A method to calculate fission-fragment yields Y(Z,N) versus proton and neutron number in the Brownian shape-motion model

DOE PAGES

Moller, Peter; Ichikawa, Takatoshi

2015-12-23

In this study, we propose a method to calculate the two-dimensional (2D) fission-fragment yield Y(Z,N) versus both proton and neutron number, with inclusion of odd-even staggering effects in both variables. The approach is to use the Brownian shape-motion on a macroscopic-microscopic potential-energy surface which, for a particular compound system is calculated versus four shape variables: elongation (quadrupole moment Q 2), neck d, left nascent fragment spheroidal deformation ϵ f1, right nascent fragment deformation ϵ f2 and two asymmetry variables, namely proton and neutron numbers in each of the two fragments. The extension of previous models 1) introduces a method tomore » calculate this generalized potential-energy function and 2) allows the correlated transfer of nucleon pairs in one step, in addition to sequential transfer. In the previous version the potential energy was calculated as a function of Z and N of the compound system and its shape, including the asymmetry of the shape. We outline here how to generalize the model from the “compound-system” model to a model where the emerging fragment proton and neutron numbers also enter, over and above the compound system composition.« less

Application of Tandem Two-Dimensional Mass Spectrometry for Top-Down Deep Sequencing of Calmodulin

NASA Astrophysics Data System (ADS)

Floris, Federico; Chiron, Lionel; Lynch, Alice M.; Barrow, Mark P.; Delsuc, Marc-André; O'Connor, Peter B.

2018-06-01

Two-dimensional mass spectrometry (2DMS) involves simultaneous acquisition of the fragmentation patterns of all the analytes in a mixture by correlating their precursor and fragment ions by modulating precursor ions systematically through a fragmentation zone. Tandem two-dimensional mass spectrometry (MS/2DMS) unites the ultra-high accuracy of Fourier transform ion cyclotron resonance (FT-ICR) MS/MS and the simultaneous data-independent fragmentation of 2DMS to achieve extensive inter-residue fragmentation of entire proteins. 2DMS was recently developed for top-down proteomics (TDP), and applied to the analysis of calmodulin (CaM), reporting a cleavage coverage of about 23% using infrared multiphoton dissociation (IRMPD) as fragmentation technique. The goal of this work is to expand the utility of top-down protein analysis using MS/2DMS in order to extend the cleavage coverage in top-down proteomics further into the interior regions of the protein. In this case, using MS/2DMS, the cleavage coverage of CaM increased from 23% to 42%.

Noise-free accurate count of microbial colonies by time-lapse shadow image analysis.

PubMed

Ogawa, Hiroyuki; Nasu, Senshi; Takeshige, Motomu; Funabashi, Hisakage; Saito, Mikako; Matsuoka, Hideaki

2012-12-01

Microbial colonies in food matrices could be counted accurately by a novel noise-free method based on time-lapse shadow image analysis. An agar plate containing many clusters of microbial colonies and/or meat fragments was trans-illuminated to project their 2-dimensional (2D) shadow images on a color CCD camera. The 2D shadow images of every cluster distributed within a 3-mm thick agar layer were captured in focus simultaneously by means of a multiple focusing system, and were then converted to 3-dimensional (3D) shadow images. By time-lapse analysis of the 3D shadow images, it was determined whether each cluster comprised single or multiple colonies or a meat fragment. The analytical precision was high enough to be able to distinguish a microbial colony from a meat fragment, to recognize an oval image as two colonies contacting each other, and to detect microbial colonies hidden under a food fragment. The detection of hidden colonies is its outstanding performance in comparison with other systems. The present system attained accuracy for counting fewer than 5 colonies and is therefore of practical importance. Copyright © 2012 Elsevier B.V. All rights reserved.

Characteristic fragment size distributions in dynamic fragmentation

NASA Astrophysics Data System (ADS)

Zhou, Fenghua; Molinari, Jean-François; Ramesh, K. T.

2006-06-01

The one-dimensional fragmentation of a dynamically expanding ring (Mott's problem) is studied numerically to obtain the fragment signatures under different strain rates. An empirical formula is proposed to calculate an average fragment size. Rayleigh distribution is found to describe the statistical properties of the fragment populations.

Fission fragment charge and mass distributions in 239Pu(n ,f ) in the adiabatic nuclear energy density functional theory

NASA Astrophysics Data System (ADS)

Regnier, D.; Dubray, N.; Schunck, N.; Verrière, M.

2016-05-01

Background: Accurate knowledge of fission fragment yields is an essential ingredient of numerous applications ranging from the formation of elements in the r process to fuel cycle optimization for nuclear energy. The need for a predictive theory applicable where no data are available, together with the variety of potential applications, is an incentive to develop a fully microscopic approach to fission dynamics. Purpose: In this work, we calculate the pre-neutron emission charge and mass distributions of the fission fragments formed in the neutron-induced fission of 239Pu using a microscopic method based on nuclear density functional theory (DFT). Methods: Our theoretical framework is the nuclear energy density functional (EDF) method, where large-amplitude collective motion is treated adiabatically by using the time-dependent generator coordinate method (TDGCM) under the Gaussian overlap approximation (GOA). In practice, the TDGCM is implemented in two steps. First, a series of constrained EDF calculations map the configuration and potential-energy landscape of the fissioning system for a small set of collective variables (in this work, the axial quadrupole and octupole moments of the nucleus). Then, nuclear dynamics is modeled by propagating a collective wave packet on the potential-energy surface. Fission fragment distributions are extracted from the flux of the collective wave packet through the scission line. Results: We find that the main characteristics of the fission charge and mass distributions can be well reproduced by existing energy functionals even in two-dimensional collective spaces. Theory and experiment agree typically within two mass units for the position of the asymmetric peak. As expected, calculations are sensitive to the structure of the initial state and the prescription for the collective inertia. We emphasize that results are also sensitive to the continuity of the collective landscape near scission. Conclusions: Our analysis confirms that the adiabatic approximation provides an effective scheme to compute fission fragment yields. It also suggests that, at least in the framework of nuclear DFT, three-dimensional collective spaces may be a prerequisite to reach 10% accuracy in predicting pre-neutron emission fission fragment yields.

Emergence of energy dependence in the fragmentation of heterogeneous materials

NASA Astrophysics Data System (ADS)

Pál, Gergő; Varga, Imre; Kun, Ferenc

2014-12-01

The most important characteristics of the fragmentation of heterogeneous solids is that the mass (size) distribution of pieces is described by a power law functional form. The exponent of the distribution displays a high degree of universality depending mainly on the dimensionality and on the brittle-ductile mechanical response of the system. Recently, experiments and computer simulations have reported an energy dependence of the exponent increasing with the imparted energy. These novel findings question the phase transition picture of fragmentation phenomena, and have also practical importance for industrial applications. Based on large scale computer simulations here we uncover a robust mechanism which leads to the emergence of energy dependence in fragmentation processes resolving controversial issues on the problem: studying the impact induced breakup of platelike objects with varying thickness in three dimensions we show that energy dependence occurs when a lower dimensional fragmenting object is embedded into a higher dimensional space. The reason is an underlying transition between two distinct fragmentation mechanisms controlled by the impact velocity at low plate thicknesses, while it is hindered for three-dimensional bulk systems. The mass distributions of the subsets of fragments dominated by the two cracking mechanisms proved to have an astonishing robustness at all plate thicknesses, which implies that the nonuniversality of the complete mass distribution is the consequence of blending the contributions of universal partial processes.

Fragment based drug discovery: practical implementation based on ¹⁹F NMR spectroscopy.

PubMed

Jordan, John B; Poppe, Leszek; Xia, Xiaoyang; Cheng, Alan C; Sun, Yax; Michelsen, Klaus; Eastwood, Heather; Schnier, Paul D; Nixey, Thomas; Zhong, Wenge

2012-01-26

Fragment based drug discovery (FBDD) is a widely used tool for discovering novel therapeutics. NMR is a powerful means for implementing FBDD, and several approaches have been proposed utilizing (1)H-(15)N heteronuclear single quantum coherence (HSQC) as well as one-dimensional (1)H and (19)F NMR to screen compound mixtures against a target of interest. While proton-based NMR methods of fragment screening (FBS) have been well documented and are widely used, the use of (19)F detection in FBS has been only recently introduced (Vulpetti et al. J. Am. Chem. Soc.2009, 131 (36), 12949-12959) with the aim of targeting "fluorophilic" sites in proteins. Here, we demonstrate a more general use of (19)F NMR-based fragment screening in several areas: as a key tool for rapid and sensitive detection of fragment hits, as a method for the rapid development of structure-activity relationship (SAR) on the hit-to-lead path using in-house libraries and/or commercially available compounds, and as a quick and efficient means of assessing target druggability.

Using DNase Hi-C techniques to map global and local three-dimensional genome architecture at high resolution.

PubMed

Ma, Wenxiu; Ay, Ferhat; Lee, Choli; Gulsoy, Gunhan; Deng, Xinxian; Cook, Savannah; Hesson, Jennifer; Cavanaugh, Christopher; Ware, Carol B; Krumm, Anton; Shendure, Jay; Blau, C Anthony; Disteche, Christine M; Noble, William S; Duan, ZhiJun

2018-06-01

The folding and three-dimensional (3D) organization of chromatin in the nucleus critically impacts genome function. The past decade has witnessed rapid advances in genomic tools for delineating 3D genome architecture. Among them, chromosome conformation capture (3C)-based methods such as Hi-C are the most widely used techniques for mapping chromatin interactions. However, traditional Hi-C protocols rely on restriction enzymes (REs) to fragment chromatin and are therefore limited in resolution. We recently developed DNase Hi-C for mapping 3D genome organization, which uses DNase I for chromatin fragmentation. DNase Hi-C overcomes RE-related limitations associated with traditional Hi-C methods, leading to improved methodological resolution. Furthermore, combining this method with DNA capture technology provides a high-throughput approach (targeted DNase Hi-C) that allows for mapping fine-scale chromatin architecture at exceptionally high resolution. Hence, targeted DNase Hi-C will be valuable for delineating the physical landscapes of cis-regulatory networks that control gene expression and for characterizing phenotype-associated chromatin 3D signatures. Here, we provide a detailed description of method design and step-by-step working protocols for these two methods. Copyright © 2018 Elsevier Inc. All rights reserved.

Fragment-based quantitative structure-activity relationship (FB-QSAR) for fragment-based drug design.

PubMed

Du, Qi-Shi; Huang, Ri-Bo; Wei, Yu-Tuo; Pang, Zong-Wen; Du, Li-Qin; Chou, Kuo-Chen

2009-01-30

In cooperation with the fragment-based design a new drug design method, the so-called "fragment-based quantitative structure-activity relationship" (FB-QSAR) is proposed. The essence of the new method is that the molecular framework in a family of drug candidates are divided into several fragments according to their substitutes being investigated. The bioactivities of molecules are correlated with the physicochemical properties of the molecular fragments through two sets of coefficients in the linear free energy equations. One coefficient set is for the physicochemical properties and the other for the weight factors of the molecular fragments. Meanwhile, an iterative double least square (IDLS) technique is developed to solve the two sets of coefficients in a training data set alternately and iteratively. The IDLS technique is a feedback procedure with machine learning ability. The standard Two-dimensional quantitative structure-activity relationship (2D-QSAR) is a special case, in the FB-QSAR, when the whole molecule is treated as one entity. The FB-QSAR approach can remarkably enhance the predictive power and provide more structural insights into rational drug design. As an example, the FB-QSAR is applied to build a predictive model of neuraminidase inhibitors for drug development against H5N1 influenza virus. (c) 2008 Wiley Periodicals, Inc.

Route to three-dimensional fragments using diversity-oriented synthesis

PubMed Central

Hung, Alvin W.; Ramek, Alex; Wang, Yikai; Kaya, Taner; Wilson, J. Anthony; Clemons, Paul A.; Young, Damian W.

2011-01-01

Fragment-based drug discovery (FBDD) has proven to be an effective means of producing high-quality chemical ligands as starting points for drug-discovery pursuits. The increasing number of clinical candidate drugs developed using FBDD approaches is a testament of the efficacy of this approach. The success of fragment-based methods is highly dependent on the identity of the fragment library used for screening. The vast majority of FBDD has centered on the use of sp2-rich aromatic compounds. An expanded set of fragments that possess more 3D character would provide access to a larger chemical space of fragments than those currently used. Diversity-oriented synthesis (DOS) aims to efficiently generate a set of molecules diverse in skeletal and stereochemical properties. Molecules derived from DOS have also displayed significant success in the modulation of function of various “difficult” targets. Herein, we describe the application of DOS toward the construction of a unique set of fragments containing highly sp3-rich skeletons for fragment-based screening. Using cheminformatic analysis, we quantified the shapes and physical properties of the new 3D fragments and compared them with a database containing known fragment-like molecules. PMID:21482811

Route to three-dimensional fragments using diversity-oriented synthesis.

PubMed

Hung, Alvin W; Ramek, Alex; Wang, Yikai; Kaya, Taner; Wilson, J Anthony; Clemons, Paul A; Young, Damian W

2011-04-26

Fragment-based drug discovery (FBDD) has proven to be an effective means of producing high-quality chemical ligands as starting points for drug-discovery pursuits. The increasing number of clinical candidate drugs developed using FBDD approaches is a testament of the efficacy of this approach. The success of fragment-based methods is highly dependent on the identity of the fragment library used for screening. The vast majority of FBDD has centered on the use of sp(2)-rich aromatic compounds. An expanded set of fragments that possess more 3D character would provide access to a larger chemical space of fragments than those currently used. Diversity-oriented synthesis (DOS) aims to efficiently generate a set of molecules diverse in skeletal and stereochemical properties. Molecules derived from DOS have also displayed significant success in the modulation of function of various "difficult" targets. Herein, we describe the application of DOS toward the construction of a unique set of fragments containing highly sp(3)-rich skeletons for fragment-based screening. Using cheminformatic analysis, we quantified the shapes and physical properties of the new 3D fragments and compared them with a database containing known fragment-like molecules.

Enhanced Conformational Sampling in Molecular Dynamics Simulations of Solvated Peptides: Fragment-Based Local Elevation Umbrella Sampling.

PubMed

Hansen, Halvor S; Daura, Xavier; Hünenberger, Philippe H

2010-09-14

A new method, fragment-based local elevation umbrella sampling (FB-LEUS), is proposed to enhance the conformational sampling in explicit-solvent molecular dynamics (MD) simulations of solvated polymers. The method is derived from the local elevation umbrella sampling (LEUS) method [ Hansen and Hünenberger , J. Comput. Chem. 2010 , 31 , 1 - 23 ], which combines the local elevation (LE) conformational searching and the umbrella sampling (US) conformational sampling approaches into a single scheme. In LEUS, an initial (relatively short) LE build-up (searching) phase is used to construct an optimized (grid-based) biasing potential within a subspace of conformationally relevant degrees of freedom, which is then frozen and used in a (comparatively longer) US sampling phase. This combination dramatically enhances the sampling power of MD simulations but, due to computational and memory costs, is only applicable to relevant subspaces of low dimensionalities. As an attempt to expand the scope of the LEUS approach to solvated polymers with more than a few relevant degrees of freedom, the FB-LEUS scheme involves an US sampling phase that relies on a superposition of low-dimensionality biasing potentials optimized using LEUS at the fragment level. The feasibility of this approach is tested using polyalanine (poly-Ala) and polyvaline (poly-Val) oligopeptides. Two-dimensional biasing potentials are preoptimized at the monopeptide level, and subsequently applied to all dihedral-angle pairs within oligopeptides of 4,  6,  8, or 10 residues. Two types of fragment-based biasing potentials are distinguished: (i) the basin-filling (BF) potentials act so as to "fill" free-energy basins up to a prescribed free-energy level above the global minimum; (ii) the valley-digging (VD) potentials act so as to "dig" valleys between the (four) free-energy minima of the two-dimensional maps, preserving barriers (relative to linearly interpolated free-energy changes) of a prescribed magnitude. The application of these biasing potentials may lead to an impressive enhancement of the searching power (volume of conformational space visited in a given amount of simulation time). However, this increase is largely offset by a deterioration of the statistical efficiency (representativeness of the biased ensemble in terms of the conformational distribution appropriate for the physical ensemble). As a result, it appears difficult to engineer FB-LEUS schemes representing a significant improvement over plain MD, at least for the systems considered here.

The 4-dimensional Langevin approach to low energy nuclear fission

NASA Astrophysics Data System (ADS)

Ivanyuk, F. A.; Ishizuka, C.; Usang, M. D.; Chiba, S.

2018-03-01

We applied the four-dimensional Langevin approach to the description of fission of 235U by neutrons and calculated the dependence of the excitation energy of fission fragments on their mass number. For this we have fitted the compact just-before-scission configuration obtained by the Langevin calculations by the two separated fragments and calculated the intrinsic excitation and the deformation energy of each fragment accurately taking into account the shell and pairing effects and their dependence on the temperature and mass of the fragments. For the sharing of energy between the fission fragments we have used the simplest and most reliable assumption - the temperature of each fragment immediately after the neck rupture is the same as the temperature of mother nucleus just before scission. The calculated excitation energy of fission fragments clearly demonstrates the saw-tooth structure in the dependence on fragment mass number.

A probabilistic and continuous model of protein conformational space for template-free modeling.

PubMed

Zhao, Feng; Peng, Jian; Debartolo, Joe; Freed, Karl F; Sosnick, Tobin R; Xu, Jinbo

2010-06-01

One of the major challenges with protein template-free modeling is an efficient sampling algorithm that can explore a huge conformation space quickly. The popular fragment assembly method constructs a conformation by stringing together short fragments extracted from the Protein Data Base (PDB). The discrete nature of this method may limit generated conformations to a subspace in which the native fold does not belong. Another worry is that a protein with really new fold may contain some fragments not in the PDB. This article presents a probabilistic model of protein conformational space to overcome the above two limitations. This probabilistic model employs directional statistics to model the distribution of backbone angles and 2(nd)-order Conditional Random Fields (CRFs) to describe sequence-angle relationship. Using this probabilistic model, we can sample protein conformations in a continuous space, as opposed to the widely used fragment assembly and lattice model methods that work in a discrete space. We show that when coupled with a simple energy function, this probabilistic method compares favorably with the fragment assembly method in the blind CASP8 evaluation, especially on alpha or small beta proteins. To our knowledge, this is the first probabilistic method that can search conformations in a continuous space and achieves favorable performance. Our method also generated three-dimensional (3D) models better than template-based methods for a couple of CASP8 hard targets. The method described in this article can also be applied to protein loop modeling, model refinement, and even RNA tertiary structure prediction.

Dimensional crossover in fragmentation

NASA Astrophysics Data System (ADS)

Sotolongo-Costa, Oscar; Rodriguez, Arezky H.; Rodgers, G. J.

2000-11-01

Experiments in which thick clay plates and glass rods are fractured have revealed different behavior of fragment mass distribution function in the small and large fragment regions. In this paper we explain this behavior using non-extensive Tsallis statistics and show how the crossover between the two regions is caused by the change in the fragments’ dimensionality during the fracture process. We obtain a physical criterion for the position of this crossover and an expression for the change in the power-law exponent between the small and large fragment regions. These predictions are in good agreement with the experiments on thick clay plates.

Modularity of Protein Folds as a Tool for Template-Free Modeling of Structures.

PubMed

Vallat, Brinda; Madrid-Aliste, Carlos; Fiser, Andras

2015-08-01

Predicting the three-dimensional structure of proteins from their amino acid sequences remains a challenging problem in molecular biology. While the current structural coverage of proteins is almost exclusively provided by template-based techniques, the modeling of the rest of the protein sequences increasingly require template-free methods. However, template-free modeling methods are much less reliable and are usually applicable for smaller proteins, leaving much space for improvement. We present here a novel computational method that uses a library of supersecondary structure fragments, known as Smotifs, to model protein structures. The library of Smotifs has saturated over time, providing a theoretical foundation for efficient modeling. The method relies on weak sequence signals from remotely related protein structures to create a library of Smotif fragments specific to the target protein sequence. This Smotif library is exploited in a fragment assembly protocol to sample decoys, which are assessed by a composite scoring function. Since the Smotif fragments are larger in size compared to the ones used in other fragment-based methods, the proposed modeling algorithm, SmotifTF, can employ an exhaustive sampling during decoy assembly. SmotifTF successfully predicts the overall fold of the target proteins in about 50% of the test cases and performs competitively when compared to other state of the art prediction methods, especially when sequence signal to remote homologs is diminishing. Smotif-based modeling is complementary to current prediction methods and provides a promising direction in addressing the structure prediction problem, especially when targeting larger proteins for modeling.

A double-labeling procedure for sequence analysis of picomole amounts of nonradioactive RNA fragments.

PubMed Central

Gupta, R C; Randerath, E; Randerath, K

1976-01-01

A double-labeling procedure for sequence analysis of nonradioactive polyribonucleotides is detailed, which is based on controlled endonucleolytic degradation of 3'-terminally (3H)-labeled oligonucleotide-(3') dialcohols and 5"-terminal analysis of the partial (3H)-labeled fragments following their separation according to chain length by polyethyleneimine- (PEI-)cellulose TLC and detection by fluorography. Undesired nonradioactive partial digestion products are eliminated by periodate oxidation. The 5'-termini are assayed by enzymic incorporation of (32p)-label into the isolated fragments, enzymic release of (32p)-labeled nucleoside-(5') monophosphates, two-dimensional PEI-cellulose chromatography, and autoradiography. Using this procedure, as little as 0.1 - 0.3 A260 unit of tRNA is needed to sequence all fragments in complete ribonuclease T1 and A digests, whereas radioactive derivative methods previously described by us1-4 required 4 - 6 A260 units. Images PMID:826884

Fragment-based drug discovery using rational design.

PubMed

Jhoti, H

2007-01-01

Fragment-based drug discovery (FBDD) is established as an alternative approach to high-throughput screening for generating novel small molecule drug candidates. In FBDD, relatively small libraries of low molecular weight compounds (or fragments) are screened using sensitive biophysical techniques to detect their binding to the target protein. A lower absolute affinity of binding is expected from fragments, compared to much higher molecular weight hits detected by high-throughput screening, due to their reduced size and complexity. Through the use of iterative cycles of medicinal chemistry, ideally guided by three-dimensional structural data, it is often then relatively straightforward to optimize these weak binding fragment hits into potent and selective lead compounds. As with most other lead discovery methods there are two key components of FBDD; the detection technology and the compound library. In this review I outline the two main approaches used for detecting the binding of low affinity fragments and also some of the key principles that are used to generate a fragment library. In addition, I describe an example of how FBDD has led to the generation of a drug candidate that is now being tested in clinical trials for the treatment of cancer.

Causes and consequences of habitat fragmentation in river networks.

PubMed

Fuller, Matthew R; Doyle, Martin W; Strayer, David L

2015-10-01

Increases in river fragmentation globally threaten freshwater biodiversity. Rivers are fragmented by many agents, both natural and anthropogenic. We review the distribution and frequency of these major agents, along with their effects on connectivity and habitat quality. Most fragmentation research has focused on terrestrial habitats, but theories and generalizations developed in terrestrial habitats do not always apply well to river networks. For example, terrestrial habitats are usually conceptualized as two-dimensional, whereas rivers often are conceptualized as one-dimensional or dendritic. In addition, river flow often leads to highly asymmetric effects of barriers on habitat and permeability. New approaches tailored to river networks can be applied to describe the network-wide effects of multiple barriers on both connectivity and habitat quality. The net effects of anthropogenic fragmentation on freshwater biodiversity are likely underestimated, because of time lags in effects and the difficulty of generating a single, simple signal of fragmentation that applies to all aquatic species. We conclude by presenting a decision tree for managing freshwater fragmentation, as well as some research horizons for evaluating fragmented riverscapes. © 2015 New York Academy of Sciences.

Topological analysis of group fragmentation in multiagent systems

NASA Astrophysics Data System (ADS)

DeLellis, Pietro; Porfiri, Maurizio; Bollt, Erik M.

2013-02-01

In social animals, the presence of conflicts of interest or multiple leaders can promote the emergence of two or more subgroups. Such subgroups are easily recognizable by human observers, yet a quantitative and objective measure of group fragmentation is currently lacking. In this paper, we explore the feasibility of detecting group fragmentation by embedding the raw data from the individuals' motions on a low-dimensional manifold and analyzing the topological features of this manifold. To perform the embedding, we employ the isomap algorithm, which is a data-driven machine learning tool extensively used in computer vision. We implement this procedure on a data set generated by a modified à la Vicsek model, where agents are partitioned into two or more subsets and an independent leader is assigned to each subset. The dimensionality of the embedding manifold is shown to be a measure of the number of emerging subgroups in the selected observation window and a cluster analysis is proposed to aid the interpretation of these findings. To explore the feasibility of using this approach to characterize group fragmentation in real time and thus reduce the computational cost in data processing and storage, we propose an interpolation method based on an inverse mapping from the embedding space to the original space. The effectiveness of the interpolation technique is illustrated on a test-bed example with potential impact on the regulation of collective behavior of animal groups using robotic stimuli.

Scaling invariance of spherical projectile fragmentation upon high-velocity impact on a thin continuous shield

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

Myagkov, N. N., E-mail: nn-myagkov@mail.ru

The problem of aluminum projectile fragmentation upon high-velocity impact on a thin aluminum shield is considered. A distinctive feature of this description is that the fragmentation has been numerically simulated using the complete system of equations of deformed solid mechanics by a method of smoothed particle hydrodynamics in three-dimensional setting. The transition from damage to fragmentation is analyzed and scaling relations are derived in terms of the impact velocity (V), ratio of shield thickness to projectile diameter (h/D), and ultimate strength (σ{sub p}) in the criterion of projectile and shield fracture. Analysis shows that the critical impact velocity V{sub c}more » (separating the damage and fragmentation regions) is a power function of σ{sub p} and h/D. In the supercritical region (V > V{sub c}), the weight-average fragment mass asymptotically tends to a power function of the impact velocity with exponent independent of h/D and σ{sub p}. Mean cumulative fragment mass distributions at the critical point are scale-invariant with respect to parameters h/D and σ{sub p}. Average masses of the largest fragments are also scale-invariant at V > V{sub c}, but only with respect to variable parameter σ{sub p}.« less

DISCO: Distance and Spectrum Correlation Optimization Alignment for Two Dimensional Gas Chromatography Time-of-Flight Mass Spectrometry-based Metabolomics

PubMed Central

Wang, Bing; Fang, Aiqin; Heim, John; Bogdanov, Bogdan; Pugh, Scott; Libardoni, Mark; Zhang, Xiang

2010-01-01

A novel peak alignment algorithm using a distance and spectrum correlation optimization (DISCO) method has been developed for two-dimensional gas chromatography time-of-flight mass spectrometry (GC×GC/TOF-MS) based metabolomics. This algorithm uses the output of the instrument control software, ChromaTOF, as its input data. It detects and merges multiple peak entries of the same metabolite into one peak entry in each input peak list. After a z-score transformation of metabolite retention times, DISCO selects landmark peaks from all samples based on both two-dimensional retention times and mass spectrum similarity of fragment ions measured by Pearson’s correlation coefficient. A local linear fitting method is employed in the original two-dimensional retention time space to correct retention time shifts. A progressive retention time map searching method is used to align metabolite peaks in all samples together based on optimization of the Euclidean distance and mass spectrum similarity. The effectiveness of the DISCO algorithm is demonstrated using data sets acquired under different experiment conditions and a spiked-in experiment. PMID:20476746

Mapping High Dimensional Sparse Customer Requirements into Product Configurations

NASA Astrophysics Data System (ADS)

Jiao, Yao; Yang, Yu; Zhang, Hongshan

2017-10-01

Mapping customer requirements into product configurations is a crucial step for product design, while, customers express their needs ambiguously and locally due to the lack of domain knowledge. Thus the data mining process of customer requirements might result in fragmental information with high dimensional sparsity, leading the mapping procedure risk uncertainty and complexity. The Expert Judgment is widely applied against that background since there is no formal requirements for systematic or structural data. However, there are concerns on the repeatability and bias for Expert Judgment. In this study, an integrated method by adjusted Local Linear Embedding (LLE) and Naïve Bayes (NB) classifier is proposed to map high dimensional sparse customer requirements to product configurations. The integrated method adjusts classical LLE to preprocess high dimensional sparse dataset to satisfy the prerequisite of NB for classifying different customer requirements to corresponding product configurations. Compared with Expert Judgment, the adjusted LLE with NB performs much better in a real-world Tablet PC design case both in accuracy and robustness.

Dynamics of formation of low-angle tilt boundaries in metals and alloys at high loading rates

NASA Astrophysics Data System (ADS)

Gutkin, M. Yu.; Rzhavtsev, E. A.

2015-12-01

A computer model has been developed in which the process of formation of low-angle tilt boundaries and fragmentation of initial subgrains during shock loading of metals and alloys is clearly demonstrated by the of two-dimensional discrete dislocation-disclination dynamics method. The formation and evolution of such grains proceeds under the action of an external stress and the stress field of grain boundary disclinations distributed on the subgrain boundaries. With the D16 aluminum alloy as an example, three cases of fragmented structures formed in accordance with the initial configuration of the disclination ensemble have been considered for a dipole, quadrupole, and arbitrary octupole of wedge disclinations. It has been shown that, in all these cases, the formation of a stable fragmented structure requires a stress of ~0.5 GPa and time of 10 ns. The main results of computer simulation (the finite form of a fragmented structure, typical level of applied stress, and small fragmentation time) agree well with known experimental results on shock compression of the D16 aluminum alloy.

FLASHFLOOD: A 3D Field-based similarity search and alignment method for flexible molecules

NASA Astrophysics Data System (ADS)

Pitman, Michael C.; Huber, Wolfgang K.; Horn, Hans; Krämer, Andreas; Rice, Julia E.; Swope, William C.

2001-07-01

A three-dimensional field-based similarity search and alignment method for flexible molecules is introduced. The conformational space of a flexible molecule is represented in terms of fragments and torsional angles of allowed conformations. A user-definable property field is used to compute features of fragment pairs. Features are generalizations of CoMMA descriptors (Silverman, B.D. and Platt, D.E., J. Med. Chem., 39 (1996) 2129.) that characterize local regions of the property field by its local moments. The features are invariant under coordinate system transformations. Features taken from a query molecule are used to form alignments with fragment pairs in the database. An assembly algorithm is then used to merge the fragment pairs into full structures, aligned to the query. Key to the method is the use of a context adaptive descriptor scaling procedure as the basis for similarity. This allows the user to tune the weights of the various feature components based on examples relevant to the particular context under investigation. The property fields may range from simple, phenomenological fields, to fields derived from quantum mechanical calculations. We apply the method to the dihydrofolate/methotrexate benchmark system, and show that when one injects relevant contextual information into the descriptor scaling procedure, better results are obtained more efficiently. We also show how the method works and include computer times for a query from a database that represents approximately 23 million conformers of seventeen flexible molecules.

Automated building of organometallic complexes from 3D fragments.

PubMed

Foscato, Marco; Venkatraman, Vishwesh; Occhipinti, Giovanni; Alsberg, Bjørn K; Jensen, Vidar R

2014-07-28

A method for the automated construction of three-dimensional (3D) molecular models of organometallic species in design studies is described. Molecular structure fragments derived from crystallographic structures and accurate molecular-level calculations are used as 3D building blocks in the construction of multiple molecular models of analogous compounds. The method allows for precise control of stereochemistry and geometrical features that may otherwise be very challenging, or even impossible, to achieve with commonly available generators of 3D chemical structures. The new method was tested in the construction of three sets of active or metastable organometallic species of catalytic reactions in the homogeneous phase. The performance of the method was compared with those of commonly available methods for automated generation of 3D models, demonstrating higher accuracy of the prepared 3D models in general, and, in particular, a much wider range with respect to the kind of chemical structures that can be built automatically, with capabilities far beyond standard organic and main-group chemistry.

Virtual fragment preparation for computational fragment-based drug design.

PubMed

Ludington, Jennifer L

2015-01-01

Fragment-based drug design (FBDD) has become an important component of the drug discovery process. The use of fragments can accelerate both the search for a hit molecule and the development of that hit into a lead molecule for clinical testing. In addition to experimental methodologies for FBDD such as NMR and X-ray Crystallography screens, computational techniques are playing an increasingly important role. The success of the computational simulations is due in large part to how the database of virtual fragments is prepared. In order to prepare the fragments appropriately it is necessary to understand how FBDD differs from other approaches and the issues inherent in building up molecules from smaller fragment pieces. The ultimate goal of these calculations is to link two or more simulated fragments into a molecule that has an experimental binding affinity consistent with the additive predicted binding affinities of the virtual fragments. Computationally predicting binding affinities is a complex process, with many opportunities for introducing error. Therefore, care should be taken with the fragment preparation procedure to avoid introducing additional inaccuracies.This chapter is focused on the preparation process used to create a virtual fragment database. Several key issues of fragment preparation which affect the accuracy of binding affinity predictions are discussed. The first issue is the selection of the two-dimensional atomic structure of the virtual fragment. Although the particular usage of the fragment can affect this choice (i.e., whether the fragment will be used for calibration, binding site characterization, hit identification, or lead optimization), general factors such as synthetic accessibility, size, and flexibility are major considerations in selecting the 2D structure. Other aspects of preparing the virtual fragments for simulation are the generation of three-dimensional conformations and the assignment of the associated atomic point charges.

[Analysis of tension-distraction state in the shin bones fractures in conditions of external fixation with application of apparatuses with different spatially oriented supports].

PubMed

Hutsuliak, V I

2014-09-01

In Autodesk Inventor 11 program, using method of end-capping elements, a three- dimensional computeric modelling of biomechanical systems of two models was conducted: I - "tibia - Ilizarov's apparatus with concentric location of supports"; II - "tibia - Ilizarov's apparatus with excentric location of supports". The loading, which was applied towards distal fragment in 6 standard degrees of freedom, was modelled for studying of the fixation rigidity of tibial fragments in these systems. Determination of the loading value in various directions, in which the fragment have had shifted by 1 mm, have constituted the main task of the investigation. In a model II a rigidity of the fragments fixation, in comparison with such in a model I, is bigger by 631.43% - while applying a compression loading, by 8.35 - 31.75% - the transversal one and by 19.72% - the rotation loading. While choosing the method of transosteal osteosynthesis of the shin bones the advantage, have the apparatuses with excentric location of supports, what secures the enhanced rigidity of the fragments fixation in comparison with such in apparatuses with concentric location of supports. Although, even in excentric location of supports in the apparatus the fixation rigidity is insufficient for early full loading of the traumatized extremity while walking. It is necessary to elaborate such apparatus, the form of which may be adopted toanatomic configuration of segment.

FragFit: a web-application for interactive modeling of protein segments into cryo-EM density maps.

PubMed

Tiemann, Johanna K S; Rose, Alexander S; Ismer, Jochen; Darvish, Mitra D; Hilal, Tarek; Spahn, Christian M T; Hildebrand, Peter W

2018-05-21

Cryo-electron microscopy (cryo-EM) is a standard method to determine the three-dimensional structures of molecular complexes. However, easy to use tools for modeling of protein segments into cryo-EM maps are sparse. Here, we present the FragFit web-application, a web server for interactive modeling of segments of up to 35 amino acids length into cryo-EM density maps. The fragments are provided by a regularly updated database containing at the moment about 1 billion entries extracted from PDB structures and can be readily integrated into a protein structure. Fragments are selected based on geometric criteria, sequence similarity and fit into a given cryo-EM density map. Web-based molecular visualization with the NGL Viewer allows interactive selection of fragments. The FragFit web-application, accessible at http://proteinformatics.de/FragFit, is free and open to all users, without any login requirements.

The direct exchange mechanism of induced spin polarization of low-dimensional π-conjugated carbon- and h-BN fragments at LSMO(001) MnO-terminated interfaces

NASA Astrophysics Data System (ADS)

Kuklin, Artem V.; Kuzubov, Alexander A.; Kovaleva, Evgenia A.; Lee, Hyosun; Sorokin, Pavel B.; Sakai, Seiji; Entani, Shiro; Naramoto, Hiroshi; Avramov, Paul

2017-10-01

Induced spin polarization of π-conjugated carbon and h-BN low dimensional fragments at the interfaces formed by deposition of pentacene molecule and narrow zigzag graphene and h-BN nanoribbons on MnO2-terminated LSMO(001) thin film was studied using GGA PBE+U PAW D3-corrected approach. Induced spin polarization of π-conjugated low-dimensional fragments is caused by direct exchange with Mn ions of LSMO(001) MnO-derived surface. Due to direct exchange, the pentacene molecule changes its diamagnetic narrow-band gap semiconducting nature to the ferromagnetic semiconducting state with 0.15 eV energy shift between spin-up and spin-down valence bands and total magnetic moment of 0.11 μB. Direct exchange converts graphene nanoribbon to 100% spin-polarized half-metal with large amplitude of spin-up electronic density at the Fermi level. The direct exchange narrows the h-BN nanoribbon band gap from 4.04 to 1.72 eV in spin-up channel and converts the h-BN ribbon semiconducting diamagnetic nature to a semiconducting magnetic one. The electronic structure calculations demonstrate a possibility to control the spin properties of low-dimensional π-conjugated carbon and h-BN fragments by direct exchange with MnO-derived LSMO(001) surface for spin-related applications.

The linearly scaling 3D fragment method for large scale electronic structure calculations

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

Zhao, Zhengji; Meza, Juan; Lee, Byounghak

2009-07-28

The Linearly Scaling three-dimensional fragment (LS3DF) method is an O(N) ab initio electronic structure method for large-scale nano material simulations. It is a divide-and-conquer approach with a novel patching scheme that effectively cancels out the artificial boundary effects, which exist in all divide-and-conquer schemes. This method has made ab initio simulations of thousand-atom nanosystems feasible in a couple of hours, while retaining essentially the same accuracy as the direct calculation methods. The LS3DF method won the 2008 ACM Gordon Bell Prize for algorithm innovation. Our code has reached 442 Tflop/s running on 147,456 processors on the Cray XT5 (Jaguar) atmore » OLCF, and has been run on 163,840 processors on the Blue Gene/P (Intrepid) at ALCF, and has been applied to a system containing 36,000 atoms. In this paper, we will present the recent parallel performance results of this code, and will apply the method to asymmetric CdSe/CdS core/shell nanorods, which have potential applications in electronic devices and solar cells.« less

The Linearly Scaling 3D Fragment Method for Large Scale Electronic Structure Calculations

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

Zhao, Zhengji; Meza, Juan; Lee, Byounghak

2009-06-26

The Linearly Scaling three-dimensional fragment (LS3DF) method is an O(N) ab initio electronic structure method for large-scale nano material simulations. It is a divide-and-conquer approach with a novel patching scheme that effectively cancels out the artificial boundary effects, which exist in all divide-and-conquer schemes. This method has made ab initio simulations of thousand-atom nanosystems feasible in a couple of hours, while retaining essentially the same accuracy as the direct calculation methods. The LS3DF method won the 2008 ACM Gordon Bell Prize for algorithm innovation. Our code has reached 442 Tflop/s running on 147,456 processors on the Cray XT5 (Jaguar) atmore » OLCF, and has been run on 163,840 processors on the Blue Gene/P (Intrepid) at ALCF, and has been applied to a system containing 36,000 atoms. In this paper, we will present the recent parallel performance results of this code, and will apply the method to asymmetric CdSe/CdS core/shell nanorods, which have potential applications in electronic devices and solar cells.« less

On the fragmentation of filaments in a molecular cloud simulation

NASA Astrophysics Data System (ADS)

Chira, R.-A.; Kainulainen, J.; Ibáñez-Mejía, J. C.; Henning, Th.; Mac Low, M.-M.

2018-03-01

Context. The fragmentation of filaments in molecular clouds has attracted a lot of attention recently as there seems to be a close relation between the evolution of filaments and star formation. The study of the fragmentation process has been motivated by simple analytical models. However, only a few comprehensive studies have analysed the evolution of filaments using numerical simulations where the filaments form self-consistently as part of large-scale molecular cloud evolution. Aim. We address the early evolution of parsec-scale filaments that form within individual clouds. In particular, we focus on three questions: How do the line masses of filaments evolve? How and when do the filaments fragment? How does the fragmentation relate to the line masses of the filaments? Methods: We examine three simulated molecular clouds formed in kiloparsec-scale numerical simulations performed with the FLASH adaptive mesh refinement magnetohydrodynamic code. The simulations model a self-gravitating, magnetised, stratified, supernova-driven interstellar medium, including photoelectric heating and radiative cooling. We follow the evolution of the clouds for 6 Myr from the time self-gravity starts to act. We identify filaments using the DisPerSe algorithm, and compare the results to other filament-finding algorithms. We determine the properties of the identified filaments and compare them with the predictions of analytic filament stability models. Results: The average line masses of the identified filaments, as well as the fraction of mass in filamentary structures, increases fairly continuously after the onset of self-gravity. The filaments show fragmentation starting relatively early: the first fragments appear when the line masses lie well below the critical line mass of Ostriker's isolated hydrostatic equilibrium solution ( 16 M⊙ pc-1), commonly used as a fragmentation criterion. The average line masses of filaments identified in three-dimensional volume density cubes increases far more quickly than those identified in two-dimensional column density maps. Conclusions: Our results suggest that hydrostatic or dynamic compression from the surrounding cloud has a significant impact on the early dynamical evolution of filaments. A simple model of an isolated, isothermal cylinder may not provide a good approach for fragmentation analysis. Caution must be exercised in interpreting distributions of properties of filaments identified in column density maps, especially in the case of low-mass filaments. Comparing or combining results from studies that use different filament finding techniques is strongly discouraged.

Crystallized N-terminal domain of influenza virus matrix protein M1 and method of determining and using same

NASA Technical Reports Server (NTRS)

Luo, Ming (Inventor); Sha, Bingdong (Inventor)

2000-01-01

The matrix protein, M1, of influenza virus strain A/PR/8/34 has been purified from virions and crystallized. The crystals consist of a stable fragment (18 Kd) of the M1 protein. X-ray diffraction studies indicated that the crystals have a space group of P3.sub.t 21 or P3.sub.2 21. Vm calculations showed that there are two monomers in an asymmetric unit. A crystallized N-terminal domain of M1, wherein the N-terminal domain of M1 is crystallized such that the three dimensional structure of the crystallized N-terminal domain of M1 can be determined to a resolution of about 2.1 .ANG. or better, and wherein the three dimensional structure of the uncrystallized N-terminal domain of M1 cannot be determined to a resolution of about 2.1 .ANG. or better. A method of purifying M1 and a method of crystallizing M1. A method of using the three-dimensional crystal structure of M1 to screen for antiviral, influenza virus treating or preventing compounds. A method of using the three-dimensional crystal structure of M1 to screen for improved binding to or inhibition of influenza virus M1. The use of the three-dimensional crystal structure of the M1 protein of influenza virus in the manufacture of an inhibitor of influenza virus M1. The use of the three-dimensional crystal structure of the M1 protein of influenza virus in the screening of candidates for inhibition of influenza virus M1.

Increasing the Coverage of Medicinal Chemistry-Relevant Space in Commercial Fragments Screening

PubMed Central

2014-01-01

Analyzing the chemical space coverage in commercial fragment screening collections revealed the overlap between bioactive medicinal chemistry substructures and rule-of-three compliant fragments is only ∼25%. We recommend including these fragments in fragment screening libraries to maximize confidence in discovering hit matter within known bioactive chemical space, while incorporation of nonoverlapping substructures could offer novel hits in screening libraries. Using principal component analysis, polar and three-dimensional substructures display a higher-than-average enrichment of bioactive compounds, indicating increasing representation of these substructures may be beneficial in fragment screening. PMID:24405118

Three-dimensionally derived interlandmark distances for sex estimation in intact and fragmentary crania.

PubMed

Small, Candice; Schepartz, Lynne; Hemingway, Jason; Brits, Desiré

2018-06-01

The skull is the element most frequently presented to forensic anthropologists for analysis yet weathering, corpse maiming, and scavenger activity often result in damage and fragmentation. This fragmentation results in a reduction in the number of traditional calliper derived measurements that can be obtained and subjected to discriminant based analyses for sex estimation. In this investigation, we employed three-dimensional geometric morphometric methods to derive novel interlandmark distance measures across six regions of the cranium including the basicranium, basipalate, zygoma, orbits and the cranium globally to create functions to discriminate sex with high efficacy, even in the event of fragmentation. Forty-five homologous landmarks were digitised across each of 227 (114 males and 113 females) South African crania of European descent (white) sampled from the Raymond A Dart Collection of Human Skeletons, housed in the School of Anatomical Sciences, University of the Witwatersrand, South Africa. A total of 990 interlandmark distances (ILDs) were mathematically derived using Pythagorean geometry. These ILDs were then filtered by region and subjected to both direct and stepwise discriminant function analyses. Discriminant equations where derived for each region and achieved the following average cross-validated sex estimation accuracies: basicranium-74%; basipalate-80.2%; zygomatic-82.4; orbits-71.8%; nasomaxilla-83.7%; global cranium-88.2%. A large number of the ILDs used to derive the discriminant functions are novel, demonstrating the efficacy of geometric morphometric methods and illustrating the need to reassess old methods of data collection using modern methods to determine whether they best capture biological differences. The results of this study provide an invaluable contribution to forensic anthropology in South Africa as it provides an accurate, practical means of assessing sex using fragmentary material that may otherwise have been disregarded. These will undeniable aid in accurate sex estimation and ultimately, victim identification. Copyright © 2018 Elsevier B.V. All rights reserved.

On the effect of grain burnback on STS-SRM fragment velocity

NASA Astrophysics Data System (ADS)

Eck, Marshall B.; Mukunda, Meera

Concerns raised during the Ulysses Final Safety Analysis Review (FSAR) process called the solid rocket motor (SRM) fragment velocity prediction model into question. The specific area of concern was that there was a section of the SRM casing which was exposed to SRM chamber pressure as the grain (fuel) was consumed. These questions centered on the velocity of fragments which originated from the field joint region given that failure occurred between 37 and 72 seconds mission elapsed time (MET). Two dimensional coupled Eulerian-Lagrangian calculations were performed to assess the hot gas flow field which resulted from SRM casing fragmentation. The fragment to gas interface-pressure time-history obtained from these analyses was reduced to a boundary condition algorithm which was applied to an explicit-time-integration, finite element, three dimensional shell model of the SRM casing and unburned fuel. The results of these calculations showed that the velocity of fragments originating in the field joint was adequately described by the range of velocities given in the Shuttle Data Book (1988). Based on these results, no further analyses were required, and approval was obtained from the Launch Abort Subpanel of the Interagency Nuclear Safety Review Panel to use the SRM fragment velocity environments presented in the Ulysses FSAR (1990).

On the effect of grain burnback on STS-SRM fragment velocity

NASA Astrophysics Data System (ADS)

Eck, Marshall B.; Mukunda, Meera

1991-01-01

Concerns raised during the Ulysses Final Safety Analysis Review (FSAR) process called the solid rocket motor (SRM) fragment velocity prediction model into question. The specific area of concern was that there was a section of the SRM casing which was exposed to SRM chamber pressure as the grain (fuel) was consumed. These questions centered on the velocity of fragments which originated from the field joint region given that failure occurred between 37 and 72 seconds mission elapsed time (MET). Two dimensional coupled Eulerian-Lagrangian calculations were performed to assess the hot gas flow field which resulted from SRM casing fragmentation. The fragment to gas interface-pressure time-history obtained from these analyses was reduced to a boundary condition algorithm which was applied to an explicit-time-integration, finite element, three dimensional shell model of the SRM casing and unburned fuel. The results of these calculations showed that the velocity of fragments originating in the field joint was adequately described by the range of velocities given in the Shuttle Data Book (1988). Based on these results, no further analyses were required, and approval was obtained from the Launch Abort Subpanel of the Interagency Nuclear Safety Review Panel to use the SRM fragment velocity environments presented in the Ulysses FSAR (1990).

Fragmentation study of iridoid glycosides including epimers by liquid chromatography-diode array detection/electrospray ionization mass spectrometry and its application in metabolic fingerprint analysis of Gardenia jasminoides Ellis.

PubMed

Zhou, Tingting; Liu, Hua; Wen, Jun; Fan, Guorong; Chai, Yifeng; Wu, Yutian

2010-09-15

A high-performance liquid chromatography-diode array detection/electrospray ionization mass spectrometry (HPLC-DAD/ESI-MS) method was applied to the characterization of ten iridoid glycosides in Gardenia jasminoides Ellis, a traditional Chinese medicine. During the process of structural elucidation, two groups of isomers including two epimers were structurally characterized and differentiated according to their distinctive fragmentation patterns which were closely related to their isomeric differentiations. Subsequently, the major compounds were purified by multi-dimensional chromatography and semi-preparative HPLC and the structure identification was confirmed with NMR techniques. The major fragmentation pathways of iridoid glycosides in Gardenia jasminoides Ellis obtained through the MS data were schemed systematically, which provided the best sensitivity and specificity for characterization of the iridoid glycosides especially the isomers so far. Based on the fragmentation patterns of iridoid glycosides concluded, seven major iridoid glycosides were characterized in rat plasma after intravenous administration of Gardenia jasminoides Ellis. Copyright 2010 John Wiley & Sons, Ltd.

Investigation of the Rock Fragmentation Process by a Single TBM Cutter Using a Voronoi Element-Based Numerical Manifold Method

NASA Astrophysics Data System (ADS)

Liu, Quansheng; Jiang, Yalong; Wu, Zhijun; Xu, Xiangyu; Liu, Qi

2018-04-01

In this study, a two-dimensional Voronoi element-based numerical manifold method (VE-NMM) is developed to analyze the granite fragmentation process by a single tunnel boring machine (TBM) cutter under different confining stresses. A Voronoi tessellation technique is adopted to generate the polygonal grain assemblage to approximate the microstructure of granite sample from the Gubei colliery of Huainan mining area in China. A modified interface contact model with cohesion and tensile strength is embedded into the numerical manifold method (NMM) to interpret the interactions between the rock grains. Numerical uniaxial compression and Brazilian splitting tests are first conducted to calibrate and validate the VE-NMM models based on the laboratory experiment results using a trial-and-error method. On this basis, numerical simulations of rock fragmentation by a single TBM cutter are conducted. The simulated crack initiation and propagation process as well as the indentation load-penetration depth behaviors in the numerical models accurately predict the laboratory indentation test results. The influence of confining stress on rock fragmentation is also investigated. Simulation results show that radial tensile cracks are more likely to be generated under a low confining stress, eventually coalescing into a major fracture along the loading axis. However, with the increase in confining stress, more side cracks initiate and coalesce, resulting in the formation of rock chips at the upper surface of the model. In addition, the peak indentation load also increases with the increasing confining stress, indicating that a higher thrust force is usually needed during the TBM boring process in deep tunnels.

Reading angles in maps.

PubMed

Izard, Véronique; O'Donnell, Evan; Spelke, Elizabeth S

2014-01-01

Preschool children can navigate by simple geometric maps of the environment, but the nature of the geometric relations they use in map reading remains unclear. Here, children were tested specifically on their sensitivity to angle. Forty-eight children (age 47:15-53:30 months) were presented with fragments of geometric maps, in which angle sections appeared without any relevant length or distance information. Children were able to read these map fragments and compare two-dimensional to three-dimensional angles. However, this ability appeared both variable and fragile among the youngest children of the sample. These findings suggest that 4-year-old children begin to form an abstract concept of angle that applies both to two-dimensional and three-dimensional displays and that serves to interpret novel spatial symbols. © 2013 The Authors. Child Development © 2013 Society for Research in Child Development, Inc.

OPTIMIZATION OF EXPERIMENTAL DESIGNS BY INCORPORATING NIF FACILITY IMPACTS

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

Eder, D C; Whitman, P K; Koniges, A E

2005-08-31

For experimental campaigns on the National Ignition Facility (NIF) to be successful, they must obtain useful data without causing unacceptable impact on the facility. Of particular concern is excessive damage to optics and diagnostic components. There are 192 fused silica main debris shields (MDS) exposed to the potentially hostile target chamber environment on each shot. Damage in these optics results either from the interaction of laser light with contamination and pre-existing imperfections on the optic surface or from the impact of shrapnel fragments. Mitigation of this second damage source is possible by identifying shrapnel sources and shielding optics from them.more » It was recently demonstrated that the addition of 1.1-mm thick borosilicate disposable debris shields (DDS) block the majority of debris and shrapnel fragments from reaching the relatively expensive MDS's. However, DDS's cannot stop large, faster moving fragments. We have experimentally demonstrated one shrapnel mitigation technique showing that it is possible to direct fast moving fragments by changing the source orientation, in this case a Ta pinhole array. Another mitigation method is to change the source material to one that produces smaller fragments. Simulations and validating experiments are necessary to determine which fragments can penetrate or break 1-3 mm thick DDS's. Three-dimensional modeling of complex target-diagnostic configurations is necessary to predict the size, velocity, and spatial distribution of shrapnel fragments. The tools we are developing will be used to set the allowed level of debris and shrapnel generation for all NIF experimental campaigns.« less

Formation of highly toxic hydrogen cyanide upon ruby laser irradiation of the tattoo pigment phthalocyanine blue.

PubMed

Schreiver, Ines; Hutzler, Christoph; Laux, Peter; Berlien, Hans-Peter; Luch, Andreas

2015-08-05

Since laser treatment of tattoos is the favored method for the removing of no longer wanted permanent skin paintings, analytical, biokinetics and toxicological data on the fragmentation pattern of commonly used pigments are urgently required for health safety reasons. Applying dynamic headspace-gas chromatography with mass spectrometric detection (DHS-GC/MS) and comprehensive two-dimensional gas chromatography coupled to time-of-flight mass spectrometry (GCxGC-ToF-MS), we identified 1,2-benzene dicarbonitrile, benzonitrile, benzene, and the poisonous gas hydrogen cyanide (HCN) as main fragmentation products emerging dose-dependently upon ruby laser irradiation of the popular blue pigment copper phthalocyanine in suspension. Skin cell viability was found to be significantly compromised at cyanide levels of ≥1 mM liberated during ruby laser irradiation of >1.5 mg/ml phthalocyanine blue. Further, for the first time we introduce pyrolysis-GC/MS as method suitable to simulate pigment fragmentation that may occur spontaneously or during laser removal of organic pigments in the living skin of tattooed people. According to the literature such regular tattoos hold up to 9 mg pigment/cm(2) skin.

Formation of highly toxic hydrogen cyanide upon ruby laser irradiation of the tattoo pigment phthalocyanine blue

PubMed Central

Schreiver, Ines; Hutzler, Christoph; Laux, Peter; Berlien, Hans-Peter; Luch, Andreas

2015-01-01

Since laser treatment of tattoos is the favored method for the removing of no longer wanted permanent skin paintings, analytical, biokinetics and toxicological data on the fragmentation pattern of commonly used pigments are urgently required for health safety reasons. Applying dynamic headspace—gas chromatography with mass spectrometric detection (DHS—GC/MS) and comprehensive two-dimensional gas chromatography coupled to time-of-flight mass spectrometry (GCxGC—ToF-MS), we identified 1,2-benzene dicarbonitrile, benzonitrile, benzene, and the poisonous gas hydrogen cyanide (HCN) as main fragmentation products emerging dose-dependently upon ruby laser irradiation of the popular blue pigment copper phthalocyanine in suspension. Skin cell viability was found to be significantly compromised at cyanide levels of ≥1 mM liberated during ruby laser irradiation of >1.5 mg/ml phthalocyanine blue. Further, for the first time we introduce pyrolysis-GC/MS as method suitable to simulate pigment fragmentation that may occur spontaneously or during laser removal of organic pigments in the living skin of tattooed people. According to the literature such regular tattoos hold up to 9 mg pigment/cm2 skin. PMID:26243473

Formation of highly toxic hydrogen cyanide upon ruby laser irradiation of the tattoo pigment phthalocyanine blue

NASA Astrophysics Data System (ADS)

Schreiver, Ines; Hutzler, Christoph; Laux, Peter; Berlien, Hans-Peter; Luch, Andreas

2015-08-01

Since laser treatment of tattoos is the favored method for the removing of no longer wanted permanent skin paintings, analytical, biokinetics and toxicological data on the fragmentation pattern of commonly used pigments are urgently required for health safety reasons. Applying dynamic headspace—gas chromatography with mass spectrometric detection (DHS—GC/MS) and comprehensive two-dimensional gas chromatography coupled to time-of-flight mass spectrometry (GCxGC—ToF-MS), we identified 1,2-benzene dicarbonitrile, benzonitrile, benzene, and the poisonous gas hydrogen cyanide (HCN) as main fragmentation products emerging dose-dependently upon ruby laser irradiation of the popular blue pigment copper phthalocyanine in suspension. Skin cell viability was found to be significantly compromised at cyanide levels of ≥1 mM liberated during ruby laser irradiation of >1.5 mg/ml phthalocyanine blue. Further, for the first time we introduce pyrolysis-GC/MS as method suitable to simulate pigment fragmentation that may occur spontaneously or during laser removal of organic pigments in the living skin of tattooed people. According to the literature such regular tattoos hold up to 9 mg pigment/cm2 skin.

Method translation and full metadata transfer from thermal to differential flow modulated comprehensive two dimensional gas chromatography: Profiling of suspected fragrance allergens.

PubMed

Cordero, Chiara; Rubiolo, Patrizia; Reichenbach, Stephen E; Carretta, Andrea; Cobelli, Luigi; Giardina, Matthew; Bicchi, Carlo

2017-01-13

The possibility to transfer methods from thermal to differential-flow modulated comprehensive two-dimensional gas chromatographic (GC×GC) platforms is of high interest to improve GC×GC flexibility and increase the compatibility of results from different platforms. The principles of method translation are here applied to an original method, developed for a loop-type thermal modulated GC×GC-MS/FID system, suitable for quali-quantitative screening of suspected fragrance allergens. The analysis conditions were translated to a reverse-injection differential flow modulated platform (GC×2GC-MS/FID) with a dual-parallel secondary column and dual detection. The experimental results, for a model mixture of suspected volatile allergens and for raw fragrance mixtures of different composition, confirmed the feasibility of translating methods by preserving 1 D elution order, as well as the relative alignment of resulting 2D peak patterns. A correct translation produced several benefits including an effective transfer of metadata (compound names, MS fragmentation pattern, response factors) by automatic template transformation and matching from the original/reference method to its translated counterpart. The correct translation provided: (a) 2D pattern repeatability, (b) MS fragmentation pattern reliability for identity confirmation, and (c) comparable response factors and quantitation accuracy within a concentration range of three orders of magnitude. The adoption of a narrow bore (i.e. 0.1mm d c ) first-dimension column to operate under close-to-optimal conditions with the differential-flow modulation GC×GC platform was also advantageous in halving the total analysis under the translated conditions. Copyright © 2016 Elsevier B.V. All rights reserved.

Characterization of drop aerodynamic fragmentation in the bag and sheet-thinning regimes by crossed-beam, two-view, digital in-line holography

DOE PAGES

Guildenbecher, Daniel R.; Gao, Jian; Chen, Jun; ...

2017-04-19

When a spherical liquid drop is subjected to a step change in relative gas velocity, aerodynamic forces lead to drop deformation and possible breakup into a number of secondary fragments. In order to investigate this flow, a digital in-line holography (DIH) diagnostic is proposed which enables rapid quantification of spatial statistics with limited experimental repetition. To overcome the high uncertainty in the depth direction experienced in previous applications of DIH, a crossed-beam, two-view configuration is introduced. With appropriate calibration, this diagnostic is shown to provide accurate quantification of fragment sizes, three-dimensional positions and three-component velocities in a large measurement volume.more » We apply these capabilities in order to investigate the aerodynamic breakup of drops at two non-dimensional Weber numbers, We, corresponding to the bag (We = 14) and sheet-thinning (We = 55) regimes. Ensemble average results show the evolution of fragment size and velocity statistics during the course of breakup. Our results indicate that mean fragment sizes increase throughout the course of breakup. For the bag breakup case, the evolution of a multi-mode fragment size probability density is observed. This is attributed to separate fragmentation mechanisms for the bag and rim structures. In contrast, for the sheet-thinning case, the fragment size probability density shows only one distinct peak indicating a single fragmentation mechanism. Compared to previous related investigations of this flow, many orders of magnitude more fragments are measured per condition, resulting in a significant improvement in data fidelity. For this reason, this experimental dataset is likely to provide new opportunities for detailed validation of analytic and computational models of this flow.« less

Adipose tissue-organotypic culture system as a promising model for studying adipose tissue biology and regeneration

PubMed Central

Uchihashi, Kazuyoshi; Aoki, Shigehisa; Sonoda, Emiko; Yamasaki, Fumio; Piao, Meihua; Ootani, Akifumi; Yonemitsu, Nobuhisa; Sugihara, Hajime

2009-01-01

Adipose tissue consists of mature adipocytes, preadipocytes and mesenchymal stem cells (MSCs), but a culture system for analyzing their cell types within the tissue has not been established. We have recently developed “adipose tissue-organotypic culture system” that maintains unilocular structure, proliferative ability and functions of mature adipocytes for a long term, using three-dimensional collagen gel culture of the tissue fragments. In this system, both preadipocytes and MSCs regenerate actively at the peripheral zone of the fragments. Our method will open up a new way for studying both multiple cell types within adipose tissue and the cell-based mechanisms of obesity and metabolic syndrome. Thus, it seems to be a promising model for investigating adipose tissue biology and regeneration. In this article, we introduce adipose tissue-organotypic culture, and propose two theories regarding the mechanism of tissue regeneration that occurs specifically at peripheral zone of tissue fragments in vitro. PMID:19794899

Fourier optics of constant-thickness three-dimensional objects on the basis of diffraction models

NASA Astrophysics Data System (ADS)

Chugui, Yu. V.

2017-09-01

Results of investigations of diffraction phenomena on constant-thickness three-dimensional objects with flat inner surfaces (thick plates) are summarized on the basis of our constructive theory of their calculation as applied to dimensional inspection. It is based on diffraction models of 3D objects with the use of equivalent diaphragms (distributions), which allow the Kirchhoff-Fresnel approximation to be effectively used. In contrast to available rigorous and approximate methods, the present approach does not require cumbersome calculations; it is a clearly arranged method, which ensures sufficient accuracy for engineering applications. It is found that the fundamental diffraction parameter for 3D objects of constant thickness d is the critical diffraction angle {θ _{cr}} = √ {λ /d} at which the effect of three-dimensionality on the spectrum of the 3D object becomes appreciable. Calculated Fraunhofer diffraction patterns (spectra) and images of constant-thickness 3D objects with absolutely absorbing, absolutely reflecting, and gray internal faces are presented. It is demonstrated that selection of 3D object fragments can be performed by choosing an appropriate configuration of the wave illuminating the object (plane normal or inclined waves, spherical waves).

Modeling of biologically motivated self-learning equivalent-convolutional recurrent-multilayer neural structures (BLM_SL_EC_RMNS) for image fragments clustering and recognition

NASA Astrophysics Data System (ADS)

Krasilenko, Vladimir G.; Lazarev, Alexander A.; Nikitovich, Diana V.

2018-03-01

The biologically-motivated self-learning equivalence-convolutional recurrent-multilayer neural structures (BLM_SL_EC_RMNS) for fragments images clustering and recognition will be discussed. We shall consider these neural structures and their spatial-invariant equivalental models (SIEMs) based on proposed equivalent two-dimensional functions of image similarity and the corresponding matrix-matrix (or tensor) procedures using as basic operations of continuous logic and nonlinear processing. These SIEMs can simply describe the signals processing during the all training and recognition stages and they are suitable for unipolar-coding multilevel signals. The clustering efficiency in such models and their implementation depends on the discriminant properties of neural elements of hidden layers. Therefore, the main models and architecture parameters and characteristics depends on the applied types of non-linear processing and function used for image comparison or for adaptive-equivalent weighing of input patterns. We show that these SL_EC_RMNSs have several advantages, such as the self-study and self-identification of features and signs of the similarity of fragments, ability to clustering and recognize of image fragments with best efficiency and strong mutual correlation. The proposed combined with learning-recognition clustering method of fragments with regard to their structural features is suitable not only for binary, but also color images and combines self-learning and the formation of weight clustered matrix-patterns. Its model is constructed and designed on the basis of recursively continuous logic and nonlinear processing algorithms and to k-average method or method the winner takes all (WTA). The experimental results confirmed that fragments with a large numbers of elements may be clustered. For the first time the possibility of generalization of these models for space invariant case is shown. The experiment for an images of different dimensions (a reference array) and fragments with diferent dimensions for clustering is carried out. The experiments, using the software environment Mathcad showed that the proposed method is universal, has a significant convergence, the small number of iterations is easily, displayed on the matrix structure, and confirmed its prospects. Thus, to understand the mechanisms of self-learning equivalence-convolutional clustering, accompanying her to the competitive processes in neurons, and the neural auto-encoding-decoding and recognition principles with the use of self-learning cluster patterns is very important which used the algorithm and the principles of non-linear processing of two-dimensional spatial functions of images comparison. The experimental results show that such models can be successfully used for auto- and hetero-associative recognition. Also they can be used to explain some mechanisms, known as "the reinforcementinhibition concept". Also we demonstrate a real model experiments, which confirm that the nonlinear processing by equivalent function allow to determine the neuron-winners and customize the weight matrix. At the end of the report, we will show how to use the obtained results and to propose new more efficient hardware architecture of SL_EC_RMNS based on matrix-tensor multipliers. Also we estimate the parameters and performance of such architectures.

Modeling and experimental examination of water level effects on radon exhalation from fragmented uranium ore.

PubMed

Ye, Yong-Jun; Dai, Xin-Tao; Ding, De-Xin; Zhao, Ya-Li

2016-12-01

In this study, a one-dimensional steady-state mathematical model of radon transport in fragmented uranium ore was established according to Fick's law and radon transfer theory in an air-water interface. The model was utilized to obtain an analytical solution for radon concentration in the air-water, two-phase system under steady state conditions, as well as a corresponding radon exhalation rate calculation formula. We also designed a one-dimensional experimental apparatus for simulating radon diffusion migration in the uranium ore with various water levels to verify the mathematical model. The predicted results were in close agreement with the measured results, suggesting that the proposed model can be readily used to determine radon concentrations and exhalation rates in fragmented uranium ore with varying water levels. Copyright © 2016. Published by Elsevier Ltd.

Life Origination Hydrate Theory (LOH-Theory) and Mitosis and Replication Hydrate Theory (MRH-Theory): three-dimensional PC validation

NASA Astrophysics Data System (ADS)

Kadyshevich, E. A.; Dzyabchenko, A. V.; Ostrovskii, V. E.

2014-04-01

Size compatibility of the CH4-hydrate structure II and multi-component DNA fragments is confirmed by three-dimensional simulation; it is validation of the Life Origination Hydrate Theory (LOH-Theory).

Evidence for the proteolytic processing of dentin matrix protein 1. Identification and characterization of processed fragments and cleavage sites.

PubMed

Qin, Chunlin; Brunn, Jan C; Cook, Richard G; Orkiszewski, Ralph S; Malone, James P; Veis, Arthur; Butler, William T

2003-09-05

Full-length cDNA coding for dentin matrix protein 1 (DMP1) has been cloned and sequenced, but the corresponding complete protein has not been isolated. In searching for naturally occurring DMP1, we recently discovered that the extracellular matrix of bone contains fragments originating from DMP1. Shortened forms of DMP1, termed 37K and 57K fragments, were treated with alkaline phosphatase and then digested with trypsin. The resultant peptides were purified by a two-dimensional method: size exclusion followed by reversed-phase high performance liquid chromatography. Purified peptides were sequenced by Edman degradation and mass spectrometry, and the sequences compared with the DMP1 sequence predicted from cDNA. Extensive sequencing of tryptic peptides revealed that the 37K fragments originated from the NH2-terminal region, and the 57K fragments were from the COOH-terminal part of DMP1. Phosphate analysis indicated that the 37K fragments contained 12 phosphates, and the 57K fragments had 41. From 37K fragments, two peptides lacked a COOH-terminal lysine or arginine; instead they ended at Phe173 and Ser180 and were thus COOH termini of 37K fragments. Two peptides were from the NH2 termini of 57K fragments, starting at Asp218 and Asp222. These findings indicated that DMP1 is proteolytically cleaved at four bonds, Phe173-Asp174, Ser180-Asp181, Ser217-Asp218, and Gln221-Asp222, forming eight fragments. The uniformity of cleavages at the NH2-terminal peptide bonds of aspartyl residues suggests that a single proteinase is involved. Based on its reported specificity, we hypothesize that these scissions are catalyzed by PHEX protein. We envision that the proteolytic processing of DMP1 plays a crucial role during osteogenesis and dentinogenesis.

Toward a virtual reconstruction of an antique three-dimensional marble puzzle

NASA Astrophysics Data System (ADS)

Benamar, Fatima Zahra; Fauvet, Eric; Hostein, Antony; Laligant, Olivier; Truchetet, Frederic

2017-01-01

The reconstruction of broken objects is an important field of research for many applications, such as art restoration, surgery, forensics, and solving puzzles. In archaeology, the reconstruction of broken artifacts is a very time-consuming task due to the handling of fractured objects, which are generally fragile. However, it can now be supported by three-dimensional (3-D) data acquisition devices and computer processing. Those techniques are very useful in this domain because they allow the remote handling of very accurate models of fragile parts, they permit the extensive testing of reconstruction solutions, and they provide access to the parts for the entire research community. An interesting problem has recently been proposed by archaeologists in the form of a huge puzzle composed of a thousand fragments of Pentelic marble of different sizes found in Autun (France), and all attempts to reconstruct the puzzle during the last two centuries have failed. Archaeologists are sure that some fragments are missing and that some of the ones we have come from different slabs. We propose an inexpensive transportable system for 3-D acquisition setup and a 3-D reconstruction method that is applied to this Roman inscription but is also relevant to other applications.

Three-dimensional structure of phosphoribosyl pyrophosphate synthetase from E. coli at 2.71 Å resolution

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

Timofeev, V. I., E-mail: inna@ns.crys.ras.ru, E-mail: tostars@mail.ru, E-mail: ugama@yandex.ru; Abramchik, Yu. A.; Zhukhlistova, N. E.

2016-01-15

Phosphoribosyl pyrophosphate synthetase from Escherichia coli was cloned, purified, and crystallized. Single crystals of the enzyme were grown under microgravity. The X-ray diffraction data set was collected at the Spring-8 synchrotron facility and used to determine the three-dimensional structure of the enzyme by the molecular-replacement method at 2.71 Å resolution. The active and regulatory sites in the molecule of E. coli phosphoribosyl pyrophosphate synthetase were revealed by comparison with the homologous protein from Bacillus subtilis, the structure of which was determined in a complex with functional ligands. The conformations of polypeptide-chain fragments surrounding and composing the active and regulatory sitesmore » were shown to be identical in both proteins.« less

Verification and Validation Plan for Three-Dimensional Probability of Incapacitation Methodology for Masonry Structures (3DPIMMS)

DTIC Science & Technology

2011-01-01

all panels of a test were recorded, it was reduced into text format and then input into the code. B. Current Development The capabilities...due to fragmentation. Any or all of these models can be activated for a particular lethality assessment. Incapacitation criteria of different times...defined for all fragments represented in the file. Only the fragment material density needs to be set by the user. 3DPIMMS accounts for some statistical

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

Niemi, Merja, E-mail: merja.niemi@joensuu.fi; Jänis, Janne; Jylhä, Sirpa

The high-resolution mass-spectrometric characterization, crystallization and X-ray diffraction studies of a recombinant IgE Fab fragment in complex with bovine β-lactoglobulin are reported. A D1 Fab fragment containing the allergen-binding variable domains of the IgE antibody was characterized by ESI FT–ICR mass spectrometry and crystallized with bovine β-lactoglobulin (BLG) using the hanging-drop vapour-diffusion method at 293 K. X-ray data suitable for structure determination were collected to 2.8 Å resolution using synchrotron radiation. The crystal belonged to the orthorhombic space group P2{sub 1}2{sub 1}2{sub 1}, with unit-cell parameters a = 67.0, b = 100.6, c = 168.1 Å. The three-dimensional structure ofmore » the D1 Fab fragment–BLG complex will provide the first insight into IgE antibody–allergen interactions at the molecular level.« less

Structural Refinement of Proteins by Restrained Molecular Dynamics Simulations with Non-interacting Molecular Fragments.

PubMed

Shen, Rong; Han, Wei; Fiorin, Giacomo; Islam, Shahidul M; Schulten, Klaus; Roux, Benoît

2015-10-01

The knowledge of multiple conformational states is a prerequisite to understand the function of membrane transport proteins. Unfortunately, the determination of detailed atomic structures for all these functionally important conformational states with conventional high-resolution approaches is often difficult and unsuccessful. In some cases, biophysical and biochemical approaches can provide important complementary structural information that can be exploited with the help of advanced computational methods to derive structural models of specific conformational states. In particular, functional and spectroscopic measurements in combination with site-directed mutations constitute one important source of information to obtain these mixed-resolution structural models. A very common problem with this strategy, however, is the difficulty to simultaneously integrate all the information from multiple independent experiments involving different mutations or chemical labels to derive a unique structural model consistent with the data. To resolve this issue, a novel restrained molecular dynamics structural refinement method is developed to simultaneously incorporate multiple experimentally determined constraints (e.g., engineered metal bridges or spin-labels), each treated as an individual molecular fragment with all atomic details. The internal structure of each of the molecular fragments is treated realistically, while there is no interaction between different molecular fragments to avoid unphysical steric clashes. The information from all the molecular fragments is exploited simultaneously to constrain the backbone to refine a three-dimensional model of the conformational state of the protein. The method is illustrated by refining the structure of the voltage-sensing domain (VSD) of the Kv1.2 potassium channel in the resting state and by exploring the distance histograms between spin-labels attached to T4 lysozyme. The resulting VSD structures are in good agreement with the consensus model of the resting state VSD and the spin-spin distance histograms from ESR/DEER experiments on T4 lysozyme are accurately reproduced.

Lessons from hot spot analysis for fragment-based drug discovery

PubMed Central

Hall, David R.; Vajda, Sandor

2015-01-01

Analysis of binding energy hot spots at protein surfaces can provide crucial insights into the prospects for successful application of fragment-based drug discovery (FBDD), and whether a fragment hit can be advanced into a high affinity, druglike ligand. The key factor is the strength of the top ranking hot spot, and how well a given fragment complements it. We show that published data are sufficient to provide a sophisticated and quantitative understanding of how hot spots derive from protein three-dimensional structure, and how their strength, number and spatial arrangement govern the potential for a surface site to bind to fragment-sized and larger ligands. This improved understanding provides important guidance for the effective application of FBDD in drug discovery. PMID:26538314

Renormalization of the fragmentation equation: exact self-similar solutions and turbulent cascades.

PubMed

Saveliev, V L; Gorokhovski, M A

2012-12-01

Using an approach developed earlier for renormalization of the Boltzmann collision integral [Saveliev and Nanbu, Phys. Rev. E 65, 051205 (2002)], we derive an exact divergence form for the fragmentation operator. Then we reduce the fragmentation equation to the continuity equation in size space, with the flux given explicitly. This allows us to obtain self-similar solutions and to find the integral of motion for these solutions (we call it the bare flux). We show how these solutions can be applied as a description of cascade processes in three- and two-dimensional turbulence. We also suggested an empirical cascade model of impact fragmentation of brittle materials.

Minimization of three-dimensional beam emittance growth in rare-isotope accelerator

NASA Astrophysics Data System (ADS)

Oh, B. H.; Yoon, M.

2016-12-01

In this paper, we describe a research to minimize the three-dimensional (3D) emittance growth (EG) in the RAON accelerator, a heavy ion accelerator currently being developed in Korea to produce various rare isotopes. The emittance minimization is performed using the multi-objective genetic algorithm and the simplex method. We use them to analyze the driver linac for the in-flight fragmentation separator of the RAON facility and show that redesign of the 90-degree bending section of the RAON accelerator together with adjustment of optics in the upstream and downstream superconducting linacs can limit the 3D EG to 20 % in the entire region of the driver linac. Effects of various magnet and rf accelerating cavity errors on the beam-EG are also discussed.

Enhancing the intense field control of molecular fragmentation.

PubMed

Anis, Fatima; Esry, B D

2012-09-28

We describe a pump-probe scheme with which the spatial asymmetry of dissociating molecular fragments-as controlled by the carrier-envelope phase of an intense few-cycle laser pulse-can be enhanced by an order of magnitude or more. We illustrate the scheme using extensive, full-dimensional calculations for dissociation of H(2)(+) and include the averaging necessary for comparison with experiment.

Neon-20 depth-dose relations in water

NASA Technical Reports Server (NTRS)

Wilson, J. W.; Townsend, L. W.; Bidasaria, H. B.; Schimmerling, W.; Wong, M.; Howard, J.

1984-01-01

The dose from heavy ion beams has been calculated using a one-dimensional transport theory and evaluated for 670 MeV/amu 20 Ne beams in water. The result is presented so as to be applicable to arbitrary ions for which the necessary interaction data are known. The present evaluation is based on thar Silberg-Tsao fragmentation parameters augmented with light fragment production from intranuclear cascades, recently calculated nuclear absorption cross sections, and evaluated stopping power data. Comparison with recent experimental data obtained at the Lawrence Berkeley Laboratory reveals the need for more accurate fragmentation data.

Neon-20 depth-dose relations in water

NASA Astrophysics Data System (ADS)

Wilson, J. W.; Townsend, L. W.; Bidasaria, H. B.; Schimmerling, W.; Wong, M.; Howard, J.

1984-05-01

The dose from heavy ion beams has been calculated using a one-dimensional transport theory and evaluated for 670 MeV/amu 20 Ne beams in water. The result is presented so as to be applicable to arbitrary ions for which the necessary interaction data are known. The present evaluation is based on thar Silberg-Tsao fragmentation parameters augmented with light fragment production from intranuclear cascades, recently calculated nuclear absorption cross sections, and evaluated stopping power data. Comparison with recent experimental data obtained at the Lawrence Berkeley Laboratory reveals the need for more accurate fragmentation data.

Two-Tailed Comet Assay (2T-Comet): Simultaneous Detection of DNA Single and Double Strand Breaks.

PubMed

Cortés-Gutiérrez, Elva I; Fernández, José Luis; Dávila-Rodríguez, Martha I; López-Fernández, Carmen; Gosálvez, Jaime

2017-01-01

A modification of the original comet assay was developed for the simultaneous evaluation of DNA single strand breaks (SSBs) and double strand breaks (DSBs) in human spermatozoa. The two-dimensional perpendicular tail comet assay (2T-comet) combines non-denaturing and denaturant conditions to the same sperm nucleoid. In this case, the species-specific deproteinized sperm is first subjected to an electrophoretic field under non-denaturing conditions to mobilize isolated free discrete DNA fragments produced from DSBs; this is then followed by a second electrophoresis running perpendicular to the first one but under alkaline conditions to produce DNA denaturation, exposing SSBs on the same linear DNA chain or DNA fragments flanked by DSBs. This procedure results in a two dimensional comet tail emerging from the core where two types of original DNA affected molecule can be simultaneously discriminated. The 2T-comet is a fast, sensitive, and reliable procedure to distinguish between single and double strand DNA damage within the same cell. It is an innovative method for assessing sperm DNA integrity, which has important implications for human fertility and andrological pathology. This technique may be adapted to assess different DNA break types in other species and other cell types.

Comparison Simulations of Gas Giant Planet Formation via Disk Instability

NASA Astrophysics Data System (ADS)

Pickett, Megan K.; Cai, K.; Durisen, R.; Milne, M.

2011-01-01

There has been disagreement about whether cooling in protoplanetary disks can be sufficiently fast to induce the formation of gas giant protoplanets via gravitational instabilities. Simulations by our own group and others indicate that this method of planet formation does not work for disks around young, low-mass stars inside several tens of AU, while simulations by other groups show fragmentation into protoplanetary clumps in this region. To allow direct comparison in hopes of isolating the cause of the differences, we here present a comparison high-resolution three-dimensional hydrodynamics simulation of a protoplanetary disk,using an improved version of one of our own radiative schemes. We find that the disk does not fragment in our code but instead quickly settles into a state with only low amplitude nonaxisymmetric structure, which persists for at least several outer disk rotations. Further, we see no rapid radiative or convective cooling.

Fragment-Based Screening of a Natural Product Library against 62 Potential Malaria Drug Targets Employing Native Mass Spectrometry

PubMed Central

2018-01-01

Natural products are well known for their biological relevance, high degree of three-dimensionality, and access to areas of largely unexplored chemical space. To shape our understanding of the interaction between natural products and protein targets in the postgenomic era, we have used native mass spectrometry to investigate 62 potential protein targets for malaria using a natural-product-based fragment library. We reveal here 96 low-molecular-weight natural products identified as binding partners of 32 of the putative malarial targets. Seventy-nine (79) fragments have direct growth inhibition on Plasmodium falciparum at concentrations that are promising for the development of fragment hits against these protein targets. This adds a fragment library to the published HTS active libraries in the public domain. PMID:29436819

Fragment-Based Screening of a Natural Product Library against 62 Potential Malaria Drug Targets Employing Native Mass Spectrometry.

PubMed

Vu, Hoan; Pedro, Liliana; Mak, Tin; McCormick, Brendan; Rowley, Jessica; Liu, Miaomiao; Di Capua, Angela; Williams-Noonan, Billy; Pham, Ngoc B; Pouwer, Rebecca; Nguyen, Bao; Andrews, Katherine T; Skinner-Adams, Tina; Kim, Jessica; Hol, Wim G J; Hui, Raymond; Crowther, Gregory J; Van Voorhis, Wesley C; Quinn, Ronald J

2018-04-13

Natural products are well known for their biological relevance, high degree of three-dimensionality, and access to areas of largely unexplored chemical space. To shape our understanding of the interaction between natural products and protein targets in the postgenomic era, we have used native mass spectrometry to investigate 62 potential protein targets for malaria using a natural-product-based fragment library. We reveal here 96 low-molecular-weight natural products identified as binding partners of 32 of the putative malarial targets. Seventy-nine (79) fragments have direct growth inhibition on Plasmodium falciparum at concentrations that are promising for the development of fragment hits against these protein targets. This adds a fragment library to the published HTS active libraries in the public domain.

Crystal structure of an Okazaki fragment at 2-A resolution

NASA Technical Reports Server (NTRS)

Egli, M.; Usman, N.; Zhang, S. G.; Rich, A.

1992-01-01

In DNA replication, Okazaki fragments are formed as double-stranded intermediates during synthesis of the lagging strand. They are composed of the growing DNA strand primed by RNA and the template strand. The DNA oligonucleotide d(GGGTATACGC) and the chimeric RNA-DNA oligonucleotide r(GCG)d(TATACCC) were combined to form a synthetic Okazaki fragment and its three-dimensional structure was determined by x-ray crystallography. The fragment adopts an overall A-type conformation with 11 residues per turn. Although the base-pair geometry, particularly in the central TATA part, is distorted, there is no evidence for a transition from the A- to the B-type conformation at the junction between RNA.DNA hybrid and DNA duplex. The RNA trimer may, therefore, lock the complete fragment in an A-type conformation.

A 2.5-D Representation of the Human Hand

ERIC Educational Resources Information Center

Longo, Matthew R.; Haggard, Patrick

2012-01-01

Primary somatosensory maps in the brain represent the body as a discontinuous, fragmented set of two-dimensional (2-D) skin regions. We nevertheless experience our body as a coherent three-dimensional (3-D) volumetric object. The links between these different aspects of body representation, however, remain poorly understood. Perceiving the body's…

Anisotropy of the angular distribution of fission fragments in heavy-ion fusion-fission reactions: The influence of the level-density parameter and the neck thickness

NASA Astrophysics Data System (ADS)

Naderi, D.; Pahlavani, M. R.; Alavi, S. A.

2013-05-01

Using the Langevin dynamical approach, the neutron multiplicity and the anisotropy of angular distribution of fission fragments in heavy ion fusion-fission reactions were calculated. We applied one- and two-dimensional Langevin equations to study the decay of a hot excited compound nucleus. The influence of the level-density parameter on neutron multiplicity and anisotropy of angular distribution of fission fragments was investigated. We used the level-density parameter based on the liquid drop model with two different values of the Bartel approach and Pomorska approach. Our calculations show that the anisotropy and neutron multiplicity are affected by level-density parameter and neck thickness. The calculations were performed on the 16O+208Pb and 20Ne+209Bi reactions. Obtained results in the case of the two-dimensional Langevin with a level-density parameter based on Bartel and co-workers approach are in better agreement with experimental data.

The COSMIC-DANCE project: Unravelling the origin of the mass function

NASA Astrophysics Data System (ADS)

Bouy, H.; Bertin, E.; Sarro, L. M.; Barrado, D.; Berihuete, A.; Olivares, J.; Moraux, E.; Bouvier, J.; Tamura, M.; Cuillandre, J.-C.; Beletsky, Y.; Wright, N.; Huelamo, N.; Allen, L.; Solano, E.; Brandner, B.

2017-03-01

The COSMIC-DANCE project is an observational program aiming at understanding the origin and evolution of ultracool objects by measuring the mass function and internal dynamics of young nearby associations down to the fragmentation limit. The least massive members of young nearby associations are identified using modern statistical methods in a multi-dimensional space made of optical and infrared luminosities and colors and proper motions. The photometry and astrometry are obtained by combining ground and in some case space based archival observations with new observations, covering between one and two decades.

Renormalization of the fragmentation equation: Exact self-similar solutions and turbulent cascades

NASA Astrophysics Data System (ADS)

Saveliev, V. L.; Gorokhovski, M. A.

2012-12-01

Using an approach developed earlier for renormalization of the Boltzmann collision integral [Saveliev and Nanbu, Phys. Rev. E1539-375510.1103/PhysRevE.65.051205 65, 051205 (2002)], we derive an exact divergence form for the fragmentation operator. Then we reduce the fragmentation equation to the continuity equation in size space, with the flux given explicitly. This allows us to obtain self-similar solutions and to find the integral of motion for these solutions (we call it the bare flux). We show how these solutions can be applied as a description of cascade processes in three- and two-dimensional turbulence. We also suggested an empirical cascade model of impact fragmentation of brittle materials.

A statistical model of aggregate fragmentation

NASA Astrophysics Data System (ADS)

Spahn, F.; Vieira Neto, E.; Guimarães, A. H. F.; Gorban, A. N.; Brilliantov, N. V.

2014-01-01

A statistical model of fragmentation of aggregates is proposed, based on the stochastic propagation of cracks through the body. The propagation rules are formulated on a lattice and mimic two important features of the process—a crack moves against the stress gradient while dissipating energy during its growth. We perform numerical simulations of the model for two-dimensional lattice and reveal that the mass distribution for small- and intermediate-size fragments obeys a power law, F(m)∝m-3/2, in agreement with experimental observations. We develop an analytical theory which explains the detected power law and demonstrate that the overall fragment mass distribution in our model agrees qualitatively with that one observed in experiments.

Measurement of cell death by oxidative stress in three-dimensional spheroids from trophoblast and in fragments of decidua tissue.

PubMed

Theuerkauf, Regine-Susanne; Ahammer, Helmut; Siwetz, Monika; Helige, Christine; Dohr, Gottfried; Walcher, Wolfgang; Palacio, José Ramón; Martinez, Paz; Sedlmayr, Peter

2010-05-01

We report a new morphometric method for measurement of the amount of cell death in three-dimensional multicellular spheroids of the trophoblast-like cell line AC1-M59 and of cultured pieces of decidua tissue (decidua spheroids) in response to a cytotoxic agent. The viability of the spheroids was assessed by adding propidium iodide to the culture medium at the end of the toxic treatment. On fluorescence and brightfield images of serial cryosections the areas of propidium iodide fluorescence and the entire corresponding spheroids were measured by applying digital image processing and ratiometrical quantification. As an example, we evaluated the cytotoxic effect of hydrogen peroxide on both types of spheroids. The relative potency of hydrogen peroxide to induce tissue damage was assessed quantitatively for determination of the minimal concentration that leads to an increase in cytotoxicity. The method presented suggests general applicability for in vitro determination of toxicity against tissues. Copyright (c) 2010 Elsevier Ireland Ltd. All rights reserved.

Recognition and characterization of hierarchical interstellar structure. II - Structure tree statistics

NASA Technical Reports Server (NTRS)

Houlahan, Padraig; Scalo, John

1992-01-01

A new method of image analysis is described, in which images partitioned into 'clouds' are represented by simplified skeleton images, called structure trees, that preserve the spatial relations of the component clouds while disregarding information concerning their sizes and shapes. The method can be used to discriminate between images of projected hierarchical (multiply nested) and random three-dimensional simulated collections of clouds constructed on the basis of observed interstellar properties, and even intermediate systems formed by combining random and hierarchical simulations. For a given structure type, the method can distinguish between different subclasses of models with different parameters and reliably estimate their hierarchical parameters: average number of children per parent, scale reduction factor per level of hierarchy, density contrast, and number of resolved levels. An application to a column density image of the Taurus complex constructed from IRAS data is given. Moderately strong evidence for a hierarchical structural component is found, and parameters of the hierarchy, as well as the average volume filling factor and mass efficiency of fragmentation per level of hierarchy, are estimated. The existence of nested structure contradicts models in which large molecular clouds are supposed to fragment, in a single stage, into roughly stellar-mass cores.

Comparison and combination of "direct" and fragment based local correlation methods: Cluster in molecules and domain based local pair natural orbital perturbation and coupled cluster theories

NASA Astrophysics Data System (ADS)

Guo, Yang; Becker, Ute; Neese, Frank

2018-03-01

Local correlation theories have been developed in two main flavors: (1) "direct" local correlation methods apply local approximation to the canonical equations and (2) fragment based methods reconstruct the correlation energy from a series of smaller calculations on subsystems. The present work serves two purposes. First, we investigate the relative efficiencies of the two approaches using the domain-based local pair natural orbital (DLPNO) approach as the "direct" method and the cluster in molecule (CIM) approach as the fragment based approach. Both approaches are applied in conjunction with second-order many-body perturbation theory (MP2) as well as coupled-cluster theory with single-, double- and perturbative triple excitations [CCSD(T)]. Second, we have investigated the possible merits of combining the two approaches by performing CIM calculations with DLPNO methods serving as the method of choice for performing the subsystem calculations. Our cluster-in-molecule approach is closely related to but slightly deviates from approaches in the literature since we have avoided real space cutoffs. Moreover, the neglected distant pair correlations in the previous CIM approach are considered approximately. Six very large molecules (503-2380 atoms) were studied. At both MP2 and CCSD(T) levels of theory, the CIM and DLPNO methods show similar efficiency. However, DLPNO methods are more accurate for 3-dimensional systems. While we have found only little incentive for the combination of CIM with DLPNO-MP2, the situation is different for CIM-DLPNO-CCSD(T). This combination is attractive because (1) the better parallelization opportunities offered by CIM; (2) the methodology is less memory intensive than the genuine DLPNO-CCSD(T) method and, hence, allows for large calculations on more modest hardware; and (3) the methodology is applicable and efficient in the frequently met cases, where the largest subsystem calculation is too large for the canonical CCSD(T) method.

Improvement of Simulation Method in Validation of Software of the Coordinate Measuring Systems

NASA Astrophysics Data System (ADS)

Nieciąg, Halina

2015-10-01

Software is used in order to accomplish various tasks at each stage of the functioning of modern measuring systems. Before metrological confirmation of measuring equipment, the system has to be validated. This paper discusses the method for conducting validation studies of a fragment of software to calculate the values of measurands. Due to the number and nature of the variables affecting the coordinate measurement results and the complex character and multi-dimensionality of measurands, the study used the Monte Carlo method of numerical simulation. The article presents an attempt of possible improvement of results obtained by classic Monte Carlo tools. The algorithm LHS (Latin Hypercube Sampling) was implemented as alternative to the simple sampling schema of classic algorithm.

Complex Osteotomies of Tibial Plateau Malunions Using Computer-Assisted Planning and Patient-Specific Surgical Guides.

PubMed

Fürnstahl, Philipp; Vlachopoulos, Lazaros; Schweizer, Andreas; Fucentese, Sandro F; Koch, Peter P

2015-08-01

The accurate reduction of tibial plateau malunions can be challenging without guidance. In this work, we report on a novel technique that combines 3-dimensional computer-assisted planning with patient-specific surgical guides for improving reliability and accuracy of complex intraarticular corrective osteotomies. Preoperative planning based on 3-dimensional bone models was performed to simulate fragment mobilization and reduction in 3 cases. Surgical implementation of the preoperative plan using patient-specific cutting and reduction guides was evaluated; benefits and limitations of the approach were identified and discussed. The preliminary results are encouraging and show that complex, intraarticular corrective osteotomies can be accurately performed with this technique. For selective patients with complex malunions around the tibia plateau, this method might be an attractive option, with the potential to facilitate achieving the most accurate correction possible.

Native State Mass Spectrometry, Surface Plasmon Resonance, and X-ray Crystallography Correlate Strongly as a Fragment Screening Combination.

PubMed

Woods, Lucy A; Dolezal, Olan; Ren, Bin; Ryan, John H; Peat, Thomas S; Poulsen, Sally-Ann

2016-03-10

Fragment-based drug discovery (FBDD) is contingent on the development of analytical methods to identify weak protein-fragment noncovalent interactions. Herein we have combined an underutilized fragment screening method, native state mass spectrometry, together with two proven and popular fragment screening methods, surface plasmon resonance and X-ray crystallography, in a fragment screening campaign against human carbonic anhydrase II (CA II). In an initial fragment screen against a 720-member fragment library (the "CSIRO Fragment Library") seven CA II binding fragments, including a selection of nonclassical CA II binding chemotypes, were identified. A further 70 compounds that comprised the initial hit chemotypes were subsequently sourced from the full CSIRO compound collection and screened. The fragment results were extremely well correlated across the three methods. Our findings demonstrate that there is a tremendous opportunity to apply native state mass spectrometry as a complementary fragment screening method to accelerate drug discovery.

User's guide to computer programs JET 5A and CIVM-JET 5B to calculate the large elastic-plastic dynamically-induced deformations of multilayer partial and/or complete structural rings

NASA Technical Reports Server (NTRS)

Wu, R. W. H.; Stagliano, T. R.; Witmer, E. A.; Spilker, R. L.

1978-01-01

These structural ring deflections lie essentially in one plane and, hence, are called two-dimensional (2-d). The structural rings may be complete or partial; the former may be regarded as representing a fragment containment ring while the latter may be viewed as a 2-d fragment-deflector structure. These two types of rings may be either free or supported in various ways (pinned-fixed, locally clamped, elastic-foundation supported, mounting-bracket supported, etc.). The initial geometry of each ring may be circular or arbitrarily curved; uniform-thickness or variable-thickness rings may be analyzed. Strain-hardening and strain-rate effects of initially-isotropic material are taken into account. An approximate analysis utilizing kinetic energy and momentum conservation relations is used to predict the after-impact velocities of each fragment and of the impact-affected region of the ring; this procedure is termed the collision-imparted velocity method (CIVM) and is used in the CIVM-JET 5 B program. This imparted-velocity information is used in conjunction with a finite-element structural response computation code to predict the transient, large-deflection, elastic-plastic responses of the ring. Similarly, the equations of motion of each fragment are solved in small steps in time. Provisions are made in the CIVM-JET 5B code to analyze structural ring response to impact attack by from 1 to 3 fragments, each with its own size, mass, translational velocity components, and rotational velocity. The effects of friction between each fragment and the impacted ring are included.

Effective one-dimensional images of arterial trees in the cardiovascular system

NASA Astrophysics Data System (ADS)

Kozlov, V. A.; Nazarov, S. A.

2017-03-01

An exponential smallness of the errors in the one-dimensional model of the Stokes flow in a branching thin vessel with rigid walls is achieved by introducing effective lengths of the one-dimensional image of internodal fragments of vessels. Such lengths are eluated through the pressure-drop matrix at each node describing the boundary-layer phenomenon. The medical interpretation and the accessible generalizations of the result, in particular, for the Navier-Stokes equations are presented.

Electron beam enhanced surface modification for making highly resolved structures

DOEpatents

Pitts, John R.

1986-01-01

A method for forming high resolution submicron structures on a substrate is provided by direct writing with a submicron electron beam in a partial pressure of a selected gas phase characterized by the ability to dissociate under the beam into a stable gaseous leaving group and a reactant fragment that combines with the substrate material under beam energy to form at least a surface compound. Variations of the method provide semiconductor device regions on doped silicon substrates, interconnect lines between active sites, three dimensional electronic chip structures, electron beam and optical read mass storage devices that may include color differentiated data areas, and resist areas for use with selective etching techniques.

Electron beam enhanced surface modification for making highly resolved structures

DOEpatents

Pitts, J.R.

1984-10-10

A method for forming high resolution submicron structures on a substrate is provided by direct writing with a submicron electron beam in a partial pressure of a selected gas phase characterized by the ability to dissociate under the beam into a stable gaseous leaving group and a reactant fragment that combines with the substrate material under beam energy to form at least a surface compound. Variations of the method provide semiconductor device regions on doped silicon substrates, interconnect lines between active sites, three dimensional electronic chip structures, electron beam and optical read mass storage devices that may include color differentiated data areas, and resist areas for use with selective etching techniques.

Tungsten fragmentation in nuclear reactions induced by high-energy cosmic-ray protons

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

Chechenin, N. G., E-mail: chechenin@sinp.msu.ru; Chuvilskaya, T. V.; Shirokova, A. A.

2015-01-15

Tungsten fragmentation arising in nuclear reactions induced by cosmic-ray protons in space-vehicle electronics is considered. In modern technologies of integrated circuits featuring a three-dimensional layered architecture, tungsten is frequently used as a material for interlayer conducting connections. Within the preequilibrium model, tungsten-fragmentation features, including the cross sections for the elastic and inelastic scattering of protons of energy between 30 and 240 MeV; the yields of isotopes and isobars; their energy, charge, and mass distributions; and recoil energy spectra, are calculated on the basis of the TALYS and EMPIRE-II-19 codes. It is shown that tungsten fragmentation affects substantially forecasts of failuresmore » of space-vehicle electronics.« less

Number-squeezed and fragmented states of strongly interacting bosons in a double well

NASA Astrophysics Data System (ADS)

Corbo, Joel C.; DuBois, Jonathan L.; Whaley, K. Birgitta

2017-11-01

We present a systematic study of the phenomena of number squeezing and fragmentation for a repulsive Bose-Einstein condensate (BEC) in a three-dimensional double-well potential over a range of interaction strengths and barrier heights, including geometries that exhibit appreciable overlap in the one-body wave functions localized in the left and right wells. We compute the properties of the condensate with numerically exact, full-dimensional path-integral ground-state (PIGS) quantum Monte Carlo simulations and compare with results obtained from using two- and eight-mode truncated basis models. The truncated basis models are found to agree with the numerically exact PIGS simulations for weak interactions, but fail to correctly predict the amount of number squeezing and fragmentation exhibited by the PIGS simulations for strong interactions. We find that both number squeezing and fragmentation of the BEC show nonmonotonic behavior at large values of interaction strength a . The number squeezing shows a universal scaling with the product of number of particles and interaction strength (N a ), but no such universal behavior is found for fragmentation. Detailed analysis shows that the introduction of repulsive interactions not only suppresses number fluctuations to enhance number squeezing, but can also enhance delocalization across wells and tunneling between wells, each of which may suppress number squeezing. This results in a dynamical competition whose resolution shows a complex dependence on all three physical parameters defining the system: interaction strength, number of particles, and barrier height.

Aromaticity of graphene nanoflakes in a new way: fragment analysis by combination of the nucleus-independent chemical shifts and the anisotropy of current induced density.

PubMed

Li, Qing; Li, Chun-Min; Xu, Hong-Liang; Su, Zhong-Min

2017-08-01

A graphene nanoflake (GNF) is a polycyclic aromatic hydrocarbon (PAH) with a huge two-dimensional π-conjugated carbon material in which a central benzene ring is surrounded by identical benzene-type rings through infinite alternant method. In this paper, we explore the structure-aromaticity relationship of the GNFs and the GNFs with hollow sites (GNFHs) by combining the nucleus-independent chemical shifts (NICS) with the anisotropy of the current induced density (ACID). Firstly, the benzene is a typical aromatic molecule (NICS = -9.671 ppm), GNFs 1-6 is darned with benzene and the corresponding GNFHs 1'-6'. Secondly, the NICS values of GNFs 1-6 alternately vary: -1.214 (1) > -13.847 (2) < -2.662 (3) > -14.530 (4) < -3.932 (5) > -13.978 (6) ppm, the GNFs (2, 4, 6) with even fragments of annulene have larger aromaticity than that of GNFs (1, 3, 5) with odd fragments of annulene. Significantly, the NICS values of GNFs 1-6 can also be fragment analyzed by the NICS values and ACID of benzene and corresponding GNFHs 1'-6'. The NICS values for GNFs (2, 4, 6) can be roughly estimated by the NICS value of benzene minus the NICS value of the GNFHs (2', 4', 6'), respectively. The NICS values for GNFs (1, 3, 5) can be roughly estimated by the NICS value of the GNFHs (1', 3', 5') minus the NICS value of benzene, respectively. We hope that the present work can provide a simple and reliable method for the rational design of the GNF with aromaticity, which may be used to understand the origin of the graphene nanoflake aromatic properties.

Fast Biological Modeling for Voxel-based Heavy Ion Treatment Planning Using the Mechanistic Repair-Misrepair-Fixation Model and Nuclear Fragment Spectra

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

Kamp, Florian; Department of Radiation Oncology, Technische Universität München, Klinikum Rechts der Isar, München; Physik-Department, Technische Universität München, Garching

2015-11-01

Purpose: The physical and biological differences between heavy ions and photons have not been fully exploited and could improve treatment outcomes. In carbon ion therapy, treatment planning must account for physical properties, such as the absorbed dose and nuclear fragmentation, and for differences in the relative biological effectiveness (RBE) of ions compared with photons. We combined the mechanistic repair-misrepair-fixation (RMF) model with Monte Carlo-generated fragmentation spectra for biological optimization of carbon ion treatment plans. Methods and Materials: Relative changes in double-strand break yields and radiosensitivity parameters with particle type and energy were determined using the independently benchmarked Monte Carlo damagemore » simulation and the RMF model to estimate the RBE values for primary carbon ions and secondary fragments. Depth-dependent energy spectra were generated with the Monte Carlo code FLUKA for clinically relevant initial carbon ion energies. The predicted trends in RBE were compared with the published experimental data. Biological optimization for carbon ions was implemented in a 3-dimensional research treatment planning tool. Results: We compared the RBE and RBE-weighted dose (RWD) distributions of different carbon ion treatment scenarios with and without nuclear fragments. The inclusion of fragments in the simulations led to smaller RBE predictions. A validation of RMF against measured cell survival data reported in published studies showed reasonable agreement. We calculated and optimized the RWD distributions on patient data and compared the RMF predictions with those from other biological models. The RBE values in an astrocytoma tumor ranged from 2.2 to 4.9 (mean 2.8) for a RWD of 3 Gy(RBE) assuming (α/β){sub X} = 2 Gy. Conclusions: These studies provide new information to quantify and assess uncertainties in the clinically relevant RBE values for carbon ion therapy based on biophysical mechanisms. We present results from the first biological optimization of carbon ion radiation therapy beams on patient data using a combined RMF and Monte Carlo damage simulation modeling approach. The presented method is advantageous for fast biological optimization.« less

Three dimensional reconstruction of therapeutic carbon ion beams in phantoms using single secondary ion tracks

NASA Astrophysics Data System (ADS)

Reinhart, Anna Merle; Spindeldreier, Claudia Katharina; Jakubek, Jan; Martišíková, Mária

2017-06-01

Carbon ion beam radiotherapy enables a very localised dose deposition. However, even small changes in the patient geometry or positioning errors can significantly distort the dose distribution. A live, non-invasive monitoring system of the beam delivery within the patient is therefore highly desirable, and could improve patient treatment. We present a novel three-dimensional method for imaging the beam in the irradiated object, exploiting the measured tracks of single secondary ions emerging under irradiation. The secondary particle tracks are detected with a TimePix stack—a set of parallel pixelated semiconductor detectors. We developed a three-dimensional reconstruction algorithm based on maximum likelihood expectation maximization. We demonstrate the applicability of the new method in the irradiation of a cylindrical PMMA phantom of human head size with a carbon ion pencil beam of {226} MeV u-1. The beam image in the phantom is reconstructed from a set of nine discrete detector positions between {-80}^\\circ and {50}^\\circ from the beam axis. Furthermore, we demonstrate the potential to visualize inhomogeneities by irradiating a PMMA phantom with an air gap as well as bone and adipose tissue surrogate inserts. We successfully reconstructed a three-dimensional image of the treatment beam in the phantom from single secondary ion tracks. The beam image corresponds well to the beam direction and energy. In addition, cylindrical inhomogeneities with a diameter of {2.85} cm and density differences down to {0.3} g cm-3 to the surrounding material are clearly visualized. This novel three-dimensional method to image a therapeutic carbon ion beam in the irradiated object does not interfere with the treatment and requires knowledge only of single secondary ion tracks. Even with detectors with only a small angular coverage, the three-dimensional reconstruction of the fragmentation points presented in this work was found to be feasible.

Three dimensional reconstruction of therapeutic carbon ion beams in phantoms using single secondary ion tracks.

PubMed

Reinhart, Anna Merle; Spindeldreier, Claudia Katharina; Jakubek, Jan; Martišíková, Mária

2017-06-21

Carbon ion beam radiotherapy enables a very localised dose deposition. However, even small changes in the patient geometry or positioning errors can significantly distort the dose distribution. A live, non-invasive monitoring system of the beam delivery within the patient is therefore highly desirable, and could improve patient treatment. We present a novel three-dimensional method for imaging the beam in the irradiated object, exploiting the measured tracks of single secondary ions emerging under irradiation. The secondary particle tracks are detected with a TimePix stack-a set of parallel pixelated semiconductor detectors. We developed a three-dimensional reconstruction algorithm based on maximum likelihood expectation maximization. We demonstrate the applicability of the new method in the irradiation of a cylindrical PMMA phantom of human head size with a carbon ion pencil beam of [Formula: see text] MeV u -1 . The beam image in the phantom is reconstructed from a set of nine discrete detector positions between [Formula: see text] and [Formula: see text] from the beam axis. Furthermore, we demonstrate the potential to visualize inhomogeneities by irradiating a PMMA phantom with an air gap as well as bone and adipose tissue surrogate inserts. We successfully reconstructed a three-dimensional image of the treatment beam in the phantom from single secondary ion tracks. The beam image corresponds well to the beam direction and energy. In addition, cylindrical inhomogeneities with a diameter of [Formula: see text] cm and density differences down to [Formula: see text] g cm -3 to the surrounding material are clearly visualized. This novel three-dimensional method to image a therapeutic carbon ion beam in the irradiated object does not interfere with the treatment and requires knowledge only of single secondary ion tracks. Even with detectors with only a small angular coverage, the three-dimensional reconstruction of the fragmentation points presented in this work was found to be feasible.

Postfragmentation density function for bacterial aggregates in laminar flow

PubMed Central

Byrne, Erin; Dzul, Steve; Solomon, Michael; Younger, John

2014-01-01

The postfragmentation probability density of daughter flocs is one of the least well-understood aspects of modeling flocculation. We use three-dimensional positional data of Klebsiella pneumoniae bacterial flocs in suspension and the knowledge of hydrodynamic properties of a laminar flow field to construct a probability density function of floc volumes after a fragmentation event. We provide computational results which predict that the primary fragmentation mechanism for large flocs is erosion. The postfragmentation probability density function has a strong dependence on the size of the original floc and indicates that most fragmentation events result in clumps of one to three bacteria eroding from the original floc. We also provide numerical evidence that exhaustive fragmentation yields a limiting density inconsistent with the log-normal density predicted in the literature, most likely due to the heterogeneous nature of K. pneumoniae flocs. To support our conclusions, artificial flocs were generated and display similar postfragmentation density and exhaustive fragmentation. PMID:21599205

Fragmentation Energy-Saving Theory of Full Face Rock Tunnel Boring Machine Disc Cutters

NASA Astrophysics Data System (ADS)

Zhang, Zhao-Huang; Gong, Guo-Fang; Gao, Qing-Feng; Sun, Fei

2017-07-01

Attempts to minimize energy consumption of a tunnel boring machine disc cutter during the process of fragmentation have largely focused on optimizing disc-cutter spacing, as determined by the minimum specific energy required for fragmentation; however, indentation tests showed that rock deforms plastically beneath the cutters. Equations for thrust were developed for both the traditional, popularly employed disc cutter and anew design based on three-dimensional theory. The respective energy consumption for penetration, rolling, and side-slip fragmentations were obtained. A change in disc-cutter fragmentation angles resulted in a change in the nature of the interaction between the cutter and rock, which lowered the specific energy of fragmentation. During actual field excavations to the same penetration length, the combined energy consumption for fragmentation using the newly designed cutters was 15% lower than that when using the traditional design. This paper presents a theory for energy saving in tunnel boring machines. Investigation results showed that the disc cutters designed using this theory were more durable than traditional designs, and effectively lowered the energy consumption.

Characterization of Hypervelocity Metal Fragments for Explosive Initiation

NASA Astrophysics Data System (ADS)

Yeager, John; Bowden, Patrick; Guildenbecher, Daniel; Olles, Joseph

2017-06-01

The off-normal detonation behavior of two plastic-bonded explosive (PBX) formulations was studied using explosively-driven aluminum fragments moving at hypersonic velocity. Witness plate materials, including copper and polycarbonate, were used to characterize the distribution of particles, finding that the aluminum did not fragment homogeneously but rather with larger particles in a ring surrounding finer particles. Digital holography experiments were conducted to measure three-dimensional shape and size of the fastest-moving fragments, which ranged between 100 and 700 microns and traveled between 2 and 3.5 km/s. Crucially, these experiments showed variability in the fragmentation in terms of the number of fragments at the leading edge of the fragment field, indicating that both single and multiple shock impacts could be imparted to the target material. Lower density PBX 9407 (RDX-based) was initiable at up to 4.5 inches, while higher density PBX 9501 (HMX-based) was only initiable at up to 0.25 inches. This type of data is critical for safety experiments and hydrocode simulations to quantify shock-to-detonation transition mechanisms and the associated risk-margins for these materials.

Analysis of dose heterogeneity using a subvolume-DVH

NASA Astrophysics Data System (ADS)

Said, M.; Nilsson, P.; Ceberg, C.

2017-11-01

The dose-volume histogram (DVH) is universally used in radiation therapy for its highly efficient way of summarizing three-dimensional dose distributions. An apparent limitation that is inherent to standard histograms is the loss of spatial information, e.g. it is no longer possible to tell where low- and high-dose regions are, and whether they are connected or disjoint. Two methods for overcoming the spatial fragmentation of low- and high-dose regions are presented, both based on the gray-level size zone matrix, which is a two-dimensional histogram describing the frequencies of connected regions of similar intensities. The first approach is a quantitative metric which can be likened to a homogeneity index. The large cold spot metric (LCS) is here defined to emphasize large contiguous regions receiving too low a dose; emphasis is put on both size, and deviation from the prescribed dose. In contrast, the subvolume-DVH (sDVH) is an extension to the standard DVH and allows for a qualitative evaluation of the degree of dose heterogeneity. The information retained from the two-dimensional histogram is overlaid on top of the DVH and the two are presented simultaneously. Both methods gauge the underlying heterogeneity in ways that the DVH alone cannot, and both have their own merits—the sDVH being more intuitive and the LCS being quantitative.

Numerical modeling of interaction of the aircraft engine with concrete protective structures

NASA Astrophysics Data System (ADS)

Radchenko, P. A.; Batuev, S. P.; Radchenko, A. V.; Plevkov, V. S.

2018-01-01

The paper presents numerical modeling results considering interaction of Boeing 747 aircraft engine with nuclear power station protective shell. Protective shell has been given as a reinforced concrete structure with complex scheme of reinforcement. The engine has been simulated by cylinder projectile made from titanium alloy. The interaction velocity has comprised 180 m/s. The simulation is three-dimensional solved by finite element method using the author’s own software package EFES. Fracture and fragmentation of materials have been considered in calculations. Program software has been assessed to be used in calculation of multiple-contact objectives.

Pseudodeep hologram and its properties

NASA Astrophysics Data System (ADS)

Denisiuk, Iu. N.; Ganzherli, N. M.

A pseudodeep hologram is a thin, inclined hologram on which a one-dimensional line object is recorded by a sagittal beam system; at reconstruction, the object is read within the limits of the narrow line which corresponds to it. High angular and spectral selectivities have been obtained by these means. Attention is presently given to the possibility of recording and associative reading, in view of results from experiments in which the associative reading of a pseudodeep hologram was performed on the bases of fragments of the object in question by a simple graphic-reconstruction method. Components of images caused by the recording medium's nonlinearities are noted.

Fully coupled six-dimensional calculations of the water dimer vibration-rotation-tunneling states with split Wigner pseudospectral approach. II. Improvements and tests of additional potentials

NASA Astrophysics Data System (ADS)

Fellers, R. S.; Braly, L. B.; Saykally, R. J.; Leforestier, C.

1999-04-01

The SWPS method is improved by the addition of H.E.G. contractions for generating a more compact basis. An error in the definition of the internal fragment axis system used in our previous calculation is described and corrected. Fully coupled 6D (rigid monomers) VRT states are computed for several new water dimer potential surfaces and compared with experiment and our earlier SWPS results. This work sets the stage for refinement of such potential surfaces via regression analysis of VRT spectroscopic data.

A numerical fragment basis approach to SCF calculations.

NASA Astrophysics Data System (ADS)

Hinde, Robert J.

1997-11-01

The counterpoise method is often used to correct for basis set superposition error in calculations of the electronic structure of bimolecular systems. One drawback of this approach is the need to specify a ``reference state'' for the system; for reactive systems, the choice of an unambiguous reference state may be difficult. An example is the reaction F^- + HCl arrow HF + Cl^-. Two obvious reference states for this reaction are F^- + HCl and HF + Cl^-; however, different counterpoise-corrected interaction energies are obtained using these two reference states. We outline a method for performing SCF calculations which employs numerical basis functions; this method attempts to eliminate basis set superposition errors in an a priori fashion. We test the proposed method on two one-dimensional, three-center systems and discuss the possibility of extending our approach to include electron correlation effects.

Fragment-Based, Structure-Enabled Discovery of Novel Pyridones and Pyridone Macrocycles as Potent Bromodomain and Extra-Terminal Domain (BET) Family Bromodomain Inhibitors

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

Wang, Le; Pratt, John K.; Soltwedel, Todd

Members of the BET family of bromodomain containing proteins have been identified as potential targets for blocking proliferation in a variety of cancer cell lines. A two-dimensional NMR fragment screen for binders to the bromodomains of BRD4 identified a phenylpyridazinone fragment with a weak binding affinity (1, Ki = 160 μM). SAR investigation of fragment 1, aided by X-ray structure-based design, enabled the synthesis of potent pyridone and macrocyclic pyridone inhibitors exhibiting single digit nanomolar potency in both biochemical and cell based assays. Advanced analogs in these series exhibited high oral exposures in rodent PK studies and demonstrated significant tumormore » growth inhibition efficacy in mouse flank xenograft models.« less

From Large-scale to Protostellar Disk Fragmentation into Close Binary Stars

NASA Astrophysics Data System (ADS)

Sigalotti, Leonardo Di G.; Cruz, Fidel; Gabbasov, Ruslan; Klapp, Jaime; Ramírez-Velasquez, José

2018-04-01

Recent observations of young stellar systems with the Atacama Large Millimeter/submillimeter Array (ALMA) and the Karl G. Jansky Very Large Array are helping to cement the idea that close companion stars form via fragmentation of a gravitationally unstable disk around a protostar early in the star formation process. As the disk grows in mass, it eventually becomes gravitationally unstable and fragments, forming one or more new protostars in orbit with the first at mean separations of 100 au or even less. Here, we report direct numerical calculations down to scales as small as ∼0.1 au, using a consistent Smoothed Particle Hydrodynamics code, that show the large-scale fragmentation of a cloud core into two protostars accompanied by small-scale fragmentation of their circumstellar disks. Our results demonstrate the two dominant mechanisms of star formation, where the disk forming around a protostar (which in turn results from the large-scale fragmentation of the cloud core) undergoes eccentric (m = 1) fragmentation to produce a close binary. We generate two-dimensional emission maps and simulated ALMA 1.3 mm continuum images of the structure and fragmentation of the disks that can help explain the dynamical processes occurring within collapsing cloud cores.

Analysis of supercritical vapor explosions using thermal detonation wave theory

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

Shamoun, B.I.; Corradini, M.L.

The interaction of certain materials such as Al{sub 2}O{sub 3} with water results in vapor explosions with very high (supercritical) pressures and propagation velocities. A quasi-steady state analysis of supercritical detonation in one-dimensional multiphase flow was applied to analyze experimental data of the KROTOS (26-30) set of experiments conducted at the Joint Research Center at Ispra, Italy. In this work we have applied a new method of solution which allows for partial fragmentation of the fuel in the shock adiabatic thermodynamic model. This method uses known experiment values of the shock pressure and propagation velocity to estimate the initial mixingmore » conditions of the experiment. The fuel and coolant were both considered compressible in this analysis. In KROTOS 26, 28, 29, and 30 the measured values of the shock pressure by the experiment were found to be higher than 25, 50, 100, and 100 Mpa respectively. Using the above data for the wave velocity and our best estimate for the values of the pressure, the predicted minimum values of the fragmented mass of the fuel were found to be 0.026. 0.04, 0.057, and 0.068 kg respectively. The predicted values of the work output corresponding to the above fragmented masses of the fuel were found to be 40, 84, 126, and 150 kJ respectively, with predicted initial void fractions of 112%, 12.5%, 8%, and 6% respectively.« less

Room-temperature ballistic energy transport in molecules with repeating units

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

Rubtsova, Natalia I.; Nyby, Clara M.; Zhang, Hong

2015-06-07

In materials, energy can propagate by means of two limiting regimes: diffusive and ballistic. Ballistic energy transport can be fast and efficient and often occurs with a constant speed. Using two-dimensional infrared spectroscopy methods, we discovered ballistic energy transport via individual polyethylene chains with a remarkably high speed of 1440 m/s and the mean free path length of 14.6 Å in solution at room temperature. Whereas the transport via the chains occurs ballistically, the mechanism switches to diffusive with the effective transport speed of 130 m/s at the end-groups attached to the chains. A unifying model of the transport inmore » molecules is presented with clear time separation and additivity among the transport along oligomeric fragments, which occurs ballistically, and the transport within the disordered fragments, occurring diffusively. The results open new avenues for making novel elements for molecular electronics, including ultrafast energy transporters, controlled chemical reactors, and sub-wavelength quantum nanoseparators.« less

An accurate algorithm for the detection of DNA fragments from dilution pool sequencing experiments.

PubMed

Bansal, Vikas

2018-01-01

The short read lengths of current high-throughput sequencing technologies limit the ability to recover long-range haplotype information. Dilution pool methods for preparing DNA sequencing libraries from high molecular weight DNA fragments enable the recovery of long DNA fragments from short sequence reads. These approaches require computational methods for identifying the DNA fragments using aligned sequence reads and assembling the fragments into long haplotypes. Although a number of computational methods have been developed for haplotype assembly, the problem of identifying DNA fragments from dilution pool sequence data has not received much attention. We formulate the problem of detecting DNA fragments from dilution pool sequencing experiments as a genome segmentation problem and develop an algorithm that uses dynamic programming to optimize a likelihood function derived from a generative model for the sequence reads. This algorithm uses an iterative approach to automatically infer the mean background read depth and the number of fragments in each pool. Using simulated data, we demonstrate that our method, FragmentCut, has 25-30% greater sensitivity compared with an HMM based method for fragment detection and can also detect overlapping fragments. On a whole-genome human fosmid pool dataset, the haplotypes assembled using the fragments identified by FragmentCut had greater N50 length, 16.2% lower switch error rate and 35.8% lower mismatch error rate compared with two existing methods. We further demonstrate the greater accuracy of our method using two additional dilution pool datasets. FragmentCut is available from https://bansal-lab.github.io/software/FragmentCut. vibansal@ucsd.edu. Supplementary data are available at Bioinformatics online. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com

Characterization of Anthocyanins in Perilla frutescens var. acuta Extract by Advanced UPLC-ESI-IT-TOF-MSn Method and Their Anticancer Bioactivity.

PubMed

He, Yan-Kang; Yao, You-Yuan; Chang, Ya-Ning

2015-05-19

The anthocyanin extract from a domestic Perilla cultivar (Perilla frutescens var. acuta) were isolated and characterized with high mass accuracy and multi-dimensional fragmentation by means of ultra-performance liquid chromatography (UPLC) and electrospray ionization-ion trap-time of flight mass spectrometry analysis (ESI-IT-TOF-MSn). The new developed and applied LC-MS method focused on in-depth screening of anthocyanin compounds with similar structures which also provided a new approach of anthocyanin characterization without the use of external standards. Selective detection of interested anthocyanins was achieved utilizing extracted ion chromatogram (EIC) analysis, while MSn spectra were recorded to allow identification of the anthocyanin based on characteristic fragmentation patterns. Seven anthocyanins including one feruloyl (Cyanidin 3-O-feruloylglucoside-5-O-glucoside), two caffeoyl (Cyanidin 3-O-caffeoylglucoside-5-O-glucoside, Cyanidin 3-O-caffeoylglucoside-5-O-malonylglucoside) and four coumaroyl substituted anthocyanins (Cis-shisonin, Malonyl-cis-shisonin, Shisonin, and Malonyl-shisonin) were identified. Annexin-V FITC/PI flow cytometric assay was performed to analyze the influence of anthocyanin extract of P. frutescens var. acuta on cell apoptosis. The results suggested that Perilla anthocyanins can induce Hela cell apoptosis by a dose dependent manner.

Measurement of Satellite Impact Test Fragments for Modeling Orbital Debris

NASA Technical Reports Server (NTRS)

Hill, Nicole M.

2009-01-01

There are over 13,000 pieces of catalogued objects 10cm and larger in orbit around Earth [ODQN, January 2009, p12]. More than 6000 of these objects are fragments from explosions and collisions. As the earth-orbiting object count increases, debris-generating collisions in the future become a statistical inevitability. To aid in understanding this collision risk, the NASA Orbital Debris Program Office has developed computer models that calculate quantity and orbits of debris both currently in orbit and in future epochs. In order to create a reasonable computer model of the orbital debris environment, it is important to understand the mechanics of creation of debris as a result of a collision. The measurement of the physical characteristics of debris resulting from ground-based, hypervelocity impact testing aids in understanding the sizes and shapes of debris produced from potential impacts in orbit. To advance the accuracy of fragment shape/size determination, the NASA Orbital Debris Program Office recently implemented a computerized measurement system. The goal of this system is to improve knowledge and understanding of the relation between commonly used dimensions and overall shape. The technique developed involves scanning a single fragment with a hand-held laser device, measuring its size properties using a sophisticated software tool, and creating a three-dimensional computer model to demonstrate how the object might appear in orbit. This information is used to aid optical techniques in shape determination. This more automated and repeatable method provides higher accuracy in the size and shape determination of debris.

Code C# for chaos analysis of relativistic many-body systems

NASA Astrophysics Data System (ADS)

Grossu, I. V.; Besliu, C.; Jipa, Al.; Bordeianu, C. C.; Felea, D.; Stan, E.; Esanu, T.

2010-08-01

This work presents a new Microsoft Visual C# .NET code library, conceived as a general object oriented solution for chaos analysis of three-dimensional, relativistic many-body systems. In this context, we implemented the Lyapunov exponent and the “fragmentation level” (defined using the graph theory and the Shannon entropy). Inspired by existing studies on billiard nuclear models and clusters of galaxies, we tried to apply the virial theorem for a simplified many-body system composed by nucleons. A possible application of the “virial coefficient” to the stability analysis of chaotic systems is also discussed. Catalogue identifier: AEGH_v1_0 Program summary URL:http://cpc.cs.qub.ac.uk/summaries/AEGH_v1_0.html Program obtainable from: CPC Program Library, Queen's University, Belfast, N. Ireland Licensing provisions: Standard CPC licence, http://cpc.cs.qub.ac.uk/licence/licence.html No. of lines in distributed program, including test data, etc.: 30 053 No. of bytes in distributed program, including test data, etc.: 801 258 Distribution format: tar.gz Programming language: Visual C# .NET 2005 Computer: PC Operating system: .Net Framework 2.0 running on MS Windows Has the code been vectorized or parallelized?: Each many-body system is simulated on a separate execution thread RAM: 128 Megabytes Classification: 6.2, 6.5 External routines: .Net Framework 2.0 Library Nature of problem: Chaos analysis of three-dimensional, relativistic many-body systems. Solution method: Second order Runge-Kutta algorithm for simulating relativistic many-body systems. Object oriented solution, easy to reuse, extend and customize, in any development environment which accepts .Net assemblies or COM components. Implementation of: Lyapunov exponent, “fragmentation level”, “average system radius”, “virial coefficient”, and energy conservation precision test. Additional comments: Easy copy/paste based deployment method. Running time: Quadratic complexity.

Numerical Simulation of Self-gravitational Instability of Isothermal Gaseous Slab Under High External Pressure

NASA Astrophysics Data System (ADS)

Miyaji, S.; Umekawa, M.; Matsumoto, R.; Yoshida, T.

1996-05-01

Gaseous slab is formed with shock waves from super novae, collision of interstellar clouds, etc. When the mass in the Jeans scale is more than Jeans mass, the slab fragments into many clumps by gravitational instability. But in high external pressure environment, even the slab which is stable against Jeans mode can fragment(Elmegreen and Elmegreen 1978).This phenomenon results from incompressible mode instability(Lubow and Pringle 1993). These works are by linear analysis. We study numerically this isothermal gaseous slab which is formed by high external pressure and whose thickness is much smaller than its scale height. We assume self-gravitational fluid, and use two dimensional flux split method. Our model size is taken about the scale of linear maximum growth rate wave length and its five times length, which is an example of much longer than the maximum growth rate wave length. When the incompressible mode instability takes place, it becomes clumps. Each mass of the clumps is less than the Jeans mass. Then the clumps approach each other by gravitational interaction to form bigger clumps. In the presentation we will show results of numerical simulation and discuss about the interaction of fragments on star formation or initial mass function.

Discovery of Clinical Candidate 1-{[(2 S ,3 S ,4 S )-3-Ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide (PF-06650833), a Potent, Selective Inhibitor of Interleukin-1 Receptor Associated Kinase 4 (IRAK4), by Fragment-Based Drug Design

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

Lee, Katherine L.; Ambler, Catherine M.; Anderson, David R.

Through fragment-based drug design focused on engaging the active site of IRAK4 and leveraging three-dimensional topology in a ligand-efficient manner, a micromolar hit identified from a screen of a Pfizer fragment library was optimized to afford IRAK4 inhibitors with nanomolar potency in cellular assays. The medicinal chemistry effort featured the judicious placement of lipophilicity, informed by co-crystal structures with IRAK4 and optimization of ADME properties to deliver clinical candidate PF-06650833 (compound 40). This compound displays a 5-unit increase in lipophilic efficiency from the fragment hit, excellent kinase selectivity, and pharmacokinetic properties suitable for oral administration.

Dynamic aspects of the contractile system in Physarum plasmodium. III. Cyclic contraction-relaxation of the plasmodial fragment in accordance with the generation-degeneration of cytoplasmic actomyosin fibrils

PubMed Central

1987-01-01

Plasmodial fragments of Physarum polycephalum, excised from anterior regions of a thin-spread plasmodium, contracted-relaxed cyclicly with a period of 3-5 min. The area of the fragments decreased approximately 10% during contraction. In most cases, there was little endoplasmic streaming which indicates that contractions were synchronized throughout the fragment. By both polarized light and fluorescence microscopy, the organization and distribution of the cytoplasmic actomyosin fibrils in the fragments changed in synchrony with the contraction cycle. The fibrils formed during the contraction phase, and finally became a highly organized framework consisting of a three- dimensional network of numerous fibrils with many converging points (the nodes). During relaxation, the fibrils degenerated and disappeared almost completely, though some very weak fibrils remained near the nodes and the periphery. The results obtained by fluorometry of the fragments, stained with rhodamine-phalloidin, suggested that the G-F transformation of actin is not the main underlying process of the fibrillar formation. PMID:3611192

Postfragmentation density function for bacterial aggregates in laminar flow.

PubMed

Byrne, Erin; Dzul, Steve; Solomon, Michael; Younger, John; Bortz, David M

2011-04-01

The postfragmentation probability density of daughter flocs is one of the least well-understood aspects of modeling flocculation. We use three-dimensional positional data of Klebsiella pneumoniae bacterial flocs in suspension and the knowledge of hydrodynamic properties of a laminar flow field to construct a probability density function of floc volumes after a fragmentation event. We provide computational results which predict that the primary fragmentation mechanism for large flocs is erosion. The postfragmentation probability density function has a strong dependence on the size of the original floc and indicates that most fragmentation events result in clumps of one to three bacteria eroding from the original floc. We also provide numerical evidence that exhaustive fragmentation yields a limiting density inconsistent with the log-normal density predicted in the literature, most likely due to the heterogeneous nature of K. pneumoniae flocs. To support our conclusions, artificial flocs were generated and display similar postfragmentation density and exhaustive fragmentation. ©2011 American Physical Society

Mechanics of fragmentation of crocodile skin and other thin films.

PubMed

Qin, Zhao; Pugno, Nicola M; Buehler, Markus J

2014-05-27

Fragmentation of thin layers of materials is mediated by a network of cracks on its surface. It is commonly seen in dehydrated paintings or asphalt pavements and even in graphene or other two-dimensional materials, but is also observed in the characteristic polygonal pattern on a crocodile's head. Here, we build a simple mechanical model of a thin film and investigate the generation and development of fragmentation patterns as the material is exposed to various modes of deformation. We find that the characteristic size of fragmentation, defined by the mean diameter of polygons, is strictly governed by mechanical properties of the film material. Our result demonstrates that skin fragmentation on the head of crocodiles is dominated by that it features a small ratio between the fracture energy and Young's modulus, and the patterns agree well with experimental observations. Understanding this mechanics-driven process could be applied to improve the lifetime and reliability of thin film coatings by mimicking crocodile skin.

Mechanics of fragmentation of crocodile skin and other thin films

PubMed Central

Qin, Zhao; Pugno, Nicola M.; Buehler, Markus J.

2014-01-01

Fragmentation of thin layers of materials is mediated by a network of cracks on its surface. It is commonly seen in dehydrated paintings or asphalt pavements and even in graphene or other two-dimensional materials, but is also observed in the characteristic polygonal pattern on a crocodile's head. Here, we build a simple mechanical model of a thin film and investigate the generation and development of fragmentation patterns as the material is exposed to various modes of deformation. We find that the characteristic size of fragmentation, defined by the mean diameter of polygons, is strictly governed by mechanical properties of the film material. Our result demonstrates that skin fragmentation on the head of crocodiles is dominated by that it features a small ratio between the fracture energy and Young's modulus, and the patterns agree well with experimental observations. Understanding this mechanics-driven process could be applied to improve the lifetime and reliability of thin film coatings by mimicking crocodile skin. PMID:24862190

Mechanics of fragmentation of crocodile skin and other thin films

NASA Astrophysics Data System (ADS)

Qin, Zhao; Pugno, Nicola M.; Buehler, Markus J.

2014-05-01

Fragmentation of thin layers of materials is mediated by a network of cracks on its surface. It is commonly seen in dehydrated paintings or asphalt pavements and even in graphene or other two-dimensional materials, but is also observed in the characteristic polygonal pattern on a crocodile's head. Here, we build a simple mechanical model of a thin film and investigate the generation and development of fragmentation patterns as the material is exposed to various modes of deformation. We find that the characteristic size of fragmentation, defined by the mean diameter of polygons, is strictly governed by mechanical properties of the film material. Our result demonstrates that skin fragmentation on the head of crocodiles is dominated by that it features a small ratio between the fracture energy and Young's modulus, and the patterns agree well with experimental observations. Understanding this mechanics-driven process could be applied to improve the lifetime and reliability of thin film coatings by mimicking crocodile skin.

Self-consistent field for fragmented quantum mechanical model of large molecular systems.

PubMed

Jin, Yingdi; Su, Neil Qiang; Xu, Xin; Hu, Hao

2016-01-30

Fragment-based linear scaling quantum chemistry methods are a promising tool for the accurate simulation of chemical and biomolecular systems. Because of the coupled inter-fragment electrostatic interactions, a dual-layer iterative scheme is often employed to compute the fragment electronic structure and the total energy. In the dual-layer scheme, the self-consistent field (SCF) of the electronic structure of a fragment must be solved first, then followed by the updating of the inter-fragment electrostatic interactions. The two steps are sequentially carried out and repeated; as such a significant total number of fragment SCF iterations is required to converge the total energy and becomes the computational bottleneck in many fragment quantum chemistry methods. To reduce the number of fragment SCF iterations and speed up the convergence of the total energy, we develop here a new SCF scheme in which the inter-fragment interactions can be updated concurrently without converging the fragment electronic structure. By constructing the global, block-wise Fock matrix and density matrix, we prove that the commutation between the two global matrices guarantees the commutation of the corresponding matrices in each fragment. Therefore, many highly efficient numerical techniques such as the direct inversion of the iterative subspace method can be employed to converge simultaneously the electronic structure of all fragments, reducing significantly the computational cost. Numerical examples for water clusters of different sizes suggest that the method shall be very useful in improving the scalability of fragment quantum chemistry methods. © 2015 Wiley Periodicals, Inc.

Effect of palladium doping on the stability and fragmentation patterns of cationic gold clusters

NASA Astrophysics Data System (ADS)

Ferrari, P.; Hussein, H. A.; Heard, C. J.; Vanbuel, J.; Johnston, R. L.; Lievens, P.; Janssens, E.

2018-05-01

We analyze in detail how the interplay between electronic structure and cluster geometry determines the stability and the fragmentation channels of single Pd-doped cationic Au clusters, PdA uN-1+ (N =2 -20 ). For this purpose, a combination of photofragmentation experiments and density functional theory calculations was employed. A remarkable agreement between the experiment and the calculations is obtained. Pd doping is found to modify the structure of the Au clusters, in particular altering the two-dimensional to three-dimensional transition size, with direct consequences on the stability of the clusters. Analysis of the electronic density of states of the clusters shows that depending on cluster size, Pd delocalizes one 4 d electron, giving an enhanced stability to PdA u6 + , or remains with all 4 d10 electrons localized, closing an electronic shell in PdA u9 + . Furthermore, it is observed that for most clusters, Au evaporation is the lowest-energy decay channel, although for some sizes Pd evaporation competes. In particular, PdA u7 + and PdA u9 + decay by Pd evaporation due to the high stability of the A u7 + and A u9 + fragmentation products.

Computer-based image analysis of one-dimensional electrophoretic gels used for the separation of DNA restriction fragments.

PubMed Central

Gray, A J; Beecher, D E; Olson, M V

1984-01-01

A stand-alone, interactive computer system has been developed that automates the analysis of ethidium bromide-stained agarose and acrylamide gels on which DNA restriction fragments have been separated by size. High-resolution digital images of the gels are obtained using a camera that contains a one-dimensional, 2048-pixel photodiode array that is mechanically translated through 2048 discrete steps in a direction perpendicular to the gel lanes. An automatic band-detection algorithm is used to establish the positions of the gel bands. A color-video graphics system, on which both the gel image and a variety of operator-controlled overlays are displayed, allows the operator to visualize and interact with critical stages of the analysis. The principal interactive steps involve defining the regions of the image that are to be analyzed and editing the results of the band-detection process. The system produces a machine-readable output file that contains the positions, intensities, and descriptive classifications of all the bands, as well as documentary information about the experiment. This file is normally further processed on a larger computer to obtain fragment-size assignments. Images PMID:6320097

The Fragmented Mitochondrial Ribosomal RNAs of Plasmodium falciparum

PubMed Central

Feagin, Jean E.; Harrell, Maria Isabel; Lee, Jung C.; Coe, Kevin J.; Sands, Bryan H.; Cannone, Jamie J.; Tami, Germaine; Schnare, Murray N.; Gutell, Robin R.

2012-01-01

Background The mitochondrial genome in the human malaria parasite Plasmodium falciparum is most unusual. Over half the genome is composed of the genes for three classic mitochondrial proteins: cytochrome oxidase subunits I and III and apocytochrome b. The remainder encodes numerous small RNAs, ranging in size from 23 to 190 nt. Previous analysis revealed that some of these transcripts have significant sequence identity with highly conserved regions of large and small subunit rRNAs, and can form the expected secondary structures. However, these rRNA fragments are not encoded in linear order; instead, they are intermixed with one another and the protein coding genes, and are coded on both strands of the genome. This unorthodox arrangement hindered the identification of transcripts corresponding to other regions of rRNA that are highly conserved and/or are known to participate directly in protein synthesis. Principal Findings The identification of 14 additional small mitochondrial transcripts from P. falcipaurm and the assignment of 27 small RNAs (12 SSU RNAs totaling 804 nt, 15 LSU RNAs totaling 1233 nt) to specific regions of rRNA are supported by multiple lines of evidence. The regions now represented are highly similar to those of the small but contiguous mitochondrial rRNAs of Caenorhabditis elegans. The P. falciparum rRNA fragments cluster on the interfaces of the two ribosomal subunits in the three-dimensional structure of the ribosome. Significance All of the rRNA fragments are now presumed to have been identified with experimental methods, and nearly all of these have been mapped onto the SSU and LSU rRNAs. Conversely, all regions of the rRNAs that are known to be directly associated with protein synthesis have been identified in the P. falciparum mitochondrial genome and RNA transcripts. The fragmentation of the rRNA in the P. falciparum mitochondrion is the most extreme example of any rRNA fragmentation discovered. PMID:22761677

Impacts of fragmented accretion streams onto classical T Tauri stars: UV and X-ray emission lines

NASA Astrophysics Data System (ADS)

Colombo, S.; Orlando, S.; Peres, G.; Argiroffi, C.; Reale, F.

2016-10-01

Context. The accretion process in classical T Tauri stars (CTTSs) can be studied through the analysis of some UV and X-ray emission lines which trace hot gas flows and act as diagnostics of the post-shock downfalling plasma. In the UV-band, where higher spectral resolution is available, these lines are characterized by rather complex profiles whose origin is still not clear. Aims: We investigate the origin of UV and X-ray emission at impact regions of density structured (fragmented) accretion streams. We study if and how the stream fragmentation and the resulting structure of the post-shock region determine the observed profiles of UV and X-ray emission lines. Methods: We modeled the impact of an accretion stream consisting of a series of dense blobs onto the chromosphere of a CTTS through two-dimensional (2D) magnetohydrodynamic (MHD) simulations. We explored different levels of stream fragmentation and accretion rates. From the model results, we synthesize C IV (1550 Å) and O VIII (18.97 Å) line profiles. Results: The impacts of accreting blobs onto the stellar chromosphere produce reverse shocks propagating through the blobs and shocked upflows. These upflows, in turn, hit and shock the subsequent downfalling fragments. As a result, several plasma components differing for the downfalling velocity, density, and temperature are present altoghether. The profiles of C IV doublet are characterized by two main components: one narrow and redshifted to speed ≈ 50 km s-1 and the other broader and consisting of subcomponents with redshift to speed in the range 200-400 km s-1. The profiles of O VIII lines appear more symmetric than C IV and are redshifted to speed ≈ 150 km s-1. Conclusions: Our model predicts profiles of C IV line remarkably similar to those observed and explains their origin in a natural way as due to stream fragmentation. Movies are available at http://www.aanda.org

Fully coupled six-dimensional calculations of the water dimer vibration-rotation-tunneling states with split Wigner pseudospectral approach. II. Improvements and tests of additional potentials

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

Fellers, R.S.; Braly, L.B.; Saykally, R.J.

The SWPS method is improved by the addition of H.E.G. contractions for generating a more compact basis. An error in the definition of the internal fragment axis system used in our previous calculation is described and corrected. Fully coupled 6D (rigid monomers) VRT states are computed for several new water dimer potential surfaces and compared with experiment and our earlier SWPS results. This work sets the stage for refinement of such potential surfaces via regression analysis of VRT spectroscopic data. {copyright} {ital 1999 American Institute of Physics.}

Juxta-articular Plate Fixation in Distal Radius Intra-articular Fractures with Accompanying Volar Free Fragments beyond the Watershed Line

PubMed Central

Lee, Jun-Ku; Lee, Soo-Hyun; Sim, Young-Suk; Kim, Tae-Ho; Baek, Eugene

2018-01-01

Background Although distal radius fractures (DRF) are common fractures, intra-articular comminuted DRF with volar free fragments are uncommon. There is considerable difficulty in the fixation of free fragments beyond the watershed line using the existing volar locking plate. We aimed to examine the efficacy and potential complications associated with the use of juxta-articular volar plates in intra-articular DRF accompanied by free fragments beyond the watershed line. Methods The patients were enrolled in a consecutive manner between 2007 and 2016. In cases of DRF with free fragments beyond the watershed line, we employed a 2.4-mm small fragment juxta-articular volar locking compression plate using a volar Henry approach. A total of 32 patients were included in this study. There were 15 males and 17 females with a mean age of 52.3 years (range, 33 to 69 years). The mean follow-up period was 14.5 months (range, 10 to 24 months). Preoperative radiographs and three-dimensional computed tomography images were used to analyze fracture patterns and assess the free fragments beyond the watershed line. The mean number of free fracture fragments beyond the watershed line was 2.33. Plain radiographs of immediate postoperative and last follow-up were used to confirm fracture union, incongruence, radial height, volar tilt, radial inclination, and arthritic changes. For functional assessment, we measured grip strength, range of motion (ROM), modified Mayo wrist score (MMWS) and determined Disabilities of Arm, Shoulder and Hand (DASH) scores at the last follow-up. Postoperative complications were monitored during the follow-up period. Results All patients obtained sound union without significant complications. At the last follow-up, 16 cases presented with an articular step-off of more than 1 mm (mean, 1.10 mm). The mean MMWS was 76.3 (range, 55 to 90), mean DASH score was 15.38 (range, 9 to 22), mean visual analogue scale score for pain was 1.2 and mean grip strength was 75.5% of the opposite side. The mean ROM was 74.3° for volar flexion and 71.5° for dorsiflexion. Conclusions In cases of intra-articular DRF with free fragments beyond the watershed line, a volar approach with use of a juxtaarticular plate provided favorable outcomes without significant complications. PMID:29854335

Quantitative computed tomography and cranial burr holes: a model to evaluate the quality of cranial reconstruction in humans.

PubMed

Worm, Paulo Valdeci; Ferreira, Nelson Pires; Ferreira, Marcelo Paglioli; Kraemer, Jorge Luiz; Lenhardt, Rene; Alves, Ronnie Peterson Marcondes; Wunderlich, Ricardo Castilho; Collares, Marcus Vinicius Martins

2012-05-01

Current methods to evaluate the biologic development of bone grafts in human beings do not quantify results accurately. Cranial burr holes are standardized critical bone defects, and the differences between bone powder and bone grafts have been determined in numerous experimental studies. This study evaluated quantitative computed tomography (QCT) as a method to objectively measure cranial bone density after cranial reconstruction with autografts. In each of 8 patients, 2 of 4 surgical burr holes were reconstructed with autogenous wet bone powder collected during skull trephination, and the other 2 holes, with a circular cortical bone fragment removed from the inner table of the cranial bone flap. After 12 months, the reconstructed areas and a sample of normal bone were studied using three-dimensional QCT; bone density was measured in Hounsfield units (HU). Mean (SD) bone density was 1535.89 (141) HU for normal bone (P < 0.0001), 964 (176) HU for bone fragments, and 453 (241) HU for bone powder (P < 0.001). As expected, the density of the bone fragment graft was consistently greater than that of bone powder. Results confirm the accuracy and reproducibility of QCT, already demonstrated for bone in other locations, and suggest that it is an adequate tool to evaluate cranial reconstructions. The combination of QCT and cranial burr holes is an excellent model to accurately measure the quality of new bone in cranial reconstructions and also seems to be an appropriate choice of experimental model to clinically test any cranial bone or bone substitute reconstruction.

Fragment approach to the electronic structure of τ -boron allotrope

NASA Astrophysics Data System (ADS)

Karmodak, Naiwrit; Jemmis, Eluvathingal D.

2017-04-01

The presence of nonconventional bonding features is an intriguing part of elemental boron. The recent addition of τ boron to the family of three-dimensional boron allotropes is no exception. We provide an understanding of the electronic structure of τ boron using a fragment molecular approach, where the effect of symmetry reduction on skeletal bands of B12 and the B57 fragments are examined qualitatively by analyzing the projected density of states of these fragments. In spite of the structural resemblance to β boron, the reduction of symmetry from a rhombohedral space group to the orthorhombic one destabilizes the bands and reduces the electronic requirements. This suggests the presence of the partially occupied boron sites, as seen for a β boron unit cell, and draws the possibility for the existence of different energetically similar polymorphs. τ boron has a lower binding energy than β boron.

Nucleic acid indexing

DOEpatents

Guilfoyle, Richard A.; Guo, Zhen

2001-01-01

A restriction site indexing method for selectively amplifying any fragment generated by a Class II restriction enzyme includes adaptors specific to fragment ends containing adaptor indexing sequences complementary to fragment indexing sequences near the termini of fragments generated by Class II enzyme cleavage. A method for combinatorial indexing facilitates amplification of restriction fragments whose sequence is not known.

Nucleic acid indexing

DOEpatents

Guilfoyle, Richard A.; Guo, Zhen

1999-01-01

A restriction site indexing method for selectively amplifying any fragment generated by a Class II restriction enzyme includes adaptors specific to fragment ends containing adaptor indexing sequences complementary to fragment indexing sequences near the termini of fragments generated by Class II enzyme cleavage. A method for combinatorial indexing facilitates amplification of restriction fragments whose sequence is not known.

Incorporation of charge transfer into the explicit polarization fragment method by grand canonical density functional theory.

PubMed

Isegawa, Miho; Gao, Jiali; Truhlar, Donald G

2011-08-28

Molecular fragmentation algorithms provide a powerful approach to extending electronic structure methods to very large systems. Here we present a method for including charge transfer between molecular fragments in the explicit polarization (X-Pol) fragment method for calculating potential energy surfaces. In the conventional X-Pol method, the total charge of each fragment is preserved, and charge transfer between fragments is not allowed. The description of charge transfer is made possible by treating each fragment as an open system with respect to the number of electrons. To achieve this, we applied Mermin's finite temperature method to the X-Pol wave function. In the application of this method to X-Pol, the fragments are open systems that partially equilibrate their number of electrons through a quasithermodynamics electron reservoir. The number of electrons in a given fragment can take a fractional value, and the electrons of each fragment obey the Fermi-Dirac distribution. The equilibrium state for the electrons is determined by electronegativity equalization with conservation of the total number of electrons. The amount of charge transfer is controlled by re-interpreting the temperature parameter in the Fermi-Dirac distribution function as a coupling strength parameter. We determined this coupling parameter so as to reproduce the charge transfer energy obtained by block localized energy decomposition analysis. We apply the new method to ten systems, and we show that it can yield reasonable approximations to potential energy profiles, to charge transfer stabilization energies, and to the direction and amount of charge transferred. © 2011 American Institute of Physics

Incorporation of charge transfer into the explicit polarization fragment method by grand canonical density functional theory

PubMed Central

Isegawa, Miho; Gao, Jiali; Truhlar, Donald G.

2011-01-01

Molecular fragmentation algorithms provide a powerful approach to extending electronic structure methods to very large systems. Here we present a method for including charge transfer between molecular fragments in the explicit polarization (X-Pol) fragment method for calculating potential energy surfaces. In the conventional X-Pol method, the total charge of each fragment is preserved, and charge transfer between fragments is not allowed. The description of charge transfer is made possible by treating each fragment as an open system with respect to the number of electrons. To achieve this, we applied Mermin's finite temperature method to the X-Pol wave function. In the application of this method to X-Pol, the fragments are open systems that partially equilibrate their number of electrons through a quasithermodynamics electron reservoir. The number of electrons in a given fragment can take a fractional value, and the electrons of each fragment obey the Fermi–Dirac distribution. The equilibrium state for the electrons is determined by electronegativity equalization with conservation of the total number of electrons. The amount of charge transfer is controlled by re-interpreting the temperature parameter in the Fermi–Dirac distribution function as a coupling strength parameter. We determined this coupling parameter so as to reproduce the charge transfer energy obtained by block localized energy decomposition analysis. We apply the new method to ten systems, and we show that it can yield reasonable approximations to potential energy profiles, to charge transfer stabilization energies, and to the direction and amount of charge transferred. PMID:21895159

Self-aligning and compressed autosophy video databases

NASA Astrophysics Data System (ADS)

Holtz, Klaus E.

1993-04-01

Autosophy, an emerging new science, explains `self-assembling structures,' such as crystals or living trees, in mathematical terms. This research provides a new mathematical theory of `learning' and a new `information theory' which permits the growing of self-assembling data network in a computer memory similar to the growing of `data crystals' or `data trees' without data processing or programming. Autosophy databases are educated very much like a human child to organize their own internal data storage. Input patterns, such as written questions or images, are converted to points in a mathematical omni dimensional hyperspace. The input patterns are then associated with output patterns, such as written answers or images. Omni dimensional information storage will result in enormous data compression because each pattern fragment is only stored once. Pattern recognition in the text or image files is greatly simplified by the peculiar omni dimensional storage method. Video databases will absorb input images from a TV camera and associate them with textual information. The `black box' operations are totally self-aligning where the input data will determine their own hyperspace storage locations. Self-aligning autosophy databases may lead to a new generation of brain-like devices.

Levothyroxine sodium revisited: A wholistic structural elucidation approach of new impurities via HPLC-HRMS/MS, on-line H/D exchange, NMR spectroscopy and chemical synthesis.

PubMed

Ruggenthaler, M; Grass, J; Schuh, W; Huber, C G; Reischl, R J

2017-02-20

The structural elucidation of unknown pharmaceutical impurities plays an important role in the quality control of newly developed and well-established active pharmaceutical ingredients (APIs). The United States Pharmacopeia (USP) monograph for the API Levothyroxine Sodium, a synthetic thyroid hormone, features two high pressure liquid chromatography (HPLC) methods using UV-VIS absorption detection to determine organic impurities in the drug substance. The impurity profile of the first USP method ("Procedure 1") has already been extensively studied, however for the second method ("Procedure 2"), which exhibits a significantly different impurity profile, no wholistic structural elucidation of impurities has been performed yet. Applying minor modifications to the chromatographic parameters of USP "Procedure 2" and using various comprehensive structural elucidation methods such as high resolution tandem mass spectrometry with on-line hydrogen-deuterium (H/D) exchange or two-dimensional nuclear magnetic resonance spectroscopy (NMR) we gained new insights about the complex impurity profile of the synthetic thyroid hormone. This resulted in the characterization of 24 compounds previously unknown to literature and the introduction of two new classes of Levothyroxine Sodium impurities. Five novel compounds were unambiguously identified via isolation or synthesis of reference substances and subsequent NMR spectroscopic investigation. Additionally, Collision-Induced Dissociation (CID)-type fragmentation of identified major impurities as well as neutral loss fragmentation patterns of many characterized impurities were discussed. Copyright © 2016 Elsevier B.V. All rights reserved.

Evaluation of Impact Damage to the Burster Detonation Vessel Caused by Fragments from a Drained M121A1 Chemical Munition Detonated with an Initiation Charge

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

KIPP, MARLIN E.

2001-12-01

Explosive charges placed on the fuze end of a drained chemical munition are expected to be used as a means to destroy the fuze and burster charges of the munition. Analyses are presented to evaluate the effect of these additional initiation charges on the fragmentation characteristics for the M121A1 155mm chemical munition, modeled with a T244 fuze attached, and to assess the consequences of these fragment impacts on the walls of a containment chamber--the Burster Detonation Vessel. A numerical shock physics code (CTH) is used to characterize the mass and velocity of munition fragments. Both two- and three-dimensional simulations ofmore » the munition have been completed in this study. Based on threshold fragment velocity/mass results drawn from both previous and current analyses, it is determined that under all fragment impact conditions from the munition configurations considered in this study, no perforation of the inner chamber wall will occur, and the integrity of the Burster Detonation Vessel is retained. However, the munition case fragments have sufficient mass and velocity to locally damage the surface of the inner wall of the containment vessel.« less

Inferring Resilience to Fragmentation-Induced Changes in Plant Communities in a Semi-Arid Mediterranean Ecosystem

PubMed Central

de Frutos, Ángel; Navarro, Teresa; Pueyo, Yolanda; Alados, Concepción L.

2015-01-01

Predicting the capacity of ecosystems to absorb impacts from disturbance events (resilience), including land-use intensification and landscape fragmentation, is challenging in the face of global change. Little is known about the impacts of fragmentation on ecosystem functioning from a multi-dimensional perspective (multiple traits). This study used 58 500-m linear transects to quantify changes in the functional composition and resilience of vascular plant communities in response to an increase in landscape fragmentation in 18 natural scrubland fragments embedded within a matrix of abandoned crop fields in Cabo de Gata-Níjar Natural Park, Almería, Spain. Changes in functional community composition were measured using functional diversity indices (functional richness and functional dispersion) that were based on 12 plant traits. Resilience was evaluated using the functional redundancy and response diversity from the perspective of plant dispersal, which is important, particularly, in fragmented landscapes. Scrubland fragmentation was measured using the Integral Index of Connectivity (IIC). The functional richness of the plant communities was higher in the most fragmented scrubland. Conversely, the functional dispersion (i.e., spread) of trait values among species in the functional trait space was lower at the most fragmented sites; consequently, the ecological tolerance of the vegetation to scrubland fragmentation decreased. Classifying the plant species into four functional groups indicated that fragmentation favoured an increase in functional redundancy in the ‘short basal annual forbs and perennial forbs’ group, most of which are species adapted to degraded soils. An assessment based on the traits associated with plant dispersal indicated that the resilience of ‘woody plants’, an important component in the Mediterranean scrubland, and habitat fragmentation were negatively correlated; however, the correlation was positive in the ‘short basal annual forbs and perennial forbs’ and the ‘grasses’ groups. PMID:25790432

The Cascadia Paradox: Understanding Mantle Flow in the Cascadia Subduction System

NASA Astrophysics Data System (ADS)

Long, M. D.

2015-12-01

The pattern of mantle flow in subduction systems, and the processes that control the mantle flow field, is a fundamental but still poorly understood aspect of subduction dynamics. Mantle flow plays a key role in controlling the transport of volatiles and melt in the wedge, deformation of the overriding plate, mass transfer between the upper and lower mantle, and the morphology and dynamics of slabs. The Cascadia subduction zone provides a compelling system in which to understand the controls on mantle flow, particularly given the dense geophysical observations provided by EarthScope, GeoPRISMS, the Cascadia Initiative, and related efforts. Cascadia is a particularly intriguing system because observations of seismic anisotropy, which provide relatively direct constraints on mantle flow, seem to yield contradictory views of the mantle flow field in different parts of the system. Observations of seismic anisotropy on the overriding plate apparently require a significant component of three-dimensional, toroidal flow around the slab edge, while new observations from offshore stations are compellingly explained with a simple two-dimensional entrained flow model. Recent evidence from seismic tomography for the fragmentation of the Cascadia slab at depth provides a further puzzle: how can a fragmented slab provide a driving force for either two-dimensional entrained flow or three-dimensional toroidal flow due to slab rollback? I will present a synthesis of recent observations of seismic anisotropy in the Cascadia subduction system, and how they can be integrated with constraints from geodynamical modeling, geochemistry, and the history and timing of Pacific Northwest volcanism. I will discuss the compelling but contradictory evidence for each of the endmember mantle flow models (two-dimensional entrained flow vs. three-dimensional toroidal flow) and explore possible avenues for resolving the Cascadia Paradox.

Quantification of eggshell microstructure using X-ray micro computed tomography

PubMed Central

Riley, A.; Sturrock, C. J.; Mooney, S. J.

2014-01-01

1. X-ray microcomputed tomography can be used to produce rapid, fully analysable, three-dimensional images of biological and other materials without the need for complex or tedious sample preparation and sectioning. We describe the use of this technique to visualise and analyse the microstructure of fragments of shell taken from three regions of chicken eggs (sharp pole, blunt pole and equatorial region). 2. Two- and three-dimensional images and data were obtained at a resolution of 1.5 microns. The images were analysed to provide measurements of shell thickness, the spacial density of mammillary bodies, the frequency, shape, volume and effective diameter of individual pore spaces, and the intrinsic sponginess (proportion of non-X-ray dense material formed by vesicles) of the shell matrix. Measurements of these parameters were comparable with those derived by traditional methods and reported in the literature. 3. The advantages of using this technology for the quantification of eggshell microstructural parameters and its potential application for commercial, research and other purposes are discussed. PMID:24875292

Development of Turbulent Magnetic Reconnection in a Magnetic Island

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

Huang, Can; Lu, Quanming; Wang, Rongsheng

In this paper, with two-dimensional particle-in-cell simulations, we report that the electron Kelvin–Helmholtz instability is unstable in the current layer associated with a large-scale magnetic island, which is formed in multiple X-line guide field reconnections. The current sheet is fragmented into many small current sheets with widths down to the order of the electron inertial length. Secondary magnetic reconnection then occurs in these fragmented current sheets, which leads to a turbulent state. The electrons are highly energized in such a process.

Characterization of hypervelocity metal fragments for explosive initiation

DOE PAGES

Yeager, John D.; Bowden, Patrick R.; Guildenbecher, Daniel R.; ...

2017-07-17

The fragment impact response of two plastic-bonded explosive (PBX) formulations was studied using explosively driven aluminum fragments. A generic aluminum-capped detonator generated sub-mm aluminum particles moving at hypersonic velocities. The ability of these fragments to initiate reaction or otherwise damage two PBX materials was assessed using go/no-go experiments at standoff distances of up to 160 mm. Lower density PBX 9407 (RDX-based) was initiable at up to 115 mm, while higher density PBX 9501 (HMX-based) was only initiable at up to 6 mm. Several techniques were used to characterize the size, distribution, and velocity of the particles. Witness plate materials, includingmore » copper and polycarbonate, and backlit high speed video were used to characterize the distribution of particles, finding that the aluminum cap did not fragment homogeneously but rather with larger particles in a ring surrounding finer particles. Finally, precise digital holography experiments were conducted to measure the three-dimensional shape and size of the fastest-moving fragments, which ranged between 100 and 700 μm and traveled between 2.2 and 3.2 km/s. Crucially, these experiments showed variability in the fragmentation in terms of the number of fragments at the leading edge of the fragment field, indicating that both single and multiple shock impacts could be imparted to the target material. As a result, these types of data are critical for safety experiments and hydrocode simulations to quantify shock-to-detonation transition mechanisms and the associated risk-margins for these materials.« less

Characterization of hypervelocity metal fragments for explosive initiation

NASA Astrophysics Data System (ADS)

Yeager, John D.; Bowden, Patrick R.; Guildenbecher, Daniel R.; Olles, Joseph D.

2017-07-01

The fragment impact response of two plastic-bonded explosive (PBX) formulations was studied using explosively driven aluminum fragments. A generic aluminum-capped detonator generated sub-mm aluminum particles moving at hypersonic velocities. The ability of these fragments to initiate reaction or otherwise damage two PBX materials was assessed using go/no-go experiments at standoff distances of up to 160 mm. Lower density PBX 9407 (RDX-based) was initiable at up to 115 mm, while higher density PBX 9501 (HMX-based) was only initiable at up to 6 mm. Several techniques were used to characterize the size, distribution, and velocity of the particles. Witness plate materials, including copper and polycarbonate, and backlit high speed video were used to characterize the distribution of particles, finding that the aluminum cap did not fragment homogeneously but rather with larger particles in a ring surrounding finer particles. Finally, precise digital holography experiments were conducted to measure the three-dimensional shape and size of the fastest-moving fragments, which ranged between 100 and 700 μm and traveled between 2.2 and 3.2 km/s. Crucially, these experiments showed variability in the fragmentation in terms of the number of fragments at the leading edge of the fragment field, indicating that both single and multiple shock impacts could be imparted to the target material. These types of data are critical for safety experiments and hydrocode simulations to quantify shock-to-detonation transition mechanisms and the associated risk-margins for these materials.

An adaptively refined phase-space element method for cosmological simulations and collisionless dynamics

NASA Astrophysics Data System (ADS)

Hahn, Oliver; Angulo, Raul E.

2016-01-01

N-body simulations are essential for understanding the formation and evolution of structure in the Universe. However, the discrete nature of these simulations affects their accuracy when modelling collisionless systems. We introduce a new approach to simulate the gravitational evolution of cold collisionless fluids by solving the Vlasov-Poisson equations in terms of adaptively refineable `Lagrangian phase-space elements'. These geometrical elements are piecewise smooth maps between Lagrangian space and Eulerian phase-space and approximate the continuum structure of the distribution function. They allow for dynamical adaptive splitting to accurately follow the evolution even in regions of very strong mixing. We discuss in detail various one-, two- and three-dimensional test problems to demonstrate the performance of our method. Its advantages compared to N-body algorithms are: (I) explicit tracking of the fine-grained distribution function, (II) natural representation of caustics, (III) intrinsically smooth gravitational potential fields, thus (IV) eliminating the need for any type of ad hoc force softening. We show the potential of our method by simulating structure formation in a warm dark matter scenario. We discuss how spurious collisionality and large-scale discreteness noise of N-body methods are both strongly suppressed, which eliminates the artificial fragmentation of filaments. Therefore, we argue that our new approach improves on the N-body method when simulating self-gravitating cold and collisionless fluids, and is the first method that allows us to explicitly follow the fine-grained evolution in six-dimensional phase-space.

Comparison of originator and biosimilar therapeutic monoclonal antibodies using comprehensive two-dimensional liquid chromatography coupled with time-of-flight mass spectrometry.

PubMed

Sorensen, Matthew; Harmes, David C; Stoll, Dwight R; Staples, Gregory O; Fekete, Szabolcs; Guillarme, Davy; Beck, Alain

2016-10-01

As research, development, and manufacturing of biosimilar protein therapeutics proliferates, there is great interest in the continued development of a portfolio of complementary analytical methods that can be used to efficiently and effectively characterize biosimilar candidate materials relative to the respective reference (i.e., originator) molecule. Liquid phase separation techniques such as liquid chromatography and capillary electrophoresis are powerful tools that can provide both qualitative and quantitative information about similarities and differences between reference and biosimilar materials, especially when coupled with mass spectrometry. However, the inherent complexity of these protein materials challenges even the most modern one-dimensional (1D) separation methods. Two-dimensional (2D) separations present a number of potential advantages over 1D methods, including increased peak capacity, 2D peak patterns that can facilitate unknown identification, and improvement in the compatibility of some separation methods with mass spectrometry. In this study, we demonstrate the use of comprehensive 2D-LC separations involving cation-exchange (CEX) and reversed-phase (RP) separations in the first and second dimensions to compare 3 reference/biosimilar pairs of monoclonal antibodies (cetuximab, trastuzumab and infliximab) that cover a range of similarity/disimilarity in a middle-up approach. The second dimension RP separations are coupled to time-of-flight mass spectrometry, which enables direct identification of features in the chromatograms obtained from mAbs digested with the IdeS enzyme, or digestion with IdeS followed by reduction with dithiothreitol. As many as 23 chemically unique mAb fragments were detected in a single sample. Our results demonstrate that these rich datasets enable facile assesment of the degree of similarity between reference and biosimilar materials.

NMR studies on the structure and dynamics of lac operator DNA

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

Lee, S.C.

Nuclear Magnetic Resonance spectroscopy was used to elucidate the relationships between structure, dynamics and function of the gene regulatory sequence corresponding to the lactose operon operator of Escherichia coli. The length of the DNA fragments examined varied from 13 to 36 base pair, containing all or part of the operator sequence. These DNA fragments are either derived genetically or synthesized chemically. Resonances of the imino protons were assigned by one dimensional inter-base pair nuclear Overhauser enhancement (NOE) measurements. Imino proton exchange rates were measured by saturation recovery methods. Results from the kinetic measurements show an interesting dynamic heterogeneity with amore » maximum opening rate centered about a GTG/CAC sequence which correlates with the biological function of the operator DNA. This particular three base pair sequence occurs frequently and often symmetrically in prokaryotic nd eukaryotic DNA sites where one anticipates specific protein interaction for gene regulation. The observed sequence dependent imino proton exchange rate may be a reflection of variation of the local structure of regulatory DNA. The results also indicate that the observed imino proton exchange rates are length dependent.« less

Predicting "Hot" and "Warm" Spots for Fragment Binding.

PubMed

Rathi, Prakash Chandra; Ludlow, R Frederick; Hall, Richard J; Murray, Christopher W; Mortenson, Paul N; Verdonk, Marcel L

2017-05-11

Computational fragment mapping methods aim to predict hotspots on protein surfaces where small fragments will bind. Such methods are popular for druggability assessment as well as structure-based design. However, to date researchers developing or using such tools have had no clear way of assessing the performance of these methods. Here, we introduce the first diverse, high quality validation set for computational fragment mapping. The set contains 52 diverse examples of fragment binding "hot" and "warm" spots from the Protein Data Bank (PDB). Additionally, we describe PLImap, a novel protocol for fragment mapping based on the Protein-Ligand Informatics force field (PLIff). We evaluate PLImap against the new fragment mapping test set, and compare its performance to that of simple shape-based algorithms and fragment docking using GOLD. PLImap is made publicly available from https://bitbucket.org/AstexUK/pli .

Identifying and analysing protostellar disc fragments in smoothed particle hydrodynamics simulations

NASA Astrophysics Data System (ADS)

Hall, Cassandra; Forgan, Duncan; Rice, Ken

2017-09-01

We present a new method of identifying protostellar disc fragments in a simulation based on density derivatives, and analyse our data using this and the existing CLUMPFIND method, which is based on an ordered search over all particles in gravitational potential energy. Using smoothed particle hydrodynamics, we carry out nine simulations of a 0.25 M⊙ disc around a 1 M⊙ star, all of which fragment to form at least two bound objects. We find that when using all particles ordered in gravitational potential space, only fragments that survive the duration of the simulation are detected. When we use the density derivative method, all fragments are detected, so the two methods are complementary, as using the two methods together allows us to identify all fragments, and to then determine those that are likely to be destroyed. We find a tentative empirical relationship between the dominant azimuthal wavenumber in the disc m and the maximum semimajor axis a fragment may achieve in a simulation, such that amax∝1/m. We find the fragment destruction rate to be around half that predicted from population synthesis models. This is due to fragment-fragment interactions in the early gas phase of the disc, which can cause scattering and eccentricity pumping on short time-scales, and affects the fragment's internal structure. We therefore caution that measurements of eccentricity as a function of semimajor axis may not necessarily constrain the formation mechanism of giant planets and brown dwarfs.

Modeling and possible implementation of self-learning equivalence-convolutional neural structures for auto-encoding-decoding and clusterization of images

NASA Astrophysics Data System (ADS)

Krasilenko, Vladimir G.; Lazarev, Alexander A.; Nikitovich, Diana V.

2017-08-01

Self-learning equivalent-convolutional neural structures (SLECNS) for auto-coding-decoding and image clustering are discussed. The SLECNS architectures and their spatially invariant equivalent models (SI EMs) using the corresponding matrix-matrix procedures with basic operations of continuous logic and non-linear processing are proposed. These SI EMs have several advantages, such as the ability to recognize image fragments with better efficiency and strong cross correlation. The proposed clustering method of fragments with regard to their structural features is suitable not only for binary, but also color images and combines self-learning and the formation of weight clustered matrix-patterns. Its model is constructed and designed on the basis of recursively processing algorithms and to k-average method. The experimental results confirmed that larger images and 2D binary fragments with a large numbers of elements may be clustered. For the first time the possibility of generalization of these models for space invariant case is shown. The experiment for an image with dimension of 256x256 (a reference array) and fragments with dimensions of 7x7 and 21x21 for clustering is carried out. The experiments, using the software environment Mathcad, showed that the proposed method is universal, has a significant convergence, the small number of iterations is easily, displayed on the matrix structure, and confirmed its prospects. Thus, to understand the mechanisms of self-learning equivalence-convolutional clustering, accompanying her to the competitive processes in neurons, and the neural auto-encoding-decoding and recognition principles with the use of self-learning cluster patterns is very important which used the algorithm and the principles of non-linear processing of two-dimensional spatial functions of images comparison. These SIEMs can simply describe the signals processing during the all training and recognition stages and they are suitable for unipolar-coding multilevel signals. We show that the implementation of SLECNS based on known equivalentors or traditional correlators is possible if they are based on proposed equivalental two-dimensional functions of image similarity. The clustering efficiency in such models and their implementation depends on the discriminant properties of neural elements of hidden layers. Therefore, the main models and architecture parameters and characteristics depends on the applied types of non-linear processing and function used for image comparison or for adaptive-equivalental weighing of input patterns. Real model experiments in Mathcad are demonstrated, which confirm that non-linear processing on equivalent functions allows you to determine the neuron winners and adjust the weight matrix. Experimental results have shown that such models can be successfully used for auto- and hetero-associative recognition. They can also be used to explain some mechanisms known as "focus" and "competing gain-inhibition concept". The SLECNS architecture and hardware implementations of its basic nodes based on multi-channel convolvers and correlators with time integration are proposed. The parameters and performance of such architectures are estimated.

A Novel Method Using Abstract Convex Underestimation in Ab-Initio Protein Structure Prediction for Guiding Search in Conformational Feature Space.

PubMed

Hao, Xiao-Hu; Zhang, Gui-Jun; Zhou, Xiao-Gen; Yu, Xu-Feng

2016-01-01

To address the searching problem of protein conformational space in ab-initio protein structure prediction, a novel method using abstract convex underestimation (ACUE) based on the framework of evolutionary algorithm was proposed. Computing such conformations, essential to associate structural and functional information with gene sequences, is challenging due to the high-dimensionality and rugged energy surface of the protein conformational space. As a consequence, the dimension of protein conformational space should be reduced to a proper level. In this paper, the high-dimensionality original conformational space was converted into feature space whose dimension is considerably reduced by feature extraction technique. And, the underestimate space could be constructed according to abstract convex theory. Thus, the entropy effect caused by searching in the high-dimensionality conformational space could be avoided through such conversion. The tight lower bound estimate information was obtained to guide the searching direction, and the invalid searching area in which the global optimal solution is not located could be eliminated in advance. Moreover, instead of expensively calculating the energy of conformations in the original conformational space, the estimate value is employed to judge if the conformation is worth exploring to reduce the evaluation time, thereby making computational cost lower and the searching process more efficient. Additionally, fragment assembly and the Monte Carlo method are combined to generate a series of metastable conformations by sampling in the conformational space. The proposed method provides a novel technique to solve the searching problem of protein conformational space. Twenty small-to-medium structurally diverse proteins were tested, and the proposed ACUE method was compared with It Fix, HEA, Rosetta and the developed method LEDE without underestimate information. Test results show that the ACUE method can more rapidly and more efficiently obtain the near-native protein structure.

First assembly times and equilibration in stochastic coagulation-fragmentation

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

D’Orsogna, Maria R.; Department of Mathematics, CSUN, Los Angeles, California 91330-8313; Lei, Qi

2015-07-07

We develop a fully stochastic theory for coagulation and fragmentation (CF) in a finite system with a maximum cluster size constraint. The process is modeled using a high-dimensional master equation for the probabilities of cluster configurations. For certain realizations of total mass and maximum cluster sizes, we find exact analytical results for the expected equilibrium cluster distributions. If coagulation is fast relative to fragmentation and if the total system mass is indivisible by the mass of the largest allowed cluster, we find a mean cluster-size distribution that is strikingly broader than that predicted by the corresponding mass-action equations. Combinations ofmore » total mass and maximum cluster size under which equilibration is accelerated, eluding late-stage coarsening, are also delineated. Finally, we compute the mean time it takes particles to first assemble into a maximum-sized cluster. Through careful state-space enumeration, the scaling of mean assembly times is derived for all combinations of total mass and maximum cluster size. We find that CF accelerates assembly relative to monomer kinetic only in special cases. All of our results hold in the infinite system limit and can be only derived from a high-dimensional discrete stochastic model, highlighting how classical mass-action models of self-assembly can fail.« less

Assessing nest-building behavior of mice using a 3D depth camera.

PubMed

Okayama, Tsuyoshi; Goto, Tatsuhiko; Toyoda, Atsushi

2015-08-15

We developed a novel method to evaluate the nest-building behavior of mice using an inexpensive depth camera. The depth camera clearly captured nest-building behavior. Using three-dimensional information from the depth camera, we obtained objective features for assessing nest-building behavior, including "volume," "radius," and "mean height". The "volume" represents the change in volume of the nesting material, a pressed cotton square that a mouse shreds and untangles in order to build its nest. During the nest-building process, the total volume of cotton fragments is increased. The "radius" refers to the radius of the circle enclosing the fragments of cotton. It describes the extent of nesting material dispersion. The "radius" averaged approximately 60mm when a nest was built. The "mean height" represents the change in the mean height of objects. If the nest walls were high, the "mean height" was also high. These features provided us with useful information for assessment of nest-building behavior, similar to conventional methods for the assessment of nest building. However, using the novel method, we found that JF1 mice built nests with higher walls than B6 mice, and B6 mice built nests faster than JF1 mice. Thus, our novel method can evaluate the differences in nest-building behavior that cannot be detected or quantified by conventional methods. In future studies, we will evaluate nest-building behaviors of genetically modified, as well as several inbred, strains of mice, with several nesting materials. Copyright © 2015 Elsevier B.V. All rights reserved.

The oligonucleotide frequency derived error gradient and its application to the binning of metagenome fragments

PubMed Central

2009-01-01

Background The characterisation, or binning, of metagenome fragments is an important first step to further downstream analysis of microbial consortia. Here, we propose a one-dimensional signature, OFDEG, derived from the oligonucleotide frequency profile of a DNA sequence, and show that it is possible to obtain a meaningful phylogenetic signal for relatively short DNA sequences. The one-dimensional signal is essentially a compact representation of higher dimensional feature spaces of greater complexity and is intended to improve on the tetranucleotide frequency feature space preferred by current compositional binning methods. Results We compare the fidelity of OFDEG against tetranucleotide frequency in both an unsupervised and semi-supervised setting on simulated metagenome benchmark data. Four tests were conducted using assembler output of Arachne and phrap, and for each, performance was evaluated on contigs which are greater than or equal to 8 kbp in length and contigs which are composed of at least 10 reads. Using both G-C content in conjunction with OFDEG gave an average accuracy of 96.75% (semi-supervised) and 95.19% (unsupervised), versus 94.25% (semi-supervised) and 82.35% (unsupervised) for tetranucleotide frequency. Conclusion We have presented an observation of an alternative characteristic of DNA sequences. The proposed feature representation has proven to be more beneficial than the existing tetranucleotide frequency space to the metagenome binning problem. We do note, however, that our observation of OFDEG deserves further anlaysis and investigation. Unsupervised clustering revealed OFDEG related features performed better than standard tetranucleotide frequency in representing a relevant organism specific signal. Further improvement in binning accuracy is given by semi-supervised classification using OFDEG. The emphasis on a feature-driven, bottom-up approach to the problem of binning reveals promising avenues for future development of techniques to characterise short environmental sequences without bias toward cultivable organisms. PMID:19958473

Apparatus and method for igniting an in situ oil shale retort

DOEpatents

Chambers, Carlon C.

1981-01-01

A method and apparatus for conducting such method are disclosed for igniting a fragmented permeable mass of formation particles in an in situ oil shale retort. The method is conducted by forming a hole through unfragmented formation to the fragmented mass. An oxygen-containing gas is introduced into the hole. A fuel is introduced into a portion of the hole spaced apart from the fragmented mass. The fuel and oxygen-containing gas mix forming a combustible mixture which is ignited for establishing a combustion zone in a portion of the hole spaced apart from the fragmented mass. The hot gas generated in the combustion zone is conducted from the hole into the fragmented mass for heating a portion of the fragmented mass above an ignition temperature of oil shale.

The breakup of a main-belt asteroid 450 thousand years ago.

PubMed

Nesvorný, David; Vokrouhlický, David; Bottke, William F

2006-06-09

Collisions in the asteroid belt frequently lead to catastrophic breakups, where more than half of the target's mass is ejected into space. Several dozen large asteroids have been disrupted by impacts over the past several billion years. These impact events have produced groups of fragments with similar orbits called asteroid families. Here we report the discovery of a very young asteroid family around the object 1270 Datura. Our work takes advantage of a method for identification of recent breakups in the asteroid belt using catalogs of osculating (i.e., instantaneous) asteroid orbits. The very young families show up in these catalogs as clusters in a five-dimensional space of osculating orbital elements.

Extension of moment projection method to the fragmentation process

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

Wu, Shaohua; Yapp, Edward K.Y.; Akroyd, Jethro

2017-04-15

The method of moments is a simple but efficient method of solving the population balance equation which describes particle dynamics. Recently, the moment projection method (MPM) was proposed and validated for particle inception, coagulation, growth and, more importantly, shrinkage; here the method is extended to include the fragmentation process. The performance of MPM is tested for 13 different test cases for different fragmentation kernels, fragment distribution functions and initial conditions. Comparisons are made with the quadrature method of moments (QMOM), hybrid method of moments (HMOM) and a high-precision stochastic solution calculated using the established direct simulation algorithm (DSA) and advantagesmore » of MPM are drawn.« less

Case report highlighting how wound path identification on CT can help identify organ damage in abdominal blast injuries.

PubMed

Fischer, Tatjana V; Folio, Les R; Backus, Christopher E; Bunger, Rolf

2012-01-01

Penetrating trauma is frequently encountered in forward deployed military combat hospitals. Abdominal blast injuries represent nearly 11% of combat injuries, and multiplanar computed tomography imaging is optimal for injury assessment and surgical planning. We describe a multiplanar approach to assessment of blast and ballistic injuries, which allows for more expeditious detection of missile tracts and damage caused along the path. Precise delineation of the trajectory path and localization of retained fragments enables time-saving and detailed evaluation of associated tissue and vascular injury. For consistent and reproducible documentation of fragment locations in the body, we propose a localization scheme based on Cartesian coordinates to report 3-dimensional locations of fragments and demonstrating the application in three cases of abdominal blast injury.

The current status and future prospects of computer-assisted hip surgery.

PubMed

Inaba, Yutaka; Kobayashi, Naomi; Ike, Hiroyuki; Kubota, So; Saito, Tomoyuki

2016-03-01

The advances in computer assistance technology have allowed detailed three-dimensional preoperative planning and simulation of preoperative plans. The use of a navigation system as an intraoperative assistance tool allows more accurate execution of the preoperative plan, compared to manual operation without assistance of the navigation system. In total hip arthroplasty using CT-based navigation, three-dimensional preoperative planning with computer software allows the surgeon to determine the optimal angle of implant placement at which implant impingement is unlikely to occur in the range of hip joint motion necessary for daily activities of living, and to determine the amount of three-dimensional correction for leg length and offset. With the use of computer navigation for intraoperative assistance, the preoperative plan can be precisely executed. In hip osteotomy using CT-based navigation, the navigation allows three-dimensional preoperative planning, intraoperative confirmation of osteotomy sites, safe performance of osteotomy even under poor visual conditions, and a reduction in exposure doses from intraoperative fluoroscopy. Positions of the tips of chisels can be displayed on the computer monitor during surgery in real time, and staff other than the operator can also be aware of the progress of surgery. Thus, computer navigation also has an educational value. On the other hand, its limitations include the need for placement of trackers, increased radiation exposure from preoperative CT scans, and prolonged operative time. Moreover, because the position of a bone fragment cannot be traced after osteotomy, methods to find its precise position after its movement need to be developed. Despite the need to develop methods for the postoperative evaluation of accuracy for osteotomy, further application and development of these systems are expected in the future. Copyright © 2016 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.

A comparison of DNA fragmentation methods - Applications for the biochip technology.

PubMed

Sapojnikova, Nelly; Asatiani, Nino; Kartvelishvili, Tamar; Asanishvili, Lali; Zinkevich, Vitaly; Bogdarina, Irina; Mitchell, Julian; Al-Humam, Abdulmohsen

2017-08-20

The efficiency of hybridization signal detection in a biochip is affected by the method used for test DNA preparation, such as fragmentation, amplification and fluorescent labelling. DNA fragmentation is the commonest methods used and it is recognised as a critical step in biochip analysis. Currently methods used for DNA fragmentation are based either on sonication or on the enzymatic digestion. In this study, we compared the effect of different types of enzymatic DNA fragmentations, using DNase I to generate ssDNA breaks, NEBNext dsDNA fragmentase and SaqAI restrictase, on DNA labelling. DNA from different Desulfovibrio species was used as a substrate for these enzymes. Of the methods used, DNA fragmented by NEBNext dsDNA Fragmentase digestion was subsequently labelled with the greatest efficiency. As a result of this, the use of this enzyme to fragment target DNA increases the sensitivity of biochip-based detection significantly, and this is an important consideration when determining the presence of targeted DNA in ecological and medical samples. Copyright © 2017 Elsevier B.V. All rights reserved.

Scar-less multi-part DNA assembly design automation

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

Hillson, Nathan J.

The present invention provides a method of a method of designing an implementation of a DNA assembly. In an exemplary embodiment, the method includes (1) receiving a list of DNA sequence fragments to be assembled together and an order in which to assemble the DNA sequence fragments, (2) designing DNA oligonucleotides (oligos) for each of the DNA sequence fragments, and (3) creating a plan for adding flanking homology sequences to each of the DNA oligos. In an exemplary embodiment, the method includes (1) receiving a list of DNA sequence fragments to be assembled together and an order in which tomore » assemble the DNA sequence fragments, (2) designing DNA oligonucleotides (oligos) for each of the DNA sequence fragments, and (3) creating a plan for adding optimized overhang sequences to each of the DNA oligos.« less

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

Yeager, John D.; Bowden, Patrick R.; Guildenbecher, Daniel R.

The fragment impact response of two plastic-bonded explosive (PBX) formulations was studied using explosively driven aluminum fragments. A generic aluminum-capped detonator generated sub-mm aluminum particles moving at hypersonic velocities. The ability of these fragments to initiate reaction or otherwise damage two PBX materials was assessed using go/no-go experiments at standoff distances of up to 160 mm. Lower density PBX 9407 (RDX-based) was initiable at up to 115 mm, while higher density PBX 9501 (HMX-based) was only initiable at up to 6 mm. Several techniques were used to characterize the size, distribution, and velocity of the particles. Witness plate materials, includingmore » copper and polycarbonate, and backlit high speed video were used to characterize the distribution of particles, finding that the aluminum cap did not fragment homogeneously but rather with larger particles in a ring surrounding finer particles. Finally, precise digital holography experiments were conducted to measure the three-dimensional shape and size of the fastest-moving fragments, which ranged between 100 and 700 μm and traveled between 2.2 and 3.2 km/s. Crucially, these experiments showed variability in the fragmentation in terms of the number of fragments at the leading edge of the fragment field, indicating that both single and multiple shock impacts could be imparted to the target material. As a result, these types of data are critical for safety experiments and hydrocode simulations to quantify shock-to-detonation transition mechanisms and the associated risk-margins for these materials.« less

Comet Shoemaker-Levy 9: Impact on Jupiter and plume evolution

NASA Technical Reports Server (NTRS)

Takata, Toshiko; O'Keefe, John D.; Ahrens, Thomas J.; Orton, Glenn S.

1994-01-01

The impact of fragments of Comet Shoemaker-Levy 9 on Jupiter and the resulting vapor plume expansion are investigated by conducting three-dimensional numerical simulations using the smoothed particle hydrodynamics (SPH) method. An icy body, representing the cometary fragments, with a velocity of 60 km/sec and a diameter of 2 km can penetrate to 350 km below the 1-bar pressure level in the atmosphere. Most of the initial kinetic energy of the fragment is transferred to the atmosphere between 50 km and 300 km below the 1-bar pressure level. The shock-heated atmospheric gas in the wake is totally dissociated and partially ionized. Scaling our SPH results to other sizes indicates that fragments larger than approximately 100 m in diameter can penetrate to below the visible cloud decks. The energy deposited in the atmosphere is explosively released in the upward expansion of the resulting plume. The plume preferentially expands upward rather than horizontally due to the density gradient of the ambient atmosphere. It rises greater than or equal to 10(exp 2) km in approximately 10(exp 2) sec. Eventually the total atmospheric mass ejected to above 1 bar is greater than or equal to 40 times the initial mass of the impactor. The plume temperature at a radius approximately 10(exp 3) km is greater than 10(exp 3) K for 10(exp 3) sec for a 2-km fragment. We predict that impact-induced plumes will be observable with the remote sensing instruments of the Galileo spacecraft. As the impact site rotates into the view of Earth some 20 min after the impact, the plume expansion will be observable using the Hubble Space Telescope (HST) and from visible and infrared instruments on groundbased telescopes. The rising plume reaches approximately 3000 km altitude in approximately 10 min and will be visible from Earth.

The rise of fragment-based drug discovery.

PubMed

Murray, Christopher W; Rees, David C

2009-06-01

The search for new drugs is plagued by high attrition rates at all stages in research and development. Chemists have an opportunity to tackle this problem because attrition can be traced back, in part, to the quality of the chemical leads. Fragment-based drug discovery (FBDD) is a new approach, increasingly used in the pharmaceutical industry, for reducing attrition and providing leads for previously intractable biological targets. FBDD identifies low-molecular-weight ligands (∼150 Da) that bind to biologically important macromolecules. The three-dimensional experimental binding mode of these fragments is determined using X-ray crystallography or NMR spectroscopy, and is used to facilitate their optimization into potent molecules with drug-like properties. Compared with high-throughput-screening, the fragment approach requires fewer compounds to be screened, and, despite the lower initial potency of the screening hits, offers more efficient and fruitful optimization campaigns. Here, we review the rise of FBDD, including its application to discovering clinical candidates against targets for which other chemistry approaches have struggled.

An (e, 2e+ ion) study of electron-impact ionization and fragmentation of tetrafluoromethane at low energies

NASA Astrophysics Data System (ADS)

Hossen, Khokon; Ren, Xueguang; Wang, Enliang; Kumar, S. V. K.; Dorn, Alexander

2018-03-01

We study ionization and fragmentation of tetrafluoromethane (CF4) molecule induced by electron impact at low energies ( E 0 = 38 and 67 eV). We use a reaction microscope combined with a pulsed photoemission electron beam for our experimental investigation. The momentum vectors of the two outgoing electrons (energies E 1, E 2) and one fragment ion are detected in triple coincidence (e, 2e+ ion). After dissociation, the fragment products observed are CF3 +, CF2 +, CF+, F+ and C+. For CF3 + and CF2 + channels, we measure the ionized orbitals binding energies, the kinetic energy (KE) of the charged fragments and the two-dimensional (2D) correlation map between binding energy (BE) and KE of the fragments. From the BE and KE spectra, we conclude which molecular orbitals contribute to particular fragmentation channels of CF4. We also measure the total ionization cross section for the formation of CF3 + and CF2 + ions as function of projectile energy. We compare our results with earlier experiments and calculations for electron-impact and photoionization. The major contribution to CF3 + formation originates from ionization of the 4t2 orbital while CF2 + is mainly formed after 3t2 orbital ionization. We also observe a weak contribution of the (4a1)-1 state for the channel CF3 +.

The Fragmentation Criteria in Local Vertically Stratified Self-gravitating Disk Simulations

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

Baehr, Hans; Klahr, Hubert; Kratter, Kaitlin M., E-mail: baehr@mpia.de

Massive circumstellar disks are prone to gravitational instabilities, which trigger the formation of spiral arms that can fragment into bound clumps under the right conditions. Two-dimensional simulations of self-gravitating disks are useful starting points for studying fragmentation because they allow high-resolution simulations of thin disks. However, convergence issues can arise in 2D from various sources. One of these sources is the 2D approximation of self-gravity, which exaggerates the effect of self-gravity on small scales when the potential is not smoothed to account for the assumed vertical extent of the disk. This effect is enhanced by increased resolution, resulting in fragmentationmore » at longer cooling timescales β . If true, it suggests that the 3D simulations of disk fragmentation may not have the same convergence problem and could be used to examine the nature of fragmentation without smoothing self-gravity on scales similar to the disk scale height. To that end, we have carried out local 3D self-gravitating disk simulations with simple β cooling with fixed background irradiation to determine if 3D is necessary to properly describe disk fragmentation. Above a resolution of ∼40 grid cells per scale height, we find that our simulations converge with respect to the cooling timescale. This result converges in agreement with analytic expectations which place a fragmentation boundary at β {sub crit} = 3.« less

Three-dimensional infinite order sudden quantum theory for indirect photodissociation processes. Application to the photofragment yield spectrum of NOCl in the region of the T1(13A″) ←S0(11A') transition. Fragment rotational distributions and thermal averages

NASA Astrophysics Data System (ADS)

Grinberg, Horacio; Freed, Karl F.; Williams, Carl J.

1997-08-01

The analytical infinite order sudden (IOS) quantum theory of triatomic photodissociation, developed in paper I, is applied to study the indirect photodissociation of NOCl through a real or virtual intermediate state. The theory uses the IOS approximation for the dynamics in the final dissociative channels and an Airy function approximation for the continuum functions. The transition is taken as polarized in the plane of the molecule; symmetric top wave functions are used for both the initial and intermediate bound states; and simple semiempirical model potentials are employed for each state. The theory provides analytical expressions for the photofragment yield spectrum for producing particular final fragment ro-vibrational states as a function of the photon excitation energy. Computations are made of the photofragment excitation spectrum of NOCl in the region of the T1(13A″)←S0(11A') transition for producing the NO fragment in the vibrational states nNO=0, 1, and 2. The computed spectra for the unexcited nNO==0 and excited nNO=2 states are in reasonable agreement with experiment. However, some discrepancies are observed for the singly excited nNO=1 vibrational state, indicating deficiencies in the semiempirical potential energy surface. Computations for two different orientations of the in-plane transition dipole moment produce very similar excitation spectra. Calculations of fragment rotational distributions are performed for high values of the total angular momentum J, a feature that would be very difficult to perform with close-coupled methods. Computations are also made of the thermally averaged rotational energy distributions to simulate the conditions in actual supersonic jet experiments.

Three-dimensional habitat structure and landscape genetics: a step forward in estimating functional connectivity.

PubMed

Milanesi, P; Holderegger, R; Bollmann, K; Gugerli, F; Zellweger, F

2017-02-01

Estimating connectivity among fragmented habitat patches is crucial for evaluating the functionality of ecological networks. However, current estimates of landscape resistance to animal movement and dispersal lack landscape-level data on local habitat structure. Here, we used a landscape genetics approach to show that high-fidelity habitat structure maps derived from Light Detection and Ranging (LiDAR) data critically improve functional connectivity estimates compared to conventional land cover data. We related pairwise genetic distances of 128 Capercaillie (Tetrao urogallus) genotypes to least-cost path distances at multiple scales derived from land cover data. Resulting β values of linear mixed effects models ranged from 0.372 to 0.495, while those derived from LiDAR ranged from 0.558 to 0.758. The identification and conservation of functional ecological networks suffering from habitat fragmentation and homogenization will thus benefit from the growing availability of detailed and contiguous data on three-dimensional habitat structure and associated habitat quality. © 2016 by the Ecological Society of America.

Fragmentation Cross Sections of 290 and 400 MeV/nucleon 12C Beamson Elemental Targets

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

Zeitlin, C.; Guetersloh, S.; Heilbronn, L.

Charge-changing and fragment production cross sections at 0circ have been obtained for interactions of 290 MeV/nucleon and 400MeV/nucleon carbon beams with C, CH2, Al, Cu, Sn, and Pb targets. Thesebeams are relevant to cancer therapy, space radiation, and the productionof radioactive beams. We compare to previously published results using Cand CH2 targets at similar beam energies. Due to ambiguities arising fromthe presence of multiple fragments on many events, previous publicationshave reported only cross sections for B and Be fragments. In this work wehave extracted cross sections for all fragment species, using dataobtained at three distinct values of angular acceptance, supplementedmore » bydata taken with the detector stack placed off the beam axis. A simulationof the experiment with the PHITS Monte Carlo code shows fair agreementwith the data obtained with the large acceptance detectors, but agreementis poor at small acceptance. The measured cross sections are alsocompared to the predictions of the one-dimensional cross section modelsEPAX2 and NUCFRG2; the latter is presently used in NASA's space radiationtransport calculations. Though PHITS and NUCFRG2 reproduce thecharge-changing cross sections with reasonable accuracy, none of themodels is able to accurately predict the fragment cross sections for allfragment species and target materials.« less

Analysis and interpretation of satellite fragmentation data

NASA Technical Reports Server (NTRS)

Tan, Arjun

1987-01-01

The velocity perturbations of the fragments of a satellite can shed valuable information regarding the nature and intensity of the fragmentation. A feasibility study on calculating the velocity perturbations from existing equations was carried out by analyzing 23 major documented fragmentation events. It was found that whereas the calculated values of the radial components of the velocity change were often unusually high, those in the two other orthogonal directions were mostly reasonable. Since the uncertainties in the radial component necessarily translate into uncertainties in the total velocity change, it is suggested that alternative expressions for the radial component of velocity be sought for the purpose of determining the cause of the fragmentation from the total velocity change. The calculated variances in the velocity perturbations in the two directions orthogonal to the radial vector indicate that they have the smallest values for collision induced breakups and the largest values for low-intensity explosion induced breakups. The corresponding variances for high-intensity explosion induced breakups generally have values intermediate between those of the two extreme categories. A three-dimensional plot of the variances in the two orthogonal velocity perturbations and the plane change angle shows a clear separation between the three major types of breakups. This information is used to reclassify a number of satellite fragmentation events of unknown category.

Fast Biological Modeling for Voxel-based Heavy Ion Treatment Planning Using the Mechanistic Repair-Misrepair-Fixation Model and Nuclear Fragment Spectra.

PubMed

Kamp, Florian; Cabal, Gonzalo; Mairani, Andrea; Parodi, Katia; Wilkens, Jan J; Carlson, David J

2015-11-01

The physical and biological differences between heavy ions and photons have not been fully exploited and could improve treatment outcomes. In carbon ion therapy, treatment planning must account for physical properties, such as the absorbed dose and nuclear fragmentation, and for differences in the relative biological effectiveness (RBE) of ions compared with photons. We combined the mechanistic repair-misrepair-fixation (RMF) model with Monte Carlo-generated fragmentation spectra for biological optimization of carbon ion treatment plans. Relative changes in double-strand break yields and radiosensitivity parameters with particle type and energy were determined using the independently benchmarked Monte Carlo damage simulation and the RMF model to estimate the RBE values for primary carbon ions and secondary fragments. Depth-dependent energy spectra were generated with the Monte Carlo code FLUKA for clinically relevant initial carbon ion energies. The predicted trends in RBE were compared with the published experimental data. Biological optimization for carbon ions was implemented in a 3-dimensional research treatment planning tool. We compared the RBE and RBE-weighted dose (RWD) distributions of different carbon ion treatment scenarios with and without nuclear fragments. The inclusion of fragments in the simulations led to smaller RBE predictions. A validation of RMF against measured cell survival data reported in published studies showed reasonable agreement. We calculated and optimized the RWD distributions on patient data and compared the RMF predictions with those from other biological models. The RBE values in an astrocytoma tumor ranged from 2.2 to 4.9 (mean 2.8) for a RWD of 3 Gy(RBE) assuming (α/β)X = 2 Gy. These studies provide new information to quantify and assess uncertainties in the clinically relevant RBE values for carbon ion therapy based on biophysical mechanisms. We present results from the first biological optimization of carbon ion radiation therapy beams on patient data using a combined RMF and Monte Carlo damage simulation modeling approach. The presented method is advantageous for fast biological optimization. Copyright © 2015 Elsevier Inc. All rights reserved.

A new OH5 reconstruction with an assessment of its uncertainty.

PubMed

Benazzi, Stefano; Bookstein, Fred L; Strait, David S; Weber, Gerhard W

2011-07-01

The OH5 cranium, holotype of Paranthropus boisei consists of two main portions that do not fit together: the extensively reconstructed face and a portion of the neurocranium. A physical reconstruction of the cranium was carried out by Tobias in 1967, who did not discuss problems related to deformation, although he noted a slight functional asymmetry. Nevertheless, the reconstructed cranium shows some anomalies, mainly due to the right skewed position of the upper calvariofacial fragment and uncertainty of the relative position of the neurocranium to the face, which hamper further quantitative analysis of OH5's cranial geometry. Here, we present a complete virtual reconstruction of OH5, using three-dimensional (3D) digital data, geometric morphometric (GM) methods and computer-aided design (CAD) techniques. Starting from a CT scan of Tobias's reconstruction, a semi-automatic segmentation method was used to remove Tobias's plaster. The upper calvariofacial fragment was separated from the lower facial fragment and re-aligned using superposition of their independent midsagittal planes in a range of feasible positions. The missing parts of the right hemiface were reconstructed using non-uniform rational basis-spline (NURBS) surface and subsequently mirrored using the midsagittal plane to arrive at a symmetrical facial reconstruction. A symmetric neurocranium was obtained as the average of the original shape and its mirrored version. The alignment between the two symmetric shapes (face and neurocranium) used their independent midsagittal plane and a reference shape (KNM-ER 406) to highly reduce their degrees of freedom. From the series of alternative reconstructions, we selected the middle of this rather small feasible range. When reconstructed as a range in this way, the whole cranial form of this unique specimen can be further quantified by comparative coordinate-based methods such as GM or can be used for finite element modeling (FEM) explorations of hypotheses about the mechanics of early hominin feeding and diets. Copyright © 2011 Elsevier Ltd. All rights reserved.

Top-Down Hydrogen-Deuterium Exchange Analysis of Protein Structures Using Ultraviolet Photodissociation.

PubMed

Brodie, Nicholas I; Huguet, Romain; Zhang, Terry; Viner, Rosa; Zabrouskov, Vlad; Pan, Jingxi; Petrotchenko, Evgeniy V; Borchers, Christoph H

2018-03-06

Top-down hydrogen-deuterium exchange (HDX) analysis using electron capture or transfer dissociation Fourier transform mass spectrometry (FTMS) is a powerful method for the analysis of secondary structure of proteins in solution. The resolution of the method is a function of the degree of fragmentation of backbone bonds in the proteins. While fragmentation is usually extensive near the N- and C-termini, electron capture (ECD) or electron transfer dissociation (ETD) fragmentation methods sometimes lack good coverage of certain regions of the protein, most often in the middle of the sequence. Ultraviolet photodissociation (UVPD) is a recently developed fast-fragmentation technique, which provides extensive backbone fragmentation that can be complementary in sequence coverage to the aforementioned electron-based fragmentation techniques. Here, we explore the application of electrospray ionization (ESI)-UVPD FTMS on an Orbitrap Fusion Lumos Tribrid mass spectrometer to top-down HDX analysis of proteins. We have incorporated UVPD-specific fragment-ion types and fragment-ion mixtures into our isotopic envelope fitting software (HDX Match) for the top-down HDX analysis. We have shown that UVPD data is complementary to ETD, thus improving the overall resolution when used as a combined approach.

Fragmentation-based QM/MM simulations: length dependence of chain dynamics and hydrogen bonding of polyethylene oxide and polyethylene in aqueous solutions.

PubMed

Li, Hui; Li, Wei; Li, Shuhua; Ma, Jing

2008-06-12

Molecular fragmentation quantum mechanics (QM) calculations have been combined with molecular mechanics (MM) to construct the fragmentation QM/MM method for simulations of dilute solutions of macromolecules. We adopt the electrostatics embedding QM/MM model, where the low-cost generalized energy-based fragmentation calculations are employed for the QM part. Conformation energy calculations, geometry optimizations, and Born-Oppenheimer molecular dynamics simulations of poly(ethylene oxide), PEO(n) (n = 6-20), and polyethylene, PE(n) ( n = 9-30), in aqueous solution have been performed within the framework of both fragmentation and conventional QM/MM methods. The intermolecular hydrogen bonding and chain configurations obtained from the fragmentation QM/MM simulations are consistent with the conventional QM/MM method. The length dependence of chain conformations and dynamics of PEO and PE oligomers in aqueous solutions is also investigated through the fragmentation QM/MM molecular dynamics simulations.

Morphology of the posteromedial fragment in pertrochanteric fractures: A three-dimensional computed tomography analysis.

PubMed

Sharma, Gaurav; Gn, Kiran Kumar; Khatri, Kavin; Singh, Ravijot; Gamanagatti, Shivanand; Sharma, Vijay

2017-02-01

In this study we describe the morphology of the posteromedial fragment in pertrochanteric fractures using 3D CT scans and answer two questions 1) Do differences exist between the 3D CT appearances of posteromedial fragments and the depictions made in the AO classification 2) Does the posteromedial fragment affect stability in pertrochanteric fractures, in terms of fracture collapse? Preoperative CT scans of eight 31-A1 and fifty 31-A2 fractures were analysed. The presence of PM fragment, its fragmentation, greater trochanter (GT) involvement, lesser trochanter (LT) fragment size (in terms of its posterior and medial extent as well as LT length), LT fragment displacement (in terms of medial displacement and rotation) were determined. All fractures were treated with a DHS. Fracture collapse was determined on postoperative radiographs. The relationship between fracture collapse and patient factors including age, gender, fracture type (A1 versus A2), characteristics of the posteromedial fragment, and the presence of a lateral wall fracture were determined. Three out of eight 31-A1 fractures demonstrated a separate GT fragment (three part fracture). Out of the 50 31-A2 fractures, 12 had a single PM fragment, which included the LT and GT in continuity. The more common four part fractures seem to form by further fragmentation of this basic form. In A2 fractures, the GT was almost always broken and the broken fragment comprised a mean 56% of normal GT. The LT fragment involved an average of 74% of the posterior wall, and an average of 36% of the medial wall of the proximal femur. Larger LT fragments were less displaced as compared to smaller fragments. Univariate regression analyses revealed that fracture collapse was significantly correlated with fracture type (A1 versus A2, p 0.036), GT size (p 0.002) and the presence of a lateral wall fracture (p<0.001). This study revealed some important differences between the 3D CT appearances and AO classification of pertrochanteric fractures. Further, neither fragmentation of the posteromedial fragment, nor the size of the lesser trochanter fragment was found to predict stability in pertrochanteric fractures. A perioperative lateral wall fracture is the main determinant of stability in these fractures. Copyright © 2016 Elsevier Ltd. All rights reserved.

Identification of fracture zones and its application in automatic bone fracture reduction.

PubMed

Paulano-Godino, Félix; Jiménez-Delgado, Juan J

2017-04-01

The preoperative planning of bone fractures using information from CT scans increases the probability of obtaining satisfactory results, since specialists are provided with additional information before surgery. The reduction of complex bone fractures requires solving a 3D puzzle in order to place each fragment into its correct position. Computer-assisted solutions may aid in this process by identifying the number of fragments and their location, by calculating the fracture zones or even by computing the correct position of each fragment. The main goal of this paper is the development of an automatic method to calculate contact zones between fragments and thus to ease the computation of bone fracture reduction. In this paper, an automatic method to calculate the contact zone between two bone fragments is presented. In a previous step, bone fragments are segmented and labelled from CT images and a point cloud is generated for each bone fragment. The calculated contact zones enable the automatic reduction of complex fractures. To that end, an automatic method to match bone fragments in complex fractures is also presented. The proposed method has been successfully applied in the calculation of the contact zone of 4 different bones from the ankle area. The calculated fracture zones enabled the reduction of all the tested cases using the presented matching algorithm. The performed tests show that the reduction of these fractures using the proposed methods leaded to a small overlapping between fragments. The presented method makes the application of puzzle-solving strategies easier, since it does not obtain the entire fracture zone but the contact area between each pair of fragments. Therefore, it is not necessary to find correspondences between fracture zones and fragments may be aligned two by two. The developed algorithms have been successfully applied in different fracture cases in the ankle area. The small overlapping error obtained in the performed tests demonstrates the absence of visual overlapping in the figures. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Collapse and Fragmentation of Molecular Cloud Cores. VII. Magnetic Fields and Multiple Protostar Formation

NASA Astrophysics Data System (ADS)

Boss, Alan P.

2002-04-01

Recent observations of star-forming regions suggest that binary and multiple young stars are the rule rather than the exception and implicate fragmentation as the likely mechanism for their formation. Most numerical hydrodynamic calculations of fragmentation have neglected the possibly deleterious effects of magnetic fields, despite ample evidence for the importance of magnetic support of precollapse clouds. We present here the first numerical hydrodynamic survey of the collapse and fragmentation of initially magnetically supported clouds that takes into account several magnetic field effects in an approximate manner. The models are calculated with a three-dimensional, finite differences code that solves the equations of hydrodynamics, gravitation, and radiative transfer in the Eddington and diffusion approximations. Magnetic field effects are included through two simple approximations: magnetic pressure is added to the gas pressure, and magnetic tension is approximated by gravity dilution once collapse is well underway. Ambipolar diffusion of the magnetic field leading to cloud collapse is treated approximately as well. Models are calculated for a variety of initial cloud density profiles, shapes, and rotation rates. We find that in spite of the inclusion of magnetic field effects, dense cloud cores are capable of fragmenting into binary and multiple protostar systems. Initially prolate clouds tend to fragment into binary protostars, while initially oblate clouds tend to fragment into multiple protostar systems containing a small number (of the order of 4) of fragments. The latter are likely to be subject to rapid orbital evolution, with close encounters possibly leading to the ejection of fragments. Contrary to expectation, magnetic tension effects appear to enhance fragmentation, allowing lower mass fragments to form than would otherwise be possible, because magnetic tension helps to prevent a central density singularity from forming and producing a dominant single object. Magnetically supported dense cloud cores thus seem to be capable of collapsing and fragmenting into sufficient numbers of binary and multiple protostar systems to be compatible with observations of the relative rarity of single protostars.

Boundary acquisition for setup of numerical simulation

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

Diegert, C.

1997-12-31

The author presents a work flow diagram that includes a path that begins with taking experimental measurements, and ends with obtaining insight from results produced by numerical simulation. Two examples illustrate this path: (1) Three-dimensional imaging measurement at micron scale, using X-ray tomography, provides information on the boundaries of irregularly-shaped alumina oxide particles held in an epoxy matrix. A subsequent numerical simulation predicts the electrical field concentrations that would occur in the observed particle configurations. (2) Three-dimensional imaging measurement at meter scale, again using X-ray tomography, provides information on the boundaries fossilized bone fragments in a Parasaurolophus crest recently discoveredmore » in New Mexico. A subsequent numerical simulation predicts acoustic response of the elaborate internal structure of nasal passageways defined by the fossil record. The author must both add value, and must change the format of the three-dimensional imaging measurements before the define the geometric boundary initial conditions for the automatic mesh generation, and subsequent numerical simulation. The author applies a variety of filters and statistical classification algorithms to estimate the extents of the structures relevant to the subsequent numerical simulation, and capture these extents as faceted geometries. The author will describe the particular combination of manual and automatic methods used in the above two examples.« less

Method of inactivation of an end product of energy metabolism in Zymomonas mobilis

DOEpatents

Zhang, Min [Lakewood, CO; Chou, Yat-Chen [Lakewood, CO

2008-05-20

The present invention briefly provides a method of site-specific insertion in Zymomonas, comprising, providing a Zymomonas gene fragment, interrupting a DNA sequence the fragment, and transforming the Zymomonas through homologous recombination with the interrupted fragment.

Fragment-based virtual screening approach and molecular dynamics simulation studies for identification of BACE1 inhibitor leads.

PubMed

Manoharan, Prabu; Ghoshal, Nanda

2018-05-01

Traditional structure-based virtual screening method to identify drug-like small molecules for BACE1 is so far unsuccessful. Location of BACE1, poor Blood Brain Barrier permeability and P-glycoprotein (Pgp) susceptibility of the inhibitors make it even more difficult. Fragment-based drug design method is suitable for efficient optimization of initial hit molecules for target like BACE1. We have developed a fragment-based virtual screening approach to identify/optimize the fragment molecules as a starting point. This method combines the shape, electrostatic, and pharmacophoric features of known fragment molecules, bound to protein conjugate crystal structure, and aims to identify both chemically and energetically feasible small fragment ligands that bind to BACE1 active site. The two top-ranked fragment hits were subjected for a 53 ns MD simulation. Principle component analysis and free energy landscape analysis reveal that the new ligands show the characteristic features of established BACE1 inhibitors. The potent method employed in this study may serve for the development of potential lead molecules for BACE1-directed Alzheimer's disease therapeutics.

A Distribution-Free Description of Fragmentation by Blasting Based on Dimensional Analysis

NASA Astrophysics Data System (ADS)

Sanchidrián, José A.; Ouchterlony, Finn

2017-04-01

A model for fragmentation in bench blasting is developed from dimensional analysis adapted from asteroid collision theory, to which two factors have been added: one describing the discontinuities spacing and orientation and another the delay between successive contiguous shots. The formulae are calibrated by nonlinear fits to 169 bench blasts in different sites and rock types, bench geometries and delay times, for which the blast design data and the size distributions of the muckpile obtained by sieving were available. Percentile sizes of the fragments distribution are obtained as the product of a rock mass structural factor, a rock strength-to-explosive energy ratio, a bench shape factor, a scale factor or characteristic size and a function of the in-row delay. The rock structure is described by means of the joints' mean spacing and orientation with respect to the free face. The strength property chosen is the strain energy at rupture that, together with the explosive energy density, forms a combined rock strength/explosive energy factor. The model is applicable from 5 to 100 percentile sizes, with all parameters determined from the fits significant to a 0.05 level. The expected error of the prediction is below 25% at any percentile. These errors are half to one-third of the errors expected with the best prediction models available to date.

Sixty-five years of the long march in protein secondary structure prediction: the final stretch?

PubMed Central

Yang, Yuedong; Gao, Jianzhao; Wang, Jihua; Heffernan, Rhys; Hanson, Jack; Paliwal, Kuldip; Zhou, Yaoqi

2018-01-01

Abstract Protein secondary structure prediction began in 1951 when Pauling and Corey predicted helical and sheet conformations for protein polypeptide backbone even before the first protein structure was determined. Sixty-five years later, powerful new methods breathe new life into this field. The highest three-state accuracy without relying on structure templates is now at 82–84%, a number unthinkable just a few years ago. These improvements came from increasingly larger databases of protein sequences and structures for training, the use of template secondary structure information and more powerful deep learning techniques. As we are approaching to the theoretical limit of three-state prediction (88–90%), alternative to secondary structure prediction (prediction of backbone torsion angles and Cα-atom-based angles and torsion angles) not only has more room for further improvement but also allows direct prediction of three-dimensional fragment structures with constantly improved accuracy. About 20% of all 40-residue fragments in a database of 1199 non-redundant proteins have <6 Å root-mean-squared distance from the native conformations by SPIDER2. More powerful deep learning methods with improved capability of capturing long-range interactions begin to emerge as the next generation of techniques for secondary structure prediction. The time has come to finish off the final stretch of the long march towards protein secondary structure prediction. PMID:28040746

Oriented Immobilization of Fab Fragments by Site-Specific Biotinylation at the Conserved Nucleotide Binding Site for Enhanced Antigen Detection.

PubMed

Mustafaoglu, Nur; Alves, Nathan J; Bilgicer, Basar

2015-09-08

Oriented immobilization of antibodies and antibody fragments has become increasingly important as a result of the efforts to reduce the size of diagnostic and sensor devices to miniaturized dimensions for improved accessibility to the end-user. Reduced dimensions of sensor devices necessitate the immobilized antibodies to conserve their antigen binding activity for proper operation. Fab fragments are becoming more commonly used in small-scaled diagnostic devices due to their small size and ease of manufacture. In this study, we used the previously described UV-NBS(Biotin) method to functionalize Fab fragments with IBA-EG11-Biotin linker utilizing UV energy to initiate a photo-cross-linking reaction between the nucleotide binding site (NBS) on the Fab fragment and IBA-Biotin molecule. Our results demonstrate that immobilization of biotinylated Fab fragments via UV-NBS(Biotin) method generated the highest level of immobilized Fab on surfaces when compared to other typical immobilization methods while preserving antigen binding activity. UV-NBS(Biotin) method provided 432-fold, 114-fold, and 29-fold improved antigen detection sensitivity than physical adsorption, NHS-Biotin, and ε-NH3(+), methods, respectively. Additionally, the limit of detection (LOD) for PSA utilizing Fab fragments immobilized via UV-NBS(Biotin) method was significantly lower than that of the other immobilization methods, with an LOD of 0.4 pM PSA. In summary, site-specific biotinylation of Fab fragments without structural damage or loss in antigen binding activity provides a wide range of application potential for UV-NBS immobilization technique across numerous diagnostic devices and nanotechnologies.

Coherence and superconductivity in coupled one-dimensional chains: a case study of YBa2Cu3Oy.

PubMed

Lee, Y-S; Segawa, Kouji; Ando, Yoichi; Basov, D N

2005-04-08

We report the infrared (IR) response of Cu-O chains in the high-T(c) superconductor YBa(2)Cu(3)O(y) over the doping range spanning y=6.28-6.75. We find evidence for a power law scaling at mid-IR frequencies consistent with predictions for Tomonaga-Luttinger liquid, thus supporting the notion of one-dimensional transport in the chains. We analyze the role of coupling to the CuO2 planes in establishing metallicity and superconductivity in disordered chain fragments.

Cloning and characterization of an autonomous replication sequence from Coxiella burnetii.

PubMed Central

Suhan, M; Chen, S Y; Thompson, H A; Hoover, T A; Hill, A; Williams, J C

1994-01-01

A Coxiella burnetii chromosomal fragment capable of functioning as an origin for the replication of a kanamycin resistance (Kanr) plasmid was isolated by use of origin search methods utilizing an Escherichia coli host. The 5.8-kb fragment was subcloned into phagemid vectors and was deleted progressively by an exonuclease III-S1 technique. Plasmids containing progressively shorter DNA fragments were then tested for their capability to support replication by transformation of an E. coli polA strain. A minimal autonomous replication sequence (ARS) was delimited to 403 bp. Sequencing of the entire 5.8-kb region revealed that the minimal ARS contained two consensus DnaA boxes, three A + T-rich 21-mers, a transcriptional promoter leading rightwards, and potential integration host factor and factor of inversion stimulation binding sites. Database comparisons of deduced amino acid sequences revealed that open reading frames located around the ARS were homologous to genes often, but not always, found near bacterial chromosomal origins; these included identities with rpmH and rnpA in E. coli and identities with the 9K protein and 60K membrane protein in E. coli and Pseudomonas species. These and direct hybridization data suggested that the ARS was chromosomal and not associated with the resident plasmid QpH1. Two-dimensional agarose gel electrophoresis did not reveal the presence of initiating intermediates, indicating that the ARS did not initiate chromosome replication during laboratory growth of C. burnetii. Images PMID:8071197

Towards novel therapeutics for HIV through fragment-based screening and drug design.

PubMed

Tiefendbrunn, Theresa; Stout, C David

2014-01-01

Fragment-based drug discovery has been applied with varying levels of success to a number of proteins involved in the HIV (Human Immunodeficiency Virus) life cycle. Fragment-based approaches have led to the discovery of novel binding sites within protease, reverse transcriptase, integrase, and gp41. Novel compounds that bind to known pockets within CCR5 have also been identified via fragment screening, and a fragment-based approach to target the TAR-Tat interaction was explored. In the context of HIV-1 reverse transcriptase (RT), fragment-based approaches have yielded fragment hits with mid-μM activity in an in vitro activity assay, as well as fragment hits that are active against drug-resistant variants of RT. Fragment-based drug discovery is a powerful method to elucidate novel binding sites within proteins, and the method has had significant success in the context of HIV proteins.

Rational Design of High-Number dsDNA Fragments Based on Thermodynamics for the Construction of Full-Length Genes in a Single Reaction.

PubMed

Birla, Bhagyashree S; Chou, Hui-Hsien

2015-01-01

Gene synthesis is frequently used in modern molecular biology research either to create novel genes or to obtain natural genes when the synthesis approach is more flexible and reliable than cloning. DNA chemical synthesis has limits on both its length and yield, thus full-length genes have to be hierarchically constructed from synthesized DNA fragments. Gibson Assembly and its derivatives are the simplest methods to assemble multiple double-stranded DNA fragments. Currently, up to 12 dsDNA fragments can be assembled at once with Gibson Assembly according to its vendor. In practice, the number of dsDNA fragments that can be assembled in a single reaction are much lower. We have developed a rational design method for gene construction that allows high-number dsDNA fragments to be assembled into full-length genes in a single reaction. Using this new design method and a modified version of the Gibson Assembly protocol, we have assembled 3 different genes from up to 45 dsDNA fragments at once. Our design method uses the thermodynamic analysis software Picky that identifies all unique junctions in a gene where consecutive DNA fragments are specifically made to connect to each other. Our novel method is generally applicable to most gene sequences, and can improve both the efficiency and cost of gene assembly.

Integration of magnetic solid phase fishing and off-line two-dimensional high-performance liquid chromatography-diode array detector-mass spectrometry for screening and identification of human serum albumin binders from Radix Astragali.

PubMed

Zhang, Yuping; Nie, Mingkun; Shi, Shuyun; You, Qingping; Guo, Junfang; Liu, Liangliang

2014-03-01

Radix Astragali is one of the most popular traditional medicinal herb and healthy dietary supplement. Isoflavonoids and astragalosides are the main bioactive ingredients. However, the systematic bioactive component analysis is inadequate so far. Then a facile method based on Fe3O4@SiO2-human serum albumin (Fe3O4@SiO2-HSA) magnetic solid phase fishing integrated with two-dimensional high-performance liquid chromatography-diode array detector-mass spectrometry (2D HPLC-DAD-MS(n)) was developed to fish out and identify HSA binders from Radix Astragali. The immobilized HSA displayed a high stability with 96.2% retained after ten consecutive cycles. 2D HPLC system (size exclusion chromatography×reversed phase chromatography, SEC×RP) were developed and optimised. Forty-seven bioactive compounds including thirty-four isoflavonoids and thirteen astragalosides were screened and identified or tentatively deduced based on their retention time, ultraviolet (UV), accurate molecular weight and diagnostic fragment ions. The results indicated that the integrated method could be widely applied for systematical fishing and identification of bioactive compounds, especially for low-abundance and overlapped compounds, from complex mixtures. Copyright © 2013 Elsevier Ltd. All rights reserved.

Efficient exploration of chemical space by fragment-based screening.

PubMed

Hall, Richard J; Mortenson, Paul N; Murray, Christopher W

2014-01-01

Screening methods seek to sample a vast chemical space in order to identify starting points for further chemical optimisation. Fragment based drug discovery exploits the superior sampling of chemical space that can be achieved when the molecular weight is restricted. Here we show that commercially available fragment space is still relatively poorly sampled and argue for highly sensitive screening methods to allow the detection of smaller fragments. We analyse the properties of our fragment library versus the properties of X-ray hits derived from the library. We particularly consider properties related to the degree of planarity of the fragments. Copyright © 2014 Elsevier Ltd. All rights reserved.

A note on the self-similar solutions to the spontaneous fragmentation equation

NASA Astrophysics Data System (ADS)

Breschi, Giancarlo; Fontelos, Marco A.

2017-05-01

We provide a method to compute self-similar solutions for various fragmentation equations and use it to compute their asymptotic behaviours. Our procedure is applied to specific cases: (i) the case of mitosis, where fragmentation results into two identical fragments, (ii) fragmentation limited to the formation of sufficiently large fragments, and (iii) processes with fragmentation kernel presenting a power-like behaviour.

Forming spectroscopic massive protobinaries by disc fragmentation

NASA Astrophysics Data System (ADS)

Meyer, D. M.-A.; Kuiper, R.; Kley, W.; Johnston, K. G.; Vorobyov, E.

2018-01-01

The surroundings of massive protostars constitute an accretion disc which has numerically been shown to be subject to fragmentation and responsible for luminous accretion-driven outbursts. Moreover, it is suspected to produce close binary companions which will later strongly influence the star's future evolution in the Hertzsprung-Russel diagram. We present three-dimensional gravitation-radiation-hydrodynamic numerical simulations of 100 M⊙ pre-stellar cores. We find that accretion discs of young massive stars violently fragment without preventing the (highly variable) accretion of gaseous clumps on to the protostars. While acquiring the characteristics of a nascent low-mass companion, some disc fragments migrate on to the central massive protostar with dynamical properties showing that its final Keplerian orbit is close enough to constitute a close massive protobinary system, having a young high- and a low-mass components. We conclude on the viability of the disc fragmentation channel for the formation of such short-period binaries, and that both processes - close massive binary formation and accretion bursts - may happen at the same time. FU-Orionis-type bursts, such as observed in the young high-mass star S255IR-NIRS3, may not only indicate ongoing disc fragmentation, but also be considered as a tracer for the formation of close massive binaries - progenitors of the subsequent massive spectroscopic binaries - once the high-mass component of the system will enter the main-sequence phase of its evolution. Finally, we investigate the Atacama Large (sub-)Millimeter Array observability of the disc fragments.

Fragment screening by SPR and advanced application to GPCRs.

PubMed

Shepherd, Claire A; Hopkins, Andrew L; Navratilova, Iva

2014-01-01

Surface plasmon resonance (SPR) is one of the primary biophysical methods for the screening of low molecular weight 'fragment' libraries, due to its low protein consumption and 'label-free' methodology. SPR biosensor interaction analysis is employed to both screen and confirm the binding of compounds in fragment screening experiments, as it provides accurate information on the affinity and kinetics of molecular interactions. The most advanced application of the use of SPR for fragment screening is against membrane protein drug targets, such G-protein coupled receptors (GPCRs). Biophysical GPCR assays using SPR have been validated with pharmacological measurements approximate to cell-based methods, yet provide the advantage of biophysical methods in their ability to measure the weak affinities of low molecular weight fragments. A number of SPR fragment screens against GPCRs have now been disclosed in the literature. SPR fragment screening is proving versatile to screen both thermostabilised GPCRs and solubilised wild type receptors. In this chapter, we discuss the state-of-the-art in GPCR fragment screening by SPR and the technical considerations in performing such experiments. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

Metabolite identification through multiple kernel learning on fragmentation trees.

PubMed

Shen, Huibin; Dührkop, Kai; Böcker, Sebastian; Rousu, Juho

2014-06-15

Metabolite identification from tandem mass spectrometric data is a key task in metabolomics. Various computational methods have been proposed for the identification of metabolites from tandem mass spectra. Fragmentation tree methods explore the space of possible ways in which the metabolite can fragment, and base the metabolite identification on scoring of these fragmentation trees. Machine learning methods have been used to map mass spectra to molecular fingerprints; predicted fingerprints, in turn, can be used to score candidate molecular structures. Here, we combine fragmentation tree computations with kernel-based machine learning to predict molecular fingerprints and identify molecular structures. We introduce a family of kernels capturing the similarity of fragmentation trees, and combine these kernels using recently proposed multiple kernel learning approaches. Experiments on two large reference datasets show that the new methods significantly improve molecular fingerprint prediction accuracy. These improvements result in better metabolite identification, doubling the number of metabolites ranked at the top position of the candidates list. © The Author 2014. Published by Oxford University Press.

Magnetic Fields and Multiple Protostar Formation

NASA Astrophysics Data System (ADS)

Boss, A. P.

2001-12-01

Recent observations of star-forming regions suggest that binary and multiple young stars are the rule rather than the exception, and implicate fragmentation as the likely mechanism for their formation. Most numerical hydrodynamical calculations of fragmentation have neglected the possibly deleterious effects of magnetic fields, in spite of ample evidence for the importance of magnetic support of pre-collapse clouds. We present here the first numerical hydrodynamical survey of the full effects of magnetic fields on the collapse and fragmentation of dense cloud cores. The models are calculated with a three dimensional, finite differences code which solves the equations of hydrodynamics, gravitation, and radiative transfer in the Eddington and diffusion approximations. Magnetic field effects are included through two simple approximations: magnetic pressure is added to the gas pressure, and magnetic tension is approximated by gravity dilution once collapse is well underway. Ambipolar diffusion of the magnetic field leading to cloud collapse is treated approximately as well. Models are calculated for a variety of initial cloud density profiles, shapes, and rotation rates. We find that in spite of the inclusion of magnetic field effects, dense cloud cores are capable of fragmenting into binary and multiple protostar systems. Initially prolate clouds tend to fragment into binary protostars, while initially oblate clouds tend to fragment into multiple protostar systems containing a small number (of order four) of fragments. The latter are likely to be subject to rapid orbital evolution, with close encounters possibly leading to the ejection of fragments. Contrary to expectation, magnetic tension effects appear to enhance fragmentation, allowing lower mass fragments to form than would otherwise be possible, because magnetic tension helps to prevent a central density singularity from forming and producing a dominant single object. Magnetically-supported dense cloud cores thus seem to be capable of collapsing and fragmenting into sufficient numbers of binary and multiple protostar systems to be compatible with observations of the relative rarity of single protostars. This work was partially supported by NSF grants AST-9983530 and MRI-9976645.

Investigation of geological structures with a view to HLRW disposal, as revealed through 3D inversion of aeromagnetic and gravity data and the results of CSAMT exploration

NASA Astrophysics Data System (ADS)

An, Zhiguo; Di, Qingyun

2016-12-01

The Alxa area in Inner Mongolia has been selected as a possible site for geological disposal of high-level radioactive waste (HLRW). Based on results of a previous study on crustal stability, the Tamusu rock mass has been chosen as the target. To determine the geological structure of this rock mass, aeromagnetic and gravity data are collected and inverted. Three-dimensional (3D) inversion horizontal slices show that the internal density of the rock mass and the distribution of magnetic properties are not uniform, with fractures and fragmentation being present. To confirm this result, the controlled source audio-frequency magnetotelluric method (CSAMT) was applied to explore the geological structures, the typical CSAMT sounding curve was analyzed, and the response characteristics of the geological structure and surrounding rock are distinguished. The original data were processed and interpreted in combination with data from surface geology and drilling and logging data. It is found that the CSAMT results were consistent with those from 3D inversion of the gravity and magnetic data, confirming the existence of fractures and fragmentation in the exploration area.

Site-specific fab fragment biotinylation at the conserved nucleotide binding site for enhanced Ebola detection.

PubMed

Mustafaoglu, Nur; Alves, Nathan J; Bilgicer, Basar

2015-07-01

The nucleotide binding site (NBS) is a highly conserved region between the variable light and heavy chains at the Fab domains of all antibodies, and a small molecule that we identified, indole-3-butyric acid (IBA), binds specifically to this site. Fab fragment, with its small size and simple production methods compared to intact antibody, is good candidate for use in miniaturized diagnostic devices and targeted therapeutic applications. However, commonly used modification techniques are not well suited for Fab fragments as they are often more delicate than intact antibodies. Fab fragments are of particular interest for sensor surface functionalization but immobilization results in damage to the antigen binding site and greatly reduced activity due to their truncated size that allows only a small area that can bind to surfaces without impeding antigen binding. In this study, we describe an NBS-UV photocrosslinking functionalization method (UV-NBS(Biotin) in which a Fab fragment is site-specifically biotinylated with an IBA-EG11-Biotin linker via UV energy exposure (1 J/cm(2)) without affecting its antigen binding activity. This study demonstrates successful immobilization of biotinylated Ebola detecting Fab fragment (KZ52 Fab fragment) via the UV-NBS(Biotin) method yielding 1031-fold and 2-fold better antigen detection sensitivity compared to commonly used immobilization methods: direct physical adsorption and NHS-Biotin functionalization, respectively. Utilization of the UV-NBS(Biotin) method for site-specific conjugation to Fab fragment represents a proof of concept use of Fab fragment for various diagnostic and therapeutic applications with numerous fluorescent probes, affinity molecules and peptides. © 2015 Wiley Periodicals, Inc.

Critical Features of Fragment Libraries for Protein Structure Prediction

PubMed Central

dos Santos, Karina Baptista

2017-01-01

The use of fragment libraries is a popular approach among protein structure prediction methods and has proven to substantially improve the quality of predicted structures. However, some vital aspects of a fragment library that influence the accuracy of modeling a native structure remain to be determined. This study investigates some of these features. Particularly, we analyze the effect of using secondary structure prediction guiding fragments selection, different fragments sizes and the effect of structural clustering of fragments within libraries. To have a clearer view of how these factors affect protein structure prediction, we isolated the process of model building by fragment assembly from some common limitations associated with prediction methods, e.g., imprecise energy functions and optimization algorithms, by employing an exact structure-based objective function under a greedy algorithm. Our results indicate that shorter fragments reproduce the native structure more accurately than the longer. Libraries composed of multiple fragment lengths generate even better structures, where longer fragments show to be more useful at the beginning of the simulations. The use of many different fragment sizes shows little improvement when compared to predictions carried out with libraries that comprise only three different fragment sizes. Models obtained from libraries built using only sequence similarity are, on average, better than those built with a secondary structure prediction bias. However, we found that the use of secondary structure prediction allows greater reduction of the search space, which is invaluable for prediction methods. The results of this study can be critical guidelines for the use of fragment libraries in protein structure prediction. PMID:28085928

Critical Features of Fragment Libraries for Protein Structure Prediction.

PubMed

Trevizani, Raphael; Custódio, Fábio Lima; Dos Santos, Karina Baptista; Dardenne, Laurent Emmanuel

2017-01-01

The use of fragment libraries is a popular approach among protein structure prediction methods and has proven to substantially improve the quality of predicted structures. However, some vital aspects of a fragment library that influence the accuracy of modeling a native structure remain to be determined. This study investigates some of these features. Particularly, we analyze the effect of using secondary structure prediction guiding fragments selection, different fragments sizes and the effect of structural clustering of fragments within libraries. To have a clearer view of how these factors affect protein structure prediction, we isolated the process of model building by fragment assembly from some common limitations associated with prediction methods, e.g., imprecise energy functions and optimization algorithms, by employing an exact structure-based objective function under a greedy algorithm. Our results indicate that shorter fragments reproduce the native structure more accurately than the longer. Libraries composed of multiple fragment lengths generate even better structures, where longer fragments show to be more useful at the beginning of the simulations. The use of many different fragment sizes shows little improvement when compared to predictions carried out with libraries that comprise only three different fragment sizes. Models obtained from libraries built using only sequence similarity are, on average, better than those built with a secondary structure prediction bias. However, we found that the use of secondary structure prediction allows greater reduction of the search space, which is invaluable for prediction methods. The results of this study can be critical guidelines for the use of fragment libraries in protein structure prediction.

Nudged elastic band method and density functional theory calculation for finding a local minimum energy pathway of p-benzoquinone and phenol fragmentation in mass spectrometry.

PubMed

Sugimura, Natsuhiko; Igarashi, Yoko; Aoyama, Reiko; Shibue, Toshimichi

2017-02-01

Analysis of the fragmentation pathways of molecules in mass spectrometry gives a fundamental insight into gas-phase ion chemistry. However, the conventional intrinsic reaction coordinates method requires knowledge of the transition states of ion structures in the fragmentation pathways. Herein, we use the nudged elastic band method, using only the initial and final state ion structures in the fragmentation pathways, and report the advantages and limitations of the method. We found a minimum energy path of p-benzoquinone ion fragmentation with two saddle points and one intermediate structure. The primary energy barrier, which corresponded to the cleavage of the C-C bond adjacent to the CO group, was calculated to be 1.50 eV. An additional energy barrier, which corresponded to the cleavage of the CO group, was calculated to be 0.68 eV. We also found an energy barrier of 3.00 eV, which was the rate determining step of the keto-enol tautomerization in CO elimination from the molecular ion of phenol. The nudged elastic band method allowed the determination of a minimum energy path using only the initial and final state ion structures in the fragmentation pathways, and it provided faster than the conventional intrinsic reaction coordinates method. In addition, this method was found to be effective in the analysis of the charge structures of the molecules during the fragmentation in mass spectrometry.

Hydrocode predictions of collisional outcomes: Effects of target size

NASA Technical Reports Server (NTRS)

Ryan, Eileen V.; Asphaug, Erik; Melosh, H. J.

1991-01-01

Traditionally, laboratory impact experiments, designed to simulate asteroid collisions, attempted to establish a predictive capability for collisional outcomes given a particular set of initial conditions. Unfortunately, laboratory experiments are restricted to using targets considerably smaller than the modelled objects. It is therefore necessary to develop some methodology for extrapolating the extensive experimental results to the size regime of interest. Results are reported obtained through the use of two dimensional hydrocode based on 2-D SALE and modified to include strength effects and the fragmentation equations. The hydrocode was tested by comparing its predictions for post-impact fragment size distributions to those observed in laboratory impact experiments.

Synthesis of a posterior indicator protein in normal embryos and double abdomens of Smittia sp. (Chironomidae, Diptera).

PubMed Central

Jäckle, H; Kalthoff, K

1980-01-01

In embryos of the chironomid midge Smittia, synthesis of a posterior indicator protein designated PI1 (Mr approximately 50,000; pI approximately 5.5) forecasts development of an abdomen as opposed to head and thorax. The protein is synthesized several hours before germ anlage formation. In normal embryos at early blastoderm stages, synthesis of PI1 is restricted to posterior embryonic fragments but not to pole cells. In "double-abdomen" embryos, a mirror-image duplication of the abdomen is formed by cells that would otherwise develop into head and thorax. Embryos were programmed for double-abdomen development by UV irradiation of the anterior pole, and half of them were reprogrammed for normal development by subsequent exposure to visible light (photoreversal). Correspondingly, PI1 was synthesized in anterior fragments of UV-irradiated embryos but not after photoreversal. In a control experiment, UV irradiation of the posterior pole caused neither double-abdomen formation nor PI1 synthesis in anterior fragments. The identity of PI1 formed in anterior fragments of prospective double abdomens with the protein found in posterior fragments was revealed by two-dimensional gel electrophoresis and limited proteolysis. Suppression of PI1 synthesis in anterior fragments of normal embryos is ascribed to the activity of cytoplasmic ribonucleoprotein particles thought to act as anterior determinants. Images PMID:6935679

Periacetabular osteotomy: a review of swiss experience.

PubMed

Büchler, Lorenz; Beck, Martin

2014-12-01

Symptomatic dysplasia of the hip and acetabular retroversion are possible causes of osteoarthritis in the young adult. Surgical management with reorientation of the acetabulum allows causal therapy of the deformity and preservation of the native hip joint. The Ganz' periacetabular osteotomy permits a free 3-dimensional reorientation of the acetabulum and respects the blood supply of the acetabular fragment. The posterior column remains intact with a stable fixation of the acetabular fragment and a preserved shape of the true pelvis. There is a significant learning curve with severe complications in up to 30 % of cases. Good results can be expected in the long-term follow-up if performed with correct indication at young age in hips with preserved joint cartilage and proper reorientation of the acetabular fragment. Overall survivorship is superior to the natural course of hip dysplasia with a preserved hip joint in 61 % after 20 years.

Assessment of optimal control mechanism complexity by experimental landscape Hessian analysis: fragmentation of CH2BrI

NASA Astrophysics Data System (ADS)

Xing, Xi; Rey-de-Castro, Roberto; Rabitz, Herschel

2014-12-01

Optimally shaped femtosecond laser pulses can often be effectively identified in adaptive feedback quantum control experiments, but elucidating the underlying control mechanism can be a difficult task requiring significant additional analysis. We introduce landscape Hessian analysis (LHA) as a practical experimental tool to aid in elucidating control mechanism insights. This technique is applied to the dissociative ionization of CH2BrI using shaped fs laser pulses for optimization of the absolute yields of ionic fragments as well as their ratios for the competing processes of breaking the C-Br and C-I bonds. The experimental results suggest that these nominally complex problems can be reduced to a low-dimensional control space with insights into the control mechanisms. While the optimal yield for some fragments is dominated by a non-resonant intensity-driven process, the optimal generation of other fragments maa difficult task requiring significant additionaly be explained by a non-resonant process coupled to few level resonant dynamics. Theoretical analysis and modeling is consistent with the experimental observations.

Analysis of the total kinetic energy of fission fragments with the Langevin equation

NASA Astrophysics Data System (ADS)

Usang, M. D.; Ivanyuk, F. A.; Ishizuka, C.; Chiba, S.

2017-12-01

We analyzed the total kinetic energy (TKE) of fission fragments with three-dimensional Langevin calculations for a series of actinides and Fm isotopes at various excitation energies. This allowed us to establish systematic trends of TKE with Z2/A1 /3 of the fissioning system and as a function of excitation energy. In the mass-energy distributions of fission fragments we see the contributions from the standard, super-long, and super-short (in the case of 258Fm) fission modes. For the fission fragments mass distribution of 258Fm we obtained a single peak mass distribution. The decomposition of TKE into the prescission kinetic energy and Coulomb repulsion showed that decrease of TKE with growing excitation energy is accompanied by a decrease of prescission kinetic energy. It was also found that transport coefficients (friction and inertia tensors) calculated by a microscopic model and by macroscopic models give drastically different behaviors of TKE as a function of excitation energy. The results obtained with microscopic transport coefficients are much closer to experimental data than those calculated with macroscopic ones.

Proteomic profile of dry-cured ham relative to PRKAG3 or CAST genotype, level of salt and pastiness.

PubMed

Skrlep, Martin; Candek-Potokar, Marjeta; Mandelc, Stanislav; Javornik, Branka; Gou, Pere; Chambon, Christophe; Santé-Lhoutellier, Véronique

2011-08-01

Two-dimensional electrophoresis was used to compare dry-cured biceps femoris insoluble protein fraction according to genotype (PRKAG3Ile199Val and CASTLys249Arg/Ser638Arg) as well as salt and pastiness level. The PRKAG3 affected mainly muscle metabolic enzymes, indicating its possible influence on muscle metabolism with heterozygotes Ile/Val appearing different from both homozygous genotypes. The effect of CAST was smaller, affecting the quantity of one actin fragment. Dry-cured ham salt and pastiness level affected a wide variety of protein spots including metabolic enzymes, plasma proteins, chaperones and myofibrillar proteins, including protein fragments, indicating the connection with proteolysis. Pastiness was associated with salt content, reflected also by the fact that many spots were affected by both factors. Despite the absence of extreme pastiness (or low salt samples), some protein spots (actin, MHC fragment, desmin fragment) exhibited important differences in intensity according to pastiness (and salt level) suggesting they could be used as potential quality markers. Copyright © 2011 Elsevier Ltd. All rights reserved.

Quantifying three dimensional reconnection in fragmented current layers

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

Wyper, P. F., E-mail: peter.f.wyper@nasa.gov; Hesse, M., E-mail: michael.hesse-1@nasa.gov

There is growing evidence that when magnetic reconnection occurs in high Lundquist number plasmas such as in the Solar Corona or the Earth's Magnetosphere it does so within a fragmented, rather than a smooth current layer. Within the extent of these fragmented current regions, the associated magnetic flux transfer and energy release occur simultaneously in many different places. This investigation focusses on how best to quantify the rate at which reconnection occurs in such layers. An analytical theory is developed which describes the manner in which new connections form within fragmented current layers in the absence of magnetic nulls. Itmore » is shown that the collective rate at which new connections form can be characterized by two measures; a total rate which measures the true rate at which new connections are formed and a net rate which measures the net change of connection associated with the largest value of the integral of E{sub ||} through all of the non-ideal regions. Two simple analytical models are presented which demonstrate how each should be applied and what they quantify.« less

Technique for Increasing the Selectivity of the Method of Laser Fragmentation/Laser-Induced Fluorescence

NASA Astrophysics Data System (ADS)

Bobrovnikov, S. M.; Gorlov, E. V.; Zharkov, V. I.

2018-05-01

A technique for increasing the selectivity of the method of detecting high-energy materials (HEMs) based on laser fragmentation of HEM molecules with subsequent laser excitation of fluorescence of the characteristic NO fragments from the first vibrational level of the ground state is suggested.

[Analysis of Conformational Features of Watson-Crick Duplex Fragments by Molecular Mechanics and Quantum Mechanics Methods].

PubMed

Poltev, V I; Anisimov, V M; Sanchez, C; Deriabina, A; Gonzalez, E; Garcia, D; Rivas, F; Polteva, N A

2016-01-01

It is generally accepted that the important characteristic features of the Watson-Crick duplex originate from the molecular structure of its subunits. However, it still remains to elucidate what properties of each subunit are responsible for the significant characteristic features of the DNA structure. The computations of desoxydinucleoside monophosphates complexes with Na-ions using density functional theory revealed a pivotal role of DNA conformational properties of single-chain minimal fragments in the development of unique features of the Watson-Crick duplex. We found that directionality of the sugar-phosphate backbone and the preferable ranges of its torsion angles, combined with the difference between purines and pyrimidines. in ring bases, define the dependence of three-dimensional structure of the Watson-Crick duplex on nucleotide base sequence. In this work, we extended these density functional theory computations to the minimal' fragments of DNA duplex, complementary desoxydinucleoside monophosphates complexes with Na-ions. Using several computational methods and various functionals, we performed a search for energy minima of BI-conformation for complementary desoxydinucleoside monophosphates complexes with different nucleoside sequences. Two sequences are optimized using ab initio method at the MP2/6-31++G** level of theory. The analysis of torsion angles, sugar ring puckering and mutual base positions of optimized structures demonstrates that the conformational characteristic features of complementary desoxydinucleoside monophosphates complexes with Na-ions remain within BI ranges and become closer to the corresponding characteristic features of the Watson-Crick duplex crystals. Qualitatively, the main characteristic features of each studied complementary desoxydinucleoside monophosphates complex remain invariant when different computational methods are used, although the quantitative values of some conformational parameters could vary lying within the limits typical for the corresponding family. We observe that popular functionals in density functional theory calculations lead to the overestimated distances between base pairs, while MP2 computations and the newer complex functionals produce the structures that have too close atom-atom contacts. A detailed study of some complementary desoxydinucleoside monophosphate complexes with Na-ions highlights the existence of several energy minima corresponding to BI-conformations, in other words, the complexity of the relief pattern of the potential energy surface of complementary desoxydinucleoside monophosphate complexes. This accounts for variability of conformational parameters of duplex fragments with the same base sequence. Popular molecular mechanics force fields AMBER and CHARMM reproduce most of the conformational characteristics of desoxydinucleoside monophosphates and their complementary complexes with Na-ions but fail to reproduce some details of the dependence of the Watson-Crick duplex conformation on the nucleotide sequence.

Identifying Interactions that Determine Fragment Binding at Protein Hotspots.

PubMed

Radoux, Chris J; Olsson, Tjelvar S G; Pitt, Will R; Groom, Colin R; Blundell, Tom L

2016-05-12

Locating a ligand-binding site is an important first step in structure-guided drug discovery, but current methods do little to suggest which interactions within a pocket are the most important for binding. Here we illustrate a method that samples atomic hotspots with simple molecular probes to produce fragment hotspot maps. These maps specifically highlight fragment-binding sites and their corresponding pharmacophores. For ligand-bound structures, they provide an intuitive visual guide within the binding site, directing medicinal chemists where to grow the molecule and alerting them to suboptimal interactions within the original hit. The fragment hotspot map calculation is validated using experimental binding positions of 21 fragments and subsequent lead molecules. The ligands are found in high scoring areas of the fragment hotspot maps, with fragment atoms having a median percentage rank of 97%. Protein kinase B and pantothenate synthetase are examined in detail. In each case, the fragment hotspot maps are able to rationalize a Free-Wilson analysis of SAR data from a fragment-based drug design project.

Fragment size distribution statistics in dynamic fragmentation of laser shock-loaded tin

NASA Astrophysics Data System (ADS)

He, Weihua; Xin, Jianting; Zhao, Yongqiang; Chu, Genbai; Xi, Tao; Shui, Min; Lu, Feng; Gu, Yuqiu

2017-06-01

This work investigates the geometric statistics method to characterize the size distribution of tin fragments produced in the laser shock-loaded dynamic fragmentation process. In the shock experiments, the ejection of the tin sample with etched V-shape groove in the free surface are collected by the soft recovery technique. Subsequently, the produced fragments are automatically detected with the fine post-shot analysis techniques including the X-ray micro-tomography and the improved watershed method. To characterize the size distributions of the fragments, a theoretical random geometric statistics model based on Poisson mixtures is derived for dynamic heterogeneous fragmentation problem, which reveals linear combinational exponential distribution. The experimental data related to fragment size distributions of the laser shock-loaded tin sample are examined with the proposed theoretical model, and its fitting performance is compared with that of other state-of-the-art fragment size distribution models. The comparison results prove that our proposed model can provide far more reasonable fitting result for the laser shock-loaded tin.

Effective Fragment Potential Method for H-Bonding: How To Obtain Parameters for Nonrigid Fragments.

PubMed

Dubinets, Nikita; Slipchenko, Lyudmila V

2017-07-20

Accuracy of the effective fragment potential (EFP) method was explored for describing intermolecular interaction energies in three dimers with strong H-bonded interactions, formic acid, formamide, and formamidine dimers, which are a part of HBC6 database of noncovalent interactions. Monomer geometries in these dimers change significantly as a function of intermonomer separation. Several EFP schemes were considered, in which fragment parameters were prepared for a fragment in its gas-phase geometry or recomputed for each unique fragment geometry. Additionally, a scheme in which gas-phase fragment parameters are shifted according to relaxed fragment geometries is introduced and tested. EFP data are compared against the coupled cluster with single, double, and perturbative triple excitations (CCSD(T)) method in a complete basis set (CBS) and the symmetry adapted perturbation theory (SAPT). All considered EFP schemes provide a good agreement with CCSD(T)/CBS for binding energies at equilibrium separations, with discrepancies not exceeding 2 kcal/mol. However, only the schemes that utilize relaxed fragment geometries remain qualitatively correct at shorter than equilibrium intermolecular distances. The EFP scheme with shifted parameters behaves quantitatively similar to the scheme in which parameters are recomputed for each monomer geometry and thus is recommended as a computationally efficient approach for large-scale EFP simulations of flexible systems.

FRAGSION: ultra-fast protein fragment library generation by IOHMM sampling.

PubMed

Bhattacharya, Debswapna; Adhikari, Badri; Li, Jilong; Cheng, Jianlin

2016-07-01

Speed, accuracy and robustness of building protein fragment library have important implications in de novo protein structure prediction since fragment-based methods are one of the most successful approaches in template-free modeling (FM). Majority of the existing fragment detection methods rely on database-driven search strategies to identify candidate fragments, which are inherently time-consuming and often hinder the possibility to locate longer fragments due to the limited sizes of databases. Also, it is difficult to alleviate the effect of noisy sequence-based predicted features such as secondary structures on the quality of fragment. Here, we present FRAGSION, a database-free method to efficiently generate protein fragment library by sampling from an Input-Output Hidden Markov Model. FRAGSION offers some unique features compared to existing approaches in that it (i) is lightning-fast, consuming only few seconds of CPU time to generate fragment library for a protein of typical length (300 residues); (ii) can generate dynamic-size fragments of any length (even for the whole protein sequence) and (iii) offers ways to handle noise in predicted secondary structure during fragment sampling. On a FM dataset from the most recent Critical Assessment of Structure Prediction, we demonstrate that FGRAGSION provides advantages over the state-of-the-art fragment picking protocol of ROSETTA suite by speeding up computation by several orders of magnitude while achieving comparable performance in fragment quality. Source code and executable versions of FRAGSION for Linux and MacOS is freely available to non-commercial users at http://sysbio.rnet.missouri.edu/FRAGSION/ It is bundled with a manual and example data. chengji@missouri.edu Supplementary data are available at Bioinformatics online. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Hot Fusion: an efficient method to clone multiple DNA fragments as well as inverted repeats without ligase.

PubMed

Fu, Changlin; Donovan, William P; Shikapwashya-Hasser, Olga; Ye, Xudong; Cole, Robert H

2014-01-01

Molecular cloning is utilized in nearly every facet of biological and medical research. We have developed a method, termed Hot Fusion, to efficiently clone one or multiple DNA fragments into plasmid vectors without the use of ligase. The method is directional, produces seamless junctions and is not dependent on the availability of restriction sites for inserts. Fragments are assembled based on shared homology regions of 17-30 bp at the junctions, which greatly simplifies the construct design. Hot Fusion is carried out in a one-step, single tube reaction at 50 °C for one hour followed by cooling to room temperature. In addition to its utility for multi-fragment assembly Hot Fusion provides a highly efficient method for cloning DNA fragments containing inverted repeats for applications such as RNAi. The overall cloning efficiency is in the order of 90-95%.

Hot Fusion: An Efficient Method to Clone Multiple DNA Fragments as Well as Inverted Repeats without Ligase

PubMed Central

Fu, Changlin; Donovan, William P.; Shikapwashya-Hasser, Olga; Ye, Xudong; Cole, Robert H.

2014-01-01

Molecular cloning is utilized in nearly every facet of biological and medical research. We have developed a method, termed Hot Fusion, to efficiently clone one or multiple DNA fragments into plasmid vectors without the use of ligase. The method is directional, produces seamless junctions and is not dependent on the availability of restriction sites for inserts. Fragments are assembled based on shared homology regions of 17–30 bp at the junctions, which greatly simplifies the construct design. Hot Fusion is carried out in a one-step, single tube reaction at 50°C for one hour followed by cooling to room temperature. In addition to its utility for multi-fragment assembly Hot Fusion provides a highly efficient method for cloning DNA fragments containing inverted repeats for applications such as RNAi. The overall cloning efficiency is in the order of 90–95%. PMID:25551825

Evaluation of oriented lysozyme immobilized with monoclonal antibody

NASA Astrophysics Data System (ADS)

Aoyagi, Satoka; Okada, Keigo; Shigyo, Ayako; Man, Naoki; Karen, Akiya

2008-12-01

The orientation of a lysozyme immobilized with a monoclonal antibody was evaluated based on determination of the uppermost surface structure using time-of-flight secondary ion mass spectrometry (TOF-SIMS). Specific peaks of the oriented lysozyme immobilized with monoclonal anti-lysozyme antibody were obtained in comparison with reference samples, non-oriented immobilized lysozyme and immobilized anti-lysozyme antibody. All samples were freeze-dried before TOF-SIMS measurement, and then each sample was measured using TOF-SIMS with a bismuth cluster ion source. TOF-SIMS spectra were analyzed to select peaks specific to the oriented immobilized lysozyme as well as to identify their chemical formula and ensemble of amino acids. The possible chemical formulae of the lysozyme fragments were then investigated with an element matching program and a residue matching program. The results from TOF-SIMS spectra analysis were compared to the amino acid sequence of the lysozyme and its three-dimensional structure registered in the protein data bank. Finally, the fragment-ion-generating regions of the oriented immobilized lysozyme were determined based on the suggested residues and the three-dimensional structure.

Modeling NIF experimental designs with adaptive mesh refinement and Lagrangian hydrodynamics

NASA Astrophysics Data System (ADS)

Koniges, A. E.; Anderson, R. W.; Wang, P.; Gunney, B. T. N.; Becker, R.; Eder, D. C.; MacGowan, B. J.; Schneider, M. B.

2006-06-01

Incorporation of adaptive mesh refinement (AMR) into Lagrangian hydrodynamics algorithms allows for the creation of a highly powerful simulation tool effective for complex target designs with three-dimensional structure. We are developing an advanced modeling tool that includes AMR and traditional arbitrary Lagrangian-Eulerian (ALE) techniques. Our goal is the accurate prediction of vaporization, disintegration and fragmentation in National Ignition Facility (NIF) experimental target elements. Although our focus is on minimizing the generation of shrapnel in target designs and protecting the optics, the general techniques are applicable to modern advanced targets that include three-dimensional effects such as those associated with capsule fill tubes. Several essential computations in ordinary radiation hydrodynamics need to be redesigned in order to allow for AMR to work well with ALE, including algorithms associated with radiation transport. Additionally, for our goal of predicting fragmentation, we include elastic/plastic flow into our computations. We discuss the integration of these effects into a new ALE-AMR simulation code. Applications of this newly developed modeling tool as well as traditional ALE simulations in two and three dimensions are applied to NIF early-light target designs.

Quantum mechanical fragment methods based on partitioning atoms or partitioning coordinates.

PubMed

Wang, Bo; Yang, Ke R; Xu, Xuefei; Isegawa, Miho; Leverentz, Hannah R; Truhlar, Donald G

2014-09-16

Conspectus The development of more efficient and more accurate ways to represent reactive potential energy surfaces is a requirement for extending the simulation of large systems to more complex systems, longer-time dynamical processes, and more complete statistical mechanical sampling. One way to treat large systems is by direct dynamics fragment methods. Another way is by fitting system-specific analytic potential energy functions with methods adapted to large systems. Here we consider both approaches. First we consider three fragment methods that allow a given monomer to appear in more than one fragment. The first two approaches are the electrostatically embedded many-body (EE-MB) expansion and the electrostatically embedded many-body expansion of the correlation energy (EE-MB-CE), which we have shown to yield quite accurate results even when one restricts the calculations to include only electrostatically embedded dimers. The third fragment method is the electrostatically embedded molecular tailoring approach (EE-MTA), which is more flexible than EE-MB and EE-MB-CE. We show that electrostatic embedding greatly improves the accuracy of these approaches compared with the original unembedded approaches. Quantum mechanical fragment methods share with combined quantum mechanical/molecular mechanical (QM/MM) methods the need to treat a quantum mechanical fragment in the presence of the rest of the system, which is especially challenging for those parts of the rest of the system that are close to the boundary of the quantum mechanical fragment. This is a delicate matter even for fragments that are not covalently bonded to the rest of the system, but it becomes even more difficult when the boundary of the quantum mechanical fragment cuts a bond. We have developed a suite of methods for more realistically treating interactions across such boundaries. These methods include redistributing and balancing the external partial atomic charges and the use of tuned fluorine atoms for capping dangling bonds, and we have shown that they can greatly improve the accuracy. Finally we present a new approach that goes beyond QM/MM by combining the convenience of molecular mechanics with the accuracy of fitting a potential function to electronic structure calculations on a specific system. To make the latter practical for systems with a large number of degrees of freedom, we developed a method to interpolate between local internal-coordinate fits to the potential energy. A key issue for the application to large systems is that rather than assigning the atoms or monomers to fragments, we assign the internal coordinates to reaction, secondary, and tertiary sets. Thus, we make a partition in coordinate space rather than atom space. Fits to the local dependence of the potential energy on tertiary coordinates are arrayed along a preselected reaction coordinate at a sequence of geometries called anchor points; the potential energy function is called an anchor points reactive potential. Electrostatically embedded fragment methods and the anchor points reactive potential, because they are based on treating an entire system by quantum mechanical electronic structure methods but are affordable for large and complex systems, have the potential to open new areas for accurate simulations where combined QM/MM methods are inadequate.

Practical quantum mechanics-based fragment methods for predicting molecular crystal properties.

PubMed

Wen, Shuhao; Nanda, Kaushik; Huang, Yuanhang; Beran, Gregory J O

2012-06-07

Significant advances in fragment-based electronic structure methods have created a real alternative to force-field and density functional techniques in condensed-phase problems such as molecular crystals. This perspective article highlights some of the important challenges in modeling molecular crystals and discusses techniques for addressing them. First, we survey recent developments in fragment-based methods for molecular crystals. Second, we use examples from our own recent research on a fragment-based QM/MM method, the hybrid many-body interaction (HMBI) model, to analyze the physical requirements for a practical and effective molecular crystal model chemistry. We demonstrate that it is possible to predict molecular crystal lattice energies to within a couple kJ mol(-1) and lattice parameters to within a few percent in small-molecule crystals. Fragment methods provide a systematically improvable approach to making predictions in the condensed phase, which is critical to making robust predictions regarding the subtle energy differences found in molecular crystals.

Production and characterization of anti-human IgG F(ab')2 antibody fragment.

PubMed

Valedkarimi, Zahra; Nasiri, Hadi; Aghebati-Maleki, Leili; Abdolalizadeh, Jalal; Esparvarinha, Mojghan; Majidi, Jafar

2018-04-10

In present study an optimized protocol for the separation of antibodies into antigen-binding fragments F(ab')2 using pepsin digestion was investigated. The production of these fragments is a consequential step in the development of medical research, treatment and diagnosis. For production of polyclonal antibody rabbit received antigen in four steps. The rabbit serum at 1/128000 dilution showed high absorbance in reaction with human IgG at the designed ELISA method. Rabbit IgG was purified by Ion-Exchange Chromatography (IEC) method. Purity was assessed by SDS-PAGE method. In non-reduced condition only one band was seen in about 150 kDa MW position and in reduced form, two bands were seen in 50 and 25 kDa MW positions. Rabbit IgG was digested by pepsin enzyme. The antibody fragments solution was applied to Gel filtration column to isolate the F(ab')2. Non-reduced SDS-PAGE for determining the purity of F(ab')2 fragment resulted in one band in 100 kDa corresponds to F(ab')2 fragment and a band in 150 kDa MW position corresponds to undigested IgG antibodies. The activities of FITC conjugated F(ab')2 fragment and commercial ones were compared using flowcytometry method. The activity results implied that the FITC conjugated- anti human F(ab')2 fragment worked as efficiently as the commercial one.

Hot-stage microscopy for determination of API fragmentation: comparison with other methods.

PubMed

Šimek, Michal; Grünwaldová, Veronika; Kratochvíl, Bohumil

2016-08-01

Although the fragmentation of the active pharmaceutical ingredient (API) is a phenomenon that is mentioned in many literature sources, no well-suited analytical tools for its investigation are currently known. We used the hot-stage microscopy method, already presented in our previous work, and studied the real fragmentation of the tadalafil particles in model tablets which were prepared under different compaction pressures. The morphology, spectral imaging and evaluation of plastic and elastic energies were also analyzed to support the hot-stage method. The prepared blend of tadalafil and excipients was compacted under a several forces from 5 to 35 kN to reveal the trend of fragmentation. The exact fragmentation of tadalafil with increased compaction pressure was revealed by the hot-stage microscopic method and it was in good agreement with plastic and elastic energies. Conversely, spectral imaging, which is being used for this analysis, was considered to be inaccurate methodology as mainly agglomerates, not individual particles, were measured. The availability of the hot-stage microscopic method equips pharmaceutical scientists with an in vitro assessment technique that will more reliably determine the fragmentation of the API in finished tablets and the behavior of the particles when compacted.

Reasoning on the Self-Organizing Incremental Associative Memory for Online Robot Path Planning

NASA Astrophysics Data System (ADS)

Kawewong, Aram; Honda, Yutaro; Tsuboyama, Manabu; Hasegawa, Osamu

Robot path-planning is one of the important issues in robotic navigation. This paper presents a novel robot path-planning approach based on the associative memory using Self-Organizing Incremental Neural Networks (SOINN). By the proposed method, an environment is first autonomously divided into a set of path-fragments by junctions. Each fragment is represented by a sequence of preliminarily generated common patterns (CPs). In an online manner, a robot regards the current path as the associative path-fragments, each connected by junctions. The reasoning technique is additionally proposed for decision making at each junction to speed up the exploration time. Distinct from other methods, our method does not ignore the important information about the regions between junctions (path-fragments). The resultant number of path-fragments is also less than other method. Evaluation is done via Webots physical 3D-simulated and real robot experiments, where only distance sensors are available. Results show that our method can represent the environment effectively; it enables the robot to solve the goal-oriented navigation problem in only one episode, which is actually less than that necessary for most of the Reinforcement Learning (RL) based methods. The running time is proved finite and scales well with the environment. The resultant number of path-fragments matches well to the environment.

Age-associated reduction of cellular spreading/mechanical force up-regulates matrix metalloproteinase-1 expression and collagen fibril fragmentation via c-Jun/AP-1 in human dermal fibroblasts.

PubMed

Qin, Zhaoping; Voorhees, John J; Fisher, Gary J; Quan, Taihao

2014-12-01

The dermal compartment of human skin is largely composed of dense collagen-rich fibrils, which provide structural and mechanical support. Skin dermal fibroblasts, the major collagen-producing cells, are interact with collagen fibrils to maintain cell spreading and mechanical force for function. A characteristic feature of aged human skin is fragmentation of collagen fibrils, which is initiated by matrix metalloproteinase 1 (MMP-1). Fragmentation impairs fibroblast attachment and thereby reduces spreading. Here, we investigated the relationship among fibroblast spreading, mechanical force, MMP-1 expression, and collagen fibril fragmentation. Reduced fibroblast spreading due to cytoskeletal disruption was associated with reduced cellular mechanical force, as determined by atomic force microscopy. These reductions substantially induced MMP-1 expression, which led to collagen fibril fragmentation and disorganization in three-dimensional collagen lattices. Constraining fibroblast size by culturing on slides coated with collagen micropatterns also significantly induced MMP-1 expression. Reduced spreading/mechanical force induced transcription factor c-Jun and its binding to a canonical AP-1 binding site in the MMP-1 proximal promoter. Blocking c-Jun function with dominant negative mutant c-Jun significantly reduced induction of MMP-1 expression in response to reduced spreading/mechanical force. Furthermore, restoration of fibroblast spreading/mechanical force led to decline of c-Jun and MMP-1 levels and eliminated collagen fibril fragmentation and disorganization. These data reveal a novel mechanism by which alteration of fibroblast shape/mechanical force regulates c-Jun/AP-1-dependent expression of MMP-1 and consequent collagen fibril fragmentation. This mechanism provides a foundation for understanding the cellular and molecular basis of age-related collagen fragmentation in human skin. © 2014 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

Very low-molecular-mass fragments of albumin in the plasma of patients with focal segmental glomerulosclerosis.

PubMed

Hellin, Joan Lopez; Bech-Serra, Joan J; Moctezuma, Enrique Lara; Chocron, Sara; Santin, Sheila; Madrid, Alvaro; Vilalta, Ramon; Canals, Francesc; Torra, Roser; Meseguer, Anna; Nieto, Jose L

2009-11-01

Primary focal segmental glomerulosclerosis (FSGS) is a glomerular disease that frequently does not respond to treatment and progresses to kidney failure. FSGS can be of either genetic origin, caused by mutations in slit diaphragm proteins, such as podocin, or idiopathic origin of unknown cause. Case series. Children with FSGS (aged 3-18 years); 15 with idiopathic and 11 with genetic forms of FSGS. Genetic versus idiopathic forms. Differentially expressed proteins in the plasma proteome, detected using 2-dimensional electrophoresis and identified using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, Western blot, and liquid chromatography electron spray ionization tandem mass spectrometry for fragmentation and identification of the peptides. We found 3 very low-molecular-mass (9.2, 6.9, and 4.7 kDa; isoelectric point, 5.7) spots that were present in pooled samples from patients with genetic FSGS, but missing in patients with idiopathic FSGS and healthy individuals. Spots were identified using mass spectrometry as fragments of albumin, 2 of them apparently containing peptides from both C- and N-terminal parts of the whole protein. Proteomic analyses were carried out on all genetic patients individually; of these, 10 of 11 patients had > or =1 albumin fragment detected in the pool. We did not find an evident relationship between type of mutation or clinical status of patients and albumin fragments observed. Very low-molecular-weight albumin fragments also can be produced by other diseases. We describe for the first time the presence of very low-molecular-mass albumin fragments in plasma of patients with FSGS with podocyte protein mutations that are absent in patients with idiopathic FSGS or healthy individuals. Additional studies are necessary to determine whether these fragments could be potential biomarkers to distinguish between genetic and idiopathic forms of FSGS.

Photoionization and Photofragmentation of Carbon Fullerene Molecular Ions

NASA Astrophysics Data System (ADS)

Baral, Kiran Kumar

Cross sections are reported for single and double photoionization accompanied by the loss of as many as seven pairs of C atoms of C60 + and C70+ fullerene molecular ions in the photon energy range 18 eV to 150 eV. These measurements were performed at the Advanced Light Source (ALS) by merging a mass-selected ion beam with a beam of monochromatized synchrotron radiation. Threshold energies were determined for the formation of doubly and triply charged fragment ions from parent ions C60+ and C70+. The energy dependences of cross-sections for direct photoionization yielding C60 2+ and C702+ are compared with those for forming different doubly and triply charged fullerene fragment ions. Two-dimensional product ion scans were measured and quantified at four discrete photon energies: 35 eV, 65 eV, 105 eV and 140 eV, in the vacuum ultraviolet region, providing a comprehensive mapping of the product channels involving single ionization of fullerene ions C60+ and C 70+ accompanied by fragmentation. Since fullerenes are composed of even numbers of carbon atoms, the fragmentation occurs by the loss of differing numbers of carbon atom pairs. In addition to pure ionization, fragmentation product channels become relatively more important at higher photon energies.

Crystallization of SHARPIN using an automated two-dimensional grid screen for optimization.

PubMed

Stieglitz, Benjamin; Rittinger, Katrin; Haire, Lesley F

2012-07-01

An N-terminal fragment of human SHARPIN was recombinantly expressed in Escherichia coli, purified and crystallized. Crystals suitable for X-ray diffraction were obtained by a one-step optimization of seed dilution and protein concentration using a two-dimensional grid screen. The crystals belonged to the primitive tetragonal space group P4(3)2(1)2, with unit-cell parameters a = b = 61.55, c = 222.81 Å. Complete data sets were collected from native and selenomethionine-substituted protein crystals at 100 K to 2.6 and 2.0 Å resolution, respectively.

Calculated fission-fragment yield systematics in the region 74 <=Z <= 94 and 90 <=N <= 150

DOE PAGES

Möller, Peter; Randrup, Jørgen

2015-04-01

Background: In the seminal experiment by Schmidt et al. [Nucl. Phys. A 665, 221 (2000)] in which fission-fragment charge distributions were obtained for 70 nuclides, asymmetric distributions were seen above nucleon number A ≈ 226 and symmetric ones below. Because asymmetric fission had often loosely been explained as a preference for the nucleus to always exploit the extra binding of fragments near ¹³²Sn it was assumed that all systems below A ≈ 226 would fission symmetrically because available isotopes do not have a proton-to-neutron Z/N ratio that allows division into fragments near ¹³²Sn. But the finding by Andreyev et al.more » [Phys. Rev. Lett. 105, 252502 (2010)] did not conform to this expectation because the compound system ¹⁸⁰Hg was shown to fission asymmetrically. It was suggested that this was a new type of asymmetric fission, because no strong shell effects occur for any possible fragment division. Purpose: We calculate a reference database for fission-fragment mass yields for a large region of the nuclear chart comprising 987 nuclides. A particular aim is to establish whether ¹⁸⁰Hg is part of a contiguous region of asymmetric fission, and if so, its extent, or if not, in contrast to the actinides, there are scattered smaller groups of nuclei that fission asymmetrically in this area of the nuclear chart. Methods: We use the by now well benchmarked Brownian shape-motion method and perform random walks on the previously calculated five-dimensional potential-energy surfaces. The calculated shell corrections are damped out with energy according to a prescription developed earlier. Results: We have obtained a theoretical reference database of fission-fragment mass yields for 987 nuclides. These results show an extended region of asymmetric fission with approximate extension 74 ≤ Z ≤ 85 and 100 ≤ N ≤ 120. The calculated yields are highly variable. We show 20 representative plots of these variable features and summarize the main aspects of our results in terms of “nuclear-chart” plots showing calculated degrees of asymmetry versus N and Z. Conclusions: Experimental data in this region are rare: only ten or so yield distributions have been measured, some with very limited statistics. We agree with several measurements with higher statistics. Regions where there might be differences between our calculated results and measurements lie near the calculated transition line between symmetric and asymmetric fission. To draw more definite conclusions about the accuracy of the present implementation of the Brownian shape-motion approach in this region experimental data, with reliable statistics, for a fair number of suitably located additional nuclides are clearly needed. Because the nuclear potential-energy structure is so different in this region compared to the actinide region, additional experimental data together with fission theory studies that incorporate additional, dynamical aspects should provide much new insight.« less

Mass-energy distribution of fragments within Langevin dynamics of fission induced by heavy ions

NASA Astrophysics Data System (ADS)

Anischenko, Yu. A.; Adeev, G. D.

2012-08-01

A stochastic approach based on four-dimensional Langevin fission dynamics is applied to calculating mass-energy distributions of fragments originating from the fission of excited compound nuclei. In the model under investigation, the coordinate K representing the projection of the total angular momentum onto the symmetry axis of the nucleus is taken into account in addition to three collective shape coordinates introduced on the basis of the { c, h, α} parametrization. The evolution of the orientation degree of freedom ( K mode) is described by means of the Langevin equation in the overdamped regime. The tensor of friction is calculated under the assumption of the reducedmechanismof one-body dissipation in the wall-plus-window model. The calculations are performed for two values of the coefficient that takes into account the reduction of the contribution from the wall formula: k s = 0.25 and k s = 1.0. Calculations with a modified wall-plus-window formula are also performed, and the quantity measuring the degree to which the single-particle motion of nucleons within the nuclear system being considered is chaotic is used for k s in this calculation. Fusion-fission reactions leading to the production of compound nuclei are considered for values of the parameter Z 2/ A in the range between 21 and 44. So wide a range is chosen in order to perform a comparative analysis not only for heavy but also for light compound nuclei in the vicinity of the Businaro-Gallone point. For all of the reactions considered in the present study, the calculations performed within four-dimensional Langevin dynamics faithfully reproduce mass-energy and mass distributions obtained experimentally. The inclusion of the K mode in the Langevin equation leads to an increase in the variances of mass and energy distributions in relation to what one obtains from three-dimensional Langevin calculations. The results of the calculations where one associates k s with the measure of chaoticity in the single-particle motion of nucleons within the nuclear system under study are in good agreement for variances of mass distributions. The results of calculations for the correlations between the prescission neutron multiplicity and the fission-fragment mass, < n pre( M)>, and between, this multiplicity and the kinetic energy of fission fragments, < n pre( E k )>, are also presented.

Application of high-resolution, two-dimensional 1H and 13C nuclear magnetic resonance techniques to the characterization of lipid oxidation products in autoxidized linoleoyl/linolenoylglycerols.

PubMed

Silwood, C J; Grootveld, M

1999-07-01

Subjection of polyunsaturated fatty acid (PUFA)-rich culinary oils to standard frying episodes generates a range of lipid oxidation products (LOP), including saturated and alpha,beta-unsaturated aldehydes which arise from the thermally induced fragmentation of conjugated hydroperoxydiene precursors. Since such LOP are damaging to human health, we have employed high-resolution, two-dimensional 1H-1H relayed coherence transfer, 1H-1H total correlation, 1H-13C heteronuclear multiple quantum correlation, and 1H-1H J-resolved nuclear magnetic resonance (NMR) spectroscopic techniques to further elucidate the molecular structures of these components present in (i) a model linoleoylglycerol compound (1,3-dilinolein) allowed to autoxidize at ambient temperature and (ii) PUFA-rich culinary oils subjected to repeated frying episodes. The above techniques readily facilitate the resolution of selected vinylic and aldehydic resonances of LOP which appear as complex overlapping patterns in conventional one-dimensional spectra, particularly when employed in combination with solvent-induced spectral shift modifications. Hence, much useful multi-component information regarding the identity and/or classification of glycerol-bound conjugated hydroperoxydiene and hydroxydiene adducts, and saturated and alpha,beta-unsaturated aldehydes, present in autoxidized PUFA matrices is provided by these NMR methods. Such molecular information is of much value to researchers investigating the deleterious health effects of LOP available in the diet.

Three-dimensional printing as a technology supporting the treatment of lower limb deformity and shortening with the Ilizarov method.

PubMed

Morasiewicz, Piotr; Burzyńska, Karolina; Orzechowski, Wiktor; Dragan, Szymon Łukasz; Dragan, Szymon Feliks; Filipiak, Jarosław

2018-04-20

Treatment of multiplanar deformities, especially in younger children, requires construction of a complex Ilizarov fixator, frequently with small dimensions. The aim of this study is to verify clinical application of a3D-printed bone model in treatment with the Ilizarov method. The study involved a 6-year-old child in whom clinical and radiological examination revealed multiplanar deformity of the right leg. Then, 3D models of individual bones were printed by means of additive manufacturing and were used as a scaffold to install the Ilizarov apparatus. To compare the expected and factual axial correction and lengthening, we measured spatial orientation of bone fragments three times. The factual axial correction and lengthening were determined with a photometric technique. Ilizarov fixator with a configuration developed using a 3D model of the treated bone was mounted on the patient's leg. Corticotomy was carried out at the proximal metaphysis of the right tibia, along with osteotomy of the right talus. The treatment resulted in a 3.5-cm lengthening of the limb and a 7° correction of valgus angle. The values of actual lengthening and axial correction were 4.1% lower than the expected values of these parameters. Orthopedists should consider differences between the expected and actual lengthening and axial correction in planning treatment with the Ilizarov method. Three-dimensional printing is a useful technology that can be used to support treatment with the Ilizarov method. Copyright © 2018 IPEM. Published by Elsevier Ltd. All rights reserved.

Transfer of chromosome 3 fragments suppresses tumorigenicity of an ovarian cancer cell line monoallelic for chromosome 3p.

PubMed

Cody, N A L; Ouellet, V; Manderson, E N; Quinn, M C J; Filali-Mouhim, A; Tellis, P; Zietarska, M; Provencher, D M; Mes-Masson, A-M; Chevrette, M; Tonin, P N

2007-01-25

Multiple chromosome 3p tumor suppressor genes (TSG) have been proposed in the pathogenesis of ovarian cancer based on complex patterns of 3p loss. To attain functional evidence in support of TSGs and identify candidate regions, we applied a chromosome transfer method involving cell fusions of the tumorigenic OV90 human ovarian cancer cell line, monoallelic for 3p and an irradiated mouse cell line containing a human chromosome 3 in order to derive OV90 hybrids containing normal 3p fragments. The resulting hybrids showed complete or incomplete suppression of tumorigenicity in nude mouse xenograft assays, and varied in their ability to form colonies in soft agarose and three-dimensional spheroids in a manner consistent with alteration of their in vivo tumorigenic phenotypes. Expression microarray analysis identified a set of common differentially expressed genes, such as SPARC, DAB2 and VEGF, some of which have been shown implicated in ovarian cancer. Genotyping assays revealed that they harbored normal 3p fragments, some of which overlapped candidate TSG regions (3p25-p26, 3p24 and 3p14-pcen) identified previously in loss of heterozygosity analyses of ovarian cancers. However, only the 3p12-pcen region was acquired in common by all hybrids where expression microarray analysis identified differentially expressed genes. The correlation of 3p12-pcen transfer and tumor suppression with a concerted re-programming of the cellular transcriptome suggest that the putative TSG may have affected key underlying events in ovarian cancer.

Sizing of single fluorescently stained DNA fragments by scanning microscopy

PubMed Central

Laib, Stephan; Rankl, Michael; Ruckstuhl, Thomas; Seeger, Stefan

2003-01-01

We describe an approach to determine DNA fragment sizes based on the fluorescence detection of single adsorbed fragments on specifically coated glass cover slips. The brightness of single fragments stained with the DNA bisintercalation dye TOTO-1 is determined by scanning the surface with a confocal microscope. The brightness of adsorbed fragments is found to be proportional to the fragment length. The method needs only minute amount of DNA, beyond inexpensive and easily available surface coatings, like poly-l-lysine, 3-aminoproyltriethoxysilane and polyornithine, are utilizable. We performed DNA-sizing of fragment lengths between 2 and 14 kb. Further, we resolved the size distribution before and after an enzymatic restriction digest. At this a separation of buffers or enzymes was unnecessary. DNA sizes were determined within an uncertainty of 7–14%. The proposed method is straightforward and can be applied to standardized microtiter plates. PMID:14602931

The study of the proteome of healthy human blood plasma under conditions of long-term confinement in an isolation chamber.

PubMed

Trifonova, O P; Pastushkova, L Kh; Samenkova, N F; Chernobrovkin, A L; Karuzina, I I; Lisitsa, A V; Larina, I M

2013-05-01

We identified changes in the proteome of healthy human blood plasma caused by exposure to 105-day confinement in an isolation chamber. After removal of major proteins and concentration of minor proteins, plasma fractions were analyzed by two-dimensional electrophoresis followed by identification of significantly different protein spots by mass spectrometric analysis of the peptide fragments. The levels of α- and β-chains of fibrinogen, a fragment of complement factor C4, apolipoproteins AI and E, plasminogen factor C1 complement, and immunoglobulin M changed in participants during the isolation period. These changes probably reflect the adaptive response to altered conditions of life.

Application of microtomography and image analysis to the quantification of fragmentation in ceramics after impact loading

NASA Astrophysics Data System (ADS)

Forquin, Pascal; Ando, Edward

2017-01-01

Silicon carbide ceramics are widely used in personal body armour and protective solutions. However, during impact, an intense fragmentation develops in the ceramic tile due to high-strain-rate tensile loadings. In this work, microtomography equipment was used to analyse the fragmentation patterns of two silicon carbide grades subjected to edge-on impact (EOI) tests. The EOI experiments were conducted in two configurations. The so-called open configuration relies on the use of an ultra-high-speed camera to visualize the fragmentation process with an interframe time set to 1 µs. The so-called sarcophagus configuration consists in confining the target in a metallic casing to avoid any dispersion of fragments. The target is infiltrated after impact so the final damage pattern is entirely scanned using X-ray tomography and a microfocus source. Thereafter, a three-dimensional (3D) segmentation algorithm was tested and applied in order to separate fragments in 3D allowing a particle size distribution to be obtained. Significant differences between the two specimens of different SiC grades were noted. To explain such experimental results, numerical simulations were conducted considering the Denoual-Forquin-Hild anisotropic damage model. According to the calculations, the difference of crack pattern in EOI tests is related to the population of defects within the two ceramics. This article is part of the themed issue 'Experimental testing and modelling of brittle materials at high strain rates'.

NMR characterization of weak interactions between RhoGDI2 and fragment screening hits.

PubMed

Liu, Jiuyang; Gao, Jia; Li, Fudong; Ma, Rongsheng; Wei, Qingtao; Wang, Aidong; Wu, Jihui; Ruan, Ke

2017-01-01

The delineation of intrinsically weak interactions between novel targets and fragment screening hits has long limited the pace of hit-to-lead evolution. Rho guanine-nucleotide dissociation inhibitor 2 (RhoGDI2) is a novel target that lacks any chemical probes for the treatment of tumor metastasis. Protein-observed and ligand-observed NMR spectroscopy was used to characterize the weak interactions between RhoGDI2 and fragment screening hits. We identified three hits of RhoGDI2 using streamlined NMR fragment-based screening. The binding site residues were assigned using non-uniformly sampled C α - and H α -based three dimensional NMR spectra. The molecular docking to the proposed geranylgeranyl binding pocket of RhoGDI2 was guided by NMR restraints of chemical shift perturbations and ligand-observed transferred paramagnetic relaxation enhancement. We further validated the weak RhoGDI2-hit interactions using mutagenesis and structure-affinity analysis. Weak interactions between RhoGDI2 and fragment screening hits were delineated using an integrated NMR approach. Binders to RhoGDI2 as a potential anti-cancer target have been first reported, and their weak interactions were depicted using NMR spectroscopy. Our work highlights the powerfulness and the versatility of the integrative NMR techniques to provide valuable structural insight into the intrinsically weak interactions between RhoGDI2 and the fragment screening hits, which could hardly be conceived using other biochemical techniques. Copyright © 2016 Elsevier B.V. All rights reserved.

Recent progress in boron nanomaterials

PubMed Central

Kondo, Takahiro

2017-01-01

Abstract Various types of zero, one, and two-dimensional boron nanomaterials such as nanoclusters, nanowires, nanotubes, nanobelts, nanoribbons, nanosheets, and monolayer crystalline sheets named borophene have been experimentally synthesized and identified in the last 20 years. Owing to their low dimensionality, boron nanomaterials have different bonding configurations from those of three-dimensional bulk boron crystals composed of icosahedra or icosahedral fragments. The resulting intriguing physical and chemical properties of boron nanomaterials are fascinating from the viewpoint of material science. Moreover, the wide variety of boron nanomaterials themselves could be the building blocks for combining with other existing nanomaterials, molecules, atoms, and/or ions to design and create materials with new functionalities and properties. Here, the progress of the boron nanomaterials is reviewed and perspectives and future directions are described. PMID:29152014

[Fragment-based drug discovery: concept and aim].

PubMed

Tanaka, Daisuke

2010-03-01

Fragment-Based Drug Discovery (FBDD) has been recognized as a newly emerging lead discovery methodology that involves biophysical fragment screening and chemistry-driven fragment-to-lead stages. Although fragments, defined as structurally simple and small compounds (typically <300 Da), have not been employed in conventional high-throughput screening (HTS), the recent significant progress in the biophysical screening methods enables fragment screening at a practical level. The intention of FBDD primarily turns our attention to weakly but specifically binding fragments (hit fragments) as the starting point of medicinal chemistry. Hit fragments are then promoted to more potent lead compounds through linking or merging with another hit fragment and/or attaching functional groups. Another positive aspect of FBDD is ligand efficiency. Ligand efficiency is a useful guide in screening hit selection and hit-to-lead phases to achieve lead-likeness. Owing to these features, a number of successful applications of FBDD to "undruggable targets" (where HTS and other lead identification methods failed to identify useful lead compounds) have been reported. As a result, FBDD is now expected to complement more conventional methodologies. This review, as an introduction of the following articles, will summarize the fundamental concepts of FBDD and will discuss its advantages over other conventional drug discovery approaches.

Fragment-based design of kinase inhibitors: a practical guide.

PubMed

Erickson, Jon A

2015-01-01

Fragment-based drug design has become an important strategy for drug design and development over the last decade. It has been used with particular success in the development of kinase inhibitors, which are one of the most widely explored classes of drug targets today. The application of fragment-based methods to discovering and optimizing kinase inhibitors can be a complicated and daunting task; however, a general process has emerged that has been highly fruitful. Here a practical outline of the fragment process used in kinase inhibitor design and development is laid out with specific examples. A guide to the overall process from initial discovery through fragment screening, including the difficulties in detection, to the computational methods available for use in optimization of the discovered fragments is reported.

Design of a fragment library that maximally represents available chemical space.

PubMed

Schulz, M N; Landström, J; Bright, K; Hubbard, R E

2011-07-01

Cheminformatics protocols have been developed and assessed that identify a small set of fragments which can represent the compounds in a chemical library for use in fragment-based ligand discovery. Six different methods have been implemented and tested on Input Libraries of compounds from three suppliers. The resulting Fragment Sets have been characterised on the basis of computed physico-chemical properties and their similarity to the Input Libraries. A method that iteratively identifies fragments with the maximum number of similar compounds in the Input Library (Nearest Neighbours) produces the most diverse library. This approach could increase the success of experimental ligand discovery projects, by providing fragments that can be progressed rapidly to larger compounds through access to available similar compounds (known as SAR by Catalog).

Screening a fragment cocktail library using ultrafiltration

PubMed Central

Shibata, Sayaka; Zhang, Zhongsheng; Korotkov, Konstantin V.; Delarosa, Jaclyn; Napuli, Alberto; Kelley, Angela M.; Mueller, Natasha; Ross, Jennifer; Zucker, Frank H.; Buckner, Frederick S.; Merritt, Ethan A.; Verlinde, Christophe L. M. J.; Van Voorhis, Wesley C.; Hol, Wim G. J.; Fan, Erkang

2011-01-01

Ultrafiltration provides a generic method to discover ligands for protein drug targets with millimolar to micromolar Kd, the typical range of fragment-based drug discovery. This method was tailored to a 96-well format, and cocktails of fragment-sized molecules, with molecular masses between 150 and 300 Da, were screened against medical structural genomics target proteins. The validity of the method was confirmed through competitive binding assays in the presence of ligands known to bind the target proteins. PMID:21750879

Opportunity Landing Spot Panorama (3-D Model)

NASA Technical Reports Server (NTRS)

2004-01-01

The rocky outcrop traversed by the Mars Exploration Rover Opportunity is visible in this three-dimensional model of the rover's landing site. Opportunity has acquired close-up images along the way, and scientists are using the rover's instruments to closely examine portions of interest. The white fragments that look crumpled near the center of the image are portions of the airbags. Distant scenery is displayed on a spherical backdrop or 'billboard' for context. Artifacts near the top rim of the crater are a result of the transition between the three-dimensional model and the billboard. Portions of the terrain model lacking sufficient data appear as blank spaces or gaps, colored reddish-brown for better viewing. This image was generated using special software from NASA's Ames Research Center and a mosaic of images taken by the rover's panoramic camera.

[figure removed for brevity, see original site] Click on image for larger view

The rocky outcrop traversed by the Mars Exploration Rover Opportunity is visible in this zoomed-in portion of a three-dimensional model of the rover's landing site. Opportunity has acquired close-up images along the way, and scientists are using the rover's instruments to closely examine portions of interest. The white fragments that look crumpled near the center of the image are portions of the airbags. Distant scenery is displayed on a spherical backdrop or 'billboard' for context. Artifacts near the top rim of the crater are a result of the transition between the three-dimensional model and the billboard. Portions of the terrain model lacking sufficient data appear as blank spaces or gaps, colored reddish-brown for better viewing. This image was generated using special software from NASA's Ames Research Center and a mosaic of images taken by the rover's panoramic camera.

Modeling The Shock Initiation of PBX-9501 in ALE3D

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

Leininger, L; Springer, H K; Mace, J

The SMIS (Specific Munitions Impact Scenario) experimental series performed at Los Alamos National Laboratory has determined the 3-dimensional shock initiation behavior of the HMX-based heterogeneous high explosive, PBX 9501. A series of finite element impact calculations have been performed in the ALE3D [1] hydrodynamic code and compared to the SMIS results to validate the code predictions. The SMIS tests use a powder gun to shoot scaled NATO standard fragments at a cylinder of PBX 9501, which has a PMMA case and a steel impact cover. The SMIS real-world shot scenario creates a unique test-bed because many of the fragments arrivemore » at the impact plate off-center and at an angle of impact. The goal of this model validation experiments is to demonstrate the predictive capability of the Tarver-Lee Ignition and Growth (I&G) reactive flow model [2] in this fully 3-dimensional regime of Shock to Detonation Transition (SDT). The 3-dimensional Arbitrary Lagrange Eulerian hydrodynamic model in ALE3D applies the Ignition and Growth (I&G) reactive flow model with PBX 9501 parameters derived from historical 1-dimensional experimental data. The model includes the off-center and angle of impact variations seen in the experiments. Qualitatively, the ALE3D I&G calculations accurately reproduce the 'Go/No-Go' threshold of the Shock to Detonation Transition (SDT) reaction in the explosive, as well as the case expansion recorded by a high-speed optical camera. Quantitatively, the calculations show good agreement with the shock time of arrival at internal and external diagnostic pins. This exercise demonstrates the utility of the Ignition and Growth model applied in a predictive fashion for the response of heterogeneous high explosives in the SDT regime.« less

Photoacoustic tomography using a fiber based Fabry-Perot interferometer as an integrating line detector and image reconstruction by model-based time reversal method

NASA Astrophysics Data System (ADS)

Grün, H.; Paltauf, G.; Haltmeier, M.; Burgholzer, P.

2007-07-01

Photoacoustic imaging is based on the generation of acoustic waves in a semitransparent sample (e.g. soft tissue) after illumination with short pulses of light or radio waves. The goal is to recover the spatial distribution of absorbed energy density inside the sample from acoustic pressure signals measured outside the sample (photoacoustic inverse problem). If the acoustic pressure outside the illuminated sample is measured with a large-aperture detector, the signal at a certain time is given by an integral of the generated acoustic pressure distribution over an area that is determined by the shape of the detector. For example a planar detector measures the projections of the initial pressure distribution over planes parallel to the detector plane, which is the Radon transform of the initial pressure distribution. Stable and exact three-dimensional imaging with planar integrating detector requires measurements in all directions of space and so the receiver plane has to be rotated to cover the entire detection surface. We have recently presented a simpler set-up for exact imaging which requires only a single rotation axis and therefor the fragmentation of the area detector into line detectors perpendicular to the rotation axis. Using a two-dimensional reconstruction method and applying the inverse two-dimensional Radon transform afterwards gives an exact reconstruction of the three-dimensional sample with this set-up. In order to achieve high resolution, a fiber based Fabry-Perot interferometer is used. It is a single mode fiber with two fiber bragg gratings on both ends of the line detector. Thermal shifts and vibrations are compensated by frequency locking of the laser. The high resolution and the good performance of this integrating line detector has been demonstrated by photoacoustic measurements with line grid samples and phantoms using a model-based time reversal method for image reconstruction. The time reversed pressure field can be calculated directly by retransmitting the measured pressure on the detector positions in a reversed temporal order.

Formation of Spiral-Arm Spurs and Bound Clouds in Vertically Stratified Galactic Gas Disks

NASA Astrophysics Data System (ADS)

Kim, Woong-Tae; Ostriker, Eve C.

2006-07-01

We investigate the growth of spiral-arm substructure in vertically stratified, self-gravitating, galactic gas disks, using local numerical MHD simulations. Our new models extend our previous two-dimensional studies, which showed that a magnetized spiral shock in a thin disk can undergo magneto-Jeans instability (MJI), resulting in regularly spaced interarm spur structures and massive gravitationally bound fragments. Similar spur (or ``feather'') features have recently been seen in high-resolution observations of several galaxies. Here we consider two sets of numerical models: two-dimensional simulations that use a ``thick-disk'' gravitational kernel, and three-dimensional simulations with explicit vertical stratification. Both models adopt an isothermal equation of state with cs=7 km s-1. When disks are sufficiently magnetized and self-gravitating, the result in both sorts of models is the growth of spiral-arm substructure similar to that in our previous razor-thin models. Reduced self-gravity due to nonzero disk thickness increases the spur spacing to ~10 times the Jeans length at the arm peak. Bound clouds that form from spur fragmentation have masses ~(1-3)×107 Msolar each, similar to the largest observed GMCs. The mass-to-flux ratios and specific angular momenta of the bound condensations are lower than large-scale galactic values, as is true for observed GMCs. We find that unmagnetized or weakly magnetized two-dimensional models are unstable to the ``wiggle instability'' previously identified by Wada & Koda. However, our fully three-dimensional models do not show this effect. Nonsteady motions and strong vertical shear prevent coherent vortical structures from forming, evidently suppressing the wiggle instability. We also find no clear traces of Parker instability in the nonlinear spiral arm substructures that emerge, although conceivably Parker modes may help seed the MJI at early stages since azimuthal wavelengths are similar.

Modeling Three-Dimensional Shock Initiation of PBX 9501 in ALE3D

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

Leininger, L; Springer, H K; Mace, J

A recent SMIS (Specific Munitions Impact Scenario) experimental series performed at Los Alamos National Laboratory has provided 3-dimensional shock initiation behavior of the HMX-based heterogeneous high explosive, PBX 9501. A series of finite element impact calculations have been performed in the ALE3D [1] hydrodynamic code and compared to the SMIS results to validate and study code predictions. These SMIS tests used a powder gun to shoot scaled NATO standard fragments into a cylinder of PBX 9501, which has a PMMA case and a steel impact cover. This SMIS real-world shot scenario creates a unique test-bed because (1) SMIS tests facilitatemore » the investigation of 3D Shock to Detonation Transition (SDT) within the context of a considerable suite of diagnostics, and (2) many of the fragments arrive at the impact plate off-center and at an angle of impact. A particular goal of these model validation experiments is to demonstrate the predictive capability of the ALE3D implementation of the Tarver-Lee Ignition and Growth reactive flow model [2] within a fully 3-dimensional regime of SDT. The 3-dimensional Arbitrary Lagrange Eulerian (ALE) hydrodynamic model in ALE3D applies the Ignition and Growth (I&G) reactive flow model with PBX 9501 parameters derived from historical 1-dimensional experimental data. The model includes the off-center and angle of impact variations seen in the experiments. Qualitatively, the ALE3D I&G calculations reproduce observed 'Go/No-Go' 3D Shock to Detonation Transition (SDT) reaction in the explosive, as well as the case expansion recorded by a high-speed optical camera. Quantitatively, the calculations show good agreement with the shock time of arrival at internal and external diagnostic pins. This exercise demonstrates the utility of the Ignition and Growth model applied for the response of heterogeneous high explosives in the SDT regime.« less

[Detection of UGT1A1*28 Polymorphism Using Fragment Analysis].

PubMed

Huang, Ying; Su, Jian; Huang, Xiaosui; Lu, Danxia; Xie, Zhi; Yang, Suqing; Guo, Weibang; Lv, Zhiyi; Wu, Hongsui; Zhang, Xuchao

2017-12-20

Uridine-diphosphoglucuronosyl transferase 1A1 (UGT1A1), UGT1A1*28 polymorphism can reduce UGT1A1 enzymatic activity, which may lead to severe toxicities in patients who receive irinotecan. This study tries to build a fragment analysis method to detect UGT1A1*28 polymorphism. A total of 286 blood specimens from the lung cancer patients who were hospitalized in Guangdong General Hospital between April 2014 to May 2015 were detected UGT1A1*28 polymorphism by fragment analysis method. Comparing with Sanger sequencing, precision and accuracy of the fragment analysis method were 100%. Of the 286 patients, 236 (82.5% harbored TA6/6 genotype, 48 (16.8%) TA 6/7 genotype and 2 (0.7%) TA7/7 genotype. Our data suggest hat the fragment analysis method is robust for detecting UGT1A1*28 polymorphism in clinical practice. It's simple, time-saving, and easy-to-carry.

Many-body expansion of the Fock matrix in the fragment molecular orbital method

NASA Astrophysics Data System (ADS)

Fedorov, Dmitri G.; Kitaura, Kazuo

2017-09-01

A many-body expansion of the Fock matrix in the fragment molecular orbital method is derived up to three-body terms for restricted Hartree-Fock and density functional theory in the atomic orbital basis and compared to the expansion in the basis of fragment molecular orbitals (MOs). The physical nature of many-body corrections is revealed in terms of charge transfer terms. An improvement of the fragment MO expansion is proposed by adding exchange to the embedding. The accuracy of all developed methods is demonstrated in comparison to unfragmented results for polyalanines, a water cluster, Trp-cage (PDB: 1L2Y) and crambin (PDB: 1CRN) proteins, a zeolite cluster, a Si nano-wire, and a boron nitride ribbon. The physical nature of metallicity is discussed, and it is shown what kinds of metallic systems can be treated by fragment-based methods. The density of states is calculated for a fully closed and a partially open nano-ring of boron nitride with a diameter of 105 nm.

MaRaCluster: A Fragment Rarity Metric for Clustering Fragment Spectra in Shotgun Proteomics.

PubMed

The, Matthew; Käll, Lukas

2016-03-04

Shotgun proteomics experiments generate large amounts of fragment spectra as primary data, normally with high redundancy between and within experiments. Here, we have devised a clustering technique to identify fragment spectra stemming from the same species of peptide. This is a powerful alternative method to traditional search engines for analyzing spectra, specifically useful for larger scale mass spectrometry studies. As an aid in this process, we propose a distance calculation relying on the rarity of experimental fragment peaks, following the intuition that peaks shared by only a few spectra offer more evidence than peaks shared by a large number of spectra. We used this distance calculation and a complete-linkage scheme to cluster data from a recent large-scale mass spectrometry-based study. The clusterings produced by our method have up to 40% more identified peptides for their consensus spectra compared to those produced by the previous state-of-the-art method. We see that our method would advance the construction of spectral libraries as well as serve as a tool for mining large sets of fragment spectra. The source code and Ubuntu binary packages are available at https://github.com/statisticalbiotechnology/maracluster (under an Apache 2.0 license).

Scarless assembly of unphosphorylated DNA fragments with a simplified DATEL method.

PubMed

Ding, Wenwen; Weng, Huanjiao; Jin, Peng; Du, Guocheng; Chen, Jian; Kang, Zhen

2017-05-04

Efficient assembly of multiple DNA fragments is a pivotal technology for synthetic biology. A scarless and sequence-independent DNA assembly method (DATEL) using thermal exonucleases has been developed recently. Here, we present a simplified DATEL (sDATEL) for efficient assembly of unphosphorylated DNA fragments with low cost. The sDATEL method is only dependent on Taq DNA polymerase and Taq DNA ligase. After optimizing the committed parameters of the reaction system such as pH and the concentration of Mg 2+ and NAD+, the assembly efficiency was increased by 32-fold. To further improve the assembly capacity, the number of thermal cycles was optimized, resulting in successful assembly 4 unphosphorylated DNA fragments with an accuracy of 75%. sDATEL could be a desirable method for routine manual and automated assembly.

A new approach to simulating collisionless dark matter fluids

NASA Astrophysics Data System (ADS)

Hahn, Oliver; Abel, Tom; Kaehler, Ralf

2013-09-01

Recently, we have shown how current cosmological N-body codes already follow the fine grained phase-space information of the dark matter fluid. Using a tetrahedral tessellation of the three-dimensional manifold that describes perfectly cold fluids in six-dimensional phase space, the phase-space distribution function can be followed throughout the simulation. This allows one to project the distribution function into configuration space to obtain highly accurate densities, velocities and velocity dispersions. Here, we exploit this technique to show first steps on how to devise an improved particle-mesh technique. At its heart, the new method thus relies on a piecewise linear approximation of the phase-space distribution function rather than the usual particle discretization. We use pseudo-particles that approximate the masses of the tetrahedral cells up to quadrupolar order as the locations for cloud-in-cell (CIC) deposit instead of the particle locations themselves as in standard CIC deposit. We demonstrate that this modification already gives much improved stability and more accurate dynamics of the collisionless dark matter fluid at high force and low mass resolution. We demonstrate the validity and advantages of this method with various test problems as well as hot/warm dark matter simulations which have been known to exhibit artificial fragmentation. This completely unphysical behaviour is much reduced in the new approach. The current limitations of our approach are discussed in detail and future improvements are outlined.

Dynameomics: data-driven methods and models for utilizing large-scale protein structure repositories for improving fragment-based loop prediction.

PubMed

Rysavy, Steven J; Beck, David A C; Daggett, Valerie

2014-11-01

Protein function is intimately linked to protein structure and dynamics yet experimentally determined structures frequently omit regions within a protein due to indeterminate data, which is often due protein dynamics. We propose that atomistic molecular dynamics simulations provide a diverse sampling of biologically relevant structures for these missing segments (and beyond) to improve structural modeling and structure prediction. Here we make use of the Dynameomics data warehouse, which contains simulations of representatives of essentially all known protein folds. We developed novel computational methods to efficiently identify, rank and retrieve small peptide structures, or fragments, from this database. We also created a novel data model to analyze and compare large repositories of structural data, such as contained within the Protein Data Bank and the Dynameomics data warehouse. Our evaluation compares these structural repositories for improving loop predictions and analyzes the utility of our methods and models. Using a standard set of loop structures, containing 510 loops, 30 for each loop length from 4 to 20 residues, we find that the inclusion of Dynameomics structures in fragment-based methods improves the quality of the loop predictions without being dependent on sequence homology. Depending on loop length, ∼ 25-75% of the best predictions came from the Dynameomics set, resulting in lower main chain root-mean-square deviations for all fragment lengths using the combined fragment library. We also provide specific cases where Dynameomics fragments provide better predictions for NMR loop structures than fragments from crystal structures. Online access to these fragment libraries is available at http://www.dynameomics.org/fragments. © 2014 The Protein Society.

Dynameomics: Data-driven methods and models for utilizing large-scale protein structure repositories for improving fragment-based loop prediction

PubMed Central

Rysavy, Steven J; Beck, David AC; Daggett, Valerie

2014-01-01

Protein function is intimately linked to protein structure and dynamics yet experimentally determined structures frequently omit regions within a protein due to indeterminate data, which is often due protein dynamics. We propose that atomistic molecular dynamics simulations provide a diverse sampling of biologically relevant structures for these missing segments (and beyond) to improve structural modeling and structure prediction. Here we make use of the Dynameomics data warehouse, which contains simulations of representatives of essentially all known protein folds. We developed novel computational methods to efficiently identify, rank and retrieve small peptide structures, or fragments, from this database. We also created a novel data model to analyze and compare large repositories of structural data, such as contained within the Protein Data Bank and the Dynameomics data warehouse. Our evaluation compares these structural repositories for improving loop predictions and analyzes the utility of our methods and models. Using a standard set of loop structures, containing 510 loops, 30 for each loop length from 4 to 20 residues, we find that the inclusion of Dynameomics structures in fragment-based methods improves the quality of the loop predictions without being dependent on sequence homology. Depending on loop length, ∼25–75% of the best predictions came from the Dynameomics set, resulting in lower main chain root-mean-square deviations for all fragment lengths using the combined fragment library. We also provide specific cases where Dynameomics fragments provide better predictions for NMR loop structures than fragments from crystal structures. Online access to these fragment libraries is available at http://www.dynameomics.org/fragments. PMID:25142412

Method for rapid base sequencing in DNA and RNA

DOEpatents

Jett, J.H.; Keller, R.A.; Martin, J.C.; Moyzis, R.K.; Ratliff, R.L.; Shera, E.B.; Stewart, C.C.

1987-10-07

A method is provided for the rapid base sequencing of DNA or RNA fragments wherein a single fragment of DNA or RNA is provided with identifiable bases and suspended in a moving flow stream. An exonuclease sequentially cleaves individual bases from the end of the suspended fragment. The moving flow stream maintains the cleaved bases in an orderly train for subsequent detection and identification. In a particular embodiment, individual bases forming the DNA or RNA fragments are individually tagged with a characteristic fluorescent dye. The train of bases is then excited to fluorescence with an output spectrum characteristic of the individual bases. Accordingly, the base sequence of the original DNA or RNA fragment can be reconstructed. 2 figs.

Method for rapid base sequencing in DNA and RNA

DOEpatents

Jett, J.H.; Keller, R.A.; Martin, J.C.; Moyzis, R.K.; Ratliff, R.L.; Shera, E.B.; Stewart, C.C.

1990-10-09

A method is provided for the rapid base sequencing of DNA or RNA fragments wherein a single fragment of DNA or RNA is provided with identifiable bases and suspended in a moving flow stream. An exonuclease sequentially cleaves individual bases from the end of the suspended fragment. The moving flow stream maintains the cleaved bases in an orderly train for subsequent detection and identification. In a particular embodiment, individual bases forming the DNA or RNA fragments are individually tagged with a characteristic fluorescent dye. The train of bases is then excited to fluorescence with an output spectrum characteristic of the individual bases. Accordingly, the base sequence of the original DNA or RNA fragment can be reconstructed. 2 figs.

Method for rapid base sequencing in DNA and RNA

DOEpatents

Jett, James H.; Keller, Richard A.; Martin, John C.; Moyzis, Robert K.; Ratliff, Robert L.; Shera, E. Brooks; Stewart, Carleton C.

1990-01-01

A method is provided for the rapid base sequencing of DNA or RNA fragments wherein a single fragment of DNA or RNA is provided with identifiable bases and suspended in a moving flow stream. An exonuclease sequentially cleaves individual bases from the end of the suspended fragment. The moving flow stream maintains the cleaved bases in an orderly train for subsequent detection and identification. In a particular embodiment, individual bases forming the DNA or RNA fragments are individually tagged with a characteristic fluorescent dye. The train of bases is then excited to fluorescence with an output spectrum characteristic of the individual bases. Accordingly, the base sequence of the original DNA or RNA fragment can be reconstructed.

RNA FRABASE 2.0: an advanced web-accessible database with the capacity to search the three-dimensional fragments within RNA structures

PubMed Central

2010-01-01

Background Recent discoveries concerning novel functions of RNA, such as RNA interference, have contributed towards the growing importance of the field. In this respect, a deeper knowledge of complex three-dimensional RNA structures is essential to understand their new biological functions. A number of bioinformatic tools have been proposed to explore two major structural databases (PDB, NDB) in order to analyze various aspects of RNA tertiary structures. One of these tools is RNA FRABASE 1.0, the first web-accessible database with an engine for automatic search of 3D fragments within PDB-derived RNA structures. This search is based upon the user-defined RNA secondary structure pattern. In this paper, we present and discuss RNA FRABASE 2.0. This second version of the system represents a major extension of this tool in terms of providing new data and a wide spectrum of novel functionalities. An intuitionally operated web server platform enables very fast user-tailored search of three-dimensional RNA fragments, their multi-parameter conformational analysis and visualization. Description RNA FRABASE 2.0 has stored information on 1565 PDB-deposited RNA structures, including all NMR models. The RNA FRABASE 2.0 search engine algorithms operate on the database of the RNA sequences and the new library of RNA secondary structures, coded in the dot-bracket format extended to hold multi-stranded structures and to cover residues whose coordinates are missing in the PDB files. The library of RNA secondary structures (and their graphics) is made available. A high level of efficiency of the 3D search has been achieved by introducing novel tools to formulate advanced searching patterns and to screen highly populated tertiary structure elements. RNA FRABASE 2.0 also stores data and conformational parameters in order to provide "on the spot" structural filters to explore the three-dimensional RNA structures. An instant visualization of the 3D RNA structures is provided. RNA FRABASE 2.0 is freely available at http://rnafrabase.cs.put.poznan.pl. Conclusions RNA FRABASE 2.0 provides a novel database and powerful search engine which is equipped with new data and functionalities that are unavailable elsewhere. Our intention is that this advanced version of the RNA FRABASE will be of interest to all researchers working in the RNA field. PMID:20459631

RNA FRABASE 2.0: an advanced web-accessible database with the capacity to search the three-dimensional fragments within RNA structures.

PubMed

Popenda, Mariusz; Szachniuk, Marta; Blazewicz, Marek; Wasik, Szymon; Burke, Edmund K; Blazewicz, Jacek; Adamiak, Ryszard W

2010-05-06

Recent discoveries concerning novel functions of RNA, such as RNA interference, have contributed towards the growing importance of the field. In this respect, a deeper knowledge of complex three-dimensional RNA structures is essential to understand their new biological functions. A number of bioinformatic tools have been proposed to explore two major structural databases (PDB, NDB) in order to analyze various aspects of RNA tertiary structures. One of these tools is RNA FRABASE 1.0, the first web-accessible database with an engine for automatic search of 3D fragments within PDB-derived RNA structures. This search is based upon the user-defined RNA secondary structure pattern. In this paper, we present and discuss RNA FRABASE 2.0. This second version of the system represents a major extension of this tool in terms of providing new data and a wide spectrum of novel functionalities. An intuitionally operated web server platform enables very fast user-tailored search of three-dimensional RNA fragments, their multi-parameter conformational analysis and visualization. RNA FRABASE 2.0 has stored information on 1565 PDB-deposited RNA structures, including all NMR models. The RNA FRABASE 2.0 search engine algorithms operate on the database of the RNA sequences and the new library of RNA secondary structures, coded in the dot-bracket format extended to hold multi-stranded structures and to cover residues whose coordinates are missing in the PDB files. The library of RNA secondary structures (and their graphics) is made available. A high level of efficiency of the 3D search has been achieved by introducing novel tools to formulate advanced searching patterns and to screen highly populated tertiary structure elements. RNA FRABASE 2.0 also stores data and conformational parameters in order to provide "on the spot" structural filters to explore the three-dimensional RNA structures. An instant visualization of the 3D RNA structures is provided. RNA FRABASE 2.0 is freely available at http://rnafrabase.cs.put.poznan.pl. RNA FRABASE 2.0 provides a novel database and powerful search engine which is equipped with new data and functionalities that are unavailable elsewhere. Our intention is that this advanced version of the RNA FRABASE will be of interest to all researchers working in the RNA field.

Radiative signals from impact of Shoemaker-Levy on Jupiter

NASA Technical Reports Server (NTRS)

Ahrens, Thomas J.; Orton, Glenn S.; Takata, Toshiko; Okeefe, John D.

1994-01-01

The temperature and internal energy fields calculated by Takata et al. in the plume are used to calculate the greybody thermal radiation emitted versus wavelength to predict what might be observed by several spectral sensors operating from different platforms when fragments of Comet Shoemaker-Levy 9 (SL-9) impact Jupiter in July 1994. A SPH code was used by Takata et al. to calculate the full three dimensional flow and thermodynamic fields in the comet fragment and the atmosphere of Jupiter. We determined the fragment penetration depth, energy partitioning between the atmosphere and the impactor, and energy density deposited per unit length over the trajectory. Once the impactor had disintegrated and stopped, and the strong atmospheric shock decayed, the flow is driven by buoyancy effects. We then used our SPH code to calculate the flow and thermodynamic fields: pressure, article velocity, temperature, and internal energy distributions in the plume. The calculations for 2 and 10 km cometary fragments yield maximum deposition depths of approximately 175 and 525 km, respectively (1 bar = 0 km depth). We also calculated that 0.7 and 0.6 of the initial kinetic energy of the 10 and 2 km bolides, respectively, are deposited as internal energy in Jupiter's atmosphere.

A kinematic model for the formation of the Siletz-Crescent forearc terrane by capture of coherent fragments of the Farallon and Resurrection plates

USGS Publications Warehouse

McCrory, Patricia A.; Wilson, Douglas S.

2013-01-01

The volcanic basement of the Oregon and Washington Coast ranges has been proposed to represent a pair of tracks of the Yellowstone hotspot formed at a mid-ocean ridge during the early Cenozoic. This interpretation has been questioned on many grounds, especially that the range of ages does not match the offshore spreading rates and that the presence of continental coarse clastic sediments is difficult to reconcile with fast convergence rates between the oceanic plates and North America. Updates to basement geochronology and plate motion history reveal that these objections are much less serious than when they were first raised. Forward plate kinematic modeling reveals that predicted basement ages can be consistent with the observed range of about 55–49 Ma, and that the entire basement terrane can form within about 300 km of continental sources for clastic sediments. This kinematic model indicates that there is no firm reason to reject the near-ridge hotspot hypothesis on the basis of plate motions. A novel element of the model is the Resurrection plate, previously proposed to exist between the Farallon and Kula plates. By including the defunct Resurrection plate in our reconstruction, we are able to model the Farallon hotspot track as docking against the Oregon subduction margin starting about 53 Ma, followed by docking of the Resurrection track to the north starting about 48 Ma. Accretion of the Farallon plate fragment and partial subduction of the Resurrection fragment complicates the three-dimensional structure of the modern Cascadia forearc. We interpret the so-called “E” layer beneath Vancouver Island to be part of the Resurrection fragment. Our new kinematic model of mobile terranes within the Paleogene North American plate boundary allows reinterpretation of the three-dimensional structure of the Cascadia forearc and its relationship to ongoing seismotectonic processes.

Methods for producing partially digested restriction DNA fragments and for producing a partially modified PCR product

DOEpatents

Wong, Kwong-Kwok

2000-01-01

The present invention is an improved method of making a partially modified PCR product from a DNA fragment with a polymerase chain reaction (PCR). In a standard PCR process, the DNA fragment is combined with starting deoxynucleoside triphosphates, a primer, a buffer and a DNA polymerase in a PCR mixture. The PCR mixture is then reacted in the PCR producing copies of the DNA fragment. The improvement of the present invention is adding an amount of a modifier at any step prior to completion of the PCR process thereby randomly and partially modifying the copies of the DNA fragment as a partially modified PCR product. The partially modified PCR product may then be digested with an enzyme that cuts the partially modified PCR product at unmodified sites thereby producing an array of DNA restriction fragments.

Effects of semen storage and separation techniques on sperm DNA fragmentation.

PubMed

Jackson, Robert E; Bormann, Charles L; Hassun, Pericles A; Rocha, André M; Motta, Eduardo L A; Serafini, Paulo C; Smith, Gary D

2010-12-01

To determine the effect of semen storage and separation techniques on sperm DNA fragmentation. Controlled clinical study. An assisted reproductive technology laboratory. Thirty normoozospermic semen samples obtained from patients undergoing infertility evaluation. One aliquot from each sample was immediately prepared (control) for the sperm chromatin dispersion assay (SCD). Aliquots used to assess storage techniques were treated in the following ways: snap frozen by liquid nitrogen immersion, slow frozen with Tris-yolk buffer and glycerol, kept on ice for 24 hours or maintained at room temperature for 4 and 24 hours. Aliquots used to assess separation techniques were processed by the following methods: washed and centrifuged in media, swim-up from washed sperm pellet, density gradient separation, density gradient followed by swim-up. DNA integrity was then measured by SCD. DNA fragmentation as measured by SCD. There was no significant difference in fragmentation among the snap frozen, slow frozen, and wet-ice groups. Compared to other storage methods short-term storage at room temperature did not impact DNA fragmentation yet 24 hours storage significantly increased fragmentation. Swim-up, density gradient and density gradient/swim-up had significantly reduced DNA fragmentation levels compared with washed semen. Postincubation, density gradient/swim-up showed the lowest fragmentation levels. The effect of sperm processing methods on DNA fragmentation should be considered when selecting storage or separation techniques for clinical use. Copyright © 2010 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Evaluation of coal-related model compounds using a tandem mass spectrometry.

PubMed

Li, Guo-Sheng; Dong, Xueming; Fan, Xing; You, Chun-Yan; Wu, Ge; Zhao, Yun-Peng; Lu, Yao; Wei, Xian-Yong; Ma, Feng-Yun

2018-05-08

Gas chromotography/mass spectrometry (GC/MS) is a routine and basic instrumental method for the analysis of complex coal conversion products in chemical industry. To further enhance practical potentials of GC/MS in chemical industry, a tandem MS method for the selection of ion pair applied in monitoring coal conversions was established by using GC/quadrupole time-of-flight MS (GC/Q-TOF MS). The corresponding fragmentation pathways were explored and suitable ion pairs were screened. Fourteen coal-related model compounds (CRMCs) were analyzed using a GC/Q-TOF MS with different collision induced dissociation (CID) energies (5-20 eV). The fragmentation pathways can offer a better understanding of chemical bond breaking, hydrogen transfer, rearrangement reactions and elimination of neutral fragments for CRMCs during the CID process. The precursor ions of aromatic hydrocarbons without alkyl chain were hard to fragment with a CID energy of 20 eV. But aromatic hydrocarbons with branched chains were prone to fragment via the loss of alkyl chains and further fragmented through ring-open reactions. Compared to C alk -C ar bond, C ar -C ar bond was hard to fragment duo to its high bond dissociation energy. The existence of heteroatoms facilitated fragmentation that was conducive to screening ion pair. The CID technique of GC/Q-TOF MS will contribute to the studies on the organic composition of coals and building monitoring methods for coal conversions via fragmentation and ion pair selection. This article is protected by copyright. All rights reserved.

Mining protein loops using a structural alphabet and statistical exceptionality

PubMed Central

2010-01-01

Background Protein loops encompass 50% of protein residues in available three-dimensional structures. These regions are often involved in protein functions, e.g. binding site, catalytic pocket... However, the description of protein loops with conventional tools is an uneasy task. Regular secondary structures, helices and strands, have been widely studied whereas loops, because they are highly variable in terms of sequence and structure, are difficult to analyze. Due to data sparsity, long loops have rarely been systematically studied. Results We developed a simple and accurate method that allows the description and analysis of the structures of short and long loops using structural motifs without restriction on loop length. This method is based on the structural alphabet HMM-SA. HMM-SA allows the simplification of a three-dimensional protein structure into a one-dimensional string of states, where each state is a four-residue prototype fragment, called structural letter. The difficult task of the structural grouping of huge data sets is thus easily accomplished by handling structural letter strings as in conventional protein sequence analysis. We systematically extracted all seven-residue fragments in a bank of 93000 protein loops and grouped them according to the structural-letter sequence, named structural word. This approach permits a systematic analysis of loops of all sizes since we consider the structural motifs of seven residues rather than complete loops. We focused the analysis on highly recurrent words of loops (observed more than 30 times). Our study reveals that 73% of loop-lengths are covered by only 3310 highly recurrent structural words out of 28274 observed words). These structural words have low structural variability (mean RMSd of 0.85 Å). As expected, half of these motifs display a flanking-region preference but interestingly, two thirds are shared by short (less than 12 residues) and long loops. Moreover, half of recurrent motifs exhibit a significant level of amino-acid conservation with at least four significant positions and 87% of long loops contain at least one such word. We complement our analysis with the detection of statistically over-represented patterns of structural letters as in conventional DNA sequence analysis. About 30% (930) of structural words are over-represented, and cover about 40% of loop lengths. Interestingly, these words exhibit lower structural variability and higher sequential specificity, suggesting structural or functional constraints. Conclusions We developed a method to systematically decompose and study protein loops using recurrent structural motifs. This method is based on the structural alphabet HMM-SA and not on structural alignment and geometrical parameters. We extracted meaningful structural motifs that are found in both short and long loops. To our knowledge, it is the first time that pattern mining helps to increase the signal-to-noise ratio in protein loops. This finding helps to better describe protein loops and might permit to decrease the complexity of long-loop analysis. Detailed results are available at http://www.mti.univ-paris-diderot.fr/publication/supplementary/2009/ACCLoop/. PMID:20132552

Mining protein loops using a structural alphabet and statistical exceptionality.

PubMed

Regad, Leslie; Martin, Juliette; Nuel, Gregory; Camproux, Anne-Claude

2010-02-04

Protein loops encompass 50% of protein residues in available three-dimensional structures. These regions are often involved in protein functions, e.g. binding site, catalytic pocket... However, the description of protein loops with conventional tools is an uneasy task. Regular secondary structures, helices and strands, have been widely studied whereas loops, because they are highly variable in terms of sequence and structure, are difficult to analyze. Due to data sparsity, long loops have rarely been systematically studied. We developed a simple and accurate method that allows the description and analysis of the structures of short and long loops using structural motifs without restriction on loop length. This method is based on the structural alphabet HMM-SA. HMM-SA allows the simplification of a three-dimensional protein structure into a one-dimensional string of states, where each state is a four-residue prototype fragment, called structural letter. The difficult task of the structural grouping of huge data sets is thus easily accomplished by handling structural letter strings as in conventional protein sequence analysis. We systematically extracted all seven-residue fragments in a bank of 93000 protein loops and grouped them according to the structural-letter sequence, named structural word. This approach permits a systematic analysis of loops of all sizes since we consider the structural motifs of seven residues rather than complete loops. We focused the analysis on highly recurrent words of loops (observed more than 30 times). Our study reveals that 73% of loop-lengths are covered by only 3310 highly recurrent structural words out of 28274 observed words). These structural words have low structural variability (mean RMSd of 0.85 A). As expected, half of these motifs display a flanking-region preference but interestingly, two thirds are shared by short (less than 12 residues) and long loops. Moreover, half of recurrent motifs exhibit a significant level of amino-acid conservation with at least four significant positions and 87% of long loops contain at least one such word. We complement our analysis with the detection of statistically over-represented patterns of structural letters as in conventional DNA sequence analysis. About 30% (930) of structural words are over-represented, and cover about 40% of loop lengths. Interestingly, these words exhibit lower structural variability and higher sequential specificity, suggesting structural or functional constraints. We developed a method to systematically decompose and study protein loops using recurrent structural motifs. This method is based on the structural alphabet HMM-SA and not on structural alignment and geometrical parameters. We extracted meaningful structural motifs that are found in both short and long loops. To our knowledge, it is the first time that pattern mining helps to increase the signal-to-noise ratio in protein loops. This finding helps to better describe protein loops and might permit to decrease the complexity of long-loop analysis. Detailed results are available at http://www.mti.univ-paris-diderot.fr/publication/supplementary/2009/ACCLoop/.

An Enumerative Combinatorics Model for Fragmentation Patterns in RNA Sequencing Provides Insights into Nonuniformity of the Expected Fragment Starting-Point and Coverage Profile.

PubMed

Prakash, Celine; Haeseler, Arndt Von

2017-03-01

RNA sequencing (RNA-seq) has emerged as the method of choice for measuring the expression of RNAs in a given cell population. In most RNA-seq technologies, sequencing the full length of RNA molecules requires fragmentation into smaller pieces. Unfortunately, the issue of nonuniform sequencing coverage across a genomic feature has been a concern in RNA-seq and is attributed to biases for certain fragments in RNA-seq library preparation and sequencing. To investigate the expected coverage obtained from fragmentation, we develop a simple fragmentation model that is independent of bias from the experimental method and is not specific to the transcript sequence. Essentially, we enumerate all configurations for maximal placement of a given fragment length, F, on transcript length, T, to represent every possible fragmentation pattern, from which we compute the expected coverage profile across a transcript. We extend this model to incorporate general empirical attributes such as read length, fragment length distribution, and number of molecules of the transcript. We further introduce the fragment starting-point, fragment coverage, and read coverage profiles. We find that the expected profiles are not uniform and that factors such as fragment length to transcript length ratio, read length to fragment length ratio, fragment length distribution, and number of molecules influence the variability of coverage across a transcript. Finally, we explore a potential application of the model where, with simulations, we show that it is possible to correctly estimate the transcript copy number for any transcript in the RNA-seq experiment.

An Enumerative Combinatorics Model for Fragmentation Patterns in RNA Sequencing Provides Insights into Nonuniformity of the Expected Fragment Starting-Point and Coverage Profile

PubMed Central

Haeseler, Arndt Von

2017-01-01

Abstract RNA sequencing (RNA-seq) has emerged as the method of choice for measuring the expression of RNAs in a given cell population. In most RNA-seq technologies, sequencing the full length of RNA molecules requires fragmentation into smaller pieces. Unfortunately, the issue of nonuniform sequencing coverage across a genomic feature has been a concern in RNA-seq and is attributed to biases for certain fragments in RNA-seq library preparation and sequencing. To investigate the expected coverage obtained from fragmentation, we develop a simple fragmentation model that is independent of bias from the experimental method and is not specific to the transcript sequence. Essentially, we enumerate all configurations for maximal placement of a given fragment length, F, on transcript length, T, to represent every possible fragmentation pattern, from which we compute the expected coverage profile across a transcript. We extend this model to incorporate general empirical attributes such as read length, fragment length distribution, and number of molecules of the transcript. We further introduce the fragment starting-point, fragment coverage, and read coverage profiles. We find that the expected profiles are not uniform and that factors such as fragment length to transcript length ratio, read length to fragment length ratio, fragment length distribution, and number of molecules influence the variability of coverage across a transcript. Finally, we explore a potential application of the model where, with simulations, we show that it is possible to correctly estimate the transcript copy number for any transcript in the RNA-seq experiment. PMID:27661099

Interaction between two discontiguous chain segments from the beta-sheet of Escherichia coli thioredoxin suggests an initiation site for folding.

PubMed

Tasayco, M L; Fuchs, J; Yang, X M; Dyalram, D; Georgescu, R E

2000-09-05

The approach of comparing folding and folding/binding processes is exquisitely poised to narrow down the regions of the sequence that drive protein folding. We have dissected the small single alpha/beta domain of oxidized Escherichia coli thioredoxin (Trx) into three complementary fragments (N, residues 1-37; M, residues 38-73; and C, residues 74-108) to study them in isolation and upon recombination by far-UV CD and NMR spectroscopy. The isolated fragments show a minimum of ellipticity of ca. 197 nm in their far-UV CD spectra without concentration dependence, chemical shifts of H(alpha) that are close to the random coil values, and no medium- and long-range NOE connectivities in their three-dimensional NMR spectra. These fragments behave as disordered monomers. Only the far-UV CD spectra of binary or ternary mixtures that contain N- and C-fragments are different from the sum of their individual spectra, which is indicative of folding and/or binding of these fragments. Indeed, the cross-peaks corresponding to the rather hydrophobic beta(2) and beta(4) regions of the beta-sheet of Trx disappear from the (1)H-(15)N HSQC spectra of isolated labeled N- and C-fragments, respectively, upon addition of the unlabeled complementary fragments. The disappearing cross-peaks indicate interactions between the beta(2) and beta(4) regions, and their reappearance at lower temperatures indicates unfolding and/or dissociation of heteromers that are predominantly held by hydrophobic forces. Our results argue that the folding of Trx begins by zippering two discontiguous and rather hydrophobic chain segments (beta(2) and beta(4)) corresponding to neighboring strands of the native beta-sheet.

A hybrid method for solutes in complex solvents: Density functional theory combined with empirical force fields

NASA Astrophysics Data System (ADS)

Eichinger, M.; Tavan, P.; Hutter, J.; Parrinello, M.

1999-06-01

We present a hybrid method for molecular dynamics simulations of solutes in complex solvents as represented, for example, by substrates within enzymes. The method combines a quantum mechanical (QM) description of the solute with a molecular mechanics (MM) approach for the solvent. The QM fragment of a simulation system is treated by ab initio density functional theory (DFT) based on plane-wave expansions. Long-range Coulomb interactions within the MM fragment and between the QM and the MM fragment are treated by a computationally efficient fast multipole method. For the description of covalent bonds between the two fragments, we introduce the scaled position link atom method (SPLAM), which removes the shortcomings of related procedures. The various aspects of the hybrid method are scrutinized through test calculations on liquid water, the water dimer, ethane and a small molecule related to the retinal Schiff base. In particular, the extent to which vibrational spectra obtained by DFT for the solute can be spoiled by the lower quality force field of the solvent is checked, including cases in which the two fragments are covalently joined. The results demonstrate that our QM/MM hybrid method is especially well suited for the vibrational analysis of molecules in condensed phase.

SPLICE: A program to assemble partial query solutions from three-dimensional database searches into novel ligands

NASA Astrophysics Data System (ADS)

Ho, Chris M. W.; Marshall, Garland R.

1993-12-01

SPLICE is a program that processes partial query solutions retrieved from 3D, structural databases to generate novel, aggregate ligands. It is designed to interface with the database searching program FOUNDATION, which retrieves fragments containing any combination of a user-specified minimum number of matching query elements. SPLICE eliminates aspects of structures that are physically incapable of binding within the active site. Then, a systematic rule-based procedure is performed upon the remaining fragments to ensure receptor complementarity. All modifications are automated and remain transparent to the user. Ligands are then assembled by linking components into composite structures through overlapping bonds. As a control experiment, FOUNDATION and SPLICE were used to reconstruct a know HIV-1 protease inhibitor after it had been fragmented, reoriented, and added to a sham database of fifty different small molecules. To illustrate the capabilities of this program, a 3D search query containing the pharmacophoric elements of an aspartic proteinase-inhibitor crystal complex was searched using FOUNDATION against a subset of the Cambridge Structural Database. One hundred thirty-one compounds were retrieved, each containing any combination of at least four query elements. Compounds were automatically screened and edited for receptor complementarity. Numerous combinations of fragments were discovered that could be linked to form novel structures, containing a greater number of pharmacophoric elements than any single retrieved fragment.

Unimolecular dissociation of protonated trans-1,4-diphenyl-2-butene-1,4-dione in the gas phase: rearrangement versus simple cleavage.

PubMed

Wu, Lianming; Liu, David Q; Vogt, Frederick G

2006-01-01

Fragmentation mechanisms of trans-1,4-diphenyl-2-butene-1,4-dione were studied using a variety of mass spectrometric techniques. The major fragmentation pathways occur by various rearrangements by loss of H(2)O, CO, H(2)O and CO, and CO(2). The other fragmentation pathways via simple alpha cleavages were also observed but accounted for the minor dissociation channels in both a two-dimensional (2-D) linear ion trap and a quadrupole time-of-flight (Q-TOF) mass spectrometer. The elimination of CO(2) (rather than CH(3)CHO or C(3)H(8)), which was confirmed by an exact mass measurement using the Q-TOF instrument, represented a major fragmentation pathway in the 2-D linear ion trap mass spectrometer. However, the elimination of H(2)O and CO becomes more competitive in the beam-type Q-TOF instrument. The loss of CO is observed in both the MS(2) experiment of m/z 237 and the MS(3) experiment of m/z 219 but via the different transition states. The data suggest that the olefinic double bond in protonated trans-1,4-diphenyl-2-butene-1,4-dione plays a key role in stabilizing the rearrangement transition states and increasing the bond dissociation (cleavage) energy to give favorable rearrangement fragmentation pathways. Copyright (c) 2006 John Wiley & Sons, Ltd.

Density-functional theory study of the geometries, stabilities, and electronic properties of Au n Rb (n = 1-10) clusters: comparison with pure gold clusters

NASA Astrophysics Data System (ADS)

Hu, Yan-Fei; Jiang, Gang; Meng, Da-Qiao

2012-01-01

The density functional method with the relativistic effective core potential has been employed to investigate systematically the geometric structures, relative stabilities, growth-pattern behavior, and electronic properties of small bimetallic Au n Rb (n = 1-10) and pure gold Au n (n ≤ 11) clusters. For the geometric structures of the Au n Rb (n = 1-10) clusters, the dominant growth pattern is for a Rb-substituted Au n +1 cluster or one Au atom capped on a Au n -1Rb cluster, and the turnover point from a two-dimensional to a three-dimensional structure occurs at n = 4. Moreover, the stability of the ground-state structures of these clusters has been examined via an analysis of the average atomic binding energies, fragmentation energies, and the second-order difference of energies as a function of cluster size. The results exhibit a pronounced even-odd alternation phenomenon. The same pronounced even-odd alternations are found for the HOMO-LUMO gap, VIPs, VEAs, and the chemical hardness. In addition, about one electron charge transfers from the Au n host to the Rb atom in each corresponding Au n Rb cluster.

Many-body physics in two-component Bose–Einstein condensates in a cavity: fragmented superradiance and polarization

NASA Astrophysics Data System (ADS)

Lode, Axel U. J.; Diorico, Fritz S.; Wu, RuGway; Molignini, Paolo; Papariello, Luca; Lin, Rui; Lévêque, Camille; Exl, Lukas; Tsatsos, Marios C.; Chitra, R.; Mauser, Norbert J.

2018-05-01

We consider laser-pumped one-dimensional two-component bosons in a parabolic trap embedded in a high-finesse optical cavity. Above a threshold pump power, the photons that populate the cavity modify the effective atom trap and mediate a coupling between the two components of the Bose–Einstein condensate. We calculate the ground state of the laser-pumped system and find different stages of self-organization depending on the power of the laser. The modified potential and the laser-mediated coupling between the atomic components give rise to rich many-body physics: an increase of the pump power triggers a self-organization of the atoms while an even larger pump power causes correlations between the self-organized atoms—the BEC becomes fragmented and the reduced density matrix acquires multiple macroscopic eigenvalues. In this fragmented superradiant state, the atoms can no longer be described as two-level systems and the mapping of the system to the Dicke model breaks down.

Blow Flies from Forest Fragments Embedded in Different Land Uses: Implications for Selecting Indicators in Forensic Entomology.

PubMed

de Souza, Mirian S; Pepinelli, Mateus; de Almeida, Eduardo C; Ochoa-Quintero, Jose M; Roque, Fabio O

2016-01-01

Given the general expectation that forest loss can alter biodiversity patterns, we hypothesize that blow fly species abundances differ in a gradient of native vegetation cover. This study was conducted in 17 fragments across different landscapes in central Brazil. Different land cover type proportions were used to represent landscape structure. In total, 2334 specimens of nine species of Calliphoridae were collected. We used principal component analysis (PCA) to reduce dimensionality and multicollinearity of the landscape data. The first component explained 70%, and it represented a gradient of forest-pasture land uses. Alien species showed a wide distribution in different fragments with no clear relationship between the abundance values and the scores of PCA axes, whereas native species occurred only in areas with a predominance of forest cover. Our study revealed that certain native species may be sensitive to forest loss at the landscape scale, and they represent a bioindicator in forensic entomology. © 2015 American Academy of Forensic Sciences.

Role of preoperative 3-dimensional computed tomography reconstruction in depressed skull fractures treated with craniectomy: a case report of forensic interest.

PubMed

Viel, Guido; Cecchetto, Giovanni; Manara, Renzo; Cecchetto, Attilio; Montisci, Massimo

2011-06-01

Patients affected by cranial trauma with depressed skull fractures and increased intracranial pressure generally undergo neurosurgical intervention. Because craniotomy and craniectomy remove skull fragments and generate new fracture lines, they complicate forensic examination and sometimes prevent a clear identification of skull fracture etiology. A 3-dimensional reconstruction based on preoperative computed tomography (CT) scans, giving a picture of the injuries before surgical intervention, can help the forensic examiner in identifying skull fracture origin and the means of production.We report the case of a 41-year-old-man presenting at the emergency department with a depressed skull fracture at the vertex and bilateral subdural hemorrhage. The patient underwent 2 neurosurgical interventions (craniotomy and craniectomy) but died after 40 days of hospitalization in an intensive care unit. At autopsy, the absence of various bone fragments did not allow us to establish if the skull had been stricken by a blunt object or had hit the ground with high kinetic energy. To analyze bone injuries before craniectomy, a 3-dimensional CT reconstruction based on preoperative scans was performed. A comparative analysis between autoptic and radiological data allowed us to differentiate surgical from traumatic injuries. Moreover, based on the shape and size of the depressed skull fracture (measured from the CT reformations), we inferred that the man had been stricken by a cylindric blunt object with a diameter of about 3 cm.

Study the fragment size distribution in dynamic fragmentation of laser shock loding tin

NASA Astrophysics Data System (ADS)

He, Weihua; Xin, Jianting; Chu, Genbai; Shui, Min; Xi, Tao; Zhao, Yongqiang; Gu, Yuqiu

2017-06-01

Characterizing the distribution of fragment size produced from dynamic fragmentation process is very important for fundamental science like predicting material dymanic response performance and for a variety of engineering applications. However, only a few data about fragment mass or size have been obtained due to its great challenge in its dynamic measurement. This paper would focus on investigating the fragment size distribution from the dynamic fragmentation of laser shock-loaded metal. Material ejection of tin sample with wedge shape groove in the free surface is collected with soft recovery technique. Via fine post-shot analysis techniques including X-ray micro-tomography and the improved watershed method, it is found that fragments can be well detected. To characterize their size distributions, a random geometric statistics method based on Poisson mixtures was derived for dynamic heterogeneous fragmentation problem, which leads to a linear combinational exponential distribution. Finally we examined the size distribution of laser shock-loaded tin with the derived model, and provided comparisons with other state-of-art models. The resulting comparisons prove that our proposed model can provide more reasonable fitting result for laser shock-loaded metal.

Genetic effects of habitat fragmentation and population isolation on Etheostoma raneyi (Percidae)

Treesearch

Ken A. Sterling; David H. Reed; Brice P. Noonan; Melvin L. Warren

2012-01-01

The use of genetic methods to quantify the effects of anthropogenic habitat fragmentation on population structure has become increasingly common. However, in today’s highly fragmented habitats, researchers have sometimes concluded that populations are currently genetically isolated due to habitat fragmentation without testing the possibility that populations were...

Ranking Fragment Ions Based on Outlier Detection for Improved Label-Free Quantification in Data-Independent Acquisition LC-MS/MS

PubMed Central

Bilbao, Aivett; Zhang, Ying; Varesio, Emmanuel; Luban, Jeremy; Strambio-De-Castillia, Caterina; Lisacek, Frédérique; Hopfgartner, Gérard

2016-01-01

Data-independent acquisition LC-MS/MS techniques complement supervised methods for peptide quantification. However, due to the wide precursor isolation windows, these techniques are prone to interference at the fragment ion level, which in turn is detrimental for accurate quantification. The “non-outlier fragment ion” (NOFI) ranking algorithm has been developed to assign low priority to fragment ions affected by interference. By using the optimal subset of high priority fragment ions these interfered fragment ions are effectively excluded from quantification. NOFI represents each fragment ion as a vector of four dimensions related to chromatographic and MS fragmentation attributes and applies multivariate outlier detection techniques. Benchmarking conducted on a well-defined quantitative dataset (i.e. the SWATH Gold Standard), indicates that NOFI on average is able to accurately quantify 11-25% more peptides than the commonly used Top-N library intensity ranking method. The sum of the area of the Top3-5 NOFIs produces similar coefficients of variation as compared to the library intensity method but with more accurate quantification results. On a biologically relevant human dendritic cell digest dataset, NOFI properly assigns low priority ranks to 85% of annotated interferences, resulting in sensitivity values between 0.92 and 0.80 against 0.76 for the Spectronaut interference detection algorithm. PMID:26412574

Characterization of Protein-Excipient Microheterogeneity in Biopharmaceutical Solid-State Formulations by Confocal Fluorescence Microscopy.

PubMed

Koshari, Stijn H S; Ross, Jean L; Nayak, Purnendu K; Zarraga, Isidro E; Rajagopal, Karthikan; Wagner, Norman J; Lenhoff, Abraham M

2017-02-06

Protein-stabilizer microheterogeneity is believed to influence long-term protein stability in solid-state biopharmaceutical formulations and its characterization is therefore essential for the rational design of stable formulations. However, the spatial distribution of the protein and the stabilizer in a solid-state formulation is, in general, difficult to characterize because of the lack of a functional, simple, and reliable characterization technique. We demonstrate the use of confocal fluorescence microscopy with fluorescently labeled monoclonal antibodies (mAbs) and antibody fragments (Fabs) to directly visualize three-dimensional particle morphologies and protein distributions in dried biopharmaceutical formulations, without restrictions on processing conditions or the need for extensive data analysis. While industrially relevant lyophilization procedures of a model IgG1 mAb generally lead to uniform protein-excipient distribution, the method shows that specific spray-drying conditions lead to distinct protein-excipient segregation. Therefore, this method can enable more definitive optimization of formulation conditions than has previously been possible.

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

PubMed

Luo, Yao; Wang, Ling

2017-11-16

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

Capturing Three-Dimensional Genome Organization in Individual Cells by Single-Cell Hi-C.

PubMed

Nagano, Takashi; Wingett, Steven W; Fraser, Peter

2017-01-01

Hi-C is a powerful method to investigate genome-wide, higher-order chromatin and chromosome conformations averaged from a population of cells. To expand the potential of Hi-C for single-cell analysis, we developed single-cell Hi-C. Similar to the existing "ensemble" Hi-C method, single-cell Hi-C detects proximity-dependent ligation events between cross-linked and restriction-digested chromatin fragments in cells. A major difference between the single-cell Hi-C and ensemble Hi-C protocol is that the proximity-dependent ligation is carried out in the nucleus. This allows the isolation of individual cells in which nearly the entire Hi-C procedure has been carried out, enabling the production of a Hi-C library and data from individual cells. With this new method, we studied genome conformations and found evidence for conserved topological domain organization from cell to cell, but highly variable interdomain contacts and chromosome folding genome wide. In addition, we found that the single-cell Hi-C protocol provided cleaner results with less technical noise suggesting it could be used to improve the ensemble Hi-C technique.

PLATYPUS: A code for reaction dynamics of weakly-bound nuclei at near-barrier energies within a classical dynamical model

NASA Astrophysics Data System (ADS)

Diaz-Torres, Alexis

2011-04-01

A self-contained Fortran-90 program based on a three-dimensional classical dynamical reaction model with stochastic breakup is presented, which is a useful tool for quantifying complete and incomplete fusion, and breakup in reactions induced by weakly-bound two-body projectiles near the Coulomb barrier. The code calculates (i) integrated complete and incomplete fusion cross sections and their angular momentum distribution, (ii) the excitation energy distribution of the primary incomplete-fusion products, (iii) the asymptotic angular distribution of the incomplete-fusion products and the surviving breakup fragments, and (iv) breakup observables, such as angle, kinetic energy and relative energy distributions. Program summaryProgram title: PLATYPUS Catalogue identifier: AEIG_v1_0 Program summary URL:http://cpc.cs.qub.ac.uk/summaries/AEIG_v1_0.html Program obtainable from: CPC Program Library, Queen's University, Belfast, N. Ireland Licensing provisions: Standard CPC licence, http://cpc.cs.qub.ac.uk/licence/licence.html No. of lines in distributed program, including test data, etc.: 332 342 No. of bytes in distributed program, including test data, etc.: 344 124 Distribution format: tar.gz Programming language: Fortran-90 Computer: Any Unix/Linux workstation or PC with a Fortran-90 compiler Operating system: Linux or Unix RAM: 10 MB Classification: 16.9, 17.7, 17.8, 17.11 Nature of problem: The program calculates a wide range of observables in reactions induced by weakly-bound two-body nuclei near the Coulomb barrier. These include integrated complete and incomplete fusion cross sections and their spin distribution, as well as breakup observables (e.g. the angle, kinetic energy, and relative energy distributions of the fragments). Solution method: All the observables are calculated using a three-dimensional classical dynamical model combined with the Monte Carlo sampling of probability-density distributions. See Refs. [1,2] for further details. Restrictions: The program is suited for a weakly-bound two-body projectile colliding with a stable target. The initial orientation of the segment joining the two breakup fragments is considered to be isotropic. Additional comments: Several source routines from Numerical Recipies, and the Mersenne Twister random number generator package are included to enable independent compilation. Running time: About 75 minutes for input provided, using a PC with 1.5 GHz processor.

Research on the photoelectric measuring method of warhead fragment velocity

NASA Astrophysics Data System (ADS)

Liu, Ji; Yu, Lixia; Zhang, Bin; Liu, Xiaoyan

2016-09-01

The velocity of warhead fragment is the key criteria to determine its mutilation efficiency. But owing to the small size, larger quantity, irregular shape, high speed, arbitrary direction, large dispersion of warhead fragment and adverse environment, the test of fragment velocity parameter is very difficult. The paper designed an optoelectronic system to measure the average velocity of warhead fragments accurately. The apparatus included two parallel laser screens spaced apart at a known fixed distance for providing time measurement between start and stop signals. The large effective screen area was composed of laser source, retro-reflector and large area photo-diode. Whenever a moving fragment interrupted two optical screens, the system would generate a target signal. Due to partial obscuration of the incident energy and the poor test condition of the explosion, fragment target signal is easily disturbed. Therefore, fragments signal processing technology has become a key technology of the system. The noise of signal was reduced by employing wavelet decomposition and reconstruction. The time of fragment passing though the target was obtained by adopting peak detection algorithm. Based on the method of search peak in different width scale and waveform trend by using optima wavelet, the problem of rolling waveform was solved. Lots of fragments experiments of the different types of the warheads were conducted. Experimental results show that: warhead fragments capture rate of system is better than 98%, which can give velocity of each fragment in the density of less than 20 pieces per m2.

Effects of the processing methods of corn grain and soybean meal on milk protein expression profiles in dairy cows.

PubMed

Li, S S; Shen, J S; Ren, D X; Liu, J X

2015-02-01

A proteomic approach was used to investigate the effects of the processing method of corn grain and soybean meal on the milk protein expression profile in lactating dairy cows. A total of 12 multiparous Holstein dairy cows were used in a 4×4 Latin square design with a 2×2 factorial arrangement. The primary factors examined were corn (finely ground (FGC) v. steam-flaked (SFC)) and soybean meal (solvent-extracted (SSBM) v. heat-treated (HSBM)), which were used to formulate four diets with the same basal ingredient: 27% FGC and 9% SSBM; 27% SFC and 9% SSBM; 27% FGC and 9% HSBM; and 27% SFC and 9% HSBM. Each period lasted for 21 days. Milk samples were collected on days 18, 19 and 20 of each period. Changes in the milk proteins were assessed by two-dimensional (2D) electrophoresis and ImageMaster 2D Platinum 6.0 software. A total of 13 spots displayed variations in protein spot abundance according to the statistical analysis. These spots were identified by a matrix-assisted laser desorption/ionization-time of flight/time of flight MS. According to the gels, the relative abundance of α(s2)-casein (CN) fragments was higher in the cows fed the SFC-HSBM than that for SFC-SSBM, whereas β-CN, α-lactalbumin and zinc-alpha-2-glycoprotein fragments were down-regulated in HSBM-fed cows. The relative decrease of β-CN expression was validated by western blot and agreed with the MS data. These results suggested that the method used to process soybean meal modified the synthesis and secretion of milk proteins in lactating dairy cows' mammary glands.

Three-Dimensional Seismic Imaging of Eastern Russia

DTIC Science & Technology

2008-09-01

small blocks or microplates within the ancient suture and present-day plate boundary zones. We assembled catalog picks from ~13,000 events and ~100... oceanic fragments that have been disrupted, deformed, and juxtaposed. The Kolyma-Omolon superterrane consists of a number of cratonal (Omolon...Prikolyma), continental margin (Omulevka), island arc (Alazeya, Khetachan), and oceanic terranes of diverse ages that amalgamated in the Early Mesozoic

DNA fragment sizing and sorting by laser-induced fluorescence

DOEpatents

Hammond, Mark L.; Jett, James H.; Keller, Richard A.; Marrone, Babetta L.; Martin, John C.

1996-01-01

A method is provided for sizing DNA fragments using high speed detection systems, such as flow cytometry to determine unique characteristics of DNA pieces from a sample. In one characterization the DNA piece is fragmented at preselected sites to produce a plurality of DNA fragments. The DNA piece or the resulting DNA fragments are treated with a dye effective to stain stoichiometrically the DNA piece or the DNA fragments. The fluorescence from the dye in the stained fragments is then examined to generate an output functionally related to the number of nucleotides in each one of the DNA fragments. In one embodiment, the intensity of the fluorescence emissions from each fragment is linearly related to the fragment length. The distribution of DNA fragment sizes forms a characterization of the DNA piece for use in forensic and research applications.

Method to separate and determine the amount of ejecta produced in a second-shock material-fragmentation event

NASA Astrophysics Data System (ADS)

Buttler, W. T.; Hixson, R. S.; King, N. S. P.; Olson, R. T.; Rigg, P. A.; Zellner, M. B.; Routley, N.; Rimmer, A.

2007-04-01

The authors consider a mathematical method to separate and determine the amount of ejecta produced in a second-shock material-fragmentation process. The technique is theoretical and assumes that a material undergoing a shock release at a vacuum interface ejects particulate material or fragments as the initial shock unloads and reflects at the vacuum-surface interface. In this case it is thought that the reflected shock may reflect again at the source of the shock and return to the vacuum-surface interface and eject another amount of fragments or particulate material.

Nuclear fuel element

DOEpatents

Zocher, Roy W.

1991-01-01

A nuclear fuel element and a method of manufacturing the element. The fuel element is comprised of a metal primary container and a fuel pellet which is located inside it and which is often fragmented. The primary container is subjected to elevated pressure and temperature to deform the container such that the container conforms to the fuel pellet, that is, such that the container is in substantial contact with the surface of the pellet. This conformance eliminates clearances which permit rubbing together of fuel pellet fragments and rubbing of fuel pellet fragments against the container, thus reducing the amount of dust inside the fuel container and the amount of dust which may escape in the event of container breach. Also, as a result of the inventive method, fuel pellet fragments tend to adhere to one another to form a coherent non-fragmented mass; this reduces the tendency of a fragment to pierce the container in the event of impact.

Fragment Screening and HIV Therapeutics

PubMed Central

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

2013-01-01

Fragment screening has proven to be a powerful alternative to traditional methods for drug discovery. Biophysical methods, such as X-ray crystallography, NMR spectroscopy, and surface plasmon resonance, are used to screen a diverse library of small molecule compounds. Although compounds identified via this approach have relatively weak affinity, they provide a good platform for lead development and are highly efficient binders with respect to their size. Fragment screening has been utilized for a wide-range of targets, including HIV-1 proteins. Here, we review the fragment screening studies targeting HIV-1 proteins using X-ray crystallography or surface plasmon resonance. These studies have successfully detected binding of novel fragments to either previously established or new sites on HIV-1 protease and reverse transcriptase. In addition, fragment screening against HIV-1 reverse transcriptase has been used as a tool to better understand the complex nature of ligand binding to a flexible target. PMID:21972022

Partial filling affinity capillary electrophoresis as a useful tool for fragment-based drug discovery: A proof of concept on thrombin.

PubMed

Farcaş, E; Bouckaert, C; Servais, A-C; Hanson, J; Pochet, L; Fillet, M

2017-09-01

With the emergence of more challenging targets, a relatively new approach, fragment-based drug discovery (FBDD), proved its efficacy and gained increasing importance in the pharmaceutical industry. FBDD identifies low molecular-weight (MW) ligands (fragments) that bind to biologically important macromolecules, then a structure-guided fragment growing or merging approach is performed, contributing to the quality of the lead. However, to select the appropriate fragment to be evolved, sensitive analytical screening methods must be used to measure the affinity in the μM or even mM range. In this particular context, we developed a robust and selective partial filling affinity CE (ACE) method for the direct binding screening of a small fragment library in order to identify new thrombin inhibitors. To demonstrate the accuracy of our assay, the complex dissociation constants of three known thrombin inhibitors, namely benzamidine, p-aminobenzamidine and nafamostat were determined and found to be in good concordance with the previously reported values. Finally, the screening of a small library was performed and demonstrated the high discriminatory power of our method towards weak binders compared to classical spectrophotometric activity assay, proving the interest of our method in the context of FBDD. Copyright © 2017 Elsevier B.V. All rights reserved.

Crystal structure of ethyl (E)-2-cyano-3-(thio-phen-2-yl)acrylate: two conformers forming a discrete disorder.

PubMed

Castro Agudelo, Brian; Cárdenas, Juan C; Macías, Mario A; Ochoa-Puentes, Cristian; Sierra, Cesar A

2017-09-01

In the title compound, C 10 H 9 NO 2 S, all the non-H atoms, except for the ethyl fragment, lie nearly in the same plane. Despite the mol-ecular planarity, the ethyl fragment presents more than one conformation, giving rise to a discrete disorder, which was modelled with two different crystallographic sites for the eth-oxy O and eth-oxy α-C atoms, with occupancy values of 0.5. In the crystal, the three-dimensional array is mainly directed by C-H⋯(O,N) inter-actions, giving rise to inversion dimers with R 2 2 (10) and R 2 2 (14) motifs and infinite chains running along the [100] direction.

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

PubMed

Fukunishi, Yoshifumi

2010-01-01

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

Identifying areas of relative change in forest fragmentation in New Hampshire between 1990 and 2000

Treesearch

Tonya Lister; Andrew Lister; William McWilliams; Rachel Riemann

2007-01-01

Forest fragmentation potentially can impact many facets of natural ecosystems. Numerous methods have been employed to assess static forest fragmentation. Few studies, however, have analyzed changes in forest fragmentation over time. In this study, we developed new classifications from Landsat imagery data acquired in 1990 and 2000 for New Hampshire, assessed...

Regolith evolution in the laboratory - Scaling dissimilar comminution experiments

NASA Technical Reports Server (NTRS)

Cintala, Mark J.; Horz, Friedrich

1990-01-01

Repeated impacts into fragmental targets simulating unconsolidated debris on planetary surfaces have provided empirical insight into the evolution of planetary regoliths. The techniques of dimensional analysis have been employed to quantify and examine the relationships between the more important variables in the evolution of these experimental regoliths. Application of this method to the results of 10 experimental series shows that the quantity of comminuted target mass is directly proportional to (1) the number of impacts, (2) the diameter of the projectile, (3) the mean size of the crystals, (4) the mean grain size of the evolving regolith, (5) the total target mass, (6) the impactor density, and (7) the ratio of the impact velocity to the velocity of sound in the target rock. The comminuted mass is inversely proportional to the density of the target rock and the sorting of the regolith.

Micro-Satellite Impact Tests to Investigate Multi-Layer Insulation Fragments

NASA Astrophysics Data System (ADS)

Murakami, Junko; Hanada, Toshiya; Liou, J.-C.; Stansbery, Eugene

2009-03-01

This paper summarizes two satellite impact experiments completed in 2008. The objective of the experiments is to investigate the physical properties of satellite fragments, including those originated from Multi-Layer Insulation and a solar panel. One test generated approximately 1,800 fragments while the other produced only 1,000 fragments. This difference came from the number of needle-like fragments from carbon fiber reinforced plastics. All collected fragments were analyzed using the same method as described in the NASA standard breakup model and compared with the breakup model. This paper will present: (1) the area-to-mass ratio, size, and mass distributions of the fragments, and (2) the differences in fragment properties between the two tests.

Microcanonical thermodynamics and statistical fragmentation of dissipative systems. The topological structure of the N-body phase space

NASA Astrophysics Data System (ADS)

Gross, D. H. E.

1997-01-01

This review is addressed to colleagues working in different fields of physics who are interested in the concepts of microcanonical thermodynamics, its relation and contrast to ordinary, canonical or grandcanonical thermodynamics, and to get a first taste of the wide area of new applications of thermodynamical concepts like hot nuclei, hot atomic clusters and gravitating systems. Microcanonical thermodynamics describes how the volume of the N-body phase space depends on the globally conserved quantities like energy, angular momentum, mass, charge, etc. Due to these constraints the microcanonical ensemble can behave quite differently from the conventional, canonical or grandcanonical ensemble in many important physical systems. Microcanonical systems become inhomogeneous at first-order phase transitions, or with rising energy, or with external or internal long-range forces like Coulomb, centrifugal or gravitational forces. Thus, fragmentation of the system into a spatially inhomogeneous distribution of various regions of different densities and/or of different phases is a genuine characteristic of the microcanonical ensemble. In these cases which are realized by the majority of realistic systems in nature, the microcanonical approach is the natural statistical description. We investigate this most fundamental form of thermodynamics in four different nontrivial physical cases: (I) Microcanonical phase transitions of first and second order are studied within the Potts model. The total energy per particle is a nonfluctuating order parameter which controls the phase which the system is in. In contrast to the canonical form the microcanonical ensemble allows to tune the system continuously from one phase to the other through the region of coexisting phases by changing the energy smoothly. The configurations of coexisting phases carry important informations about the nature of the phase transition. This is more remarkable as the canonical ensemble is blind against these configurations. It is shown that the three basic quantities which specify a phase transition of first order - Transition temperature, latent heat, and interphase surface entropy - can be well determined for finite systems from the caloric equation of state T( E) in the coexistence region. Their values are already for a lattice of only ~ 30 ∗ 30 spins close to the ones of the corresponding infinite system. The significance of the backbending of the caloric equation of state T( E) is clarified. It is the signal for a phase transition of first order in a finite isolated system. (II) Fragmentation is shown to be a specific and generic phase transition of finite systems. The caloric equation of state T( E) for hot nuclei is calculated. The phase transition towards fragmentation can unambiguously be identified by the anomalies in T( E). As microcanonical thermodynamics is a full N-body theory it determines all many-body correlations as well. Consequently, various statistical multi-fragment correlations are investigated which give insight into the details of the equilibration mechanism. (III) Fragmentation of neutral and multiply charged atomic clusters is the next example of a realistic application of microcanonical thermodynamics. Our simulation method, microcanonical Metropolis Monte Carlo, combines the explicit microscopic treatment of the fragmentational degrees of freedom with the implicit treatment of the internal degrees of freedom of the fragments described by the experimental bulk specific heat. This micro-macro approach allows us to study the fragmentation of also larger fragments. Characteristic details of the fission of multiply charged metal clusters find their explanation by the different bulk properties. (IV) Finally, the fragmentation of strongly rotating nuclei is discussed as an example for a microcanonical ensemble under the action of a two-dimensional repulsive force.

The complex metal-rich boride Ti1+xRh2-x+yIr3-yB3 (x=0.68, y=1.06) with a new structure type containing B4 zigzag fragments: Synthesis, crystal chemistry and theoretical calculations

NASA Astrophysics Data System (ADS)

Goerens, Christian; Fokwa, Boniface P. T.

2012-08-01

Polycrystalline samples and single crystals of the new complex boride Ti1+xRh2-x+yIr3-yB3 (x=0.68; y=1.06) were synthesized by arc-melting the elements in a water-cooled copper crucible under an argon atmosphere and characterized by X-Ray diffraction as well as EDX measurements. The crystal structure was refined on the basis of single crystal data. The new phase, which represents a new structure type containing trans zigzag B4 fragments as well as isolated boron atoms crystallizes in the orthorhombic space group Pbam (Nr. 55) with the lattice parameters a=8.620(1) Å, b=14.995(2) Å and c=3.234(1) Å. First-principles density functional theory calculations using the Vienna ab-initio simulation package (VASP) were performed on an appropriate structural model (using a supercell approach) and the experimental crystallographic data could be reproduced accurately. Based on this model, the density of states and crystal orbital Hamilton population (for bonding analysis) were calculated, using the linear muffin-tin orbital atomic sphere approximation (LMTO-ASA) method. According to these calculations, this metal-rich compound should be metallic, as expected. Furthermore, very strong boron-boron interactions are observed in the trans zigzag B4 fragment, which induce a clear differentiation of two types of metal-boron contacts with different strength. The observed three-dimensional metal-metal interaction is in good agreement with the predicted metallic behavior.

Membrane-Active Epithelial Keratin 6A Fragments (KAMPs) Are Unique Human Antimicrobial Peptides with a Non-αβ Structure

PubMed Central

Lee, Judy T. Y.; Wang, Guangshun; Tam, Yu Tong; Tam, Connie

2016-01-01

Antibiotic resistance is a pressing global health problem that threatens millions of lives each year. Natural antimicrobial peptides and their synthetic derivatives, including peptoids and peptidomimetics, are promising candidates as novel antibiotics. Recently, the C-terminal glycine-rich fragments of human epithelial keratin 6A were found to have bactericidal and cytoprotective activities. Here, we used an improved 2-dimensional NMR method coupled with a new protocol for structural refinement by low temperature simulated annealing to characterize the solution structure of these kerain-derived antimicrobial peptides (KAMPs). Two specific KAMPs in complex with membrane mimicking sodium dodecyl sulfate (SDS) micelles displayed amphipathic conformations with only local bends and turns, and a central 10-residue glycine-rich hydrophobic strip that is central to bactericidal activity. To our knowledge, this is the first report of non-αβ structure for human antimicrobial peptides. Direct observation of Staphylococcus aureus and Pseudomonas aeruginosa by scanning and transmission electron microscopy showed that KAMPs deformed bacterial cell envelopes and induced pore formation. Notably, in competitive binding experiments, KAMPs demonstrated binding affinities to LPS and LTA that did not correlate with their bactericidal activities, suggesting peptide-LPS and peptide-LTA interactions are less important in their mechanisms of action. Moreover, immunoprecipitation of KAMPs-bacterial factor complexes indicated that membrane surface lipoprotein SlyB and intracellular machineries NQR sodium pump and ribosomes are potential molecular targets for the peptides. Results of this study improve our understanding of the bactericidal function of epithelial cytokeratin fragments, and highlight an unexplored class of human antimicrobial peptides, which may serve as non-αβ peptide scaffolds for the design of novel peptide-based antibiotics. PMID:27891122

The dual role of fragments in fragment-assembly methods for de novo protein structure prediction

PubMed Central

Handl, Julia; Knowles, Joshua; Vernon, Robert; Baker, David; Lovell, Simon C.

2013-01-01

In fragment-assembly techniques for protein structure prediction, models of protein structure are assembled from fragments of known protein structures. This process is typically guided by a knowledge-based energy function and uses a heuristic optimization method. The fragments play two important roles in this process: they define the set of structural parameters available, and they also assume the role of the main variation operators that are used by the optimiser. Previous analysis has typically focused on the first of these roles. In particular, the relationship between local amino acid sequence and local protein structure has been studied by a range of authors. The correlation between the two has been shown to vary with the window length considered, and the results of these analyses have informed directly the choice of fragment length in state-of-the-art prediction techniques. Here, we focus on the second role of fragments and aim to determine the effect of fragment length from an optimization perspective. We use theoretical analyses to reveal how the size and structure of the search space changes as a function of insertion length. Furthermore, empirical analyses are used to explore additional ways in which the size of the fragment insertion influences the search both in a simulation model and for the fragment-assembly technique, Rosetta. PMID:22095594

Regioselective chemical modification of monoclonal antibodies

DOEpatents

Ranadive, Girish; Rosenzweig, Howard S.; Epperly, Michael; Bloomer, William

1993-01-01

A method of selectively modifying an immunoglobulin having at least one Fab region and at least one Fc region, each region having an isoelectric point wherein said isoelectric point of the Fab fragment of said immunoglobulin is different than the isoelectric point of the Fc fragment of the immunoglobulin, said method comprising modification of the immunoglobulin at a pH between the respective isoelectric points of the Fab and Fc fragments of the immunoglobulin.

Workflow Design Using Fragment Composition

NASA Astrophysics Data System (ADS)

Mosser, Sébastien; Blay-Fornarino, Mireille; France, Robert

The Service-Oriented Architecture (Soa) paradigm supports the assembly of atomic services to create applications that implement complex business processes. Assembly can be accomplished by service orchestrations defined by Soa architects. The Adore method allows Soa architects to model complex orchestrations of services by composing models of smaller orchestrations called orchestration fragments. The Adore method can also be used to weave fragments that address new concerns into existing application models. In this paper we illustrate how the Adore method can be used to separate and compose process aspects in a Soa design of the Car Crash Crisis Management System. The paper also includes a discussion of the benefits and limitations of the Adore method.

SHOP: a method for structure-based fragment and scaffold hopping.

PubMed

Fontaine, Fabien; Cross, Simon; Plasencia, Guillem; Pastor, Manuel; Zamora, Ismael

2009-03-01

A new method for fragment and scaffold replacement is presented that generates new families of compounds with biological activity, using GRID molecular interaction fields (MIFs) and the crystal structure of the targets. In contrast to virtual screening strategies, this methodology aims only to replace a fragment of the original molecule, maintaining the other structural elements that are known or suspected to have a critical role in ligand binding. First, we report a validation of the method, recovering up to 95% of the original fragments searched among the top-five proposed solutions, using 164 fragment queries from 11 diverse targets. Second, six key customizable parameters are investigated, concluding that filtering the receptor MIF using the co-crystallized ligand atom type has the greatest impact on the ranking of the proposed solutions. Finally, 11 examples using more realistic scenarios have been performed; diverse chemotypes are returned, including some that are similar to compounds that are known to bind to similar targets.

Assembly and analysis of fragmentation data for liquid propellant vessels

NASA Technical Reports Server (NTRS)

Baker, W. E.; Parr, V. B.; Bessey, R. L.; Cox, P. A.

1974-01-01

Fragmentation data was assembled and analyzed for exploding liquid propellant vessels. These data were to be retrieved from reports of tests and accidents, including measurements or estimates of blast yield, etc. A significant amount of data was retrieved from a series of tests conducted for measurement of blast and fireball effects of liquid propellant explosions (Project PYRO), a few well-documented accident reports, and a series of tests to determine auto-ignition properties of mixing liquid propellants. The data were reduced and fitted to various statistical functions. Comparisons were made with methods of prediction for blast yield, initial fragment velocities, and fragment range. Reasonably good correlation was achieved. Methods presented in the report allow prediction of fragment patterns, given type and quantity of propellant, type of accident, and time of propellant mixing.

Building a Better Fragment Library for De Novo Protein Structure Prediction

PubMed Central

de Oliveira, Saulo H. P.; Shi, Jiye; Deane, Charlotte M.

2015-01-01

Fragment-based approaches are the current standard for de novo protein structure prediction. These approaches rely on accurate and reliable fragment libraries to generate good structural models. In this work, we describe a novel method for structure fragment library generation and its application in fragment-based de novo protein structure prediction. The importance of correct testing procedures in assessing the quality of fragment libraries is demonstrated. In particular, the exclusion of homologs to the target from the libraries to correctly simulate a de novo protein structure prediction scenario, something which surprisingly is not always done. We demonstrate that fragments presenting different predominant predicted secondary structures should be treated differently during the fragment library generation step and that exhaustive and random search strategies should both be used. This information was used to develop a novel method, Flib. On a validation set of 41 structurally diverse proteins, Flib libraries presents both a higher precision and coverage than two of the state-of-the-art methods, NNMake and HHFrag. Flib also achieves better precision and coverage on the set of 275 protein domains used in the two previous experiments of the the Critical Assessment of Structure Prediction (CASP9 and CASP10). We compared Flib libraries against NNMake libraries in a structure prediction context. Of the 13 cases in which a correct answer was generated, Flib models were more accurate than NNMake models for 10. “Flib is available for download at: http://www.stats.ox.ac.uk/research/proteins/resources”. PMID:25901595

BcL-xL Conformational Changes upon Fragment Binding Revealed by NMR

PubMed Central

Aguirre, Clémentine; ten Brink, Tim; Walker, Olivier; Guillière, Florence; Davesne, Dany; Krimm, Isabelle

2013-01-01

Protein-protein interactions represent difficult but increasingly important targets for the design of therapeutic compounds able to interfere with biological processes. Recently, fragment-based strategies have been proposed as attractive approaches for the elaboration of protein-protein surface inhibitors from fragment-like molecules. One major challenge in targeting protein-protein interactions is related to the structural adaptation of the protein surface upon molecular recognition. Methods capable of identifying subtle conformational changes of proteins upon fragment binding are therefore required at the early steps of the drug design process. In this report we present a fast NMR method able to probe subtle conformational changes upon fragment binding. The approach relies on the comparison of experimental fragment-induced Chemical Shift Perturbation (CSP) of amine protons to CSP simulated for a set of docked fragment poses, considering the ring-current effect from fragment binding. We illustrate the method by the retrospective analysis of the complex between the anti-apoptotic Bcl-xL protein and the fragment 4′-fluoro-[1,1′-biphenyl]-4-carboxylic acid that was previously shown to bind one of the Bcl-xL hot spots. The CSP-based approach shows that the protein undergoes a subtle conformational rearrangement upon interaction, for residues located in helices 2, 3 and the very beginning of 5. Our observations are corroborated by residual dipolar coupling measurements performed on the free and fragment-bound forms of the Bcl-xL protein. These NMR-based results are in total agreement with previous molecular dynamic calculations that evidenced a high flexibility of Bcl-xL around the binding site. Here we show that CSP of protein amine protons are useful and reliable structural probes. Therefore, we propose to use CSP simulation to assess protein conformational changes upon ligand binding in the fragment-based drug design approach. PMID:23717610

Two-dimensional gas chromatography-online hydrogenation for improved characterization of petrochemical samples.

PubMed

Potgieter, H; Bekker, R; Govender, A; Rohwer, E

2016-05-06

The Fischer-Tropsch (FT) process produces a variety of hydrocarbons over a wide carbon number range and during subsequent product workup a large variety of synthetic fuels and chemicals are produced. The complexity of the product slate obtained from this process is well documented and the high temperature FT (HT-FT) process products are spread over gas, oil and water phases. The characterization of these phases is very challenging even when using comprehensive two-dimensional gas chromatography time-of-flight mass spectrometry (GC×GC-TOFMS). Despite the increase in separation power, peak co-elution still occurs when samples containing isomeric compounds are analysed by comprehensive two dimensional GC. The separation of isomeric compounds with the same double bond equivalents is especially difficult since these compounds elute in a similar position on the GC×GC chromatogram and have identical molecular masses and similar fragmentation patterns in their electron ionization (EI) mass spectra. On-line hydrogenation after GC×GC separation is a possible way to distinguish between these isomeric compounds since the number of rings and alkene double bonds can be determined from the mass spectra of the compounds before and after hydrogenation. This paper describes development of a GC×GC method with post column hydrogenation for the determination of the backbone of cyclic/olefinic structures enabling us to differentiate between classes like dienes and cyclic olefins in complex petrochemical streams. Copyright © 2016 Elsevier B.V. All rights reserved.

Fragment screening of cyclin G-associated kinase by weak affinity chromatography.

PubMed

Meiby, Elinor; Knapp, Stefan; Elkins, Jonathan M; Ohlson, Sten

2012-11-01

Fragment-based drug discovery (FBDD) has become a new strategy for drug discovery where lead compounds are evolved from small molecules. These fragments form low affinity interactions (dissociation constant (K(D)) = mM - μM) with protein targets, which require fragment screening methods of sufficient sensitivity. Weak affinity chromatography (WAC) is a promising new technology for fragment screening based on selective retention of fragments by a drug target. Kinases are a major pharmaceutical target, and FBDD has been successfully applied to several of these targets. In this work, we have demonstrated the potential to use WAC in combination with mass spectrometry (MS) detection for fragment screening of a kinase target-cyclin G-associated kinase (GAK). One hundred seventy fragments were selected for WAC screening by virtual screening of a commercial fragment library against the ATP-binding site of five different proteins. GAK protein was immobilized on a capillary HPLC column, and compound binding was characterized by frontal affinity chromatography. Compounds were screened in sets of 13 or 14, in combination with MS detection for enhanced throughput. Seventy-eight fragments (46 %) with K(D) < 200 μM were detected, including a few highly efficient GAK binders (K(D) of 2 μM; ligand efficiency = 0.51). Of special interest is that chiral screening by WAC may be possible, as two stereoisomeric fragments, which both contained one chiral center, demonstrated twin peaks. This ability, in combination with the robustness, sensitivity, and simplicity of WAC makes it a new method for fragment screening of considerable potential.

A simple method for semi-random DNA amplicon fragmentation using the methylation-dependent restriction enzyme MspJI.

PubMed

Shinozuka, Hiroshi; Cogan, Noel O I; Shinozuka, Maiko; Marshall, Alexis; Kay, Pippa; Lin, Yi-Han; Spangenberg, German C; Forster, John W

2015-04-11

Fragmentation at random nucleotide locations is an essential process for preparation of DNA libraries to be used on massively parallel short-read DNA sequencing platforms. Although instruments for physical shearing, such as the Covaris S2 focused-ultrasonicator system, and products for enzymatic shearing, such as the Nextera technology and NEBNext dsDNA Fragmentase kit, are commercially available, a simple and inexpensive method is desirable for high-throughput sequencing library preparation. MspJI is a recently characterised restriction enzyme which recognises the sequence motif CNNR (where R = G or A) when the first base is modified to 5-methylcytosine or 5-hydroxymethylcytosine. A semi-random enzymatic DNA amplicon fragmentation method was developed based on the unique cleavage properties of MspJI. In this method, random incorporation of 5-methyl-2'-deoxycytidine-5'-triphosphate is achieved through DNA amplification with DNA polymerase, followed by DNA digestion with MspJI. Due to the recognition sequence of the enzyme, DNA amplicons are fragmented in a relatively sequence-independent manner. The size range of the resulting fragments was capable of control through optimisation of 5-methyl-2'-deoxycytidine-5'-triphosphate concentration in the reaction mixture. A library suitable for sequencing using the Illumina MiSeq platform was prepared and processed using the proposed method. Alignment of generated short reads to a reference sequence demonstrated a relatively high level of random fragmentation. The proposed method may be performed with standard laboratory equipment. Although the uniformity of coverage was slightly inferior to the Covaris physical shearing procedure, due to efficiencies of cost and labour, the method may be more suitable than existing approaches for implementation in large-scale sequencing activities, such as bacterial artificial chromosome (BAC)-based genome sequence assembly, pan-genomic studies and locus-targeted genotyping-by-sequencing.

Searching for substructures in fragment spaces.

PubMed

Ehrlich, Hans-Christian; Volkamer, Andrea; Rarey, Matthias

2012-12-21

A common task in drug development is the selection of compounds fulfilling specific structural features from a large data pool. While several methods that iteratively search through such data sets exist, their application is limited compared to the infinite character of molecular space. The introduction of the concept of fragment spaces (FSs), which are composed of molecular fragments and their connection rules, made the representation of large combinatorial data sets feasible. At the same time, search algorithms face the problem of structural features spanning over multiple fragments. Due to the combinatorial nature of FSs, an enumeration of all products is impossible. In order to overcome these time and storage issues, we present a method that is able to find substructures in FSs without explicit product enumeration. This is accomplished by splitting substructures into subsubstructures and mapping them onto fragments with respect to fragment connectivity rules. The method has been evaluated on three different drug discovery scenarios considering the exploration of a molecule class, the elaboration of decoration patterns for a molecular core, and the exhaustive query for peptides in FSs. FSs can be searched in seconds, and found products contain novel compounds not present in the PubChem database which may serve as hints for new lead structures.

Binding-Site Assessment by Virtual Fragment Screening

PubMed Central

Huang, Niu; Jacobson, Matthew P.

2010-01-01

The accurate prediction of protein druggability (propensity to bind high-affinity drug-like small molecules) would greatly benefit the fields of chemical genomics and drug discovery. We have developed a novel approach to quantitatively assess protein druggability by computationally screening a fragment-like compound library. In analogy to NMR-based fragment screening, we dock ∼11000 fragments against a given binding site and compute a computational hit rate based on the fraction of molecules that exceed an empirically chosen score cutoff. We perform a large-scale evaluation of the approach on four datasets, totaling 152 binding sites. We demonstrate that computed hit rates correlate with hit rates measured experimentally in a previously published NMR-based screening method. Secondly, we show that the in silico fragment screening method can be used to distinguish known druggable and non-druggable targets, including both enzymes and protein-protein interaction sites. Finally, we explore the sensitivity of the results to different receptor conformations, including flexible protein-protein interaction sites. Besides its original aim to assess druggability of different protein targets, this method could be used to identifying druggable conformations of flexible binding site for lead discovery, and suggesting strategies for growing or joining initial fragment hits to obtain more potent inhibitors. PMID:20404926

A Biomechanical Study of Posteromedial Tibial Plateau Fracture Stability: Do They All Require Fixation?

PubMed

Cuéllar, Vanessa G; Martinez, Danny; Immerman, Igor; Oh, Cheongeun; Walker, Peter S; Egol, Kenneth A

2015-07-01

Although the posteromedial fragment in tibial plateau fractures is often considered unstable, biomechanical evidence supporting this view is lacking. We aimed to evaluate the stability of the fragment in a cadaver model. Our hypothesis was that under the expected small axial force during rehabilitation and the combined effects of this force with shear force, internal rotation torque, and varus moment, the most common posteromedial tibial fragment morphology could maintain stability in early flexion. Axial compression force alone or combined with posterior shear, internal rotation torque, or varus moment was applied to the femurs of 5 fresh cadaveric knees. A Tekscan pressure mapping system was used to measure pressure and contact area between the femoral condyles, meniscus, and tibial plateau. A Microscribe 3D digitizer was used to define the 3-dimensional positions of the femur and tibia. A 10-mm and then a 20-mm osteotomy was created with a saw at an angle of 30 degrees in the axial plane with respect to the tangent of the posterior tibial plateau and 75 degrees in the sagittal plane, representing a typical posteromedial fracture fragment. At each flexion angle (15, 30, 60, 90, and 120 degrees) and loading condition (axial compression only, compression with shear force, torque, and varus moment), distal displacement of the medial femoral condyle and the tibial fracture fragments was determined. For the 10-mm fragment, medial femoral condyle displacement was little affected up to approximately 30-degree flexion, after which it increased. For the 20-mm fragment, there was progressive medial femoral condyle displacement with increasing flexion from baseline. However, for the 10- and 20-mm fragments themselves, displacements were noted at every flexion angle, starting at 1.7 mm inferior displacement with 15 degrees of flexion and internal rotation torque and up to 10.2 mm displacement with 90 degrees of flexion and varus bending moment. In this cadaveric model of a posteromedial tibial plateau fracture, both fracture fragments studied displaced with knee flexion, even at low flexion angles. Although such fragments may initially seem nondisplaced after injury, posteromedial fragments similar to these tested are likely to displace during knee range of motion exercises in non-weight-bearing conditions.

Immobilization of Fab' fragments onto substrate surfaces: A survey of methods and applications.

PubMed

Crivianu-Gaita, Victor; Thompson, Michael

2015-08-15

Antibody immobilization onto surfaces has widespread applications in many different fields. It is desirable to bind antibodies such that their fragment-antigen-binding (Fab) units are oriented away from the surface in order to maximize analyte binding. The immobilization of only Fab' fragments yields benefits over the more traditional whole antibody immobilization technique. Bound Fab' fragments display higher surface densities, yielding a higher binding capacity for the analyte. The nucleophilic sulfide of the Fab' fragments allows for specific orientations to be achieved. For biosensors, this indicates a higher sensitivity and lower detection limit for a target analyte. The last thirty years have shown tremendous progress in the immobilization of Fab' fragments onto gold, Si-based, polysaccharide-based, plastic-based, magnetic, and inorganic surfaces. This review will show the current scope of Fab' immobilization techniques available and illustrate methods employed to minimize non-specific adsorption of undesirables. Furthermore, a variety of examples will be given to show the versatility of immobilized Fab' fragments in different applications and future directions of the field will be addressed, especially regarding biosensors. Copyright © 2015 Elsevier B.V. All rights reserved.

Aleatory Uncertainty and Scale Effects in Computational Damage Models for Failure and Fragmentation

DTIC Science & Technology

2014-09-01

larger specimens, small specimens have, on average, higher strengths. Equivalently, because curves for small specimens fall below those of larger...the material strength associated with each realization parameter R in Equation (7), and strength distribution curves associated with multiple...effects in brittle media [58], which applies micromorphological dimensional analysis to obtain a universal curve which closely fits rate-dependent

Analysis of Fragmentation During Dynamic Loading: Investigations in the Ries Impact Crater, Germany

NASA Astrophysics Data System (ADS)

Weimer, D.; Hergarten, S.; Kenkmann, T.

2015-09-01

We tested three methods to quantify fragmentation of rocks during dynamic loading and found a trend of decreasing fracture density with increasing distance from crater center. Fragmentation attenuation rates in the near- and far-field are different.

Regioselective chemical modification of monoclonal antibodies

DOEpatents

Ranadive, G.; Rozenzweig, H.S.; Epperly, M.; Bloomer, W.

1993-05-04

A method is presented of selectively modifying an immunoglobulin having at least one Fab region and at least one Fc region. Each region has an isoelectric point where the isoelectric point of the Fab fragment of the immunoglobulin is different from the isoelectric point of the Fc fragment of the immunoglobulin. The method comprises of a modification of the immunoglobulin at a pH between the respective isoelectric points of the Fab and Fc fragments of the immunoglobulin.

Oscar — Using Byte Pairs to Find File Type and Camera Make of Data Fragments

NASA Astrophysics Data System (ADS)

Karresand, Martin; Shahmehri, Nahid

Mapping out the contents of fragmented storage media is hard if the file system has been corrupted, especially as the current forensic tools rely on meta information to do their job. If it was possible to find all fragments belonging to a certain file type, it would also be possible to recover a lost file. Such a tool could for example be used in the hunt for child pornography. The Oscar method identifies the file type of data fragments based solely on statistics calculated from their structure. The method does not need any meta data to work. We have previously used the byte frequency distribution and the rate of change between consecutive bytes as basis for the statistics, as well as calculating the 2-gram frequency distribution to create a model of different file types. This paper present a variant of the 2-gram method, in that it uses a dynamic smoothing factor. In this way we take the amount of data used to create the centroid into consideration. A previous experiment on file type identification is extended with .mp3 files reaching a detection rate of 76% with a false positives rate of 0.4%. We also use the method to identify the camera make used to capture a .jpg picture from a fragment of the picture. The result shows that we can clearly separate a picture fragment coming from a Fuji or Olympus cameras from a fragment of a picture of the other camera makes used in our test.

The intervening removable affinity tag (iRAT) production system facilitates Fv antibody fragment‐mediated crystallography

PubMed Central

Nomura, Yayoi; Sato, Yumi; Suno, Ryoji; Horita, Shoichiro

2016-01-01

Abstract Fv antibody fragments have been used as co‐crystallization partners in structural biology, particularly in membrane protein crystallography. However, there are inherent technical issues associated with the large‐scale production of soluble, functional Fv fragments through conventional methods in various expression systems. To circumvent these problems, we developed a new method, in which a single synthetic polyprotein consisting of a variable light (VL) domain, an intervening removable affinity tag (iRAT), and a variable heavy (VH) domain is expressed by a Gram‐positive bacterial secretion system. This method ensures stoichiometric expression of VL and VH from the monocistronic construct followed by proper folding and assembly of the two variable domains. The iRAT segment can be removed by a site‐specific protease during the purification process to yield tag‐free Fv fragments suitable for crystallization trials. In vitro refolding step is not required to obtain correctly folded Fv fragments. As a proof of concept, we tested the iRAT‐based production of multiple Fv fragments, including a crystallization chaperone for a mammalian membrane protein as well as FDA‐approved therapeutic antibodies. The resulting Fv fragments were functionally active and crystallized in complex with the target proteins. The iRAT system is a reliable, rapid and broadly applicable means of producing milligram quantities of Fv fragments for structural and biochemical studies. PMID:27595817

F-RAG: Generating Atomic Coordinates from RNA Graphs by Fragment Assembly.

PubMed

Jain, Swati; Schlick, Tamar

2017-11-24

Coarse-grained models represent attractive approaches to analyze and simulate ribonucleic acid (RNA) molecules, for example, for structure prediction and design, as they simplify the RNA structure to reduce the conformational search space. Our structure prediction protocol RAGTOP (RNA-As-Graphs Topology Prediction) represents RNA structures as tree graphs and samples graph topologies to produce candidate graphs. However, for a more detailed study and analysis, construction of atomic from coarse-grained models is required. Here we present our graph-based fragment assembly algorithm (F-RAG) to convert candidate three-dimensional (3D) tree graph models, produced by RAGTOP into atomic structures. We use our related RAG-3D utilities to partition graphs into subgraphs and search for structurally similar atomic fragments in a data set of RNA 3D structures. The fragments are edited and superimposed using common residues, full atomic models are scored using RAGTOP's knowledge-based potential, and geometries of top scoring models is optimized. To evaluate our models, we assess all-atom RMSDs and Interaction Network Fidelity (a measure of residue interactions) with respect to experimentally solved structures and compare our results to other fragment assembly programs. For a set of 50 RNA structures, we obtain atomic models with reasonable geometries and interactions, particularly good for RNAs containing junctions. Additional improvements to our protocol and databases are outlined. These results provide a good foundation for further work on RNA structure prediction and design applications. Copyright © 2017 Elsevier Ltd. All rights reserved.

Label-free three-dimensional imaging of cell nucleus using third-harmonic generation microscopy

NASA Astrophysics Data System (ADS)

Lin, Jian; Zheng, Wei; Wang, Zi; Huang, Zhiwei

2014-09-01

We report the implementation of the combined third-harmonic generation (THG) and two-photon excited fluorescence (TPEF) microscopy for label-free three-dimensional (3-D) imaging of cell nucleus morphological changes in liver tissue. THG imaging shows regular spherical shapes of normal hepatocytes nuclei with inner chromatin structures while revealing the condensation of chromatins and nuclear fragmentations in hepatocytes of diseased liver tissue. Colocalized THG and TPEF imaging provides complementary information of cell nuclei and cytoplasm in tissue. This work suggests that 3-D THG microscopy has the potential for quantitative analysis of nuclear morphology in cells at a submicron-resolution without the need for DNA staining.

Label-free three-dimensional imaging of cell nucleus using third-harmonic generation microscopy

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

Lin, Jian; Zheng, Wei; Wang, Zi

2014-09-08

We report the implementation of the combined third-harmonic generation (THG) and two-photon excited fluorescence (TPEF) microscopy for label-free three-dimensional (3-D) imaging of cell nucleus morphological changes in liver tissue. THG imaging shows regular spherical shapes of normal hepatocytes nuclei with inner chromatin structures while revealing the condensation of chromatins and nuclear fragmentations in hepatocytes of diseased liver tissue. Colocalized THG and TPEF imaging provides complementary information of cell nuclei and cytoplasm in tissue. This work suggests that 3-D THG microscopy has the potential for quantitative analysis of nuclear morphology in cells at a submicron-resolution without the need for DNA staining.

The successful merger of theoretical thermochemistry with fragment-based methods in quantum chemistry.

PubMed

Ramabhadran, Raghunath O; Raghavachari, Krishnan

2014-12-16

CONSPECTUS: Quantum chemistry and electronic structure theory have proven to be essential tools to the experimental chemist, in terms of both a priori predictions that pave the way for designing new experiments and rationalizing experimental observations a posteriori. Translating the well-established success of electronic structure theory in obtaining the structures and energies of small chemical systems to increasingly larger molecules is an exciting and ongoing central theme of research in quantum chemistry. However, the prohibitive computational scaling of highly accurate ab initio electronic structure methods poses a fundamental challenge to this research endeavor. This scenario necessitates an indirect fragment-based approach wherein a large molecule is divided into small fragments and is subsequently reassembled to compute its energy accurately. In our quest to further reduce the computational expense associated with the fragment-based methods and overall enhance the applicability of electronic structure methods to large molecules, we realized that the broad ideas involved in a different area, theoretical thermochemistry, are transferable to the area of fragment-based methods. This Account focuses on the effective merger of these two disparate frontiers in quantum chemistry and how new concepts inspired by theoretical thermochemistry significantly reduce the total number of electronic structure calculations needed to be performed as part of a fragment-based method without any appreciable loss of accuracy. Throughout, the generalized connectivity based hierarchy (CBH), which we developed to solve a long-standing problem in theoretical thermochemistry, serves as the linchpin in this merger. The accuracy of our method is based on two strong foundations: (a) the apt utilization of systematic and sophisticated error-canceling schemes via CBH that result in an optimal cutting scheme at any given level of fragmentation and (b) the use of a less expensive second layer of electronic structure method to recover all the missing long-range interactions in the parent large molecule. Overall, the work featured here dramatically decreases the computational expense and empowers the execution of very accurate ab initio calculations (gold-standard CCSD(T)) on large molecules and thereby facilitates sophisticated electronic structure applications to a wide range of important chemical problems.

An efficient and reliable DNA-based sex identification method for archaeological Pacific salmonid (Oncorhynchus spp.) remains.

PubMed

Royle, Thomas C A; Sakhrani, Dionne; Speller, Camilla F; Butler, Virginia L; Devlin, Robert H; Cannon, Aubrey; Yang, Dongya Y

2018-01-01

Pacific salmonid (Oncorhynchus spp.) remains are routinely recovered from archaeological sites in northwestern North America but typically lack sexually dimorphic features, precluding the sex identification of these remains through morphological approaches. Consequently, little is known about the deep history of the sex-selective salmonid fishing strategies practiced by some of the region's Indigenous peoples. Here, we present a DNA-based method for the sex identification of archaeological Pacific salmonid remains that integrates two PCR assays that each co-amplify fragments of the sexually dimorphic on the Y chromosome (sdY) gene and an internal positive control (Clock1a or D-loop). The first assay co-amplifies a 95 bp fragment of sdY and a 108 bp fragment of the autosomal Clock1a gene, whereas the second assay co-amplifies the same sdY fragment and a 249 bp fragment of the mitochondrial D-loop region. This method's reliability, sensitivity, and efficiency, were evaluated by applying it to 72 modern Pacific salmonids from five species and 75 archaeological remains from six Pacific salmonids. The sex identities assigned to each of the modern samples were concordant with their known phenotypic sex, highlighting the method's reliability. Applications of the method to dilutions of modern DNA samples indicate it can correctly identify the sex of samples with as little as ~39 pg of total genomic DNA. The successful sex identification of 70 of the 75 (93%) archaeological samples further demonstrates the method's sensitivity. The method's reliance on two co-amplifications that preferentially amplify sdY helps validate the sex identities assigned to samples and reduce erroneous identifications caused by allelic dropout and contamination. Furthermore, by sequencing the D-loop fragment used as a positive control, species-level and sex identifications can be simultaneously assigned to samples. Overall, our results indicate the DNA-based method reported in this study is a sensitive and reliable sex identification method for ancient salmonid remains.

Vascular Morphogenesis in the Context of Inflammation: Self-Organization in a Fibrin-Based 3D Culture System.

PubMed

Rüger, Beate M; Buchacher, Tanja; Giurea, Alexander; Kubista, Bernd; Fischer, Michael B; Breuss, Johannes M

2018-01-01

Introduction: New vessel formation requires a continuous and tightly regulated interplay between endothelial cells with cells of the perivascular microenvironment supported by mechanic-physical and chemical cues from the extracellular matrix. Aim: Here we investigated the potential of small fragments of synovial tissue to form de novo vascular structures in the context of inflammation within three dimensional (3D) fibrin-based matrices in vitro , and assessed the contribution of mesenchymal stromal cell (MSC)-immune cell cross-talk to neovascularization considering paracrine signals in a fibrin-based co-culture model. Material and Methods: Synovial tissue fragments from patients with rheumatoid arthritis (RA) and inflammatory osteoarthritis (OA) were cultivated within 3D fibrin matrices for up to 4 weeks. Cellular and structural re-arrangement of the initially acellular matrix were documented by phase contrast microscopy and characterized by confocal laser-scanning microscopy of topographically intact 3D cultures and by immunohistochemistry. MSC-peripheral blood mononuclear cell (PBMC) co-cultures in the 3D fibrin system specifically addressed the influence of perivascular cell interactions to neo-vessel formation in a pro-inflammatory microenvironment. Cytokine levels in the supernatants of cultured explant tissues and co-cultures were evaluated by the Bio-Plex cytokine assay and ELISA. Results: Vascular outgrowth from the embedded tissue into the fibrin matrix was preceded by leukocyte egress from the tissue fragments. Neo-vessels originating from both the embedded sample and from clusters locally formed by emigrated mononuclear cells were consistently associated with CD45 + leukocytes. MSC and PBMC in co-culture formed vasculogenic clusters. Clusters and cells with endothelial phenotype emerging from them, were surrounded by a collagen IV scaffold. No vascular structures were observed in control 3D monocultures of PBMC or MSC. Paracrine signals released by cultured OA tissue fragments corresponded with elevated levels of granulocyte-colony stimulating factor, vascular endothelial growth factor and interleukin-6 secreted by MSC-PBMC co-cultures. Conclusion: Our results show that synovial tissue fragments with immune cell infiltrates have the potential to form new vessels in initially avascular 3D fibrin-based matrices. Cross-talk and cluster formation of MSC with immune cells within the 3D fibrin environment through self-organization and secretion of pro-angiogenic paracrine factors can support neo-vessel growth.

Multi-energy method of digital radiography for imaging of biological objects

NASA Astrophysics Data System (ADS)

Ryzhikov, V. D.; Naydenov, S. V.; Opolonin, O. D.; Volkov, V. G.; Smith, C. F.

2016-03-01

This work has been dedicated to the search for a new possibility to use multi-energy digital radiography (MER) for medical applications. Our work has included both theoretical and experimental investigations of 2-energy (2E) and 3- energy (3D) radiography for imaging the structure of biological objects. Using special simulation methods and digital analysis based on the X-ray interaction energy dependence for each element of importance to medical applications in the X-ray range of energy up to 150 keV, we have implemented a quasi-linear approximation for the energy dependence of the X-ray linear mass absorption coefficient μm (E) that permits us to determine the intrinsic structure of the biological objects. Our measurements utilize multiple X-ray tube voltages (50, 100, and 150 kV) with Al and Cu filters of different thicknesses to achieve 3-energy X-ray examination of objects. By doing so, we are able to achieve significantly improved imaging quality of the structure of the subject biological objects. To reconstruct and visualize the final images, we use both two-dimensional (2D) and three-dimensional (3D) palettes of identification. The result is a 2E and/or 3E representation of the object with color coding of each pixel according to the data outputs. Following the experimental measurements and post-processing, we produce a 3D image of the biological object - in the case of our trials, fragments or parts of chicken and turkey.

The Importance of Three-Body Interactions in Molecular Dynamics Simulations of Water with the Fragment Molecular Orbital Method

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

Pruitt, Spencer R.; Nakata, Hiroya; Nagata, Takeshi

2016-04-12

The analytic first derivative with respect to nuclear coordinates is formulated and implemented in the framework of the three-body fragment molecular orbital (FMO) method. The gradient has been derived and implemented for restricted Hartree-Fock, second-order Møller-Plesset perturbation, and density functional theories. The importance of the three-body fully analytic gradient is illustrated through the failure of the two-body FMO method during molecular dynamics simulations of a small water cluster. The parallel implementation of the fragment molecular orbital method, its parallel efficiency, and its scalability on the Blue Gene/Q architecture up to 262,144 CPU cores, are also discussed.

Analytic second derivative of the energy for density-functional tight-binding combined with the fragment molecular orbital method

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

Nakata, Hiroya, E-mail: hiroya.nakata.gt@kyocera.jp; Nishimoto, Yoshio; Fedorov, Dmitri G.

2016-07-28

The analytic second derivative of the energy is developed for the fragment molecular orbital (FMO) method combined with density-functional tight-binding (DFTB), enabling simulations of infrared and Raman spectra of large molecular systems. The accuracy of the method is established in comparison to full DFTB without fragmentation for a set of representative systems. The performance of the FMO-DFTB Hessian is discussed for molecular systems containing up to 10 041 atoms. The method is applied to the study of the binding of α-cyclodextrin to polyethylene glycol, and the calculated IR spectrum of an epoxy amine oligomer reproduces experiment reasonably well.

Method for identifying mutagenic agents which induce large, multilocus deletions in DNA

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

Bradley, W.E.C.; Belouchi, A.; Dewyse, P.

1993-07-13

A method of identifying a mutagenic agent is described which includes a large, multilocus deletions in DNA in mammalian cells comprising: (i) exposing a class III heterozygous CHO cell line to a potential mutagenic agent under investigation, and allowing any mutation of the cell line to proceed, said cell line being characterized in that a restriction fragment length variation exists in on mutation it becomes resistant to 2,6-diaminopurine and in that the DNA sequence adjacent to the two alleles of the APRT gene such that the DNA sequence adjacent to one of the two alleles can be digested with themore » enzyme BclI but the DNA sequence variation adjacent to the other of the two alleles cannot be digested with BclI, (ii) isolating induced mutations of the cell line deficient in APRT function, (iii) isolating DNA from the induced mutants, (iv) digesting the isolated DNA with BclI enzyme to produce digested fragments including a 19 kb fragment and any 2 kb fragment, which fragments hybridize with the labeled probe derived from DNA fragment PDI, (v) separating any digested fragments, (vi) transferring the separated fragments of (v) to a solid support, (vii) hybridizing the supported separated fragments with a labeled probe derived from the clone DNA fragment PD 1, (viii) determining fragments having undergone loss of the 2 kb band identified by the probe, as an identification of parent mutants in which the loss occurred, and (ix) evaluating the mutating ability of the potential mutagenic agent.« less

Glycoproteomics of cerebrospinal fluid in neurodegenerative disease

NASA Astrophysics Data System (ADS)

Sihlbom, Carina; Davidsson, Pia; Emmett, Mark R.; Marshall, Alan G.; Nilsson, Carol L.

2004-05-01

Cerebrospinal fluid (CSF) from individual patients with Alzheimer's disease (AD) was separated by narrow range two-dimensional (2D) gel electrophoresis and analyzed by electrospray FT-ICR MS in this glycoproteomic study. Because several altered proteins in the comparison between AD patients and healthy controls individuals are isoforms of glycoproteins, it is important to determine if the modifying glycans are also altered. FT-ICR MS and fragmentation of glycopeptides with infrared multiphoton dissociation (IRMPD) offers abundant fragment ions through breakage at the glycosidic linkages with excellent mass accuracy, which facilitates the structural determination of the site-specific N-linked glycosylation. We present results from a structural comparison of proteins from three AD patients and three control individuals of different glycosylated isomers of [alpha]-1-antitrypsin, [beta]-trace and apolipoprotein J.

Mutations in the C-terminal fragment of DnaK affecting peptide binding.

PubMed Central

Burkholder, W F; Zhao, X; Zhu, X; Hendrickson, W A; Gragerov, A; Gottesman, M E

1996-01-01

Escherichia coli DnaK acts as a molecular chaperone through its ATP-regulated binding and release of polypeptide substrates. Overexpressing a C-terminal fragment (CTF) of DnaK (Gly-384 to Lys-638) containing the polypeptide substrate binding domain is lethal in wild-type E. coli. This dominant-negative phenotype may result from the nonproductive binding of CTF to cellular polypeptide targets of DnaK. Mutations affecting DnaK substrate binding were identified by selecting noncytotoxic CTF mutants followed by in vitro screening. The clustering of such mutations in the three-dimensional structure of CTF suggests the model that loops L1,2 and L4,5 form a rigid core structure critical for interactions with substrate. Images Fig. 1 Fig. 2 Fig. 3 PMID:8855230

AFEAP cloning: a precise and efficient method for large DNA sequence assembly.

PubMed

Zeng, Fanli; Zang, Jinping; Zhang, Suhua; Hao, Zhimin; Dong, Jingao; Lin, Yibin

2017-11-14

Recent development of DNA assembly technologies has spurred myriad advances in synthetic biology, but new tools are always required for complicated scenarios. Here, we have developed an alternative DNA assembly method named AFEAP cloning (Assembly of Fragment Ends After PCR), which allows scarless, modular, and reliable construction of biological pathways and circuits from basic genetic parts. The AFEAP method requires two-round of PCRs followed by ligation of the sticky ends of DNA fragments. The first PCR yields linear DNA fragments and is followed by a second asymmetric (one primer) PCR and subsequent annealing that inserts overlapping overhangs at both sides of each DNA fragment. The overlapping overhangs of the neighboring DNA fragments annealed and the nick was sealed by T4 DNA ligase, followed by bacterial transformation to yield the desired plasmids. We characterized the capability and limitations of new developed AFEAP cloning and demonstrated its application to assemble DNA with varying scenarios. Under the optimized conditions, AFEAP cloning allows assembly of an 8 kb plasmid from 1-13 fragments with high accuracy (between 80 and 100%), and 8.0, 11.6, 19.6, 28, and 35.6 kb plasmids from five fragments at 91.67, 91.67, 88.33, 86.33, and 81.67% fidelity, respectively. AFEAP cloning also is capable to construct bacterial artificial chromosome (BAC, 200 kb) with a fidelity of 46.7%. AFEAP cloning provides a powerful, efficient, seamless, and sequence-independent DNA assembly tool for multiple fragments up to 13 and large DNA up to 200 kb that expands synthetic biologist's toolbox.

Elucidating quantitative stability/flexibility relationships within thioredoxin and its fragments using a distance constraint model.

PubMed

Jacobs, Donald J; Livesay, Dennis R; Hules, Jeremy; Tasayco, Maria Luisa

2006-05-05

Numerous quantitative stability/flexibility relationships, within Escherichia coli thioredoxin (Trx) and its fragments are determined using a minimal distance constraint model (DCM). A one-dimensional free energy landscape as a function of global flexibility reveals Trx to fold in a low-barrier two-state process, with a voluminous transition state. Near the folding transition temperature, the native free energy basin is markedly skewed to allow partial unfolded forms. Under native conditions the skewed shape is lost, and the protein forms a compact structure with some flexibility. Predictions on ten Trx fragments are generally consistent with experimental observations that they are disordered, and that complementary fragments reconstitute. A hierarchical unfolding pathway is uncovered using an exhaustive computational procedure of breaking interfacial cross-linking hydrogen bonds that span over a series of fragment dissociations. The unfolding pathway leads to a stable core structure (residues 22-90), predicted to act as a kinetic trap. Direct connection between degree of rigidity within molecular structure and non-additivity of free energy is demonstrated using a thermodynamic cycle involving fragments and their hierarchical unfolding pathway. Additionally, the model provides insight about molecular cooperativity within Trx in its native state, and about intermediate states populating the folding/unfolding pathways. Native state cooperativity correlation plots highlight several flexibly correlated regions, giving insight into the catalytic mechanism that facilitates access to the active site disulfide bond. Residual native cooperativity correlations are present in the core substructure, suggesting that Trx can function when it is partly unfolded. This natively disordered kinetic trap, interpreted as a molten globule, has a wide temperature range of metastability, and it is identified as the "slow intermediate state" observed in kinetic experiments. These computational results are found to be in overall agreement with a large array of experimental data.

Affinity-reversed-phase liquid chromatography assay to quantitate recombinant antibodies and antibody fragments in fermentation broth.

PubMed

Battersby, J E; Snedecor, B; Chen, C; Champion, K M; Riddle, L; Vanderlaan, M

2001-08-24

An automated dual-column liquid chromatography assay comprised of affinity and reversed-phase separations that quantifies the majority of antibody-related protein species found in crude cell extracts of recombinant origin is described. Although potentially applicable to any antibody preparation, we here use samples of anti-CD18 (Fab'2LZ) and a full-length antibody, anti-tissue factor (anti-TF), from various stages throughout a biopharmaceutical production process to describe the assay details. The targeted proteins were captured on an affinity column containing an anti-light-chain (kappa) Fab antibody (AME5) immobilized on controlled pore glass. The affinity column was placed in-line with a reversed-phase column and the captured components were transferred by elution with dilute acid and subsequently resolved by eluting the reversed-phase column with a shallow acetonitrile gradient. Characterization of the resolved components showed that most antibody fragment preparations contained a light-chain fragment, free light chain, light-chain dimer and multiple forms of Fab'. Analysis of full-length antibody preparations also resolved these fragments as well as a completely assembled form. Co-eluting with the full-length antibody were high-molecular-mass variants that were missing one or both light chains. Resolved components were quantified by comparison with peak areas of similarly treated standards. By comparing the two-dimensional polyacrylamide gel electrophoresis patterns of an Escherichia coli blank run, a production run and the material affinity captured (AME5) from a production run, it was determined that the AME5 antibody captured isoforms of light chain, light chain covalently attached to heavy chain, and truncated light chain isoforms. These forms comprise the bulk of the soluble product-related fragments found in E. coli cell extracts of recombinantly produced antibody fragments.

Conversion of fullerenes to diamond

DOEpatents

Gruen, Dieter M.

1994-01-01

A method of forming synthetic hydrogen defect free diamond or diamond like films on a substrate. The method involves providing vapor containing fullerene molecules with or without an inert gas, providing a device to impart energy to the fullerene molecules, fragmenting at least in part some of the fullerene molecules in the vapor or energizing the molecules to incipient fragmentation, ionizing the fullerene molecules, impinging ionized fullerene molecules on the substrate to assist in causing fullerene fragmentation to obtain a thickness of diamond on the substrate.

A New Device for Percutaneous Elevation of the Depressed Fractures of Tibial Condyles

PubMed Central

Ravindranath, V.S.; Kumar, Madhusudan; Murthy, G.V.S.

2012-01-01

Introduction: Monocondylar tibia plateau fractures with non-comminuted fragments can be treated using percutaneous screws. Currently indirect methods of reduction are used and thus the technique is limited to fragments with less than 5 mm depression. The first author has designed a device for direct elevation and reduction of the fragments thus potentially expanding the indications of percutaneous screws to fragments with >5mm depression Technical Note: A total of ten cases were treated by this method of percutaneous elevation of the depressed fractures of lateral condyles of the Tibia using this device. Device was inserted through a bony window on the anteromedial surface of tibia. The inner piston of the device in slowly hammered inside thus elevating the depressed fragment. Elevation of fragment could be achieved in all the cases. The fractures were fixed with cancellous screws applied percutaneously. There were no cases with loss of fixation or subsidence of the fragment. All cases achieved radiological union and have good knee function at follow up Conclusion: The new device is able to elevate unicondylar tibia plateau fragments with no subsidence or loss of fixation in our series. A longer follow up in a larger sample will be needed to establish the technique. PMID:27298860

Three-dimensional ultrastructure of osteocytes assessed by focused ion beam-scanning electron microscopy (FIB-SEM).

PubMed

Hasegawa, Tomoka; Yamamoto, Tomomaya; Hongo, Hiromi; Qiu, Zixuan; Abe, Miki; Kanesaki, Takuma; Tanaka, Kawori; Endo, Takashi; de Freitas, Paulo Henrique Luiz; Li, Minqi; Amizuka, Norio

2018-04-01

The aim of this study is to demonstrate the application of focused ion beam-scanning electron microscopy, FIB-SEM for revealing the three-dimensional features of osteocytic cytoplasmic processes in metaphyseal (immature) and diaphyseal (mature) trabeculae. Tibiae of eight-week-old male mice were fixed with aldehyde solution, and treated with block staining prior to FIB-SEM observation. While two-dimensional backscattered SEM images showed osteocytes' cytoplasmic processes in a fragmented fashion, three-dimensional reconstructions of FIB-SEM images demonstrated that osteocytes in primary metaphyseal trabeculae extended their cytoplasmic processes randomly, thus maintaining contact with neighboring osteocytes and osteoblasts. In contrast, diaphyseal osteocytes extended thin cytoplasmic processes from their cell bodies, which ran perpendicular to the bone surface. In addition, these osteocytes featured thick processes that branched into thinner, transverse cytoplasmic processes; at some point, however, these transverse processes bend at a right angle to run perpendicular to the bone surface. Osteoblasts also possessed thicker cytoplasmic processes that branched off as thinner processes, which then connected with cytoplasmic processes of neighboring osteocytes. Thus, FIB-SEM is a useful technology for visualizing the three-dimensional structures of osteocytes and their cytoplasmic processes.

Heart Rate Fragmentation: A Symbolic Dynamical Approach.

PubMed

Costa, Madalena D; Davis, Roger B; Goldberger, Ary L

2017-01-01

Background: We recently introduced the concept of heart rate fragmentation along with a set of metrics for its quantification. The term was coined to refer to an increase in the percentage of changes in heart rate acceleration sign, a dynamical marker of a type of anomalous variability. The effort was motivated by the observation that fragmentation, which is consistent with the breakdown of the neuroautonomic-electrophysiologic control system of the sino-atrial node, could confound traditional short-term analysis of heart rate variability. Objective: The objectives of this study were to: (1) introduce a symbolic dynamical approach to the problem of quantifying heart rate fragmentation; (2) evaluate how the distribution of the different dynamical patterns ("words") varied with the participants' age in a group of healthy subjects and patients with coronary artery disease (CAD); and (3) quantify the differences in the fragmentation patterns between the two sample populations. Methods: The symbolic dynamical method employed here was based on a ternary map of the increment NN interval time series and on the analysis of the relative frequency of symbolic sequences (words) with a pre-defined set of features. We analyzed annotated, open-access Holter databases of healthy subjects and patients with CAD, provided by the University of Rochester Telemetric and Holter ECG Warehouse (THEW). Results: The degree of fragmentation was significantly higher in older individuals than in their younger counterparts. However, the fragmentation patterns were different in the two sample populations. In healthy subjects, older age was significantly associated with a higher percentage of transitions from acceleration/deceleration to zero acceleration and vice versa (termed "soft" inflection points). In patients with CAD, older age was also significantly associated with higher percentages of frank reversals in heart rate acceleration (transitions from acceleration to deceleration and vice versa , termed "hard" inflection points). Compared to healthy subjects, patients with CAD had significantly higher percentages of soft and hard inflection points, an increased percentage of words with a high degree of fragmentation and a decreased percentage of words with a lower degree of fragmentation. Conclusion: The symbolic dynamical method employed here was useful to probe the newly recognized property of heart rate fragmentation. The findings from these cross-sectional studies confirm that CAD and older age are associated with higher levels of heart rate fragmentation. Furthermore, fragmentation with healthy aging appears to be phenotypically different from fragmentation in the context of CAD.

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

PubMed Central

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

2015-01-01

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

Brickworx builds recurrent RNA and DNA structural motifs into medium- and low-resolution electron-density maps

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

Chojnowski, Grzegorz, E-mail: gchojnowski@genesilico.pl; Waleń, Tomasz; University of Warsaw, Banacha 2, 02-097 Warsaw

2015-03-01

A computer program that builds crystal structure models of nucleic acid molecules is presented. Brickworx is a computer program that builds crystal structure models of nucleic acid molecules using recurrent motifs including double-stranded helices. In a first step, the program searches for electron-density peaks that may correspond to phosphate groups; it may also take into account phosphate-group positions provided by the user. Subsequently, comparing the three-dimensional patterns of the P atoms with a database of nucleic acid fragments, it finds the matching positions of the double-stranded helical motifs (A-RNA or B-DNA) in the unit cell. If the target structure ismore » RNA, the helical fragments are further extended with recurrent RNA motifs from a fragment library that contains single-stranded segments. Finally, the matched motifs are merged and refined in real space to find the most likely conformations, including a fit of the sequence to the electron-density map. The Brickworx program is available for download and as a web server at http://iimcb.genesilico.pl/brickworx.« less

Effects of Fragmented Fe Intermetallic Compounds on Ductility in Al-Si-Mg Alloys.

PubMed

Kim, JaeHwang; Kim, DaeHwan

2018-03-01

Fe is intentionally added in order to form the Fe intermetallic compounds (Fe-IMCs) during casting. Field emission scanning electron microscope with energy dispersive spectrometer (EDS) was conducted to understand microstructural changes and chemical composition analyses. The needlelike Fe-IMCs based on two dimensional observation with hundreds of micro size are modified to fragmented particles with the minimum size of 300 nm through clod rolling with 80% thickness reduction. The ratio of Fe:Si on the fragmented Fe-IMCs after 80% reduction is close to 1:1, representing the β-Al5FeSi. The yield and tensile strengths are increased with increasing reduction rate. On the other hand, the elongation is decreased with the 40% reduction, but slightly increased with the 60% reduction. The elongation is dramatically increased over two times for the specimen of 80% reduction compared with that of the as-cast. Fracture behavior is strongly affected by the morphology and size of Fe-IMCs. The fracture mode is changed from brittle to ductile with the microstructure modification of Fe-IMCs.

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

PubMed

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

2014-01-01

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

One Question, Multiple Answers: Biochemical and Biophysical Screening Methods Retrieve Deviating Fragment Hit Lists.

PubMed

Schiebel, Johannes; Radeva, Nedyalka; Köster, Helene; Metz, Alexander; Krotzky, Timo; Kuhnert, Maren; Diederich, Wibke E; Heine, Andreas; Neumann, Lars; Atmanene, Cedric; Roecklin, Dominique; Vivat-Hannah, Valérie; Renaud, Jean-Paul; Meinecke, Robert; Schlinck, Nina; Sitte, Astrid; Popp, Franziska; Zeeb, Markus; Klebe, Gerhard

2015-09-01

Fragment-based lead discovery is gaining momentum in drug development. Typically, a hierarchical cascade of several screening techniques is consulted to identify fragment hits which are then analyzed by crystallography. Because crystal structures with bound fragments are essential for the subsequent hit-to-lead-to-drug optimization, the screening process should distinguish reliably between binders and non-binders. We therefore investigated whether different screening methods would reveal similar collections of putative binders. First we used a biochemical assay to identify fragments that bind to endothiapepsin, a surrogate for disease-relevant aspartic proteases. In a comprehensive screening approach, we then evaluated our 361-entry library by using a reporter-displacement assay, saturation-transfer difference NMR, native mass spectrometry, thermophoresis, and a thermal shift assay. While the combined results of these screening methods retrieve 10 of the 11 crystal structures originally predicted by the biochemical assay, the mutual overlap of individual hit lists is surprisingly low, highlighting that each technique operates on different biophysical principles and conditions. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

NMR screening in fragment-based drug design: a practical guide.

PubMed

Kim, Hai-Young; Wyss, Daniel F

2015-01-01

Fragment-based drug design (FBDD) comprises both fragment-based screening (FBS) to find hits and elaboration of these hits to lead compounds. Typical fragment hits have lower molecular weight (<300-350 Da) and lower initial potency but higher ligand efficiency when compared to those from high-throughput screening. NMR spectroscopy has been widely used for FBDD since it identifies and localizes the binding site of weakly interacting hits on the target protein. Here we describe ligand-based NMR methods for hit identification from fragment libraries and for functional cross-validation of primary hits.

Mapping replication origins in yeast chromosomes.

PubMed

Brewer, B J; Fangman, W L

1991-07-01

The replicon hypothesis, first proposed in 1963 by Jacob and Brenner, states that DNA replication is controlled at sites called origins. Replication origins have been well studied in prokaryotes. However, the study of eukaryotic chromosomal origins has lagged behind, because until recently there has been no method for reliably determining the identity and location of origins from eukaryotic chromosomes. Here, we review a technique we developed with the yeast Saccharomyces cerevisiae that allows both the mapping of replication origins and an assessment of their activity. Two-dimensional agarose gel electrophoresis and Southern hybridization with total genomic DNA are used to determine whether a particular restriction fragment acquires the branched structure diagnostic of replication initiation. The technique has been used to localize origins in yeast chromosomes and assess their initiation efficiency. In some cases, origin activation is dependent upon the surrounding context. The technique is also being applied to a variety of eukaryotic organisms.

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

PubMed

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

2015-01-01

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

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

PubMed Central

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

2015-01-01

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

Sparse Coding for N-Gram Feature Extraction and Training for File Fragment Classification

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

Wang, Felix; Quach, Tu-Thach; Wheeler, Jason

File fragment classification is an important step in the task of file carving in digital forensics. In file carving, files must be reconstructed based on their content as a result of their fragmented storage on disk or in memory. Existing methods for classification of file fragments typically use hand-engineered features such as byte histograms or entropy measures. In this paper, we propose an approach using sparse coding that enables automated feature extraction. Sparse coding, or sparse dictionary learning, is an unsupervised learning algorithm, and is capable of extracting features based simply on how well those features can be used tomore » reconstruct the original data. With respect to file fragments, we learn sparse dictionaries for n-grams, continuous sequences of bytes, of different sizes. These dictionaries may then be used to estimate n-gram frequencies for a given file fragment, but for significantly larger n-gram sizes than are typically found in existing methods which suffer from combinatorial explosion. To demonstrate the capability of our sparse coding approach, we used the resulting features to train standard classifiers such as support vector machines (SVMs) over multiple file types. Experimentally, we achieved significantly better classification results with respect to existing methods, especially when the features were used in supplement to existing hand-engineered features.« less

Sparse Coding for N-Gram Feature Extraction and Training for File Fragment Classification

DOE PAGES

Wang, Felix; Quach, Tu-Thach; Wheeler, Jason; ...

2018-04-05

File fragment classification is an important step in the task of file carving in digital forensics. In file carving, files must be reconstructed based on their content as a result of their fragmented storage on disk or in memory. Existing methods for classification of file fragments typically use hand-engineered features such as byte histograms or entropy measures. In this paper, we propose an approach using sparse coding that enables automated feature extraction. Sparse coding, or sparse dictionary learning, is an unsupervised learning algorithm, and is capable of extracting features based simply on how well those features can be used tomore » reconstruct the original data. With respect to file fragments, we learn sparse dictionaries for n-grams, continuous sequences of bytes, of different sizes. These dictionaries may then be used to estimate n-gram frequencies for a given file fragment, but for significantly larger n-gram sizes than are typically found in existing methods which suffer from combinatorial explosion. To demonstrate the capability of our sparse coding approach, we used the resulting features to train standard classifiers such as support vector machines (SVMs) over multiple file types. Experimentally, we achieved significantly better classification results with respect to existing methods, especially when the features were used in supplement to existing hand-engineered features.« less

Computational fragment-based screening using RosettaLigand: the SAMPL3 challenge

NASA Astrophysics Data System (ADS)

Kumar, Ashutosh; Zhang, Kam Y. J.

2012-05-01

SAMPL3 fragment based virtual screening challenge provides a valuable opportunity for researchers to test their programs, methods and screening protocols in a blind testing environment. We participated in SAMPL3 challenge and evaluated our virtual fragment screening protocol, which involves RosettaLigand as the core component by screening a 500 fragments Maybridge library against bovine pancreatic trypsin. Our study reaffirmed that the real test for any virtual screening approach would be in a blind testing environment. The analyses presented in this paper also showed that virtual screening performance can be improved, if a set of known active compounds is available and parameters and methods that yield better enrichment are selected. Our study also highlighted that to achieve accurate orientation and conformation of ligands within a binding site, selecting an appropriate method to calculate partial charges is important. Another finding is that using multiple receptor ensembles in docking does not always yield better enrichment than individual receptors. On the basis of our results and retrospective analyses from SAMPL3 fragment screening challenge we anticipate that chances of success in a fragment screening process could be increased significantly with careful selection of receptor structures, protein flexibility, sufficient conformational sampling within binding pocket and accurate assignment of ligand and protein partial charges.

Trapping of Embolic Particles in a Vessel Phantom by Cavitation-Enhanced Acoustic Streaming

PubMed Central

Maxwell, Adam D.; Park, Simone; Vaughan, Benjamin L.; Cain, Charles A.; Grotberg, James B.; Xu, Zhen

2014-01-01

Cavitation clouds generated by short, high-amplitude, focused ultrasound pulses were previously observed to attract, trap, and erode thrombus fragments in a vessel phantom. This phenomenon may offer a noninvasive method to capture and eliminate embolic fragments flowing through the bloodstream during a cardiovascular intervention. In this article, the mechanism of embolus trapping was explored by particle image velocimetry (PIV). PIV was used to examine the fluid streaming patterns generated by ultrasound in a vessel phantom with and without crossflow of blood-mimicking fluid. Cavitation enhanced streaming, which generated fluid vortices adjacent to the focus. The focal streaming velocity, uf, was as high as 120 cm/s, while mean crossflow velocities, uc, were imposed up to 14 cm/s. When a solid particle 3-4 mm diameter was introduced into crossflow, it was trapped near the focus. Increasing uf promoted particle trapping while increasing uc promoted particle escape. The maximum crossflow Reynolds number at which particles could be trapped, Rec, was approximately linear with focal streaming number, Ref, i.e. Rec = 0.25Ref + 67.44 (R2=0.76) corresponding to dimensional velocities uc=0.084uf + 3.122 for 20 < uf < 120 cm/s. The fluidic pressure map was estimated from PIV and indicated a negative pressure gradient towards the focus, trapping the embolus near this location. PMID:25109407

Optimization of the linear-scaling local natural orbital CCSD(T) method: Redundancy-free triples correction using Laplace transform.

PubMed

Nagy, Péter R; Kállay, Mihály

2017-06-07

An improved algorithm is presented for the evaluation of the (T) correction as a part of our local natural orbital (LNO) coupled-cluster singles and doubles with perturbative triples [LNO-CCSD(T)] scheme [Z. Rolik et al., J. Chem. Phys. 139, 094105 (2013)]. The new algorithm is an order of magnitude faster than our previous one and removes the bottleneck related to the calculation of the (T) contribution. First, a numerical Laplace transformed expression for the (T) fragment energy is introduced, which requires on average 3 to 4 times fewer floating point operations with negligible compromise in accuracy eliminating the redundancy among the evaluated triples amplitudes. Second, an additional speedup factor of 3 is achieved by the optimization of our canonical (T) algorithm, which is also executed in the local case. These developments can also be integrated into canonical as well as alternative fragmentation-based local CCSD(T) approaches with minor modifications. As it is demonstrated by our benchmark calculations, the evaluation of the new Laplace transformed (T) correction can always be performed if the preceding CCSD iterations are feasible, and the new scheme enables the computation of LNO-CCSD(T) correlation energies with at least triple-zeta quality basis sets for realistic three-dimensional molecules with more than 600 atoms and 12 000 basis functions in a matter of days on a single processor.

Optimization of the linear-scaling local natural orbital CCSD(T) method: Redundancy-free triples correction using Laplace transform

PubMed Central

2017-01-01

An improved algorithm is presented for the evaluation of the (T) correction as a part of our local natural orbital (LNO) coupled-cluster singles and doubles with perturbative triples [LNO-CCSD(T)] scheme [Z. Rolik et al., J. Chem. Phys. 139, 094105 (2013)]. The new algorithm is an order of magnitude faster than our previous one and removes the bottleneck related to the calculation of the (T) contribution. First, a numerical Laplace transformed expression for the (T) fragment energy is introduced, which requires on average 3 to 4 times fewer floating point operations with negligible compromise in accuracy eliminating the redundancy among the evaluated triples amplitudes. Second, an additional speedup factor of 3 is achieved by the optimization of our canonical (T) algorithm, which is also executed in the local case. These developments can also be integrated into canonical as well as alternative fragmentation-based local CCSD(T) approaches with minor modifications. As it is demonstrated by our benchmark calculations, the evaluation of the new Laplace transformed (T) correction can always be performed if the preceding CCSD iterations are feasible, and the new scheme enables the computation of LNO-CCSD(T) correlation energies with at least triple-zeta quality basis sets for realistic three-dimensional molecules with more than 600 atoms and 12 000 basis functions in a matter of days on a single processor. PMID:28576082

Three-Dimensional Radiative Hydrodynamics for Disk Stability Simulations: A Proposed Testing Standard and New Results

NASA Astrophysics Data System (ADS)

Boley, Aaron C.; Durisen, Richard H.; Nordlund, Åke; Lord, Jesse

2007-08-01

Recent three-dimensional radiative hydrodynamics simulations of protoplanetary disks report disparate disk behaviors, and these differences involve the importance of convection to disk cooling, the dependence of disk cooling on metallicity, and the stability of disks against fragmentation and clump formation. To guarantee trustworthy results, a radiative physics algorithm must demonstrate the capability to handle both the high and low optical depth regimes. We develop a test suite that can be used to demonstrate an algorithm's ability to relax to known analytic flux and temperature distributions, to follow a contracting slab, and to inhibit or permit convection appropriately. We then show that the radiative algorithm employed by Mejía and Boley et al. and the algorithm employed by Cai et al. pass these tests with reasonable accuracy. In addition, we discuss a new algorithm that couples flux-limited diffusion with vertical rays, we apply the test suite, and we discuss the results of evolving the Boley et al. disk with this new routine. Although the outcome is significantly different in detail with the new algorithm, we obtain the same qualitative answers. Our disk does not cool fast due to convection, and it is stable to fragmentation. We find an effective α~10-2. In addition, transport is dominated by low-order modes.

A 3-dimensional-printed patient-specific guide system for minimally invasive plate osteosynthesis of a comminuted mid-diaphyseal humeral fracture in a cat.

PubMed

Oxley, Bill

2018-04-01

To report the use of a 3-dimensional (3D)-printed patient-specific reduction guide system to facilitate minimally invasive plate osteosynthesis (MIPO) of a humeral fracture in a cat. Case report. A 9-year-old male neutered domestic short hair cat weighing 4.4 kg. A 9-year-old male domestic short hair cat was presented with a comminuted, mid-diaphyseal left humeral fracture. Computed tomographic data were processed to yield 3D mesh representations of both humeri and subsequently manipulated in computer-aided design software. The mirrored, intact humerus was used as a template for appropriate spatial orientation of the major proximal and distal fracture fragments. Patient-specific Ellis pin orientation guides and a reduction guide were designed and 3D printed. The guide system was used intraoperatively to align the major fracture fragments before application of locking internal fixation via standard MIPO surgical portals. Internal fixation of the fracture resulted in appropriate bone alignment. Recovery was uncomplicated, with early return to normal limb function and radiographic evidence of advanced fracture healing after 4 months. A 3D-printed patient-specific reduction guide system facilitated accurate alignment of a comminuted humeral fracture during MIPO without intraoperative imaging. © 2018 The American College of Veterinary Surgeons.

Fragmentation of protoplanetary discs around M-dwarfs

NASA Astrophysics Data System (ADS)

Backus, Isaac; Quinn, Thomas

2016-12-01

We investigate the conditions required for planet formation via gravitational instability (GI) and protoplanetary disc (PPD) fragmentation around M-dwarfs. Using a suite of 64 SPH simulations with 106 particles, the parameter space of disc mass, temperature, and radius is explored, bracketing reasonable values based on theory and observation. Our model consists of an equilibrium, gaseous, and locally isothermal disc orbiting a central star of mass M* = M⊙/3. Discs with a minimum Toomre Q of Qmin ≲ 0.9 will fragment and form gravitationally bound clumps. Some previous literature has found Qmin < 1.3-1.5 to be sufficient for fragmentation. Increasing disc height tends to stabilize discs, and when incorporated into Q as Qeff ∝ Q(H/R)α for α = 0.18 is sufficient to predict fragmentation. Some discrepancies in the literature regarding Qcrit may be due to different methods of generating initial conditions (ICs). A series of 15 simulations demonstrates that perturbing ICs slightly out of equilibrium can cause discs to fragment for higher Q. Our method for generating ICs is presented in detail. We argue that GI likely plays a role in PPDs around M-dwarfs and that disc fragmentation at large radii is a plausible outcome for these discs.

Molecularly Imprinted Polymers with DNA Aptamer Fragments as Macromonomers.

PubMed

Zhang, Zijie; Liu, Juewen

2016-03-01

Molecularly imprinted polymers (MIPs) are produced in the presence of a template molecule. After removing the template, the cavity can selectively rebind the template. MIPs are attractive functional materials with a low cost and high stability, but traditional MIPs often suffer from low binding affinity. This study employs DNA aptamer fragments as macromonomers to improve MIPs. The DNA aptamer for adenosine was first split into two halves, fluorescently labeled, and copolymerized into MIPs. With a fluorescence quenching assay, the importance of imprinting was confirmed. Further studies were carried out using isothermal titration calorimetry (ITC). Compared to the mixture of the free aptamer fragments, their MIPs doubled the binding affinity. Each free aptamer fragment alone cannot bind adenosine, whereas MIPs containing each fragment are effective binders. We further shortened one of the aptamer fragments, and the DNA length was pushed to as short as six nucleotides, yielding MIPs with a dissociation constant of 27 μM adenosine. This study provides a new method for preparing functional MIP materials by combining high-affinity biopolymer fragments with low-cost synthetic monomers, allowing higher binding affinity and providing a method for signaling binding based on DNA chemistry.

Multiprimer PCR system for differential identification of mycobacteria in clinical samples.

PubMed Central

Del Portillo, P; Thomas, M C; Martínez, E; Marañón, C; Valladares, B; Patarroyo, M E; Carlos López, M

1996-01-01

A novel multiprimer PCR method with the potential to identify mycobacteria in clinical samples is presented. The assay relies on the simultaneous amplification of three bacterial DNA genomic fragments by using different sets of oligonucleotide primers. The first set of primers amplifies a 506-bp fragment from the gene for the 32-kDa antigen of Mycobacterium tuberculosis, which is present in most of the species belonging to the genus Mycobacterium. The second set of primers amplifies a 984-bp fragment from the IS6110 insertion sequence of the bacteria belonging to the M. tuberculosis complex. The third set of primers, derived from an M. tuberculosis species-specific sequence named MTP40, amplifies a 396-bp genomic fragment. Thus, while the multiprimer system would render three amplification fragments from the M. tuberculosis genome and two fragments from the Mycobacterium bovis genome, a unique amplification fragment would be obtained from nontuberculous mycobacteria. The results obtained, using reference mycobacterial strains and typed clinical isolates, show that the multiprimer PCR method may be a rapid, sensitive, and specific tool for the differential identification of various mycobacterial strains in a single-step assay. PMID:8789008

Fragment-based drug discovery as alternative strategy to the drug development for neglected diseases.

PubMed

Mello, Juliana da Fonseca Rezende E; Gomes, Renan Augusto; Vital-Fujii, Drielli Gomes; Ferreira, Glaucio Monteiro; Trossini, Gustavo Henrique Goulart

2017-12-01

Neglected diseases (NDs) affect large populations and almost whole continents, representing 12% of the global health burden. In contrast, the treatment available today is limited and sometimes ineffective. Under this scenery, the Fragment-Based Drug Discovery emerged as one of the most promising alternatives to the traditional methods of drug development. This method allows achieving new lead compounds with smaller size of fragment libraries. Even with the wide Fragment-Based Drug Discovery success resulting in new effective therapeutic agents against different diseases, until this moment few studies have been applied this approach for NDs area. In this article, we discuss the basic Fragment-Based Drug Discovery process, brief successful ideas of general applications and show a landscape of its use in NDs, encouraging the implementation of this strategy as an interesting way to optimize the development of new drugs to NDs. © 2017 John Wiley & Sons A/S.

Research on Splicing Method of Digital Relic Fragment Model

NASA Astrophysics Data System (ADS)

Yan, X.; Hu, Y.; Hou, M.

2018-04-01

In the course of archaeological excavation, a large number of pieces of cultural relics were unearthed, and the restoration of these fragments was done manually by traditional arts and crafts experts. In this process, cultural relics experts often try to splice the existing cultural relics, and then use adhesive to stick together the fragments of correct location, which will cause irreversible secondary damage to cultural relics. In order to minimize such damage, the surveyors combine 3D laser scanning with computer technology, and use the method of establishing digital cultural relics fragments model to make virtual splicing of cultural relics. The 3D software on the common market can basically achieve the model translation and rotation, using this two functions can be achieved manually splicing between models, mosaic records after the completion of the specific location of each piece of fragments, so as to effectively reduce the damage to the relics had tried splicing process.

Population Response to Habitat Fragmentation in a Stream-Dwelling Brook Trout Population

PubMed Central

Letcher, Benjamin H.; Nislow, Keith H.; Coombs, Jason A.; O'Donnell, Matthew J.; Dubreuil, Todd L.

2007-01-01

Fragmentation can strongly influence population persistence and expression of life-history strategies in spatially-structured populations. In this study, we directly estimated size-specific dispersal, growth, and survival of stream-dwelling brook trout in a stream network with connected and naturally-isolated tributaries. We used multiple-generation, individual-based data to develop and parameterize a size-class and location-based population projection model, allowing us to test effects of fragmentation on population dynamics at local (i.e., subpopulation) and system-wide (i.e., metapopulation) scales, and to identify demographic rates which influence the persistence of isolated and fragmented populations. In the naturally-isolated tributary, persistence was associated with higher early juvenile survival (∼45% greater), shorter generation time (one-half) and strong selection against large body size compared to the open system, resulting in a stage-distribution skewed towards younger, smaller fish. Simulating barriers to upstream migration into two currently-connected tributary populations caused rapid (2–6 generations) local extinction. These local extinctions in turn increased the likelihood of system-wide extinction, as tributaries could no longer function as population sources. Extinction could be prevented in the open system if sufficient immigrants from downstream areas were available, but the influx of individuals necessary to counteract fragmentation effects was high (7–46% of the total population annually). In the absence of sufficient immigration, a demographic change (higher early survival characteristic of the isolated tributary) was also sufficient to rescue the population from fragmentation, suggesting that the observed differences in size distributions between the naturally-isolated and open system may reflect an evolutionary response to isolation. Combined with strong genetic divergence between the isolated tributary and open system, these results suggest that local adaptation can ‘rescue’ isolated populations, particularly in one-dimensional stream networks where both natural and anthropogenically-mediated isolation is common. However, whether rescue will occur before extinction depends critically on the race between adaptation and reduced survival in response to fragmentation. PMID:18188404

Population response to habitat fragmentation in a stream-dwelling brook trout population

USGS Publications Warehouse

Letcher, B.H.; Nislow, K.H.; Coombs, J.A.; O'Donnell, M. J.; Dubreuil, T.L.

2007-01-01

Fragmentation can strongly influence population persistence and expression of life-history strategies in spatially-structured populations. In this study, we directly estimated size-specific dispersal, growth, and survival of stream-dwelling brook trout in a stream network with connected and naturally-isolated tributaries. We used multiple-generation, individual-based data to develop and parameterize a size-class and location-based population projection model, allowing us to test effects of fragmentation on population dynamics at local (i.e., subpopulation) and system-wide (i.e., metapopulation) scales, and to identify demographic rates which influence the persistence of isolated and fragmented populations. In the naturally-isolated tributary, persistence was associated with higher early juvenile survival (-45% greater), shorter generation time (one-half) and strong selection against large body size compared to the open system, resulting in a stage-distribution skewed towards younger, smaller fish. Simulating barriers to upstream migration into two currently-connected tribuory populations caused rapid (2-6 generations) local extinction. These local extinctions in turn increased the likelihood of system-wide extinction, as tributaries could no longer function as population sources. Extinction could be prevented in the open system if sufficient immigrants from downstream areas were available, but the influx of individuals necessary to counteract fragmentation effects was high (7-46% of the total population annually). In the absence of sufficient immigration, a demographic change (higher early survival characteristic of the isolated tributary) was also sufficient to rescue the population from fragmentation, suggesting that the observed differences in size distributions between the naturally-isolated and open system may reflect an evolutionary response to isolation. Combined with strong genetic divergence between the isolated tributary and open system, these results suggest that local adaptation can 'rescue' isolated populations, particularly in one-dimensional stream networks where both natural and anthropegenically-mediated isolation is common. However, whether rescue will occur before extinction depends critically on the race between adaptation and reduced survival in response to fragmentation.

TACOA – Taxonomic classification of environmental genomic fragments using a kernelized nearest neighbor approach

PubMed Central

Diaz, Naryttza N; Krause, Lutz; Goesmann, Alexander; Niehaus, Karsten; Nattkemper, Tim W

2009-01-01

Background Metagenomics, or the sequencing and analysis of collective genomes (metagenomes) of microorganisms isolated from an environment, promises direct access to the "unculturable majority". This emerging field offers the potential to lay solid basis on our understanding of the entire living world. However, the taxonomic classification is an essential task in the analysis of metagenomics data sets that it is still far from being solved. We present a novel strategy to predict the taxonomic origin of environmental genomic fragments. The proposed classifier combines the idea of the k-nearest neighbor with strategies from kernel-based learning. Results Our novel strategy was extensively evaluated using the leave-one-out cross validation strategy on fragments of variable length (800 bp – 50 Kbp) from 373 completely sequenced genomes. TACOA is able to classify genomic fragments of length 800 bp and 1 Kbp with high accuracy until rank class. For longer fragments ≥ 3 Kbp accurate predictions are made at even deeper taxonomic ranks (order and genus). Remarkably, TACOA also produces reliable results when the taxonomic origin of a fragment is not represented in the reference set, thus classifying such fragments to its known broader taxonomic class or simply as "unknown". We compared the classification accuracy of TACOA with the latest intrinsic classifier PhyloPythia using 63 recently published complete genomes. For fragments of length 800 bp and 1 Kbp the overall accuracy of TACOA is higher than that obtained by PhyloPythia at all taxonomic ranks. For all fragment lengths, both methods achieved comparable high specificity results up to rank class and low false negative rates are also obtained. Conclusion An accurate multi-class taxonomic classifier was developed for environmental genomic fragments. TACOA can predict with high reliability the taxonomic origin of genomic fragments as short as 800 bp. The proposed method is transparent, fast, accurate and the reference set can be easily updated as newly sequenced genomes become available. Moreover, the method demonstrated to be competitive when compared to the most current classifier PhyloPythia and has the advantage that it can be locally installed and the reference set can be kept up-to-date. PMID:19210774

[Construction of large fragment metagenome library of natural mangrove soil].

PubMed

Jiang, Yun-Xia; Zheng, Tian-Ling

2007-11-01

Applying our optimized direct extraction method, the percentage of large fragment DNA in the total extracted mangrove soil DNA was significant increased. The large fragment metagenome library derived from natural mangrove soil over four seasons was successfully constructed by the optimized DNA extraction and electro elution purification method. All of the clones had recombinant Cosmids and each differed in their fragment profiles when Cosmid DNA was extracted from 12 randomly picked colonies and digested with BamHI. The average insert size for this library was larger than 35 kbp. This culturing-independent library at least encompassed 335 Mbp valuable genetic information of mangrove soil microbes. It allowed mining of valuable intertidal microbial resource to become a reality. It is a recommended method for those researchers who have still not circumvented the large insert environmental libraries or for those beginning research in this field, so as to avoid them attempting repetitive, fussy work.

Enhanced Wang Landau sampling of adsorbed protein conformations.

PubMed

Radhakrishna, Mithun; Sharma, Sumit; Kumar, Sanat K

2012-03-21

Using computer simulations to model the folding of proteins into their native states is computationally expensive due to the extraordinarily low degeneracy of the ground state. In this paper, we develop an efficient way to sample these folded conformations using Wang Landau sampling coupled with the configurational bias method (which uses an unphysical "temperature" that lies between the collapse and folding transition temperatures of the protein). This method speeds up the folding process by roughly an order of magnitude over existing algorithms for the sequences studied. We apply this method to study the adsorption of intrinsically disordered hydrophobic polar protein fragments on a hydrophobic surface. We find that these fragments, which are unstructured in the bulk, acquire secondary structure upon adsorption onto a strong hydrophobic surface. Apparently, the presence of a hydrophobic surface allows these random coil fragments to fold by providing hydrophobic contacts that were lost in protein fragmentation. © 2012 American Institute of Physics

Comparison of PHITS, GEANT4, and HIBRAC simulations of depth-dependent yields of β(+)-emitting nuclei during therapeutic particle irradiation to measured data.

PubMed

Rohling, Heide; Sihver, Lembit; Priegnitz, Marlen; Enghardt, Wolfgang; Fiedler, Fine

2013-09-21

For quality assurance in particle therapy, a non-invasive, in vivo range verification is highly desired. Particle therapy positron-emission-tomography (PT-PET) is the only clinically proven method up to now for this purpose. It makes use of the β(+)-activity produced during the irradiation by the nuclear fragmentation processes between the therapeutic beam and the irradiated tissue. Since a direct comparison of β(+)-activity and dose is not feasible, a simulation of the expected β(+)-activity distribution is required. For this reason it is essential to have a quantitatively reliable code for the simulation of the yields of the β(+)-emitting nuclei at every position of the beam path. In this paper results of the three-dimensional Monte-Carlo simulation codes PHITS, GEANT4, and the one-dimensional deterministic simulation code HIBRAC are compared to measurements of the yields of the most abundant β(+)-emitting nuclei for carbon, lithium, helium, and proton beams. In general, PHITS underestimates the yields of positron-emitters. With GEANT4 the overall most accurate results are obtained. HIBRAC and GEANT4 provide comparable results for carbon and proton beams. HIBRAC is considered as a good candidate for the implementation to clinical routine PT-PET.

Comparison of PHITS, GEANT4, and HIBRAC simulations of depth-dependent yields of β+-emitting nuclei during therapeutic particle irradiation to measured data

NASA Astrophysics Data System (ADS)

Rohling, Heide; Sihver, Lembit; Priegnitz, Marlen; Enghardt, Wolfgang; Fiedler, Fine

2013-09-01

For quality assurance in particle therapy, a non-invasive, in vivo range verification is highly desired. Particle therapy positron-emission-tomography (PT-PET) is the only clinically proven method up to now for this purpose. It makes use of the β+-activity produced during the irradiation by the nuclear fragmentation processes between the therapeutic beam and the irradiated tissue. Since a direct comparison of β+-activity and dose is not feasible, a simulation of the expected β+-activity distribution is required. For this reason it is essential to have a quantitatively reliable code for the simulation of the yields of the β+-emitting nuclei at every position of the beam path. In this paper results of the three-dimensional Monte-Carlo simulation codes PHITS, GEANT4, and the one-dimensional deterministic simulation code HIBRAC are compared to measurements of the yields of the most abundant β+-emitting nuclei for carbon, lithium, helium, and proton beams. In general, PHITS underestimates the yields of positron-emitters. With GEANT4 the overall most accurate results are obtained. HIBRAC and GEANT4 provide comparable results for carbon and proton beams. HIBRAC is considered as a good candidate for the implementation to clinical routine PT-PET.

Multidimensional profiling of components in complex mixtures of natural products for metabolic analysis, proof of concept: application to Quillaja saponins.

PubMed

Bankefors, Johan; Nord, Lars I; Kenne, Lennart

2010-02-01

A method for separation and detection of major and minor components in complex mixtures has been developed, utilising two-dimensional high-performance liquid chromatography (2D-HPLC) combined with electrospray ionisation ion-trap multiple-stage mass spectrometry (ESI-ITMS(n)). Chromatographic conditions were matched with mass spectrometric detection to maximise the number of components that could be separated. The described procedure has proven useful to discern several hundreds of saponin components when applied to Quillaja saponaria Molina bark extracts. The discrimination of each saponin component relies on the fact that three coordinates (x, y, z) for each component can be derived from the retention time of the two chromatographic steps (x, y) and the m/z-values from the multiple-stage mass spectrometry (z(n), n=1, 2, ...). Thus an improved graphical representation was obtained by combining retention times from the two-stage separation with +MS(1) (z(1)) and the additional structural information from the second mass stage +MS(2) (z(2), z(3)) corresponding to the main fragment ions. By this approach three-dimensional plots can be made that reveal both the chromatographic and structural properties of a specific mixture which can be useful in fingerprinting of complex mixtures. 2009 Elsevier B.V. All rights reserved.

Fragment library design: using cheminformatics and expert chemists to fill gaps in existing fragment libraries.

PubMed

Kutchukian, Peter S; So, Sung-Sau; Fischer, Christian; Waller, Chris L

2015-01-01

Fragment based screening (FBS) has emerged as a mainstream lead discovery strategy in academia, biotechnology start-ups, and large pharma. As a prerequisite of FBS, a structurally diverse library of fragments is desirable in order to identify chemical matter that will interact with the range of diverse target classes that are prosecuted in contemporary screening campaigns. In addition, it is also desirable to offer synthetically amenable starting points to increase the probability of a successful fragment evolution through medicinal chemistry. Herein we describe a method to identify biologically relevant chemical substructures that are missing from an existing fragment library (chemical gaps), and organize these chemical gaps hierarchically so that medicinal chemists can efficiently navigate the prioritized chemical space and subsequently select purchasable fragments for inclusion in an enhanced fragment library.

Dynamic Simulation of Three Dimensional Architectural and Mechanical Alterations in Human Trabecular Bone during Menopause

PubMed Central

Liu, X. Sherry; Huang, Angela H.; Zhang, X. Henry; Sajda, Paul; Ji, Baohua; Guo, X. Edward

2008-01-01

A three dimensional (3D) computational simulation of dynamic process of trabecular bone remodeling was developed with all the parameters derived from physiological and clinical data. Contributions of the microstructural bone formation deficits: trabecular plate perforations, trabecular rod breakages, and isolated bone fragments, to the rapid bone loss and disruption of trabecular microarchitecture during menopause were studied. Eighteen human trabecular bone samples from femoral neck (FN) and spine were scanned using a micro computed tomography (μCT) system. Bone resorption and formation were simulated as a computational cycle corresponding to 40-day resorption/160-day formation. Resorption cavities were randomly created over the bone surface according to the activation frequency, which was strictly based on clinical data. Every resorption cavity was refilled during formation unless it caused trabecular plate perforation, trabecular rod breakage or isolated fragments. A 20-year-period starting 5 years before and ending 15 years after menopause was simulated for each specimen. Elastic moduli, standard and individual trabeculae segmentation (ITS)-based morphological parameters were evaluated for each simulated 3D image. For both spine and FN groups, the time courses of predicted bone loss pattern by microstructural bone formation deficits were fairly consistent with the clinical measurements. The percentage of bone loss due to trabecular plate perforation, trabecular rod breakage, and isolated bone fragments were 73.2%, 18.9% and 7.9% at the simulated 15 years after menopause. The ITS-based plate fraction (pBV/BV), mean plate surface area (pTb.S), plate number density (pTb.N), and mean rod thickness (rTb.Th) decreased while rod fraction (rBV/BV) and rod number density (rTb.N) increased after the simulated menopause. The dynamic bone remodeling simulation based on microstructural bone formation deficits predicted the time course of menopausal bone loss pattern of spine and FN. Microstructural plate perforation could be the primary cause of menopausal trabecular bone loss. The combined effect of trabeculae perforation, breakage, and isolated fragments resulted in fewer and smaller trabecular plates and more but thinner trabecular rods. PMID:18550463

Phylogenetic Placement of Exact Amplicon Sequences Improves Associations with Clinical Information

PubMed Central

McDonald, Daniel; Gonzalez, Antonio; Navas-Molina, Jose A.; Jiang, Lingjing; Xu, Zhenjiang Zech; Winker, Kevin; Kado, Deborah M.; Orwoll, Eric; Manary, Mark; Mirarab, Siavash

2018-01-01

ABSTRACT Recent algorithmic advances in amplicon-based microbiome studies enable the inference of exact amplicon sequence fragments. These new methods enable the investigation of sub-operational taxonomic units (sOTU) by removing erroneous sequences. However, short (e.g., 150-nucleotide [nt]) DNA sequence fragments do not contain sufficient phylogenetic signal to reproduce a reasonable tree, introducing a barrier in the utilization of critical phylogenetically aware metrics such as Faith’s PD or UniFrac. Although fragment insertion methods do exist, those methods have not been tested for sOTUs from high-throughput amplicon studies in insertions against a broad reference phylogeny. We benchmarked the SATé-enabled phylogenetic placement (SEPP) technique explicitly against 16S V4 sequence fragments and showed that it outperforms the conceptually problematic but often-used practice of reconstructing de novo phylogenies. In addition, we provide a BSD-licensed QIIME2 plugin (https://github.com/biocore/q2-fragment-insertion) for SEPP and integration into the microbial study management platform QIITA. IMPORTANCE The move from OTU-based to sOTU-based analysis, while providing additional resolution, also introduces computational challenges. We demonstrate that one popular method of dealing with sOTUs (building a de novo tree from the short sequences) can provide incorrect results in human gut metagenomic studies and show that phylogenetic placement of the new sequences with SEPP resolves this problem while also yielding other benefits over existing methods. PMID:29719869

Magnetic bead purification of labeled DNA fragments forhigh-throughput capillary electrophoresis sequencing

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

Elkin, Christopher; Kapur, Hitesh; Smith, Troy

2001-09-15

We have developed an automated purification method for terminator sequencing products based on a magnetic bead technology. This 384-well protocol generates labeled DNA fragments that are essentially free of contaminates for less than $0.005 per reaction. In comparison to laborious ethanol precipitation protocols, this method increases the phred20 read length by forty bases with various DNA templates such as PCR fragments, Plasmids, Cosmids and RCA products. Our method eliminates centrifugation and is compatible with both the MegaBACE 1000 and ABIPrism 3700 capillary instruments. As of September 2001, this method has produced over 1.6 million samples with 93 percent averaging 620more » phred20 bases as part of Joint Genome Institutes Production Process.« less

Searching molecular structure databases with tandem mass spectra using CSI:FingerID

PubMed Central

Dührkop, Kai; Shen, Huibin; Meusel, Marvin; Rousu, Juho; Böcker, Sebastian

2015-01-01

Metabolites provide a direct functional signature of cellular state. Untargeted metabolomics experiments usually rely on tandem MS to identify the thousands of compounds in a biological sample. Today, the vast majority of metabolites remain unknown. We present a method for searching molecular structure databases using tandem MS data of small molecules. Our method computes a fragmentation tree that best explains the fragmentation spectrum of an unknown molecule. We use the fragmentation tree to predict the molecular structure fingerprint of the unknown compound using machine learning. This fingerprint is then used to search a molecular structure database such as PubChem. Our method is shown to improve on the competing methods for computational metabolite identification by a considerable margin. PMID:26392543

Implementing landscape fragmentation as an indicator in the Swiss Monitoring System Of Sustainable Development (Monet).

PubMed

Jaeger, Jochen A G; Bertiller, René; Schwick, Christian; Müller, Kalin; Steinmeier, Charlotte; Ewald, Klaus C; Ghazoul, Jaboury

2008-09-01

There is an increasing need and interest in including indicators of landscape fragmentation in monitoring systems of sustainable landscape management. Landscape fragmentation due to transportation infrastructure and urban development threatens human and environmental well-being by noise and pollution from traffic, reducing the size and viability of wildlife populations, facilitating the spread of invasive species, and impairing the scenic and recreational qualities of the landscape. This paper provides the rationale, method, and data for including landscape fragmentation in monitoring systems, using as an example the Swiss Monitoring System of Sustainable Development (Monet). We defined and compared four levels of fragmentation analysis, or fragmentation geometries (FGs), each based on different fragmenting elements, e.g., only anthropogenic, or combinations of anthropogenic and natural elements. As each FG has specific strengths and weaknesses, the most appropriate choice of FG depends on the context and objectives of a study. We present data on the current degree of landscape fragmentation for the five ecoregions and 26 cantons in Switzerland for all four FGs. Our results show that the degree of landscape fragmentation as quantified by the effective mesh size method is strongly supported by the postulates and indicator selection criteria of Monet, and we identify the most suitable FG focusing on the land area below 2,100 m (e.g., excluding lakes) and allowing for an equitable comparison of fragmentation degrees among regions that differ in area covered by lakes and high mountains. For a more detailed analysis of landscape fragmentation in the context of environmental impact assessments and strategic environmental assessments, a combination of all four FGs may provide a more informative tool than any single FG.

The use of many-body expansions and geometry optimizations in fragment-based methods.

PubMed

Fedorov, Dmitri G; Asada, Naoya; Nakanishi, Isao; Kitaura, Kazuo

2014-09-16

Conspectus Chemists routinely work with complex molecular systems: solutions, biochemical molecules, and amorphous and composite materials provide some typical examples. The questions one often asks are what are the driving forces for a chemical phenomenon? How reasonable are our views of chemical systems in terms of subunits, such as functional groups and individual molecules? How can one quantify the difference in physicochemical properties of functional units found in a different chemical environment? Are various effects on functional units in molecular systems additive? Can they be represented by pairwise potentials? Are there effects that cannot be represented in a simple picture of pairwise interactions? How can we obtain quantitative values for these effects? Many of these questions can be formulated in the language of many-body effects. They quantify the properties of subunits (fragments), referred to as one-body properties, pairwise interactions (two-body properties), couplings of two-body interactions described by three-body properties, and so on. By introducing the notion of fragments in the framework of quantum chemistry, one obtains two immense benefits: (a) chemists can finally relate to quantum chemistry, which now speaks their language, by discussing chemically interesting subunits and their interactions and (b) calculations become much faster due to a reduced computational scaling. For instance, the somewhat academic sounding question of the importance of three-body effects in water clusters is actually another way of asking how two hydrogen bonds affect each other, when they involve three water molecules. One aspect of this is the many-body charge transfer (CT), because the charge transfers in the two hydrogen bonds are coupled to each other (not independent). In this work, we provide a generalized view on the use of many-body expansions in fragment-based methods, focusing on the general aspects of the property expansion and a contraction of a many-body expansion in a formally two-body series, as exemplified in the development of the fragment molecular orbital (FMO) method. Fragment-based methods have been very successful in delivering the properties of fragments, as well as the fragment interactions, providing insights into complex chemical processes in large molecular systems. We briefly review geometry optimizations performed with fragment-based methods and present an efficient geometry optimization method based on the combination of FMO with molecular mechanics (MM), applied to the complex of a subunit of protein kinase 2 (CK2) with a ligand. FMO results are discussed in comparison with experimental and MM-optimized structures.

A low-cost efficient multiplex PCR for prenatal sex determination in bovine fetus using free fetal DNA in maternal plasma.

PubMed

Davoudi, Arash; Seighalani, Ramin; Aleyasin, Seyed Ahmad; Tarang, Alireza; Salehi, Abdolreza Salehi; Tahmoressi, Farideh

2012-04-01

In order to establish a reliable non-invasive method for sex determination in a bovine fetus in a routine setting, the possibility of identifying specific sequence in the fetal X and Y-chromosomes has been evaluated in maternal plasma using conventional multiplex polymerase chain reaction (PCR) analysis. The aim of this study was to provide a rapid and reliable method for sexing bovine fetuses. In this experimental study, peripheral blood samples were taken from 38 pregnant heifers with 8 to 38 weeks of gestation. DNA template was extracted by phenol-chloroform method from 350 µl maternal plasma. Two primer pairs for bovine amelogenin gene (bAML) and BC1.2 were used to amplify fragments from X and Y chromosomes. A multiplex PCR reaction has been optimized for amplification of 467 bp and 341 bp fragments from X and Y bAML gene and a 190 bp fragment from BC1.2 related to Y chromosome. The 467 bp fragment was observed in all 38 samples. Both 341 and 190 bp fragments were detected only in 24 plasma samples from male calves. The sensitivity and specificity of test were 100% with no false negative or false positive results. The results showed that phenol-chloroform method is a simple and suitable method for isolation of fetal DNA in maternal plasma. The multiplex PCR method is an available non-invasive approach which is cost efficient and reliable for sexing bovine fetuses.

Multiple tag labeling method for DNA sequencing

DOEpatents

Mathies, Richard A.; Huang, Xiaohua C.; Quesada, Mark A.

1995-01-01

A DNA sequencing method described which uses single lane or channel electrophoresis. Sequencing fragments are separated in said lane and detected using a laser-excited, confocal fluorescence scanner. Each set of DNA sequencing fragments is separated in the same lane and then distinguished using a binary coding scheme employing only two different fluorescent labels. Also described is a method of using radio-isotope labels.

Shifted termination assay (STA) fragment analysis to detect BRAF V600 mutations in papillary thyroid carcinomas

PubMed Central

2013-01-01

Background BRAF mutation is an important diagnostic and prognostic marker in patients with papillary thyroid carcinoma (PTC). To be applicable in clinical laboratories with limited equipment, diverse testing methods are required to detect BRAF mutation. Methods A shifted termination assay (STA) fragment analysis was used to detect common V600 BRAF mutations in 159 PTCs with DNAs extracted from formalin-fixed paraffin-embedded tumor tissue. The results of STA fragment analysis were compared to those of direct sequencing. Serial dilutions of BRAF mutant cell line (SNU-790) were used to calculate limit of detection (LOD). Results BRAF mutations were detected in 119 (74.8%) PTCs by STA fragment analysis. In direct sequencing, BRAF mutations were observed in 118 (74.2%) cases. The results of STA fragment analysis had high correlation with those of direct sequencing (p < 0.00001, κ = 0.98). The LOD of STA fragment analysis and direct sequencing was 6% and 12.5%, respectively. In PTCs with pT3/T4 stages, BRAF mutation was observed in 83.8% of cases. In pT1/T2 carcinomas, BRAF mutation was detected in 65.9% and this difference was statistically significant (p = 0.007). Moreover, BRAF mutation was more frequent in PTCs with extrathyroidal invasion than tumors without extrathyroidal invasion (84.7% versus 62.2%, p = 0.001). To prepare and run the reactions, direct sequencing required 450 minutes while STA fragment analysis needed 290 minutes. Conclusions STA fragment analysis is a simple and sensitive method to detect BRAF V600 mutations in formalin-fixed paraffin-embedded clinical samples. Virtual Slides The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/5684057089135749 PMID:23883275

Measurement Techniques for Hypervelocity Impact Test Fragments

NASA Technical Reports Server (NTRS)

Hill, Nicole E.

2008-01-01

The ability to classify the size and shape of individual orbital debris fragments provides a better understanding of the orbital debris environment as a whole. The characterization of breakup fragmentation debris has gradually evolved from a simplistic, spherical assumption towards that of describing debris in terms of size, material, and shape parameters. One of the goals of the NASA Orbital Debris Program Office is to develop high-accuracy techniques to measure these parameters and apply them to orbital debris observations. Measurement of the physical characteristics of debris resulting from groundbased, hypervelocity impact testing provides insight into the shapes and sizes of debris produced from potential impacts in orbit. Current techniques for measuring these ground-test fragments require determination of dimensions based upon visual judgment. This leads to reduced accuracy and provides little or no repeatability for the measurements. With the common goal of mitigating these error sources, allaying any misunderstandings, and moving forward in fragment shape determination, the NASA Orbital Debris Program Office recently began using a computerized measurement system. The goal of using these new techniques is to improve knowledge of the relation between commonly used dimensions and overall shape. The immediate objective is to scan a single fragment, measure its size and shape properties, and import the fragment into a program that renders a 3D model that adequately demonstrates how the object could appear in orbit. This information would then be used to aid optical methods in orbital debris shape determination. This paper provides a description of the measurement techniques used in this initiative and shows results of this work. The tradeoffs of the computerized methods are discussed, as well as the means of repeatability in the measurements of these fragments. This paper serves as a general description of methods for the measurement and shape analysis of orbital debris.

Preparation of next-generation sequencing libraries using Nextera™ technology: simultaneous DNA fragmentation and adaptor tagging by in vitro transposition.

PubMed

Caruccio, Nicholas

2011-01-01

DNA library preparation is a common entry point and bottleneck for next-generation sequencing. Current methods generally consist of distinct steps that often involve significant sample loss and hands-on time: DNA fragmentation, end-polishing, and adaptor-ligation. In vitro transposition with Nextera™ Transposomes simultaneously fragments and covalently tags the target DNA, thereby combining these three distinct steps into a single reaction. Platform-specific sequencing adaptors can be added, and the sample can be enriched and bar-coded using limited-cycle PCR to prepare di-tagged DNA fragment libraries. Nextera technology offers a streamlined, efficient, and high-throughput method for generating bar-coded libraries compatible with multiple next-generation sequencing platforms.

Detection of fragments from internal insects in wheat samples using a laboratory entoleter

USDA-ARS?s Scientific Manuscript database

A simple, rapid method was developed for estimating the number of insect fragments in flour caused by hidden, internal-feeding insects in whole grains during storage. The method uses a small mechanical rotary device (entoleter), which accelerates whole wheat kernels to high speeds and projects them...

High-throughput analysis of the protein sequence-stability landscape using a quantitative "yeast surface two-hybrid" system and fragment reconstitution

PubMed Central

Dutta, Sanjib; Koide, Akiko; Koide, Shohei

2008-01-01

Stability evaluation of many mutants can lead to a better understanding of the sequence determinants of a structural motif and of factors governing protein stability and protein evolution. The traditional biophysical analysis of protein stability is low throughput, limiting our ability to widely explore the sequence space in a quantitative manner. In this study, we have developed a high-throughput library screening method for quantifying stability changes, which is based on protein fragment reconstitution and yeast surface display. Our method exploits the thermodynamic linkage between protein stability and fragment reconstitution and the ability of the yeast surface display technique to quantitatively evaluate protein-protein interactions. The method was applied to a fibronectin type III (FN3) domain. Characterization of fragment reconstitution was facilitated by the co-expression of two FN3 fragments, thus establishing a "yeast surface two-hybrid" method. Importantly, our method does not rely on competition between clones and thus eliminates a common limitation of high-throughput selection methods in which the most stable variants are predominantly recovered. Thus, it allows for the isolation of sequences that exhibits a desired level of stability. We identified over one hundred unique sequences for a β-bulge motif, which was significantly more informative than natural sequences of the FN3 family in revealing the sequence determinants for the β-bulge. Our method provides a powerful means to rapidly assess stability of many variants, to systematically assess contribution of different factors to protein stability and to enhance protein stability. PMID:18674545

Molecular organization of various collagen fragments as revealed by atomic force microscopy and diffusion-ordered NMR spectroscopy.

PubMed

Stötzel, Sabine; Schurink, Marloes; Wienk, Hans; Siebler, Uschi; Burg-Roderfeld, Monika; Eckert, Thomas; Kulik, Bianca; Wechselberger, Rainer; Sewing, Judith; Steinmeyer, Jürgen; Oesser, Steffen; Boelens, Rolf; Siebert, Hans-Christian

2012-09-17

Heterogeneous mixtures of collagen fragments can be used as nutrition supplement or as key ingredients for ointments with therapeutic relevance in wound healing. Some mixtures of collagen fragments are referred to as collagen hydrolysates owing to the production process with hydrolytic enzymes. Since the precise composition of collagen hydrolysates is generally unknown, it is of interest to analyze samples containing various collagen fragments with appropriate biophysical methods. Any product optimization without a profound knowledge concerning the size and the molecular weight distribution of its components is nearly impossible. It turned out that a combination of AFM methods with NMR techniques is exceptionally suited to examine the size range and the aggregation behavior of the collagen fragments in the hydrolysates of fish, jellyfish, chicken, porcine and bovine collagen. Supported by molecular modeling calculations, the AFM and NMR experiments provide a detailed knowledge about the composition of collagen hydrolysates and collagen ointments. Furthermore, the data allow a correlation between the size of the fragments and their potential bioactivity. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Design of compound libraries for fragment screening

NASA Astrophysics Data System (ADS)

Blomberg, Niklas; Cosgrove, David A.; Kenny, Peter W.; Kolmodin, Karin

2009-08-01

Approaches to the design of libraries for fragment screening are illustrated with reference to a 20 k generic fragment screening library and a 1.2 k generic NMR screening library. Tools and methods for library design that have been developed within AstraZeneca are described, including Foyfi fingerprints and the Flush program for neighborhood characterization. It will be shown how Flush and the BigPicker, which selects maximally diverse sets of compounds, are used to apply the Core and Layer method for library design. Approaches to partitioning libraries into cocktails are also described.

Conversion of fullerenes to diamonds

DOEpatents

Gruen, Dieter M.

1995-01-01

A method of forming synthetic diamond or diamond-like films on a substrate surface. The method involves the steps of providing a vapor selected from the group of fullerene molecules or an inert gas/fullerene molecule mixture, providing energy to the fullerene molecules consisting of carbon-carbon bonds, the energized fullerene molecules breaking down to form fragments of fullerene molecules including C.sub.2 molecules and depositing the energized fullerene molecules with C.sub.2 fragments onto the substrate with farther fragmentation occurring and forming a thickness of diamond or diamond-like films on the substrate surface.

Local meshing plane analysis as a source of information about the gear quality

NASA Astrophysics Data System (ADS)

Mączak, Jędrzej

2013-07-01

In the paper the application of the local meshing plane concept is discussed and applied for detecting of tooth degradation due to fatigue, and for overall gear quality assessment. Knowing the kinematic properties of the machine (i.e. gear tooth numbers) it is possible to modify the diagnostic signal in such a manner that its fragments will be linked to different rotating parts. This allows for presentation of either raw or processed gearbox signal in a form of three dimensional map on the plane "pinion teeth×gear teeth", called local meshing plane. The meshing plane in Cartesian coordinates z1×z2 allows for precise location and assessment of gear faults in terms of meshing quality of consecutive tooth pairs. Although the method was applied to simulated signals generated by the gearbox model, similar results were obtained for the measurement signals recorded during the back-to-back test stand experiment. The described method could be used for assessing the manufacturing quality of gears, the assembly quality as well as for the gear failure evaluation during normal exploitation.

Ab initio RNA folding by discrete molecular dynamics: From structure prediction to folding mechanisms

PubMed Central

Ding, Feng; Sharma, Shantanu; Chalasani, Poornima; Demidov, Vadim V.; Broude, Natalia E.; Dokholyan, Nikolay V.

2008-01-01

RNA molecules with novel functions have revived interest in the accurate prediction of RNA three-dimensional (3D) structure and folding dynamics. However, existing methods are inefficient in automated 3D structure prediction. Here, we report a robust computational approach for rapid folding of RNA molecules. We develop a simplified RNA model for discrete molecular dynamics (DMD) simulations, incorporating base-pairing and base-stacking interactions. We demonstrate correct folding of 150 structurally diverse RNA sequences. The majority of DMD-predicted 3D structures have <4 Å deviations from experimental structures. The secondary structures corresponding to the predicted 3D structures consist of 94% native base-pair interactions. Folding thermodynamics and kinetics of tRNAPhe, pseudoknots, and mRNA fragments in DMD simulations are in agreement with previous experimental findings. Folding of RNA molecules features transient, non-native conformations, suggesting non-hierarchical RNA folding. Our method allows rapid conformational sampling of RNA folding, with computational time increasing linearly with RNA length. We envision this approach as a promising tool for RNA structural and functional analyses. PMID:18456842

Fragmentation of mercury compounds under ultraviolet light irradiation

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

Kokkonen, E.; Hautala, L.; Jänkälä, K.

2015-08-21

Ultraviolet light induced photofragmentation of mercury compounds is studied experimentally with electron energy resolved photoelectron-photoion coincidence techniques and theoretically with computational quantum chemical methods. A high resolution photoelectron spectrum using synchrotron radiation is presented. Fragmentation of the molecule is studied subsequent to ionization to the atomic-mercury-like d orbitals. State dependent fragmentation behaviour is presented and specific reactions for dissociation pathways are given. The fragmentation is found to differ distinctly in similar orbitals of different mercury compounds.

Fast metastable fragments produced by dissociative excitation of carbonyl sulfide

NASA Technical Reports Server (NTRS)

Van Brunt, R. J.; Mumma, M. J.

1975-01-01

Dissociative excitation of OCS by electron impact has been studied using the method of translational spectroscopy. Time-of-flight distributions and excitation functions of the fast metastable fragments have been measured. The results are compared with similar measurements on CO2 and show that a variety of metastable fragments including CO(a 3Pi), S(5S), O(5S) as well as long-lived high-lying atomic and molecular Rydberg fragments can contribute to dissociation.

Cavitation Enhancing Nanodroplets Mediate Efficient DNA Fragmentation in a Bench Top Ultrasonic Water Bath

PubMed Central

Malc, Ewa P.; Jayakody, Chatura N.; Tsuruta, James K.; Mieczkowski, Piotr A.; Janzen, William P.; Dayton, Paul A.

2015-01-01

A perfluorocarbon nanodroplet formulation is shown to be an effective cavitation enhancement agent, enabling rapid and consistent fragmentation of genomic DNA in a standard ultrasonic water bath. This nanodroplet-enhanced method produces genomic DNA libraries and next-generation sequencing results indistinguishable from DNA samples fragmented in dedicated commercial acoustic sonication equipment, and with higher throughput. This technique thus enables widespread access to fast bench-top genomic DNA fragmentation. PMID:26186461

Dissociation Behavior of a TEMPO-Active Ester Cross-Linker for Peptide Structure Analysis by Free Radical Initiated Peptide Sequencing (FRIPS) in Negative ESI-MS.

PubMed

Hage, Christoph; Ihling, Christian H; Götze, Michael; Schäfer, Mathias; Sinz, Andrea

2017-01-01

We have synthesized a homobifunctional amine-reactive cross-linking reagent, containing a TEMPO (2,2,6,6-tetramethylpiperidine-1-oxy) and a benzyl group (Bz), termed TEMPO-Bz-linker, to derive three-dimensional structural information of proteins. The aim for designing this novel cross-linker was to facilitate the mass spectrometric analysis of cross-linked products by free radical initiated peptide sequencing (FRIPS). In an initial study, we had investigated the fragmentation behavior of TEMPO-Bz-derivatized peptides upon collision activation in (+)-electrospray ionization collision-induced dissociation tandem mass spectrometry (ESI-CID-MS/MS) experiments. In addition to the homolytic NO-C bond cleavage FRIPS pathway delivering the desired odd-electron product ions, an alternative heterolytic NO-C bond cleavage, resulting in even-electron product ions mechanism was found to be relevant. The latter fragmentation route clearly depends on the protonation of the TEMPO-Bz-moiety itself, which motivated us to conduct (-)-ESI-MS, CID-MS/MS, and MS 3 experiments of TEMPO-Bz-cross-linked peptides to further clarify the fragmentation behavior of TEMPO-Bz-peptide molecular ions. We show that the TEMPO-Bz-linker is highly beneficial for conducting FRIPS in negative ionization mode as the desired homolytic cleavage of the NO-C bond is the major fragmentation pathway. Based on characteristic fragments, the isomeric amino acids leucine and isoleucine could be discriminated. Interestingly, we observed pronounced amino acid side chain losses in cross-linked peptides if the cross-linked peptides contain a high number of acidic amino acids. Graphical Abstract ᅟ.

Fragment-based approaches to TB drugs.

PubMed

Marchetti, Chiara; Chan, Daniel S H; Coyne, Anthony G; Abell, Chris

2018-02-01

Tuberculosis is an infectious disease associated with significant mortality and morbidity worldwide, particularly in developing countries. The rise of antibiotic resistance in Mycobacterium tuberculosis (Mtb) urgently demands the development of new drug leads to tackle resistant strains. Fragment-based methods have recently emerged at the forefront of pharmaceutical development as a means to generate more effective lead structures, via the identification of fragment molecules that form weak but high quality interactions with the target biomolecule and subsequent fragment optimization. This review highlights a number of novel inhibitors of Mtb targets that have been developed through fragment-based approaches in recent years.

Adaptation of multidimensional group particle tracking and particle wall-boundary condition model to the FDNS code

NASA Technical Reports Server (NTRS)

Chen, Y. S.; Farmer, R. C.

1992-01-01

A particulate two-phase flow CFD model was developed based on the FDNS code which is a pressure based predictor plus multi-corrector Navier-Stokes flow solver. Turbulence models with compressibility correction and the wall function models were employed as submodels. A finite-rate chemistry model was used for reacting flow simulation. For particulate two-phase flow simulations, a Eulerian-Lagrangian solution method using an efficient implicit particle trajectory integration scheme was developed in this study. Effects of particle-gas reaction and particle size change to agglomeration or fragmentation were not considered in this investigation. At the onset of the present study, a two-dimensional version of FDNS which had been modified to treat Lagrangian tracking of particles (FDNS-2DEL) had already been written and was operational. The FDNS-2DEL code was too slow for practical use, mainly because it had not been written in a form amenable to vectorization on the Cray, nor was the full three-dimensional form of FDNS utilized. The specific objective of this study was to reorder to calculations into long single arrays for automatic vectorization on the Cray and to implement the full three-dimensional version of FDNS to produce the FDNS-3DEL code. Since the FDNS-2DEL code was slow, a very limited number of test cases had been run with it. This study was also intended to increase the number of cases simulated to verify and improve, as necessary, the particle tracking methodology coded in FDNS.

Identification of ubiquitin/ubiquitin-like protein modification from tandem mass spectra with various PTMs

PubMed Central

2011-01-01

Background Various solutions have been introduced for the identification of post-translational modification (PTM) from tandem mass spectrometry (MS/MS) in proteomics field but the identification of peptide modifiers, such as Ubiquitin (Ub) and ubiquitin-like proteins (Ubls), is still a challenge. The fragmentation of peptide modifier produce complex shifted ion mass patterns in combination with other PTMs, which makes it difficult to identify and locate the PTMs on a protein sequence. Currently, most PTM identification methods do not consider the complex fragmentation of peptide modifier or deals it separately from the other PTMs. Results We developed an advanced PTM identification method that inspects possible ion patterns of the most known peptide modifiers as well as other known biological and chemical PTMs to make more comprehensive and accurate conclusion. The proposed method searches all detectable mass differences of measured peaks from their theoretical values and the mass differences within mass tolerance range are grouped as mass shift classes. The most possible locations of multiple PTMs including peptide modifiers can be determined by evaluating all possible scenarios generated by the combination of the qualified mass shift classes.The proposed method showed excellent performance in the test with simulated spectra having various PTMs including peptide modifiers and in the comparison with recently developed methods such as QuickMod and SUMmOn. In the analysis of HUPO Brain Proteome Project (BPP) datasets, the proposed method could find the ubiquitin modification sites that were not identified by other conventional methods. Conclusions This work presents a novel method for identifying bothpeptide modifiers that generate complex fragmentation patternsand PTMs that are not fragmented during fragmentation processfrom tandem mass spectra. PMID:22373085

SSEP: secondary structural elements of proteins

PubMed Central

Shanthi, V.; Selvarani, P.; Kiran Kumar, Ch.; Mohire, C. S.; Sekar, K.

2003-01-01

SSEP is a comprehensive resource for accessing information related to the secondary structural elements present in the 25 and 90% non-redundant protein chains. The database contains 1771 protein chains from 1670 protein structures and 6182 protein chains from 5425 protein structures in 25 and 90% non-redundant protein chains, respectively. The current version provides information about the α-helical segments and β-strand fragments of varying lengths. In addition, it also contains the information about 310-helix, β- and ν-turns and hairpin loops. The free graphics program RASMOL has been interfaced with the search engine to visualize the three-dimensional structures of the user queried secondary structural fragment. The database is updated regularly and is available through Bioinformatics web server at http://cluster.physics.iisc.ernet.in/ssep/ or http://144.16.71.148/ssep/. PMID:12824336

Multiple tag labeling method for DNA sequencing

DOEpatents

Mathies, R.A.; Huang, X.C.; Quesada, M.A.

1995-07-25

A DNA sequencing method is described which uses single lane or channel electrophoresis. Sequencing fragments are separated in the lane and detected using a laser-excited, confocal fluorescence scanner. Each set of DNA sequencing fragments is separated in the same lane and then distinguished using a binary coding scheme employing only two different fluorescent labels. Also described is a method of using radioisotope labels. 5 figs.

Structure of glycosylated and unglycosylated gag polyproteins of Rauscher murine leukemia virus: carbohydrate attachment sites.

PubMed Central

Schultz, A M; Lockhart, S M; Rabin, E M; Oroszlan, S

1981-01-01

The structural relationships among the gag polyproteins Pr65gag, Pr75gag, and gPr80gag of Rauscher murine leukemia virus were studied by endoglycosidase H digestion and formic acid cleavage. Fragments were identified by precipitation with specific antisera to constituent virion structural proteins followed by one-dimensional mapping. Endoglycosidase H reduced the size of gPr80gag to that of Pr75gag. By comparing fragments of gPr80gag and the apoprotein Pr75gag, the former was shown to contain two mannose-rich oligosaccharide units. By comparing fragments of Pr65gag and Pr75gag, the latter was shown to differ from Pr65gag at the amino terminus by the presence of a leader peptide approximately 7,000 daltons in size. The internal and carboxyl-terminal peptides of the two unglycosylated polyproteins were not detectably different. The location of the two N-linked carbohydrate chains in gPr80gag has been specified. One occurs in the carboxyl-terminal half of the polyprotein at asparagine177 of the p30 sequence and the other is found in a 23,000-dalton fragment located in the amino-terminal region of gPr80gag and containing the additional amino acid sequences not found in Pr65gag plus a substantial portion of p15. Images PMID:7241663

Nanometer-Scale Dissection of Chromosomes by Atomic Force Microscopy Combined with Heat-Denaturing Treatment

NASA Astrophysics Data System (ADS)

Tsukamoto, Kazumi; Kuwazaki, Seigo; Yamamoto, Kimiko; Shichiri, Motoharu; Yoshino, Tomoyuki; Ohtani, Toshio; Sugiyama, Shigeru

2006-03-01

We have developed a method for dissecting chromosome fragments with a size of a few hundred nanometers by atomic force microscopy (AFM). By using this method, we demonstrated reproducible dissections of silkworm chromosomes in the pachytene phase. The dissected fragments were successfully recovered on the cantilever tips, as confirmed by fluorescent microscopy using fluorescent stained chromosomes. To recover dissected chromosome fragments from a larger chromosome, such as the human metaphase chromosome of a somatic cell, heat denaturation was found to be effective. Further improvements in this method may lead to a novel tool for isolating valuable genes and/or investigating local genome structures in the near future.

Synthesis of the proteinase inhibitor LEKTI domain 6 by the fragment condensation method and regioselective disulfide bond formation.

PubMed

Vasileiou, Zoe; Barlos, Kostas K; Gatos, Dimitrios; Adermann, Knut; Deraison, Celine; Barlos, Kleomenis

2010-01-01

Proteinase inhibitors are of high pharmaceutical interest and are drug candidates for a variety of indications. Specific kallikrein inhibitors are important for their antitumor activity and their potential application to the treatment of skin diseases. In this study we describe the synthesis of domain 6 of the kallikrein inhibitor Lympho-Epithilial Kazal-Type Inhibitor (LEKTI) by the fragment condensation method and site-directed cystine bridge formation. To obtain the linear LEKTI precursor, the condensation was best performed in solution, coupling the protected fragment 1-22 to 23-68. This method yielded LEKTI domain 6 of high purity and equipotent to the recombinantly produced peptide. (c) 2010 Wiley Periodicals, Inc.

On the nature of the fragment environment created by the range destruction or random failure of solid rocket motor casings

NASA Technical Reports Server (NTRS)

Eck, M.; Mukunda, M.

1988-01-01

Given here are predictions of fragment velocities and azimuths resulting from the Space Transportation System Solid Rocket Motor range destruct, or random failure occurring at any time during the 120 seconds of Solid Rocket Motor burn. Results obtained using the analytical methods described showed good agreement between predictions and observations for two specific events. It was shown that these methods have good potential for use in predicting the fragmentation process of a number of generically similar casing systems. It was concluded that coupled Eulerian-Lagrangian calculational methods of the type described here provide a powerful tool for predicting Solid Rocket Motor response.

Social fragmentation, deprivation and urbanicity: relation to first-admission rates for psychoses.

PubMed

Allardyce, Judith; Gilmour, Harper; Atkinson, Jacqueline; Rapson, Tracey; Bishop, Jennifer; McCreadie, R G

2005-11-01

Social disorganisation, fragmentation and isolation have long been posited as influencing the rate of psychoses at area level. Measuring such societal constructs is difficult. A census-based index measuring social fragmentation has been proposed. To investigate the association between first-admission rates for psychosis and area-based measures of social fragmentation, deprivation and urban/rural index. We used indirect standardisation methods and logistic regression models to examine associations of social fragmentation, deprivation and urban/rural categories with first admissions for psychoses in Scotland for the 5-year period 1989-1993. Areas characterised by high social fragmentation had higher first-ever admission rates for psychosis independent of deprivation and urban/rural status. There was a dose-response relationship between social fragmentation category and first-ever admission rates for psychosis. There was no statistically significant interaction between social fragmentation, deprivation and urban/rural index. First-admission rates are strongly associated with measures of social fragmentation, independent of material deprivation and urban/rural category.

Finite element analysis of the three different posterior malleolus fixation strategies in relation to different fracture sizes.

PubMed

Anwar, Adeel; Lv, Decheng; Zhao, Zhi; Zhang, Zhen; Lu, Ming; Nazir, Muhammad Umar; Qasim, Wasim

2017-04-01

Appropriate fixation method for the posterior malleolar fractures (PMF) according to the fracture size is still not clear. Aim of this study was to evaluate the outcomes of the different fixation methods used for fixation of PMF by finite element analysis (FEA) and to compare the effect of fixation constructs on the size of the fracture computationally. Three dimensional model of the tibia was reconstructed from computed tomography (CT) images. PMF of 30%, 40% and 50% fragment sizes were simulated through computational processing. Two antero-posterior (AP) lag screws, two postero-anterior (PA) lag screws and posterior buttress plate were analysed for three different fracture volumes. The simulated loads of 350N and 700N were applied to the proximal tibial end. Models were fixed distally in all degrees of freedom. In single limb standing condition, the posterior plate group produced the lowest relative displacement (RD) among all the groups (0.01, 0.03 and 0.06mm). Further nodal analysis of the highest RD fracture group showed a higher mean displacement of 4.77mm and 4.23mm in AP and PA lag screws model (p=0.000). The amounts of stress subjected to these implants, 134.36MPa and 140.75MPa were also significantly lower (p=0.000). There was a negative correlation (p=0.021) between implant stress and the displacement which signifies a less stable fixation using AP and PA lag screws. Progressively increasing fracture size demands more stable fixation construct because RD increases significantly. Posterior buttress plate produces superior stability and lowest RD in PMF models irrespective of the fragment size. Copyright © 2017 Elsevier Ltd. All rights reserved.

Sex determination from the mandibular ramus flexure of Koreans by discrimination function analysis using three-dimensional mandible models.

PubMed

Lin, Chenghe; Jiao, Benzheng; Liu, Shanshan; Guan, Feng; Chung, Nak-Eun; Han, Seung-Ho; Lee, U-Young

2014-03-01

It has been known that mandible ramus flexure is an important morphologic trait for sex determination. However, it will be unavailable when mandible is incomplete or fragmented. Therefore, the anthropometric analysis on incomplete or fragmented mandible becomes more important. The aim of this study is to investigate the sex-discriminant potential of mandible ramus flexure on the Korean three-dimensional (3D) mandible models with anthropometric analysis. The sample consists of 240 three dimensional mandibular models obtained from Korean population (M:F; 120:120, mean age 46.2 y), collected by The Catholic Institute for Applied Anatomy, The Catholic University of Korea. Anthropometric information about 11 metric was taken with Mimics, anthropometry libraries toolkit. These parameters were subjected to different discriminant function analyses using SPSS 17.0. Univariate analyses showed that the resubstitution accuracies for sex determination range from 50.4 to 77.1%. Mandibular flexure upper border (MFUB), maximum ramus vertical height (MRVH), and upper ramus vertical height (URVH) expressed the greatest dimorphism, 72.1 to 77.1%. Bivariate analyses indicated that the combination of MFUB and MRVH hold even higher resubstitution accuracy of 81.7%. Furthermore, the direct and stepwise discriminant analyses with the variables on the upper ramus above flexure could predict sex in 83.3 and 85.0%, respectively. When all variables of mandibular ramus flexure were input in stepwise discriminant analysis, the resubstitution accuracy arrived as high as 88.8%. Therefore, we concluded that the upper ramus above flexure hold the larger potentials than the mandibular ramus flexure itself to predict sexes, and that the equations in bivariate and multivariate analysis from our study will be helpful for sex determination on Korean population in forensic science and law. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Production of functional sperm by subcutaneous auto-grafting of immature testes in rainbow trout.

PubMed

Hayashi, Makoto; Sakuma, Daika; Yoshizaki, Goro

2018-02-01

Sexually mature individuals are indispensable for breeding programs. Salmonids require a long period before reaching sexual maturity, so we aimed to shorten the period required to obtain functional sperm by grafting immature testicular fragments into mature recipients, which we predicted would allow the grafted testicular fragments to skip the long pre-pubertal period. First, we demonstrated successful subcutaneous auto-grafting of testicular fragments in rainbow trout. Unilateral testectomy was performed, and the isolated immature testicular fragment was auto-grafted into the subcutaneous space along the back of recipient fish. The grafted testicular fragments developed synchronously with the recipients' testis remaining in its body cavity, and both eventually produced functional sperm. Next, immature testicular fragments were auto-grafted into the subcutaneous space of sexually mature males. We achieved this, without immune rejection, by isolating and cryopreserving testes from immature fish, and rearing these unilaterally testectomized fish until sexual maturity. The cryopreserved testes were then auto-grafted into the original, now spermiating fish. The grated immature testicular fragments differentiated and produced functional sperm within 5 months after grafting. By combining this grafting method with a technique to avoid immune rejection, we expect to develop a practical method for producing sperm in a shorter period in salmonids. © 2017 Wiley Periodicals, Inc.

Combinatorial Labeling Method for Improving Peptide Fragmentation in Mass Spectrometry

NASA Astrophysics Data System (ADS)

Kuchibhotla, Bhanuramanand; Kola, Sankara Rao; Medicherla, Jagannadham V.; Cherukuvada, Swamy V.; Dhople, Vishnu M.; Nalam, Madhusudhana Rao

2017-06-01

Annotation of peptide sequence from tandem mass spectra constitutes the central step of mass spectrometry-based proteomics. Peptide mass spectra are obtained upon gas-phase fragmentation. Identification of the protein from a set of experimental peptide spectral matches is usually referred as protein inference. Occurrence and intensity of these fragment ions in the MS/MS spectra are dependent on many factors such as amino acid composition, peptide basicity, activation mode, protease, etc. Particularly, chemical derivatizations of peptides were known to alter their fragmentation. In this study, the influence of acetylation, guanidinylation, and their combination on peptide fragmentation was assessed initially on a lipase (LipA) from Bacillus subtilis followed by a bovine six protein mix digest. The dual modification resulted in improved fragment ion occurrence and intensity changes, and this resulted in the equivalent representation of b- and y-type fragment ions in an ion trap MS/MS spectrum. The improved representation has allowed us to accurately annotate the peptide sequences de novo. Dual labeling has significantly reduced the false positive protein identifications in standard bovine six peptide digest. Our study suggests that the combinatorial labeling of peptides is a useful method to validate protein identifications for high confidence protein inference. [Figure not available: see fulltext.

Fragment-based drug discovery and its application to challenging drug targets.

PubMed

Price, Amanda J; Howard, Steven; Cons, Benjamin D

2017-11-08

Fragment-based drug discovery (FBDD) is a technique for identifying low molecular weight chemical starting points for drug discovery. Since its inception 20 years ago, FBDD has grown in popularity to the point where it is now an established technique in industry and academia. The approach involves the biophysical screening of proteins against collections of low molecular weight compounds (fragments). Although fragments bind to proteins with relatively low affinity, they form efficient, high quality binding interactions with the protein architecture as they have to overcome a significant entropy barrier to bind. Of the biophysical methods available for fragment screening, X-ray protein crystallography is one of the most sensitive and least prone to false positives. It also provides detailed structural information of the protein-fragment complex at the atomic level. Fragment-based screening using X-ray crystallography is therefore an efficient method for identifying binding hotspots on proteins, which can then be exploited by chemists and biologists for the discovery of new drugs. The use of FBDD is illustrated here with a recently published case study of a drug discovery programme targeting the challenging protein-protein interaction Kelch-like ECH-associated protein 1:nuclear factor erythroid 2-related factor 2. © 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

Precise Sequential DNA Ligation on A Solid Substrate: Solid-Based Rapid Sequential Ligation of Multiple DNA Molecules

PubMed Central

Takita, Eiji; Kohda, Katsunori; Tomatsu, Hajime; Hanano, Shigeru; Moriya, Kanami; Hosouchi, Tsutomu; Sakurai, Nozomu; Suzuki, Hideyuki; Shinmyo, Atsuhiko; Shibata, Daisuke

2013-01-01

Ligation, the joining of DNA fragments, is a fundamental procedure in molecular cloning and is indispensable to the production of genetically modified organisms that can be used for basic research, the applied biosciences, or both. Given that many genes cooperate in various pathways, incorporating multiple gene cassettes in tandem in a transgenic DNA construct for the purpose of genetic modification is often necessary when generating organisms that produce multiple foreign gene products. Here, we describe a novel method, designated PRESSO (precise sequential DNA ligation on a solid substrate), for the tandem ligation of multiple DNA fragments. We amplified donor DNA fragments with non-palindromic ends, and ligated the fragment to acceptor DNA fragments on solid beads. After the final donor DNA fragments, which included vector sequences, were joined to the construct that contained the array of fragments, the ligation product (the construct) was thereby released from the beads via digestion with a rare-cut meganuclease; the freed linear construct was circularized via an intra-molecular ligation. PRESSO allowed us to rapidly and efficiently join multiple genes in an optimized order and orientation. This method can overcome many technical challenges in functional genomics during the post-sequencing generation. PMID:23897972

Validating the use of rectus muscle fragment welding to control presacral bleeding during rectal mobilization.

PubMed

Ayuste, Edwardo; Roxas, Manuel Francisco T

2004-01-01

The incidence of presacral bleeding during rectal mobilization is low, but such bleeding may be massive and even fatal. Haemostasis can be difficult to achieve using conventional methods because of the complex interlacing of the venous network at the sacral periosteum. Historically, pelvic packing and metallic thumbtacks have been the more commonly used methods in our institution. However, the need for repeat surgery to remove the packs and the difficulties encountered in tack application have forced us to explore other methods. In 1994, the procedure termed muscle fragment welding, which uses electrocautery through a rectum muscle fragment, was introduced to control presacral bleeding. From January 1999 to February 2002, six of 416 patients undergoing pelvic surgery in our institution developed massive presacral haemorrhage and therefore, this technique was used. Haemostasis was immediate and permanent. No major untoward postoperative events such as re-bleeding or infection were noted. One cas developed a second-degree burn in the right elbow due to a misplaced ground conduction plate. Rectus muscle fragment welding is , in our experience, an effective and practical method of controlling presacral haemorrhage.

Biological effectiveness of nuclear fragments produced by high-energy protons interacting in tissues near the bone- soft tissue interface

NASA Astrophysics Data System (ADS)

Shavers, Mark Randall

1999-12-01

High-energy protons in the galactic cosmic rays (GCR)-or generated by nuclear interactions of GCR heavy-ions with material-are capable of penetrating great thicknesses of shielding to irradiate humans in spacecraft or in lunar or Martian habitats. As protons interact with the nuclei of the elemental constituents of soft tissue and bone, low energy nuclei-target fragments-are emitted into the cells responsible for bone development and maintenance and for hematopoiesis. Leukemogenesis is the principal endpoint of concern because it is the most likely deleterious effect, and it has a short latency period and comparatively low survival rate, although other myelo- proliferative disorders and osteosarcoma also may be induced. A one-dimensional proton-target fragment transport model was used to calculate the energy spectra of fragments produced in bone and soft tissue, and present in marrow cavities at distances from a bone interface. In terms of dose equivalent, the target fragments are as significant as the incident protons. An average radiation quality factor was found to be between 1.8 and 2.6. Biological response to the highly non- uniform energy deposition of the target fragments is such that an alternative approach to conventional predictive risk assessment is needed. Alternative procedures are presented. In vitro cell response and relative biological effectiveness were calculated from the radial dose distribution of each fragment produced by 1-GeV protons using parameters of a modified Ion-Gamma- Kill (IGK) model of radiation action. The modelled endpoints were survival of C3H10t 1/2 and V79 cells, neoplastic transformation of C3H10t1/2 cells, and mutation of the X-linked hypoxanthine phosphoribosyltransferase (HPRT) locus in V79 cells. The dose equivalent and cell responses increased by 10% or less near the interface. Since RBE increases with decreasing dose in the IGK model, comparisons with quality factors were made at dose levels 0.01 <= D [Gy] <= 2. Applying average quality factors derived herein to GCR exposures results in a <= 5% increase of in average quality. Calculated RBEs indicate that accepted quality factors for high-energy protons may be too low due to the relatively high effectiveness of the low-charged target fragments. Derived RBEs for target fragments increase the calculated biological effectiveness of GCR by 20% to 180%.

Fragment-assisted hit investigation involving integrated HTS and fragment screening: Application to the identification of phosphodiesterase 10A (PDE10A) inhibitors.

PubMed

Varnes, Jeffrey G; Geschwindner, Stefan; Holmquist, Christopher R; Forst, Janet; Wang, Xia; Dekker, Niek; Scott, Clay W; Tian, Gaochao; Wood, Michael W; Albert, Jeffrey S

2016-01-01

Fragment-based drug design (FBDD) relies on direct elaboration of fragment hits and typically requires high resolution structural information to guide optimization. In fragment-assisted drug discovery (FADD), fragments provide information to guide selection and design but do not serve as starting points for elaboration. We describe FADD and high-throughput screening (HTS) campaign strategies conducted in parallel against PDE10A where fragment hit co-crystallography was not available. The fragment screen led to prioritized fragment hits (IC50's ∼500μM), which were used to generate a hypothetical core scaffold. Application of this scaffold as a filter to HTS output afforded a 4μM hit, which, after preparation of a small number of analogs, was elaborated into a 16nM lead. This approach highlights the strength of FADD, as fragment methods were applied despite the absence of co-crystallographical information to efficiently identify a lead compound for further optimization. Copyright © 2015 Elsevier Ltd. All rights reserved.

Apparatus and method for producing fragment-free openings

DOEpatents

Cherry, Christopher R.

2001-01-01

An apparatus and method for explosively penetrating hardened containers such as steel drums without producing metal fragmentation is disclosed. The apparatus can be used singularly or in combination with water disrupters and other disablement tools. The apparatus is mounted in close proximity to the target and features a main sheet explosive that is initiated at least three equidistant points along the sheet's periphery. A buffer material is placed between the sheet explosive and the target. As a result, the metallic fragments generated from the detonation of the detonator are attenuated so that no fragments from the detonator are transferred to the target. As a result, an opening can be created in containers such as steel drums through which access to the IED is obtained to defuse it with projectiles or fluids.

ProTox: a web server for the in silico prediction of rodent oral toxicity

PubMed Central

Drwal, Malgorzata N.; Banerjee, Priyanka; Dunkel, Mathias; Wettig, Martin R.; Preissner, Robert

2014-01-01

Animal trials are currently the major method for determining the possible toxic effects of drug candidates and cosmetics. In silico prediction methods represent an alternative approach and aim to rationalize the preclinical drug development, thus enabling the reduction of the associated time, costs and animal experiments. Here, we present ProTox, a web server for the prediction of rodent oral toxicity. The prediction method is based on the analysis of the similarity of compounds with known median lethal doses (LD50) and incorporates the identification of toxic fragments, therefore representing a novel approach in toxicity prediction. In addition, the web server includes an indication of possible toxicity targets which is based on an in-house collection of protein–ligand-based pharmacophore models (‘toxicophores’) for targets associated with adverse drug reactions. The ProTox web server is open to all users and can be accessed without registration at: http://tox.charite.de/tox. The only requirement for the prediction is the two-dimensional structure of the input compounds. All ProTox methods have been evaluated based on a diverse external validation set and displayed strong performance (sensitivity, specificity and precision of 76, 95 and 75%, respectively) and superiority over other toxicity prediction tools, indicating their possible applicability for other compound classes. PMID:24838562

A random forest learning assisted "divide and conquer" approach for peptide conformation search.

PubMed

Chen, Xin; Yang, Bing; Lin, Zijing

2018-06-11

Computational determination of peptide conformations is challenging as it is a problem of finding minima in a high-dimensional space. The "divide and conquer" approach is promising for reliably reducing the search space size. A random forest learning model is proposed here to expand the scope of applicability of the "divide and conquer" approach. A random forest classification algorithm is used to characterize the distributions of the backbone φ-ψ units ("words"). A random forest supervised learning model is developed to analyze the combinations of the φ-ψ units ("grammar"). It is found that amino acid residues may be grouped as equivalent "words", while the φ-ψ combinations in low-energy peptide conformations follow a distinct "grammar". The finding of equivalent words empowers the "divide and conquer" method with the flexibility of fragment substitution. The learnt grammar is used to improve the efficiency of the "divide and conquer" method by removing unfavorable φ-ψ combinations without the need of dedicated human effort. The machine learning assisted search method is illustrated by efficiently searching the conformations of GGG/AAA/GGGG/AAAA/GGGGG through assembling the structures of GFG/GFGG. Moreover, the computational cost of the new method is shown to increase rather slowly with the peptide length.

Assessing the composition of fragmented agglutinated foraminiferal assemblages in ancient sediments: comparison of counting and area-based methods in Famennian samples (Late Devonian)

NASA Astrophysics Data System (ADS)

Girard, Catherine; Dufour, Anne-Béatrice; Charruault, Anne-Lise; Renaud, Sabrina

2018-01-01

Benthic foraminifera have been used as proxies for various paleoenvironmental variables such as food availability, carbon flux from surface waters, microhabitats, and indirectly water depth. Estimating assemblage composition based on morphotypes, as opposed to genus- or species-level identification, potentially loses important ecological information but opens the way to the study of ancient time periods. However, the ability to accurately constrain benthic foraminiferal assemblages has been questioned when the most abundant foraminifera are fragile agglutinated forms, particularly prone to fragmentation. Here we test an alternate method for accurately estimating the composition of fragmented assemblages. The cumulated area per morphotype method is assessed, i.e., the sum of the area of all tests or fragments of a given morphotype in a sample. The percentage of each morphotype is calculated as a portion of the total cumulated area. Percentages of different morphotypes based on counting and cumulated area methods are compared one by one and analyzed using principal component analyses, a co-inertia analysis, and Shannon diversity indices. Morphotype percentages are further compared to an estimate of water depth based on microfacies description. Percentages of the morphotypes are not related to water depth. In all cases, counting and cumulated area methods deliver highly similar results, suggesting that the less time-consuming traditional counting method may provide robust estimates of assemblages. The size of each morphotype may deliver paleobiological information, for instance regarding biomass, but should be considered carefully due to the pervasive issue of fragmentation.

Assessment of fragment projection hazard: probability distributions for the initial direction of fragments.

PubMed

Tugnoli, Alessandro; Gubinelli, Gianfilippo; Landucci, Gabriele; Cozzani, Valerio

2014-08-30

The evaluation of the initial direction and velocity of the fragments generated in the fragmentation of a vessel due to internal pressure is an important information in the assessment of damage caused by fragments, in particular within the quantitative risk assessment (QRA) of chemical and process plants. In the present study an approach is proposed to the identification and validation of probability density functions (pdfs) for the initial direction of the fragments. A detailed review of a large number of past accidents provided the background information for the validation procedure. A specific method was developed for the validation of the proposed pdfs. Validated pdfs were obtained for both the vertical and horizontal angles of projection and for the initial velocity of the fragments. Copyright © 2014 Elsevier B.V. All rights reserved.

Application of the Collision-Imparted Velocity Method for Analyzing the Responses of Containment and Deflector Structures to Engine Rotor Fragment Impact

NASA Technical Reports Server (NTRS)

Collins, T. P.; Witmer, E. A.

1973-01-01

An approximate analysis, termed the Collision Imparted Velocity Method (CIVM), was employed for predicting the transient structural responses of containment rings or deflector rings which are subjected to impact from turbojet-engine rotor burst fragments. These 2-d structural rings may be initially circular or arbitrarily curved and may have either uniform or variable thickness; elastic, strain hardening, and strain rate material properties are accommodated. This approximate analysis utilizes kinetic energy and momentum conservation relations in order to predict the after-impact velocities of the fragment and the impacted ring segment. This information is then used in conjunction with a finite element structural response computation code to predict the transient, large deflection responses of the ring. Similarly, the equations of motion for each fragment are solved in small steps in time. Also, some comparisons of predictions with experimental data for fragment-impacted free containment rings are presented.

Use of indicator chemicals to characterize the plastic fragments ingested by Laysan albatross.

PubMed

Nilsen, Frances; David Hyrenbach, K; Fang, Jiasong; Jensen, Brenda

2014-10-15

Laysan albatross (Phoebastria immutabilis) ingest plastic marine debris of a wide range of shape, sizes and sources. To better characterize this plastic and provide insights regarding its provenance and persistence in the environment, we developed a simple method to classify plastic fragments of unknown origin according to the resin codes used by the Society of Plastics Industry. Known plastics were analyzed by gas chromatography-mass spectroscopy (GC-MS) to identify indicator chemicals characteristic of each plastic resin. Application of this method to fragments of ingested plastic debris from boluses of Laysan albatross from Kure Atoll, Hawai'i, yielded proportions of 0.8% High Density Polyethylene, 6.8% Polystyrene, 8.5% Polyethylene Terephthalate, 20.5% Polyvinyl Chloride and 68.4% Polypropylene. Some fragments were composed of multiple resin types. These results suggest that infrequently recycled plastics are the dominant fragments ingested by albatross, and that these are the most prevalent and persistent resin types in the marine environment. Copyright © 2014 Elsevier Ltd. All rights reserved.

Femtosecond spectroscopy probes the folding quality of antibody fragments expressed as GFP fusions in the cytoplasm

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

Didier, P.; Weiss, E.; Sibler, A.-P.

2008-02-22

Time-resolved femtosecond spectroscopy can improve the application of green fluorescent proteins (GFPs) as protein-folding reporters. The study of ultrafast excited-state dynamics (ESD) of GFP fused to single chain variable fragment (scFv) antibody fragments, allowed us to define and measure an empirical parameter that only depends on the folding quality (FQ) of the fusion. This method has been applied to the analysis of genetic fusions expressed in the bacterial cytoplasm and allowed us to distinguish folded and thus functional antibody fragments (high FQ) with respect to misfolded antibody fragments. Moreover, these findings were strongly correlated to the behavior of the samemore » scFvs expressed in animal cells. This method is based on the sensitivity of the ESD to the modifications in the tertiary structure of the GFP induced by the aggregation state of the fusion partner. This approach may be applicable to the study of the FQ of polypeptides over-expressed under reducing conditions.« less

Fast Fragmentation of Networks Using Module-Based Attacks

PubMed Central

Requião da Cunha, Bruno; González-Avella, Juan Carlos; Gonçalves, Sebastián

2015-01-01

In the multidisciplinary field of Network Science, optimization of procedures for efficiently breaking complex networks is attracting much attention from a practical point of view. In this contribution, we present a module-based method to efficiently fragment complex networks. The procedure firstly identifies topological communities through which the network can be represented using a well established heuristic algorithm of community finding. Then only the nodes that participate of inter-community links are removed in descending order of their betweenness centrality. We illustrate the method by applying it to a variety of examples in the social, infrastructure, and biological fields. It is shown that the module-based approach always outperforms targeted attacks to vertices based on node degree or betweenness centrality rankings, with gains in efficiency strongly related to the modularity of the network. Remarkably, in the US power grid case, by deleting 3% of the nodes, the proposed method breaks the original network in fragments which are twenty times smaller in size than the fragments left by betweenness-based attack. PMID:26569610

A LDR-PCR approach for multiplex polymorphisms genotyping of severely degraded DNA with fragment sizes <100 bp.

PubMed

Zhang, Zhen; Wang, Bao-Jie; Guan, Hong-Yu; Pang, Hao; Xuan, Jin-Feng

2009-11-01

Reducing amplicon sizes has become a major strategy for analyzing degraded DNA typical of forensic samples. However, amplicon sizes in current mini-short tandem repeat-polymerase chain reaction (PCR) and mini-sequencing assays are still not suitable for analysis of severely degraded DNA. In this study, we present a multiplex typing method that couples ligase detection reaction with PCR that can be used to identify single nucleotide polymorphisms and small-scale insertion/deletions in a sample of severely fragmented DNA. This method adopts thermostable ligation for allele discrimination and subsequent PCR for signal enhancement. In this study, four polymorphic loci were used to assess the ability of this technique to discriminate alleles in an artificially degraded sample of DNA with fragment sizes <100 bp. Our results showed clear allelic discrimination of single or multiple loci, suggesting that this method might aid in the analysis of extremely degraded samples in which allelic drop out of larger fragments is observed.

Real-time Tracking of DNA Fragment Separation by Smartphone.

PubMed

Tao, Chunxian; Yang, Bo; Li, Zhenqing; Zhang, Dawei; Yamaguchi, Yoshinori

2017-06-01

Slab gel electrophoresis (SGE) is the most common method for the separation of DNA fragments; thus, it is broadly applied to the field of biology and others. However, the traditional SGE protocol is quite tedious, and the experiment takes a long time. Moreover, the chemical consumption in SGE experiments is very high. This work proposes a simple method for the separation of DNA fragments based on an SGE chip. The chip is made by an engraving machine. Two plastic sheets are used for the excitation and emission wavelengths of the optical signal. The fluorescence signal of the DNA bands is collected by smartphone. To validate this method, 50, 100, and 1,000 bp DNA ladders were separated. The results demonstrate that a DNA ladder smaller than 5,000 bp can be resolved within 12 min and with high resolution when using this method, indicating that it is an ideal substitute for the traditional SGE method.

Syntheses, structures and properties of three new two-dimensional Cu(I)-Ln(III) heterometallic coordination polymers based on 2,2'-dipyridyl-5,5'-dicarboxylate ligands.

PubMed

Zhao, Junwei; Cheng, Yamin; Shang, Sensen; Zhang, Fang; Chen, Li; Chen, Lijuan

2013-12-01

Three new two-dimensional Cu(I)-Ln(III) heterometallic coordination polymers [Ln(III)Cu2(I)(Hbpdc)4] · Cl · xH2O [Ln(III) = La(III), x = 8 (1); Ln(III) = Pr(III), x=9 (2); Ln(III) = Eu(III), x = 8 (3)] (H2bpdc = 2,2'-bipyridyl-5,5'-dicarboxylic acid) have been prepared under hydrothermal conditions and structurally characterized by elemental analyses, inductively coupled plasma atomic emission spectrometry (ICP-AES) analyses, IR spectra, X-ray photoelectron spectroscopy (XPS) and single-crystal X-ray diffraction. X-ray diffraction indicates that the isomorphic 1-3 display the two-dimensional sheet structure constructed from [Cu(I)(Hbpdc)2](-) fragments through Ln(3+) connectors. Moreover, the solid-state photoluminescence measurements of 3 indicate that the Eu(III) ions, Hbpdc(-) ligands and Cu(I) cations make contributions to its luminescent properties simultaneously. Copyright © 2013 Elsevier B.V. All rights reserved.

Full-dimensional and reduced-dimensional calculations of initial state-selected reaction probabilities studying the H + CH{sub 4} → H{sub 2} + CH{sub 3} reaction on a neural network PES

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

Welsch, Ralph, E-mail: rwelsch@uni-bielefeld.de; Manthe, Uwe, E-mail: uwe.manthe@uni-bielefeld.de

2015-02-14

Initial state-selected reaction probabilities of the H + CH{sub 4} → H{sub 2} + CH{sub 3} reaction are calculated in full and reduced dimensionality on a recent neural network potential [X. Xu, J. Chen, and D. H. Zhang, Chin. J. Chem. Phys. 27, 373 (2014)]. The quantum dynamics calculation employs the quantum transition state concept and the multi-layer multi-configurational time-dependent Hartree approach and rigorously studies the reaction for vanishing total angular momentum (J = 0). The calculations investigate the accuracy of the neutral network potential and study the effect resulting from a reduced-dimensional treatment. Very good agreement is found betweenmore » the present results obtained on the neural network potential and previous results obtained on a Shepard interpolated potential energy surface. The reduced-dimensional calculations only consider motion in eight degrees of freedom and retain the C{sub 3v} symmetry of the methyl fragment. Considering reaction starting from the vibrational ground state of methane, the reaction probabilities calculated in reduced dimensionality are moderately shifted in energy compared to the full-dimensional ones but otherwise agree rather well. Similar agreement is also found if reaction probabilities averaged over similar types of vibrational excitation of the methane reactant are considered. In contrast, significant differences between reduced and full-dimensional results are found for reaction probabilities starting specifically from symmetric stretching, asymmetric (f{sub 2}-symmetric) stretching, or e-symmetric bending excited states of methane.« less

Study of Tnp1, Tekt1, and Plzf Genes Expression During an in vitro Three-Dimensional Neonatal Male Mice Testis Culture

PubMed

Alrahel, Ahmad; Movahedin, Mansoureh; Mazaheri, Zohre; Amidi, Fardin

2018-07-01

In vitro spermatogenesis has a long research history beginning in the early 20th century. This organ culture method was therefore abandoned, and alternative cell culture methods were chosen by many researchers. Here, whether Tnp1, Tekt1, and Plzf, which play a crucial role in spermatogenesis, can be expressed during testis organ culture was assessed. Testes of 10 mouse pups were first removed, and the testis tissue was then separated into smaller pieces of seminiferous tubules. The size of the pieces was arbitrary; approximately 1 mg in weight or 1 mm3 in size when compacted. Afterwards, the testis tissue fragments (1–3) were transferred to the hexahedrons, incubated in a culture incubator and cultured for 12 weeks. Histological assessment and molecular evaluation were carried out at the end of the study. The results showed that the expression of Tekt1 as a mitotic gene in mouse pups decreased significantly (p ≤ 0.05) in comparison to adult mouse testis. Meanwhile, the expression of Tnp1 as a meiotic gene increased significantly (p ≤ 0.05) as compared to neonate mouse testis at the beginning of the culture. The expression of Plzf showed no significant difference during the 12 weeks of culture (p ≥ 0.05). Based on histological study, different types of spermatocytes and post-meiotic stages of germ cells could not be detected. This kind of three-dimensional culture can induce expression of post-meiotic gene, Tnp1, but only at the molecular level and not beyond meiosis.

Bacterial DNA in water and dialysate: detection and significance for patient outcomes.

PubMed

Handelman, Garry J; Megdal, Peter A; Handelman, Samuel K

2009-01-01

The fluid used for hemodialysis may contain DNA fragments from bacteria, which could be harmful for patient outcomes. DNA fragments from bacteria, containing the nonmethylated CpG motif, can trigger inflammation through the monocyte and lymphocyte Toll-like receptor 9, and these DNA fragments have been observed in dialysate. The fragments may transfer across the dialyzer into the patient's bloodstream during hemodialysis treatment. During hemodiafiltration, the fragments would be introduced directly into the bloodstream. The DNA fragments may arise from biofilm in the pipes of the water system, from growth of bacteria in the water, or as contaminants in the bicarbonate and salt mixture used for preparation of dialysate. Current filtration methods, such as Diasafe filters, are not able to remove these fragments. It would be prudent to seek to reduce or eliminate these contaminants. However, the cost and effort of decreasing bacterial DNA content may ultimately require substantial facility improvements; we therefore need to fund research studies to determine if modifications to reduce bacterial DNA content are clinically warranted. This research will require methods to accurately determine the species of bacteria that contribute the DNA, since this information will allow the source to be established as biofilm, bicarbonate mixtures, or other problems in the dialysis system such as bacterial growth or leakage during water preparation. In this review, the evidence for bacterial DNA fragments will be examined and suggestions for further studies will be described.

Lead generation and examples opinion regarding how to follow up hits.

PubMed

Orita, Masaya; Ohno, Kazuki; Warizaya, Masaichi; Amano, Yasushi; Niimi, Tatsuya

2011-01-01

In fragment-based drug discovery (FBDD), not only identifying the starting fragment hit to be developed but also generating a drug lead from that starting fragment hit is important. Converting fragment hits to leads is generally similar to a high-throughput screening (HTS) hits-to-leads approach in that properties associated with activity for a target protein, such as selectivity against other targets and absorption, distribution, metabolism, excretion, and toxicity (ADME/Tox), and physicochemical properties should be taken into account. However, enhancing the potency of the fragment hit is a key requirement in FBDD, unlike HTS, because initial fragment hits are generally weak. This enhancement is presently achieved by adding additional chemical groups which bind to additional parts of the target protein or by joining or combining two or more hit fragments; however, strategies for effecting greater improvements in effective activity are needed. X-ray analysis is a key technology attractive for converting fragments to drug leads. This method makes it clear whether a fragment hit can act as an anchor and provides insight regarding introduction of functional groups to improve fragment activity. Data on follow-up chemical synthesis of fragment hits has allowed for the differentiation of four different strategies: fragment optimization, fragment linking, fragment self-assembly, and fragment evolution. Here, we discuss our opinion regarding how to follow up on fragment hits, with a focus on the importance of fragment hits as an anchor moiety to so-called hot spots in the target protein using crystallographic data. Copyright © 2011 Elsevier Inc. All rights reserved.

Stepwise synthesis of oligonucleotides. XXII. The synthesis of Tpsi-loop fragments of yeast tRNAIVal and their analogs.

PubMed Central

Zhenodarova, S M; Klyagina, V P; Smolyaninova, O A; Khabarova, M I; Antonovich, E G; Prokof'yev, M A

1977-01-01

The method of the combined use of nucleolytic enzymes was used for the synthesis of Tpsi-loop fragments of yeast valine tRNA and their analogs. Dinucleoside monophosphates, trinucleoside diphosphates and tetranucleoside triphosphates having the sequences of fragments 54-57 and 59-62 or their analogs were synthesized. PMID:896487

Northeastern Regional Forest Fragmentation Assessment: Rationale, Methods, and Comparisons With Other Studies

Treesearch

Andrew Lister; Rachel Riemann; Tonya Lister; Will McWilliams

2005-01-01

Forest fragmentation is thought to impact many biotic and abiotic processes important to ecosystem function. We assessed forest fragmentation in 13 Northeastern States to gain a greater understanding of the trends in and status of this region?s forests. We reclassified and then statistically filtered and updated classified Landsat imagery from the early 1990s, and...

Use of Road Maps in National Assessments of Forest Fragmentation in the United States

Treesearch

Kurt H. Riitters; James Wickham; John Coulston

2004-01-01

The question of incorporating road maps into U.S. national assessments of forest fragmentation has been a contentious issue, but there has not been a comparative national analysis to inform the debate. Using data and indices from previous national assessments, we compared fragmentation as calculated from high-resolution land-cover maps alone (Method 1) and after...

Quantifying forest fragmentation using Geographic Information Systems and Forest Inventory and Analysis plot data

Treesearch

Dacia M. Meneguzzo; Mark H. Hansen

2009-01-01

Fragmentation metrics provide a means of quantifying and describing forest fragmentation. The most common method of calculating these metrics is through the use of Geographic Information System software to analyze raster data, such as a satellite or aerial image of the study area; however, the spatial resolution of the imagery has a significant impact on the results....

Complexity Reduction in Large Quantum Systems: Fragment Identification and Population Analysis via a Local Optimized Minimal Basis

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

Mohr, Stephan; Masella, Michel; Ratcliff, Laura E.

We present, within Kohn-Sham Density Functional Theory calculations, a quantitative method to identify and assess the partitioning of a large quantum mechanical system into fragments. We then introduce a simple and efficient formalism (which can be written as generalization of other well-known population analyses) to extract, from first principles, electrostatic multipoles for these fragments. The corresponding fragment multipoles can in this way be seen as reliable (pseudo-) observables. By applying our formalism within the code BigDFT, we show that the usage of a minimal set of in-situ optimized basis functions is of utmost importance for having at the same timemore » a proper fragment definition and an accurate description of the electronic structure. With this approach it becomes possible to simplify the modeling of environmental fragments by a set of multipoles, without notable loss of precision in the description of the active quantum mechanical region. Furthermore, this leads to a considerable reduction of the degrees of freedom by an effective coarsegraining approach, eventually also paving the way towards efficient QM/QM and QM/MM methods coupling together different levels of accuracy.« less

Complexity Reduction in Large Quantum Systems: Fragment Identification and Population Analysis via a Local Optimized Minimal Basis

DOE PAGES

Mohr, Stephan; Masella, Michel; Ratcliff, Laura E.; ...

2017-07-21

We present, within Kohn-Sham Density Functional Theory calculations, a quantitative method to identify and assess the partitioning of a large quantum mechanical system into fragments. We then introduce a simple and efficient formalism (which can be written as generalization of other well-known population analyses) to extract, from first principles, electrostatic multipoles for these fragments. The corresponding fragment multipoles can in this way be seen as reliable (pseudo-) observables. By applying our formalism within the code BigDFT, we show that the usage of a minimal set of in-situ optimized basis functions is of utmost importance for having at the same timemore » a proper fragment definition and an accurate description of the electronic structure. With this approach it becomes possible to simplify the modeling of environmental fragments by a set of multipoles, without notable loss of precision in the description of the active quantum mechanical region. Furthermore, this leads to a considerable reduction of the degrees of freedom by an effective coarsegraining approach, eventually also paving the way towards efficient QM/QM and QM/MM methods coupling together different levels of accuracy.« less

Separation efficiency of free-solution conjugated electrophoresis with drag-tags incorporating a synthetic amino acid.

PubMed

Seo, Kyung-Ho; Chu, Hun-Su; Yoo, Tae Hyeon; Lee, Sun-Gu; Won, Jong-In

2016-03-01

DNA sequencing or separation by conventional capillary electrophoresis with a polymer matrix has some inherent drawbacks, such as the expense of polymer matrix and limitations in sequencing read length. As DNA fragments have a linear charge-to-friction ratio in free solution, DNA fragments cannot be separated by size. However, size-based separation of DNA is possible in free-solution conjugate electrophoresis (FSCE) if a "drag-tag" is attached to DNA fragments because the tag breaks the linear charge-to-friction scaling. Although several previous studies have demonstrated the feasibility of DNA separation by free-solution conjugated electrophoresis, generation of a monodisperse drag-tag and identification of a strong, site-specific conjugation method between a DNA fragment and a drag-tag are challenges that still remain. In this study, we demonstrate an efficient FSCE method by conjugating a biologically synthesized elastin-like polypeptide (ELP) and green fluorescent protein (GFP) to DNA fragments. In addition, to produce strong and site-specific conjugation, a methionine residue in drag-tags is replaced with homopropargylglycine (Hpg), which can be conjugated specifically to a DNA fragment with an azide site. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Measurement of the velocity of neutral fragments by the "correlated ion and neutral time of flight" method combined with "velocity-map imaging"

NASA Astrophysics Data System (ADS)

Berthias, F.; Feketeová, L.; Della Negra, R.; Dupasquier, T.; Fillol, R.; Abdoul-Carime, H.; Farizon, B.; Farizon, M.; Märk, T. D.

2017-08-01

In the challenging field of imaging molecular dynamics, a novel method has been developed and implemented that allows the measurement of the velocity of neutral fragments produced in collision induced dissociation experiments on an event-by-event basis. This has been made possible by combining a correlated ion and neutral time of flight method with a velocity map imaging technique. This new method relies on a multiparametric correlated detection of the neutral and charged fragments from collision induced dissociation on one single detector. Its implementation on the DIAM device (Device for irradiation of biomolecular clusters) (Dispositif d'Irradiation d'Agrégats bioMoléculaires) allowed us to measure the velocity distribution of water molecules evaporated from collision induced dissociation of mass- and energy-selected protonated water clusters.

The Effect of Varied Initial Conditions on the Evolution of Protoplanetary Disks

NASA Astrophysics Data System (ADS)

Michael, Scott A.; Durisen, R. H.; Boley, A. C.

2006-12-01

We present a series of three-dimensional hydrodynamics simulations of gravitationally unstable protoplanetary disks with globally constant cooling times. The purpose of these simulations is to study the effects of varying the initial surface density profile, equation of state, and cooling time. All non-fragmenting disks exhibit the same phases of evolution described by Mejía et al. (2005) axisymmetric cooling, a burst in a well-defined multi-armed mode, and a transition to an asymptotic behavior in which heating and cooling are roughly balanced over much of the disk. The burst tends to be weaker for initial surface density profiles that fall more steeply with r. Regardless of initial surface density profile, the outer disk redistributes its mass to follow an approximate Σ ∝ r-5/2 power law. Comparison of different equations of state show that, for a given cooling time, a disk with γ = 7/5 is more likely to fragment than one with γ = 5/3. By varying the cooling time with both equations of state, we are able to confirm the tcoolΩ < 8.25 and 5.14 fragmentation criterion for γ = 7/5 and 5/3, respectively, as found by Rice et al. (2005).

Modelling fragmentations of aminoacids after resonant electron attachment: quantum evidence of possible direct -OH detachment

NASA Astrophysics Data System (ADS)

Panosetti, C.; Baccarelli, I.; Sebastianelli, F.; Gianturco, F. A.

2010-10-01

We investigate some aspects of the radiation damage mechanisms in biomolecules, focusing on the modelling of resonant fragmentation caused by the attachment of low-energy electrons (LEEs) initially ejected by biological tissues when exposed to ionizing radiation. Scattering equations are formulated within a symmetry-adapted, single-center expansion of both continuum and bound electrons, and the interaction forces are obtained from a combination of ab initio calculations and a nonempirical model of exchange and correlation effects developped in our group. We present total elastic scattering cross-sections and resonance features obtained for the equilibrium geometries of glycine, alanine, proline and valine. Our results at those geometries of the target molecules are briefly shown to qualitatively explain some of the fragmentation patterns obtained in experiments. We further carry out a one-dimensional (1D) modeling for the dynamics of intramolecular energy transfers mediated by the vibrational activation of selected bonds: our calculations indicate that resonant electron attachment to glycine can trigger direct, dissociative evolution of the complex into (Gly-OH)- and -OH losses, while they also find that the same process does not occur via a direct, 1D dissociative path in the larger aminoacids of the present study.

Protein-Templated Fragment Ligations-From Molecular Recognition to Drug Discovery.

PubMed

Jaegle, Mike; Wong, Ee Lin; Tauber, Carolin; Nawrotzky, Eric; Arkona, Christoph; Rademann, Jörg

2017-06-19

Protein-templated fragment ligation is a novel concept to support drug discovery and can help to improve the efficacy of protein ligands. Protein-templated fragment ligations are chemical reactions between small molecules ("fragments") utilizing a protein's surface as a reaction vessel to catalyze the formation of a protein ligand with increased binding affinity. The approach exploits the molecular recognition of reactive small-molecule fragments by proteins both for ligand assembly and for the identification of bioactive fragment combinations. In this way, chemical synthesis and bioassay are integrated in one single step. This Review discusses the biophysical basis of reversible and irreversible fragment ligations and gives an overview of the available methods to detect protein-templated ligation products. The chemical scope and recent applications as well as future potential of the concept in drug discovery are reviewed. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Management of Fractured Inferior Vena Cava Filters: Outcomes by Fragment Location.

PubMed

Trerotola, Scott O; Stavropoulos, S William

2017-09-01

Purpose To inform the management of fractured inferior vena cava filters on the basis of results from a tertiary referral center specializing in complex filter retrieval. Materials and Methods This study had institutional review board approval and was HIPAA compliant. Retrospective analysis of all patients with fractured filters and/or filter fragments evaluated for removal in a complex filter removal program was performed. Removal was attempted when fragments were intravascular or immediately extravascular by using primarily endobronchial forceps for caval fragments and snares for cardiac and pulmonary fragments. Data collected included success rate and complications of filter and fragment removal, symptoms relating to the filter or fragment, techniques used for removal, and follow-up of retained fragments. Results Sixty-five patients (12 men, 53 women) of a total of 222 patients referred for complex retrieval had fractured filters. Of these patients, two had undergone filter removal elsewhere and had retained fragments. All 63 filters were removed successfully with forceps (n = 61), a cone (n = 1), or a snare (n = 1). There were 116 separate filter fragments; removal was attempted for 78 fragments. Removal was successful for 63 (81%) of 78 fragments and varied by location. All extravascular fragments except one were retained. In all, 63 (54%) of 116 fragments were removed percutaneously, rendering 34 (54%) of 63 patients fragment free. Five minor (7.7% [five of 65]) and four major (6.2% [four of 65]) complications occurred. Conclusion Intravascular filter fragments can be removed safely with success rates that vary according to location. Because extravascular fragments are not readily accessible for removal, many patients are not rendered fragment free. © RSNA, 2017 Online supplemental material is available for this article.

Purification of polymorphic components of complex genomes

DOEpatents

Stodolsky, Marvin

1991-01-01

A method is disclosed for processing related subject and reference macromolecule populations composed of complementary strands into their respective subject and reference populations of representative fragments and effectuating purification of unique polymorphic subject fragments.

Purification of polymorphic components of complex genomes

DOEpatents

Stodolsky, M.

1988-01-21

A method for processing related subject and reference macromolecule composed of complementary strand into their respective subject and reference populations of representative fragments and effectuating purification of unique polymorphic subject fragments. 1 fig.

Performance of combined fragmentation and retention prediction for the identification of organic micropollutants by LC-HRMS.

PubMed

Hu, Meng; Müller, Erik; Schymanski, Emma L; Ruttkies, Christoph; Schulze, Tobias; Brack, Werner; Krauss, Martin

2018-03-01

In nontarget screening, structure elucidation of small molecules from high resolution mass spectrometry (HRMS) data is challenging, particularly the selection of the most likely candidate structure among the many retrieved from compound databases. Several fragmentation and retention prediction methods have been developed to improve this candidate selection. In order to evaluate their performance, we compared two in silico fragmenters (MetFrag and CFM-ID) and two retention time prediction models (based on the chromatographic hydrophobicity index (CHI) and on log D). A set of 78 known organic micropollutants was analyzed by liquid chromatography coupled to a LTQ Orbitrap HRMS with electrospray ionization (ESI) in positive and negative mode using two fragmentation techniques with different collision energies. Both fragmenters (MetFrag and CFM-ID) performed well for most compounds, with average ranking the correct candidate structure within the top 25% and 22 to 37% for ESI+ and ESI- mode, respectively. The rank of the correct candidate structure slightly improved when MetFrag and CFM-ID were combined. For unknown compounds detected in both ESI+ and ESI-, generally positive mode mass spectra were better for further structure elucidation. Both retention prediction models performed reasonably well for more hydrophobic compounds but not for early eluting hydrophilic substances. The log D prediction showed a better accuracy than the CHI model. Although the two fragmentation prediction methods are more diagnostic and sensitive for candidate selection, the inclusion of retention prediction by calculating a consensus score with optimized weighting can improve the ranking of correct candidates as compared to the individual methods. Graphical abstract Consensus workflow for combining fragmentation and retention prediction in LC-HRMS-based micropollutant identification.

Extraction of Extended Small-Scale Objects in Digital Images

NASA Astrophysics Data System (ADS)

Volkov, V. Y.

2015-05-01

Detection and localization problem of extended small-scale objects with different shapes appears in radio observation systems which use SAR, infra-red, lidar and television camera. Intensive non-stationary background is the main difficulty for processing. Other challenge is low quality of images, blobs, blurred boundaries; in addition SAR images suffer from a serious intrinsic speckle noise. Statistics of background is not normal, it has evident skewness and heavy tails in probability density, so it is hard to identify it. The problem of extraction small-scale objects is solved here on the basis of directional filtering, adaptive thresholding and morthological analysis. New kind of masks is used which are open-ended at one side so it is possible to extract ends of line segments with unknown length. An advanced method of dynamical adaptive threshold setting is investigated which is based on isolated fragments extraction after thresholding. Hierarchy of isolated fragments on binary image is proposed for the analysis of segmentation results. It includes small-scale objects with different shape, size and orientation. The method uses extraction of isolated fragments in binary image and counting points in these fragments. Number of points in extracted fragments is normalized to the total number of points for given threshold and is used as effectiveness of extraction for these fragments. New method for adaptive threshold setting and control maximises effectiveness of extraction. It has optimality properties for objects extraction in normal noise field and shows effective results for real SAR images.

Colonisation of soilless growing media for tomato by Trichoderma harzianum.

PubMed

De Schutter, B; Aerts, R; Rombouts, L

2001-01-01

An experiment was conducted to evaluate the distribution of T. harzianum in soilless media used in greenhouse growing systems for tomatoes. Growing media based on rockwool and based on coconut fibre were included. The fungus was applied to the roots of the plant by means of a conidial suspension. The upper plant parts were removed from the coconut fibre an the rockwool slab after 10 and 15 weeks respectively. Both the coconut fibre and the rockwool slab were divided into fragments with a width of 10 cm. The coconut fibre medium fragments were again divided in an upper and a lower part. For every fragment the CFU/g was determined by two different methods. In the first method a known volume of growing medium was brought into suspension using a blender and diluted. Appropriate dilutions were plated on a selective medium. In the second method a known volume of growing medium was spread directly upon a selective medium in petri dishes. All dishes were incubated at room temperature and colonies were counted. Results showed that in the case of the coconut fibre growing medium T. harzianum was isolated in every fragment of the substrate. Highest densities were measured at the site of inoculation. In the lower part of the fragments less CFU/g were counted than in the upper part. In the case of the rockwool growing medium, there were several fragments in which no T. harzianum was isolated. The dilution technique demonstrated to be most useful in cases of high density. The direct spreading-method is best applied when low densities are expected. These observations demonstrate that the growing medium based upon coconut fibre is more appropriate for colonisation by T. harzianum. However, densities are higher at the site of inoculation in both tested growing media.

Fragmentation scaling of percolation clusters in two and three dimensions: Large-cell Monte Carlo RG approach

NASA Astrophysics Data System (ADS)

Cheon, M.; Chang, I.

1999-04-01

The scaling behavior for a binary fragmentation of critical percolation clusters is investigated by a large-cell Monte Carlo real-space renormalization group method in two and three dimensions. We obtain accurate values of critical exponents λ and phi describing the scaling of fragmentation rate and the distribution of fragments' masses produced by a binary fragmentation. Our results for λ and phi show that the fragmentation rate is proportional to the size of mother cluster, and the scaling relation σ = 1 + λ - phi conjectured by Edwards et al. to be valid for all dimensions is satisfied in two and three dimensions, where σ is the crossover exponent of the average cluster number in percolation theory, which excludes the other scaling relations.

Method for establishing a combustion zone in an in situ oil shale retort having a pocket at the top

DOEpatents

Cha, Chang Y.

1980-01-01

An in situ oil shale retort having a top boundary of unfragmented formation and containing a fragmented permeable mass has a pocket at the top, that is, an open space between a portion of the top of the fragmented mass and the top boundary of unfragmented formation. To establish a combustion zone across the fragmented mass, a combustion zone is established in a portion of the fragmented mass which is proximate to the top boundary. A retort inlet mixture comprising oxygen is introduced to the fragmented mass to propagate the combustion zone across an upper portion of the fragmented mass. Simultaneously, cool fluid is introduced to the pocket to prevent overheating and thermal sloughing of formation from the top boundary into the pocket.

Quantification of habitat fragmentation reveals extinction risk in terrestrial mammals

PubMed Central

Crooks, Kevin R.; Burdett, Christopher L.; Theobald, David M.; King, Sarah R. B.; Rondinini, Carlo; Boitani, Luigi

2017-01-01

Although habitat fragmentation is often assumed to be a primary driver of extinction, global patterns of fragmentation and its relationship to extinction risk have not been consistently quantified for any major animal taxon. We developed high-resolution habitat fragmentation models and used phylogenetic comparative methods to quantify the effects of habitat fragmentation on the world’s terrestrial mammals, including 4,018 species across 26 taxonomic Orders. Results demonstrate that species with more fragmentation are at greater risk of extinction, even after accounting for the effects of key macroecological predictors, such as body size and geographic range size. Species with higher fragmentation had smaller ranges and a lower proportion of high-suitability habitat within their range, and most high-suitability habitat occurred outside of protected areas, further elevating extinction risk. Our models provide a quantitative evaluation of extinction risk assessments for species, allow for identification of emerging threats in species not classified as threatened, and provide maps of global hotspots of fragmentation for the world’s terrestrial mammals. Quantification of habitat fragmentation will help guide threat assessment and strategic priorities for global mammal conservation. PMID:28673992

A comparison of charcoal measurements for reconstruction of Mediterranean paleo-fire frequency in the mountains of Corsica

NASA Astrophysics Data System (ADS)

Leys, Bérangère; Carcaillet, Christopher; Dezileau, Laurent; Ali, Adam A.; Bradshaw, Richard H. W.

2013-05-01

Fire-history reconstructions inferred from sedimentary charcoal records are based on measuring sieved charcoal fragment area, estimating fragment volume, or counting fragments. Similar fire histories are reconstructed from these three approaches for boreal lake sediment cores, using locally defined thresholds. Here, we test the same approach for a montane Mediterranean lake in which taphonomical processes might differ from boreal lakes through fragmentation of charcoal particles. The Mediterranean charcoal series are characterized by highly variable charcoal accumulation rates. Results there indicate that the three proxies do not provide comparable fire histories. The differences are attributable to charcoal fragmentation. This could be linked to fire type (crown or surface fires) or taphonomical processes, including charcoal transportation in the catchment area or in the sediment. The lack of correlation between the concentration of charcoal and of mineral matter suggests that fragmentation is not linked to erosion. Reconstructions based on charcoal area are more robust and stable than those based on fragment counts. Area-based reconstructions should therefore be used instead of the particle-counting method when fragmentation may influence the fragment abundance.

Quantification of habitat fragmentation reveals extinction risk in terrestrial mammals.

PubMed

Crooks, Kevin R; Burdett, Christopher L; Theobald, David M; King, Sarah R B; Di Marco, Moreno; Rondinini, Carlo; Boitani, Luigi

2017-07-18

Although habitat fragmentation is often assumed to be a primary driver of extinction, global patterns of fragmentation and its relationship to extinction risk have not been consistently quantified for any major animal taxon. We developed high-resolution habitat fragmentation models and used phylogenetic comparative methods to quantify the effects of habitat fragmentation on the world's terrestrial mammals, including 4,018 species across 26 taxonomic Orders. Results demonstrate that species with more fragmentation are at greater risk of extinction, even after accounting for the effects of key macroecological predictors, such as body size and geographic range size. Species with higher fragmentation had smaller ranges and a lower proportion of high-suitability habitat within their range, and most high-suitability habitat occurred outside of protected areas, further elevating extinction risk. Our models provide a quantitative evaluation of extinction risk assessments for species, allow for identification of emerging threats in species not classified as threatened, and provide maps of global hotspots of fragmentation for the world's terrestrial mammals. Quantification of habitat fragmentation will help guide threat assessment and strategic priorities for global mammal conservation.

Minim typing--a rapid and low cost MLST based typing tool for Klebsiella pneumoniae.

PubMed

Andersson, Patiyan; Tong, Steven Y C; Bell, Jan M; Turnidge, John D; Giffard, Philip M

2012-01-01

Here we report a single nucleotide polymorphism (SNP) based genotyping method for Klebsiella pneumoniae utilising high-resolution melting (HRM) analysis of fragments within the multilocus sequence typing (MLST) loci. The approach is termed mini-MLST or Minim typing and it has previously been applied to Streptococcus pyogenes, Staphylococcus aureus and Enterococcus faecium. Six SNPs were derived from concatenated MLST sequences on the basis of maximisation of the Simpsons Index of Diversity (D). DNA fragments incorporating these SNPs and predicted to be suitable for HRM analysis were designed. Using the assumption that HRM alleles are defined by G+C content, Minim typing using six fragments was predicted to provide a D = 0.979 against known STs. The method was tested against 202 K. pneumoniae using a blinded approach in which the MLST analyses were performed after the HRM analyses. The HRM-based alleles were indeed in accordance with G+C content, and the Minim typing identified known STs and flagged new STs. The tonB MLST locus was determined to be very diverse, and the two Minim fragments located herein contribute greatly to the resolving power. However these fragments are refractory to amplification in a minority of isolates. Therefore, we assessed the performance of two additional formats: one using only the four fragments located outside the tonB gene (D = 0.929), and the other using HRM data from these four fragments in conjunction with sequencing of the tonB MLST fragment (D = 0.995). The HRM assays were developed on the Rotorgene 6000, and the method was shown to also be robust on the LightCycler 480, allowing a 384-well high through-put format. The assay provides rapid, robust and low-cost typing with fully portable results that can directly be related to current MLST data. Minim typing in combination with molecular screening for antibiotic resistance markers can be a powerful surveillance tool kit.

Minim Typing – A Rapid and Low Cost MLST Based Typing Tool for Klebsiella pneumoniae

PubMed Central

Andersson, Patiyan; Tong, Steven Y. C.; Bell, Jan M.; Turnidge, John D.; Giffard, Philip M.

2012-01-01

Here we report a single nucleotide polymorphism (SNP) based genotyping method for Klebsiella pneumoniae utilising high-resolution melting (HRM) analysis of fragments within the multilocus sequence typing (MLST) loci. The approach is termed mini-MLST or Minim typing and it has previously been applied to Streptococcus pyogenes, Staphylococcus aureus and Enterococcus faecium. Six SNPs were derived from concatenated MLST sequences on the basis of maximisation of the Simpsons Index of Diversity (D). DNA fragments incorporating these SNPs and predicted to be suitable for HRM analysis were designed. Using the assumption that HRM alleles are defined by G+C content, Minim typing using six fragments was predicted to provide a D = 0.979 against known STs. The method was tested against 202 K. pneumoniae using a blinded approach in which the MLST analyses were performed after the HRM analyses. The HRM-based alleles were indeed in accordance with G+C content, and the Minim typing identified known STs and flagged new STs. The tonB MLST locus was determined to be very diverse, and the two Minim fragments located herein contribute greatly to the resolving power. However these fragments are refractory to amplification in a minority of isolates. Therefore, we assessed the performance of two additional formats: one using only the four fragments located outside the tonB gene (D = 0.929), and the other using HRM data from these four fragments in conjunction with sequencing of the tonB MLST fragment (D = 0.995). The HRM assays were developed on the Rotorgene 6000, and the method was shown to also be robust on the LightCycler 480, allowing a 384-well high through-put format. The assay provides rapid, robust and low-cost typing with fully portable results that can directly be related to current MLST data. Minim typing in combination with molecular screening for antibiotic resistance markers can be a powerful surveillance tool kit. PMID:22428067

First Monte Carlo analysis of fragmentation functions from single-inclusive e + e - annihilation

DOE PAGES

Sato, Nobuo; Ethier, J. J.; Melnitchouk, W.; ...

2016-12-02

Here, we perform the first iterative Monte Carlo (IMC) analysis of fragmentation functions constrained by all available data from single-inclusive $e^+ e^-$ annihilation into pions and kaons. The IMC method eliminates potential bias in traditional analyses based on single fits introduced by fixing parameters not well contrained by the data, and provides a statistically rigorous determination of uncertainties. Our analysis reveals specific features of fragmentation functions using the new IMC methodology and those obtained from previous analyses, especially for light quarks and for strange quark fragmentation to kaons.

Satellite disintegration dynamics

NASA Technical Reports Server (NTRS)

Dasenbrock, R. R.; Kaufman, B.; Heard, W. B.

1975-01-01

The subject of satellite disintegration is examined in detail. Elements of the orbits of individual fragments, determined by DOD space surveillance systems, are used to accurately predict the time and place of fragmentation. Dual time independent and time dependent analyses are performed for simulated and real breakups. Methods of statistical mechanics are used to study the evolution of the fragment clouds. The fragments are treated as an ensemble of non-interacting particles. A solution of Liouville's equation is obtained which enables the spatial density to be calculated as a function of position, time and initial velocity distribution.

Accurate Binding Free Energy Predictions in Fragment Optimization.

PubMed

Steinbrecher, Thomas B; Dahlgren, Markus; Cappel, Daniel; Lin, Teng; Wang, Lingle; Krilov, Goran; Abel, Robert; Friesner, Richard; Sherman, Woody

2015-11-23

Predicting protein-ligand binding free energies is a central aim of computational structure-based drug design (SBDD)--improved accuracy in binding free energy predictions could significantly reduce costs and accelerate project timelines in lead discovery and optimization. The recent development and validation of advanced free energy calculation methods represents a major step toward this goal. Accurately predicting the relative binding free energy changes of modifications to ligands is especially valuable in the field of fragment-based drug design, since fragment screens tend to deliver initial hits of low binding affinity that require multiple rounds of synthesis to gain the requisite potency for a project. In this study, we show that a free energy perturbation protocol, FEP+, which was previously validated on drug-like lead compounds, is suitable for the calculation of relative binding strengths of fragment-sized compounds as well. We study several pharmaceutically relevant targets with a total of more than 90 fragments and find that the FEP+ methodology, which uses explicit solvent molecular dynamics and physics-based scoring with no parameters adjusted, can accurately predict relative fragment binding affinities. The calculations afford R(2)-values on average greater than 0.5 compared to experimental data and RMS errors of ca. 1.1 kcal/mol overall, demonstrating significant improvements over the docking and MM-GBSA methods tested in this work and indicating that FEP+ has the requisite predictive power to impact fragment-based affinity optimization projects.

(E)-N′-(4-Meth­oxy­benzyl­idene)pyridine-3-carbohydrazide dihydrate

PubMed Central

Novina, J. Josephine; Vasuki, G.; Suresh, M.; Padusha, M. Syed Ali

2013-01-01

In the title compound, C14H13N3O2·2H2O, the hydrazone mol­ecule adopts an E conformation with respect to the C=N bond. The dihedral angle between the benzene and pyridine rings is 8.55 (10)°. The methyl­idene–hydrazide [–C(=O)–N–N=C–] fragment is essentially planar, with a maximum deviation of 0.0375 (13) Å. The mean planes of the benzene and pyridine rings make dihedral angles of 2.71 (14) and 11.25 (13)°, respectively, with mean plane of the methyl­idene-hydrazide fragment. In the crystal, the benzohydrazide and water mol­ecules are linked by N—H⋯O, O—H⋯O and O—H⋯N hydrogen bonds into a three-dimensional network. PMID:24046719

Measurement of multiplicities of charged hadrons, pions and kaons in DIS at COMPASS

NASA Astrophysics Data System (ADS)

Mitrofanov, Nikolai

2018-04-01

Precise measurements of multiplicities of charged hadrons, pions and kaons in deep inelastic scattering were performed. The data were obtained by the COMPASS Collaboration by scattering 160 GeV muons off an isoscalar 6LiD target. The results were obtained in three-dimensional bins of the Bjorken scaling variable x, the relative virtual-photon energy y, and the fraction z of the virtual-photon energy carried by the produced hadron. A leading-order pQCD analysis was performed using the pion multiplicity results to extract quark fragmentation functions into pions. The results for the sum of the z-integrated multiplicities for pions and for kaons, differ from earlier results from the HERMES experiment. The results from the sum of the z-integrated K+ and K- multiplicities at high x point to a value of the non-strange quark fragmentation function larger than obtained by the earlier DSS fit.

Topological Anisotropy of Stone-Wales Waves in Graphenic Fragments

PubMed Central

Ori, Ottorino; Cataldo, Franco; Putz, Mihai V.

2011-01-01

Stone-Wales operators interchange four adjacent hexagons with two pentagon-heptagon 5|7 pairs that, graphically, may be iteratively propagated in the graphene layer, originating a new interesting structural defect called here Stone-Wales wave. By minimization, the Wiener index topological invariant evidences a marked anisotropy of the Stone-Wales defects that, topologically, are in fact preferably generated and propagated along the diagonal of the graphenic fragments, including carbon nanotubes and graphene nanoribbons. This peculiar edge-effect is shown in this paper having a predominant topological origin, leaving to future experimental investigations the task of verifying the occurrence in nature of wave-like defects similar to the ones proposed here. Graph-theoretical tools used in this paper for the generation and the propagation of the Stone-Wales defects waves are applicable to investigate isomeric modifications of chemical structures with various dimensionality like fullerenes, nanotubes, graphenic layers, schwarzites, zeolites. PMID:22174641

Solid-state NMR spectroscopy of 18.5 kDa myelin basic protein reconstituted with lipid vesicles: spectroscopic characterisation and spectral assignments of solvent-exposed protein fragments.

PubMed

Zhong, Ligang; Bamm, Vladimir V; Ahmed, Mumdooh A M; Harauz, George; Ladizhansky, Vladimir

2007-12-01

Myelin basic protein (MBP, 18.5 kDa isoform) is a peripheral membrane protein that is essential for maintaining the structural integrity of the multilamellar myelin sheath of the central nervous system. Reconstitution of the most abundant 18.5 kDa MBP isoform with lipid vesicles yields an aggregated assembly mimicking the protein's natural environment, but which is not amenable to standard solution NMR spectroscopy. On the other hand, the mobility of MBP in such a system is variable, depends on the local strength of the protein-lipid interaction, and in general is of such a time scale that the dipolar interactions are averaged out. Here, we used a combination of solution and solid-state NMR (ssNMR) approaches: J-coupling-driven polarization transfers were combined with magic angle spinning and high-power decoupling to yield high-resolution spectra of the mobile fragments of 18.5 kDa murine MBP in membrane-associated form. To partially circumvent the problem of short transverse relaxation, we implemented three-dimensional constant-time correlation experiments (NCOCX, NCACX, CONCACX, and CAN(CO)CX) that were able to provide interresidue and intraresidue backbone correlations. These experiments resulted in partial spectral assignments for mobile fragments of the protein. Additional nuclear Overhauser effect spectroscopy (NOESY)-based experiments revealed that the mobile fragments were exposed to solvent and were likely located outside the lipid bilayer, or in its hydrophilic portion. Chemical shift index analysis showed that the fragments were largely disordered under these conditions. These combined approaches are applicable to ssNMR investigations of other peripheral membrane proteins reconstituted with lipids.

Political fragmentation and widening disparities in African-American and white mortality, 1972-1988.

PubMed

Kim, Yonsu; Bruckner, Tim A

2016-12-01

During the 1970s and 1980s in the U.S., population movement, urban sprawl and urban governance reform led to a proliferation of local, autonomous jurisdictions. Prior literature examines how this creation of local governments, also referred to as political fragmentation, contributes to economic growth and social inequality. We examine the impact of political fragmentation on health equity by testing the hypothesis that the mortality disparity between whites and African-Americans varies positively with political fragmentation. We retrieved mortality data from the multiple cause-of-death file and calculated total number of local governments per 1000 residents in a county to measure the degree of political fragmentation. We focused on 226 U.S. counties with population size greater than 200,000 and restricted the analysis to four distinct periods with overlapping government and mortality data (1972-73, 1977-78, 1982-83, and 1987-88). We applied generalized estimating equation methods that permit analysis of clustered data over time. Methods also controlled for the age structure of the population, reductions in mortality over time, and confounding by county-level sociodemographic variables. Adjusted coefficients of fragmentation are positive and statistically significant for both whites (coef: 2.60, SE: 0.60, p <0.001) and African-Americans (coef: 5.31, SE: 1.56, p <0.001). The two-fold larger positive coefficient for African-Americans than for whites indicates a greater racial disparity in mortality among more politically fragmented urban counties and/or time periods. From 1972 to 1988, political fragmentation in large urban counties moves positively with the racial/ethnic gap in mortality between whites and African-Americans. We discuss intervening mechanisms through which political fragmentation may disproportionately affect mortality among African-Americans.

Direct isolation of differentially expressed genes from a specific chromosome region of common wheat: application of the amplified fragment length polymorphism-based mRNA fingerprinting (AMF) method in combination with a deletion line of wheat.

PubMed

Kojima, T; Habu, Y; Iida, S; Ogihara, Y

2000-05-01

The amplified restriction fragment length polymorphism (AFLP)-based mRNA fingerprinting (AMF) method makes it possible systematically and conveniently to identify differentially expressed cDNAs with high reproducibility. We have applied the AMF method to the cloning of the Q gene of common wheat, which is located on the long arm of chromosome 5A and pleiotropically controls the spike morphology and the threshing character of seeds. Using the AMF method, we compared the fingerprints of mRNA samples extracted from the young spikes of Triticum aestivum cv. Chinese Spring (CS) carrying the Q gene to those of a chromosome deletion line of CS, namely, q5, which lacks 15% of 5AL including the Q gene. Approximately 12,200 fragments were produced after PCR with 256 primer combinations. Of these, 92 fragments were differentially expressed between CS and q5. Northern and Southern analyses showed that 16 fragments gave specific or relatively stronger transcript signals in CS, and these clones were present in single copy or in low copy numbers in the wheat genome. Four clones were genetically mapped to the region deleted in q5. Subsequently, one clone, pTaQ22, was mapped at the same locus as the Q gene, indicating that pTaQ22 corresponds to the Q gene or is tightly linked to it. DNA sequence data showed that pTaQ22 had no homology to any known genes, thus suggesting a novel function for this gene in flower morphogenesis. This AMF method might provide a straightforward method for isolating genes in the hexaploid background of common wheat.

Giant Planet Formation by Disk Instability: A Comparison Simulation with an Improved Radiative Scheme

NASA Astrophysics Data System (ADS)

Cai, Kai; Pickett, Megan K.; Durisen, Richard H.; Milne, Anne M.

2010-06-01

There has been disagreement about whether cooling in protoplanetary disks can be sufficiently fast to induce the formation of gas giant protoplanets via gravitational instabilities. Simulations by our own group and others indicate that this method of planet formation does not work for disks around young, low-mass stars inside several tens of AU, while simulations by other groups show fragmentation into protoplanetary clumps in this region. To allow direct comparison in hopes of isolating the cause of the differences, we here present a high-resolution three-dimensional hydrodynamics simulation of a protoplanetary disk, where the disk model, initial perturbation, and simulation conditions are essentially identical to those used in a recent set of simulations by Boss in 2007, hereafter B07. As in earlier papers by the same author, B07 purports to show that cooling is fast enough to produce protoplanetary clumps. Here, we evolve the same B07 disk using an improved version of one of our own radiative schemes and find that the disk does not fragment in our code but instead quickly settles into a state with only low amplitude nonaxisymmetric structure, which persists for at least several outer disk rotations. We see no rapid radiative or convective cooling. We conclude that the differences in results are due to different treatments of regions at and above the disk photosphere, and we explain at least one way in which the scheme in B07 may lead to artificially fast cooling.

Individual tooth macrowear pattern guides the reconstruction of Sts 52 (Australopithecus africanus) dental arches.

PubMed

Benazzi, Stefano; Kullmer, Ottmar; Schulz, Dieter; Gruppioni, Giorgio; Weber, Gerhard W

2013-02-01

The functional restoration of the occlusal relationship between maxillary and mandibular tooth rows is a major challenge in modern dentistry and maxillofacial surgery. Similar technical challenges are present in paleoanthropology when considering fragmented and deformed mandibular and maxillary fossils. Sts 52, an Australopithecus africanus specimen from Sterkfontein Member 4, represents a typical case where the original shape of the dental arches is no longer preserved. It includes a partial lower face (Sts 52a) and a fragmented mandible (Sts 52b), both incomplete and damaged to such an extent to thwart attempts at matching upper and lower dentitions. We show how the preserved macro wear pattern of the tooth crowns can be used to functionally reconstruct Sts 52's dental arches. High-resolution dental stone casts of Sts 52 maxillary and mandibular dentition were mounted and repositioned in a dental articulator. The occlusal relationship between antagonists was restored based on the analysis of the occlusal wear pattern of each preserved tooth, considering all dental contact movements represented in the occlusal compass. The reconstructed dental arches were three-dimensional surface scanned and their occlusal kinematics tested in a simulation. The outcome of this contribution is the first functional restoration of A. africanus dental arches providing new morphometric data for specimen Sts 52. It is noteworthy that the method described in this case study might be applied to several other fossil specimens. Copyright © 2013 Wiley Periodicals, Inc.

Experimental and data analysis techniques for deducing collision-induced forces from photographic histories of engine rotor fragment impact/interaction with a containment ring

NASA Technical Reports Server (NTRS)

Yeghiayan, R. P.; Leech, J. W.; Witmer, E. A.

1973-01-01

An analysis method termed TEJ-JET is described whereby measured transient elastic and inelastic deformations of an engine-rotor fragment-impacted structural ring are analyzed to deduce the transient external forces experienced by that ring as a result of fragment impact and interaction with the ring. Although the theoretical feasibility of the TEJ-JET concept was established, its practical feasibility when utilizing experimental measurements of limited precision and accuracy remains to be established. The experimental equipment and the techniques (high-speed motion photography) employed to measure the transient deformations of fragment-impacted rings are described. Sources of error and data uncertainties are identified. Techniques employed to reduce data reading uncertainties and to correct the data for optical-distortion effects are discussed. These procedures, including spatial smoothing of the deformed ring shape by Fourier series and timewise smoothing by Gram polynomials, are applied illustratively to recent measurements involving the impact of a single T58 turbine rotor blade against an aluminum containment ring. Plausible predictions of the fragment-ring impact/interaction forces are obtained by one branch of this TEJ-JET method; however, a second branch of this method, which provides an independent estimate of these forces, remains to be evaluated.

Intramolecular carbon and nitrogen isotope analysis by quantitative dry fragmentation of the phenylurea herbicide isoproturon in a combined injector/capillary reactor prior to GC separation.

PubMed

Penning, Holger; Elsner, Martin

2007-11-01

Potentially, compound-specific isotope analysis may provide unique information on source and fate of pesticides in natural systems. Yet for isotope analysis, LC-based methods that are based on the use of organic solvents often cannot be used and GC-based analysis is frequently not possible due to thermolability of the analyte. A typical example of a compound with such properties is isoproturon (3-(4-isopropylphenyl)-1,1-dimethylurea), belonging to the worldwide extensively used phenylurea herbicides. To make isoproturon accessible to carbon and nitrogen isotope analysis, we developed a GC-based method during which isoproturon was quantitatively fragmented to dimethylamine and 4-isopropylphenylisocyanate. Fragmentation occurred only partially in the injector but was mainly achieved on a heated capillary column. The fragments were then chromatographically separated and individually measured by isotope ratio mass spectrometry. The reliability of the method was tested in hydrolysis experiments with three isotopically different batches of isoproturon. For all three products, the same isotope fractionation factors were observed during conversion and the difference in isotope composition between the batches was preserved. This study demonstrates that fragmentation of phenylurea herbicides does not only make them accessible to isotope analysis but even enables determination of intramolecular isotope fractionation.

A novel Python program for implementation of quality control in the ELISA.

PubMed

Wetzel, Hanna N; Cohen, Cinder; Norman, Andrew B; Webster, Rose P

2017-09-01

The use of semi-quantitative assays such as the enzyme-linked immunosorbent assay (ELISA) requires stringent quality control of the data. However, such quality control is often lacking in academic settings due to unavailability of software and knowledge. Therefore, our aim was to develop methods to easily implement Levey-Jennings quality control methods. For this purpose, we created a program written in Python (a programming language with an open-source license) and tested it using a training set of ELISA standard curves quantifying the Fab fragment of an anti-cocaine monoclonal antibody in mouse blood. A colorimetric ELISA was developed using a goat anti-human anti-Fab capture method. Mouse blood samples spiked with the Fab fragment were tested against a standard curve of known concentrations of Fab fragment in buffer over a period of 133days stored at 4°C to assess stability of the Fab fragment and to generate a test dataset to assess the program. All standard curves were analyzed using our program to batch process the data and to generate Levey-Jennings control charts and statistics regarding the datasets. The program was able to identify values outside of two standard deviations, and this identification of outliers was consistent with the results of a two-way ANOVA. This program is freely available, which will help laboratories implement quality control methods, thus improving reproducibility within and between labs. We report here successful testing of the program with our training set and development of a method for quantification of the Fab fragment in mouse blood. Copyright © 2017 Elsevier B.V. All rights reserved.

Exploiting distant homologues for phasing through the generation of compact fragments, local fold refinement and partial solution combination.

PubMed

Millán, Claudia; Sammito, Massimo Domenico; McCoy, Airlie J; Nascimento, Andrey F Ziem; Petrillo, Giovanna; Oeffner, Robert D; Domínguez-Gil, Teresa; Hermoso, Juan A; Read, Randy J; Usón, Isabel

2018-04-01

Macromolecular structures can be solved by molecular replacement provided that suitable search models are available. Models from distant homologues may deviate too much from the target structure to succeed, notwithstanding an overall similar fold or even their featuring areas of very close geometry. Successful methods to make the most of such templates usually rely on the degree of conservation to select and improve search models. ARCIMBOLDO_SHREDDER uses fragments derived from distant homologues in a brute-force approach driven by the experimental data, instead of by sequence similarity. The new algorithms implemented in ARCIMBOLDO_SHREDDER are described in detail, illustrating its characteristic aspects in the solution of new and test structures. In an advance from the previously published algorithm, which was based on omitting or extracting contiguous polypeptide spans, model generation now uses three-dimensional volumes respecting structural units. The optimal fragment size is estimated from the expected log-likelihood gain (LLG) values computed assuming that a substructure can be found with a level of accuracy near that required for successful extension of the structure, typically below 0.6 Å root-mean-square deviation (r.m.s.d.) from the target. Better sampling is attempted through model trimming or decomposition into rigid groups and optimization through Phaser's gyre refinement. Also, after model translation, packing filtering and refinement, models are either disassembled into predetermined rigid groups and refined (gimble refinement) or Phaser's LLG-guided pruning is used to trim the model of residues that are not contributing signal to the LLG at the target r.m.s.d. value. Phase combination among consistent partial solutions is performed in reciprocal space with ALIXE. Finally, density modification and main-chain autotracing in SHELXE serve to expand to the full structure and identify successful solutions. The performance on test data and the solution of new structures are described.

Application of a trap-free two-dimensional liquid chromatography combined with ion trap/time-of-flight mass spectrometry for separation and characterization of impurities and isomers in cefpiramide.

PubMed

Wang, Jian; Xu, Yu; Wen, Chunmei; Wang, Zhijian

2017-11-01

High-resolution mass spectrometry had been routinely used for structure identification of impurity. However, all LC-MS methods were based on a volatile mobile phase, and a non-volatile system is used in the official analytical method of United States Pharmacopoeia for cefpiramide which limited the use of mass spectrometry for structure characterization of the impurities. Here we presented the utilization of a trap-free two-dimensional liquid chromatography coupled to high resolution ion trap/time-of-flight mass spectrometry (2D LC-IT-TOF MS) with positive and negative modes of electrospray ionization for characterization of eight impurities in cefpiramide. Trap-free two-dimensional liquid chromatography and online desalting technique made it possible to characterize the impurity in cefpiramide in the condition of official standard, and the TIC chromatogram of LC-MS was in conformity with the LC chromatogram of the official analytical method in the peak sequence of impurities, which could further improve the method of official monographs in pharmacopoeias. Each peak separated by the non-volatile mobile phase was trapped by a 20 μL quantitative loop then transferred into a system with a volatile mobile phase connected to a MS detector. In the first dimension, the column was Kromasil C 8 analytical column (250 mm × 4.6 mm, 5 μm) with a non-volatile salt mobile phase at the flow rate of 0.8 mL min -1 . In the second dimension, the column was Shimadzu Shim-pack GISS C 18 (50 mm × 2.1 mm, 1.9 μm) with a volatile salt mobile phase at the flow rate of 0.3 mL min -1 . Through the multiple heart-cutting 2D-LC approach and online desalting technique, the problem of incompatibility between non-volatile salt mobile phase and mass spectrometry was solved completely. The fragmentation behavior of cefpiramide and its eight impurities were studied. The structures of eight impurities in cefpiramide drug substance were deduced based on the HPLC-MS n data, in which seven impurities were novel impurities. The forming mechanisms of degradation products in cefpiramide were also studied. Copyright © 2017 Elsevier B.V. All rights reserved.

Practical method to identify orbital anomaly as spacecraft breakup in the geostationary region

NASA Astrophysics Data System (ADS)

Hanada, Toshiya; Uetsuhara, Masahiko; Nakaniwa, Yoshitaka

2012-07-01

Identifying a spacecraft breakup is an essential issue to define the current orbital debris environment. This paper proposes a practical method to identify an orbital anomaly, which appears as a significant discontinuity in the observation data, as a spacecraft breakup. The proposed method is applicable to orbital anomalies in the geostationary region. Long-term orbital evolutions of breakup fragments may conclude that their orbital planes will converge into several corresponding regions in inertial space even if the breakup epoch is not specified. This empirical method combines the aforementioned conclusion with the search strategy developed at Kyushu University, which can identify origins of observed objects as fragments released from a specified spacecraft. This practical method starts with selecting a spacecraft that experienced an orbital anomaly, and formulates a hypothesis to generate fragments from the anomaly. Then, the search strategy is applied to predict the behavior of groups of fragments hypothetically generated. Outcome of this predictive analysis specifies effectively when, where and how we should conduct optical measurements using ground-based telescopes. Objects detected based on the outcome are supposed to be from the anomaly, so that we can confirm the anomaly as a spacecraft breakup to release the detected objects. This paper also demonstrates observation planning for a spacecraft anomaly in the geostationary region.

Assembly of greek marble inscriptions by isotopic methods.

PubMed

Herz, N; Wenner, D B

1978-03-10

Classical Greek inscriptions cut in marble, whose association as original stelai by archeological methods was debatable, were selected for study. Using traditional geological techniques and determinations of the per mil increments in carbon-13 and oxygen-18, it was determined that fragments could be positively assigned to three stelai, but that fragments from three other stelai had been incorrectly associated.

A Simple yet Accurate Method for Students to Determine Asteroid Rotation Periods from Fragmented Light Curve Data

ERIC Educational Resources Information Center

Beare, R. A.

2008-01-01

Professional astronomers use specialized software not normally available to students to determine the rotation periods of asteroids from fragmented light curve data. This paper describes a simple yet accurate method based on Microsoft Excel[R] that enables students to find periods in asteroid light curve and other discontinuous time series data of…

De novo protein structure prediction by dynamic fragment assembly and conformational space annealing.

PubMed

Lee, Juyong; Lee, Jinhyuk; Sasaki, Takeshi N; Sasai, Masaki; Seok, Chaok; Lee, Jooyoung

2011-08-01

Ab initio protein structure prediction is a challenging problem that requires both an accurate energetic representation of a protein structure and an efficient conformational sampling method for successful protein modeling. In this article, we present an ab initio structure prediction method which combines a recently suggested novel way of fragment assembly, dynamic fragment assembly (DFA) and conformational space annealing (CSA) algorithm. In DFA, model structures are scored by continuous functions constructed based on short- and long-range structural restraint information from a fragment library. Here, DFA is represented by the full-atom model by CHARMM with the addition of the empirical potential of DFIRE. The relative contributions between various energy terms are optimized using linear programming. The conformational sampling was carried out with CSA algorithm, which can find low energy conformations more efficiently than simulated annealing used in the existing DFA study. The newly introduced DFA energy function and CSA sampling algorithm are implemented into CHARMM. Test results on 30 small single-domain proteins and 13 template-free modeling targets of the 8th Critical Assessment of protein Structure Prediction show that the current method provides comparable and complementary prediction results to existing top methods. Copyright © 2011 Wiley-Liss, Inc.

Purification of polymorphic components of complex genomes

DOEpatents

Stodolsky, M.

1991-07-16

A method is disclosed for processing related subject and reference macromolecule populations composed of complementary strands into their respective subject and reference populations of representative fragments and effectuating purification of unique polymorphic subject fragments. 1 figure.

Exploring the temperature dependence of failure mechanisms in fragmenting metal cylinders

NASA Astrophysics Data System (ADS)

Jones, David; Chapman, David; Hazell, Paul; Bland, Simon; Eakins, Daniel

2011-06-01

We present current work to investigate the influence of temperature on the dynamic fragmentation of metals. Pre-heated/cooled cylinders of Ti-6Al-4V were subjected to rapid radial expansion up to and past the point of failure using a modified expanding insert method on a single stage gas gun. Additional experiments were performed using an electromagnetic drive system to produce uniform deformations on targets of differing dimensions (radius, wall thickness). Issues concerning the geometry of the experiments, methods of heating and cooling the sample and diagnostics are covered. Finally, the role of temperature on adiabatic shear banding and fragment distribution statistics is discussed.

The Thick Level-Set model for dynamic fragmentation

DOE PAGES

Stershic, Andrew J.; Dolbow, John E.; Moës, Nicolas

2017-01-04

The Thick Level-Set (TLS) model is implemented to simulate brittle media undergoing dynamic fragmentation. This non-local model is discretized by the finite element method with damage represented as a continuous field over the domain. A level-set function defines the extent and severity of damage, and a length scale is introduced to limit the damage gradient. Numerical studies in one dimension demonstrate that the proposed method reproduces the rate-dependent energy dissipation and fragment length observations from analytical, numerical, and experimental approaches. In conclusion, additional studies emphasize the importance of appropriate bulk constitutive models and sufficient spatial resolution of the length scale.

Force Evaluation in the Lattice Boltzmann Method Involving Curved Geometry

NASA Technical Reports Server (NTRS)

Mei, Renwei; Yu, Dazhi; Shyy, Wei; Luo, Li-Shi; Bushnell, Dennis M. (Technical Monitor)

2002-01-01

The present work investigates two approaches for force evaluation in the lattice Boltzmann equation: the momentum- exchange method and the stress-integration method on the surface of a body. The boundary condition for the particle distribution functions on curved geometries is handled with second order accuracy based on our recent works. The stress-integration method is computationally laborious for two-dimensional flows and in general difficult to implement for three-dimensional flows, while the momentum-exchange method is reliable, accurate, and easy to implement for both two-dimensional and three-dimensional flows. Several test cases are selected to evaluate the present methods, including: (i) two-dimensional pressure-driven channel flow; (ii) two-dimensional uniform flow past a column of cylinders; (iii) two-dimensional flow past a cylinder asymmetrically placed in a channel (with vortex shedding); (iv) three-dimensional pressure-driven flow in a circular pipe; and (v) three-dimensional flow past a sphere. The drag evaluated by using the momentum-exchange method agrees well with the exact or other published results.

The fragmented testis method: development and its advantages of a new quantitative evaluation technique for detection of testis-ova in male fish.

PubMed

Lin, Bin-Le; Hagino, Satoshi; Kagoshima, Michio; Iwamatsu, Takashi

2009-02-01

A new quantitative evaluation technique, termed the fragmented testis method, has been developed for the detection of testis-ova in genotypic male fish using the medaka (Oryzias latipes). The routine traditional histological method for detection of testis-ova in male fish exposed to estrogens or suspected endocrine-disrupting chemicals has several disadvantages, including possible oversight of testis-ova due to limited sampling of selected tissue sections. The method we have developed here allows for the accurate determination of the developmental stages and the number and the size of testis-ova in a whole testis. Each testis was removed from the fish specimen, fixed with 10% buffered formalin solution, and then divided into small fragments on a glass slide with a dissecting needle or scalpel and aciform forceps in glycerin solution containing a small amount of methylene blue or toluidine blue. If present, all developing testis-ova of various sizes in fragmented testicular tissues were clearly stained and were observable under a dissecting microscope. Testis-ova occurred in controls were ascertained, while spermatozoa were also distinguishable using this method. This proved to be a convenient and cost-effective method for quantitatively evaluating testis-ova appearance in fish, and it may help to clarify the mechanism of testis-ova formation and the biological significance of testis-ova in future studies of endocrine disruption.

UNDERSTANDING HOW PLANETS BECOME MASSIVE. I. DESCRIPTION AND VALIDATION OF A NEW TOY MODEL

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

Ormel, C. W.; Kobayashi, H., E-mail: ormel@astro.berkeley.edu, E-mail: hkobayas@nagoya-u.ac.jp

2012-03-10

The formation of giant planets requires the accumulation of {approx}10 Earth masses in solids; but how do protoplanets acquire their mass? There are many, often competing, processes that regulate the accretion rate of protoplanets. To assess their effects we present a new, publicly available toy model. The rationale behind the toy model is that it encompasses as many physically relevant processes as possible, but at the same time does not compromise its simplicity, speed, and physical insight. The toy model follows a modular structure, where key features-e.g., planetesimal fragmentation, radial orbital decay, nebula turbulence-can be switched on or off. Ourmore » model assumes three discrete components (fragments, planetesimals, and embryos) and is zero dimensional in space. We have tested the outcomes of the toy model against literature results and generally find satisfactory agreement. We include, for the first time, model features that capture the three-way interactions among small particles, gas, and protoplanets. Collisions among planetesimals will result in fragmentation, transferring a substantial amount of the solid mass to small particles, which couple strongly to the gas. Our results indicate that the efficiency of the accretion process then becomes very sensitive to the gas properties-especially to the turbulent state and the magnitude of the disk headwind (the decrease of the orbital velocity of the gas with respect to Keplerian)-as well as to the characteristic fragment size.« less

Fragment-based Quantum Mechanical/Molecular Mechanical Simulations of Thermodynamic and Kinetic Process of the Ru2+-Ru3+ Self-Exchange Electron Transfer.

PubMed

Zeng, Xiancheng; Hu, Xiangqian; Yang, Weitao

2012-12-11

A fragment-based fractional number of electron (FNE) approach, is developed to study entire electron transfer (ET) processes from the electron donor region to the acceptor region in condensed phase. Both regions are described by the density-fragment interaction (DFI) method while FNE as an efficient ET order parameter is applied to simulate the electron transfer process. In association with the QM/MM energy expression, the DFI-FNE method is demonstrated to describe ET processes robustly with the Ru 2+ -Ru 3+ self-exchange ET as a proof-of-concept example. This method allows for systematic calculations of redox free energies, reorganization energies, and electronic couplings, and the absolute ET rate constants within the Marcus regime.

[Possibility of the species identification using blood stains located on the material evidences and bone fragments with the method of solid phase enzyme immunoassay with "IgG general-EIA-BEST" kit and human immunoglobulin G].

PubMed

Sidorov, V L; Shvetsova, I V; Isakova, I V

2007-01-01

The authors give the comparative analysis of Russian and foreign forensic medical methods of species character identification of the blood from the stains on the material evidences and bone fragments. It is shown that for this purpose it is feasible to apply human immunoglobulin G (IgG) and solid phase enzyme immunoassay (EIA) with the kit "IgG general-EIA-BEST". In comparison with the methods used in Russia this method is more sensitive, convenient for objective registration and computer processing. The results of experiments shown that it is possible to use the kit "IgG general-EIA-BEST" in forensic medicine for the species character identification of the blood from the stains on the material evidences and bone fragments.

Human jagged polypeptide, encoding nucleic acids and methods of use

DOEpatents

Li, Linheng; Hood, Leroy

2000-01-01

The present invention provides an isolated polypeptide exhibiting substantially the same amino acid sequence as JAGGED, or an active fragment thereof, provided that the polypeptide does not have the amino acid sequence of SEQ ID NO:5 or SEQ ID NO:6. The invention further provides an isolated nucleic acid molecule containing a nucleotide sequence encoding substantially the same amino acid sequence as JAGGED, or an active fragment thereof, provided that the nucleotide sequence does not encode the amino acid sequence of SEQ ID NO:5 or SEQ ID NO:6. Also provided herein is a method of inhibiting differentiation of hematopoietic progenitor cells by contacting the progenitor cells with an isolated JAGGED polypeptide, or active fragment thereof. The invention additionally provides a method of diagnosing Alagille Syndrome in an individual. The method consists of detecting an Alagille Syndrome disease-associated mutation linked to a JAGGED locus.

Methods of diagnosing alagille syndrome

DOEpatents

Li, Linheng; Hood, Leroy; Krantz, Ian D.; Spinner, Nancy B.

2004-03-09

The present invention provides an isolated polypeptide exhibiting substantially the same amino acid sequence as JAGGED, or an active fragment thereof, provided that the polypeptide does not have the amino acid sequence of SEQ ID NO:5 or SEQ ID NO:6. The invention further provides an isolated nucleic acid molecule containing a nucleotide sequence encoding substantially the same amino acid sequence as JAGGED, or an active fragment thereof, provided that the nucleotide sequence does not encode the amino acid sequence of SEQ ID NO:5 or SEQ ID NO:6. Also provided herein is a method of inhibiting differentiation of hematopoietic progenitor cells by contacting the progenitor cells with an isolated JAGGED polypeptide, or active fragment thereof. The invention additionally provides a method of diagnosing Alagille Syndrome in an individual. The method consists of detecting an Alagille Syndrome disease-associated mutation linked to a JAGGED locus.

Solution structure of the tandem acyl carrier protein domains from a polyunsaturated fatty acid synthase reveals beads-on-a-string configuration.

PubMed

Trujillo, Uldaeliz; Vázquez-Rosa, Edwin; Oyola-Robles, Delise; Stagg, Loren J; Vassallo, David A; Vega, Irving E; Arold, Stefan T; Baerga-Ortiz, Abel

2013-01-01

The polyunsaturated fatty acid (PUFA) synthases from deep-sea bacteria invariably contain multiple acyl carrier protein (ACP) domains in tandem. This conserved tandem arrangement has been implicated in both amplification of fatty acid production (additive effect) and in structural stabilization of the multidomain protein (synergistic effect). While the more accepted model is one in which domains act independently, recent reports suggest that ACP domains may form higher oligomers. Elucidating the three-dimensional structure of tandem arrangements may therefore give important insights into the functional relevance of these structures, and hence guide bioengineering strategies. In an effort to elucidate the three-dimensional structure of tandem repeats from deep-sea anaerobic bacteria, we have expressed and purified a fragment consisting of five tandem ACP domains from the PUFA synthase from Photobacterium profundum. Analysis of the tandem ACP fragment by analytical gel filtration chromatography showed a retention time suggestive of a multimeric protein. However, small angle X-ray scattering (SAXS) revealed that the multi-ACP fragment is an elongated monomer which does not form a globular unit. Stokes radii calculated from atomic monomeric SAXS models were comparable to those measured by analytical gel filtration chromatography, showing that in the gel filtration experiment, the molecular weight was overestimated due to the elongated protein shape. Thermal denaturation monitored by circular dichroism showed that unfolding of the tandem construct was not cooperative, and that the tandem arrangement did not stabilize the protein. Taken together, these data are consistent with an elongated beads-on-a-string arrangement of the tandem ACP domains in PUFA synthases, and speak against synergistic biocatalytic effects promoted by quaternary structuring. Thus, it is possible to envision bioengineering strategies which simply involve the artificial linking of multiple ACP domains for increasing the yield of fatty acids in bacterial cultures.

Solution Structure of the Tandem Acyl Carrier Protein Domains from a Polyunsaturated Fatty Acid Synthase Reveals Beads-on-a-String Configuration

PubMed Central

Trujillo, Uldaeliz; Vázquez-Rosa, Edwin; Oyola-Robles, Delise; Stagg, Loren J.; Vassallo, David A.; Vega, Irving E.; Arold, Stefan T.; Baerga-Ortiz, Abel

2013-01-01

The polyunsaturated fatty acid (PUFA) synthases from deep-sea bacteria invariably contain multiple acyl carrier protein (ACP) domains in tandem. This conserved tandem arrangement has been implicated in both amplification of fatty acid production (additive effect) and in structural stabilization of the multidomain protein (synergistic effect). While the more accepted model is one in which domains act independently, recent reports suggest that ACP domains may form higher oligomers. Elucidating the three-dimensional structure of tandem arrangements may therefore give important insights into the functional relevance of these structures, and hence guide bioengineering strategies. In an effort to elucidate the three-dimensional structure of tandem repeats from deep-sea anaerobic bacteria, we have expressed and purified a fragment consisting of five tandem ACP domains from the PUFA synthase from Photobacterium profundum. Analysis of the tandem ACP fragment by analytical gel filtration chromatography showed a retention time suggestive of a multimeric protein. However, small angle X-ray scattering (SAXS) revealed that the multi-ACP fragment is an elongated monomer which does not form a globular unit. Stokes radii calculated from atomic monomeric SAXS models were comparable to those measured by analytical gel filtration chromatography, showing that in the gel filtration experiment, the molecular weight was overestimated due to the elongated protein shape. Thermal denaturation monitored by circular dichroism showed that unfolding of the tandem construct was not cooperative, and that the tandem arrangement did not stabilize the protein. Taken together, these data are consistent with an elongated beads-on-a-string arrangement of the tandem ACP domains in PUFA synthases, and speak against synergistic biocatalytic effects promoted by quaternary structuring. Thus, it is possible to envision bioengineering strategies which simply involve the artificial linking of multiple ACP domains for increasing the yield of fatty acids in bacterial cultures. PMID:23469090

A three-dimensional quality-guided phase unwrapping method for MR elastography

NASA Astrophysics Data System (ADS)

Wang, Huifang; Weaver, John B.; Perreard, Irina I.; Doyley, Marvin M.; Paulsen, Keith D.

2011-07-01

Magnetic resonance elastography (MRE) uses accumulated phases that are acquired at multiple, uniformly spaced relative phase offsets, to estimate harmonic motion information. Heavily wrapped phase occurs when the motion is large and unwrapping procedures are necessary to estimate the displacements required by MRE. Two unwrapping methods were developed and compared in this paper. The first method is a sequentially applied approach. The three-dimensional MRE phase image block for each slice was processed by two-dimensional unwrapping followed by a one-dimensional phase unwrapping approach along the phase-offset direction. This unwrapping approach generally works well for low noise data. However, there are still cases where the two-dimensional unwrapping method fails when noise is high. In this case, the baseline of the corrupted regions within an unwrapped image will not be consistent. Instead of separating the two-dimensional and one-dimensional unwrapping in a sequential approach, an interleaved three-dimensional quality-guided unwrapping method was developed to combine both the two-dimensional phase image continuity and one-dimensional harmonic motion information. The quality of one-dimensional harmonic motion unwrapping was used to guide the three-dimensional unwrapping procedures and it resulted in stronger guidance than in the sequential method. In this work, in vivo results generated by the two methods were compared.

Probing peptide fragment ion structures by combining sustained off-resonance collision-induced dissociation and gas-phase H/D exchange (SORI-HDX) in Fourier transform ion-cyclotron resonance (FT-ICR) instruments.

PubMed

Somogyi, Arpád

2008-12-01

The usefulness of gas-phase H/D exchange is demonstrated to probe heterogeneous fragment and parent ion populations. Singly and multiply protonated peptides/proteins were fragmented by using sustained off-resonance irradiation collision-induced dissociation (SORI-CID). The fragments and the surviving precursor ions then all undergo H/D exchange in the gas-phase with either D(2)O or CD(3)OD under the same experimental conditions. Usually, 10 to 60 s of reaction time is adequate to monitor characteristic differences in the H/D exchange kinetic rates. These differences are then correlated to isomeric ion structures. The SORI-HDX method can be used to rapidly test fragment ion structures and provides useful insights into peptide fragmentation mechanisms.

Method development and application of offline two-dimensional liquid chromatography/quadrupole time-of-flight mass spectrometry-fast data directed analysis for comprehensive characterization of the saponins from Xueshuantong Injection.

PubMed

Yang, Wenzhi; Zhang, Jingxian; Yao, Changliang; Qiu, Shi; Chen, Ming; Pan, Huiqin; Shi, Xiaojian; Wu, Wanying; Guo, Dean

2016-09-05

Xueshuantong Injection (XSTI), derived from Notoginseng total saponins, is a popular traditional Chinese medicine injection for the treatment of thrombus-resultant diseases. Current knowledge on its therapeutic basis is limited to five major saponins, whereas those minor ones are rarely investigated. We herein develop an offline two-dimensional liquid chromatography/quadrupole time-of-flight mass spectrometry-fast data directed analysis (offline 2D LC/QTOF-Fast DDA) approach to systematically characterize the saponins contained in XSTI. Key parameters affecting chromatographic separation in 2D LC (including stationary phase, mobile phase, column temperature, and gradient elution program) and the detection by QTOF MS (involving spray voltage, cone voltage, and ramp collision energy) were optimized in sequence. The configured offline 2D LC system showed an orthogonality of 0.84 and a theoretical peak capacity of 8976. Total saponins in XSTI were fractionated into eleven samples by the first-dimensional hydrophilic interaction chromatography, which were further analyzed by reversed-phase UHPLC/QTOF-Fast DDA in negative ion mode. The fragmentation features evidenced from 36 saponin reference standards, high-accuracy MS and Fast-DDA-MS(2) data, elemental composition (C<80, H<120, O<50), double-bond equivalent (DBE 5-15), and searching an in-house library of Panax notoginseng, were simultaneously utilized for structural elucidation. Ultimately, 148 saponins were separated and characterized, and 80 have not been isolated from P. notoginseng. An in-depth depiction of the chemical composition of XSTI was achieved. The results obtained would benefit better understanding of the therapeutic basis and significant promotion on the quality standard of XSTI as well as other homologous products. Copyright © 2016. Published by Elsevier B.V.

A new assay based on terminal restriction fragment length polymorphism of homocitrate synthase gene fragments for Candida species identification.

PubMed

Szemiako, Kasjan; Śledzińska, Anna; Krawczyk, Beata

2017-08-01

Candida sp. have been responsible for an increasing number of infections, especially in patients with immunodeficiency. Species-specific differentiation of Candida sp. is difficult in routine diagnosis. This identification can have a highly significant association in therapy and prophylaxis. This work has shown a new application of the terminal restriction fragment length polymorphism (t-RFLP) method in the molecular identification of six species of Candida, which are the most common causes of fungal infections. Specific for fungi homocitrate synthase gene was chosen as a molecular target for amplification. The use of three restriction enzymes, DraI, RsaI, and BglII, for amplicon digestion can generate species-specific fluorescence labeled DNA fragment profiles, which can be used to determine the diagnostic algorithm. The designed method can be a cost-efficient high-throughput molecular technique for the identification of six clinically important Candida species.

Multiplex analysis of DNA

DOEpatents

Church, George M.; Kieffer-Higgins, Stephen

1992-01-01

This invention features vectors and a method for sequencing DNA. The method includes the steps of: a) ligating the DNA into a vector comprising a tag sequence, the tag sequence includes at least 15 bases, wherein the tag sequence will not hybridize to the DNA under stringent hybridization conditions and is unique in the vector, to form a hybrid vector, b) treating the hybrid vector in a plurality of vessels to produce fragments comprising the tag sequence, wherein the fragments differ in length and terminate at a fixed known base or bases, wherein the fixed known base or bases differs in each vessel, c) separating the fragments from each vessel according to their size, d) hybridizing the fragments with an oligonucleotide able to hybridize specifically with the tag sequence, and e) detecting the pattern of hybridization of the tag sequence, wherein the pattern reflects the nucleotide sequence of the DNA.

The role of fragment-based and computational methods in polypharmacology.

PubMed

Bottegoni, Giovanni; Favia, Angelo D; Recanatini, Maurizio; Cavalli, Andrea

2012-01-01

Polypharmacology-based strategies are gaining increased attention as a novel approach to obtaining potentially innovative medicines for multifactorial diseases. However, some within the pharmaceutical community have resisted these strategies because they can be resource-hungry in the early stages of the drug discovery process. Here, we report on fragment-based and computational methods that might accelerate and optimize the discovery of multitarget drugs. In particular, we illustrate that fragment-based approaches can be particularly suited for polypharmacology, owing to the inherent promiscuous nature of fragments. In parallel, we explain how computer-assisted protocols can provide invaluable insights into how to unveil compounds theoretically able to bind to more than one protein. Furthermore, several pragmatic aspects related to the use of these approaches are covered, thus offering the reader practical insights on multitarget-oriented drug discovery projects. Copyright © 2011 Elsevier Ltd. All rights reserved.

Fast conversion of scFv to Fab antibodies using type IIs restriction enzymes.

PubMed

Sanmark, Hanna; Huovinen, Tuomas; Matikka, Tero; Pettersson, Tiina; Lahti, Maria; Lamminmäki, Urpo

2015-11-01

Single chain variable fragment (scFv) antibody libraries are widely used for developing novel bioaffinity reagents, although Fab or IgG molecules are the preferred antibody formats in many final applications. Therefore, rapid conversion methods for combining multiple DNA fragments are needed to attach constant domains to the scFv derived variable domains. In this study we describe a fast and easy cloning method for the conversion of single framework scFv fragments to Fab fragments using type IIS restriction enzymes. All cloning steps excluding plating of the Fab transformants can be done in 96 well plates and the procedure can be completed in one working day. The concept was tested by converting 69 scFv clones into Fab format on 96 well plates, which resulted in 93% success rate. The method is particularly useful as a high-throughput tool for the conversion of the chosen scFv clones into Fab molecules in order to analyze them as early as possible, as the conversion can significantly affect the binding properties of the chosen clones. Copyright © 2015 Elsevier B.V. All rights reserved.

Identification and Quantification of Alkaloid in KHR98 and Fragmentation Pathways in HPLC-Q-TOF-MS.

PubMed

Long, Jiakun; Wang, Yang; Xu, Chen; Liu, Tingting; Duan, Gengli; Yu, Yingjia

2018-05-01

Uncaria rhynchophylla is woody climber plant distributed mainly in China and Japan, the stems and hooks of which can be collected as "Gou-Teng" for the treatment of hyperpyrexia, epilepsy and preeclampsia. Fudan University first manufactured KHR98, the extract of Uncaria rhynchophylla. In order to study the active components and structural information of KHR98, we established a HPLC coupled with quadrupole time-of-flight (Q-TOF)-MS method for rapid analysis of alkaloids. In qualitative analysis, a total of eight compounds, including four known alkaloids and four unknown components, were detected and identified. The fragmentation behaviors, such as the fragment ion information and the fragmentation pathways of the eight components were summarized simultaneously, and the concentration of the above components was determined by HPLC-MS method. The quantitative method was proved to be reproducible, precise and accurate. This study shed light on the standardization and quality control of the KHR98 and provided a foundation for the further research on pharmacology, follow-up clinical research and New Drug Applications.

An electro-active system of immuno-assay (EASI assay) utilising self assembled monolayer modified electrodes.

PubMed

Porter, R; van der Logt, P; Howell, S; Kyröläinen-Reay, M; Badley, A

2001-12-01

Most immunoassays currently rely on optical methods for signal generation e.g. in ELISA and rapid assay formats. It has become apparent as in the Glucose sensor market that there is a need for simple direct electrical immuno-sensors. We have investigated the novel use of organic conducting monolayers used as a direct electrochemical detection support for an immuno-reaction. It was found that antibodies raised to a carbazole dimer monolayer could increase the charge movement across that monolayer surface. Antibody fragments were taken from a specific anti-carbazole antibody fragment library and combined with an antibody fragment directed to the hormone estrone 3 glucuronide (E3G), the target antigen to form a bispecific antibody fragment. The device utilised these specific antibody fragments and incorporated them on the top plate of a capillary fill format as the immuno-assay components. The immuno-reaction utilised a competition assay. Free E3G analyte in the sample displaced the bispecific antibody fragment from the immuno-surface leaving it free to bind the carbazole monolayer surface. There the binding was detected using amperometric or coulometric methods. By combining all there element it was possible to develop a sensitive immuno-assay that could detect E3G in a reproducible calibrated fashion down to 10 ng/ml.

Theoretical Modeling of Hydrogen Bonding in omolecular Solutions: The Combination of Quantum Mechanics and Molecular Mechanics

NASA Astrophysics Data System (ADS)

Ma, Jing; Jiang, Nan; Li, Hui

Hydrogen bonding interaction takes an important position in solutions. The non-classic nature of hydrogen bonding requires the resource-demanding quantum mechanical (QM) calculations. The molecular mechanics (MM) method, with much lower computational load, is applicable to the large-sized system. The combination of QM and MM is an efficient way in the treatment of solution. Taking advantage of the low-cost energy-based fragmentation QM approach (in which the o-molecule is divided into several subsystems, and QM calculation is carried out on each subsystem that is embedded in the environment of background charges of distant parts), the fragmentation-based QM/MM and polarization models have been implemented for the modeling of o-molecule in aqueous solutions, respectively. Within the framework of the fragmentation-based QM/MM hybrid model, the solute is treated by the fragmentation QM calculation while the numerous solvent molecules are described by MM. In the polarization model, the polarizability is considered by allowing the partial charges and fragment-centered dipole moments to be variables, with values coming from the energy-based fragmentation QM calculations. Applications of these two methods to the solvated long oligomers and cyclic peptides have demonstrated that the hydrogen bonding interaction affects the dynamic change in chain conformations of backbone.

Hypothesis-driven and field-validated method to prioritize fragmentation mitigation efforts in road projects.

PubMed

Vanthomme, Hadrien; Kolowski, Joseph; Nzamba, Brave S; Alonso, Alfonso

2015-10-01

The active field of connectivity conservation has provided numerous methods to identify wildlife corridors with the aim of reducing the ecological effect of fragmentation. Nevertheless, these methods often rely on untested hypotheses of animal movements, usually fail to generate fine-scale predictions of road crossing sites, and do not allow managers to prioritize crossing sites for implementing road fragmentation mitigation measures. We propose a new method that addresses these limitations. We illustrate this method with data from southwestern Gabon (central Africa). We used stratified random transect surveys conducted in two seasons to model the distribution of African forest elephant (Loxodonta cyclotis), forest buffalo (Syncerus caffer nanus), and sitatunga (Tragelaphus spekii) in a mosaic landscape along a 38.5 km unpaved road scheduled for paving. Using a validation data set of recorded crossing locations, we evaluated the performance of three types of models (local suitability, local least-cost movement, and regional least-cost movement) in predicting actual road crossings for each species, and developed a unique and flexible scoring method for prioritizing road sections for the implementation of road fragmentation mitigation measures. With a data set collected in <10 weeks of fieldwork, the method was able to identify seasonal changes in animal movements for buffalo and sitatunga that shift from a local exploitation of the site in the wet season to movements through the study site in the dry season, whereas elephants use the entire study area in both seasons. These three species highlighted the need to use species- and season-specific modeling of movement. From these movement models, the method ranked road sections for their suitability for implementing fragmentation mitigation efforts, allowing managers to adjust priority thresholds based on budgets and management goals. The method relies on data that can be obtained in a period compatible with environmental impact assessment constraints, and is flexible enough to incorporate other potential movement models and scoring criteria. This approach improves upon available methods and can help inform prioritization of road and other linear infrastructure segments that require impact mitigation methods to ensure long-term landscape connectivity.