lipogenesis and glycogenesis through multiple molecular interactions.

  6. DNA Sequences from Formalin-Fixed Nematodes: Integrating Molecular and Morphological Approaches to Taxonomy

    PubMed Central

    Thomas, W. Kelley; Vida, J. T.; Frisse, Linda M.; Mundo, Manuel; Baldwin, James G.

    1997-01-01

    To effectively integrate DNA sequence analysis and classical nematode taxonomy, we must be able to obtain DNA sequences from formalin-fixed specimens. Microdissected sections of nematodes were removed from specimens fixed in formalin, using standard protocols and without destroying morphological features. The fixed sections provided sufficient template for multiple polymerase chain reaction-based DNA sequence analyses. PMID:19274156

  7. A note on the use of multiple linear regression in molecular ecology.

    PubMed

    Frasier, Timothy R

    2016-03-01

    Multiple linear regression analyses (also often referred to as generalized linear models--GLMs, or generalized linear mixed models--GLMMs) are widely used in the analysis of data in molecular ecology, often to assess the relative effects of genetic characteristics on individual fitness or traits, or how environmental characteristics influence patterns of genetic differentiation. However, the coefficients resulting from multiple regression analyses are sometimes misinterpreted, which can lead to incorrect interpretations and conclusions within individual studies, and can propagate to wider-spread errors in the general understanding of a topic. The primary issue revolves around the interpretation of coefficients for independent variables when interaction terms are also included in the analyses. In this scenario, the coefficients associated with each independent variable are often interpreted as the independent effect of each predictor variable on the predicted variable. However, this interpretation is incorrect. The correct interpretation is that these coefficients represent the effect of each predictor variable on the predicted variable when all other predictor variables are zero. This difference may sound subtle, but the ramifications cannot be overstated. Here, my goals are to raise awareness of this issue, to demonstrate and emphasize the problems that can result and to provide alternative approaches for obtaining the desired information.

  8. Multiple Molecular and Cellular Mechanisms of Action of Lycopene in Cancer Inhibition

    PubMed Central

    Trejo-Solís, Cristina; Pedraza-Chaverrí, Jose; Torres-Ramos, Mónica; Jiménez-Farfán, Dolores; Cruz Salgado, Arturo; Serrano-García, Norma; Osorio-Rico, Laura; Sotelo, Julio

    2013-01-01

    Epidemiological studies suggest that including fruits, vegetables, and whole grains in regular dietary intake might prevent and reverse cellular carcinogenesis, reducing the incidence of primary tumours. Bioactive components present in food can simultaneously modulate more than one carcinogenic process, including cancer metabolism, hormonal balance, transcriptional activity, cell-cycle control, apoptosis, inflammation, angiogenesis and metastasis. Some studies have shown an inverse correlation between a diet rich in fruits, vegetables, and carotenoids and a low incidence of different types of cancer. Lycopene, the predominant carotenoid found in tomatoes, exhibits a high antioxidant capacity and has been shown to prevent cancer, as evidenced by clinical trials and studies in cell culture and animal models. In vitro studies have shown that lycopene treatment can selectively arrest cell growth and induce apoptosis in cancer cells without affecting normal cells. In vivo studies have revealed that lycopene treatment inhibits tumour growth in the liver, lung, prostate, breast, and colon. Clinical studies have shown that lycopene protects against prostate cancer. One of the main challenges in cancer prevention is the integration of new molecular findings into clinical practice. Thus, the identification of molecular biomarkers associated with lycopene levels is essential for improving our understanding of the mechanisms underlying its antineoplastic activity. PMID:23970935

  9. Multiple molecular and cellular mechanisms of action of lycopene in cancer inhibition.

    PubMed

    Trejo-Solís, Cristina; Pedraza-Chaverrí, Jose; Torres-Ramos, Mónica; Jiménez-Farfán, Dolores; Cruz Salgado, Arturo; Serrano-García, Norma; Osorio-Rico, Laura; Sotelo, Julio

    2013-01-01

    Epidemiological studies suggest that including fruits, vegetables, and whole grains in regular dietary intake might prevent and reverse cellular carcinogenesis, reducing the incidence of primary tumours. Bioactive components present in food can simultaneously modulate more than one carcinogenic process, including cancer metabolism, hormonal balance, transcriptional activity, cell-cycle control, apoptosis, inflammation, angiogenesis and metastasis. Some studies have shown an inverse correlation between a diet rich in fruits, vegetables, and carotenoids and a low incidence of different types of cancer. Lycopene, the predominant carotenoid found in tomatoes, exhibits a high antioxidant capacity and has been shown to prevent cancer, as evidenced by clinical trials and studies in cell culture and animal models. In vitro studies have shown that lycopene treatment can selectively arrest cell growth and induce apoptosis in cancer cells without affecting normal cells. In vivo studies have revealed that lycopene treatment inhibits tumour growth in the liver, lung, prostate, breast, and colon. Clinical studies have shown that lycopene protects against prostate cancer. One of the main challenges in cancer prevention is the integration of new molecular findings into clinical practice. Thus, the identification of molecular biomarkers associated with lycopene levels is essential for improving our understanding of the mechanisms underlying its antineoplastic activity.

  10. Functional integration between brain regions at rest occurs in multiple-frequency bands.

    PubMed

    Gohel, Suril R; Biswal, Bharat B

    2015-02-01

    Studies of resting-state fMRI have shown that blood oxygen level dependent (BOLD) signals giving rise to temporal correlation across voxels (or regions) are dominated by low-frequency fluctuations in the range of ∼ 0.01-0.1 Hz. These low-frequency fluctuations have been further divided into multiple distinct frequency bands (slow-5 and -4) based on earlier neurophysiological studies, though low sampling frequency of fMRI (∼ 0.5 Hz) has substantially limited the exploration of other known frequency bands of neurophysiological origins (slow-3, -2, and -1). In this study, we used resting-state fMRI data acquired from 21 healthy subjects at a higher sampling frequency of 1.5 Hz to assess the presence of resting-state functional connectivity (RSFC) across multiple frequency bands: slow-5 to slow-1. The effect of different frequency bands on spatial extent and connectivity strength for known resting-state networks (RSNs) was also evaluated. RSNs were derived using independent component analysis and seed-based correlation. Commonly known RSNs, such as the default mode, the fronto-parietal, the dorsal attention, and the visual networks, were consistently observed at multiple frequency bands. Significant inter-hemispheric connectivity was observed between each seed and its contra lateral brain region across all frequency bands, though overall spatial extent of seed-based correlation maps decreased in slow-2 and slow-1 frequency bands. These results suggest that functional integration between brain regions at rest occurs over multiple frequency bands and RSFC is a multiband phenomenon. These results also suggest that further investigation of BOLD signal in multiple frequency bands for related cognitive processes should be undertaken.

  11. 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

  12. Integrative Genomic Analysis of Cholangiocarcinoma Identifies Distinct IDH-Mutant Molecular Profiles.

    PubMed

    Farshidfar, Farshad; Zheng, Siyuan; Gingras, Marie-Claude; Newton, Yulia; Shih, Juliann; Robertson, A Gordon; Hinoue, Toshinori; Hoadley, Katherine A; Gibb, Ewan A; Roszik, Jason; Covington, Kyle R; Wu, Chia-Chin; Shinbrot, Eve; Stransky, Nicolas; Hegde, Apurva; Yang, Ju Dong; Reznik, Ed; Sadeghi, Sara; Pedamallu, Chandra Sekhar; Ojesina, Akinyemi I; Hess, Julian M; Auman, J Todd; Rhie, Suhn K; Bowlby, Reanne; Borad, Mitesh J; Zhu, Andrew X; Stuart, Josh M; Sander, Chris; Akbani, Rehan; Cherniack, Andrew D; Deshpande, Vikram; Mounajjed, Taofic; Foo, Wai Chin; Torbenson, Michael S; Kleiner, David E; Laird, Peter W; Wheeler, David A; McRee, Autumn J; Bathe, Oliver F; Andersen, Jesper B; Bardeesy, Nabeel; Roberts, Lewis R; Kwong, Lawrence N

    2017-03-14

    Cholangiocarcinoma (CCA) is an aggressive malignancy of the bile ducts, with poor prognosis and limited treatment options. Here, we describe the integrated analysis of somatic mutations, RNA expression, copy number, and DNA methylation by The Cancer Genome Atlas of a set of predominantly intrahepatic CCA cases and propose a molecular classification scheme. We identified an IDH mutant-enriched subtype with distinct molecular features including low expression of chromatin modifiers, elevated expression of mitochondrial genes, and increased mitochondrial DNA copy number. Leveraging the multi-platform data, we observed that ARID1A exhibited DNA hypermethylation and decreased expression in the IDH mutant subtype. More broadly, we found that IDH mutations are associated with an expanded histological spectrum of liver tumors with molecular features that stratify with CCA. Our studies reveal insights into the molecular pathogenesis and heterogeneity of cholangiocarcinoma and provide classification information of potential therapeutic significance. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  13. Toward molecular trait-based ecology through integration of biogeochemical, geographical and metagenomic data

    PubMed Central

    Raes, Jeroen; Letunic, Ivica; Yamada, Takuji; Jensen, Lars Juhl; Bork, Peer

    2011-01-01

    Using metagenomic ‘parts lists' to infer global patterns on microbial ecology remains a significant challenge. To deduce important ecological indicators such as environmental adaptation, molecular trait dispersal, diversity variation and primary production from the gene pool of an ecosystem, we integrated 25 ocean metagenomes with geographical, meteorological and geophysicochemical data. We find that climatic factors (temperature, sunlight) are the major determinants of the biomolecular repertoire of each sample and the main limiting factor on functional trait dispersal (absence of biogeographic provincialism). Molecular functional richness and diversity show a distinct latitudinal gradient peaking at 20°N and correlate with primary production. The latter can also be predicted from the molecular functional composition of an environmental sample. Together, our results show that the functional community composition derived from metagenomes is an important quantitative readout for molecular trait-based biogeography and ecology. PMID:21407210

  14. Toward molecular trait-based ecology through integration of biogeochemical, geographical and metagenomic data.

    PubMed

    Raes, Jeroen; Letunic, Ivica; Yamada, Takuji; Jensen, Lars Juhl; Bork, Peer

    2011-03-15

    Using metagenomic 'parts lists' to infer global patterns on microbial ecology remains a significant challenge. To deduce important ecological indicators such as environmental adaptation, molecular trait dispersal, diversity variation and primary production from the gene pool of an ecosystem, we integrated 25 ocean metagenomes with geographical, meteorological and geophysicochemical data. We find that climatic factors (temperature, sunlight) are the major determinants of the biomolecular repertoire of each sample and the main limiting factor on functional trait dispersal (absence of biogeographic provincialism). Molecular functional richness and diversity show a distinct latitudinal gradient peaking at 20° N and correlate with primary production. The latter can also be predicted from the molecular functional composition of an environmental sample. Together, our results show that the functional community composition derived from metagenomes is an important quantitative readout for molecular trait-based biogeography and ecology.

  15. Determination of the experimental equilibrium structure of solid nitromethane using path-integral molecular dynamics simulations

    NASA Astrophysics Data System (ADS)

    Reilly, Anthony M.; Habershon, Scott; Morrison, Carole A.; Rankin, David W. H.

    2010-03-01

    Path-integral molecular dynamics (PIMD) simulations with an empirical interaction potential have been used to determine the experimental equilibrium structure of solid nitromethane at 4.2 and 15 K. By comparing the time-averaged molecular structure determined in a PIMD simulation to the calculated minimum-energy (zero-temperature) molecular structure, we have derived structural corrections that describe the effects of thermal motion. These corrections were subsequently used to determine the equilibrium structure of nitromethane from the experimental time-averaged structure. We find that the corrections to the intramolecular and intermolecular bond distances, as well as to the torsion angles, are quite significant, particularly for those atoms participating in the anharmonic motion of the methyl group. Our results demonstrate that simple harmonic models of thermal motion may not be sufficiently accurate, even at low temperatures, while molecular simulations employing more realistic potential-energy surfaces can provide important insight into the role and magnitude of anharmonic atomic motions.

  16. 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.

  17. Photometric Detection of Multiple Populations in Globular Clusters Using Integrated Light

    NASA Astrophysics Data System (ADS)

    Bowman, William P.; Pilachowski, Catherine A.; van Zee, Liese; Winans, Amanda; Ciardullo, Robin; Gronwall, Caryl

    2017-10-01

    We investigate the multiple stellar populations of the globular clusters (GCs) M3, M5, M13, and M71 using {g}{\\prime } and intermediate-band CN-λ 3883 photometry obtained with the WIYN 0.9 m telescope on Kitt Peak. We find a strong correlation between red giant stars’ CN-{g}{\\prime } colors and their spectroscopic sodium abundances, thus demonstrating the efficacy of the two-filter system for stellar population studies. In all four clusters, the observed spread in red giant branch CN-{g}{\\prime } colors is wider than that expected from photometric uncertainty, confirming the well-known chemical inhomogeneity of these systems. M3 and M13 show clear evidence for a radial dependence in the CN-band strengths of its red giants, while the evidence for such a radial dependence of CN strengths in M5 is ambiguous. Our data suggest that the dynamically old, relatively metal-rich M71 system is well mixed, as it shows no evidence for chemical segregation. Finally, we measure the radial gradients in the integrated CN-{g}{\\prime } color of the clusters and find that such gradients are easily detectable in the integrated light. We suggest that photometric observations of color gradients within GCs throughout the Local Group can be used to characterize their multiple populations, and thereby constrain the formation history of GCs in different galactic environments.

  18. Multi-Scale Segmentation of High Resolution Remote Sensing Images by Integrating Multiple Features

    NASA Astrophysics Data System (ADS)

    Di, Y.; Jiang, G.; Yan, L.; Liu, H.; Zheng, S.

    2017-05-01

    Most of multi-scale segmentation algorithms are not aiming at high resolution remote sensing images and have difficulty to communicate and use layers' information. In view of them, we proposes a method of multi-scale segmentation of high resolution remote sensing images by integrating multiple features. First, Canny operator is used to extract edge information, and then band weighted distance function is built to obtain the edge weight. According to the criterion, the initial segmentation objects of color images can be gained by Kruskal minimum spanning tree algorithm. Finally segmentation images are got by the adaptive rule of Mumford-Shah region merging combination with spectral and texture information. The proposed method is evaluated precisely using analog images and ZY-3 satellite images through quantitative and qualitative analysis. The experimental results show that the multi-scale segmentation of high resolution remote sensing images by integrating multiple features outperformed the software eCognition fractal network evolution algorithm (highest-resolution network evolution that FNEA) on the accuracy and slightly inferior to FNEA on the efficiency.

  19. Calculation of heat capacities of light and heavy water by path-integral molecular dynamics

    NASA Astrophysics Data System (ADS)

    Shiga, Motoyuki; Shinoda, Wataru

    2005-10-01

    As an application of atomistic simulation methods to heat capacities, path-integral molecular dynamics has been used to calculate the constant-volume heat capacities of light and heavy water in the gas, liquid, and solid phases. While the classical simulation based on conventional molecular dynamics has estimated the heat capacities too high, the quantum simulation based on path-integral molecular dynamics has given reasonable results based on the simple point-charge/flexible potential model. The calculated heat capacities (divided by the Boltzmann constant) in the quantum simulation are 3.1 in the vapor H2O at 300 K, 6.9 in the liquid H2O at 300 K, and 4.1 in the ice IhH2O at 250 K, respectively, which are comparable to the experimental data of 3.04, 8.9, and 4.1, respectively. The quantum simulation also reproduces the isotope effect. The heat capacity in the liquid D2O has been calculated to be 10% higher than that of H2O, while it is 13% higher in the experiment. The results demonstrate that the path-integral simulation is a promising approach to quantitatively evaluate the heat capacities for molecular systems, taking account of quantum-mechanical vibrations as well as strongly anharmonic motions.

  20. 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

  1. Biogeography of soil organic matter molecular structure across multiple soil size fractions

    NASA Astrophysics Data System (ADS)

    Meier, C. L.; Neff, J.

    2009-12-01

    Recent work suggests that there is a common soil decomposition sequence whereby plant inputs are metabolized into a physiologically constrained set of compounds originating from microbes that may persist in soil over relatively long time-scales. Plant inputs tend to be found in coarse particulate fractions (>180 μm) with relatively fast turnover times, while microbially derived compounds tend to accrue in the finer silt + clay fractions (<53 μm) with relatively long turnover times. To investigate whether a common decomposition sequence exists, we used pyrolysis gas chromatography/mass spectrometry (py-GC/MS) to characterize the molecular structure of soil organic matter (SOM) in three size fractions (590-180 μm, 180-53 μm, and <53 μm), using soils sampled from multiple biomes (alpine tundra, sub-alpine forest, boreal forest, temperate coniferous, temperate deciduous, dry desert/savannah, and tropical forest). We hypothesized that: 1) regardless of biome, fractions >180 μm would be chemically similar, and would be characterized by lignin and other plant-derived compounds; and 2) fractions <53 μm would also be similar across biomes but would be dominated by microbially-derived compounds like polysaccharides. Across all biomes, we found that there was significantly less lignin in <53 μm fractions compared to >180 μm fractions (p<0.0001), providing some support for the idea that plant material is not incorporated into soil C pools with relatively long turnover times. However, a principal components analysis (PCA) showed that the >180 μm coarse particulate fractions also contained compounds associated with microbial origins, indicating that microbial C is not limited to <53 μm size fractions. The PCA also revealed that samples within each of the three size fractions did not cluster together (i.e. they did not share a common molecular structure), but we did note that: 1) cold alpine and sub-alpine sites were unique and chemically similar; and 2) tropical

  2. A Microfluidic Localized, Multiple Cell Culture Array using Vacuum Actuated Cell Seeding: Integrated Anticancer Drug Testing

    PubMed Central

    Gao, Yan; Li, Peng

    2013-01-01

    In this study, we introduced a novel and convenient approach to culture multiple cells in localized arrays of microfluidic chambers using one-step vacuum actuation. In one device, we integrated 8 individually addressable regions of culture chambers, each only requiring one simple vacuum operation to seed cells lines. Four cell lines were seeded in designated regions in one device via sequential injection with high purity (99.9%-100%) and cultured for long-term. The on-chip simultaneous culture of HuT 78, Ramos, PC-3 and C166-GFP cells for 48 h was demonstrated with viabilities of 92%+/−2%, 94%+/−4%, 96%+/−2% and 97%+/−2%, respectively. The longest culture period for C166-GFP cells in this study was 168 h with a viability of 96%+/−10%. Cell proliferation in each individual side channel can be tracked. Mass transport between the main channel and side channels was achieved through diffusion and studied using fluorescein solution. The main advantage of this device is the capability to perform multiple cell-based assays on the same device for better comparative studies. After treating cells with staurosporine or anti-human CD95 for 16 h, the apoptotic cell percentage of HuT 78, CCRF-CEM, PC-3 and Ramos cells were 36%+/−3%, 24%+/−4%, 12%+/−2%, 18%+/−4% for staurosporine, and 63%+/−2%, 45%+/−1%, 3%+/−3%, 27%+/−12% for anti-human CD95, respectively. With the advantages of enhanced integration, ease of use and fabrication, and flexibility, this device will be suitable for long-term multiple cell monitoring and cell based assays. PMID:23813077

  3. 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)

  4. 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.

  5. 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.

  6. 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.

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

    PubMed Central

    Müller, Klaus-Robert

    2015-01-01

    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

  8. 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.

  9. Integration of multiple determinants in the neuronal computation of economic values.

    PubMed

    Raghuraman, Anantha P; Padoa-Schioppa, Camillo

    2014-08-27

    Economic goods may vary on multiple dimensions (determinants). A central conjecture in decision neuroscience is that choices between goods are made by comparing subjective values computed through the integration of all relevant determinants. Previous work identified three groups of neurons in the orbitofrontal cortex (OFC) of monkeys engaged in economic choices: (1) offer value cells, which encode the value of individual offers; (2) chosen value cells, which encode the value of the chosen good; and (3) chosen juice cells, which encode the identity of the chosen good. In principle, these populations could be sufficient to generate a decision. Critically, previous work did not assess whether offer value cells (the putative input to the decision) indeed encode subjective values as opposed to physical properties of the goods, and/or whether offer value cells integrate multiple determinants. To address these issues, we recorded from the OFC while monkeys chose between risky outcomes. Confirming previous observations, three populations of neurons encoded the value of individual offers, the value of the chosen option, and the value-independent choice outcome. The activity of both offer value cells and chosen value cells encoded values defined by the integration of juice quantity and probability. Furthermore, both populations reflected the subjective risk attitude of the animals. We also found additional groups of neurons encoding the risk associated with a particular option, the risky nature of the chosen option, and whether the trial outcome was positive or negative. These results provide substantial support for the conjecture described above and for the involvement of OFC in good-based decisions.

  10. 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…

  11. 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…

  12. 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.

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

    PubMed

    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.

  14. 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

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

    PubMed

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

    2014-02-22

    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.

  16. 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.

  17. 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.

  18. Molecular weight recognition in the multiple-stranded helix of a synthetic polymer without specific monomer-monomer interaction.

    PubMed

    Kumaki, Jiro; Kawauchi, Takehiro; Ute, Koichi; Kitayama, Tatsuki; Yashima, Eiji

    2008-05-21

    Stereoregular isotactic and syndiotactic poly(methyl methacrylate)s (it- and st-PMMAs) are known to form a multiple-stranded complementary helix, so-called stereocomplex (SC) through van der Waals interactions, which is a rare example of helical supramolecular structures formed by a commodity polymer. In this study, we prepared SCs by using uniform it- and st-PMMAs and those with a narrow molecular weight distribution having different molecular weights and investigated their structures in detail using high-resolution atomic force microscopy as a function of the molecular weight and molecular weight distribution of the component PMMAs. We found that complementary it- and st-PMMAs with the longer molecular length determine the total length of the SC, and molecules of the shorter component associate until they fill up or cover the longer component. These observations support a supramolecular triple-stranded helical structure of the SCs composed of a double-stranded helix of two intertwined it-PMMA chains included in a single helix of st-PMMA, and this triple-stranded helix model of the SCs appears to be applicable to the it- and st-PMMAs having a wide range of molecular weights we employed in this study. In homogeneous double-stranded helices of it-PMMA, it has been found that, in mixtures of two it-PMMAs with different molecular weights, chains of the same molecular weight selectively form a double-stranded it-PMMA helix, or recognize the molecular weights of each other ("molecular sorting"). We thus demonstrate that molecular weight recognition is possible, without any specific interaction between monomer units, through the formation of a topological multiple-stranded helical structure based upon van der Waals interaction.

  19. No double-dissociation between optic ataxia and visual agnosia: multiple sub-streams for multiple visuo-manual integrations.

    PubMed

    Pisella, L; Binkofski, F; Lasek, K; Toni, I; Rossetti, Y

    2006-01-01

    The current dominant view of the visual system is marked by the functional and anatomical dissociation between a ventral stream specialised for perception and a dorsal stream specialised for action. The "double-dissociation" between visual agnosia (VA), a deficit of visual recognition, and optic ataxia (OA), a deficit of visuo-manual guidance, considered as consecutive to ventral and dorsal damage, respectively, has provided the main argument for this dichotomic view. In the first part of this paper, we show that the currently available empirical data do not suffice to support a double-dissociation between OA and VA. In the second part, we review evidence coming from human neuropsychology and monkey data, which cast further doubts on the validity of a simple double-dissociation between perception and action because they argue for a far more complex organisation with multiple parallel visual-to-motor connections: 1. A dorso-dorsal pathway (involving the most dorsal part of the parietal and pre-motor cortices): for immediate visuo-motor control--with OA as typical disturbance. The latest research about OA is reviewed, showing how these patients exhibit deficits restricted to the most direct and fast visuo-motor transformations. We also propose that mild mirror ataxia, consisting of misreaching errors when the controlesional hand is guided to a visual goal though a mirror, could correspond to OA with an isolated "hand effect". 2. A ventral stream-prefrontal pathway (connections from the ventral visual stream to pre-frontal areas, by-passing the parietal areas): for "mediate" control (involving spatial or temporal transpositions [Rossetti, Y., & Pisella, L. (2003). Mediate responses as direct evidence for intention: Neuropsychology of Not to-, Not now- and Not there-tasks. In S. Johnson (Ed.), Cognitive Neuroscience perspectives on the problem of intentional action (pp. 67-105). MIT Press.])--with VA as typical disturbance. Preserved visuo-manual guidance in patients

  20. A comprehensive protein-centric ID mapping service for molecular data integration

    PubMed Central

    Huang, Hongzhan; Suzek, Baris E.; Mazumder, Raja; Zhang, Jian; Chen, Yongxing; Wu, Cathy H.

    2011-01-01

    Motivation: Identifier (ID) mapping establishes links between various biological databases and is an essential first step for molecular data integration and functional annotation. ID mapping allows diverse molecular data on genes and proteins to be combined and mapped to functional pathways and ontologies. We have developed comprehensive protein-centric ID mapping services providing mappings for 90 IDs derived from databases on genes, proteins, pathways, diseases, structures, protein families, protein interaction, literature, ontologies, etc. The services are widely used and have been regularly updated since 2006. Availability: www.uniprot.org/mappingandproteininformation-resource.org/pirwww/search/idmapping.shtml Contact: huang@dbi.udel.edu PMID:21478197

  1. Multiple kernel learning with random effects for predicting longitudinal outcomes and data integration.

    PubMed

    Chen, Tianle; Zeng, Donglin; Wang, Yuanjia

    2015-12-01

    Predicting disease risk and progression is one of the main goals in many clinical research studies. Cohort studies on the natural history and etiology of chronic diseases span years and data are collected at multiple visits. Although, kernel-based statistical learning methods are proven to be powerful for a wide range of disease prediction problems, these methods are only well studied for independent data, but not for longitudinal data. It is thus important to develop time-sensitive prediction rules that make use of the longitudinal nature of the data. In this paper, we develop a novel statistical learning method for longitudinal data by introducing subject-specific short-term and long-term latent effects through a designed kernel to account for within-subject correlation of longitudinal measurements. Since the presence of multiple sources of data is increasingly common, we embed our method in a multiple kernel learning framework and propose a regularized multiple kernel statistical learning with random effects to construct effective nonparametric prediction rules. Our method allows easy integration of various heterogeneous data sources and takes advantage of correlation among longitudinal measures to increase prediction power. We use different kernels for each data source taking advantage of the distinctive feature of each data modality, and then optimally combine data across modalities. We apply the developed methods to two large epidemiological studies, one on Huntington's disease and the other on Alzheimer's Disease (Alzheimer's Disease Neuroimaging Initiative, ADNI) where we explore a unique opportunity to combine imaging and genetic data to study prediction of mild cognitive impairment, and show a substantial gain in performance while accounting for the longitudinal aspect of the data. © 2015, The International Biometric Society.

  2. Adaptive multi-stage integrators for optimal energy conservation in molecular simulations

    NASA Astrophysics Data System (ADS)

    Fernández-Pendás, Mario; Akhmatskaya, Elena; Sanz-Serna, J. M.

    2016-12-01

    We introduce a new Adaptive Integration Approach (AIA) to be used in a wide range of molecular simulations. Given a simulation problem and a step size, the method automatically chooses the optimal scheme out of an available family of numerical integrators. Although we focus on two-stage splitting integrators, the idea may be used with more general families. In each instance, the system-specific integrating scheme identified by our approach is optimal in the sense that it provides the best conservation of energy for harmonic forces. The AIA method has been implemented in the BCAM-modified GROMACS software package. Numerical tests in molecular dynamics and hybrid Monte Carlo simulations of constrained and unconstrained physical systems show that the method successfully realizes the fail-safe strategy. In all experiments, and for each of the criteria employed, the AIA is at least as good as, and often significantly outperforms the standard Verlet scheme, as well as fixed parameter, optimized two-stage integrators. In particular, for the systems where harmonic forces play an important role, the sampling efficiency found in simulations using the AIA is up to 5 times better than the one achieved with other tested schemes.

  3. On using a too large integration time step in molecular dynamics simulations of coarse-grained molecular models.

    PubMed

    Winger, Moritz; Trzesniak, Daniel; Baron, Riccardo; van Gunsteren, Wilfred F

    2009-03-28

    The use of a coarse-grained (CG) model that is widely used in molecular dynamics simulations of biomolecular systems is investigated with respect to the dependence of a variety of quantities upon the size of the used integration time step and cutoff radius. The results suggest that when using a non-bonded interaction-cutoff radius of 1.4 nm a time step of maximally 10 fs should be used, in order not to produce energy sinks or wells. Using a too-large time step, e.g. 50 fs with a cutoff of 1.2 nm, as is done in the coarse-grained model of Marrink et al. (J. Phys. Chem. B, 2004, 108, 250 and 2007, 111, 7812), induces errors due to the linear approximation of the integrators that are commonly used to integrate the equations of motion. As a spin-off of the investigation of the mentioned CG models, we found that the parameters of the CG water model place it at physiological temperatures well into the solid phase of the phase diagram.

  4. Integrative clustering of multiple genomic data types using a joint latent variable model with application to breast and lung cancer subtype analysis.

    PubMed

    Shen, Ronglai; Olshen, Adam B; Ladanyi, Marc

    2009-11-15

    The molecular complexity of a tumor manifests itself at the genomic, epigenomic, transcriptomic and proteomic levels. Genomic profiling at these multiple levels should allow an integrated characterization of tumor etiology. However, there is a shortage of effective statistical and bioinformatic tools for truly integrative data analysis. The standard approach to integrative clustering is separate clustering followed by manual integration. A more statistically powerful approach would incorporate all data types simultaneously and generate a single integrated cluster assignment. We developed a joint latent variable model for integrative clustering. We call the resulting methodology iCluster. iCluster incorporates flexible modeling of the associations between different data types and the variance-covariance structure within data types in a single framework, while simultaneously reducing the dimensionality of the datasets. Likelihood-based inference is obtained through the Expectation-Maximization algorithm. We demonstrate the iCluster algorithm using two examples of joint analysis of copy number and gene expression data, one from breast cancer and one from lung cancer. In both cases, we identified subtypes characterized by concordant DNA copy number changes and gene expression as well as unique profiles specific to one or the other in a completely automated fashion. In addition, the algorithm discovers potentially novel subtypes by combining weak yet consistent alteration patterns across data types. R code to implement iCluster can be downloaded at http://www.mskcc.org/mskcc/html/85130.cfm

  5. Transport coefficients of normal liquid helium-4 calculated by path integral centroid molecular dynamics simulation

    NASA Astrophysics Data System (ADS)

    Imaoka, Haruna; Kinugawa, Kenichi

    2017-03-01

    Thermal conductivity, shear viscosity, and bulk viscosity of normal liquid 4He at 1.7-4.0 K are calculated using path integral centroid molecular dynamics (CMD) simulations. The calculated thermal conductivity and shear viscosity above lambda transition temperature are on the same order of magnitude as experimental values, while the agreement of shear viscosity is better. Above 2.3 K the CMD well reproduces the temperature dependences of isochoric shear viscosity and of the time integral of the energy current and off-diagonal stress tensor correlation functions. The calculated bulk viscosity, not known in experiments, is several times larger than shear viscosity.

  6. Multiple Molecular Outflows in the Proto-Planetary Nebula AFGL 618

    NASA Astrophysics Data System (ADS)

    Huggins, P. J.; Cox, P.; Maillard, J.-P.; Muthu, C.; Bachiller, R.; Forveille, T.

    2002-12-01

    We report high resolution (0.5'' times 9 km s-1) spectro-imaging of the 2.12 micron H2 v=1-0 S(1) line in the proto-planetary nebula AFGL 618. The observations were made with the BEAR imaging Fourier transform spectrometer at the CFHT. The results provide a detailed picture of the structure and kinematics of the H2 emission in AFGL 618, and shed light on a long standing problem of the origin of high velocity H2 seen in the line wings of spatially unresolved spectra (Burton & Geballe 1986, MNRAS 223, 13p). At low expansion velocities the H2 distribution forms a tilted, bi-conical structure, which is typical of that seen in proto-PNe and young PNe. At high expansion velocities, the H2 emission is resolved into multiple, molecular outflows that align with the remarkable optical jets seen in HST images reported by Trammel and Goodrich (2002, ApJ in press). The H2 velocity increases along the jets away from the center, to as much as 200-350 km s-1 when corrected for inclination, although the line widths are quite narrow ~ 30 km s-1. The H2 emission signals shock interaction of the jets with the circumstellar gas, and likely arises from entrained envelope material. AFGL 618 is one of several proto-PNe and young PNe in which optical jets are seen: the structure and kinematics of the molecular outflows reported here illustrate how these jets interact with circumstellar gas and shape the environment in which planetary nebulae form. This work was supported in part by NSF AST-9986159.

  7. Mechanically untying a protein slipknot: multiple pathways revealed by force spectroscopy and steered molecular dynamics simulations.

    PubMed

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

    2012-06-27

    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 mechanical 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 via either a two- 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 providing 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 was 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 mechanical unfolding pathway of AFV3-109 and point to the generality of a kinetic partitioning mechanism for protein folding/unfolding.

  8. 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

  9. Molecular and functional analysis of SUMF1 mutations in multiple sulfatase deficiency.

    PubMed

    Cosma, Maria Pia; Pepe, Stefano; Parenti, Giancarlo; Settembre, Carmine; Annunziata, Ida; Wade-Martins, Richard; Di Domenico, Carmela; Di Natale, Paola; Mankad, Anuj; Cox, Barbara; Uziel, Graziella; Mancini, Grazia M S; Zammarchi, Enrico; Donati, Maria Alice; Kleijer, Wim J; Filocamo, Mirella; Carrozzo, Romeo; Carella, Massimo; Ballabio, Andrea

    2004-06-01

    Multiple sulfatase deficiency (MSD) is a rare disorder characterized by impaired activity of all known sulfatases. The gene mutated in this disease is SUMF1, which encodes a protein involved in a post-translational modification at the catalytic site of all sulfatases that is necessary for their function. SUMF1 strongly enhances the activity of sulfatases when coexpressed with sulfatase in Cos-7 cells. We performed a mutational analysis of SUMF1 in 20 MSD patients of different ethnic origin. The clinical presentation of these patients was variable, ranging from severe neonatal forms to mild phenotypes showing mild neurological involvement. A total of 22 SUMF1 mutations were identified, including missense, nonsense, microdeletion, and splicing mutations. We expressed all missense mutations in culture to study their ability to enhance the activity of sulfatases. Of the predicted amino acid changes, 11 (p.R349W, p.R224W, p.L20F, p.A348P, p.S155P, p.C218Y, p.N259I, p.A279V, p.R349Q, p.C336R, p.A177P) resulted in severely impaired sulfatase-enhancing activity. Two (p.R345C and p.P266L) showed a high residual activity on some, but not all, of the nine sulfatases tested, suggesting that some SUMF1 mutations may have variable effects on the activity of each sulfatase. This study compares, for the first time, clinical, biochemical, and molecular data in MSD patients. Our results show lack of a direct correlation between the type of molecular defect and the severity of phenotype.

  10. Characterization of the uncertainty of divergence time estimation under relaxed molecular clock models using multiple loci.

    PubMed

    Zhu, Tianqi; Dos Reis, Mario; Yang, Ziheng

    2015-03-01

    Genetic sequence data provide information about the distances between species or branch lengths in a phylogeny, but not about the absolute divergence times or the evolutionary rates directly. Bayesian methods for dating species divergences estimate times and rates by assigning priors on them. In particular, the prior on times (node ages on the phylogeny) incorporates information in the fossil record to calibrate the molecular tree. Because times and rates are confounded, our posterior time estimates will not approach point values even if an infinite amount of sequence data are used in the analysis. In a previous study we developed a finite-sites theory to characterize the uncertainty in Bayesian divergence time estimation in analysis of large but finite sequence data sets under a strict molecular clock. As most modern clock dating analyses use more than one locus and are conducted under relaxed clock models, here we extend the theory to the case of relaxed clock analysis of data from multiple loci (site partitions). Uncertainty in posterior time estimates is partitioned into three sources: Sampling errors in the estimates of branch lengths in the tree for each locus due to limited sequence length, variation of substitution rates among lineages and among loci, and uncertainty in fossil calibrations. Using a simple but analogous estimation problem involving the multivariate normal distribution, we predict that as the number of loci ([Formula: see text]) goes to infinity, the variance in posterior time estimates decreases and approaches the infinite-data limit at the rate of 1/[Formula: see text], and the limit is independent of the number of sites in the sequence alignment. We then confirmed the predictions by using computer simulation on phylogenies of two or three species, and by analyzing a real genomic data set for six primate species. Our results suggest that with the fossil calibrations fixed, analyzing multiple loci or site partitions is the most effective way

  11. Planarian shows decision-making behavior in response to multiple stimuli by integrative brain function.

    PubMed

    Inoue, Takeshi; Hoshino, Hajime; Yamashita, Taiga; Shimoyama, Seira; Agata, Kiyokazu

    2015-01-01

    Planarians belong to an evolutionarily early group of organisms that possess a central nervous system including a well-organized brain with a simple architecture but many types of neurons. Planarians display a number of behaviors, such as phototaxis and thermotaxis, in response to external stimuli, and it has been shown that various molecules and neural pathways in the brain are involved in controlling these behaviors. However, due to the lack of combinatorial assay methods, it remains obscure whether planarians possess higher brain functions, including integration in the brain, in which multiple signals coming from outside are coordinated and used in determining behavioral strategies. In the present study, we designed chemotaxis and thigmotaxis/kinesis tracking assays to measure several planarian behaviors in addition to those measured by phototaxis and thermotaxis assays previously established by our group, and used these tests to analyze planarian chemotactic and thigmotactic/kinetic behaviors. We found that headless planarian body fragments and planarians that had specifically lost neural activity following regeneration-dependent conditional gene knockdown (Readyknock) of synaptotagmin in the brain lost both chemotactic and thigmotactic behaviors, suggesting that neural activity in the brain is required for the planarian's chemotactic and thigmotactic behaviors. Furthermore, we compared the strength of phototaxis, chemotaxis, thigmotaxis/kinesis, and thermotaxis by presenting simultaneous binary stimuli to planarians. We found that planarians showed a clear order of predominance of these behaviors. For example, when planarians were simultaneously exposed to 400 lux of light and a chemoattractant, they showed chemoattractive behavior irrespective of the direction of the light source, although exposure to light of this intensity alone induces evasive behavior away from the light source. In contrast, when the light intensity was increased to 800 or 1600 lux and

  12. Molecular evolution of multiple-level control of heme biosynthesis pathway in animal kingdom.

    PubMed

    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.

  13. Impact of primary molecular cytogenetic abnormalities and risk of progression in smoldering multiple myeloma.

    PubMed

    Rajkumar, S V; Gupta, V; Fonseca, R; Dispenzieri, A; Gonsalves, W I; Larson, D; Ketterling, R P; Lust, J A; Kyle, R A; Kumar, S K

    2013-08-01

    We studied 351 patients with smoldering multiple myeloma (SMM) in whom the underlying primary molecular cytogenetic subtype could be determined based on cytoplasmic immunoglobulin fluorescent in situ hybridization studies. Hundred and fifty-four patients (43.9%) had trisomies, 127 (36.2%) had immunoglobulin heavy chain (IgH) translocations, 14 (4%) both trisomies and IgH translocations, 53 (15.1%) no abnormalities detected and 3 (0.9%) had monosomy13/del(13q) in the absence of any other abnormality. Among 127 patients with IgH translocations, 57 were t(11;14), 36 t(4;14), 11 musculoaponeurotic fibrosarcoma (MAF) translocations, and 23 other or unknown IgH translocation partner. Time to progression (TTP) to symptomatic multiple myeloma was significantly shorter in patients with the t(4;14) compared with patients with t(11;14), median 28 versus 55 months, respectively, P=0.025. The median TTP was 28 months with t(4;14) (high-risk), 34 months with trisomies alone (intermediate-risk), 55 months with t(11;14), MAF translocations, other/unknown IgH translocations, monosomy13/del(13q) without other abnormalities, and those with both trisomies and IgH translocations (standard-risk), and not reached in patients with no detectable abnormalities (low-risk), P=0.001. There was a trend to shorter TTP with deletion 17p (median TTP, 24 months). Overall survival from diagnosis of SMM was significantly inferior with t(4;14) compared with t(11;14), median 105 versus 147 months, respectively, P=0.036.

  14. Impact of primary molecular cytogenetic abnormalities and risk of progression in smoldering multiple myeloma

    PubMed Central

    Rajkumar, SV; Gupta, V; Fonseca, R; Dispenzieri, A; Gonsalves, WI; Larson, D; Ketterling, RP; Lust, JA; Kyle, RA; Kumar, SK

    2013-01-01

    We studied 351 patients with smoldering multiple myeloma (SMM) in whom the underlying primary molecular cytogenetic subtype could be determined based on cytoplasmic immunoglobulin fluorescent in situ hybridization studies. Hundred and fifty-four patients (43.9%) had trisomies, 127 (36.2%) had immunoglobulin heavy chain (IgH) translocations, 14 (4%) both trisomies and IgH translocations, 53 (15.1%) no abnormalities detected and 3 (0.9%) had monosomy13/del(13q) in the absence of any other abnormality. Among 127 patients with IgH translocations, 57 were t(11;14), 36 t(4;14), 11 musculoaponeurotic fibrosarcoma (MAF) translocations, and 23 other or unknown IgH translocation partner. Time to progression (TTP) to symptomatic multiple myeloma was significantly shorter in patients with the t(4;14) compared with patients with t(11;14), median 28 versus 55 months, respectively, P = 0.025. The median TTP was 28 months with t(4;14) (high-risk), 34 months with trisomies alone (intermediate-risk), 55 months with t(11;14), MAF translocations, other/unknown IgH translocations, monosomy13/del(13q) without other abnormalities, and those with both trisomies and IgH translocations (standard-risk), and not reached in patients with no detectable abnormalities (low-risk), P = 0.001. There was a trend to shorter TTP with deletion 17p (median TTP, 24 months). Overall survival from diagnosis of SMM was significantly inferior with t(4;14) compared with t(11;14), median 105 versus 147 months, respectively, P = 0.036. PMID:23515097

  15. Identification of novel adhesins of M. tuberculosis H37Rv using integrated approach of multiple computational algorithms and experimental analysis.

    PubMed

    Kumar, Sanjiv; Puniya, Bhanwar Lal; Parween, Shahila; Nahar, Pradip; Ramachandran, Srinivasan

    2013-01-01

    Pathogenic bacteria interacting with eukaryotic host express adhesins on their surface. These adhesins aid in bacterial attachment to the host cell receptors during colonization. A few adhesins such as Heparin binding hemagglutinin adhesin (HBHA), Apa, Malate Synthase of M. tuberculosis have been identified using specific experimental interaction models based on the biological knowledge of the pathogen. In the present work, we carried out computational screening for adhesins of M. tuberculosis. We used an integrated computational approach using SPAAN for predicting adhesins, PSORTb, SubLoc and LocTree for extracellular localization, and BLAST for verifying non-similarity to human proteins. These steps are among the first of reverse vaccinology. Multiple claims and attacks from different algorithms were processed through argumentative approach. Additional filtration criteria included selection for proteins with low molecular weights and absence of literature reports. We examined binding potential of the selected proteins using an image based ELISA. The protein Rv2599 (membrane protein) binds to human fibronectin, laminin and collagen. Rv3717 (N-acetylmuramoyl-L-alanine amidase) and Rv0309 (L,D-transpeptidase) bind to fibronectin and laminin. We report Rv2599 (membrane protein), Rv0309 and Rv3717 as novel adhesins of M. tuberculosis H37Rv. Our results expand the number of known adhesins of M. tuberculosis and suggest their regulated expression in different stages.

  16. Integrated analysis of phenome, genome, and transcriptome of hybrid rice uncovered multiple heterosis-related loci for yield increase

    PubMed Central

    Li, Dayong; Huang, Zhiyuan; Song, Shuhui; Xin, Yeyun; Mao, Donghai; Lv, Qiming; Zhou, Ming; Tian, Dongmei; Tang, Mingfeng; Wu, Qi; Liu, Xue; Chen, Tingting; Song, Xianwei; Fu, Xiqin; Zhao, Bingran; Liang, Chengzhi; Li, Aihong; Liu, Guozhen; Li, Shigui; Hu, Songnian; Cao, Xiaofeng; Yu, Jun; Yuan, Longping; Chen, Caiyan; Zhu, Lihuang

    2016-01-01

    Hybrid rice is the dominant form of rice planted in China, and its use has extended worldwide since the 1970s. It offers great yield advantages and has contributed greatly to the world’s food security. However, the molecular mechanisms underlying heterosis have remained a mystery. In this study we integrated genetics and omics analyses to determine the candidate genes for yield heterosis in a model two-line rice hybrid system, Liang-you-pei 9 (LYP9) and its parents. Phenomics study revealed that the better parent heterosis (BPH) of yield in hybrid is not ascribed to BPH of all the yield components but is specific to the BPH of spikelet number per panicle (SPP) and paternal parent heterosis (PPH) of effective panicle number (EPN). Genetic analyses then identified multiple quantitative trait loci (QTLs) for these two components. Moreover, a number of differentially expressed genes and alleles in the hybrid were mapped by transcriptome profiling to the QTL regions as possible candidate genes. In parallel, a major QTL for yield heterosis, rice heterosis 8 (RH8), was found to be the DTH8/Ghd8/LHD1 gene. Based on the shared allelic heterozygosity of RH8 in many hybrid rice cultivars, a common mechanism for yield heterosis in the present commercial hybrid rice is proposed. PMID:27663737

  17. Integrated analysis of phenome, genome, and transcriptome of hybrid rice uncovered multiple heterosis-related loci for yield increase.

    PubMed

    Li, Dayong; Huang, Zhiyuan; Song, Shuhui; Xin, Yeyun; Mao, Donghai; Lv, Qiming; Zhou, Ming; Tian, Dongmei; Tang, Mingfeng; Wu, Qi; Liu, Xue; Chen, Tingting; Song, Xianwei; Fu, Xiqin; Zhao, Bingran; Liang, Chengzhi; Li, Aihong; Liu, Guozhen; Li, Shigui; Hu, Songnian; Cao, Xiaofeng; Yu, Jun; Yuan, Longping; Chen, Caiyan; Zhu, Lihuang

    2016-10-11

    Hybrid rice is the dominant form of rice planted in China, and its use has extended worldwide since the 1970s. It offers great yield advantages and has contributed greatly to the world's food security. However, the molecular mechanisms underlying heterosis have remained a mystery. In this study we integrated genetics and omics analyses to determine the candidate genes for yield heterosis in a model two-line rice hybrid system, Liang-you-pei 9 (LYP9) and its parents. Phenomics study revealed that the better parent heterosis (BPH) of yield in hybrid is not ascribed to BPH of all the yield components but is specific to the BPH of spikelet number per panicle (SPP) and paternal parent heterosis (PPH) of effective panicle number (EPN). Genetic analyses then identified multiple quantitative trait loci (QTLs) for these two components. Moreover, a number of differentially expressed genes and alleles in the hybrid were mapped by transcriptome profiling to the QTL regions as possible candidate genes. In parallel, a major QTL for yield heterosis, rice heterosis 8 (RH8), was found to be the DTH8/Ghd8/LHD1 gene. Based on the shared allelic heterozygosity of RH8 in many hybrid rice cultivars, a common mechanism for yield heterosis in the present commercial hybrid rice is proposed.

  18. 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.

  19. Potential molecular consequences of transgene integration: The R6/2 mouse example

    PubMed Central

    Jacobsen, Jessie C.; Erdin, Serkan; Chiang, Colby; Hanscom, Carrie; Handley, Renee R.; Barker, Douglas D.; Stortchevoi, Alex; Blumenthal, Ian; Reid, Suzanne J.; Snell, Russell G.; MacDonald, Marcy E.; Morton, A. Jennifer; Ernst, Carl; Gusella, James F.; Talkowski, Michael E.

    2017-01-01

    Integration of exogenous DNA into a host genome represents an important route to generate animal and cellular models for exploration into human disease and therapeutic development. In most models, little is known concerning structural integrity of the transgene, precise site of integration, or its impact on the host genome. We previously used whole-genome and targeted sequencing approaches to reconstruct transgene structure and integration sites in models of Huntington’s disease, revealing complex structural rearrangements that can result from transgenesis. Here, we demonstrate in the R6/2 mouse, a widely used Huntington’s disease model, that integration of a rearranged transgene with coincident deletion of 5,444 bp of host genome within the gene Gm12695 has striking molecular consequences. Gm12695, the function of which is unknown, is normally expressed at negligible levels in mouse brain, but transgene integration has resulted in cortical expression of a partial fragment (exons 8–11) 3’ to the transgene integration site in R6/2. This transcript shows significant expression among the extensive network of differentially expressed genes associated with this model, including synaptic transmission, cell signalling and transcription. These data illustrate the value of sequence-level resolution of transgene insertions and transcription analysis to inform phenotypic characterization of transgenic models utilized in therapeutic research. PMID:28120936

  20. 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

  1. Idiopathic failure of eruption of multiple permanent teeth: report of 2 adults with a highlight on molecular biology.

    PubMed

    Sivakumar, Arunachalam; Valiathan, Ashima; Gandhi, Sumit; Mohandas, Ashil A

    2007-11-01

    Multiple unerupted teeth with no obvious etiology is a rare dental anomaly. Various local and systemic factors have been implicated in the failure of eruption of multiple permanent teeth. But the localization of the genetic defect in the phenotype of failure of eruption is largely unknown at present. Our aims in this article were to consolidate and organize the available information regarding the molecular biology of tooth eruption and to corroborate the current evidence with the report of 2 adult cases of failure of eruption of multiple permanent teeth without a known cause.

  2. The use of the Integrated Discrete Multiple Organ Co-culture (IdMOC) system for the evaluation of multiple organ toxicity.

    PubMed

    Li, Albert P

    2009-09-01

    The application of the Integrated Discrete Multiple Organ Co-culture (IdMOC) system in the evaluation of organ-specific toxicity is reviewed. In vitro approaches to predict in vivo toxicity have met with limited success, mainly because of the complexity of in vivo toxic responses. In vivo properties that are not well-represented in vitro include organ-specific responses, multiple organ metabolism, and multiple organ interactions. The IdMOC system has been developed to address these deficiencies. The system uses a 'wells-within-a-well' concept for the co-culturing of cells or tissue slices from different organs as physically separated (discrete) entities in the small inner wells. These inner wells are nevertheless interconnected (integrated) by overlying culture medium in the large outer containing well. The IdMOC system thereby models the in vivo situation, in which multiple organs are physically separated but interconnected by the systemic circulation, permitting multiple organ interactions. The IdMOC system, with either cells or tissue slices from multiple organs, can be used to evaluate cell type-specific or organ-specific toxicity.

  3. Mapping Molecular Diffusion in the Plasma Membrane by Multiple-Target Tracing (MTT)

    PubMed Central

    Rouger, Vincent; Bertaux, Nicolas; Trombik, Tomasz; Mailfert, Sébastien; Billaudeau, Cyrille; Marguet, Didier; Sergé, Arnauld

    2012-01-01

    Our goal is to obtain a comprehensive description of molecular processes occurring at cellular membranes in different biological functions. We aim at characterizing the complex organization and dynamics of the plasma membrane at single-molecule level, by developing analytic tools dedicated to Single-Particle Tracking (SPT) at high density: Multiple-Target Tracing (MTT)1. Single-molecule videomicroscopy, offering millisecond and nanometric resolution1-11, allows a detailed representation of membrane organization12-14 by accurately mapping descriptors such as cell receptors localization, mobility, confinement or interactions. We revisited SPT, both experimentally and algorithmically. Experimental aspects included optimizing setup and cell labeling, with a particular emphasis on reaching the highest possible labeling density, in order to provide a dynamic snapshot of molecular dynamics as it occurs within the membrane. Algorithmic issues concerned each step used for rebuilding trajectories: peaks detection, estimation and reconnection, addressed by specific tools from image analysis15,16. Implementing deflation after detection allows rescuing peaks initially hidden by neighboring, stronger peaks. Of note, improving detection directly impacts reconnection, by reducing gaps within trajectories. Performances have been evaluated using Monte-Carlo simulations for various labeling density and noise values, which typically represent the two major limitations for parallel measurements at high spatiotemporal resolution. The nanometric accuracy17 obtained for single molecules, using either successive on/off photoswitching or non-linear optics, can deliver exhaustive observations. This is the basis of nanoscopy methods17 such as STORM18, PALM19,20, RESOLFT21 or STED22,23, which may often require imaging fixed samples. The central task is the detection and estimation of diffraction-limited peaks emanating from single-molecules. Hence, providing adequate assumptions such as

  4. Integration of Multiple Data Sources to Simulate the Dynamics of Land Systems.

    PubMed

    Deng, Xiangzheng; Su, Hongbo; Zhan, Jinyan

    2008-02-04

    In this paper we present and develop a new model, which we have calledDynamics of Land Systems (DLS). The DLS model is capable of integrating multiple datasources to simulate the dynamics of a land system. Three main modules are incorporatedin DLS: a spatial regression module, to explore the relationship between land uses andinfluencing factors, a scenario analysis module of the land uses of a region during thesimulation period and a spatial disaggregation module, to allocate land use changes froma regional level to disaggregated grid cells. A case study on Taips County in North Chinais incorporated in this paper to test the functionality of DLS. The simulation results underthe baseline, economic priority and environmental scenarios help to understand the landsystem dynamics and project near future land-use trajectories of a region, in order tofocus management decisions on land uses and land use planning.

  5. 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.

  6. Integration of multiple theories for the simulation of laser interference lithography processes.

    PubMed

    Lin, Te Hsun; Yang, Yin Kuang; Fu, Chien-Chung

    2017-09-22

    The periodic structure of laser interference lithography (LIL) fabrication is superior to other lithography technologies. In contrast to traditional lithography, LIL has the advantages of being a simple optical system with no mask requirements, low cost, high depth of focus, and large patterning area in a single exposure. Generally, a simulation pattern for the periodic structure is obtained through optical interference prior to its fabrication through LIL. However, the LIL process is complex and combines the fields of optical and polymer materials; thus, a single simulation theory cannot reflect the real situation. Therefore, this research integrates multiple theories, including those of optical interference, standing waves, and photoresist characteristics, to create a mathematical model for the LIL process. The mathematical model can accurately estimate the exposure time and reduce the LIL process duration through trial and error. . © 2017 IOP Publishing Ltd.

  7. 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.

  8. 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

  9. Numerical examination of the extended phase-space volume-preserving integrator by the Nosé-Hoover molecular dynamics equations.

    PubMed

    Queyroy, Séverine; Nakamura, Haruki; Fukuda, Ikuo

    2009-09-01

    This article illustrates practical applications to molecular dynamics simulations of the recently developed numerical integrators [Phys Rev E 2006, 73, 026703] for ordinary differential equations. This method consists of extending any set of ordinary differential equations in order to define a time invariant function, and then use the techniques of divergence-free solvable decomposition and symmetric composition to obtain volume-preserving integrators in the extended phase space. Here, we have developed the technique by constructing multiple extended-variable formalism in order to enhance the handling in actual simulation, and by constituting higher order integrators to obtain further accuracies. Using these integrators, we perform constant temperature molecular dynamics simulations of liquid water, liquid argon and peptide in liquid water droplet. The temperature control is obtained through an extended version of the Nosé-Hoover equations. Analyzing the effects of the simulation conditions including time step length, initial values, boundary conditions, and equation parameters, we investigate local accuracy, global accuracy, computational cost, and sensitivity along with the sampling validity. According to the results of these simulations, we show that the volume-preserving integrators developed by the current method are more effective than traditional integrators that lack the volume-preserving property.

  10. Biomarker detection in the integration of multiple multi-class genomic studies

    PubMed Central

    Lu, Shuya; Li, Jia; Song, Chi; Shen, Kui; Tseng, George C.

    2010-01-01

    Motivation: Systematic information integration of multiple-related microarray studies has become an important issue as the technology becomes mature and prevalent in the past decade. The aggregated information provides more robust and accurate biomarker detection. So far, published meta-analysis methods for this purpose mostly consider two-class comparison. Methods for combining multi-class studies and considering expression pattern concordance are rarely explored. Results: In this article, we develop three integration methods for biomarker detection in multiple multi-class microarray studies: ANOVA-maxP, min-MCC and OW-min-MCC. We first consider a natural extension of combining P-values from the traditional ANOVA model. Since P-values from ANOVA do not guarantee to reflect the concordant expression pattern information across studies, we propose a multi-class correlation (MCC) measure to specifically seek for biomarkers of concordant inter-class patterns across a pair of studies. For both ANOVA and MCC approaches, we use extreme order statistics to identify biomarkers differentially expressed (DE) in all studies (i.e. ANOVA-maxP and min-MCC). The min-MCC method is further extended to identify biomarkers DE in partial studies by incorporating a recently developed optimally weighted (OW) technique (OW-min-MCC). All methods are evaluated by simulation studies and by three meta-analysis applications to multi-tissue mouse metabolism datasets, multi-condition mouse trauma datasets and multi-malignant-condition human prostate cancer datasets. The results show complementary strength of the three methods for different biological purposes. Availability: http://www.biostat.pitt.edu/bioinfo/ Contact: ctseng@pitt.edu Supplementary information: Supplementary data is available at Bioinformatics online. PMID:19965884

  11. Integrated Anaerobic-Aerobic Biodegradation of Multiple Contaminants Including Chlorinated Ethylenes, Benzene, Toluene, and Dichloromethane.

    PubMed

    Yoshikawa, Miho; Zhang, Ming; Toyota, Koki

    2017-01-01

    Complete bioremediation of soils containing multiple volatile organic compounds (VOCs) remains a challenge. To explore the possibility of complete bioremediation through integrated anaerobic-aerobic biodegradation, laboratory feasibility tests followed by alternate anaerobic-aerobic and aerobic-anaerobic biodegradation tests were performed. Chlorinated ethylenes, including tetrachloroethylene (PCE), trichloroethylene (TCE), cis-dichloroethylene (cis-DCE), and vinyl chloride (VC), and dichloromethane (DCM) were used for anaerobic biodegradation, whereas benzene, toluene, and DCM were used for aerobic biodegradation tests. Microbial communities involved in the biodegradation tests were analyzed to characterize the major bacteria that may contribute to biodegradation. The results demonstrated that integrated anaerobic-aerobic biodegradation was capable of completely degrading the seven VOCs with initial concentration of each VOC less than 30 mg/L. Benzene and toluene were degraded within 8 days, and DCM was degraded within 20 to 27 days under aerobic conditions when initial oxygen concentrations in the headspaces of test bottles were set to 5.3% and 21.0%. Dehalococcoides sp., generally considered sensitive to oxygen, survived aerobic conditions for 28 days and was activated during the subsequent anaerobic biodegradation. However, degradation of cis-DCE was suppressed after oxygen exposure for more than 201 days, suggesting the loss of viability of Dehalococcoides sp., as they are the only known anaerobic bacteria that can completely biodegrade chlorinated ethylenes to ethylene. Anaerobic degradation of DCM following previous aerobic degradation was complete, and yet-unknown microbes may be involved in the process. The findings may provide a scientific and practical basis for the complete bioremediation of multiple contaminants in situ and a subject for further exploration.

  12. Small-molecule G-quadruplex interactions: Systematic exploration of conformational space using multiple molecular dynamics.

    PubMed

    Husby, Jarmila; Todd, Alan K; Platts, James A; Neidle, Stephen

    2013-12-01

    G-quadruplexes are higher-order four-stranded structures formed from repetitive guanine-containing tracts in nucleic acids. They comprise a core of stacked guanine-quartets linked by loops of length and sequence that vary with the context in which the quadruplex sequence occurs. Such sequences can be found in a number of genomic environments; at the telomeric ends of eukaryotic chromosomes, in promoter regions, in untranslated sequences and in open reading frames. Quadruplex formation can inhibit telomere maintenance, transcription and translation, especially when enhanced by quadruplex-binding small molecules, and quadruplex targeting is currently of considerable interest. The available experimental structural data shows that quadruplexes can have high conformational flexibility, especially in loop regions, which has hampered attempts to use high-throughput docking to find quadruplex-binding small-molecules with new scaffolds or to optimize existing ones with structure-based design methods. An approach to overcome the challenge of quadruplex conformational flexibility is presented here, which uses a combined multiple molecular dynamics and sampling approach. Two test small molecules have been used, RHPS4 and pyridostatin, which themselves have contrasting degrees of conformational flexibility. Copyright © 2013 Wiley Periodicals, Inc.

  13. New Developments in Ab Initio Multiple Spawning for Efficient Nonadiabatic Molecular Dynamics

    NASA Astrophysics Data System (ADS)

    Curchod, Basile F. E.; Sisto, Aaron; Glowacki, David R.; Martínez, Todd J.

    Ab initio multiple spawning (AIMS) describes the nonadiabatic dynamics of nuclear wavepackets by means of a linear combination of frozen Gaussians. While the Gaussian centers follow classical trajectories, the expansion coefficients are propagated according to the time-dependent Schrödinger equation. As a result of the coupling between Gaussian functions, AIMS accurately describes coherence and decoherence effects close to nonadiabatic regions. This accuracy has further been validated by the excellent agreement reported between AIMS dynamics and experimental observations. In this Contribution, we will discuss new techniques used to extend the applicability of AIMS to (i) larger molecules, (ii) long-time simulations, and (iii) dynamics involving an important number of electronic states. We will present different examples of nonadiabatic molecular dynamics in organic and atmospheric photochemistry, resulting from the interface between AIMS and the GPU-accelerated electronic structure code TeraChem. New methods improving the AIMS efficiency for larger systems will be discussed, such as the stochastic-selection AIMS. Finally, we will highlight early results on the extension of AIMS to the combined description of both internal conversion and intersystem crossing phenomena. B.F.E.C. acknowledges the Swiss National Science Foundation (fellowship P2ELP2_151927) for financial support.

  14. Direct sampling of multiple single-molecular rupture dominant pathways involving a multistep transition.

    PubMed

    Jiang, Huijun; Ding, Huai; Hou, Zhonghuai

    2014-12-14

    We report a novel single-molecular rupture mechanism revealed by direct sampling of the dominant pathway using a self-optimized path sampling method. Multiple dominant pathways involving multistep transitions are identified. The rupture may take place via a direct unfolding from the native state to the unfolding state, or through a two-step pathway bypassing a distinct intermediate metastable state (IMS). This scenario facilitates us to propose a three-state kinetic model, which can produce a nonlinear dependence of the rupture time on pulling forces similar to the ones reported in the literature. In particular, molecule conformations in the IMS maintain an elongation of the tail at one terminal, by which external pulling will enhance the relative stability of IMS. Consequently, even though the overall transition rate of the multistep pathway is relatively small, the molecule still has to be ruptured via the multistep pathway rather than the direct pathway. Thus, our work demonstrates an IMS trapping effect induced rupture mechanism involving an abnormal switching from a fast dominant pathway to a slow one.

  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. Molecular evolution of arthropod color vision deduced from multiple opsin genes of jumping spiders.

    PubMed

    Koyanagi, Mitsumasa; Nagata, Takashi; Katoh, Kazutaka; Yamashita, Shigeki; Tokunaga, Fumio

    2008-02-01

    Among terrestrial animals, only vertebrates and arthropods possess wavelength-discrimination ability, so-called "color vision". For color vision to exist, multiple opsins which encode visual pigments sensitive to different wavelengths of light are required. While the molecular evolution of opsins in vertebrates has been well investigated, that in arthropods remains to be elucidated. This is mainly due to poor information about the opsin genes of non-insect arthropods. To obtain an overview of the evolution of color vision in Arthropoda, we isolated three kinds of opsins, Rh1, Rh2, and Rh3, from two jumping spider species, Hasarius adansoni and Plexippus paykulli. These spiders belong to Chelicerata, one of the most distant groups from Hexapoda (insects), and have color vision as do insects. Phylogenetic analyses of jumping spider opsins revealed a birth and death process of color vision evolution in the arthropod lineage. Phylogenetic positions of jumping spider opsins revealed that at least three opsins had already existed before the Chelicerata-Pancrustacea split. In addition, sequence comparison between jumping spider Rh3 and the shorter wavelength-sensitive opsins of insects predicted that an opsin of the ancestral arthropod had the lysine residue responsible for UV sensitivity. These results strongly suggest that the ancestral arthropod had at least trichromatic vision with a UV pigment and two visible pigments. Thereafter, in each pancrustacean and chelicerate lineage, the opsin repertoire was reconstructed by gene losses, gene duplications, and function-altering amino acid substitutions, leading to evolution of color vision.

  17. 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.

  18. Molecular mechanism of action of immune-modulatory drugs thalidomide, lenalidomide and pomalidomide in multiple myeloma.

    PubMed

    Zhu, Yuan Xiao; Kortuem, K Martin; Stewart, A Keith

    2013-04-01

    Although several mechanisms have been proposed to explain the activity of thalidomide, lenalidomide and pomalidomide in multiple myeloma (MM), including demonstrable anti-angiogenic, anti-proliferative and immunomodulatory effects, the precise cellular targets and molecular mechanisms have only recently become clear. A landmark study recently identified cereblon (CRBN) as a primary target of thalidomide teratogenicity. Subsequently it was demonstrated that CRBN is also required for the anti-myeloma activity of thalidomide and related drugs, the so-called immune-modulatory drugs (IMiDs). Low CRBN expression was found to correlate with drug resistance in MM cell lines and primary MM cells. One of the downstream targets of CRBN identified is interferon regulatory factor 4 (IRF4), which is critical for myeloma cell survival and is down-regulated by IMiD treatment. CRBN is also implicated in several effects of IMiDs, such as down-regulation of tumor necrosis factor-α (TNF-α) and T cell immunomodulatory activity, demonstrating that the pleotropic actions of the IMiDs are initiated by binding to CRBN. Future dissection of CRBN downstream signaling will help to delineate the underlying mechanisms for IMiD action and eventually lead to development of new drugs with more specific anti-myeloma activities. It may also provide a biomarker to predict IMiD response and resistance.

  19. Multiple-Timestep ab Initio Molecular Dynamics Using an Atomic Basis Set Partitioning.

    PubMed

    Steele, Ryan P

    2015-12-17

    This work describes an approach to accelerate ab initio Born-Oppenheimer molecular dynamics (MD) simulations by exploiting the inherent timescale separation between contributions from different atom-centered Gaussian basis sets. Several MD steps are propagated with a cost-efficient, low-level basis set, after which a dynamical correction accounts for large basis set relaxation effects in a time-reversible fashion. This multiple-timestep scheme is shown to generate valid MD trajectories, on the basis of rigorous testing for water clusters, the methanol dimer, an alanine polypeptide, protonated hydrazine, and the oxidized water dimer. This new approach generates observables that are consistent with those of target basis set trajectories, including MD-based vibrational spectra. This protocol is shown to be valid for Hartree-Fock, density functional theory, and second-order Møller-Plesset perturbation theory approaches. Recommended pairings include 6-31G as a low-level basis set for 6-31G** or 6-311G**, as well as cc-pVDZ as the subset for accurate dynamics with aug-cc-pVTZ. Demonstrated cost savings include factors of 2.6-7.3 on the systems tested and are expected to remain valid across system sizes.

  20. Comparative analysis of molecular strategies attenuating positional effects in lentiviral vectors carrying multiple genes.

    PubMed

    Osti, Daniela; Marras, Emanuela; Ceriani, Isabella; Grassini, Greta; Rubino, Tiziana; Viganò, Daniela; Parolaro, Daniela; Perletti, Gianpaolo

    2006-09-01

    Efficient, high-level expression of multiple genes is often difficult to achieve in retroviral vectors, due to positional effects affecting transcription of adjacent sequences. Here we describe the comparative analysis of different strategies for co-expressing two model cDNA sequences in the context of a second generation lentiviral vector system. A first option was based on the generation of a polycistronic construct by subcloning an internal ribosome entry site (IRES) sequence between tandem cDNAs. IRES-dependent translation of the cDNA placed downstream (3') of the first transgene was poor, and the protein was barely detectable in transduced cells. A similar result was obtained when both transgenes were placed under the transcriptional control of two independent internal promoters. When these independent transcription units were separated by the 5'HS4 chromatin insulator of the chicken beta-globin locus, a marked increase of the expression of the downstream protein was observed. Similarly, insertion of a polyadenylation sequence between the tandem transcription units fully restored - in transfection experiments - the expression of the downstream sequence, whose protein pattern was identical to the single-gene control, suggesting that in this specific construct transcriptional interference was the likely cause of the observed positional effects. These results indicate that chromatin insulator sequences can be useful molecular tools to overcome positional effects in the context of lentiviral vectors.

  1. 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

  2. Vertical resonant tunneling transistors with molecular quantum dots for large-scale integration.

    PubMed

    Hayakawa, Ryoma; Chikyow, Toyohiro; Wakayama, Yutaka

    2017-08-10

    Quantum molecular devices have a potential for the construction of new data processing architectures that cannot be achieved using current complementary metal-oxide-semiconductor (CMOS) technology. The relevant basic quantum transport properties have been examined by specific methods such as scanning probe and break-junction techniques. However, these methodologies are not compatible with current CMOS applications, and the development of practical molecular devices remains a persistent challenge. Here, we demonstrate a new vertical resonant tunneling transistor for large-scale integration. The transistor channel is comprised of a MOS structure with C60 molecules as quantum dots, and the structure behaves like a double tunnel junction. Notably, the transistors enabled the observation of stepwise drain currents, which originated from resonant tunneling via the discrete molecular orbitals. Applying side-gate voltages produced depletion layers in Si substrates, to achieve effective modulation of the drain currents and obvious peak shifts in the differential conductance curves. Our device configuration thus provides a promising means of integrating molecular functions into future CMOS applications.

  3. 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

  4. Adaptive Splitting Integrators for Enhancing Sampling Efficiency of Modified Hamiltonian Monte Carlo Methods in Molecular Simulation.

    PubMed

    Akhmatskaya, Elena; Fernández-Pendás, Mario; Radivojević, Tijana; Sanz-Serna, J M

    2017-08-02

    The modified Hamiltonian Monte Carlo (MHMC) methods, i.e., importance sampling methods that use modified Hamiltonians within a Hybrid Monte Carlo (HMC) framework, often outperform in sampling efficiency standard techniques such as molecular dynamics (MD) and HMC. The performance of MHMC may be enhanced further through the rational choice of the simulation parameters and by replacing the standard Verlet integrator with more sophisticated splitting algorithms. Unfortunately, it is not easy to identify the appropriate values of the parameters that appear in those algorithms. We propose a technique, that we call MAIA (Modified Adaptive Integration Approach), which, for a given simulation system and a given time step, automatically selects the optimal integrator within a useful family of two-stage splitting formulas. Extended MAIA (or e-MAIA) is an enhanced version of MAIA, which additionally supplies a value of the method-specific parameter that, for the problem under consideration, keeps the momentum acceptance rate at a user-desired level. The MAIA and e-MAIA algorithms have been implemented, with no computational overhead during simulations, in MultiHMC-GROMACS, a modified version of the popular software package GROMACS. Tests performed on well-known molecular models demon