1,105 research outputs found

    Dose and sample size determination for multi-drug combination studies

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    Preclinical experiment on multi-drug combination has an increasingly important role in (especially cancer) drug development because of the need to reduce development time and costs. Despite recent progress in statistical methods for assessing drug interaction, there is a lack of general methods for determining the doses comprising the combinations and the sample sizes to detect departures from additivity, especially in the case of more than two drugs. We propose a general method for dose and sample size determination for detecting departures from additivity of multiple drugs based on a semiparametric statistical model applicable to both in vivo and in vitro experiments. We show that selecting doses that comprise the combinations uniformly scattered in the experimental domain maximizes the minimum power of the F-test for detecting departures from additivity. In addition, the method applies to drugs whose relative potency is not constant. With both analytic proof and a simulation, we show the proposed design has optimal properties that are not shared by the classic designs such as the fixed ratio (ray) and the checkerboard designs. Furthermore, we show the method is dependent upon the shape of the single drug dose-response curve; therefore, different classes of drugs have to be dealt with separately. To our surprise, such an extension to multi-drug case with three or more drugs is far more difficult than it appears. Using the general methodology, we derive the dose selection and sample size specifically for a common class of drugs to derive the experimental design. We illustrate the method with the SAHA and Ara-C and Etoposide combination study.postprin

    A fast em algorithm for quadratic optimization subject to Convex constraints

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    Convex constraints (CCs) such as box constraints and linear inequality constraints appear frequently in statistical inference and in applications. The problems of quadratic optimization (QO) subject to CCs occur in isotonic regression, shape-restricted non-parametric regression, variable selection (via the lasso algorithm and bridge regression), limited dependent variables models, image reconstruction, and so on. Existing packages for QO are not generally applicable to CCs. Although EM-type algorithms may be applied to such problems (Tian, Ng and Tan (2005)), the convergence rate/speed of these algorithms is painfully slow, especially for high-dimensional data. This paper develops a fast EM algorithm for QO with CCs. We construct a class of data augmentation schemes indexed by a 'working parameter' r (r ε R), and then optimize r over R under several convergence criteria. In addition, we use Cholesky decomposition to reduce both the number of latent variables and the dimension, leading to further acceleration of the EM. Standard errors of the restricted estimators are calculated using a non-parametric bootstrapping procedure. Simulation and comparison are performed and a complex multinomial dataset is analyzed to illustrate the proposed methods.published_or_final_versio

    On the Kinematic Signature of the Galactic Warp As Revealed by the LAMOST-TGAS Data

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    Using a sample of about 123,000 stars with accurate 3D velocity measurements from the LAMOST-TGAS data, we confirm the kinematic signature of the Galactic warp recently found by Schonrich & Dehnen. The data reveal a clear trend of increasing mean vertical velocity Vz as a function of absolute vertical angular momentum Lz and azimuthal velocity Vφ for guiding center radius Rg between 6.0 and 10.5 kpc. The trend is consistent with a largescale Galactic warp. Similar to Schonrich & Dehnen, we also find a wave-like pattern of Vz versus Lz with an amplitude of ∼0.9 km s-1 on a scale of ∼2.0 kpc, which could arise from bending waves or a winding warp. Finally, we confirm a prominent, localized peak in Vz near Lz ∼ 2150 kpc km s-1 (corresponding to Rg ∼ 9 kpc and Vφ ∼ 255 km s-1). The additional line-of-sight velocity information from LAMOST reveals that stars in this feature have a large, inward radial velocity of VR ∼ -13.33 ± 0.59 km s-1 and a small radial velocity dispersion of σR ∼ 25.27 ± 0.89 km s-1, suggesting that a stellar stream gives rise to this feature

    Counter-current chromatography for the separation of terpenoids: A comprehensive review with respect to the solvent systems employed

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    Copyright @ 2014 The Authors.This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.Natural products extracts are commonly highly complex mixtures of active compounds and consequently their purification becomes a particularly challenging task. The development of a purification protocol to extract a single active component from the many hundreds that are often present in the mixture is something that can take months or even years to achieve, thus it is important for the natural product chemist to have, at their disposal, a broad range of diverse purification techniques. Counter-current chromatography (CCC) is one such separation technique utilising two immiscible phases, one as the stationary phase (retained in a spinning coil by centrifugal forces) and the second as the mobile phase. The method benefits from a number of advantages when compared with the more traditional liquid-solid separation methods, such as no irreversible adsorption, total recovery of the injected sample, minimal tailing of peaks, low risk of sample denaturation, the ability to accept particulates, and a low solvent consumption. The selection of an appropriate two-phase solvent system is critical to the running of CCC since this is both the mobile and the stationary phase of the system. However, this is also by far the most time consuming aspect of the technique and the one that most inhibits its general take-up. In recent years, numerous natural product purifications have been published using CCC from almost every country across the globe. Many of these papers are devoted to terpenoids-one of the most diverse groups. Naturally occurring terpenoids provide opportunities to discover new drugs but many of them are available at very low levels in nature and a huge number of them still remain unexplored. The collective knowledge on performing successful CCC separations of terpenoids has been gathered and reviewed by the authors, in order to create a comprehensive document that will be of great assistance in performing future purifications. © 2014 The Author(s)

    The Insulin-Like Growth Factor System in the Long-Lived Naked Mole-Rat.

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    Naked mole-rats (Heterocephalus glaber) (NMRs) are the longest living rodents known. They show negligible senescence, and are resistant to cancers and certain damaging effects associated with aging. The insulin-like growth factors (IGFs) have pluripotent actions, influencing growth processes in virtually every system of the body. They are established contributors to the aging process, confirmed by the demonstration that decreased IGF signaling results in life-extending effects in a variety of species. The IGFs are likewise involved in progression of cancers by mediating survival signals in malignant cells. This report presents a full characterization of the IGF system in the NMR: ligands, receptors, IGF binding proteins (IGFBPs), and IGFBP proteases. A particular emphasis was placed on the IGFBP protease, pregnancy-associated plasma protein-A (PAPP-A), shown to be an important lifespan modulator in mice. Comparisons of IGF-related genes in the NMR with human and murine sequences indicated no major differences in essential parts of the IGF system, including PAPP-A. The protease was shown to possess an intact active site despite the report of a contradictory genome sequence. Furthermore, PAPP-A was expressed and translated in NMRs cells and retained IGF-dependent proteolytic activity towards IGFBP-4 and IGF-independent activity towards IGFBP-5. However, experimental data suggest differential regulatory mechanisms for PAPP-A expression in NMRs than those described in humans and mice. This overall description of the IGF system in the NMR represents an initial step towards elucidating the complex molecular mechanisms underlying longevity, and how these animals have evolved to ensure a delayed and healthy aging process

    Mechanical properties of double-layer and graded composite coatings of YSZ obtained by atmospheric plasma spraying

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    Double-layer and graded composite coatings of yttria-stabilized zirconia were sprayed on metallic substrates by atmospheric plasma spray. The coating architecture was built up by combining two different feedstocks: one micro- and one nanostructured. Microstructural features and mechanical properties (hardness and elastic modulus) of the coatings were determined by FE-SEM microscopy and nanoindentation technique, respectively. Additional adherence and scratch tests were carried out in order to assess the failure mechanisms occurring between the layers comprising the composites. Microstructural inspection of the coatings confirms the two-zone microstructure. This bimodal microstructure which is exclusive of the layer obtained from the nanostructured feedstock negatively affects the mechanical properties of the whole composite. Nanoindentation tests suitably reproduce the evolution of mechanical properties through coatings thickness on the basis of the position and/or amount of nanostructured feedstock used in the depositing layer. Adhesion and scratch tests show the negative effect on the coating adhesion of layer obtained from the nanostructured feedstock when this layer is deposited on the bond coat. Thus, the poor integrity of this layer results in lower normal stresses required to delaminate the coating in the adhesion test as well as minor critical load registered by using the scratch test.This work has been supported by the Spanish Ministry of Science and Innovation (Project MAT2012-38364-C03) and co-funded by ERDF (European Regional Development Funds).Carpio-Cobo, P.; Rayón Encinas, E.; Salvador Moya, MD.; Lusvarghi, L.; Sanchez, E. (2016). Mechanical properties of double-layer and graded composite coatings of YSZ obtained by atmospheric plasma spraying. Journal of Thermal Spray Technology. 25(4):778-787. https://doi.org/10.1007/s11666-016-0390-zS778787254Y.S. Tian, C.Z. Chen, D.Y. Wang, and J.I. Quianmao, Recent Developments in Zirconia Thermal Barrier Coatings, Surf. Rev. Lett., 2005, 12, p 369-378S. Sampath, U. Schulz, M.O. Jarligo, and S. Kuroda, Processing Science of Advanced Thermal-Barrier Systems, MRS Bull., 2012, 37(10), p 903-910D.R. Clarke, M. Oeschsner, and N.P. Padture, Thermal-Barrier Coatings for More Efficient Gas-Turbine Engines, MRS Bull., 2012, 37(10), p 891-898A. Feuersein, J. Knapp, T. Taylor, A. Ashary, A. Bolcavage, and N. Hitchman, Technical and Economical Aspects of Current Thermal Barrier Coating Systems for Gas Turbine Engines by Thermal Spray and EBPVD: A Review, J. Therm. Spray Technol., 2008, 17(2), p 199-213R.S. Lima and B.R. Marple, Thermal Spray Coatings Engineered from Nanostructured Ceramic Agglomerated Powders for Structural, Thermal Barrier and Biomedical Applications: A Review, J. Therm. Spray Technol., 2007, 16(1), p 40-63P. Fauchais, G. Montavon, R.S. Lima, and B.R. Marple, Engineering a New Class of Thermal Spray Nano-based Microstructures from Agglomerated Nanostructured Particles, Suspensions and Solutions: An Invited Review, J. Phys. D Appl. Phys., 2011, 44(9), p 093001P. Carpio, Q. Blochet, B. Pateyron, L. Pawlowski, M.D. Salvador, A. Borrell, and E. Sánchez, Correlation of Thermal Conductivity of Suspension Plasma Sprayed Yttira Stabilized Zirconia Coatings with some Microstructural Effects, Mater. Lett., 2013, 107, p 370-373R. Vassen, A. Stuke, and D. Stöver, Recent Developments in the Field of Thermal Barrier Coatings, J. Therm. Spray Technol., 2009, 18(2), p 181-186H. Dai, X. Zhong, J. Li, Y. Zhang, J. Meng, and X. Cao, Thermal Stability of Double-Ceramic-Layer Thermal Barrier Coatings with Various Coating Thickness, Mater. Sci. Eng. A—Struct., 2006, 433(1), p 1–7V. Viswanathan, G. Dwivedi, and S. Sampath, Multimaterial Thermal Barrier Coating Systems: Design, Synthesis, and Performance Assessment, J. Am. Ceram. Soc., 2015, 98(6), p 1769-1777M. Saremi and Z. Valefi, Thermal and Mechanical Properties of Nano-YSZ-Alumina Functionally Graded Coatings Deposited by Nano-agglomerated Powder Plasma Spraying, Ceram. Int., 2014, 40(8), p 13453-13459A. Portinham, V. Teixeira, J. Carneiro, J. Martins, M.F. Costa, R. Vassen, and D. Stoever, Characterization of Thermal Barrier Coatings with a Gradient Porosity, Surf. Coat. Technol., 2005, 195(2), p 245-251P. Carpio, E. Bannier, M.D. Salvador, R. Benavente, and E. Sánchez, Multilayer and Particle Size-Graded YSZ Coatings Obtained by Plasma Spraying of Micro- and Nanostructured Feedstocks, J. Therm. Spray Technol., 2014, 23(8), p 1362-1372S. Nath, I. Manna, and J.D. Majumdar, Nanomechanical Behavior of Yttria Stabilized Zirconia (YSZ) Based Thermal Barrier Coating, Ceram. Int., 2015, 41(4), p 5247-5256P. Carpio, E. Rayón, L. Pawlowski, A. Cattini, R. Benavente, E. Bannier, M.D. Salvador, and E. Sánchez, Microstructure and Indentation Mechanical Properties of YSZ Nanostructured Coatings Obtained by Suspension Plasma Spraying, Surf. Coat. Technol., 2013, 220, p 237-243H.B. Guo, H. Murakami, and S. Kuroda, Effect of Hollow Spherical Powder Size Distribution on Porosity and Segmentation Cracks in Thermal Barrier Coatings, J. Am. Ceram. Soc., 2006, 89(12), p 3797-3804R.S. Lima, A. Kucuk, and C.C. Berndt, Integrity of Nanostructured Partially Stabilized Zirconia After Plasma Spray Processing, Mater. Sci. Eng. A, 2001, 313(1), p 75-82E. Rayón, V. Bonache, M.D. Salvador, and E. Sánchez, Hardness and Young’s Modulus Distributions in Atmospheric Plasma Sprayed WC-Co Coatings Using Nanoindentation, Surf. Coat. Technol., 2011, 205(17), p 4192-4197J.A. Wollmershauser, B.N. Feigelson, E.P. Gorzkowski, C.T. Ellis, R. Goswami, S.B. Qadri, J.G. Tischler, F.J. Kub, and R.K. Everett, An Extend Hardness Limit in Bulk Nanoceramics, Acta Mater., 2014, 69, p 9-16L. Wang, Y. Wang, X.G. Sun, J.Q. He, Z.Y. Pan, and C.H. Wang, Microstructure and Indentation Mechanical Properties of Plasma Sprayed Nano-Bimodal and Conventional ZrO2-8 wt% Y2O3 Thermal Barrier Coatings, Vacuum, 2012, 86(8), p 1174-1185G.S. Barroso, W. Krenkel, and G. Motz, Low Thermal Conductivity Coating System for Application up to 1000 °C by Simple PDC Processing with Active and Passive Fillers, J. Eur. Ceram. Soc., 2015, 35(12), p 3339-3348R. Ghasemi, R. Shoja-Razavi, R. Mozafarinia, H. Jamali, M. Hajizadh-Oghaz, and R. Ahmadi-Pidani, The Influence of Laser Treatment on Hot Corrosion Behavior of Plasma-Sprayed Nanostructured Yttria Stabilized Zirconia Thermal Barrier Coatings, J. Eur. Ceram. Soc., 2014, 34(8), p 2013-2021E. Rayón, V. Bonache, M.D. Salvador, E. Bannier, E. Sánchez, A. Denoirjean, and H. Ageorges, Nanoindentation Study of the Mechanical and Damage Behaviour of Suspension Plasma Sprayed TiO2 Coatings, Surf. Coat. Technol., 2012, 206(10), p 2655-2660J.J. Roa, E. Jiménez-Piqué, R. Martínez, G. Ramírez, J.M. Tarragó, R. Rodríguez, and L. Llanes, Contact Damage and Fracture Micromechanisms of Multilayered TiN/CrN Coatings at Micro- and Nano-length Scales, Thin Solid Films, 2014, 571(2), p 308-31

    Imbalanced Multi-Modal Multi-Label Learning for Subcellular Localization Prediction of Human Proteins with Both Single and Multiple Sites

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    It is well known that an important step toward understanding the functions of a protein is to determine its subcellular location. Although numerous prediction algorithms have been developed, most of them typically focused on the proteins with only one location. In recent years, researchers have begun to pay attention to the subcellular localization prediction of the proteins with multiple sites. However, almost all the existing approaches have failed to take into account the correlations among the locations caused by the proteins with multiple sites, which may be the important information for improving the prediction accuracy of the proteins with multiple sites. In this paper, a new algorithm which can effectively exploit the correlations among the locations is proposed by using Gaussian process model. Besides, the algorithm also can realize optimal linear combination of various feature extraction technologies and could be robust to the imbalanced data set. Experimental results on a human protein data set show that the proposed algorithm is valid and can achieve better performance than the existing approaches

    Phenotypic Variation and Bistable Switching in Bacteria

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    Microbial research generally focuses on clonal populations. However, bacterial cells with identical genotypes frequently display different phenotypes under identical conditions. This microbial cell individuality is receiving increasing attention in the literature because of its impact on cellular differentiation, survival under selective conditions, and the interaction of pathogens with their hosts. It is becoming clear that stochasticity in gene expression in conjunction with the architecture of the gene network that underlies the cellular processes can generate phenotypic variation. An important regulatory mechanism is the so-called positive feedback, in which a system reinforces its own response, for instance by stimulating the production of an activator. Bistability is an interesting and relevant phenomenon, in which two distinct subpopulations of cells showing discrete levels of gene expression coexist in a single culture. In this chapter, we address techniques and approaches used to establish phenotypic variation, and relate three well-characterized examples of bistability to the molecular mechanisms that govern these processes, with a focus on positive feedback.
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