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Sample records for linker substructure common

  1. Towards optimization of the linker substructure common to transthyretin amyloidogenesis inhibitors using biochemical and structural studies

    PubMed Central

    Johnson, Steven M.; Connelly, Stephen; Wilson, Ian A.; Kelly, Jeffery W.

    2008-01-01

    To develop potent and highly selective transthyretin (TTR) amyloidogenesis inhibitors, it is useful to systematically optimize the three substructural elements that compose a typical TTR kinetic stabilizer: the two aryl rings and the linker joining them. Herein, we evaluated 40 bisaryl molecules based on 10 unique linker substructures to determine how these linkages influence inhibitor potency and selectivity. These linkers connect one unsubstituted aromatic ring to either a 3,5-X2 or a 3,5-X2-4-OH phenyl substructure (X=Br or CH3). Co-consideration of amyloid inhibition and ex vivo plasma TTR binding selectivity data reveal that direct connection of the two aryls, or linkage through non-polar E-olefin or –CH2CH2– substructures generates the most potent and selective TTR amyloidogenesis inhibitors exhibiting minimal undesirable binding to the thyroid hormone nuclear receptor or the COX-1 enzyme. Five high-resolution TTR•inhibitor crystal structures (1.4−1.8 Å) provide insight into why such linkers afford inhibitors with greater potency and selectivity. PMID:18811132

  2. Common substructure in otoacoustic emission spectra of land vertebrates

    NASA Astrophysics Data System (ADS)

    Manley, Geoffrey A.; Köppl, Christine; Bergevin, Christopher

    2015-12-01

    In humans, a similar spectral periodicity is found in all otoacoustic emission types and in threshold fine structure. This may reflect travelling wave phase and reflectance from "structural roughness" in the organ of Corti, or entrainment and suppressive interactions between emissions. To further understand these phenomena, we have examined spontaneous otoacoustic emission (SOAE) spectra in 9 lizard species and the barn owl and find a comparable periodicity. Importantly, the frequency spacing between SOAE peaks was independent of the physical spacing and of the frequency space constants in hearing organs. In 9 lizard species, median spectral gaps lay between 219 and 461 Hz, with no correlation to papillar length (0.3 to 2.1 mm). Similarly in much longer organs: In humans (35 mm), SOAE spectral gaps vary up to 220 Hz at 4 kHz; in the barn owl (11 mm), the median SOAE peak spacing was 395Hz. In the barn owl, a very large space constant between 5 and 10 kHz (5 mm/octave) contrasts with stable SOAE spacing between 1 and 11 kHz. Similar SOAE spectral gaps across all species suggests they represent a basic frequency grating revealing local phase-dependent interactions between active hair cells, a feature not determined by macro-structural anatomy. Emission spectral spacing is independent of cochlear length, of the frequency space constant, of the existence of travelling waves or of a tectorial membrane. Our data suggest that there are greater similarities between frequency selectivity reflected at the level of the hair cells' spontaneous mechanical output (OAEs) than there are at the level of the auditory nerve, where macro-structural anatomy links hair-cell activity differentially to the neural output. Apparently, all hair-cell arrays show a similar frequency substructure not directly replicated in neural tuning.

  3. Toward Optimization of the Second Aryl Substructure Common to Transthyretin Amyloidogenesis Inhibitors Using Biochemical and Structural Studies

    PubMed Central

    Johnson, Steven M.; Connelly, Stephen; Wilson, Ian A.; Kelly, Jeffery W.

    2009-01-01

    Transthyretin (TTR) amyloidogenesis inhibitors are typically composed of two aromatic rings and a linker. We have previously established optimal structures for one aromatic ring and the linker. Herein, we employ a suboptimal linker and an optimal aryl-X substructure to rank order the desirability of aryl-Z substructures–using a library of 56 N-(3,5-dibromo-4-hydroxyphenyl)benzamides. Co-consideration of amyloid inhibition potency and ex-vivo plasma TTR binding selectivity data reveal that 2,6; 2,5; 2; 3,4,5 and 3,5 aryls bearing small substituents generate the most potent and selective inhibitors, in descending order. These benzamides generally lack undesirable thyroid hormone receptor binding and COX-1 inhibition activity. Three high-resolution TTR•inhibitor crystal structures (1.31-1.35 Å) provide insight into why these inhibitors are potent and selective, enabling future structure-based design of TTR kinetic stabilizers. PMID:19191553

  4. Representing clusters using a maximum common edge substructure algorithm applied to reduced graphs and molecular graphs.

    PubMed

    Gardiner, Eleanor J; Gillet, Valerie J; Willett, Peter; Cosgrove, David A

    2007-01-01

    Chemical databases are routinely clustered, with the aim of grouping molecules which share similar structural features. Ideally, medicinal chemists are then able to browse a few representatives of the cluster in order to interpret the shared activity of the cluster members. However, when molecules are clustered using fingerprints, it may be difficult to decipher the structural commonalities which are present. Here, we seek to represent a cluster by means of a maximum common substructure based on the shared functionality of the cluster members. Previously, we have used reduced graphs, where each node corresponds to a generalized functional group, as topological molecular descriptors for virtual screening. In this work, we precluster a database using any clustering method. We then represent the molecules in a cluster as reduced graphs. By repeated application of a maximum common edge substructure (MCES) algorithm, we obtain one or more reduced graph cluster representatives. The sparsity of the reduced graphs means that the MCES calculations can be performed in real time. The reduced graph cluster representatives are readily interpretable in terms of functional activity and can be mapped directly back to the molecules to which they correspond, giving the chemist a rapid means of assessing potential activities contained within the cluster. Clusters of interest are then subject to a detailed R-group analysis using the same iterated MCES algorithm applied to the molecular graphs. PMID:17309248

  5. CLCA: maximum common molecular substructure queries within the MetRxn database.

    PubMed

    Kumar, Akhil; Maranas, Costas D

    2014-12-22

    The challenge of automatically identifying the preserved molecular moieties in a chemical reaction is referred to as the atom mapping problem. Reaction atom maps provide the ability to locate the fate of individual atoms across an entire metabolic network. Atom maps are used to track atoms in isotope labeling experiments for metabolic flux elucidation, trace novel biosynthetic routes to a target compound, and contrast entire pathways for structural homology. However, rapid computation of the reaction atom mappings remains elusive despite significant research. We present a novel substructure search algorithm, canonical labeling for clique approximation (CLCA), with polynomial run-time complexity to quickly generate atom maps for all the reactions present in MetRxn. CLCA uses number theory (i.e., prime factorization) to generate canonical labels or unique IDs and identify a bijection between the vertices (atoms) of two distinct molecular graphs. CLCA utilizes molecular graphs generated by combining atomistic information on reactions and metabolites from 112 metabolic models and 8 metabolic databases. CLCA offers improvements in run time, accuracy, and memory utilization over existing heuristic and combinatorial maximum common substructure (MCS) search algorithms. We provide detailed examples on the various advantages as well as failure modes of CLCA over existing algorithms. PMID:25412255

  6. O-xylosylation in a recombinant protein is directed at a common motif on glycine-serine linkers.

    PubMed

    Spencer, David; Novarra, Shabazz; Zhu, Liang; Mugabe, Sheila; Thisted, Thomas; Baca, Manuel; Depaz, Roberto; Barton, Christopher

    2013-11-01

    Glycine-serine (GS) linkers are commonly used in recombinant proteins to connect domains. Here, we report the posttranslational O-glycosylation of a GS linker in a novel fusion protein. The structure of the O-glycan moiety is a xylose-based core substituted with hexose and sulfated hexauronic acid residues. The total level of O-xylosylation was approximately 30% in the material expressed in HEK-293 cell lines. There was an approximate 10-fold reduction in O-xylosylation levels when the material was expressed in Chinese hamster ovary cell lines. Similar O-glycan structures have been reported for human urinary thrombomodulin and represent the initial building block for proteoglycans such as chondroitin sulfate and heparin. The sites of attachment, determined by electron transfer dissociation mass spectrometry, were localized to serine in the linker regions of the recombinant fusion protein. This attachment could be attributed, in part, to the inherent xylosyltransferase motif present in GS linkers. Elimination of the O-glycan moiety was achieved with modified linkers containing only glycine residues. The aggregation and fragmentation behavior of the GGG construct were comparable to the GSG-linked material during thermal stress. The O-xylosylation reported has implications for the manufacturing consistency of recombinant proteins containing GS linkers. PMID:24105735

  7. A relational extension of the notion of motifs: application to the common 3D protein substructures searching problem.

    PubMed

    Pisanti, Nadia; Soldano, Henry; Carpentier, Mathilde; Pothier, Joel

    2009-12-01

    The geometrical configurations of atoms in protein structures can be viewed as approximate relations among them. Then, finding similar common substructures within a set of protein structures belongs to a new class of problems that generalizes that of finding repeated motifs. The novelty lies in the addition of constraints on the motifs in terms of relations that must hold between pairs of positions of the motifs. We will hence denote them as relational motifs. For this class of problems, we present an algorithm that is a suitable extension of the KMR paradigm and, in particular, of the KMRC as it uses a degenerate alphabet. Our algorithm contains several improvements that become especially useful when-as it is required for relational motifs-the inference is made by partially overlapping shorter motifs, rather than concatenating them. The efficiency, correctness and completeness of the algorithm is ensured by several non-trivial properties that are proven in this paper. The algorithm has been applied in the important field of protein common 3D substructure searching. The methods implemented have been tested on several examples of protein families such as serine proteases, globins and cytochromes P450 additionally. The detected motifs have been compared to those found by multiple structural alignments methods. PMID:20047489

  8. Automated design of flexible linkers.

    PubMed

    Manion, Charles; Arlitt, Ryan; Campbell, Matthew I; Tumer, Irem; Stone, Rob; Greaney, P Alex

    2016-03-14

    This paper presents a method for the systematic and automated design of flexible organic linkers for construction of metal organic-frameworks (MOFs) in which flexibility, compliance, or other mechanically exotic properties originate at the linker level rather than from the framework kinematics. Our method couples a graph grammar method for systematically generating linker like molecules with molecular dynamics modeling of linkers' mechanical response. Using this approach we have generated a candidate pool of >59,000 hypothetical linkers. We screen linker candidates according to their mechanical behaviors under large deformation, and extract fragments common to the most performant candidate materials. To demonstrate the general approach to MOF design we apply our system to designing linkers for pressure switching MOFs-MOFs that undergo reversible structural collapse after a stress threshold is exceeded. PMID:26687337

  9. Antibodies directed to drug epitopes to investigate the structure of drug-protein photoadducts. Recognition of a common photobound substructure in tiaprofenic acid/ketoprofen cross-photoreactivity.

    PubMed

    Lahoz, A; Hernández, D; Miranda, M A; Pérez-Prieto, J; Morera, I M; Castell, J V

    2001-11-01

    Drug-induced photoallergy is an immune adverse reaction to the combined effect of drugs and light. From the mechanistic point of view, it first involves covalent binding of drug to protein resulting in the formation of a photoantigen. Hence, determination of the structures of drug-protein photoadducts is of great relevance to understand the molecular basis of photoallergy and cross-immunoreactivity among drugs. Looking for new strategies to investigate the covalent photobinding of drugs to proteins, we generated highly specific antibodies to drug chemical substructures. The availability of such antibodies has allowed us to discriminate between the different modes by which tiaprofenic acid (TPA), suprofen (SUP), and ketoprofen (KTP) photobind to proteins. The finding that the vast majority of the TPA photoadduct can be accounted for by means of antibody anti-benzoyl strongly supports the view that the drug binds preferentially via the thiophene ring, leaving the benzene ring more accessible. By contrast, selective recognition of SUP-protein photoadducts by antibody anti-thenoyl evidences a preferential coupling via the benzene ring leaving the thiophene moiety more distant from the protein matrix. In the case of KTP, photoadducts are exclusively recognized by antibody anti-benzoyl, indicating that the benzene ring is again more accessible. As a result of this research, we have been able to identify a common substructure that is present in TPA-albumin and KTP-albumin photoadducts. This is remarkable since, at a first sight, the greatest structural similarities can be found between TPA and SUP as they share the same benzoylthiophene chromophore. These findings can explain the previously reported observations of cross-reactivity to KTP (or TPA) in patients photosensitized to TPA (or KTP). PMID:11712905

  10. Substructural controller synthesis

    NASA Technical Reports Server (NTRS)

    Su, Tzu-Jeng; Craig, Roy R., Jr.

    1989-01-01

    A decentralized design procedure which combines substructural synthesis, model reduction, decentralized controller design, subcontroller synthesis, and controller reduction is proposed for the control design of flexible structures. The structure to be controlled is decomposed into several substructures, which are modeled by component mode synthesis methods. For each substructure, a subcontroller is designed by using the linear quadratic optimal control theory. Then, a controller synthesis scheme called Substructural Controller Synthesis (SCS) is used to assemble the subcontrollers into a system controller, which is to be used to control the whole structure.

  11. Jet Substructure Without Trees

    SciTech Connect

    Jankowiak, Martin; Larkoski, Andrew J.; /SLAC /Stanford U., ITP

    2011-08-19

    We present an alternative approach to identifying and characterizing jet substructure. An angular correlation function is introduced that can be used to extract angular and mass scales within a jet without reference to a clustering algorithm. This procedure gives rise to a number of useful jet observables. As an application, we construct a top quark tagging algorithm that is competitive with existing methods. In preparation for the LHC, the past several years have seen extensive work on various aspects of collider searches. With the excellent resolution of the ATLAS and CMS detectors as a catalyst, one area that has undergone significant development is jet substructure physics. The use of jet substructure techniques, which probe the fine-grained details of how energy is distributed in jets, has two broad goals. First, measuring more than just the bulk properties of jets allows for additional probes of QCD. For example, jet substructure measurements can be compared against precision perturbative QCD calculations or used to tune Monte Carlo event generators. Second, jet substructure allows for additional handles in event discrimination. These handles could play an important role at the LHC in discriminating between signal and background events in a wide variety of particle searches. For example, Monte Carlo studies indicate that jet substructure techniques allow for efficient reconstruction of boosted heavy objects such as the W{sup {+-}} and Z{sup 0} gauge bosons, the top quark, and the Higgs boson.

  12. Substructure system identification and synthesis

    NASA Technical Reports Server (NTRS)

    Su, Tzu-Jeng; Juang, Jer-Nan

    1993-01-01

    This paper explores the possibility of performing system identification at the substructure level and then synthesizing the results to obtain a mathematical model for the assembled structure. The study here shows that in order to enforce interface compatibility and equilibrium conditions to the substructure test data, it is necessary to place collocated actuator/sensor pair at every interface degree-of-freedom. Procedures for assembling substructure transfer function data, substructure state-space models, and substructure Markov parameters are presented. Testing difficulties and possible solutions are also discussed. A numerical simulation example is included to illustrate the proposed substructure synthesis methods.

  13. Chapter 6: Energy Storage in Cellulase Linker Peptides?

    SciTech Connect

    McCabe, C.; Zhao, X.; Adney, W. S.; Himmel, M. E.

    2010-01-01

    In this chapter, we discuss the use of molecular dynamics simulations and free-energy calculations to investigate the possible role the linker polypeptide, common to many cellulase enzymes, plays in the enzymatic hydrolysis of cellulose. In particular, we focus on the linker polypeptide from cellobiohydrolase I (CBH I) from Trichoderma reesei, which is one of the most active cellulase enzymes. CBH I is a multi-domain enzyme, consisting of a large catalytic domain containing an active site tunnel and a small cellulose binding module, which are joined together by a 27-amino-acid residue linker peptide. CBH I is believed to hydrolyze cellulose in a 'processive' manner; however, the exact mechanism of the depolymerization of cellulose by CBH I is not fully understood. It has been hypothesized that the flexible interdomain linker mediates a caterpillar-like motion that enables the enzyme to move along the cellodextrin strand. Although the linker polypeptide sequence is known, the spatial conformation adopted by the linker domain and its role in the hydrolysis process, if any, has yet to be determined. The simulation results obtained to date indicate that the CBH I linker's free energy is critically dependent on the existence of the cellulose substrate and the stretching/compression pathway adopted. In the presence of a cellulose surface, simulations suggest that the linker exhibits two stable states, which would support the hypothesis that the linker peptide has the capacity to store energy in a manner similar to a spring and facilitate a caterpillar-like motion.

  14. Rigid substructure search

    PubMed Central

    Shirvanyants, David; Alexandrova, Anastassia N.; Dokholyan, Nikolay V.

    2011-01-01

    Motivation: Identifying the location of binding sites on proteins is of fundamental importance for a wide range of applications, including molecular docking, de novo drug design, structure identification and comparison of functional sites. Here we present Erebus, a web server that searches the entire Protein Data Bank for a given substructure defined by a set of atoms of interest, such as the binding scaffolds for small molecules. The identified substructure contains atoms having the same names, belonging to same amino acids and separated by the same distances (within a given tolerance) as the atoms of the query structure. The accuracy of a match is measured by the root-mean-square deviation or by the normal weight with a given variance. Tests show that our approach can reliably locate rigid binding scaffolds of drugs and metal ions. Availability and Implementation: We provide this service through a web server at http://erebus.dokhlab.org. Contact: dokh@unc.edu PMID:21460026

  15. Transients by substructuring with DMAP

    NASA Technical Reports Server (NTRS)

    Butler, T. G.

    1978-01-01

    Automated substructuring in level 16 of NASTRAN was employed as a preface to the solution of a direct transient analysis. The DMAP ALTER statements written to adapt the substructuring for transient purposes are explained. Data recovery was accomplished with transfer functions. Proof of the success of the method is presented with an application to a missile structure.

  16. Design and characterization of structured protein linkers with differing flexibilities

    PubMed Central

    Klein, Joshua S.; Jiang, Siduo; Galimidi, Rachel P.; Keeffe, Jennifer R.; Bjorkman, Pamela J.

    2014-01-01

    Engineered fusion proteins containing two or more functional polypeptides joined by a peptide or protein linker are important for many fields of biological research. The separation distance between functional units can impact epitope access and the ability to bind with avidity; thus the availability of a variety of linkers with different lengths and degrees of rigidity would be valuable for protein design efforts. Here, we report a series of designed structured protein linkers incorporating naturally occurring protein domains and compare their properties to commonly used Gly4Ser repeat linkers. When incorporated into the hinge region of an immunoglobulin G (IgG) molecule, flexible Gly4Ser repeats did not result in detectable extensions of the IgG antigen-binding domains, in contrast to linkers including more rigid domains such as β2-microglobulin, Zn-α2-glycoprotein and tetratricopeptide repeats. This study adds an additional set of linkers with varying lengths and rigidities to the available linker repertoire, which may be useful for the construction of antibodies with enhanced binding properties or other fusion proteins. PMID:25301959

  17. Proposed definition of crystal substructure and substructural similarity

    NASA Astrophysics Data System (ADS)

    Yang, Lusann; Dacek, Stephen; Ceder, Gerbrand

    2014-08-01

    There is a clear need for a practical and mathematically rigorous description of local structure in inorganic compounds so that structures and chemistries can be easily compared across large data sets. Here a method for decomposing crystal structures into substructures is given, and a similarity function between those substructures is defined. The similarity function is based on both geometric and chemical similarity. This construction allows for large-scale data mining of substructural properties, and the analysis of substructures and void spaces within crystal structures. The method is validated via the prediction of Li-ion intercalation sites for the oxides. Tested on databases of known Li-ion-containing oxides, the method reproduces all Li-ion sites in an oxide with a maximum of 4 incorrect guesses 80% of the time.

  18. Surviving gas expulsion with substructure

    NASA Astrophysics Data System (ADS)

    Lee, Paweł L.; Goodwin, Simon P.

    2016-08-01

    We investigate the reaction of clumpy stellar distributions to gas expulsion. We show that regions containing highly unbound substructures/subclusters after gas expulsion can produce a significant final bound cluster. The key quantity in determining if a region is able to form a bound cluster is the global virial ratio, and so regions must be looked at as a whole rather than by an individual substructure/subclusters, when determining if they might survive as a bound cluster.

  19. Cellulase Linkers Are Optimized Based on Domain Type and Function: Insights from Sequence Analysis, Biophysical Measurements, and Molecular Simulation

    PubMed Central

    Sammond, Deanne W.; Payne, Christina M.; Brunecky, Roman; Himmel, Michael E.; Crowley, Michael F.; Beckham, Gregg T.

    2012-01-01

    Cellulase enzymes deconstruct cellulose to glucose, and are often comprised of glycosylated linkers connecting glycoside hydrolases (GHs) to carbohydrate-binding modules (CBMs). Although linker modifications can alter cellulase activity, the functional role of linkers beyond domain connectivity remains unknown. Here we investigate cellulase linkers connecting GH Family 6 or 7 catalytic domains to Family 1 or 2 CBMs, from both bacterial and eukaryotic cellulases to identify conserved characteristics potentially related to function. Sequence analysis suggests that the linker lengths between structured domains are optimized based on the GH domain and CBM type, such that linker length may be important for activity. Longer linkers are observed in eukaryotic GH Family 6 cellulases compared to GH Family 7 cellulases. Bacterial GH Family 6 cellulases are found with structured domains in either N to C terminal order, and similar linker lengths suggest there is no effect of domain order on length. O-glycosylation is uniformly distributed across linkers, suggesting that glycans are required along entire linker lengths for proteolysis protection and, as suggested by simulation, for extension. Sequence comparisons show that proline content for bacterial linkers is more than double that observed in eukaryotic linkers, but with fewer putative O-glycan sites, suggesting alternative methods for extension. Conversely, near linker termini where linkers connect to structured domains, O-glycosylation sites are observed less frequently, whereas glycines are more prevalent, suggesting the need for flexibility to achieve proper domain orientations. Putative N-glycosylation sites are quite rare in cellulase linkers, while an N-P motif, which strongly disfavors the attachment of N-glycans, is commonly observed. These results suggest that linkers exhibit features that are likely tailored for optimal function, despite possessing low sequence identity. This study suggests that cellulase

  20. Fatigue of fiberglass beam substructures

    SciTech Connect

    Mandell, J.F.; Combs, D.W.; Samborsky, D.D.

    1995-09-01

    Composite material beams representative of wind turbine blade substructure have been designed, fabricated, and tested under constant amplitude flexural fatigue loading. Beam stiffness, strength, and fatigue life are predicted based on detailed finite element analysis and the materials fatigue database developed using standard test coupons and special high frequency minicoupons.Beam results are in good agreement with predictions when premature adhesive and delamination failures are avoided in the load transfer areas. The results show that fiberglass substructures can be designed and fabricated to withstand maximum strain levels on the order of 8,000 microstrain for about 10{sup 6} cycles with proper structural detail design and the use of fatigue resistant laminate constructions. The study also demonstrates that the materials fatigue database and accurate analysis can be used to predict the fatigue life of composite substructures typical of blades.

  1. Substructure Search by Set Reduction

    ERIC Educational Resources Information Center

    Figueras, John

    1972-01-01

    The set reduction algorithm is based on set theory and Boolean algebra rather than the graph-theoretic approach. Time trials with a small file of organic chemical structures indicate that the algorithm can be economically used for substructure (or complete structure) sequential searches on a file containing 30,000-50,000 computer-coded structures.…

  2. Dynamic substructuring for shock spectrum analysis using component mode synthesis

    NASA Technical Reports Server (NTRS)

    Mcpheeters, Barton W.; Lev, Avivi; Bogert, Philip B.; Scavuzzo, Rudolph J.

    1988-01-01

    Component mode synthesis was used to analyze different types of structures with MSC NASTRAN. The theory and technique of using Multipoint Constraint Equations (MPCs) to connect substructures to each other or to a common foundation is presented. Computation of the dynamic response of the system from shack spectrum inputs was automated using the DMAP programming language of the MSC NASTRAN finite element code.

  3. A traceless photocleavable linker for the automated glycan assembly of carbohydrates with free reducing ends.

    PubMed

    Wilsdorf, M; Schmidt, D; Bartetzko, M P; Dallabernardina, P; Schuhmacher, F; Seeberger, P H; Pfrengle, F

    2016-08-01

    We report a traceless photocleavable linker for the automated glycan assembly of carbohydrates with free reducing ends. The reductive-labile functionality in the linker tolerates all commonly used reagents and protocols for automated glycan assembly, as demonstrated with the successful preparation of nine plant cell wall-related oligosaccharides, and is cleaved by hydrogenolysis. PMID:27463261

  4. Gene structure and molecular phylogeny of the linker chains from the giant annelid hexagonal bilayer hemoglobins.

    PubMed

    Chabasse, Christine; Bailly, Xavier; Sanchez, Sophie; Rousselot, Morgane; Zal, Franck

    2006-09-01

    Giant extracellular hexagonal bilayer hemoglobin (HBL-Hb), found only in annelids, is an approximately 3500-kDa heteropolymeric structure involved in oxygen transport. The HBL-Hbs are comprised of globin and linker chains, the latter being required for the assembly of the quaternary structure. The linker chains, varying in size from 225 to 283 amino acids, have a conserved cysteine-rich domain within their N-terminal moiety that is homologous to the cysteine-rich modules constituting the ligand binding domain of the low-density lipoprotein receptor (LDLR) protein family found in many metazoans. We have investigated the gene structure of linkers from Arenicola marina, Alvinella pompejana, Nereis diversicolor, Lumbricus terrestris, and Riftia pachyptila. We found, contrary to the results obtained earlier with linker genes from N. diversicolor and L. terrestris, that in all of the foregoing cases, the linker LDL-A module is flanked by two phase 1 introns, as in the human LDLR gene, with two more introns in the 3' side whose positions varied with the species. In addition, we obtained 13 linker cDNAs that have been determined experimentally or found in the EST database LumbriBASE. A molecular phylogenetic analysis of the linker primary sequences demonstrated that they cluster into two distinct families of linker proteins. We propose that the common gene ancestor to annelid linker genes exhibited a four-intron and five-exon structure and gave rise to the two families subsequent to a duplication event. PMID:16838215

  5. Development of Novel Quaternary Ammonium Linkers for Antibody-Drug Conjugates.

    PubMed

    Burke, Patrick J; Hamilton, Joseph Z; Pires, Thomas A; Setter, Jocelyn R; Hunter, Joshua H; Cochran, Julia H; Waight, Andrew B; Gordon, Kristine A; Toki, Brian E; Emmerton, Kim K; Zeng, Weiping; Stone, Ivan J; Senter, Peter D; Lyon, Robert P; Jeffrey, Scott C

    2016-05-01

    A quaternary ammonium-based drug-linker has been developed to expand the scope of antibody-drug conjugate (ADC) payloads to include tertiary amines, a functional group commonly present in biologically active compounds. The linker strategy was exemplified with a β-glucuronidase-cleavable auristatin E construct. The drug-linker was found to efficiently release free auristatin E (AE) in the presence of β-glucuronidase and provide ADCs that were highly stable in plasma. Anti-CD30 conjugates comprised of the glucuronide-AE linker were potent and immunologically specific in vitro and in vivo, displaying pharmacologic properties comparable with a carbamate-linked glucuronide-monomethylauristatin E control. The quaternary ammonium linker was then applied to a tubulysin antimitotic drug that contained an N-terminal tertiary amine that was important for activity. A glucuronide-tubulysin quaternary ammonium linker was synthesized and evaluated as an ADC payload, in which the resulting conjugates were found to be potent and immunologically specific in vitro, and displayed a high level of activity in a Hodgkin lymphoma xenograft. Furthermore, the results were superior to those obtained with a related tubulysin derivative containing a secondary amine N-terminus for conjugation using previously known linker technology. The quaternary ammonium linker represents a significant advance in linker technology, enabling stable conjugation of payloads with tertiary amine residues. Mol Cancer Ther; 15(5); 938-45. ©2016 AACR. PMID:26944920

  6. Stent linker effect in a porcine coronary restenosis model.

    PubMed

    Park, Jun-Kyu; Lim, Kyung Seob; Bae, In-Ho; Nam, Joung-Pyo; Cho, Jae Hwa; Choi, Changyong; Nah, Jae-Woon; Jeong, Myung Ho

    2016-01-01

    In this study, we aimed to evaluate the mechanical effects of different stent linker designs on in-stent restenosis in porcine coronary arteries. We fabricated stents with an open-cell structure composed of nine main cells and three linker structures in model 1 (I-type), model 2 (S-types) and model 3 (U-types)) as well as Model 4, which is similar to a commercial bare metal stent design. The stent cells were 70 mm thick and wide, with a common symmetrical wave pattern. As the radial force increased, the number of main cells increased and the length of linker decreased. Radial force was higher in model 1, with a linear I-linker, than in models with S- or U-linkers. The flexibility measured by three-point bending showed a force of 1.09 N in model 1, 0.35 N in model 2, 0.19 N in model 3, and 0.31 N in model 4. The recoil results were similar in all models except model 4 and were related to the shape of the main cells. The foreshortening results were related to linker shape, with the lowest foreshortening observed in model 3 (U-linker). Restenosis areas in the porcine restenosis model 4 weeks after implantation were 35.4 ± 8.39% (model 1), 30.4 ± 7.56% (model 2), 40.6 ± 9.87% (model 3) and 45.1 ± 12.33% (model 4). In-stent restenosis rates measured by intravascular ultrasound (IVUS) and micro-computed tomography (micro-CT) showed similar trends as percent area stenosis measured by micro-CT. Model 2, with optimized flexibility and radial force due to its S-linker, showed significantly reduced restenosis in the animal model compared to stents with different linker designs. These results suggest that the optimal stent structure has a minimum radial force for vascular support and maximum flexibility for vascular conformability. The importance of the effects of these differences in stent design and their potential relationship with restenosis remains to be determined. PMID:26318568

  7. Triple-layered QSAR studies on substituted 1,2,4-trioxanes as potential antimalarial agents: superiority of the quantitative pharmacophore-based alignment over common substructure-based alignment.

    PubMed

    Gupta, A K; Saxena, A K

    2013-01-01

    This study reports the utilization of three approaches - pharmacophore, CoMFA/CoMSIA and HQSAR studies - to identify the essential structural requirements in 3D chemical space for the modulation of the antimalarial activity of substituted 1,2,4-trioxanes. The superiority of quantitative pharmacophore-based alignment (QuantitativePBA) over global minima energy conformer-based alignment (GMCBA) has been reported in CoMFA and CoMSIA studies. The developed models showed good statistical significance in internal validation (q(2), group cross-validation and bootstrapping) and performed very well in predicting the antimalarial activity of test set compounds. Structural features in terms of their steric, electrostatic and hydrophobic interactions in 3D space have been found to be important for the antimalarial activity of substituted 1,2,4-trioxanes. Further, the HQSAR studies based on the same training and test set acted as an additional tool to find the sub-structural fingerprints of substituted 1,2,4-trioxanes for their antimalarial activity. Together, these studies may facilitate the design and discovery of new substituted 1,2,4-trioxanes with potent antimalarial activity. PMID:23194465

  8. Chemical substructure analysis in toxicology

    SciTech Connect

    Beauchamp, R.O. Jr.

    1990-12-31

    A preliminary examination of chemical-substructure analysis (CSA) demonstrates the effective use of the Chemical Abstracts compound connectivity file in conjunction with the bibliographic file for relating chemical structures to biological activity. The importance of considering the role of metabolic intermediates under a variety of conditions is illustrated, suggesting structures that should be examined that may exhibit potential activity. This CSA technique, which utilizes existing large files accessible with online personal computers, is recommended for use as another tool in examining chemicals in drugs. 2 refs., 4 figs.

  9. Mass Substructure in Abell 3128

    NASA Astrophysics Data System (ADS)

    McCleary, J.; dell'Antonio, I.; Huwe, P.

    2015-05-01

    We perform a detailed two-dimensional weak gravitational lensing analysis of the nearby (z = 0.058) galaxy cluster Abell 3128 using deep ugrz imaging from the Dark Energy Camera (DECam). We have designed a pipeline to remove instrumental artifacts from DECam images and stack multiple dithered observations without inducing a spurious ellipticity signal. We develop a new technique to characterize the spatial variation of the point-spread function that enables us to circularize the field to better than 0.5% and thereby extract the intrinsic galaxy ellipticities. By fitting photometric redshifts to sources in the observation, we are able to select a sample of background galaxies for weak-lensing analysis free from low-redshift contaminants. Photometric redshifts are also used to select a high-redshift galaxy subsample with which we successfully isolate the signal from an interloping z = 0.44 cluster. We estimate the total mass of Abell 3128 by fitting the tangential ellipticity of background galaxies with the weak-lensing shear profile of a Navarro-Frenk-White (NFW) halo and also perform NFW fits to substructures detected in the 2D mass maps of the cluster. This study yields one of the highest resolution mass maps of a low-z cluster to date and is the first step in a larger effort to characterize the redshift evolution of mass substructures in clusters.

  10. Some approaches to substructure coupling with damping

    NASA Technical Reports Server (NTRS)

    Craig, R. R., Jr.; Bachmeyer, R. C.; Howsman, T. G.

    1986-01-01

    Time-domain and frequency-domain methods for coupling substructures with general linear damping are discussed. A time-domain method is presented which employs a state variable representation of each substructure. Also presented is a method which employs frequency-domain coupling together with DFT and FFT transformations to obtain transient response solutions.

  11. Parallel Computational Environment for Substructure Optimization

    NASA Technical Reports Server (NTRS)

    Gendy, Atef S.; Patnaik, Surya N.; Hopkins, Dale A.; Berke, Laszlo

    1995-01-01

    Design optimization of large structural systems can be attempted through a substructure strategy when convergence difficulties are encountered. When this strategy is used, the large structure is divided into several smaller substructures and a subproblem is defined for each substructure. The solution of the large optimization problem can be obtained iteratively through repeated solutions of the modest subproblems. Substructure strategies, in sequential as well as in parallel computational modes on a Cray YMP multiprocessor computer, have been incorporated in the optimization test bed CometBoards. CometBoards is an acronym for Comparative Evaluation Test Bed of Optimization and Analysis Routines for Design of Structures. Three issues, intensive computation, convergence of the iterative process, and analytically superior optimum, were addressed in the implementation of substructure optimization into CometBoards. Coupling between subproblems as well as local and global constraint grouping are essential for convergence of the iterative process. The substructure strategy can produce an analytically superior optimum different from what can be obtained by regular optimization. For the problems solved, substructure optimization in a parallel computational mode made effective use of all assigned processors.

  12. Hydroquinone-pyrrole dyads with varied linkers.

    PubMed

    Huang, Hao; Karlsson, Christoffer; Strømme, Maria; Sjödin, Martin; Gogoll, Adolf

    2016-01-01

    A series of pyrroles functionalized in the 3-position with p-dimethoxybenzene via various linkers (CH2, CH2CH2, CH=CH, C≡C) has been synthesized. Their electronic properties have been deduced from (1)H NMR, (13)C NMR, and UV-vis spectra to detect possible interactions between the two aromatic subunits. The extent of conjugation between the subunits is largely controlled by the nature of the linker, with the largest conjugation found with the trans-ethene linker and the weakest with the aliphatic linkers. DFT calculations revealed substantial changes in the HOMO-LUMO gap that correlated with the extent of conjugation found experimentally. The results of this work are expected to open up for use of the investigated compounds as components of redox-active materials in sustainable, organic electrical energy storage devices. PMID:26877811

  13. Hydroquinone–pyrrole dyads with varied linkers

    PubMed Central

    Huang, Hao; Karlsson, Christoffer; Strømme, Maria; Sjödin, Martin

    2016-01-01

    Summary A series of pyrroles functionalized in the 3-position with p-dimethoxybenzene via various linkers (CH2, CH2CH2, CH=CH, C≡C) has been synthesized. Their electronic properties have been deduced from 1H NMR, 13C NMR, and UV–vis spectra to detect possible interactions between the two aromatic subunits. The extent of conjugation between the subunits is largely controlled by the nature of the linker, with the largest conjugation found with the trans-ethene linker and the weakest with the aliphatic linkers. DFT calculations revealed substantial changes in the HOMO–LUMO gap that correlated with the extent of conjugation found experimentally. The results of this work are expected to open up for use of the investigated compounds as components of redox-active materials in sustainable, organic electrical energy storage devices. PMID:26877811

  14. Substructure Main Bridge, River Piers A & V ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    Substructure - Main Bridge, River Piers A & V - Huey P. Long Bridge, Spanning Mississippi River approximately midway between nine & twelve mile points upstream from & west of New Orleans, Jefferson, Jefferson Parish, LA

  15. Algebraic Sub-Structuring for Electromagnetic Applications

    SciTech Connect

    Yang, C.; Gao, W.G.; Bai, Z.J.; Li, X.Y.S.; Lee, L.Q.; Husbands, P.; Ng, E.G.; /LBL, Berkeley /UC, Davis /SLAC

    2006-06-30

    Algebraic sub-structuring refers to the process of applying matrix reordering and partitioning algorithms to divide a large sparse matrix into smaller submatrices from which a subset of spectral components are extracted and combined to form approximate solutions to the original problem. In this paper, they show that algebraic sub-structuring can be effectively used to solve generalized eigenvalue problems arising from the finite element analysis of an accelerator structure.

  16. Algebraic sub-structuring for electromagnetic applications

    SciTech Connect

    Yang, Chao; Gao, Weiguo; Bai, Zhaojun; Li, Xiaoye; Lee, Lie-Quan; Husbands, Parry; Ng, Esmond G.

    2004-09-14

    Algebraic sub-structuring refers to the process of applying matrix reordering and partitioning algorithms to divide a large sparse matrix into smaller submatrices from which a subset of spectral components are extracted and combined to form approximate solutions to the original problem. In this paper, we show that algebraic sub-structuring can be effectively used to solve generalized eigenvalue problems arising from the finite element analysis of an accelerator structure.

  17. A structural design decomposition method utilizing substructuring

    NASA Technical Reports Server (NTRS)

    Scotti, Stephen J.

    1994-01-01

    A new method of design decomposition for structural analysis and optimization is described. For this method, the structure is divided into substructures where each substructure has its structural response described by a structural-response subproblem, and its structural sizing determined from a structural-sizing subproblem. The structural responses of substructures that have rigid body modes when separated from the remainder of the structure are further decomposed into displacements that have no rigid body components, and a set of rigid body modes. The structural-response subproblems are linked together through forces determined within a structural-sizing coordination subproblem which also determines the magnitude of any rigid body displacements. Structural-sizing subproblems having constraints local to the substructures are linked together through penalty terms that are determined by a structural-sizing coordination subproblem. All the substructure structural-response subproblems are totally decoupled from each other, as are all the substructure structural-sizing subproblems, thus there is significant potential for use of parallel solution methods for these subproblems.

  18. Solid colloids with surface-mobile linkers.

    PubMed

    van der Meulen, Stef A J; Helms, Gesa; Dogterom, Marileen

    2015-06-17

    In this report we review the possibilities of using colloids with surface mobile linkers for the study of colloidal self-assembly processes. A promising route to create systems with mobile linkers is the use of lipid (bi-)layers. These lipid layers can be either used in the form of vesicles or as coatings for hard colloids and emulsion droplets. Inside the lipid bilayers molecules can be inserted via membrane anchors. Due to the fluidity of the lipid bilayer, the anchored molecules remain mobile. The use of different lipid mixtures even allows creating Janus-like particles that exhibit directional bonding if linkers are used which have a preference for a certain lipid phase. In nature mobile linkers can be found e.g. as receptors in cells. Therefore, towards the end of the review, we also briefly address the possibility of using colloids with surface mobile linkers as model systems to mimic cell-cell interactions and cell adhesion processes. PMID:25993272

  19. Singular behavior of jet substructure observables

    NASA Astrophysics Data System (ADS)

    Larkoski, Andrew J.; Moult, Ian

    2016-01-01

    Jet substructure observables play a central role at the Large Hadron Collider for identifying the boosted hadronic decay products of electroweak scale resonances. The complete description of these observables requires understanding both the limit in which hard substructure is resolved, as well as the limit of a jet with a single hard core. In this paper we study in detail the perturbative structure of two prominent jet substructure observables, N -subjettiness and the energy correlation functions, as measured on background QCD jets. In particular, we focus on the distinction between the limits in which two-prong structure is resolved or unresolved. Depending on the choice of subjet axes, we demonstrate that at fixed order, N -subjettiness can manifest myriad behaviors in the unresolved region: smooth tails, end point singularities, or singularities in the physical region. The energy correlation functions, by contrast, only have nonsingular perturbative tails extending to the end point. We discuss the effect of hadronization on the various observables with Monte Carlo simulation and demonstrate that the modeling of these effects with nonperturbative shape functions is highly dependent on the N -subjettiness axes definitions. Our study illustrates those regions of phase space that must be controlled for high-precision jet substructure calculations, and emphasizes how such calculations can be facilitated by designing substructure observables with simple singular structures.

  20. Singular behavior of jet substructure observables

    DOE PAGESBeta

    Larkoski, Andrew J.; Moult, Ian

    2016-01-20

    Jet substructure observables play a central role at the Large Hadron Collider for identifying the boosted hadronic decay products of electroweak scale resonances. The complete description of these observables requires understanding both the limit in which hard substructure is resolved, as well as the limit of a jet with a single hard core. In this paper we study in detail the perturbative structure of two prominent jet substructure observables, N-subjettiness and the energy correlation functions, as measured on background QCD jets. In particular, we focus on the distinction between the limits in which two-prong structure is resolved or unresolved. Dependingmore » on the choice of subjet axes, we demonstrate that at fixed order, N-subjettiness can manifest myriad behaviors in the unresolved region: smooth tails, end-point singularities, or singularities in the physical region. The energy correlation functions, by contrast, only have non-singular perturbative tails extending to the end point. We discuss the effect of hadronization on the various observables with Monte Carlo simulation and demonstrate that the modeling of these effects with non-perturbative shape functions is highly dependent on the N-subjettiness axes definitions. Lastly, our study illustrates those regions of phase space that must be controlled for high-precision jet substructure calculations, and emphasizes how such calculations can be facilitated by designing substructure observables with simple singular structures.« less

  1. Particle Substructure. A Common Theme of Discovery in this Century

    DOE R&D Accomplishments Database

    Panofsky, W. K. H.

    1984-02-01

    Some example of modern developments in particle physics are given which demonstrate that the fundamental rules of quantum mechanics, applied to all forces in nature as they became understood, have retained their validity. The well-established laws of electricity and magnetism, reformulated in terms of quantum mechanics, have exhibited a truly remarkable numerical agreement between theory and experiment over an enormous range of observation. As experimental techniques have grown from the top of a laboratory bench to the large accelerators of today, the basic components of experimentation have changed vastly in scale but only little in basic function. More important, the motivation of those engaged in this type of experimentation has hardly changed at all.

  2. Particel substructure. A common theme of discovery in this century

    SciTech Connect

    Panofsky, W.K.H.

    1984-02-01

    Some example of modern developments in particel physics are given which demonstrate that the fundamental rules of quantum mechanics, applied to all forces in nature as they became understood, have retained their validity. The well-established laws of electricity and magnetism, reformulated in terms of quantum mechanics, have exhibited a truly remarkable numerical agreement between theory and experiment over an enormous range of observation. As experimental techniques have grown from the top of a laboratory bench to the large accelerators of today, the basic components of experimentation have changed vastly in scale but only little in basic function. More important, the motivation of those engaged in this type of experimentation has hardly changed at all.

  3. Quantification of Substructure in Nearby Abell Clusters

    NASA Astrophysics Data System (ADS)

    Kriessler, J. R.; Beers, T. C.; Odewahn, S. C.

    1995-05-01

    Theory, as well as numerical simulations, suggests that Omega_o may be observationally constrained by the amount of substructure observed in present-day clusters of galaxies. We have therefore begun a study of the 116 Abell clusters with richness class greater than or equal to 1 and distance class less than or equal to 4, the so-called ``volume-limited'' sample of Hoessel, Gunn, & Thuan 1980 (ApJ 241, 486) to determine the prevalence of substructure in the clusters' projected galaxy positions. We use positions of galaxies identified by the Minnesota Automated Plate Scanner to obtain contour plots of the available clusters using an adaptive kernel routine. Significance of substructure is evaluated using the 2-D Lee test as well as a likelihood-ratio test on fits made with mixtures of two-dimensional gaussians. We also present nonparametric density profile estimates obtained with the program MAPEL (Merritt and Tremblay 1994, AJ 108, 514).

  4. THE ORIGIN OF THE VIRGO STELLAR SUBSTRUCTURE

    SciTech Connect

    Carlin, Jeffrey L.; Yam, William; Willett, Benjamin A.; Newberg, Heidi J.; Casetti-Dinescu, Dana I.; Girard, Terrence M.; Majewski, Steven R.

    2012-07-10

    We present three-dimensional space velocities of stars selected to be consistent with membership in the Virgo stellar substructure. Candidates were selected from SA 103, a single 40' Multiplication-Sign 40' field from our proper-motion (PM) survey in Kapteyn's Selected Areas (SAs), based on the PMs, Sloan Digital Sky Survey (SDSS) photometry, and follow-up spectroscopy of 215 stars. The signature of the Virgo substructure is clear in the SDSS color-magnitude diagram (CMD) centered on SA 103, and 16 stars are identified that have high Galactocentric-frame radial velocities (V{sub GSR} > 50 km s{sup -1}) and lie near the CMD locus of Virgo. The implied distance to the Virgo substructure from the candidates is 14 {+-} 3 kpc. We derive mean kinematics from these 16 stars, finding a radial velocity V{sub GSR} = 153 {+-} 22 km s{sup -1} and proper motions ({mu}{sub {alpha}}cos {delta}, {mu}{sub {delta}}) = (- 5.24, -0.91) {+-} (0.43, 0.46) mas yr{sup -1}. From the mean kinematics of these members, we determine that the Virgo progenitor was on an eccentric (e {approx} 0.8) orbit that recently passed near the Galactic center (pericentric distance R{sub p} {approx} 6 kpc). This destructive orbit is consistent with the idea that the substructure(s) in Virgo originated in the tidal disruption of a Milky Way satellite. N-body simulations suggest that the entire cloud-like Virgo substructure (encompassing the 'Virgo Overdensity' and the 'Virgo Stellar Stream') is likely the tidal debris remnant from a recently disrupted massive ({approx}10{sup 9} M{sub Sun }) dwarf galaxy. The model also suggests that some other known stellar overdensities in the Milky Way halo (e.g., the Pisces Overdensity and debris near NGC 2419 and SEGUE 1) are explained by the disruption of the Virgo progenitor.

  5. The Origin of the Virgo Stellar Substructure

    NASA Astrophysics Data System (ADS)

    Carlin, Jeffrey L.; Yam, William; Casetti-Dinescu, Dana I.; Willett, Benjamin A.; Newberg, Heidi J.; Majewski, Steven R.; Girard, Terrence M.

    2012-07-01

    We present three-dimensional space velocities of stars selected to be consistent with membership in the Virgo stellar substructure. Candidates were selected from SA 103, a single 40' × 40' field from our proper-motion (PM) survey in Kapteyn's Selected Areas (SAs), based on the PMs, Sloan Digital Sky Survey (SDSS) photometry, and follow-up spectroscopy of 215 stars. The signature of the Virgo substructure is clear in the SDSS color-magnitude diagram (CMD) centered on SA 103, and 16 stars are identified that have high Galactocentric-frame radial velocities (V GSR > 50 km s-1) and lie near the CMD locus of Virgo. The implied distance to the Virgo substructure from the candidates is 14 ± 3 kpc. We derive mean kinematics from these 16 stars, finding a radial velocity V GSR = 153 ± 22 km s-1 and proper motions (μαcos δ, μδ) = (- 5.24, -0.91) ± (0.43, 0.46) mas yr-1. From the mean kinematics of these members, we determine that the Virgo progenitor was on an eccentric (e ~ 0.8) orbit that recently passed near the Galactic center (pericentric distance Rp ~ 6 kpc). This destructive orbit is consistent with the idea that the substructure(s) in Virgo originated in the tidal disruption of a Milky Way satellite. N-body simulations suggest that the entire cloud-like Virgo substructure (encompassing the "Virgo Overdensity" and the "Virgo Stellar Stream") is likely the tidal debris remnant from a recently disrupted massive (~109 M ⊙) dwarf galaxy. The model also suggests that some other known stellar overdensities in the Milky Way halo (e.g., the Pisces Overdensity and debris near NGC 2419 and SEGUE 1) are explained by the disruption of the Virgo progenitor.

  6. Inverse substructure method for model updating of structures

    NASA Astrophysics Data System (ADS)

    Weng, Shun; Xia, Yong; Zhou, Xiao-Qing; Xu, You-Lin; Zhu, Hong-Ping

    2012-12-01

    Traditional model updating of large-scale structures is usually time-consuming because the global structural model needs to be repeatedly re-analyzed as a whole to match global measurements. This paper proposes a new substructural model updating method. The modal data measured on the global structure are disassembled to obtain the independent substructural dynamic flexibility matrices under force and displacement compatibility conditions. The method is extended to the case when the measurement is carried out at partial degrees-of-freedom of the structure. The extracted substructural flexibility matrices are then used as references for updating the corresponding substructural models. An orthogonal projector is employed on both the extracted substructural measurements and the substructural models to remove the rigid body modes of the free-free substructures. Compared with the traditional model updating at the global structure level, only the sub-models at the substructural level are re-analyzed in the proposed substructure-based model updating process, resulting in a rapid convergence of optimization. Moreover, only measurement on the local area corresponding to the concerned substructures is required, and those on other components can be avoided. The effectiveness and efficiency of the proposed substructuring method are verified through applications to a laboratory-tested frame structure and a large-scale 600 m tall Guangzhou New TV Tower. The present technique is referred to as the inverse substructuring model updating method as the measured global modal data are disassembled into the substructure level and then the updating is conducted on the substructures only. This differs from the substructuring model updating method previously proposed by the authors, in which the model updating is still conducted in the global level and the numerical global modal data are assembled from those of substructures. That can be referred to as the forward substructuring model

  7. Hadronic calorimeter shower size: Challenges and opportunities for jet substructure in the superboosted regime

    NASA Astrophysics Data System (ADS)

    Bressler, Shikma; Flacke, Thomas; Kats, Yevgeny; Lee, Seung J.; Perez, Gilad

    2016-05-01

    Hadrons have finite interaction size with dense material, a basic feature common to known forms of hadronic calorimeters (HCAL). We argue that substructure variables cannot use HCAL information to access the microscopic nature of jets much narrower than the hadronic shower size, which we call superboosted massive jets. It implies that roughly 15% of their transverse energy profile remains inaccessible due to the presence of long-lived neutral hadrons. This part of the jet substructure is also subject to order-one fluctuations. We demonstrate that the effects of the fluctuations are not reduced when a global correction to jet variables is applied. The above leads to fundamental limitations in the ability to extract intrinsic information from jets in the superboosted regime. The neutral fraction of a jet is correlated with its flavor. This leads to an interesting and possibly useful difference between superboosted W / Z / h / t jets and their corresponding backgrounds. The QCD jets that form the background to the signal superboosted jets might also be qualitatively different in their substructure as their mass might lie at or below the Sudakov mass peak. Finally, we introduce a set of zero-cone longitudinal jet substructure variables and show that while they carry information that might be useful in certain situations, they are not in general sensitive to the jet substructure.

  8. Statistics of substructures in dark matter haloes

    NASA Astrophysics Data System (ADS)

    Contini, E.; De Lucia, G.; Borgani, S.

    2012-03-01

    We study the amount and distribution of dark matter substructures within dark matter haloes, using a large set of high-resolution simulations ranging from group-size to cluster-size haloes, and carried out within a cosmological model consistent with Wilkinson Microwave Anisotropy Probe (WMAP) 7-year data. In particular, we study how the measured properties of subhaloes vary as a function of the parent halo mass, the physical properties of the parent halo and redshift. The fraction of halo mass in substructures increases with increasing mass: it is of the order of 5 per cent for haloes with M200˜ 1013 M⊙ and of the order of 10 per cent for the most massive haloes in our sample, with M200˜ 1015 M⊙. There is, however, a very large halo-to-halo scatter that can be explained only in part by a range of halo physical properties, e.g. concentration. At a given halo mass, less concentrated haloes contain significantly larger fractions of mass in substructures because of the reduced strength of tidal disruption. Most of the substructure mass is located at the outskirts of the parent haloes, in relatively few massive subhaloes. This mass segregation appears to become stronger at increasing redshift, and should reflect into a more significant mass segregation of the galaxy population at different cosmic epochs. When haloes are accreted on to larger structures, their mass is significantly reduced by tidal stripping. Haloes that are more massive at the time of accretion (these should host more luminous galaxies) are brought closer to the centre on shorter time-scales by dynamical friction, and therefore suffer a more significant stripping. The halo merger rate depends strongly on the environment with substructure in more massive haloes suffering more important mergers than their counterparts residing in less massive systems. This should translate into a different morphological mix for haloes of different mass.

  9. Linker Histones Incorporation Maintains Chromatin Fiber Plasticity

    PubMed Central

    Recouvreux, Pierre; Lavelle, Christophe; Barbi, Maria; Conde e Silva, Natalia; Le Cam, Eric; Victor, Jean-Marc; Viovy, Jean-Louis

    2011-01-01

    Genomic DNA in eukaryotic cells is organized in supercoiled chromatin fibers, which undergo dynamic changes during such DNA metabolic processes as transcription or replication. Indeed, DNA-translocating enzymes like polymerases produce physical constraints in vivo. We used single-molecule micromanipulation by magnetic tweezers to study the response of chromatin to mechanical constraints in the same range as those encountered in vivo. We had previously shown that under positive torsional constraints, nucleosomes can undergo a reversible chiral transition toward a state of positive topology. We demonstrate here that chromatin fibers comprising linker histones present a torsional plasticity similar to that of naked nucleosome arrays. Chromatosomes can undergo a reversible chiral transition toward a state of positive torsion (reverse chromatosome) without loss of linker histones. PMID:21641318

  10. The gamma-ray-flux PDF from galactic halo substructure

    NASA Astrophysics Data System (ADS)

    Lee, Samuel K.; Ando, Shin'ichiro; Kamionkowski, Marc

    2009-07-01

    One of the targets of the recently launched Fermi Gamma-ray Space Telescope is a diffuse gamma-ray background from dark-matter annihilation or decay in the Galactic halo. N-body simulations and theoretical arguments suggest that the dark matter in the Galactic halo may be clumped into substructure, rather than smoothly distributed. Here we propose the gamma-ray-flux probability distribution function (PDF) as a probe of substructure in the Galactic halo. We calculate this PDF for a phenomenological model of halo substructure and determine the regions of the substructure parameter space in which the PDF may be distinguished from the PDF for a smooth distribution of dark matter. In principle, the PDF allows a statistical detection of substructure, even if individual halos cannot be detected. It may also allow detection of substructure on the smallest microhalo mass scales, ~ M⊕, for weakly-interacting massive particles (WIMPs). Furthermore, it may also provide a method to measure the substructure mass function. However, an analysis that assumes a typical halo substructure model and a conservative estimate of the diffuse background suggests that the substructure PDF may not be detectable in the lifespan of Fermi in the specific case that the WIMP is a neutralino. Nevertheless, for a large range of substructure, WIMP annihilation, and diffuse background models, PDF analysis may provide a clear signature of substructure.

  11. Improving the Serum Stability of Site-Specific Antibody Conjugates with Sulfone Linkers

    PubMed Central

    2015-01-01

    Current routes for synthesizing antibody–drug conjugates commonly rely on maleimide linkers to react with cysteine thiols. However, thioether exchange with metabolites and serum proteins can compromise conjugate stability and diminish in vivo efficacy. We report the application of a phenyloxadiazole sulfone linker for the preparation of trastuzumab conjugates. This sulfone linker site-specifically labeled engineered cysteine residues in THIOMABs and improved antibody conjugate stability in human plasma at sites previously shown to be labile for maleimide conjugates. Similarly, sulfone conjugation with selenocysteine in an anti-ROR1 scFv-Fc improved human plasma stability relative to maleimide conjugation. Kinetically controlled labeling of a THIOMAB containing two cysteine substitutions was also achieved, offering a strategy for producing antibody conjugates with expanded valency. PMID:25099687

  12. Practical applications of substructuring in shell dynamics

    SciTech Connect

    Sane, A.D.; Bitner, J.L.

    1982-01-01

    Transient dynamic stress analysis of large shell structures is often required in many industrial designs. The asymmetry features of the structure often require a full three dimensional analysis. The difficulties experienced in performing the dynamic analysis of such large and complex structures result from economic feasibility and limitations on the available computer core memory. Substructuring techniques provide a way of overcoming these difficulties. The advantages and features associated with substructuring methods are discussed in general terms. The technique is then applied to perform a transient dynamic analysis of a typical shell structure. The discussion of the example problem focused to highlight the economy, flexibility and the data handling aspects of this method. The example problem demonstrates that this method can be applied with success to a wide range of structural dynamic problems and results in significant cost savings.

  13. Substructure coupling in the frequency domain

    NASA Technical Reports Server (NTRS)

    1985-01-01

    Frequency domain analysis was found to be a suitable method for determining the transient response of systems subjected to a wide variety of loads. However, since a large number of calculations are performed within the discrete frequency loop, the method loses it computational efficiency if the loads must be represented by a large number of discrete frequencies. It was also discovered that substructure coupling in the frequency domain work particularly well for analyzing structural system with a small number of interface and loaded degrees of freedom. It was discovered that substructure coupling in the frequency domain can lead to an efficient method of obtaining natural frequencies of undamped structures. It was also found that the damped natural frequencies of a system may be determined using frequency domain techniques.

  14. Substructure decoupling without using rotational DoFs: Fact or fiction?

    NASA Astrophysics Data System (ADS)

    D`Ambrogio, Walter; Fregolent, Annalisa

    2016-05-01

    In the framework of experimental dynamic substructuring, substructure decoupling consists in the identification of the dynamic behaviour of a structural subsystem, starting from the dynamic behaviour of both the assembled system and the residual subsystem (the known portion of the assembled system). On the contrary, substructure coupling identifies an assembled system starting from the component subsystems. The degrees of freedom (DoFs) of the assembled system can be partitioned into internal DoFs (not belonging to the couplings) and coupling DoFs. In substructure coupling, whenever coupling DoFs include rotational DoFs, the related rotational FRFs must be obtained experimentally. Does this requirement holds for substructure decoupling too, as it is commonly believed? Decoupling can be ideally accomplished by adding the negative of the residual subsystem to the assembled system (direct decoupling) and by enforcing compatibility and equilibrium at enough interface DoFs. Ideally, every DoF of the residual subsystem belongs to the interface between the assembled system and the residual subsystem. Hopefully, not all the coupling DoFs are necessary to enforce compatibility and equilibrium. This may allow us to skip coupling DoFs and specifically rotational DoFs. The goal of the paper is indeed to establish if rotational FRFs at coupling DoFs can be neglected in substructure decoupling. To this aim, after highlighting the possibility of avoiding the use of coupling DoFs from a theoretical standpoint, a test bed coupled through flexural and torsional DoFs is considered. Experimental results are presented and discussed.

  15. Mapping the Galactic Halo. VIII. Quantifying Substructure

    NASA Astrophysics Data System (ADS)

    Starkenburg, Else; Helmi, Amina; Morrison, Heather L.; Harding, Paul; van Woerden, Hugo; Mateo, Mario; Olszewski, Edward W.; Sivarani, Thirupathi; Norris, John E.; Freeman, Kenneth C.; Shectman, Stephen A.; Dohm-Palmer, R. C.; Frey, Lucy; Oravetz, Dan

    2009-06-01

    We have measured the amount of kinematic substructure in the Galactic halo using the final data set from the Spaghetti project, a pencil-beam high-latitude sky survey. Our sample contains 101 photometrically selected and spectroscopically confirmed giants with accurate distance, radial velocity, and metallicity information. We have developed a new clustering estimator: the "4distance" measure, which when applied to our data set leads to the identification of one group and seven pairs of clumped stars. The group, with six members, can confidently be matched to tidal debris of the Sagittarius dwarf galaxy. Two pairs match the properties of known Virgo structures. Using models of the disruption of Sagittarius in Galactic potentials with different degrees of dark halo flattening, we show that this favors a spherical or prolate halo shape, as demonstrated by Newberg et al. using the Sloan Digital Sky Survey data. One additional pair can be linked to older Sagittarius debris. We find that 20% of the stars in the Spaghetti data set are in substructures. From comparison with random data sets, we derive a very conservative lower limit of 10% to the amount of substructure in the halo. However, comparison to numerical simulations shows that our results are also consistent with a halo entirely built up from disrupted satellites, provided that the dominating features are relatively broad due to early merging or relatively heavy progenitor satellites.

  16. Composite Octet Searches with Jet Substructure

    SciTech Connect

    Bai, Yang; Shelton, Jessie; /Yale U.

    2012-02-14

    Many new physics models with strongly interacting sectors predict a mass hierarchy between the lightest vector meson and the lightest pseudoscalar mesons. We examine the power of jet substructure tools to extend the 7 TeV LHC sensitivity to these new states for the case of QCD octet mesons, considering both two gluon and two b-jet decay modes for the pseudoscalar mesons. We develop both a simple dijet search using only the jet mass and a more sophisticated jet substructure analysis, both of which can discover the composite octets in a dijet-like signature. The reach depends on the mass hierarchy between the vector and pseudoscalar mesons. We find that for the pseudoscalar-to-vector meson mass ratio below approximately 0.2 the simple jet mass analysis provides the best discovery limit; for a ratio between 0.2 and the QCD-like value of 0.3, the sophisticated jet substructure analysis has the best discovery potential; for a ratio above approximately 0.3, the standard four-jet analysis is more suitable.

  17. Star formation and substructure in galaxy clusters

    SciTech Connect

    Cohen, Seth A.; Hickox, Ryan C.; Wegner, Gary A.; Einasto, Maret; Vennik, Jaan

    2014-03-10

    We investigate the relationship between star formation (SF) and substructure in a sample of 107 nearby galaxy clusters using data from the Sloan Digital Sky Survey. Several past studies of individual galaxy clusters have suggested that cluster mergers enhance cluster SF, while others find no such relationship. The SF fraction in multi-component clusters (0.228 ± 0.007) is higher than that in single-component clusters (0.175 ± 0.016) for galaxies with M{sub r}{sup 0.1}<−20.5. In both single- and multi-component clusters, the fraction of star-forming galaxies increases with clustercentric distance and decreases with local galaxy number density, and multi-component clusters show a higher SF fraction than single-component clusters at almost all clustercentric distances and local densities. Comparing the SF fraction in individual clusters to several statistical measures of substructure, we find weak, but in most cases significant at greater than 2σ, correlations between substructure and SF fraction. These results could indicate that cluster mergers may cause weak but significant SF enhancement in clusters, or unrelaxed clusters exhibit slightly stronger SF due to their less evolved states relative to relaxed clusters.

  18. Spectroscopic study of the light-harvesting protein C-phycocyanin associated with colorless linker peptides

    SciTech Connect

    Pizarro, Shelly A.

    2000-05-12

    The phycobilisome (PBS) light-harvesting antenna is composed of chromophore-containing biliproteins and 'colorless' linker peptides and is structurally designed to support unidirectional transfer of excitation energy from the periphery of the PBS to its core. The linker peptides have a unique role in this transfer process by modulating the spectral properties of the associated biliprotein. There is only one three-dimensional structure of a biliprotein/linker complex available to date (APC/LC7.8) and the mechanism of interaction between these two proteins remains unknown. This study brings together a detailed spectroscopic characterization of C-Phycocyanin (PC)-linker complexes (isolated from Synechococcus sp. PCC 7002) with proteomic analysis of the linker amino acid sequences to produce a model for biliprotein/linker interaction. The amino acid sequences of the rod linkers [LR8.9, LR32.3 and LRC28.5] were examined to identify evolutionarily conserved regions important to either the structure or function of this protein family. Although there is not one common homologous site among all the linkers, there are strong trends across each separate subset (LC, LR and LRC) and the N-terminal segments of both LR32.3 and LRC28.5 display multiple regions of similarity with other linkers. Predictions of the secondary structure of LR32.3 and LRC28.5, and comparison to the crystal structure of LC7.8, further narrowed the candidates for interaction sites with the PC chromophores. Measurements of the absorption, fluorescence, CD and excitation anisotropy of PC trimer, PC/LR32.3, and PC/LRC28.5, document the spectroscopic effect of each linker peptide on the PC chromophores at a series of temperatures (298 to 77 K). Because LR32.3 and LRC28.5 modulate the PC trimer spectral properties in distinct manners, it suggests different chromophore-interaction mechanisms for each linker. The low temperature absorbance spectrum of the PC trimer is consistent with an excitonic coupling

  19. Phosphorylation of histone variant regions in chromatin: unlocking the linker?

    PubMed

    Green, G R

    2001-01-01

    Histone variants illuminate the behavior of chromatin through their unique structures and patterns of postsynthetic modification. This review examines the literature on heteromorphous histone structures in chromatin, structures that are primary targets for histone kinases and phosphatases in vivo. Special attention is paid to certain well-studied experimental systems: mammalian culture cells, chicken erythrocytes, sea urchin sperm, wheat sprouts, Tetrahymena, and budding yeast. A common theme emerges from these studies. Specialized, highly basic structures in histone variants promote chromatin condensation in a variety of developmental situations. Before, and sometimes after condensed chromatin is formed, the chromatin is rendered soluble by phosphorylation of the heteromorphous regions, preventing their interaction with linker DNA. A simple structural model accounting for histone variation and phosphorylation is presented. PMID:11467741

  20. Linker dependence of interfacial electron transfer rates in Fe(II)-polypyridine sensitized solar cells

    NASA Astrophysics Data System (ADS)

    Bowman, David N.; Mukherjee, Sriparna; Barnes, Lyndsay J.; Jakubikova, Elena

    2015-04-01

    Dye-sensitized solar cells (DSSCs) convert solar energy to electricity employing dye molecules attached to a semiconductor surface. Some of the most efficient DSSCs use Ru-based chromophores. Fe-based dyes represent a cheaper and more environmentally friendly alternative to these expensive and toxic dyes. The photoactive state of Fe-based chromophores responsible for charge-separation at the dye-semiconductor interface is, however, deactivated on a sub-picosecond time scale via the intersystem crossing (ISC) into a manifold of low-lying photo-inactive quintet states. Therefore, development of Fe-based dyes capable of fast interfacial electron transfer (IET) leading to efficient charge separation on a time scale competitive with the ISC events is important. This work investigates how linker groups anchoring a prototypical Fe-based dye [Fe(bpy-L)2(CN)2] (bpy = 2,2‧-bipyridine, L = linker group) onto the TiO2 semiconductor surface influence the IET rates in the dye-semiconductor assemblies. Linker groups investigated include carboxylic acid, phosphonic acid, hydroxamate, catechol, and acetylacetonate. We employ time-dependent density functional theory (TD-DFT) to obtain absorption spectra of [Fe(bpy-L)2(CN)2] with each linker, and quantum dynamics simulations to investigate the IET rates between the dye and the (101) TiO2 anatase surface. For all attachments, TD-DFT calculations show similar absorption spectra with two main bands corresponding to the metal-to-ligand charge transfer transitions. The quantum dynamics simulations predict that the utilization of the hydroxamate linker instead of the commonly used carboxylic acid linker will lead to a more efficient IET and better photon-to-current conversion efficiencies in Fe(II)-polypyridine sensitized solar cells.

  1. Linker dependence of interfacial electron transfer rates in Fe(II)-polypyridine sensitized solar cells.

    PubMed

    Bowman, David N; Mukherjee, Sriparna; Barnes, Lyndsay J; Jakubikova, Elena

    2015-04-10

    Dye-sensitized solar cells (DSSCs) convert solar energy to electricity employing dye molecules attached to a semiconductor surface. Some of the most efficient DSSCs use Ru-based chromophores. Fe-based dyes represent a cheaper and more environmentally friendly alternative to these expensive and toxic dyes. The photoactive state of Fe-based chromophores responsible for charge-separation at the dye-semiconductor interface is, however, deactivated on a sub-picosecond time scale via the intersystem crossing (ISC) into a manifold of low-lying photo-inactive quintet states. Therefore, development of Fe-based dyes capable of fast interfacial electron transfer (IET) leading to efficient charge separation on a time scale competitive with the ISC events is important. This work investigates how linker groups anchoring a prototypical Fe-based dye [Fe(bpy-L)2(CN)2] (bpy = 2,2'-bipyridine, L = linker group) onto the TiO2 semiconductor surface influence the IET rates in the dye-semiconductor assemblies. Linker groups investigated include carboxylic acid, phosphonic acid, hydroxamate, catechol, and acetylacetonate. We employ time-dependent density functional theory (TD-DFT) to obtain absorption spectra of [Fe(bpy-L)2(CN)2] with each linker, and quantum dynamics simulations to investigate the IET rates between the dye and the (101) TiO2 anatase surface. For all attachments, TD-DFT calculations show similar absorption spectra with two main bands corresponding to the metal-to-ligand charge transfer transitions. The quantum dynamics simulations predict that the utilization of the hydroxamate linker instead of the commonly used carboxylic acid linker will lead to a more efficient IET and better photon-to-current conversion efficiencies in Fe(II)-polypyridine sensitized solar cells. PMID:25767105

  2. Extraction of Substructural Flexibility from Global Frequencies and Mode Shapes

    SciTech Connect

    Alvin, K.F.; Park, K.C.

    1999-07-16

    A computational procedure for extracting substructure-by-substructure flexibility properties from global modal parameters is presented. The present procedure consists of two key features: an element-based direct flexibility method which uniquely determines the global flexibility without resorting to case-dependent redundancy selections; and, the projection of cinematically inadmissible modes that are contained in the iterated substructural matrices. The direct flexibility method is used as the basis of an inverse problem, whose goal is to determine substructural flexibilities given the global flexibility, geometrically-determined substructural rigid-body modes, and the local-to-global assembly operators. The resulting procedure, given accurate global flexibility, extracts the exact element-by-element substructural flexibilities for determinate structures. For indeterminate structures, the accuracy depends on the iteration tolerance limits. The procedure is illustrated using both simple and complex numerical examples, and appears to be effective for structural applications such as damage localization and finite element model reconciliation.

  3. Desmosine-Inspired Cross-Linkers for Hyaluronan Hydrogels

    NASA Astrophysics Data System (ADS)

    Hagel, Valentin; Mateescu, Markus; Southan, Alexander; Wegner, Seraphine V.; Nuss, Isabell; Haraszti, Tamás; Kleinhans, Claudia; Schuh, Christian; Spatz, Joachim P.; Kluger, Petra J.; Bach, Monika; Tussetschläger, Stefan; Tovar, Günter E. M.; Laschat, Sabine; Boehm, Heike

    2013-06-01

    We designed bioinspired cross-linkers based on desmosine, the cross-linker in natural elastin, to prepare hydrogels with thiolated hyaluronic acid. These short, rigid cross-linkers are based on pyridinium salts (as in desmosine) and can connect two polymer backbones. Generally, the obtained semi-synthetic hydrogels are form-stable, can withstand repeated stress, have a large linear-elastic range, and show strain stiffening behavior typical for biopolymer networks. In addition, it is possible to introduce a positive charge to the core of the cross-linker without affecting the gelation efficiency, or consequently the network connectivity. However, the mechanical properties strongly depend on the charge of the cross-linker. The properties of the presented hydrogels can thus be tuned in a range important for engineering of soft tissues by controlling the cross-linking density and the charge of the cross-linker.

  4. Traceless cross-linker for photocleavable bioconjugation.

    PubMed

    Wang, Rong; Yan, Funing; Qiu, Dengli; Jeong, Jae-Sun; Jin, Qiaoling; Kim, Tae-Young; Chen, Liaohai

    2012-04-18

    Photoresponsive bioconjugation empowers the development of novel methods for drug discovery, disease diagnosis, and high-throughput screening, among others. In this paper, we report on the characteristics of a traceless photocleavable cross-linker, di-6-(3-succinimidyl carbonyloxymethyl-4-nitro-phenoxy)-hexanoic acid disulfide diethanol ester (SCNE). The traceless feature and the biocompatibility of this photocleavable cross-linking reagent were corroborated. Consequently, we demonstrated its application in reversible phage particle immobilization that could provide a platform for direct single-phage screening. We also applied it in protein-photoprinting, where SCNE acts as a "photo-eraser" to remove the cross-linked protein molecules at a desired region in a simple, clean, and light-controllable fashion. We further demonstrated the two-tier atomic force microscopic (AFM) method that uses SCNE to carry out two subsequent AFM tasks in situ. The approach allows guided protein delivery and subsequent high-resolution imaging at the same local area, thus opening up the possibility of monitoring protein functions in live cells. The results imply that SCNE is a versatile cross-linker that can be used for a wide range of applications where photocleavage ensures clean and remote-controllable release of biological molecules from a substrate. PMID:22432929

  5. 5. DOWNSTREAM ELEVATION OF BRIDGE AND SUBSTRUCTURE (with graduated meter ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    5. DOWNSTREAM ELEVATION OF BRIDGE AND SUBSTRUCTURE (with graduated meter pole); VIEW TO NORTH-NORTHEAST. - Auwaiakeakua Bridge, Spanning Auwaiakekua Gulch at Mamalahoa Highway, Waikoloa, Hawaii County, HI

  6. Damage detection using the eigenparameter decomposition of substructural flexibility matrix

    NASA Astrophysics Data System (ADS)

    Weng, Shun; Zhu, Hong-Ping; Xia, Yong; Mao, Ling

    2013-01-01

    The crack or local damage on a structure reduces the stiffness of the structure, and thus leads to the modification of the dynamic properties. Damage detection is widely performed by comparing the initial modal data of the intact structure with those of the damaged structure. For a large-scale structure, the local damage usually introduces slight change to the global modal data, which makes the local damage difficult to be detected. This paper proposes a new substructuring method for the damage detection of a structure. The global structure is divided into manageable substructures. The modal data measured on the global structure are disassembled for obtaining the independent substructural dynamic flexibility matrices, under the force and displacement compatibility constraints. Thereafter, the substructural flexibility matrix is decomposed into its eigenvalues and eigenvectors to be used as the indicators for damage detection. Since the substructuring method concerns the local area by treating it as an independent structure, the substructural eigenparameters are more sensitive to the local damage than the global eigenparameters. The proposed substructuring method is firstly verified by a laboratory-tested portal frame structure. The location of the artificial cuts can be detected successfully by comparing the change of substructural eigenparameters. The proposed method is then applied to the 600 m tall Guangzhou New TV Tower. As compared with the global eigenparameters, the substructural eigenparameters bear larger changes caused by the local damage and thus are more sensitive to the local damage.

  7. CHEMTRAN and the Interconversion of Chemical Substructure Systems

    ERIC Educational Resources Information Center

    Granito, Charles E.

    1973-01-01

    The need for the interconversion of chemical substructure systems is discussed and CHEMTRAN, a new service, designed especially for creating interconversion programs, is introduced. (7 references) (Author)

  8. The Smad3 linker region contains a transcriptional activation domain.

    PubMed

    Wang, Guannan; Long, Jianyin; Matsuura, Isao; He, Dongming; Liu, Fang

    2005-02-15

    Transforming growth factor-beta (TGF-beta)/Smads regulate a wide variety of biological responses through transcriptional regulation of target genes. Smad3 plays a key role in TGF-beta/Smad-mediated transcriptional responses. Here, we show that the proline-rich linker region of Smad3 contains a transcriptional activation domain. When the linker region is fused to a heterologous DNA-binding domain, it activates transcription. We show that the linker region physically interacts with p300. The adenovirus E1a protein, which binds to p300, inhibits the transcriptional activity of the linker region, and overexpression of p300 can rescue the linker-mediated transcriptional activation. In contrast, an adenovirus E1a mutant, which cannot bind to p300, does not inhibit the linker-mediated transcription. The native Smad3 protein lacking the linker region is unable to mediate TGF-beta transcriptional activation responses, although it can be phosphorylated by the TGF-beta receptor at the C-terminal tail and has a significantly increased ability to form a heteromeric complex with Smad4. We show further that the linker region and the C-terminal domain of Smad3 synergize for transcriptional activation in the presence of TGF-beta. Thus our findings uncover an important function of the Smad3 linker region in Smad-mediated transcriptional control. PMID:15588252

  9. Robustness analysis applied to substructure controller synthesis

    NASA Technical Reports Server (NTRS)

    Gonzalez-Oberdoerffer, Marcelo F.; Craig, Roy R., Jr.

    1993-01-01

    The stability and robustness of the controlled system obtained via the substructure control synthesis (SCS) method of Su et al. (1990) were examined using a six-bay truss model, and employing an LQG control design method to obtain controllers for two separate structures. It is found that the assembled controller provides a stability in this instance. A qualitative assessment of the stability robustness of the system with controller designed with the SCS method is provided by obtaining a controller using the complete truss model and comparing the robustness of the corresponding closed-loop systems.

  10. Optimal numbers of residues in linkers of DNA polymerase I, T7 primase and DNA polymerase IV.

    PubMed

    Fu, Yi-Ben; Wang, Zhan-Feng; Wang, Peng-Ye; Xie, Ping

    2016-01-01

    DNA polymerase I (PolI), T7 primase and DNA polymerase IV (Dpo4) have a common feature in their structures that the two main domains are connected by an unstructured polypeptide linker. To perform their specific enzymatic activities, the enzymes are required to rearrange the position and orientation of one domain relative to the other into an active mode. Here, we show that the three enzymes share the same mechanism of the transition from the inert to active modes and use the minimum numbers of residues in their linkers to achieve the most efficient transitions. The transition time to the finally active mode is sensitively dependent on the stretched length of the linker in the finally active mode while is insensitive to the position and orientation in the initially inert state. Moreover, we find that for any enzyme whose two domains are connected by an unstructured flexible linker, the stretched length (L) of the linker in the finally active mode and the optimal number (Nopt) of the residues in the linker satisfy relation L ≈ αNopt, with α = 0.24-0.27 nm being a constant insensitive to the system. PMID:27364863

  11. Optimal numbers of residues in linkers of DNA polymerase I, T7 primase and DNA polymerase IV

    PubMed Central

    Fu, Yi-Ben; Wang, Zhan-Feng; Wang, Peng-Ye; Xie, Ping

    2016-01-01

    DNA polymerase I (PolI), T7 primase and DNA polymerase IV (Dpo4) have a common feature in their structures that the two main domains are connected by an unstructured polypeptide linker. To perform their specific enzymatic activities, the enzymes are required to rearrange the position and orientation of one domain relative to the other into an active mode. Here, we show that the three enzymes share the same mechanism of the transition from the inert to active modes and use the minimum numbers of residues in their linkers to achieve the most efficient transitions. The transition time to the finally active mode is sensitively dependent on the stretched length of the linker in the finally active mode while is insensitive to the position and orientation in the initially inert state. Moreover, we find that for any enzyme whose two domains are connected by an unstructured flexible linker, the stretched length (L) of the linker in the finally active mode and the optimal number (Nopt) of the residues in the linker satisfy relation L ≈ αNopt, with α = 0.24–0.27 nm being a constant insensitive to the system. PMID:27364863

  12. Substructurability: the effect of interface location on a real-time dynamic substructuring test

    PubMed Central

    Neild, S. A.; Lowenberg, M.; Szalai, R.; Krauskopf, B.

    2016-01-01

    A full-scale experimental test for large and complex structures is not always achievable. This can be due to many reasons, the most prominent one being the size limitations of the test. Real-time dynamic substructuring is a hybrid testing method where part of the system is modelled numerically and the rest of the system is kept as the physical test specimen. The numerical–physical parts are connected via actuators and sensors and the interface is controlled by advanced algorithms to ensure that the tested structure replicates the emulated system with sufficient accuracy. The main challenge in such a test is to overcome the dynamic effects of the actuator and associated controller, that inevitably introduce delay into the substructured system which, in turn, can destabilize the experiment. To date, most research concentrates on developing control strategies for stable recreation of the full system when the interface location is given a priori. Therefore, substructurability is mostly studied in terms of control. Here, we consider the interface location as a parameter and study its effect on the stability of the system in the presence of delay due to actuator dynamics and define substructurability as the system’s tolerance to delay in terms of the different interface locations. It is shown that the interface location has a major effect on the tolerable delays in an experiment and, therefore, careful selection of it is necessary. PMID:27616930

  13. Substructural QSAR approaches and topological pharmacophores.

    PubMed Central

    Franke, R; Huebel, S; Streich, W J

    1985-01-01

    For large and diverse data sets, simple QSAR methods based on linear and additive models can no longer be applied. In such cases topological methods using descriptors directly derivable from two-dimensional chemical structures provide a useful alternative. The results of such analyses can be used for lead optimization, to guide biological testing and even aid in the design of novel compounds. Various types of topological descriptors and algorithms are briefly discussed. Which of those is to be selected depends on the objective of the investigation and the properties of the data set. Two new methods, LOGANA and LOCON, are discussed in some more detail. With the help of these methods, substructural patterns ("topological pharmacophores") characteristic of compounds possessing a certain biological property can be evaluated. Both methods are designed in such a way that full use can be made of the data handling capacity of computers while maintaining an optimal impact of the experience of the researcher. They are model-free and do not require any mathematical knowledge. While LOGANA deals with semiquantitative or even qualitative biological data, LOCON can be applied to activity data on a continuous scale. The basic procedure in both cases consists in the stepwise combination of substructural descriptors by the logical operations "and," "or" and "not." With a simple example the utility of the methods is demonstrated. PMID:3905376

  14. Effects of the linker region on the structure and function of modular GH5 cellulases.

    PubMed

    Ruiz, Diego M; Turowski, Valeria R; Murakami, Mario T

    2016-01-01

    The association of glycosyl hydrolases with catalytically inactive modules is a successful evolutionary strategy that is commonly used by biomass-degrading microorganisms to digest plant cell walls. The presence of accessory domains in these enzymes is associated with properties such as higher catalytic efficiency, extension of the catalytic interface and targeting of the enzyme to the proper substrate. However, the importance of the linker region in the synergistic action of the catalytic and accessory domains remains poorly understood. Thus, this study examined how the inter-domain region affects the structure and function of modular GH5 endoglucanases, by using cellulase 5A from Bacillus subtilis (BsCel5A) as a model. BsCel5A variants featuring linkers with different stiffnesses or sizes were designed and extensively characterized, revealing that changes in flexibility or rigidity in this region differentially affect kinetic behavior. Regarding the linker length, we found that precise inter-domain spacing is required to enable efficient hydrolysis because excessively long or short linkers were equally detrimental to catalysis. Together, these findings identify molecular and structural features that may contribute to the rational design of chimeric and multimodular glycosyl hydrolases. PMID:27334041

  15. Effects of the linker region on the structure and function of modular GH5 cellulases

    PubMed Central

    Ruiz, Diego M.; Turowski, Valeria R.; Murakami, Mario T.

    2016-01-01

    The association of glycosyl hydrolases with catalytically inactive modules is a successful evolutionary strategy that is commonly used by biomass-degrading microorganisms to digest plant cell walls. The presence of accessory domains in these enzymes is associated with properties such as higher catalytic efficiency, extension of the catalytic interface and targeting of the enzyme to the proper substrate. However, the importance of the linker region in the synergistic action of the catalytic and accessory domains remains poorly understood. Thus, this study examined how the inter-domain region affects the structure and function of modular GH5 endoglucanases, by using cellulase 5A from Bacillus subtilis (BsCel5A) as a model. BsCel5A variants featuring linkers with different stiffnesses or sizes were designed and extensively characterized, revealing that changes in flexibility or rigidity in this region differentially affect kinetic behavior. Regarding the linker length, we found that precise inter-domain spacing is required to enable efficient hydrolysis because excessively long or short linkers were equally detrimental to catalysis. Together, these findings identify molecular and structural features that may contribute to the rational design of chimeric and multimodular glycosyl hydrolases. PMID:27334041

  16. Halo Substructure and the Power Spectrum

    NASA Astrophysics Data System (ADS)

    Zentner, Andrew R.; Bullock, James S.

    2003-11-01

    We present a semianalytic model to investigate the merger history, destruction rate, and survival probability of substructure in hierarchically formed dark matter halos and use it to study the substructure content of halos as a function of input primordial power spectrum. For a standard cold dark matter ``concordance'' cosmology (ΛCDM n=1, σ8=0.95) we successfully reproduce the subhalo velocity function and radial distribution profile seen in N-body simulations and determine that the rate of merging and disruption peaks ~10-12 Gyr in the past for Milky Way-like halos, while surviving substructures are typically accreted within the last ~0-8 Gyr. We explore power spectra with normalizations and spectral ``tilts'' spanning the ranges σ8~=1-0.65 and n~=1-0.8, and include a ``running-index'' model with dn/dlnk=-0.03 similar to the best-fit model discussed in the first-year Wilkinson Microwave Anisotropy Probe (WMAP) report. We investigate spectra with truncated small-scale power, including a broken-scale inflation model and three warm dark matter cases with mW=0.75-3.0 keV. We find that the mass fraction in substructure is relatively insensitive to the tilt and overall normalization of the primordial power spectrum. All of the CDM-type models yield projected substructure mass fractions that are consistent with, but on the low side, of published estimates from strong lens systems: f9=0.4%-1.5% (64th percentile) for subhalos smaller than 109 Msolar within projected cylinders of radius r<10 kpc. Truncated models produce significantly smaller fractions, f9=0.02%-0.2% for mW~=1 keV, and are disfavored by lensing estimates. This suggests that lensing and similar probes can provide a robust test of the CDM paradigm and a powerful constraint on broken-scale inflation/warm particle masses, including masses larger than the ~1 keV upper limits of previous studies. We compare our predicted subhalo velocity functions with the dwarf satellite population of the Milky Way. Assuming

  17. Kluyveromyces lactis genome harbours a functional linker histone encoding gene.

    PubMed

    Staneva, Dessislava; Georgieva, Milena; Miloshev, George

    2016-06-01

    Linker histones are essential components of chromatin in eukaryotes. Through interactions with linker DNA and nucleosomes they facilitate folding and maintenance of higher-order chromatin structures and thus delicately modulate gene activity. The necessity of linker histones in lower eukaryotes appears controversial and dubious. Genomic data have shown that Schizosaccharomyces pombe does not possess genes encoding linker histones while Kluyveromyces lactis has been reported to have a pseudogene. Regarding this controversy, we have provided the first direct experimental evidence for the existence of a functional linker histone gene, KlLH1, in K. lactis genome. Sequencing of KlLH1 from both genomic DNA and copy DNA confirmed the presence of an intact open reading frame. Transcription and splicing of the KlLH1 sequence as well as translation of its mRNA have been studied. In silico analysis revealed homology of KlLH1p to the histone H1/H5 protein family with predicted three domain structure characteristic for the linker histones of higher eukaryotes. This strongly proves that the yeast K. lactis does indeed possess a functional linker histone gene thus entailing the evolutionary preservation and significance of linker histones. The nucleotide sequences of KlLH1 are deposited in the GenBank under accession numbers KT826576, KT826577 and KT826578. PMID:27189369

  18. Substructuring and poroelastic modelling of the intervertebral disc.

    PubMed

    Swider, P; Pédrono, A; Ambard, D; Accadbled, F; Sales de Gauzy, J

    2010-05-01

    We proposed a substructure technique to predict the time-dependant response of biological tissue within the framework of a finite element resolution. Theoretical considerations in poroelasticity preceded the calculation of the sub-structured poroelastic matrix. The transient response was obtained using an exponential fitting method. We computed the creep response of an MRI 3D reconstructed L(5)-S(1) intervertebral disc of a scoliotic spine. The FE model was reduced from 10,000 degrees of freedom for the full 3D disc to only 40 degrees of freedom for the sub-structured model defined by 10 nodes attached to junction nodes located on both lower and upper surfaces of the disc. Comparisons of displacement fields were made between the full poroelastic FE model and the sub-structured model in three different loading conditions: compression, offset compression and torsion. Discrepancies in displacement were lower than 10% for the first time steps when time-dependant events were significant. The substructuring technique provided an exact solution in quasi-static behavior after pressure relaxation. Couplings between vertical and transversal displacements predicted by the reference FE model were well stored by the sub-structured model despite the drastic reduction of degrees of freedom. Finally, we demonstrated that substructuring was very efficient to reduce the size of numerical models while respecting the time-dependant behavior of the structure. This result highlighted the potential interest of substructure techniques in large-scale models of musculoskeletal structures. PMID:20170917

  19. 8. Detail showing concrete abutment, showing substructure of bridge, specifically ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    8. Detail showing concrete abutment, showing substructure of bridge, specifically west side of arch and substructure. - Presumpscot Falls Bridge, Spanning Presumptscot River at Allen Avenue extension, 0.75 mile west of U.S. Interstate 95, Falmouth, Cumberland County, ME

  20. Substructure synthesis method for simulating large molecular complexes

    PubMed Central

    Ming, Dengming; Kong, Yifei; Wu, Yinghao; Ma, Jianpeng

    2003-01-01

    This paper reports a computational method for describing the conformational flexibility of very large biomolecular complexes using a reduced number of degrees of freedom. It is called the substructure synthesis method, and the basic concept is to treat the motions of a given structure as a collection of those of an assemblage of substructures. The choice of substructures is arbitrary and sometimes quite natural, such as domains, subunits, or even large segments of biomolecular complexes. To start, a group of low-frequency substructure modes is determined, for instance by normal mode analysis, to represent the motions of the substructure. Next, a desired number of substructures are joined together by a set of constraints to enforce geometric compatibility at the interface of adjacent substructures, and the modes for the assembled structure can then be synthesized from the substructure modes by applying the Rayleigh–Ritz principle. Such a procedure is computationally much more desirable than solving the full eigenvalue problem for the whole assembled structure. Furthermore, to show the applicability to biomolecular complexes, the method is used to study F-actin, a large filamentous molecular complex involved in many cellular functions. The results demonstrate that the method is capable of studying the motions of very large molecular complexes that are otherwise completely beyond the reach of any conventional methods. PMID:12518058

  1. A Simple and Effective Cleavable Linker for Chemical Proteomics Applications*

    PubMed Central

    Yang, Yinliang; Hahne, Hannes; Kuster, Bernhard; Verhelst, Steven H. L.

    2013-01-01

    The study of metabolically labeled or probe-modified proteins is an important area in chemical proteomics. Isolation and purification of the protein targets is a necessary step before MS identification. The biotin-streptavidin system is widely used in this process, but the harsh denaturing conditions also release natively biotinylated proteins and non-selectively bound proteins. A cleavable linker strategy is a promising approach for solving this problem. Though several cleavable linkers have been developed and tested, an efficient, easily synthesized, and inexpensive cleavable linker is a desirable addition to the proteomics toolbox. Here, we describe the chemical proteomics application of a vicinal diol cleavable linker. Through easy-to-handle chemistry we incorporate this linker into an activity-based probe and a biotin alkyne tag amenable for bioorthogonal ligation. With these reagents, background protein identifications are significantly reduced relative to standard on-bead digestion. PMID:23028061

  2. Mutations in Biosynthetic Enzymes for the Protein Linker Region of Chondroitin/Dermatan/Heparan Sulfate Cause Skeletal and Skin Dysplasias.

    PubMed

    Mizumoto, Shuji; Yamada, Shuhei; Sugahara, Kazuyuki

    2015-01-01

    Glycosaminoglycans, including chondroitin, dermatan, and heparan sulfate, have various roles in a wide range of biological events such as cell signaling, cell proliferation, tissue morphogenesis, and interactions with various growth factors. Their polysaccharides covalently attach to the serine residues on specific core proteins through the common linker region tetrasaccharide, -xylose-galactose-galactose-glucuronic acid, which is produced through the stepwise addition of respective monosaccharides by four distinct glycosyltransferases. Mutations in the human genes encoding the glycosyltransferases responsible for the biosynthesis of the linker region tetrasaccharide cause a number of genetic disorders, called glycosaminoglycan linkeropathies, including Desbuquois dysplasia type 2, spondyloepimetaphyseal dysplasia, Ehlers-Danlos syndrome, and Larsen syndrome. This review focused on recent studies on genetic diseases caused by defects in the biosynthesis of the common linker region tetrasaccharide. PMID:26582078

  3. Mutations in Biosynthetic Enzymes for the Protein Linker Region of Chondroitin/Dermatan/Heparan Sulfate Cause Skeletal and Skin Dysplasias

    PubMed Central

    Mizumoto, Shuji; Yamada, Shuhei; Sugahara, Kazuyuki

    2015-01-01

    Glycosaminoglycans, including chondroitin, dermatan, and heparan sulfate, have various roles in a wide range of biological events such as cell signaling, cell proliferation, tissue morphogenesis, and interactions with various growth factors. Their polysaccharides covalently attach to the serine residues on specific core proteins through the common linker region tetrasaccharide, -xylose-galactose-galactose-glucuronic acid, which is produced through the stepwise addition of respective monosaccharides by four distinct glycosyltransferases. Mutations in the human genes encoding the glycosyltransferases responsible for the biosynthesis of the linker region tetrasaccharide cause a number of genetic disorders, called glycosaminoglycan linkeropathies, including Desbuquois dysplasia type 2, spondyloepimetaphyseal dysplasia, Ehlers-Danlos syndrome, and Larsen syndrome. This review focused on recent studies on genetic diseases caused by defects in the biosynthesis of the common linker region tetrasaccharide. PMID:26582078

  4. Support Substructures: Support-Induced Part-Level Structural Representation.

    PubMed

    Huang, Shi-Sheng; Fu, Hongbo; Wei, Ling-Yu; Hu, Shi-Min

    2016-08-01

    In this work we explore a support-induced structural organization of object parts. We introduce the concept of support substructures, which are special subsets of object parts with support and stability. A bottom-up approach is proposed to identify such substructures in a support relation graph. We apply the derived high-level substructures to part-based shape reshuffling between models, resulting in nontrivial functionally plausible model variations that are difficult to achieve with symmetry-induced substructures by the state-of-the-art methods. We also show how to automatically or interactively turn a single input model to new functionally plausible shapes by structure rearrangement and synthesis, enabled by support substructures. To the best of our knowledge no single existing method has been designed for all these applications. PMID:26336128

  5. Novel Polymer Linkers for Single Molecule AFM Force Spectroscopy

    PubMed Central

    Tong, Zenghan; Mikheikin, Andrey; Krasnoslobodtsev, Alexey; Lv, Zhengjian; Lyubchenko, Yuri L.

    2013-01-01

    Flexible polymer linkers play an important role in various imaging and probing techniques that require surface immobilization, including atomic force microscopy (AFM). In AFM force spectroscopy, polymer linkers are necessary for the covalent attachment of molecules of interest to the AFM tip and the surface. The polymer linkers tether the molecules and provide their proper orientation in probing experiments. Additionally, the linkers separate specific interactions from nonspecific short-range adhesion and serve as a reference point for the quantitative analysis of single molecule probing events. In this report, we present our results on the synthesis and testing of a novel polymer linker and the identification of a number of potential applications for its use in AFM force spectroscopy experiments. The synthesis of the linker is based on the well-developed phosphoramidate (PA) chemistry that allows the routine synthesis of linkers with predetermined lengths and PA composition. These linkers are homogeneous in length and can be terminated with various functional groups. PA linkers with different functional groups were synthesized and tested in experimental systems utilizing different immobilization chemistries. We probed interactions between complementary DNA oligonucleotides; DNA and protein complexes formed by the site-specific binding protein SfiI; and interactions between amyloid peptide (Aβ42). The results of the AFM force spectroscopy experiments validated the feasibility of the proposed approach for the linker design and synthesis. Furthermore, the properties of the tether (length, functional groups) can be adjusted to meet the specific requirements for different force spectroscopy experiments and system characteristics, suggesting that it could be used for a large number of various applications. PMID:23624104

  6. Characterization of T-Even Bacteriophage Substructures

    PubMed Central

    Cummings, Donald J.; Kusy, A. R.; Chapman, V. A.; DeLong, S. S.; Stone, K. R.

    1970-01-01

    T-even bacteriophages were grown and purified in bulk quantities. The protein coats were disrupted into their component substructures by treatment with 67% dimethyl sulfoxide (DMSO). Tail fibers and tubes were purified on glycerol-CsCl-D2O gradients and examined with respect to sedimentation properties, subunit molecular weights, amino acid composition, isoelectric points, and morphology. It was found that intact tail fibers had a sedimentation coefficient of 12 to 13S and that dissociated fibers consisted of three classes of proteins having molecular weights of 150 K ± 10, 42 K ± 4, and 28 K ± 3 daltons. A model was constructed in which the 150-K subunit folded back on itself twice to give a three-stranded rope. Each 150-K subunit then represented a half-fiber and it was proposed that the role of the 42- and 28-K subunits was to hold each half-fiber together as well as serve as a possible link with other substructures. Isoelectric point studies also indicated that there were three different proteins with pI values of 3.5, 5.7, and 8.0. Amino acid analyses indicated that fibers had a composition distinct from other phage substructures. In addition, a striking difference was noted in the content of tryptophan among the phages examined. T4B had three to five times more tryptophan than did T2L, T2H, T4D, and T6. Intact tail tubes had an S20,w of 31 to 38S and dissociated tubes consisted of three proteins of molecular weights 57 K ± 5, 38 K ± 4, and 25 K ± 3 daltons. Based on degradation studies with DMSO, it was proposed that these three proteins were arranged in a helical array yielding the tube structure. Isoelectric point studies indicated that there were three major proteins in the tube whose pI values were 5.1, 5.7, and 8.5. No significant differences were observed in the amino acid content of tubes obtained from all the T-even bacteriophages. Images PMID:5497900

  7. Structural requirements for the interdomain linker of alpha subunit of Escherichia coli RNA polymerase.

    PubMed

    Fujita, N; Endo, S; Ishihama, A

    2000-05-23

    The carboxy-terminal domain of the alpha subunit of Escherichia coli RNA polymerase, which is connected with the core part of RNA polymerase through a long flexible linker, plays decisive roles in transcription activation by directly interacting with a large number of transcription factors and upstream (UP) element DNA. Here we constructed a set of mutant RNA polymerases, each containing a mutant alpha subunit with an altered interdomain linker. Deletion of three amino acids from the linker exhibited 50% inhibition of cAMP receptor protein- (CRP-) dependent lac P1 transcription. Deletion of six amino acids completely knocked out the activity. Insertion of three amino acids did not affect the activity, whereas 40-60% inhibition was observed after insertion of one, two, or four amino acids. Substitution of 10 consecutive glycine residues resulted in nearly 90% reduction of the CRP-dependent activity, whereas 50% activity was retained after substitution of 10 proline residues or a sequence expected to form a strong alpha-helix. Essentially the same results were obtained with UP element-dependent rrnB P1 transcription. These observations altogether suggest that (i) sufficient length of the interdomain linker is required for transcription activation mediated by the alpha carboxy-terminal domain, (ii) the linker is not totally unstructured but has structural and torsional preferences to facilitate positioning of the carboxy-terminal domain to a proper location for the interaction with CRP and UP element, and (iii) CRP-dependent activation and UP element-dependent activation share a common intermediary state in which the positioning of the alpha carboxy-terminal domain is of primary importance. PMID:10821700

  8. The Sam68 nuclear body is composed of two RNase-sensitive substructures joined by the adaptor HNRNPL.

    PubMed

    Mannen, Taro; Yamashita, Seisuke; Tomita, Kozo; Goshima, Naoki; Hirose, Tetsuro

    2016-07-01

    The mammalian cell nucleus contains membraneless suborganelles referred to as nuclear bodies (NBs). Some NBs are formed with an architectural RNA (arcRNA) as the structural core. Here, we searched for new NBs that are built on unidentified arcRNAs by screening for ribonuclease (RNase)-sensitive NBs using 32,651 fluorescently tagged human cDNA clones. We identified 32 tagged proteins that required RNA for their localization in distinct nuclear foci. Among them, seven RNA-binding proteins commonly localized in the Sam68 nuclear body (SNB), which was disrupted by RNase treatment. Knockdown of each SNB protein revealed that SNBs are composed of two distinct RNase-sensitive substructures. One substructure is present as a distinct NB, termed the DBC1 body, in certain conditions, and the more dynamic substructure including Sam68 joins to form the intact SNB. HNRNPL acts as the adaptor to combine the two substructures and form the intact SNB through the interaction of two sets of RNA recognition motifs with the putative arcRNAs in the respective substructures. PMID:27377249

  9. Exploring dark matter with Milky Way substructure.

    PubMed

    Kuhlen, Michael; Madau, Piero; Silk, Joseph

    2009-08-21

    The unambiguous detection of dark matter annihilation in our Galaxy would unravel one of the most outstanding puzzles in particle physics and cosmology. Recent observations have motivated models in which the annihilation rate is boosted by the Sommerfeld effect, a nonperturbative enhancement arising from a long-range attractive force. We applied the Sommerfeld correction to Via Lactea II, a high-resolution N-body simulation of a Milky Way-sized galaxy, to investigate the phase-space structure of the galactic halo. We found that the annihilation luminosity from kinematically cold substructure could be enhanced by orders of magnitude relative to previous calculations, leading to the prediction of gamma-ray fluxes from as many as several hundred dark clumps that should be detectable by the Fermi satellite. PMID:19608862

  10. Star-forming Substructure within Molecular Clouds

    NASA Astrophysics Data System (ADS)

    Di Francesco, James

    2013-03-01

    Wide-field far-infrared/submillimeter continuum maps of molecular clouds by the Herschel Space Observatory GBS and HOBYS surveys are revealing the star-forming substructures that lead to star formation in dense gas. In particular, these maps have revealed the central role in clouds of filaments, likely formed through turbulent motions. These filaments appear to be non-isothermal and fragment into cores only when their column densities exceed a stability threshold. Organizations of filament networks suggest the relative role of turbulence and gravity can be traced in different parts of a cloud, and filament intersections may lead to larger amounts of mass flow that form the precursors of high-mass stars or clusters.

  11. Probabilistic Component Mode Synthesis of Nondeterministic Substructures

    NASA Technical Reports Server (NTRS)

    Brown, Andrew M.; Ferri, Aldo A.

    1996-01-01

    Standard methods of structural dynamic analysis assume that the structural characteristics are deterministic. Recognizing that these characteristics are actually statistical in nature researchers have recently developed a variety of methods that use this information to determine probabilities of a desired response characteristic, such as natural frequency, without using expensive Monte Carlo simulations. One of the problems in these methods is correctly identifying the statistical properties of primitive variables such as geometry, stiffness, and mass. We present a method where the measured dynamic properties of substructures are used instead as the random variables. The residual flexibility method of component mode synthesis is combined with the probabilistic methods to determine the cumulative distribution function of the system eigenvalues. A simple cantilever beam test problem is presented that illustrates the theory.

  12. A case of poor substructure diagnostics

    NASA Technical Reports Server (NTRS)

    Butler, Thomas G.

    1992-01-01

    The NASTRAN Manuals in the substructuring area are all geared toward instant success, but the solution paths are fraught with many traps for human error. Thus, the probability of suffering a fatal abort is high. In such circumstances, the necessity for diagnostics that are user friendly is paramount. This paper is written in the spirit of improving the diagnostics as well as the documentation in one area where the author felt he was backed into a blind corner as a result of his having committed a data oversight. This topic is aired by referring to an analysis of a particular structure. The structure, under discussion, used a number of local coordinate systems that simplified the preparation of input data. The principle features of this problem are introduced by reference to a series of figures.

  13. Early dynamical evolution of substructured stellar clusters

    NASA Astrophysics Data System (ADS)

    Dorval, Julien; Boily, Christian

    2015-08-01

    It is now widely accepted that stellar clusters form with a high level of substructure (Kuhn et al. 2014, Bate 2009), inherited from the molecular cloud and the star formation process. Evidence from observations and simulations also indicate the stars in such young clusters form a subvirial system (Kirk et al. 2007, Maschberger et al. 2010). The subsequent dynamical evolution can cause important mass loss, ejecting a large part of the birth population in the field. It can also imprint the stellar population and still be inferred from observations of evolved clusters. Nbody simulations allow a better understanding of these early twists and turns, given realistic initial conditions. Nowadays, substructured, clumpy young clusters are usually obtained through pseudo-fractal growth (Goodwin et al. 2004) and velocity inheritance. Such models are visually realistics and are very useful, they are however somewhat artificial in their velocity distribution. I introduce a new way to create clumpy initial conditions through a "Hubble expansion" which naturally produces self consistent clumps, velocity-wise. A velocity distribution analysis shows the new method produces realistic models, consistent with the dynamical state of the newly created cores in hydrodynamic simulation of cluster formation (Klessen & Burkert 2000). I use these initial conditions to investigate the dynamical evolution of young subvirial clusters, up to 80000 stars. I find an overall soft evolution, with hierarchical merging leading to a high level of mass segregation. I investigate the influence of the mass function on the fate of the cluster, specifically on the amount of mass loss induced by the early violent relaxation. Using a new binary detection algorithm, I also find a strong processing of the native binary population.

  14. Distant Galactic Halo Substructures Observed by the Palomar Transient Factory

    NASA Astrophysics Data System (ADS)

    Sesar, Branimir

    2013-01-01

    Characterization of Galactic halo substructures is important as their kinematic and chemical properties help constrain the properties of the Galactic dark matter halo, the formation history of the Milky Way, and the galaxy formation process in general. The best practical choice for finding distant halo substructures are pulsating RR Lyrae stars, due to their intrinsic brightness (M_V = 0.6 mag) and distinct light curves. I will present kinematic and chemical properties of two distant halo substructures that were traced using RR Lyrae stars observed by the Palomar Transient Factory. One of these substructures, located at 90 kpc from the Sun in the Cancer constellation, consists of two groups of RR Lyrae stars moving away from the Galaxy at ~80 and ~20 km/s, respectively. The second substructure is located at ~65 kpc from the Sun in the Hercules constellation. The kinematics of RR Lyrae stars tracing this substructure suggest a presence of 2 or 3 stellar streams extending in the similar direction on the sky. Due to their spatial extent, both of these substructures are clearly disrupted and would be very difficult to detect using tradiitonal techniques such as the color-magnitude diagram filtering.

  15. Flexible substructure online hybrid test system using conventional testing devices

    NASA Astrophysics Data System (ADS)

    Wang, Tao; Nakashima, Masayoshi

    2013-09-01

    This paper presents a substructure online hybrid test system that is extensible for geographically distributed tests. This system consists of a set of devices conventionally used for cyclic tests to load the tested substructures onto the target displacement or the target force. Due to their robustness and portability, individual sets of conventional loading devices can be transported and reconfigured to realize physical loading in geographically remote laboratories. Another appealing feature is the flexible displacement-force mixed control that is particularly suitable for specimens having large disparities in stiffness during various performance stages. To conduct a substructure online hybrid test, an extensible framework is developed, which is equipped with a generalized interface to encapsulate each substructure. Multiple tested substructures and analyzed substructures using various structural program codes can be accommodated within the single framework, simply interfaced with the boundary displacements and forces. A coordinator program is developed to keep the boundaries among all substructures compatible and equilibrated. An Internet-based data exchange scheme is also devised to transfer data among computers equipped with different software environments. A series of online hybrid tests are introduced, and the portability, flexibility, and extensibility of the online hybrid test system are demonstrated.

  16. Tandem oligonucleotide synthesis using linker phosphoramidites

    PubMed Central

    Pon, Richard T.; Yu, Shuyuan

    2005-01-01

    Multiple oligonucleotides of the same or different sequence, linked end-to-end in tandem can be synthesized in a single automated synthesis. A linker phosphoramidite [R. T. Pon and S. Yu (2004) Nucleic Acids Res., 32, 623–631] is added to the 5′-terminal OH end of a support-bound oligonucleotide to introduce a cleavable linkage (succinic acid plus sulfonyldiethanol) and the 3′-terminal base of the new sequence. Conventional phosphoramidites are then used for the rest of the sequence. After synthesis, treatment with ammonium hydroxide releases the oligonucleotides from the support and cleaves the linkages between each sequence. Mixtures of one oligonucleotide with both 5′- and 3′-terminal OH ends and other oligonucleotides with 5′-phosphorylated and 3′-OH ends are produced, which are deprotected and worked up as a single product. Tandem synthesis can be used to make pairs of PCR primers, sets of cooperative oligonucleotides or multiple copies of the same sequence. When tandem synthesis is used to make two self-complementary sequences, double-stranded structures spontaneously form after deprotection. Tandem synthesis of oligonucleotide chains containing up to six consecutive 20mer (120 bases total), various trinucleotide codons and primer pairs for PCR, or self-complementary strands for in situ formation of double-stranded DNA fragments has been demonstrated. PMID:15814811

  17. Substructure System Identification for Finite Element Model Updating

    NASA Technical Reports Server (NTRS)

    Craig, Roy R., Jr.; Blades, Eric L.

    1997-01-01

    This report summarizes research conducted under a NASA grant on the topic 'Substructure System Identification for Finite Element Model Updating.' The research concerns ongoing development of the Substructure System Identification Algorithm (SSID Algorithm), a system identification algorithm that can be used to obtain mathematical models of substructures, like Space Shuttle payloads. In the present study, particular attention was given to the following topics: making the algorithm robust to noisy test data, extending the algorithm to accept experimental FRF data that covers a broad frequency bandwidth, and developing a test analytical model (TAM) for use in relating test data to reduced-order finite element models.

  18. Substructuring by Lagrange multipliers for solids and plates

    SciTech Connect

    Mandel, J.; Tezaur, R.; Farhat, C.

    1996-12-31

    We present principles and theoreretical foundation of a substructuring method for large structural problems. The algorithm is preconditioned conjugate gradients on a subspace for the dual problem. The preconditioning is proved asymptotically optimal and the method is shown to be parallel scalable, i.e., the condition number is bounded independently of the number of substructures. For plate problems, a special modification is needed that retains continuity of the displacement solution at substructure crosspoints, resulting in an asymptically optimal method. The results are confirmed by numerical experiments.

  19. Correlation among DNA Linker Length, Linker Histone Concentration, and Histone Tails in Chromatin.

    PubMed

    Luque, Antoni; Ozer, Gungor; Schlick, Tamar

    2016-06-01

    Eukaryotic cells condense their genetic material in the nucleus in the form of chromatin, a macromolecular complex made of DNA and multiple proteins. The structure of chromatin is intimately connected to the regulation of all eukaryotic organisms, from amoebas to humans, but its organization remains largely unknown. The nucleosome repeat length (NRL) and the concentration of linker histones (ρLH) are two structural parameters that vary among cell types and cell cycles; the NRL is the number of DNA basepairs wound around each nucleosome core plus the number of basepairs linking successive nucleosomes. Recent studies have found a linear empirical relationship between the variation of these two properties for different cells, but its underlying mechanism remains elusive. Here we apply our established mesoscale chromatin model to explore the mechanisms responsible for this relationship, by investigating chromatin fibers as a function of NRL and ρLH combinations. We find that a threshold of linker histone concentration triggers the compaction of chromatin into well-formed 30-nm fibers; this critical value increases linearly with NRL, except for long NRLs, where the fibers remain disorganized. Remarkably, the interaction patterns between core histone tails and chromatin elements are highly sensitive to the NRL and ρLH combination, suggesting a molecular mechanism that could have a key role in regulating the structural state of the fibers in the cell. An estimate of the minimized work and volume associated with storage of chromatin fibers in the nucleus further suggests factors that could spontaneously regulate the NRL as a function of linker histone concentration. Both the tail interaction map and DNA packing considerations support the empirical NRL/ρLH relationship and offer a framework to interpret experiments for different chromatin conditions in the cell. PMID:27276249

  20. Molecular Basis of Valine-Citrulline-PABC Linker Instability in Site-Specific ADCs and Its Mitigation by Linker Design.

    PubMed

    Dorywalska, Magdalena; Dushin, Russell; Moine, Ludivine; Farias, Santiago E; Zhou, Dahui; Navaratnam, Thayalan; Lui, Victor; Hasa-Moreno, Adela; Casas, Meritxell Galindo; Tran, Thomas-Toan; Delaria, Kathy; Liu, Shu-Hui; Foletti, Davide; O'Donnell, Christopher J; Pons, Jaume; Shelton, David L; Rajpal, Arvind; Strop, Pavel

    2016-05-01

    The degree of stability of antibody-drug linkers in systemic circulation, and the rate of their intracellular processing within target cancer cells are among the key factors determining the efficacy of antibody-drug conjugates (ADC) in vivo Previous studies demonstrated the susceptibility of cleavable linkers, as well as auristatin-based payloads, to enzymatic cleavage in rodent plasma. Here, we identify Carboxylesterase 1C as the enzyme responsible for the extracellular hydrolysis of valine-citrulline-p-aminocarbamate (VC-PABC)-based linkers in mouse plasma. We further show that the activity of Carboxylesterase 1C towards VC-PABC-based linkers, and consequently the stability of ADCs in mouse plasma, can be effectively modulated by small chemical modifications to the linker. While the introduced modifications can protect the VC-PABC-based linkers from extracellular cleavage, they do not significantly alter the intracellular linker processing by the lysosomal protease Cathepsin B. The distinct substrate preference of the serum Carboxylesterase 1C offers the opportunity to modulate the extracellular stability of cleavable ADCs without diminishing the intracellular payload release required for ADC efficacy. Mol Cancer Ther; 15(5); 958-70. ©2016 AACR. PMID:26944918

  1. Reactivity and applications of new amine reactive cross-linkers for mass spectrometric detection of protein-protein complexes.

    PubMed

    Bich, Claudia; Maedler, Stefanie; Chiesa, Katja; DeGiacomo, Fabio; Bogliotti, Nicolas; Zenobi, Renato

    2010-01-01

    Chemical cross-linking of proteins permits the stabilization of noncovalent complexes through introduction of covalent bonds. A crucial challenge is to find the fastest and most efficient cross-linkers in order to minimize reaction times and to handle delicate complexes. New cross-linkers were synthesized by introducing N-hydroxyphthalimide, hydroxybenzotriazole, and 1-hydroxy-7-azabenzotriazole as leaving groups instead of the commonly used N-hydroxysuccimidyl moiety. With the use of matrix-assisted laser desorption ionization (MALDI) mass spectrometry, these new cross-linkers were then compared with the commercially available disuccinimidyl suberate (DSS) for covalent stabilization of the gluthatione-S-transferase (GST) dimer and of an antibody-antigen complex. They showed a better efficiency, generated about 30% more cross-linked complex, and reacted about 10 times faster than DSS. The reaction with the GST dimer was utilized to get information about their reaction efficiency and kinetics. Their ability to stabilize only specific protein complexes was verified by incubating them with a mixture of the proteins GST and ubiquitin. Finally, the cross-linkers were incubated with synthetic peptides to study the selectivity of the binding with various amino acid side chains. Not only lysine but also tyrosine was found to react with the newly synthesized cross-linker containing 1-hydroxy-7-azabenzotriazole as the reactive group. PMID:19994840

  2. Creep induced substructures in titanium aluminide

    NASA Astrophysics Data System (ADS)

    Cerreta, Ellen Kathleen

    Many investigations have examined the creep properties of titanium aluminides. Attempts to classify observed behaviors with existing models for high temperature deformation have been met with limited success. Several researchers have shown that an understanding of substructural evolution in the early stages of the creep curve may offer insight into the mechanisms, which control the rate of deformation. Creep deformation has been shown to include twinning, recrystallization, grain boundary sliding, ordinary and super dislocation activity, and faulting depending on the microstructure of the alloy and testing conditions. However, the environments that these alloys are likely to be exposed to are not similar to the test conditions in the literature. Furthermore the emphasis of much of the research into this group of alloys has been on the effects of microstructure particularly, the volume fraction of lamellar phase and ternary elemental additions. With all of these studies little information is available on the deformation behavior of the gamma phase. The alloys in these studies are mostly composed of the gamma phase and yet its creep behavior is not well understood. For this reason single phase binary gamma titanium aluminides were investigated in this study. To understand the effects of aluminum, interstitial oxygen content, and stress on creep, five alloys of varying Al concentrations and interstitial oxygen contents were deformed at temperatures ranging from 700--800°C and at stresses of 150, 200, and 250MPa. Full creep curves were developed under these conditions and phenomenological parameters for creep were calculated from these data. Additional tests were interrupted during primary and secondary creep at 760°C. Specimens from the interrupted tests as well as from the as-processed materials were examined optically and by TEM. Creep data and the microscopy were analyzed in concert to determine rate-controlling mechanisms for creep. Evolution of the substructure

  3. Linker-mediated assembly of gold nanoparticles into multimeric motifs

    NASA Astrophysics Data System (ADS)

    Sikora, Mateusz; Szymczak, Piotr; Thompson, Damien; Cieplak, Marek

    2011-11-01

    We present a theoretical description of linker-mediated self-assembly of gold nanoparticles (Au-NP). Using mesoscale simulations with a coarse-grained model for the Au NPs and dirhenium-based linker molecules, we investigate the conditions under which large clusters can grow and construct a phase diagram that identifies favorable growth conditions in terms of floating and bound linker concentrations. The findings can be considered as generic, as we expect other NP-linker systems to behave in a qualitatively similar way. In particular, we also discuss the case of antibody-functionalised Au NPs connected by the C-reactive proteins (CRPs). We extract some general rules for NP linking that may aid the production of size- and shape-specific NP clusters for technology applications.

  4. Linker-Mediated Self-Assembly Dynamics of Charged Nanoparticles.

    PubMed

    Lin, Guanhua; Chee, See Wee; Raj, Sanoj; Král, Petr; Mirsaidov, Utkur

    2016-08-23

    Using in situ liquid cell transmission electron microscopy (TEM), we visualized a stepwise self-assembly of surfactant-coated and hydrated gold nanoparticles (NPs) into linear chains or branched networks. The NP binding is facilitated by linker molecules, ethylenediammonium, which form hydrogen bonds with surfactant molecules of neighboring NPs. The observed spacing between bound neighboring NPs, ∼15 Å, matches the combined length of two surfactants and one linker molecule. Molecular dynamics simulations reveal that for lower concentrations of linkers, NPs with charged surfactants cannot be fully neutralized by strongly binding divalent linkers, so that NPs carry higher effective charges and tend to form chains, due to poor screening. The highly polar NP surfaces polarize and partly immobilize nearby water molecules, which promotes NPs binding. The presented experimental and theoretical approach allows for detail observation and explanation of self-assembly processes in colloidal nanosystems. PMID:27494560

  5. Linker-mediated assembly of gold nanoparticles into multimeric motifs.

    PubMed

    Sikora, Mateusz; Szymczak, Piotr; Thompson, Damien; Cieplak, Marek

    2011-11-01

    We present a theoretical description of linker-mediated self-assembly of gold nanoparticles (Au-NP). Using mesoscale simulations with a coarse-grained model for the Au NPs and dirhenium-based linker molecules, we investigate the conditions under which large clusters can grow and construct a phase diagram that identifies favorable growth conditions in terms of floating and bound linker concentrations. The findings can be considered as generic, as we expect other NP-linker systems to behave in a qualitatively similar way. In particular, we also discuss the case of antibody-functionalised Au NPs connected by the C-reactive proteins (CRPs). We extract some general rules for NP linking that may aid the production of size- and shape-specific NP clusters for technology applications. PMID:21979426

  6. Linker histones in hormonal gene regulation.

    PubMed

    Vicent, G P; Wright, R H G; Beato, M

    2016-03-01

    In the present review, we summarize advances in our knowledge on the role of the histone H1 family of proteins in breast cancer cells, focusing on their response to progestins. Histone H1 plays a dual role in gene regulation by hormones, both as a structural component of chromatin and as a dynamic modulator of transcription. It contributes to hormonal regulation of the MMTV promoter by stabilizing a homogeneous nucleosome positioning, which reduces basal transcription whereas at the same time promoting progesterone receptor binding and nucleosome remodeling. These combined effects enhance hormone dependent gene transcription, which eventually requires H1 phosphorylation and displacement. Various isoforms of histone H1 have specific functions in differentiated breast cancer cells and compact nucleosomal arrays to different extents in vitro. Genome-wide studies show that histone H1 has a key role in chromatin dynamics of hormone regulated genes. A complex sequence of enzymatic events, including phosphorylation by CDK2, PARylation by PARP1 and the ATP-dependent activity of NURF, are required for H1 displacement and gene de-repression, as a prerequisite for further nucleosome remodeling. Similarly, during hormone-dependent gene repression a dedicated enzymatic mechanism controls H1 deposition at promoters by a complex containing HP1γ, LSD1 and BRG1, the ATPase of the BAF complex. Thus, a broader vision of the histone code should include histone H1, as the linker histone variants actively participate in the regulation of the chromatin structure. How modifications of the core histones tails affect H1 modifications and vice versa is one of the many questions that remains to be addressed to provide a more comprehensive view of the histone cross-talk mechanisms. PMID:26518266

  7. Functional Genomics Reveals Linkers Critical for Influenza Virus Polymerase

    PubMed Central

    Wang, Lulan; Wu, Aiping; Wang, Yao E.; Quanquin, Natalie; Li, Chunfeng; Wang, Jingfeng; Chen, Hsiang-Wen; Liu, Suyang; Liu, Ping; Zhang, Hong; Qin, F. Xiao-Feng

    2015-01-01

    ABSTRACT Influenza virus mRNA synthesis by the RNA-dependent RNA polymerase involves binding and cleavage of capped cellular mRNA by the PB2 and PA subunits, respectively, and extension of viral mRNA by PB1. However, the mechanism for such a dynamic process is unclear. Using high-throughput mutagenesis and sequencing analysis, we have not only generated a comprehensive functional map for the microdomains of individual subunits but also have revealed the PA linker to be critical for polymerase activity. This PA linker binds to PB1 and also forms ionic interactions with the PA C-terminal channel. Nearly all mutants with five-amino-acid insertions in the linker were nonviable. Our model further suggests that the PA linker plays an important role in the conformational changes that occur between stages that favor capped mRNA binding and cleavage and those associated with viral mRNA synthesis. IMPORTANCE The RNA-dependent RNA polymerase of influenza virus consists of the PB1, PB2, and PA subunits. By combining genome-wide mutagenesis analysis with the recently discovered crystal structure of the influenza polymerase heterotrimer, we generated a comprehensive functional map of the entire influenza polymerase complex. We identified the microdomains of individual subunits, including the catalytic domains, the interaction interfaces between subunits, and nine linkers interconnecting different domains. Interestingly, we found that mutants with five-amino-acid insertions in individual linkers were nonviable, suggesting the critical roles these linkers play in coordinating spatial relationships between the subunits. We further identified an extended PA linker that binds to PB1 and also forms ionic interactions with the PA C-terminal channel. PMID:26719244

  8. Linkers in the structural biology of protein–protein interactions

    PubMed Central

    Reddy Chichili, Vishnu Priyanka; Kumar, Veerendra; Sivaraman, J

    2013-01-01

    Linkers or spacers are short amino acid sequences created in nature to separate multiple domains in a single protein. Most of them are rigid and function to prohibit unwanted interactions between the discrete domains. However, Gly-rich linkers are flexible, connecting various domains in a single protein without interfering with the function of each domain. The advent of recombinant DNA technology made it possible to fuse two interacting partners with the introduction of artificial linkers. Often, independent proteins may not exist as stable or structured proteins until they interact with their binding partner, following which they gain stability and the essential structural elements. Gly-rich linkers have been proven useful for these types of unstable interactions, particularly where the interaction is weak and transient, by creating a covalent link between the proteins to form a stable protein–protein complex. Gly-rich linkers are also employed to form stable covalently linked dimers, and to connect two independent domains that create a ligand-binding site or recognition sequence. The lengths of linkers vary from 2 to 31 amino acids, optimized for each condition so that the linker does not impose any constraints on the conformation or interactions of the linked partners. Various structures of covalently linked protein complexes have been described using X-ray crystallography, nuclear magnetic resonance and cryo-electron microscopy techniques. In this review, we evaluate several structural studies where linkers have been used to improve protein quality, to produce stable protein–protein complexes, and to obtain protein dimers. PMID:23225024

  9. 98. DETAIL VIEW OF STORM DAMAGE AND EXPOSED SUBSTRUCTURE, NORTHWEST ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    98. DETAIL VIEW OF STORM DAMAGE AND EXPOSED SUBSTRUCTURE, NORTHWEST SIDE OF 4TH TEE, LOOKING WEST - Huntington Beach Municipal Pier, Pacific Coast Highway at Main Street, Huntington Beach, Orange County, CA

  10. 10. DETAIL OF BRIDGE SUBSTRUCTURE, SHOWING ORIGINAL CONNECTION WITH IRON ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    10. DETAIL OF BRIDGE SUBSTRUCTURE, SHOWING ORIGINAL CONNECTION WITH IRON PINS. VIEW LOOKING WEST FROM FACE OF EAST ABUTMENT. - Annisquam Bridge, Spanning Lobster Cove between Washington & River Streets, Gloucester, Essex County, MA

  11. Substructure view of the Young's Bay Bridge, view looking east, ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    Substructure view of the Young's Bay Bridge, view looking east, north side of the bascule trusswork - Old Young's Bay Bridge, Spanning Young's Bay at Milepoint 6.89 on Warrenton-Astoria Highway (Highway No. 9), Astoria, Clatsop County, OR

  12. EAGLE CREEK BRIDGE, EAST ELEVATION, SUBSTRUCTURE DETAIL LOOKING 333 DEGREES ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    EAGLE CREEK BRIDGE, EAST ELEVATION, SUBSTRUCTURE DETAIL LOOKING 333 DEGREES NORTH-NORTHWEST - Historic Columbia River Highway, Eagle Creek Bridge, Spanning Eagle Creek on Historic Columbia River Highway, Troutdale, Multnomah County, OR

  13. Substructure Main Bridge, Pier A Huey P. Long ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    Substructure - Main Bridge, Pier A - Huey P. Long Bridge, Spanning Mississippi River approximately midway between nine & twelve mile points upstream from & west of New Orleans, Jefferson, Jefferson Parish, LA

  14. Substructure Main Bridge, River Pier IV Huey P. ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    Substructure - Main Bridge, River Pier IV - Huey P. Long Bridge, Spanning Mississippi River approximately midway between nine & twelve mile points upstream from & west of New Orleans, Jefferson, Jefferson Parish, LA

  15. Substructure Main Bridge, River Piers I, II, III & ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    Substructure - Main Bridge, River Piers I, II, III & IV - Huey P. Long Bridge, Spanning Mississippi River approximately midway between nine & twelve mile points upstream from & west of New Orleans, Jefferson, Jefferson Parish, LA

  16. 65. VIEW LOOKING UPSTREAM FROM FLUME SUBSTRUCTURE, SHOWING COLUMBIA IMPROVEMENT ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    65. VIEW LOOKING UPSTREAM FROM FLUME SUBSTRUCTURE, SHOWING COLUMBIA IMPROVEMENT COMPANY'S NEISSON CREEK SAWMILL. Print No. 177, November 1903 - Electron Hydroelectric Project, Along Puyallup River, Electron, Pierce County, WA

  17. 3. VIEW OF SOUTH FACE AND CONSTRUCTION DETAIL OF SUBSTRUCTURE ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    3. VIEW OF SOUTH FACE AND CONSTRUCTION DETAIL OF SUBSTRUCTURE FROM NORTH BANK. RETAINING WALL OF GAUGING STATION IS VISIBLE IN BACKGROUND UNDER BRIDGE. - Old Happy Isles Bridge, Spanning Merced River on service road, Yosemite Village, Mariposa County, CA

  18. Detail view of Fanno Creek trestle, showing trestle substructure, view ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    Detail view of Fanno Creek trestle, showing trestle substructure, view looking north - Oregon Electric Railroad, Fanno Creek Trestle, Garden Home to Wilsonville Segment, Milepost 34.7, Garden Home, Washington County, OR

  19. 22. VIEW OF FIXED SPAN SUBSTRUCTURE, EAST SPAN, SHOWING CANTILEVEREDBEAM ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    22. VIEW OF FIXED SPAN SUBSTRUCTURE, EAST SPAN, SHOWING CANTILEVERED-BEAM SIDEWALK SUPPORTS, LONGITUDINAL GIRDER AND TRANSVERSE ROADBED BEAMS, LOOKING SOUTHEAST - Congress Street Bascule Bridge, Spanning Fort Point Channel at Congress Street, Boston, Suffolk County, MA

  20. Substructure view illustrating the continuous concrete Tbeams, piers, sidewalk brackets ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    Substructure view illustrating the continuous concrete T-beams, piers, sidewalk brackets and arched longitudinal beams - A Canal Bridge, Spanning the A Canal on Wall Street, Klamath Falls, Klamath County, OR

  1. 8. View of substructure showing the lower chord of the ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    8. View of substructure showing the lower chord of the Howe truss, flared board-and-batten siding, and pier configuration - Drift Creek Bridge, Spanning Drift Creek on Drift Creek County Road, Lincoln City, Lincoln County, OR

  2. Linkers Having a Crucial Role in Antibody–Drug Conjugates

    PubMed Central

    Lu, Jun; Jiang, Feng; Lu, Aiping; Zhang, Ge

    2016-01-01

    Antibody–drug conjugates (ADCs) comprised of a desirable monoclonal antibody, an active cytotoxic drug and an appropriate linker are considered to be an innovative therapeutic approach for targeted treatment of various types of tumors and cancers, enhancing the therapeutic parameter of the cytotoxic drug and reducing the possibility of systemic cytotoxicity. An appropriate linker between the antibody and the cytotoxic drug provides a specific bridge, and thus helps the antibody to selectively deliver the cytotoxic drug to tumor cells and accurately releases the cytotoxic drug at tumor sites. In addition to conjugation, the linkers maintain ADCs’ stability during the preparation and storage stages of the ADCs and during the systemic circulation period. The design of linkers for ADCs is a challenge in terms of extracellular stability and intracellular release, and intracellular circumstances, such as the acid environment, the reducing environment and cathepsin, are considered as the catalysts to activate the triggers for initiating the cleavage of ADCs. This review discusses the linkers used in the clinical and marketing stages for ADCs and details the fracture modes of the linkers for the further development of ADCs. PMID:27089329

  3. Linkers Having a Crucial Role in Antibody-Drug Conjugates.

    PubMed

    Lu, Jun; Jiang, Feng; Lu, Aiping; Zhang, Ge

    2016-01-01

    Antibody-drug conjugates (ADCs) comprised of a desirable monoclonal antibody, an active cytotoxic drug and an appropriate linker are considered to be an innovative therapeutic approach for targeted treatment of various types of tumors and cancers, enhancing the therapeutic parameter of the cytotoxic drug and reducing the possibility of systemic cytotoxicity. An appropriate linker between the antibody and the cytotoxic drug provides a specific bridge, and thus helps the antibody to selectively deliver the cytotoxic drug to tumor cells and accurately releases the cytotoxic drug at tumor sites. In addition to conjugation, the linkers maintain ADCs' stability during the preparation and storage stages of the ADCs and during the systemic circulation period. The design of linkers for ADCs is a challenge in terms of extracellular stability and intracellular release, and intracellular circumstances, such as the acid environment, the reducing environment and cathepsin, are considered as the catalysts to activate the triggers for initiating the cleavage of ADCs. This review discusses the linkers used in the clinical and marketing stages for ADCs and details the fracture modes of the linkers for the further development of ADCs. PMID:27089329

  4. Linker histone variants control chromatin dynamics during early embryogenesis

    PubMed Central

    Saeki, Hideaki; Ohsumi, Keita; Aihara, Hitoshi; Ito, Takashi; Hirose, Susumu; Ura, Kiyoe; Kaneda, Yasufumi

    2005-01-01

    Complex transitions in chromatin structure produce changes in genome function during development in metazoa. Linker histones, the last component of nucleosomes to be assembled into chromatin, comprise considerably divergent subtypes as compared with core histones. In all metazoa studied, their composition changes dramatically during early embryogenesis concomitant with zygotic gene activation, leading to distinct functional changes that are still poorly understood. Here, we show that early embryonic linker histone B4, which is maternally expressed, is functionally different from somatic histone H1 in influencing chromatin structure and dynamics. We developed a chromatin assembly system with nucleosome assembly protein-1 as a linker histone chaperone. This assay system revealed that maternal histone B4 allows chromatin to be remodeled by ATP-dependent chromatin remodeling factor, whereas somatic histone H1 prevents this remodeling. Structural analysis shows that histone B4 does not significantly restrict the accessibility of linker DNA. These findings define the functional significance of developmental changes in linker histone variants. We propose a model that holds that maternally expressed linker histones are key molecules specifying nuclear dynamics with respect to embryonic totipotency. PMID:15821029

  5. The SNAP-25 Linker as an Adaptation Toward Fast Exocytosis

    PubMed Central

    Nagy, Gábor; Milosevic, Ira; Mohrmann, Ralf; Wiederhold, Katrin; Walter, Alexander M.

    2008-01-01

    The assembly of four soluble N-ethylmaleimide-sensitive factor attachment protein receptor domains into a complex is essential for membrane fusion. In most cases, the four SNARE-domains are encoded by separate membrane-targeted proteins. However, in the exocytotic pathway, two SNARE-domains are present in one protein, connected by a flexible linker. The significance of this arrangement is unknown. We characterized the role of the linker in SNAP-25, a neuronal SNARE, by using overexpression techniques in synaptosomal-associated protein of 25 kDa (SNAP-25) null mouse chromaffin cells and fast electrophysiological techniques. We confirm that the palmitoylated linker-cysteines are important for membrane association. A SNAP-25 mutant without cysteines supported exocytosis, but the fusion rate was slowed down and the fusion pore duration prolonged. Using chimeric proteins between SNAP-25 and its ubiquitous homologue SNAP-23, we show that the cysteine-containing part of the linkers is interchangeable. However, a stretch of 10 hydrophobic and charged amino acids in the C-terminal half of the SNAP-25 linker is required for fast exocytosis and in its absence the calcium dependence of exocytosis is shifted toward higher concentrations. The SNAP-25 linker therefore might have evolved as an adaptation toward calcium triggering and a high rate of execution of the fusion process, those features that distinguish exocytosis from other membrane fusion pathways. PMID:18579690

  6. The SEGUE K Giant Survey. III. Quantifying Galactic Halo Substructure

    NASA Astrophysics Data System (ADS)

    Janesh, William; Morrison, Heather L.; Ma, Zhibo; Rockosi, Constance; Starkenburg, Else; Xue, Xiang Xiang; Rix, Hans-Walter; Harding, Paul; Beers, Timothy C.; Johnson, Jennifer; Lee, Young Sun; Schneider, Donald P.

    2016-01-01

    We statistically quantify the amount of substructure in the Milky Way stellar halo using a sample of 4568 halo K giant stars at Galactocentric distances ranging over 5-125 kpc. These stars have been selected photometrically and confirmed spectroscopically as K giants from the Sloan Digital Sky Survey’s Sloan Extension for Galactic Understanding and Exploration project. Using a position-velocity clustering estimator (the 4distance) and a model of a smooth stellar halo, we quantify the amount of substructure in the halo, divided by distance and metallicity. Overall, we find that the halo as a whole is highly structured. We also confirm earlier work using blue horizontal branch (BHB) stars which showed that there is an increasing amount of substructure with increasing Galactocentric radius, and additionally find that the amount of substructure in the halo increases with increasing metallicity. Comparing to resampled BHB stars, we find that K giants and BHBs have similar amounts of substructure over equivalent ranges of Galactocentric radius. Using a friends-of-friends algorithm to identify members of individual groups, we find that a large fraction (˜33%) of grouped stars are associated with Sgr, and identify stars belonging to other halo star streams: the Orphan Stream, the Cetus Polar Stream, and others, including previously unknown substructures. A large fraction of sample K giants (more than 50%) are not grouped into any substructure. We find also that the Sgr stream strongly dominates groups in the outer halo for all except the most metal-poor stars, and suggest that this is the source of the increase of substructure with Galactocentric radius and metallicity.

  7. Using Network Methodology to Infer Population Substructure

    PubMed Central

    Prokopenko, Dmitry; Hecker, Julian; Silverman, Edwin; Nöthen, Markus M.; Schmid, Matthias; Lange, Christoph; Loehlein Fier, Heide

    2015-01-01

    One of the main caveats of association studies is the possible affection by bias due to population stratification. Existing methods rely on model-based approaches like structure and ADMIXTURE or on principal component analysis like EIGENSTRAT. Here we provide a novel visualization technique and describe the problem of population substructure from a graph-theoretical point of view. We group the sequenced individuals into triads, which depict the relational structure, on the basis of a predefined pairwise similarity measure. We then merge the triads into a network and apply community detection algorithms in order to identify homogeneous subgroups or communities, which can further be incorporated as covariates into logistic regression. We apply our method to populations from different continents in the 1000 Genomes Project and evaluate the type 1 error based on the empirical p-values. The application to 1000 Genomes data suggests that the network approach provides a very fine resolution of the underlying ancestral population structure. Besides we show in simulations, that in the presence of discrete population structures, our developed approach maintains the type 1 error more precisely than existing approaches. PMID:26098940

  8. Finding Nonoverlapping Substructures of a Sparse Matrix

    SciTech Connect

    Pinar, Ali; Vassilevska, Virginia

    2005-08-11

    Many applications of scientific computing rely on computations on sparse matrices. The design of efficient implementations of sparse matrix kernels is crucial for the overall efficiency of these applications. Due to the high compute-to-memory ratio and irregular memory access patterns, the performance of sparse matrix kernels is often far away from the peak performance on a modern processor. Alternative data structures have been proposed, which split the original matrix A into A{sub d} and A{sub s}, so that A{sub d} contains all dense blocks of a specified size in the matrix, and A{sub s} contains the remaining entries. This enables the use of dense matrix kernels on the entries of A{sub d} producing better memory performance. In this work, we study the problem of finding a maximum number of nonoverlapping dense blocks in a sparse matrix, which is previously not studied in the sparse matrix community. We show that the maximum nonoverlapping dense blocks problem is NP-complete by using a reduction from the maximum independent set problem on cubic planar graphs. We also propose a 2/3-approximation algorithm that runs in linear time in the number of nonzeros in the matrix. This extended abstract focuses on our results for 2x2 dense blocks. However we show that our results can be generalized to arbitrary sized dense blocks, and many other oriented substructures, which can be exploited to improve the memory performance of sparse matrix operations.

  9. Mass and Substructure in Dwarf Spheroidal Galaxies

    NASA Astrophysics Data System (ADS)

    Walker, Matthew G.

    2006-12-01

    I present results from a large spectroscopic survey of individual stars in dwarf spheroidal (dSph) galaxies, conducted using the Michigan/MIKE Fiber System (MMFS) at the Magellan Telescopes. dSph galaxies have come under intense scrutiny because they represent the lower extreme of the galaxy mass function, and thereby provide important constraints on models of structure formation. The proximity of the Milky Way's (MW's) dSph satellites allows us to study the resolved stellar populations of these systems in detail. Toward this end I have acquired MMFS spectra (5140-5180 Angstroms at resolution 20000) for more than 5000 stars in the MW dSphs Carina, Fornax, Sculptor, and Sextans. The spectra yield measurements of both radial velocity (median precision ± 1.8 km/s) and [Fe/H] metallicity (± 0.2 dex). I present radial velocity dispersion profiles for each dSph, as well as halo mass profiles derived using a variety of models and nonparametric estimation techniques. In some cases, the bulk stellar component is separable into populations following distinct distributions in position, kinematics, and chemistry, indicating a surprising level of complexity in these diminutive galaxies. Taking advantage of the fine spatial sampling of the MMFS data, I identify regions showing tentative evidence of localized chemo-dynamical substructure. This work is supported by grants from the National Science Foundation and the University of Michigan.

  10. The importance of the cosmic web and halo substructure for power spectra

    NASA Astrophysics Data System (ADS)

    Pace, Francesco; Manera, Marc; Bacon, David J.; Crittenden, Robert; Percival, Will J.

    2015-11-01

    In this work, we study the relevance of the cosmic web and substructures on the matter and lensing power spectra measured from halo mock catalogues extracted from the N-body simulations. Since N-body simulations are computationally expensive, it is common to use faster methods that approximate the dark matter field as a set of haloes. In this approximation, we replace mass concentrations in N-body simulations by a spherically symmetric Navarro-Frenk-White halo density profile. We also consider the full mass field as the sum of two distinct fields: dark matter haloes (M > 9 × 1012 M⊙ h-1) and particles not included into haloes. Mock haloes reproduce well the matter power spectrum, but underestimate the lensing power spectrum on large and small scales. For sources at zs = 1 the lensing power spectrum is underestimated by up to 40 per cent at ℓ ≈ 104 with respect to the simulated haloes. The large-scale effect can be alleviated by combining the mock catalogue with the dark matter distribution outside the haloes. In addition, to evaluate the contribution of substructures we have smeared out the intrahalo substructures in an N-body simulation while keeping the halo density profiles unchanged. For the matter power spectrum the effect of this smoothing is only of the order of 5 per cent, but for lensing substructures and ellipticity are much more important: for ℓ ≈ 104 modifications to the internal structure contribute to 30 per cent of the total spectrum. These findings have important implications in the way mock catalogues have to be created, suggesting that some approximate methods currently used for galaxy surveys will be inadequate for future weak lensing surveys.

  11. Effect of Interdomain Linker Length on an Antagonistic Folding-Unfolding Equilibrium between Two Protein Domains

    PubMed Central

    Cutler, Thomas A.; Mills, Brandon M.; Lubin, David J.; Chong, Lillian T.; Loh, Stewart N.

    2009-01-01

    Fusion of one protein domain with another is a common event in both evolution and protein engineering experiments. When insertion is at an internal site (e.g., a surface loop or turn), as opposed to one of the termini, conformational strain can be introduced into both domains. Strain is manifested by an antagonistic folding-unfolding equilibrium between the two domains, which we previously showed can be parameterized by a coupling free-energy term (ΔGX). The extent of strain is predicted to depend primarily on the ratio of the N-to-C distance of the guest protein to the distance between ends of the surface loop in the host protein. Here, we test that hypothesis by inserting ubiquitin (Ub) into the bacterial ribonuclease barnase (Bn), using peptide linkers from zero to 10 amino acids each. ΔGX values are determined by measuring the extent to which Co2+ binding to an engineered site on the Ub domain destabilizes the Bn domain. All-atom, unforced Langevin dynamics simulations are employed to gain structural insight into the mechanism of mechanically induced unfolding. Experimental and computational results find that the two domains are structurally and energetically uncoupled when linkers are long and that ΔGX increases with decreasing linker length. When the linkers are fewer than two amino acids, strain is so great that one domain unfolds the other. However, the protein is able to refold as dimers and higher-order oligomers. The likely mechanism is a three-dimensional domain swap of the Bn domain, which relieves conformational strain. The simulations suggest that an effective route to mechanical unfolding begins with disruption of the hydrophobic core of Bn near the Ub insertion site. PMID:19038264

  12. Substructure and Dynamics of the Fornax Cluster

    NASA Astrophysics Data System (ADS)

    Drinkwater, Michael J.; Gregg, Michael D.; Colless, Matthew

    2001-02-01

    We present the first dynamical analysis of a galaxy cluster to include a large fraction of dwarf galaxies. Our sample of 108 Fornax Cluster members measured with the UK Schmidt Telescope FLAIR-II spectrograph contains 55 dwarf galaxies (15.5>bJ>18.0 or -16>MB>-13.5). Hα emission shows that 36%+/-8% of the dwarfs are star forming, twice the fraction implied by morphological classifications. The total sample has a mean velocity of 1493+/-36 km s-1 and a velocity dispersion of 374+/-26 km s-1. The dwarf galaxies form a distinct population: their velocity dispersion (429+/-41 km s-1) is larger than that of the giants (308+/-30 km s-1) at the 98% confidence level. This suggests that the dwarf population is dominated by infalling objects whereas the giants are virialized. The Fornax system has two components, the main Fornax Cluster centered on NGC 1399 with cz=1478 km s-1 and σcz=370 km s-1 and a subcluster centered 3° to the southwest including NGC 1316 with cz=1583 km s-1 and σcz=377 km s-1. This partition is preferred over a single cluster at the 99% confidence level. The subcluster, a site of intense star formation, is bound to Fornax and probably infalling toward the cluster core for the first time. We discuss the implications of this substructure for distance estimates of the Fornax Cluster. We determine the cluster mass profile using the method of Diaferio, which does not assume a virialized sample. The mass within a projected radius of 1.4 Mpc is (7+/-2)×1013 Msolar, and the mass-to-light ratio is 300+/-100 Msolar/Lsolar. The mass is consistent with values derived from the projected mass virial estimator and X-ray measurements at smaller radii.

  13. SUBSTRUCTURE DEPLETION IN THE MILKY WAY HALO BY THE DISK

    SciTech Connect

    D'Onghia, Elena; Hernquist, Lars; Keres, Dusan; Springel, Volker

    2010-02-01

    We employ numerical simulations and simple analytical estimates to argue that dark matter substructures orbiting in the inner regions of the Galaxy can be efficiently destroyed by disk shocking, a dynamical process known to affect globular star clusters. We carry out a set of fiducial high-resolution collisionless simulations in which we adiabatically grow a disk, allowing us to examine the impact of the disk on the substructure abundance. We also track the orbits of dark matter satellites in high-resolution Aquarius simulations and analytically estimate the cumulative halo and disk-shocking effect. Our calculations indicate that the presence of a disk with only 10% of the total Milky Way mass can significantly alter the mass function of substructures in the inner parts of halos. This has important implications especially for the relatively small number of satellites seen within approx30 kpc of the Milky Way center, where disk shocking is expected to reduce the substructure abundance by a factor of 2 at 10{sup 9} M{sub sun} and a factor of 3 at 10{sup 7} M{sub sun}. The most massive subhalos with 10{sup 10} M{sub sun} survive even in the presence of the disk. This suggests that there is no inner missing satellite problem and calls into question whether these substructures can produce transient features in disks, like multi-armed spiral patterns. Also, the depletion of dark matter substructures through shocking on the baryonic structures of the disk and central bulge may aggravate the problem to fully account for the observed flux anomalies in gravitational lens systems, and significantly reduces the dark matter annihilation signal expected from nearby substructures in the inner halo.

  14. A study on the effects of linker flexibility on acid phosphatase PhoC-GFP fusion protein using a novel linker library.

    PubMed

    Huang, Ziliang; Li, Gang; Zhang, Chong; Xing, Xin-Hui

    2016-02-01

    Fusion strategy has been widely used to construct artificial multifunction proteins. The flexibility or rigidity of linkers between two fused partners is an important parameter that affects the function of fusion proteins. By combining the flexible unit GGGGS (F) and rigid unit EAAAK (R), ten linkers consisting of five elementary units that cover the fully rigid RRRRR linker to the fully flexible FFFFF linker were used to construct acid phosphatase-green fluorescence protein fusion protein (PhoC-GFP). By varying the linker flexibility in PhoC-GFPs, the relative specific activity of phosphotransferase and phosphatase varied from ∼19.0% to 100% and ∼9.35% to 100%, respectively. There exists an optimal linker capable of achieving the highest phosphotransferase/phosphatase activity and GFP fluorescence intensity. We found that the highest activities were achieved neither with the rigid RRRRR linker nor with the flexible FFFFF linker, but with the FFFRR linker. Linker flexibility could adjust the activity ratio between phosphotransferase and phosphatase and varied between ∼30% to 100%. PhoC-GFP with FRRRR linker achieved the highest relative specific phosphotransferase activity/relative specific phosphatase activity (T/P) value. Our results show that applying a linker library with controllable flexibility to the fusion proteins will be an efficient way to adjust the function of fusion enzymes. PMID:26777244

  15. Gamma-ray probes of dark matter substructure

    SciTech Connect

    Campbell, Sheldon

    2014-06-24

    The substructure content of dark matter halos is interesting because it can be affected by complex galaxy physics and dark matter particle physics. However, observing the small scale structure of dark matter is a challenge. The subhalo abundance (mass function, minimum mass) and morphology (density profile, subhalo shape, subsubstructure) contain information about complex astrophysics (halo formation processes) and new exotic fundamental physics (dark matter interactions). Indirect detection of dark matter annihilation radiation (DMAR) in gamma rays may be the most direct method for observing small scale structure. I outline the ways in which gamma rays may probe halo substructure. If substructure is bountiful, it may be responsible for the eventual discovery of DMAR, for instance in galaxy clusters or the diffuse gamma-ray background. Otherwise, the observation of DMAR in places without much substructure, such as the Galactic center, would lead to strict limits on the properties of small scale structure. Properties of the gamma-ray angular power spectrum will also provide information or constraints on Milky Way halo substructure.

  16. Quantifying the Significance of Substructure in Coronal Loops

    NASA Astrophysics Data System (ADS)

    McKeough, K. B. D.; Kashyap, V.; McKillop, S.

    2014-12-01

    A method to infer the presence of small-scale substructure in SDO/AIA (Atmospheric Imaging Assembly on the Solar Dynamics Observatory) images of coronal loops is developed. We can classify visible loop structure based on this propensity to show substructure which puts constraints on contemporary solutions to the coronal heating problem. The method uses the Bayesian algorithm Low-count Image Reconstruction and Analysis (LIRA) to infer the multi-scale component of the loops which describes deviations from a smooth model. The increase in contrast of features in this multi-scale component is determined using a statistic that estimates the sharpness across the image. Regions with significant substructure are determined using p-value upper bounds. We are able to locate substructure visible in Hi-C (High-Resolution Coronal Imager) data that are not salient features in the corresponding AIA image. Looking at coronal loops at different regions of the Sun (e.g., low-lying structure and loops in the upper corona) we are able to map where detectable substructure exists and thus the influence of the nanoflare heating process. We acknowledge support from AIA under contract SP02H1701R from Lockheed-Martin to SAO.

  17. Substructure location and size effects on decentralized model updating

    NASA Astrophysics Data System (ADS)

    Dong, Xinjun; Zhu, Dapeng; Wang, Yang

    2015-04-01

    To improve the simulation accuracy of the finite-element (FE) model of an as-built structure, measurement data from the actual structure can be utilized for updating the model parameters, which is termed as FE model updating. During the past few decades, most efforts on FE model updating intend to update the entire structure model altogether, while using measurement data from sensors installed throughout the structure. When applied on large and complex structural models, the typical model updating approaches may fail due to computational challenges and convergence issues. In order to reduce the computational difficulty, this paper studies a decentralized FE model updating approach that intends to update one substructure at a time. The approach divides the entire structure into a substructure (currently being instrumented and updated) and the residual structure. The Craig-Bampton transform is adopted to condense the overall structural model. The optimization objective is formulated to minimize the modal dynamic residuals from the eigenvalue equations in structural dynamics involving natural frequencies and mode shapes. This paper investigates the effects of different substructure locations and sizes on updating performance. A space frame example, which is based on an actual pedestrian bridge on Georgia Tech campus, is used to study the substructure location and size effects. Keywords: substructure

  18. On substructuring algorithms and solution techniques for the numerical approximation of partial differential equations

    NASA Technical Reports Server (NTRS)

    Gunzburger, M. D.; Nicolaides, R. A.

    1986-01-01

    Substructuring methods are in common use in mechanics problems where typically the associated linear systems of algebraic equations are positive definite. Here these methods are extended to problems which lead to nonpositive definite, nonsymmetric matrices. The extension is based on an algorithm which carries out the block Gauss elimination procedure without the need for interchanges even when a pivot matrix is singular. Examples are provided wherein the method is used in connection with finite element solutions of the stationary Stokes equations and the Helmholtz equation, and dual methods for second-order elliptic equations.

  19. Phenotypic variation of erythrocyte linker histone H1.c in a pheasant (Phasianus colchicus L.) population.

    PubMed

    Kowalski, Andrzej; Pa Yga, Jan; Górnicka-Michalska, Ewa; Bernacki, Zenon; Adamski, Marek

    2010-07-01

    Our goal was to characterize a phenotypic variation of the pheasant erythrocyte linker histone subtype H1.c. By using two-dimensional polyacrylamide gel electrophoresis three histone H1.c phenotypes were identified. The differently migrating allelic variants H1.c1 and H1.c2 formed either two homozygous phenotypes, c1 and c2, or a single heterozygous phenotype, c1c2. In the pheasant population screened, birds with phenotype c2 were the most common (frequency 0.761) while individuals with phenotype c1 were rare (frequency 0.043). PMID:21637419

  20. EFFECT OF DARK MATTER HALO SUBSTRUCTURES ON GALAXY ROTATION CURVES

    SciTech Connect

    Roy, Nirupam

    2010-11-01

    In this paper, the effect of halo substructures on galaxy rotation curves is investigated using a simple model of dark matter clustering. A dark matter halo density profile is developed based only on the scale-free nature of clustering that leads to a statistically self-similar distribution of the substructures at the galactic scale. A semi-analytical method is used to derive rotation curves for such a clumpy dark matter density profile. It is found that the halo substructures significantly affect the galaxy velocity field. Based on the fractal geometry of the halo, this self-consistent model predicts a Navarro-Frenk-White-like rotation curve and a scale-free power spectrum of the rotation velocity fluctuations.

  1. Shock induced deformation substructures in a copper bicrystal

    SciTech Connect

    Cao, Fang; Beyerlein, Irene J; Cerreta, Ellen K; Trujillo, Carl P; Gray Ill, George T; Sencer, Bulent H

    2008-01-01

    Controlled shock recovery experiments have been conducted to assess the role of shock pressure and orientation dependence on the substructure evolution of a [100]/[01{ovr 1}] copper bicrystal. Electron backscatter diffraction (EBSD) and transmission electron microscopy (TEM) were utilized to characterize orientation variation and substructure evolution of the post-shock specimens. Well defined dislocation cell structures were displayed in both grains and the average cell size was observed to decrease with increasing shock pressure. Twinning was occasionally observed in the 5 GPa shocked [100] grain and became the dominant substructure at higher shock pressure. The stress and directional dependence of twinning in the bicrystal was analyzed with consideration of the energetically favorable dissociation of dislocations into Shockley partials and the stress-orientation effect on the partial width. Moreover, a critical 'tear apart' stress is proposed and a good agreement is obtained between the calculated value and the experimental observations.

  2. Functional Group and Substructure Searching as a Tool in Metabolomics

    PubMed Central

    Kotera, Masaaki; McDonald, Andrew G.; Boyce, Sinéad; Tipton, Keith F.

    2008-01-01

    Background A direct link between the names and structures of compounds and the functional groups contained within them is important, not only because biochemists frequently rely on literature that uses a free-text format to describe functional groups, but also because metabolic models depend upon the connections between enzymes and substrates being known and appropriately stored in databases. Methodology We have developed a database named “Biochemical Substructure Search Catalogue” (BiSSCat), which contains 489 functional groups, >200,000 compounds and >1,000,000 different computationally constructed substructures, to allow identification of chemical compounds of biological interest. Conclusions This database and its associated web-based search program (http://bisscat.org/) can be used to find compounds containing selected combinations of substructures and functional groups. It can be used to determine possible additional substrates for known enzymes and for putative enzymes found in genome projects. Its applications to enzyme inhibitor design are also discussed. PMID:18253485

  3. Estimation of ADME properties with substructure pattern recognition.

    PubMed

    Shen, Jie; Cheng, Feixiong; Xu, You; Li, Weihua; Tang, Yun

    2010-06-28

    Over the past decade, absorption, distribution, metabolism, and excretion (ADME) property evaluation has become one of the most important issues in the process of drug discovery and development. Since in vivo and in vitro evaluations are costly and laborious, in silico techniques had been widely used to estimate ADME properties of chemical compounds. Traditional prediction methods usually try to build a functional relationship between a set of molecular descriptors and a given ADME property. Although traditional methods have been successfully used in many cases, the accuracy and efficiency of molecular descriptors must be concerned. Herein, we report a new classification method based on substructure pattern recognition, in which each molecule is represented as a substructure pattern fingerprint based on a predefined substructure dictionary, and then a support vector machine (SVM) algorithm is applied to build the prediction model. Therefore, a direct connection between substructures and molecular properties is built. The most important substructure patterns can be identified via the information gain analysis, which could help to interpret the models from a medicinal chemistry perspective. Afterward, this method was verified with two data sets, one for blood-brain barrier (BBB) penetration and the other for human intestinal absorption (HIA). The results demonstrated that the overall predictive accuracies of the best HIA model for the training and test sets were 98.5 and 98.8%, and the overall predictive accuracies of the best BBB model for the training and test sets were 98.8 and 98.4%, which confirmed the reliability of our method. In the additional validations, the predictive accuracies were 94 and 69.5% for the HIA and the BBB models, respectively. Moreover, some of the representative key substructure patterns which significantly correlated with the HIA and BBB penetration properties were also presented. PMID:20578727

  4. Linker histone protects linker DNA on only one side of the core particle and in a sequence-dependent manner

    PubMed Central

    An, Woojin; Leuba, Sanford H.; van Holde, Kensal; Zlatanova, Jordanka

    1998-01-01

    The protection against micrococcal nuclease digestion afforded to chromatosomal DNA by the presence of a linker histone (H1o) has been quantitatively measured in two reconstituted systems. We have used chromatosomes reconstituted at two distinct positions on a DNA fragment containing the 5S rRNA gene from Lytechinus variegatus and at a specific position on a sequence containing Gal4- and USF-binding sites. In all cases, we find asymmetric protection, with ≈20 bp protected on one side of the core particle and no protection on the other. We demonstrated through crosslinking experiments that the result is not due to any sliding of the histone core caused by either linker histone addition or micrococcal nuclease cleavage. Because the core particle is itself a symmetric object, the preferred asymmetric location of a linker histone must be dictated by unknown elements in the DNA sequence. PMID:9520377

  5. A Robust Control Design Framework for Substructure Models

    NASA Technical Reports Server (NTRS)

    Lim, Kyong B.

    1994-01-01

    A framework for designing control systems directly from substructure models and uncertainties is proposed. The technique is based on combining a set of substructure robust control problems by an interface stiffness matrix which appears as a constant gain feedback. Variations of uncertainties in the interface stiffness are treated as a parametric uncertainty. It is shown that multivariable robust control can be applied to generate centralized or decentralized controllers that guarantee performance with respect to uncertainties in the interface stiffness, reduced component modes and external disturbances. The technique is particularly suited for large, complex, and weakly coupled flexible structures.

  6. System for detecting substructure microfractures and method therefore

    NASA Technical Reports Server (NTRS)

    Parthasarathy, S. P.; Narasimhan, K. Y. (Inventor)

    1979-01-01

    Bursts of signals at different frequencies are induced into substructure, adjacent to a borehole. The return signals from each burst of signals are normalized to compensate for the attenuation, experienced by more distant return signals. The peak amplitudes of return signals, above a selected level, are cut off, and an average signal is produced from the normalized amplitude-limited return signals of each burst. The averaged signals of the return signals of all the signal bursts at the different frequencies are processed to provide a combined signal, whose amplitude is related to the microfracture density of the substructure adjacent to the borehole.

  7. A substructure coupling procedure applicable to general linear time-invariant dynamic systems

    NASA Technical Reports Server (NTRS)

    Howsman, T. G.; Craig, R. R., Jr.

    1984-01-01

    A substructure synthesis procedure applicable to structural systems containing general nonconservative terms is presented. In their final form, the non-self-adjoint substructure equations of motion are cast in state vector form through the use of a variational principle. A reduced-order model for each substructure is implemented by representing the substructure as a combination of a small number of Ritz vectors. For the method presented, the substructure Ritz vectors are identified as a truncated set of substructure eigenmodes, which are typically complex, along with a set of generalized real attachment modes. The formation of the generalized attachment modes does not require any knowledge of the substructure flexible modes; hence, only the eigenmodes used explicitly as Ritz vectors need to be extracted from the substructure eigenproblem. An example problem is presented to illustrate the method.

  8. A substructure coupling procedure applicable to general linear time-invariant dynamic systems

    NASA Technical Reports Server (NTRS)

    Howsman, T. G.; Craig, R. R., Jr.

    1984-01-01

    A substructure synthesis procedure applicable to structural systems containing general nonconservative terms is presented. In their final form, the nonself-adjoint substructure equations of motion are cast in state vector form through the use of a variational principle. A reduced-order mode for each substructure is implemented by representing the substructure as a combination of a small number of Ritz vectors. For the method presented, the substructure Ritz vectors are identified as a truncated set of substructure eigenmodes, which are typically complex, along with a set of generalized real attachment modes. The formation of the generalized attachment modes does not require any knowledge of the substructure flexible modes; hence, only the eigenmodes used explicitly as Ritz vectors need to be extracted from the substructure eigenproblem. An example problem is presented to illustrate the method.

  9. Synthesis of a novel photoactivatable glucosylceramide cross-linker.

    PubMed

    Budani, Monique; Mylvaganam, Murugesapillai; Binnington, Beth; Lingwood, Clifford

    2016-09-01

    The biosynthesis of glucosylceramide (GlcCer) is a key rate-limiting step in complex glycosphingolipid (GSL) biosynthesis. To further define interacting partners of GlcCer, we have made a cleavable, biotinylated, photoreactive GlcCer analog in which the reactive nitrene is closely apposed to the GlcCer head group, by substituting the native fatty acid with d, l-2-aminohexadecanoic acid. Two amino-GlcCer diastereomer cross-linkers (XLA and XLB) were generated. XLB proved an effective lactosylceramide (LacCer) synthase substrate while XLA was inhibitory. Both probes specifically bound and cross-linked the GlcCer binding protein, glycolipid transfer protein (GLTP), but not other GSL binding proteins (Shiga toxin and cholera toxin). GlcCer inhibited GLTP cross-linking. Both GlcCer cross-linkers competed with microsomal nitrobenzoxadiazole (NBD)-GlcCer anabolism to NBD-LacCer. GLTP showed marked, ATP-dependent enhancement of cell-free intact microsomal LacCer synthesis from endogenous or exogenous liposomal GlcCer, supporting a role in the transport/membrane translocation of cytosolic and extra-Golgi GlcCer. GLTP was specifically labeled by either XLA or XLB GlcCer cross-linker during this process, together with a (the same) small subset of microsomal proteins. These cross-linkers will serve to probe physiologically relevant GlcCer-interacting cellular proteins. PMID:27412675

  10. Cleavable carbamate linkers for controlled protein delivery from hydrogels.

    PubMed

    Hammer, Nadine; Brandl, Ferdinand P; Kirchhof, Susanne; Goepferich, Achim M

    2014-06-10

    The reversible attachment of proteins to polymers is one potential strategy to control protein release from hydrogels. In this study, we report the reversible attachment of lysozyme to poly(ethylene glycol) (PEG) by degradable carbamate linkers. Phenyl groups with different substituents were used to control the rate of carbamate hydrolysis and the resulting protein release. Sodium dodecyl sulfate polyacrylamide gel electrophoresis showed modification with 1-3 PEG chains per lysozyme molecule. Protein PEGylation and PEG chain elimination occurred without changes in secondary protein structure, as demonstrated by circular dichroism spectroscopy. The lytic activity of lysozyme was restored to 73.4±1.7%-92.5±1.2% during PEG chain elimination. Attached PEG chains were eliminated within 24h to 28days, depending on the used linker molecule. When formulated into hydrogels, a maximum of about 60% of the initial dose was released within 7days to 21days. Linker elimination occurs 'traceless', so that the protein is released in its native, unmodified form. Altogether, we believe that tethering proteins by degradable carbamate linkers is a promising strategy to control their release from hydrogels. PMID:24680687

  11. Tunable pH-Sensitive Linker for Controlled Release.

    PubMed

    Choy, Cindy J; Geruntho, Jonathan J; Davis, Austen L; Berkman, Clifford E

    2016-03-16

    We have developed a novel pH-sensitive linker based on a phosphoramidate scaffold that can be tuned to release amine-containing drug molecules at various pH values. The pH-triggered phosphoramidate-based linkers are responsive to pH alone and do not require intracellular enzymatic action to initiate drug release. Key to the pH-triggered amine release from these linkers is a proximal acidic group (e.g., pyridinium or carboxylic acid) to promote the hydrolysis of the phosphoramidate P-N bond, presumably through an intramolecular general-acid type mechanism. Phosphoramidate hydrolysis is largely governed by the pKa of the leaving amine (e.g., primary, secondary, aniline). However, the proximity of the neighboring pyridine group attenuates the stability of the P-N bond to hydrolysis, thus allowing for control over the release of an amine from the phosphoramidate center. Based on the model scaffolds examined, phosphoramidate-based linkers could be selected for particular properties for controlled-release applications such as amine type, stability under physiological conditions, or release rates at various pH values such as intracellular endosomal conditions. The tunability of the phosphoramidate scaffold is expected to find broad applicability in various controlled drug-release applications such as antibody or small-molecule drug conjugates, drug-eluting stents, prodrug activation, as well as intracellular trafficking studies in which pH changes can trigger the release of turn-on dyes. PMID:26886721

  12. Single-Crystal to Single-Crystal Linker Substitution, Linker Place Exchange, and Transmetalation Reactions in Interpenetrated Pillared-Bilayer Zinc(II) Metal-Organic Frameworks.

    PubMed

    De, Dinesh; Neogi, Subhadip; Sañudo, E Carolina; Bharadwaj, Parimal K

    2015-11-23

    A twofold interpenetrated pillared-bilayer framework, {[Zn3 (L)2 (L2 )(DMF)]⋅(18DMF)(6H2 O)}n (1), has been synthesized from the ligands tris(4'-carboxybiphenyl)amine (H3 L) and 1,2-bis(4-pyridyl)ethylene (L2 ). The structure contains [Zn3 (COO)6 ] secondary building units (SBUs), in which three Zn(II) ions are almost linear with carboxylate bridging. This framework undergoes reversible pillar linker substitution reactions at the terminal Zn(II) centers with three different dipyridyl linkers of different lengths to afford three daughter frameworks, 2-4. Frameworks 2-4 are interconvertible through reversible linker substitution reactions. Also, competitive linker-exchange experiments show preferential incorporation of linker L3 in the parent framework 1. The larger linker L5 does not undergo such substitution reactions and framework 5, which contains this linker, can be synthesized solvothermally as a twofold interpenetrated structure. Interestingly, when framework 5 is dipped in a solution of L3 in DMF, linker substitution takes place as before, but linker L5 now moves and diagonally binds two Zn(II) centers to afford 6 as a nonpenetrated single framework. This linker place exchange reaction is unprecedented. All of these reactions take place in a single-crystal to single-crystal (SC-SC) manner, and have been observed directly through X-ray crystallography. In addition, each 3D framework undergoes complete copper(II) transmetalation. PMID:26462612

  13. QUANTIFYING KINEMATIC SUBSTRUCTURE IN THE MILKY WAY'S STELLAR HALO

    SciTech Connect

    Xue Xiangxiang; Zhao Gang; Luo Ali; Rix, Hans-Walter; Bell, Eric F.; Koposov, Sergey E.; Kang, Xi; Liu, Chao; Yanny, Brian; Beers, Timothy C.; Lee, Young Sun; Bullock, James S.; Johnston, Kathryn V.; Morrison, Heather; Rockosi, Constance

    2011-09-01

    We present and analyze the positions, distances, and radial velocities for over 4000 blue horizontal-branch (BHB) stars in the Milky Way's halo, drawn from SDSS DR8. We search for position-velocity substructure in these data, a signature of the hierarchical assembly of the stellar halo. Using a cumulative 'close pair distribution' as a statistic in the four-dimensional space of sky position, distance, and velocity, we quantify the presence of position-velocity substructure at high statistical significance among the BHB stars: pairs of BHB stars that are close in position on the sky tend to have more similar distances and radial velocities compared to a random sampling of these overall distributions. We make analogous mock observations of 11 numerical halo formation simulations, in which the stellar halo is entirely composed of disrupted satellite debris, and find a level of substructure comparable to that seen in the actually observed BHB star sample. This result quantitatively confirms the hierarchical build-up of the stellar halo through a signature in phase (position-velocity) space. In detail, the structure present in the BHB stars is somewhat less prominent than that seen in most simulated halos, quite possibly because BHB stars represent an older sub-population. BHB stars located beyond 20 kpc from the Galactic center exhibit stronger substructure than at r{sub gc} < 20 kpc.

  14. Experimentally implementable criteria revealing substructures of genuine multipartite entanglement

    SciTech Connect

    Huber, Marcus; Schimpf, Hans; Gabriel, Andreas; Spengler, Christoph; Bruss, Dagmar; Hiesmayr, Beatrix C.

    2011-02-15

    We present a general framework that reveals substructures of genuine multipartite entanglement. Via simple inequalities it is possible to discriminate different sets of multipartite qubit states. These inequalities are beneficial regarding experimental examinations as only local measurements are required. Furthermore, the number of observables scales favorably with system size. In exemplary cases we demonstrate the noise resistance and discuss implementations.

  15. A Frequency-Domain Substructure System Identification Algorithm

    NASA Technical Reports Server (NTRS)

    Blades, Eric L.; Craig, Roy R., Jr.

    1996-01-01

    A new frequency-domain system identification algorithm is presented for system identification of substructures, such as payloads to be flown aboard the Space Shuttle. In the vibration test, all interface degrees of freedom where the substructure is connected to the carrier structure are either subjected to active excitation or are supported by a test stand with the reaction forces measured. The measured frequency-response data is used to obtain a linear, viscous-damped model with all interface-degree of freedom entries included. This model can then be used to validate analytical substructure models. This procedure makes it possible to obtain not only the fixed-interface modal data associated with a Craig-Bampton substructure model, but also the data associated with constraint modes. With this proposed algorithm, multiple-boundary-condition tests are not required, and test-stand dynamics is accounted for without requiring a separate modal test or finite element modeling of the test stand. Numerical simulations are used in examining the algorithm's ability to estimate valid reduced-order structural models. The algorithm's performance when frequency-response data covering narrow and broad frequency bandwidths is used as input is explored. Its performance when noise is added to the frequency-response data and the use of different least squares solution techniques are also examined. The identified reduced-order models are also compared for accuracy with other test-analysis models and a formulation for a Craig-Bampton test-analysis model is also presented.

  16. View of substructure of Sixth Street Bridge overcrossing of Los ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    View of substructure of Sixth Street Bridge overcrossing of Los Angeles River. Looking west. Note dark hole at lower with is access ramp to river channel seen in HAER CA-176-56 - Sixth Street Bridge, Spanning 101 Freeway at Sixth Street, Los Angeles, Los Angeles County, CA

  17. 7. General view of substructure of bridge, taken from hills ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    7. General view of substructure of bridge, taken from hills to northeast of bridge. Note old stone abutment under existing bridge, detailing of arch and abutments. - Presumpscot Falls Bridge, Spanning Presumptscot River at Allen Avenue extension, 0.75 mile west of U.S. Interstate 95, Falmouth, Cumberland County, ME

  18. Chemical Substructure Searching: Comparing Three Commercially Available Databases.

    ERIC Educational Resources Information Center

    Wagner, A. Ben

    1986-01-01

    Compares the differences in coverage and utility of three substructure databases--Chemical Abstracts, Index Chemicus, and Chemical Information System's Nomenclature Search System. The differences between Chemical Abstracts with two different vendors--STN International and Questel--are described and a summary guide for choosing between databases is…

  19. Cold Dark Matter Substructure and Galactic Disks I: Morphological Signatures of Hierarchical SatelliteAccretion

    SciTech Connect

    Kazantzidis, Stelios; Bullock, James S.; Zentner, Andrew R.; Kravtsov, Andrey V.; Moustakas, Leonidas A.

    2007-12-03

    We conduct a series of high-resolution, fully self-consistent dissipation less N-body simulations to investigate the cumulative effect of substructure mergers onto thin disk galaxies in the context of the {Lambda}CDM paradigm of structure formation. Our simulation campaign is based on a hybrid approach combining cosmological simulations and controlled numerical experiments. Substructure mass functions, orbital distributions, internal structures, and accretion times are culled directly from cosmological simulations of galaxy-sized cold dark matter (CDM) halos. We demonstrate that accretions of massive subhalos onto the central regions of host halos, where the galactic disk resides, since z {approx} 1 should be common occurrences. In contrast, extremely few satellites in present-day CDM halos are likely to have a significant impact on the disk structure. This is due to the fact that massive subhalos with small orbital pericenters that are most capable of strongly perturbing the disk become either tidally disrupted or suffer substantial mass loss prior to z = 0. One host halo merger history is subsequently used to seed controlled N-body experiments of repeated satellite impacts on an initially-thin Milky Way-type disk galaxy. These simulations track the effects of six dark matter substructures, with initial masses in the range {approx} (0.7-2) x 10{sup 10} M{sub {circle_dot}} ({approx} 20-60% of the disk mass), crossing the disk in the past {approx} 8 Gyr. We show that these accretion events produce several distinctive observational signatures in the stellar disk including: a long-lived, low-surface brightness, ring-like feature in the outskirts; a significant flare; a central bar; and faint filamentary structures that (spuriously) resemble tidal streams in configuration space. The final distribution of disk stars exhibits a complex vertical structure that is well-described by a standard 'thin-thick' disk decomposition, where the 'thick' disk component has emerged

  20. Peptide linkers for the assembly of semiconductor quantum dot bioconjugates

    NASA Astrophysics Data System (ADS)

    Boeneman, Kelly; Mei, Bing C.; Deschamps, Jeffrey R.; Delehanty, James B.; Mattoussi, Hedi; Medintz, Igor

    2009-02-01

    The use of semiconductor luminescent quantum dots for the labeling of biomolecules is rapidly expanding, however it still requires facile methods to attach functional globular proteins to biologically optimized quantum dots. Here we discuss the development of controlled variable length peptidyl linkers to attach biomolecules to poly(ethylene) glycol (PEG) coated quantum dots for both in vitro and in vivo applications. The peptides chosen, β-sheets and alpha helices are appended to polyhistidine sequences and this allows for control of the ratio of peptide bioconjugated to QD and the distance from QD to the biomolecule. Recombinant DNA engineering, bacterial peptide expression and Ni-NTA purification of histidine labeled peptides are utilized to create the linkers. Peptide length is confirmed by in vitro fluorescent resonance energy transfer (FRET).

  1. Fast antibody fragment motion: flexible linkers act as entropic spring

    DOE PAGESBeta

    Stingaciu, Laura R.; Ivanova, Oxana; Ohl, Michael; Biehl, Ralf; Richter, Dieter

    2016-03-29

    A flexible linker region between three fragments allows antibodies to adjust their binding sites to an antigen or receptor. Using Neutron Spin Echo Spectroscopy we observed fragment motion on a timescale of 7 ns with motional amplitudes of about 1 nm relative to each other. The mechanistic complexity of the linker region can be described by a spring model with Brownian motion of the fragments in a harmonic potential. Displacements, timescale, friction and force constant of the underlying dynamics are accessed. The force constant exhibits a similar strength to an entropic spring, with friction of the fragment matching the unboundmore » state. The observed fast motions are fluctuations in pre-existing equilibrium configurations. In conclusion, the Brownian motion of domains in a harmonic potential is the appropriate model to examine functional hinge motions dependent on the structural topology and highlights the role of internal forces and friction to function.« less

  2. Fast antibody fragment motion: flexible linkers act as entropic spring

    PubMed Central

    Stingaciu, Laura R.; Ivanova, Oxana; Ohl, Michael; Biehl, Ralf; Richter, Dieter

    2016-01-01

    A flexible linker region between three fragments allows antibodies to adjust their binding sites to an antigen or receptor. Using Neutron Spin Echo Spectroscopy we observed fragment motion on a timescale of 7 ns with motional amplitudes of about 1 nm relative to each other. The mechanistic complexity of the linker region can be described by a spring model with Brownian motion of the fragments in a harmonic potential. Displacements, timescale, friction and force constant of the underlying dynamics are accessed. The force constant exhibits a similar strength to an entropic spring, with friction of the fragment matching the unbound state. The observed fast motions are fluctuations in pre-existing equilibrium configurations. The Brownian motion of domains in a harmonic potential is the appropriate model to examine functional hinge motions dependent on the structural topology and highlights the role of internal forces and friction to function. PMID:27020739

  3. Fast antibody fragment motion: flexible linkers act as entropic spring.

    PubMed

    Stingaciu, Laura R; Ivanova, Oxana; Ohl, Michael; Biehl, Ralf; Richter, Dieter

    2016-01-01

    A flexible linker region between three fragments allows antibodies to adjust their binding sites to an antigen or receptor. Using Neutron Spin Echo Spectroscopy we observed fragment motion on a timescale of 7 ns with motional amplitudes of about 1 nm relative to each other. The mechanistic complexity of the linker region can be described by a spring model with Brownian motion of the fragments in a harmonic potential. Displacements, timescale, friction and force constant of the underlying dynamics are accessed. The force constant exhibits a similar strength to an entropic spring, with friction of the fragment matching the unbound state. The observed fast motions are fluctuations in pre-existing equilibrium configurations. The Brownian motion of domains in a harmonic potential is the appropriate model to examine functional hinge motions dependent on the structural topology and highlights the role of internal forces and friction to function. PMID:27020739

  4. Ringed Substructure and a Gap at 1 au in the Nearest Protoplanetary Disk

    NASA Astrophysics Data System (ADS)

    Andrews, Sean M.; Wilner, David J.; Zhu, Zhaohuan; Birnstiel, Tilman; Carpenter, John M.; Pérez, Laura M.; Bai, Xue-Ning; Öberg, Karin I.; Hughes, A. Meredith; Isella, Andrea; Ricci, Luca

    2016-04-01

    We present long baseline Atacama Large Millimeter/submillimeter Array (ALMA) observations of the 870 μm continuum emission from the nearest gas-rich protoplanetary disk, around TW Hya, that trace millimeter-sized particles down to spatial scales as small as 1 au (20 mas). These data reveal a series of concentric ring-shaped substructures in the form of bright zones and narrow dark annuli (1-6 au) with modest contrasts (5%-30%). We associate these features with concentrations of solids that have had their inward radial drift slowed or stopped, presumably at local gas pressure maxima. No significant non-axisymmetric structures are detected. Some of the observed features occur near temperatures that may be associated with the condensation fronts of major volatile species, but the relatively small brightness contrasts may also be a consequence of magnetized disk evolution (the so-called zonal flows). Other features, particularly a narrow dark annulus located only 1 au from the star, could indicate interactions between the disk and young planets. These data signal that ordered substructures on ˜au scales can be common, fundamental factors in disk evolution and that high-resolution microwave imaging can help characterize them during the epoch of planet formation.

  5. Application substructure model synthesis method on modeling of a space camera

    NASA Astrophysics Data System (ADS)

    Sun, De-wei; Tang, Tianjin; Wu, Yong-jian; Yang, Jia-wen

    2014-11-01

    Space infrared sensor must be assembled on a small satellite platform, so its whole mass and structure dimensions are strictly restricted by the satellite platform. The mechanical structure must be compacted, light, handy and reliable. Task of space infrared sensor structure system is to integrate each parts of system and provide a stable and reliable work platform for the whole body. The transfer functions of flexible object and base are analyzed by using mechanical impedance method and compared with stiffness models. It indicates that space infrared sensor must be considered the flexible body influence for transfer function on some certain conditions. Using second order Krylov method expresses multi-DOF flexible substructure, which combines with modal synthesis method to model and analyze two substructures connecting with springs and dampers. Compared with direct FEM arithmetic, it can improve the calculation efficiency and handle variable-rate stiffness and damping model or complex stiffness model of flexible connection, which is cannot do for common commercial FEM software.

  6. Simple models for rope substructure mechanics: application to electro-mechanical lifts

    NASA Astrophysics Data System (ADS)

    Herrera, I.; Kaczmarczyk, S.

    2016-05-01

    Mechanical systems modelled as rigid mass elements connected by tensioned slender structural members such as ropes and cables represent quite common substructures used in lift engineering and hoisting applications. Special interest is devoted by engineers and researchers to the vibratory response of such systems for optimum performance and durability. This paper presents simplified models that can be employed to determine the natural frequencies of systems having substructures of two rigid masses constrained by tensioned rope/cable elements. The exact solution for free un-damped longitudinal displacement response is discussed in the context of simple two-degree-of-freedom models. The results are compared and the influence of characteristics parameters such as the ratio of the average mass of the two rigid masses with respect to the rope mass and the deviation ratio of the two rigid masses with respect to the average mass is analyzed. This analysis gives criteria for the application of such simplified models in complex elevator and hoisting system configurations.

  7. Deformation behavior of a 16-8-2 GTA weld as influenced by its solidification substructure

    SciTech Connect

    Foulds, J.R.; Moteff, J.; Sikka, V.K.; McEnerney, J.W.

    1983-07-01

    Weldment sections from formed and welded type 316 stainless steel pipe are characterized with respect to some time-independent (tensile) and time-dependent (creep) mechanical properties at temperatures between 25/sup 0/C and 649/sup 0/C. The GTA weldment, welded with 16-8-2 filler metal, is sectioned from pipe in the formed + welded + solution annealed + straightened condition, as well as in the same condition with an additional re-solution treatment. Detailed room temperature microhardness measurements on these sections before and after reannealing enable a determination of the different recovery characteristics of weld and base metal. The observed stable weld metal solidification dislocation substructure in comparison with the base metal random dislocation structure, in fact, adequately explains weld/base metal elevated temperature mechanical behavior differences from this recovery characteristic standpoint. The weld metal substructure is the only parameter common to the variety of austenitic stainless steel welds exhibiting the consistent parent/weld metal deformation behavior differences described. As such, it must be considered the key to understanding weldment mechanical behavior.

  8. A Conserved Ectodomain-Transmembrane Domain Linker Motif Tunes the Allosteric Regulation of Cell Surface Receptors.

    PubMed

    Schmidt, Thomas; Ye, Feng; Situ, Alan J; An, Woojin; Ginsberg, Mark H; Ulmer, Tobias S

    2016-08-19

    In many families of cell surface receptors, a single transmembrane (TM) α-helix separates ecto- and cytosolic domains. A defined coupling of ecto- and TM domains must be essential to allosteric receptor regulation but remains little understood. Here, we characterize the linker structure, dynamics, and resulting ecto-TM domain coupling of integrin αIIb in model constructs and relate it to other integrin α subunits by mutagenesis. Cellular integrin activation assays subsequently validate the findings in intact receptors. Our results indicate a flexible yet carefully tuned ecto-TM coupling that modulates the signaling threshold of integrin receptors. Interestingly, a proline at the N-terminal TM helix border, termed NBP, is critical to linker flexibility in integrins. NBP is further predicted in 21% of human single-pass TM proteins and validated in cytokine receptors by the TM domain structure of the cytokine receptor common subunit β and its P441A-substituted variant. Thus, NBP is a conserved uncoupling motif of the ecto-TM domain transition and the degree of ecto-TM domain coupling represents an important parameter in the allosteric regulation of diverse cell surface receptors. PMID:27365391

  9. Synthesis of shuttle vehicle damping using substructure test results

    NASA Technical Reports Server (NTRS)

    Kana, D. D.; Huzar, S.

    1972-01-01

    An empirical method is developed for predicting the modal damping of a combined parallel-stage shuttle model by means of damping measurements performed on the individual substructures. Correlations are first determined for each component in terms of damping energy as a function of peak kinetic energy and modal amplitude. The results are then used to predict component damping energies corresponding to the respective kinetic energies and amplitudes that occur for the new modes of the combined system. Modal characteristics for the system, other than damping, are obtained by a real eigenvalue solution of dynamic equations developed by Hurty's procedure of substructures. System equations, which include component modal damping, are also solved by a complex eigenvalue approach for comparison with results of the empirical method.

  10. Fold Recognition Using Sequence Fingerprints of Protein Local Substructures

    SciTech Connect

    Kryshtafovych, A A; Hvidsten, T; Komorowski, J; Fidelis, K

    2003-06-04

    A protein local substructure (descriptor) is a set of several short non-overlapping fragments of the polypeptide chain. Each descriptor describes local environment of a particular residue and includes only those segments that are located in the proximity of this residue. Similar descriptors from the representative set of proteins were analyzed to reveal links between the substructures and sequences of their segments. Using detected sequence-based fingerprints specific geometrical conformations are assigned to new sequences. The ability of the approach to recognize correct SCOP folds was tested on 273 sequences from the 49 most popular folds. Good predictions were obtained in 85% of cases. No performance drop was observed with decreasing sequence similarity between target sequences and sequences from the training set of proteins.

  11. Fossil group origins. VII. Galaxy substructures in fossil systems

    NASA Astrophysics Data System (ADS)

    Zarattini, S.; Girardi, M.; Aguerri, J. A. L.; Boschin, W.; Barrena, R.; del Burgo, C.; Castro-Rodriguez, N.; Corsini, E. M.; D'Onghia, E.; Kundert, A.; Méndez-Abreu, J.; Sánchez-Janssen, R.

    2016-02-01

    Context. Fossil groups (FG) are expected to be the final product of galaxy merging within galaxy groups. In simulations, they are predicted to assemble their mass at high redshift. This early formation allows for the innermost M∗ galaxies to merge into a massive central galaxy. Then, they are expected to maintain their fossil status because of the few interactions with the large-scale structure. In this context, the magnitude gap between the two brightest galaxies of the system is considered a good indicator of its dynamical status. As a consequence, the systems with the largest gaps should be dynamically relaxed. Aims: In order to examine the dynamical status of these systems, we systematically analyze, for the first time, the presence of galaxy substructures in a sample of 12 spectroscopically-confirmed fossil systems with redshift z ≤ 0.25. Methods: We apply a number of tests to investigate the substructure in fossil systems in the two-dimensional space of projected positions out to R200. Moreover, for a subsample of five systems with at least 30 spectroscopically-confirmed members we also analyze the substructure in the velocity and in the three-dimensional velocity-position spaces. Additionally, we look for signs of recent mergers in the regions around the central galaxies. Results: We find that an important fraction of fossil systems show substructure. The fraction depends critically on the adopted test, since each test is more sensitive to a particular type of substructure. Conclusions: Our interpretation of the results is that fossil systems are not, in general, as relaxed as expected from simulations. Our sample of 12 spectroscopically-confirmed fossil systems need to be extended to compute an accurate fraction, but our conclusion is that this fraction is similar to the fraction of substructure detected in nonfossil clusters. This result points out that the magnitude gap alone is not a good indicator of the dynamical status of a system. However, the

  12. SUBSTRUCTURE IN THE STELLAR HALOS OF THE AQUARIUS SIMULATIONS

    SciTech Connect

    Helmi, Amina; Cooper, A. P.; Cole, S.; Frenk, C. S.; White, S. D. M.; Navarro, J. F.

    2011-05-20

    We characterize the substructure in the simulated stellar halos of Cooper et al. which were formed by the disruption of satellite galaxies within the cosmological N-body simulations of galactic halos of the Aquarius project. These stellar halos exhibit a wealth of tidal features: broad overdensities and very narrow faint streams akin to those observed around the Milky Way. The substructures are distributed anisotropically on the sky, a characteristic that should become apparent in the next generation of photometric surveys. The normalized RMS of the density of stars on the sky appears to be systematically larger for our halos compared with the value estimated for the Milky Way from main-sequence turnoff stars in the Sloan Digital Sky Survey. We show that this is likely to be due in part to contamination by faint QSOs and redder main-sequence stars, and might suggest that {approx}10% of the Milky Way halo stars have formed in situ.

  13. Towards an understanding of the correlations in jet substructure

    DOE PAGESBeta

    Adams, D.; Arce, A.; Asquith, L.; Backovic, M.; Barillari, T.; Berta, P.; Bertolini, D.; Buckley, A.; Butterworth, J.; Camacho Toro, R.  C.; et al

    2015-09-09

    Over the past decade, a large number of jet substructure observables have been proposed in the literature, and explored at the LHC experiments. Such observables attempt to utilize the internal structure of jets in order to distinguish those initiated by quarks, gluons, or by boosted heavy objects, such as top quarks and W bosons. This report, originating from and motivated by the BOOST2013 workshop, presents original particle-level studies that aim to improve our understanding of the relationships between jet substructure observables, their complementarity, and their dependence on the underlying jet properties, particularly the jet radius and jet transverse momentum. Thismore » is explored in the context of quark/gluon discrimination, boosted W boson tagging and boosted top quark tagging.« less

  14. Towards an understanding of the correlations in jet substructure

    SciTech Connect

    Adams, D.; Arce, A.; Asquith, L.; Backovic, M.; Barillari, T.; Berta, P.; Bertolini, D.; Buckley, A.; Butterworth, J.; Camacho Toro, R.  C.; Caudron, J.; Chien, Y. -T.; Cogan, J.; Cooper, B.; Curtin, D.; Debenedetti, C.; Dolen, J.; Eklund, M.; El Hedri, S.; Ellis, S.  D.; Embry, T.; Ferencek, D.; Ferrando, J.; Fleischmann, S.; Freytsis, M.; Giulini, M.; Han, Z.; Hare, D.; Harris, P.; Hinzmann, A.; Hoing, R.; Hornig, A.; Jankowiak, M.; Johns, K.; Kasieczka, G.; Kogler, R.; Lampl, W.; Larkoski, A.  J.; Lee, C.; Leone, R.; Loch, P.; Lopez Mateos, D.; Lou, H. K.; Low, M.; Maksimovic, P.; Marchesini, I.; Marzani, S.; Masetti, L.; McCarthy, R.; Menke, S.; Miller, D.  W.; Mishra, K.; Nachman, B.; Nef, P.; O’Grady, F.  T.; Ovcharova, A.; Picazio, A.; Pollard, C.; Potter-Landua, B.; Potter, C.; Rappoccio, S.; Rojo, J.; Rutherfoord, J.; Salam, G.  P.; Schabinger, R.  M.; Schwartzman, A.; Schwartz, M.  D.; Shuve, B.; Sinervo, P.; Soper, D.; Sosa Corral, D.  E.; Spannowsky, M.; Strauss, E.; Swiatlowski, M.; Thaler, J.; Thomas, C.; Thompson, E.; Tran, N.  V.; Tseng, J.; Usai, E.; Valery, L.; Veatch, J.; Vos, M.; Waalewijn, W.; Wacker, J.; Young, C.

    2015-09-09

    Over the past decade, a large number of jet substructure observables have been proposed in the literature, and explored at the LHC experiments. Such observables attempt to utilize the internal structure of jets in order to distinguish those initiated by quarks, gluons, or by boosted heavy objects, such as top quarks and W bosons. This report, originating from and motivated by the BOOST2013 workshop, presents original particle-level studies that aim to improve our understanding of the relationships between jet substructure observables, their complementarity, and their dependence on the underlying jet properties, particularly the jet radius and jet transverse momentum. This is explored in the context of quark/gluon discrimination, boosted W boson tagging and boosted top quark tagging.

  15. Substructure of the inner core of the Earth.

    PubMed Central

    Herndon, J M

    1996-01-01

    The rationale is disclosed for a substructure within the Earth's inner core, consisting of an actinide subcore at the center of the Earth, surrounded by a subshell composed of the products of nuclear fission and radioactive decay. Estimates are made as to possible densities, physical dimensions, and chemical compositions. The feasibility for self-sustaining nuclear fission within the subcore is demonstrated, and implications bearing on the structure and geodynamic activity of the inner core are discussed. PMID:11607625

  16. Galaxy Properties and Substructure in the Cluster Abell 160

    NASA Astrophysics Data System (ADS)

    Koontz, Craig; Pinkney, Jason

    2009-04-01

    We have developed a procedure for building a large catalog of cluster galaxies and their photometric properties as measured with CCDs. Our first case, Abell 160, is relatively nearby and redshifts exist for its brightest galaxies. We have mosaiced this cluster in R and V filters using a CCD imager on the 1.3-meter McGraw-Hill telescope. We fitted a world coordinate system to the images using the software ``WCStools,'' then used ``Source Extractor'' to extract sources from the images. We have created software for merging catalogs in such a way as to avoid double counting, to reject cosmic rays, and to combine redundant measurements. The software also corrects magnitude differences by comparing the mean difference and adding this to each individual catalog before merging it to a master catalog. The measured properties included in this study were magnitude, ellipticity, position angle, size, and color (V-R). We investigate the efficacy of our separation of galaxies and stars and find that it begins breaking down around R=19.0. We divide our master catalog into several subsamples for substructure analysis. For one subsample, we attempt to separate cluster members from foreground and background galaxies using the color-magnitude relation. We compare the results of substructure diagnostics for the subsamples. In future work, we will examine correlation of substructure with galaxy properties (especially color, size and morphology).

  17. Volume of hippocampal substructures in borderline personality disorder.

    PubMed

    Kreisel, Stefan Henner; Labudda, Kirsten; Kurlandchikov, Oleg; Beblo, Thomas; Mertens, Markus; Thomas, Christine; Rullkötter, Nina; Wingenfeld, Katja; Mensebach, Christoph; Woermann, Friedrich G; Driessen, Martin

    2015-03-30

    Borderline personality disorder (BPD) may be associated with smaller hippocampi in comparison to hippocampal size in controls. However, specific pathology in hippocampal substructures (i.e., head, body and tail) has not been sufficiently investigated. To address hippocampal structure in greater detail, we studied 39 psychiatric inpatients and outpatients with a DSM-IV diagnosis of BPD and 39 healthy controls. The hippocampus and its substructures were segmented manually on magnetic resonance imaging scans. The volumes of hippocampal substructures (and total hippocampal volume) did not differ between BPD patients and controls. Exploratory analysis suggests that patients with a lifetime history of posttraumatic stress disorder (PTSD) may have a significantly smaller hippocampus - affecting both the hippocampal head and body - in comparison to BPD patients without comorbid PTSD (difference in total hippocampal volume: -10.5%, 95%CI -2.6 to -18.5, significant). Also, patients fulfilling seven or more DSM-IV BPD criteria showed a hippocampal volume reduction, limited to the hippocampal head (difference in volume of the hippocampal head: -16.5%, 95%CI -6.1 to -26.8, significant). Disease heterogeneity in respect to, for example, symptom severity and psychiatric comorbidities may limit direct comparability between studies; the results presented here may reflect hippocampal volumes in patients who are "less" affected or they may simply be a chance finding. However, there is also the possibility that global effects of BPD on the hippocampus may have previously been overestimated. PMID:25624067

  18. Modal Substructuring of Geometrically Nonlinear Finite-Element Models

    DOE PAGESBeta

    Kuether, Robert J.; Allen, Matthew S.; Hollkamp, Joseph J.

    2016-02-01

    The efficiency of a modal substructuring method depends on the component modes used to reduce each subcomponent model. Methods such as Craig–Bampton have been used extensively to reduce linear finite-element models with thousands or even millions of degrees of freedom down orders of magnitude while maintaining acceptable accuracy. A novel reduction method is proposed here for geometrically nonlinear finite-element models using the fixed-interface and constraint modes of the linearized system to reduce each subcomponent model. The geometric nonlinearity requires an additional cubic and quadratic polynomial function in the modal equations, and the nonlinear stiffness coefficients are determined by applying amore » series of static loads and using the finite-element code to compute the response. The geometrically nonlinear, reduced modal equations for each subcomponent are then coupled by satisfying compatibility and force equilibrium. This modal substructuring approach is an extension of the Craig–Bampton method and is readily applied to geometrically nonlinear models built directly within commercial finite-element packages. The efficiency of this new approach is demonstrated on two example problems: one that couples two geometrically nonlinear beams at a shared rotational degree of freedom, and another that couples an axial spring element to the axial degree of freedom of a geometrically nonlinear beam. The nonlinear normal modes of the assembled models are compared with those of a truth model to assess the accuracy of the novel modal substructuring approach.« less

  19. Role of the Li(+) node in the Li-BH4 substructure of double-cation tetrahydroborates.

    PubMed

    Schouwink, Pascal; Smrčok, Lubomír; Černý, Radovan

    2014-10-01

    The phase diagram LiBH4-ABH4 (A = Rb,Cs) has been screened and revealed ten new compounds LiiAj(BH4)i+j (A = Rb, Cs), with i, j ranging between 1 and 3, representing eight new structure types amongst homoleptic borohydrides. An approach based on synchrotron X-ray powder diffraction to solve crystal structures and solid-state first principles calculations to refine atomic positions allows characterizing multi-phase ball-milled samples. The Li-BH4 substructure adopts various topologies as a function of the compound's Li content, ranging from one-dimensional isolated chains to three-dimensional networks. It is revealed that the Li(+) ion has potential as a surprisingly versatile cation participating in framework building with the tetrahydroborate anion BH4 as a linker, if the framework is stabilized by large electropositive counter-cations. This utility can be of interest when designing novel hydridic frameworks based on alkaline metals and will be of use when exploring the structural and coordination chemistry of light-metal systems otherwise subject to eutectic melting. PMID:25274521

  20. Construction of a linker library with widely controllable flexibility for fusion protein design.

    PubMed

    Li, Gang; Huang, Ziliang; Zhang, Chong; Dong, Bo-Jun; Guo, Ruo-Hai; Yue, Hong-Wei; Yan, Li-Tang; Xing, Xin-Hui

    2016-01-01

    Flexibility or rigidity of the linker between two fused proteins is an important parameter that affects the function of fusion proteins. In this study, we constructed a linker library with five elementary units based on the combination of the flexible (GGGGS) and the rigid (EAAAK) units. Molecular dynamics (MD) simulation showed that more rigid units in the linkers lead to more helical conformation and hydrogen bonds, and less distance fluctuation between the N- and C-termini of the linker. The diversity of linker flexibility of the linker library was then studied by fluorescence resonance energy transfer (FRET) of cyan fluorescent protein (CFP)-yellow fluorescent protein (YFP) fusion proteins, which showed that there is a wide range of distribution of the FRET efficiency. Dissipative particle dynamics (DPD) simulation of CFP-YFP with different linkers also gave identical results with that of FRET efficiency analysis, and we further found that the combination manner of the linker peptide had a remarkable effect on the orientation of CFP and YFP domains. Our studies demonstrated that the construction of the linker library with the widely controllable flexibility could provide appropriate linkers with the desirable characteristics to engineer the fusion proteins with the expected functions. PMID:26394862

  1. Characterization of the light-regulated operon encoding the phycoerythrin-associated linker proteins from the cyanobacterium Fremyella diplosiphon.

    PubMed Central

    Federspiel, N A; Grossman, A R

    1990-01-01

    Many biological processes in photosynthetic organisms can be regulated by light quantity or light quality or both. A unique example of the effect of specific wavelengths of light on the composition of the photosynthetic apparatus occurs in cyanobacteria that undergo complementary chromatic adaptation. These organisms alter the composition of their light-harvesting organelle, the phycobilisome, and exhibit distinct morphological features as a function of the wavelength of incident light. Fremyella diplosiphon, a filamentous cyanobacterium, responds to green light by activating transcription of the cpeBA operon, which encodes the pigmented light-harvesting component phycoerythrin. We have isolated and determined the complete nucleotide sequence of another operon, cpeCD, that encodes the linker proteins associated with phycoerythrin hexamers in the phycobilisome. The cpeCD operon is activated in green light and expressed as two major transcripts with the same 5' start site but differing 3' ends. Analysis of the kinetics of transcript accumulation in cultures of F. diplosiphon shifted from red light to green light and vice versa shows that the cpeBA and cpeCD operons are regulated coordinately. A common 17-base-pair sequence is found upstream of the transcription start sites of both operons. A comparison of the predicted amino acid sequences of the phycoerythrin-associated linker proteins CpeC and CpeD with sequences of other previously characterized rod linker proteins shows 49 invariant residues, most of which are in the amino-terminal half of the proteins. Images PMID:1694529

  2. The flexibility of modified-linker MIL-53 materials.

    PubMed

    Munn, Alexis S; Pillai, Renjith S; Biswas, Shyam; Stock, Norbert; Maurin, Guillaume; Walton, Richard I

    2016-03-14

    The flexibility of eight aluminium hydroxo terephthalates [Al(OH)(BDC-X)]·n(guest) (BDC = 1,4-benzene-dicarboxylate; X = -H, -CH3, -Cl, -Br, -NH2, -NO2, -(OH)2, -CO2H) crystallising in the MIL-53-type structure was investigated upon thermal dehydration of as-made samples, superhydration and methanol adsorption/desorption using in situ powder X-ray diffraction (PXRD). Profile fitting was used to determine lattice parameters as a function of time and/or temperature to describe their structural evolution. It has thus been shown that while methanol vapour adsorption induces an opening of all the modified frameworks, except the -NH2 material, superhydration only leads to open structures for Al-MIL-53-NO2, -Br and -(OH)2. All the MIL-53 solids, except Al-MIL-53-(OH)2 are present in the open structures upon thermal dehydration. In addition to the exploration of the breathing behavior of this MIL-53 series, the issue of disorder in the distribution of the functional groups between the organic linkers was explored. As a typical illustration, density functional theory calculations were carried out on different structures of Al-MIL-53-Cl, in which the distribution of -Cl within two adjacent BDC linkers is varied. The results show that the most energetically stable configuration leads to the best agreement with the experimental PXRD pattern. This observation supports that the distribution of the selected linker substituent in the functionalised solid is governed by energetics and that there is a preference for an ordering of this arrangement. PMID:26465320

  3. A traceless perfluoroalkylsulfonyl (PFS) linker for the deoxygenation of phenols.

    PubMed

    Pan, Y; Holmes, C P

    2001-08-23

    [reaction: see text]. The synthesis of a novel perfluoroalkylsulfonyl (PFS) fluoride is described for use as a traceless linker in solid-phase organic synthesis. Attachment to the resin and subsequent coupling of a phenol affords a stable arylsulfonate that behaves as a support-bound aryl triflate. Palladium-mediated reductive cleavage of a wide variety of phenols generated the parent arenes. The resin-bound aryl triflate was shown to be stable to reductive amination conditions, and the traceless synthesis of Meclizine is reported. PMID:11506630

  4. Increasing the Depth of Mass-Spectrometry-Based Structural Analysis of Protein Complexes through the Use of Multiple Cross-Linkers.

    PubMed

    Ding, Yue-He; Fan, Sheng-Bo; Li, Shuang; Feng, Bo-Ya; Gao, Ning; Ye, Keqiong; He, Si-Min; Dong, Meng-Qiu

    2016-04-19

    Chemical cross-linking of proteins coupled with mass spectrometry (CXMS) is a powerful tool to study protein folding and to map the interfaces between interacting proteins. The most commonly used cross-linkers in CXMS are BS(3) and DSS, which have similar structures and generate the same linkages between pairs of lysine residues in spatial proximity. However, there are cases where no cross-linkable lysine pairs are present at certain regions of a protein or at the interface of two interacting proteins. In order to find the cross-linkers that can best complement the performance of BS(3) and DSS, we tested seven additional cross-linkers that either have different spacer arm structures or that target different amino acids (BS(2)G, EGS, AMAS, GMBS, Sulfo-GMBS, EDC, and TFCS). Using BSA, aldolase, the yeast H/ACA protein complex, and E. coli 70S ribosomes, we showed that, in terms of providing structural information not obtained through the use of BS(3) and DSS, EGS and Sulfo-GMBS worked better than the other cross-linkers that we tested. EGS generated a large number of cross-links not seen with the other amine-specific cross-linkers, possibly due to its hydrophilic spacer arm. We demonstrate that incorporating the cross-links contributed by the EGS and amine-sulfhydryl cross-linkers greatly increased the accuracy of Rosetta in docking the structure of the yeast H/ACA protein complex. Given the improved depth of useful information it can provide, we suggest that the multilinker CXMS approach should be used routinely when the amount of a sample permits. PMID:27010980

  5. On the use of attachment modes in substructure coupling for dynamic analysis

    NASA Technical Reports Server (NTRS)

    Craig, R. R., Jr.; Chang, C.-J.

    1977-01-01

    Substructure coupling or component-mode synthesis may be employed in the solution of dynamics problems for complex structures. Although numerous substructure-coupling methods have been devised, little attention has been devoted to methods employing attachment modes. In the present paper the various mode sets (normal modes, constraint modes, attachment modes) are defined. A generalized substructure-coupling procedure is described. Those substructure-coupling methods which employ attachment modes are described in detail. One of these methods is shown to lead to results (e.g., system natural frequencies) comparable to or better than those obtained by the Hurty (1965) method.

  6. GLAST And Dark Matter Substructure in the Milky Way

    SciTech Connect

    Kuhlen, Michael; Diemand, Jurg; Madau, Piero; /UC, Santa Cruz, Astron. Astrophys. /Garching, Max Planck Inst.

    2011-11-29

    We discuss the possibility of GLAST detecting gamma-rays from the annihilation of neutralino dark matter in the Galactic halo. We have used 'Via Lactea', currently the highest resolution simulation of cold dark matter substructure, to quantify the contribution of subhalos to the annihilation signal. We present a simulated allsky map of the expected gamma-ray counts from dark matter annihilation, assuming standard values of particle mass and cross section. In this case GLAST should be able to detect the Galactic center and several individual subhalos. One of the most exciting discoveries that the Gamma-ray Large Area Space Telescope (GLAST) could make, is the detection of gamma-rays from the annihilation of dark matter (DM). Such a measurement would directly address one of the major physics problems of our time: the nature of the DM particle. Whether or not GLAST will actually detect a DM annihilation signal depends on both unknown particle physics and unknown astrophysics theory. Particle physics uncertainties include the type of particle (axion, neutralino, Kaluza-Klein particle, etc.), its mass, and its interaction cross section. From the astrophysical side it appears that DM is not smoothly distributed throughout the Galaxy halo, but instead exhibits abundant clumpy substructure, in the form of thousands of so-called subhalos. The observability of DM annihilation radiation originating in Galactic DM subhalos depends on their abundance, distribution, and internal properties. Numerical simulations have been used in the past to estimate the annihilation flux from DM substructure, but since the subhalo properties, especially their central density profile, which determines their annihilation luminosity, are very sensitive to numerical resolution, it makes sense to re-examine their contribution with higher resolution simulations.

  7. Tides, Interactions, and Fine-Scale Substructures in Galaxy Clusters

    NASA Astrophysics Data System (ADS)

    Conselice, Christopher J.; Gallagher, John S., III

    1999-01-01

    We present the results of a study on galaxy interactions, tides, and other processes that produce luminous fine-scale substructures in the galaxy clusters: Coma, Perseus, Abell 2199, AWM 3, and AWM 5. All unusual structures in these clusters can be categorized into seven morphologies: interacting galaxies, multiple galaxies (noninteracting), distorted galaxies, tailed galaxies, line galaxies, dwarf galaxy groups, and galaxy aggregates. The various morphologies are described, and a catalog is presented, of 248 objects in these five clusters along with color, and positional information obtained from CCD images taken with the WIYN 3.5 m telescope in broadband B and R filters. Distorted, interacting, and fine-scale substructures have a range of colors extending from blue objects with B-R~0 to redder colors at B-R~2.5. We also find that the structures with the most disturbed morphology have the bluest colors. In addition, the relative number distributions of these structures suggest that two separate classes of galaxy clusters exist: one dominated by distorted structures and the other dominated by galaxy associations. The Coma and Perseus clusters, respectively, are proposed as models for these types of clusters. These structures avoid the deep potentials of the dominant D or cD galaxies in the Coma and Perseus clusters, and tend to clump together. Possible mechanisms for the production of fine-scale substructure are reviewed and compared with observations of z~0.4 Butcher-Oemler clusters. We conclude, based on color, positional, and statistical data, that the most likely mechanism for the creation of these structures is through an interaction with the gravitational potential of the cluster, possibly coupled with effects of weak interactions with cluster ellipticals.

  8. Flexible Linker Modulates Glycosaminoglycan Affinity of Decorin Binding Protein A.

    PubMed

    Morgan, Ashli; Sepuru, Krishna Mohan; Feng, Wei; Rajarathnam, Krishna; Wang, Xu

    2015-08-18

    Decorin binding protein A (DBPA) is a glycosaminoglycan (GAG)-binding adhesin found on the surface of the bacterium Borrelia burgdorferi (B. burgdorferi), the causative agent of Lyme disease. DBPA facilitates bacterial adherence to extracellular matrices of human tissues and is crucial during the early stage of the infection process. Interestingly, DBPA from different strains (B31, N40, and PBr) show significant differences in GAG affinities, but the structural basis for the differences is not clear. In this study, we show that GAG affinity of N40 DBPA is modulated in part by flexible segments that control access to the GAG binding site, such that shortening of the linker leads to higher GAG affinity when analyzed using ELISA, gel mobility shift assay, solution NMR, and isothermal titration calorimetry. Our observation that GAG affinity differences among different B. burgdorferi strains can be attributed to a flexible linker domain regulating access to the GAG-binding domain is novel. It also provides a rare example of how neutral amino acids and dynamic segments in GAG binding proteins can have a large influence on GAG affinity and provides insights into why the number of basic amino acids in the GAG-binding site may not be the only factor determining GAG affinity of proteins. PMID:26223367

  9. A Traceless Cross-linker for Photo-Cleavable Bioconjugation

    PubMed Central

    Wang, Rong; Yan, Funing; Qiu, Dengli; Jeong, Jae-Sun; Jin, Qiaoling; Kim, Tae-Young; Chen, Liaohai

    2012-01-01

    Photo-responsive bioconjugation empowers the development of novel methods for drug discovery, disease diagnosis, and high-throughput screening, among the others. In this paper, we report on the characteristics of a traceless photo-cleavable cross-linker, di 6-(3-succinimidyl carbonyloxymethyl-4-nitro-phenoxy)-hexanoic acid disulfide diethanol ester (SCNE). The traceless feature and the biocompatibility of this photo-cleavable cross-linking reagent were corroborated. Consequently, we demonstrated its application in reversible phage particle immobilization that could provide a platform for direct single phage screening. We also applied it in protein-photoprinting, where SCNE acts as a “photo-eraser” to remove the cross-linked protein molecules at a desired region in a simple, clean and light-controllable fashion. We further demonstrated the two-tier atomic force microscopic (AFM) method that uses SCNE to carry out two subsequent AFM tasks in situ. The approach allows guided protein delivery and subsequent high-resolution imaging at the same local area, thus opens up the possibility of monitoring protein functions in live cells. The results imply that SCNE is a versatile cross-linker that can be used for a wide range of applications where photo-cleavage ensures clean and remote-controllable release of biological molecules from a substrate. PMID:22432929

  10. Germline-specific H1 variants: the "sexy" linker histones.

    PubMed

    Pérez-Montero, Salvador; Carbonell, Albert; Azorín, Fernando

    2016-03-01

    The eukaryotic genome is packed into chromatin, a nucleoprotein complex mainly formed by the interaction of DNA with the abundant basic histone proteins. The fundamental structural and functional subunit of chromatin is the nucleosome core particle, which is composed by 146 bp of DNA wrapped around an octameric protein complex formed by two copies of each core histone H2A, H2B, H3, and H4. In addition, although not an intrinsic component of the nucleosome core particle, linker histone H1 directly interacts with it in a monomeric form. Histone H1 binds nucleosomes near the exit/entry sites of linker DNA, determines nucleosome repeat length and stabilizes higher-order organization of nucleosomes into the ∼30 nm chromatin fiber. In comparison to core histones, histone H1 is less well conserved through evolution. Furthermore, histone H1 composition in metazoans is generally complex with most species containing multiple variants that play redundant as well as specific functions. In this regard, a characteristic feature is the presence of specific H1 variants that replace somatic H1s in the germline and during early embryogenesis. In this review, we summarize our current knowledge about their structural and functional properties. PMID:25921218

  11. Simulating and Synthesizing Substructures Using Neural Network and Genetic Algorithms

    NASA Technical Reports Server (NTRS)

    Liu, Youhua; Kapania, Rakesh K.; VanLandingham, Hugh F.

    1997-01-01

    The feasibility of simulating and synthesizing substructures by computational neural network models is illustrated by investigating a statically indeterminate beam, using both a 1-D and a 2-D plane stress modelling. The beam can be decomposed into two cantilevers with free-end loads. By training neural networks to simulate the cantilever responses to different loads, the original beam problem can be solved as a match-up between two subsystems under compatible interface conditions. The genetic algorithms are successfully used to solve the match-up problem. Simulated results are found in good agreement with the analytical or FEM solutions.

  12. Hierarchically Parallelized Constrained Nonlinear Solvers with Automated Substructuring

    NASA Technical Reports Server (NTRS)

    Padovan, Joe; Kwang, Abel

    1994-01-01

    This paper develops a parallelizable multilevel multiple constrained nonlinear equation solver. The substructuring process is automated to yield appropriately balanced partitioning of each succeeding level. Due to the generality of the procedure,_sequential, as well as partially and fully parallel environments can be handled. This includes both single and multiprocessor assignment per individual partition. Several benchmark examples are presented. These illustrate the robustness of the procedure as well as its capability to yield significant reductions in memory utilization and calculational effort due both to updating and inversion.

  13. Aligning graphs and finding substructures by a cavity approach

    NASA Astrophysics Data System (ADS)

    Bradde, S.; Braunstein, A.; Mahmoudi, H.; Tria, F.; Weigt, M.; Zecchina, R.

    2010-02-01

    We introduce a new distributed algorithm for aligning graphs or finding substructures within a given graph. It is based on the cavity method and is used to study the maximum-clique and the graph-alignment problems in random graphs. The algorithm allows to analyze large graphs and may find applications in fields such as computational biology. As a proof of concept we use our algorithm to align the similarity graphs of two interacting protein families involved in bacterial signal transduction, and to predict actually interacting protein partners between these families.

  14. GLAST and Dark Matter Substructure in the Milky Way

    SciTech Connect

    Kuhlen, Michael; Diemand, Juerg; Madau, Piero

    2007-07-12

    We discuss the possibility of GLAST detecting gamma-rays from the annihilation of neutralino dark matter in the Galactic halo. We have used ''Via Lactea'', currently the highest resolution simulation of cold dark matter substructure, to quantify the contribution of subhalos to the annihilation signal. We present a simulated allsky map of the expected gamma-ray counts from dark matter annihilation, assuming standard values of particle mass and cross section. In this case GLAST should be able to detect the Galactic center and several individual subhalos.

  15. The construction of preconditioners for elliptic problems by substructuring, IV

    SciTech Connect

    Bramble, J.H.; Pasciak, J.E.; Schatz, A.H.

    1987-06-01

    We consider the problem of solving the algebraic system of equations which result from the discretization of elliptic boundary value problems defined on three dimensional Euclidean space. We develop preconditioners for such systems based on substructuring (also known as domain decomposition). The resulting algorithms are well suited to emerging parallel computing architectures. We describe two techniques for developing these precondictioners. A theory for the analysis of the condition number for the resulting preconditioned system is given and the results of supporting numerical experiments are presented. 16 refs., 2 tabs.

  16. The construction of preconditioners for elliptic problems by substructuring, IV

    SciTech Connect

    Bramble, J.H.; Pasciak, J.E.; Schatz, A.H.

    1989-07-01

    We consider the problem of solving the algebraic system of equations which result from the discretization of elliptic boundary value problems defined on three-dimensional Euclidean space. We develop preconditioners for such systems based on substructuring (also known as domain decomposition). The resulting algorithms are well suited to emerging parallel computing architectures. We describe two techniques for developing these preconditioners. A theory for the analysis of the condition number for the resulting preconditioned system is given and the results of supporting numerical experiments are presented.

  17. Unexpected relationships of substructured populations in Chinese Locusta migratoria

    PubMed Central

    Zhang, De-Xing; Yan, Lu-Na; Ji, Ya-Jie; Hewitt, Godfrey M; Huang, Zu-Shi

    2009-01-01

    Background Highly migratory species are usually expected to have minimal population substructure because strong gene flow has the effect of homogenizing genetic variation over geographical populations, counteracting random drift, selection and mutation. The migratory locust Locusta migratoria belongs to a monotypic genus, and is an infamous pest insect with exceptional migratory ability – with dispersal documented over a thousand kilometers. Its distributional area is greater than that of any other locust or grasshopper, occurring in practically all the temperate and tropical regions of the eastern hemisphere. Consequently, minimal population substructuring is expected. However, in marked contrast to its high dispersal ability, three geographical subspecies have been distinguished in China, with more than nine being biologically and morphologically identified in the world. Such subspecies status has been under considerable debate. Results By multilocus microsatellite genotyping analysis, we provide ample genetic evidence for strong population substructure in this highly migratory insect that conforms to geography. More importantly, our genetic data identified an unexpected cryptic subdivision and demonstrated a strong affiliation of the East China locusts to those in Northwest/Northern China. The migratory locusts in China formed three distinct groups, viz. (1) the Tibetan group, comprising locusts from Tibet and nearby West China high mountain regions; this is congruent with the previously recognized Tibetan subspecies, L. m. tibetensis; (2) the South China group, containing locusts from the Hainan islands; this corresponds to the Southeast Asia oriental tropical subspecies L. m. manilensis; (3) the North China group, including locusts from the Northwest and Northern China (the Asiatic subspecies L. m. migratoria), Central China and Eastern China regions. Therefore, the traditional concept on Locusta subspecies status established from Uvarov in 1930s needs to be

  18. Convergence of a Substructuring Method with LaGrange Multipliers

    NASA Technical Reports Server (NTRS)

    Mandel, Jan; Tezaur, Radek

    1996-01-01

    We analyze the convergence of a substructuring iterative method with Lagrange multipliers, proposed recently by Farhat and Roux. The method decomposes finite element discretization of an elliptic boundary value problem into Neumann problems on the subdomains and a coarse problem for the subdomain nullspace components. For linear conforming elements and preconditioning by the Dirichlet problems on the subdomains, we prove the asymptotic bound on the condition number C(1 + log(H/h))(sup gamma), gamma = 2 or 3, where h is the characteristic element size and H is the subdomain size.

  19. Toward quantitative proteomics of organ substructures: implications for renal physiology.

    PubMed

    Velic, Ana; Macek, Boris; Wagner, Carsten A

    2010-09-01

    Organs are complex structures that consist of multiple tissues with different levels of gene expression. To achieve comprehensive coverage and accurate quantitation data, organs ideally should be separated into morphologic and/or functional substructures before gene or protein expression analysis. However, because of complex morphology and elaborate isolation protocols, to date this often has been difficult to achieve. Kidneys are organs in which functional and morphologic subdivision is especially important. Each subunit of the kidney, the nephron, consists of more than 10 subsegments with distinct morphologic and functional characteristics. For a full understanding of kidney physiology, global gene and protein expression analyses have to be performed at the level of the nephron subsegments; however, such studies have been extremely rare to date. Here we describe the latest approaches in quantitative high-accuracy mass spectrometry-based proteomics and their application to quantitative proteomics studies of the whole kidney and nephron subsegments, both in human beings and in animal models. We compare these studies with similar studies performed on other organ substructures. We argue that the newest technologies used for preparation, processing, and measurement of small amounts of starting material are finally enabling global and subsegment-specific quantitative measurement of protein levels in the kidney and other organs. These new technologies and approaches are making a decisive impact on our understanding of the (patho)physiological processes at the molecular level. PMID:21044760

  20. Unlocking Dark Matter Physics out of Galactic Substructures

    NASA Astrophysics Data System (ADS)

    Cyr-Racine, Francis-Yan; Moustakas, Leonidas A.; Keeton, Charles R.

    2016-01-01

    Despite being ubiquitous throughout the Universe, the fundamental properties of dark matter remain a mystery. While dark matter physics plays little role in the current evolution of large-scale cosmic structures, it does have a major impact on small causal length scales. Studying the astrophysical structures that resulted from the gravitational collapse of fluctuations on these small scales can thus yield important clues about the physics of dark matter. Today, most of these structures are locked in deep inside the potential wells of galaxies, making the study of their properties difficult. Fortunately, due to fortuitous alignments between high-redshift bright sources and us, some of these galaxies act as spectacular strong gravitational lenses, allowing us to probe their inner structure. In this talk, we present a unified framework to extract information about the power spectrum of mass substructures inside lens galaxies. We determine which properties of mass substructures are most readily constrained by lensing data and forecast the constraining power of current and future observations.

  1. Jet substructures of boosted polarized hadronic top quarks

    NASA Astrophysics Data System (ADS)

    Kitadono, Yoshio; Li, Hsiang-nan

    2016-03-01

    We study jet substructures of a boosted polarized top quark, which undergoes the hadronic decay t →b u d ¯, in the perturbative QCD framework, focusing on the energy profile and the differential energy profile. These substructures are factorized into the convolution of a hard top-quark decay kernel with a bottom-quark jet function and a W -boson jet function, where the latter is further factorized into the convolution of a hard W -boson decay kernel with two light-quark jet functions. Computing the hard kernels to leading order in QCD and including the resummation effect in the jet functions, we show that the differential jet energy profile is a useful observable for differentiating the helicity of a boosted hadronic top quark: a right-handed top jet exhibits quick descent of the differential energy profile with the inner test cone radius r , which is attributed to the V -A structure of weak interaction and the dead-cone effect associated with the W -boson jet. The above helicity differentiation may help reveal the chiral structure of physics beyond the standard model at high energies.

  2. An Efficient Crankshaft Dynamic Analysis Using Substructuring with Ritz Vectors

    NASA Astrophysics Data System (ADS)

    MOURELATOS, Z. P.

    2000-11-01

    A structural analysis using dynamic substructuring with Ritz vectors is presented for predicting the dynamic response of an engine crankshaft, based on the finite-element method. A two-level dynamic substructuring is performed using a set of load-dependent Ritz vectors. The rotating crankshaft is properly coupled with the non-rotating, compliant engine block. The block compliance is represented by a distributed linear elastic foundation at each main bearing location. The stiffness of the elastic foundation can be different in the vertical and horizontal planes, thereby considering the anisotropy of the engine block compliance with respect to the crankshaft rotation. The analysis accounts for the kinematic non-linearity resulting from the crankangle-dependent circumferential contact location between each journal and the corresponding bore of the engine block. Crankshaft “bent” and block “misboring” effects due to manufacturing imperfections are considered in the analysis. The superior accuracy and reduced computational effort of the present method as compared with the equivalent superelement analysis in MSC/NASTRAN, are demonstrated using the free and forced vibrations of a slender cylindrical beam and free vibrations of a four-cylinder engine crankshaft. Subsequently, the accuracy of the present method in calculating the dynamic response of engine crankshafts is shown through comparisons between the analytical predictions and experimental results for the torsional vibrations of an in-line five cylinder engine and the bending vibrations of the crankshaft-flywheel assembly of a V6 engine.

  3. Evolutionary correlation between linker histones and microtubular structures.

    PubMed

    Kaczanowski, S; Jerzmanowski, A

    2001-07-01

    Histones of the H1 group (linker histones) are abundant components of chromatin in eukaryotes, occurring on average at one molecule per nucleosome. The recent reports on the lack of a clear phenotypic effect of knock-out mutations as well as overexpression of histone H1 genes in different organisms have seriously undermined the long-held view that linker histones are essential for the basic functions of eukaryotic cells. In an attempt to resolve the paradox of an abundant conserved protein without a clear function, we re-examined the molecular and phylogenetic data on linker histones to see if they could reveal any correlation between the features of H1 and the functional or morphological characteristics of cells or organisms. Because of an earlier demonstration that in sea urchin the chromatin-type histone H1 is also found in the flagellar microtubules (Multigner et al. 1992), we focused on the correlation between the features of H1 and those of microtubular structures. A phylogenetic tree based on multiple alignment of over 100 available HI sequences suggests that the first divergence of the globular domain of H1 (GH1) resulted in branching into separate types characteristic for plants/Dictyostelium and for animals/ascomycetes, respectively. The GH1s of these two types differ by a short region (usually 5 amino acids) placed at a specific location within the C-terminal wing subdomain of GH1. Evolutionary analysis of the diversification of H1 mRNA into cell-cycle-dependent (polyA-) and independent (polyA+) forms showed a mosaic occurrence of these two forms in plants and animals, despite the fact that the H1 proteins of plants and animals belong to two well-distinguished groups. However, among organisms from both animal and plant kingdom, only those with H1 mRNA of a polyA- type have flagellated gametes. This correlation as well as the demonstration that in Volvox carteri the accumulation of polyA- mRNA of H1 occurs concurrently with the production of new flagella

  4. Resolving the chemical substructure of Orion-KL

    NASA Astrophysics Data System (ADS)

    Feng, S.; Beuther, H.; Henning, Th.; Semenov, D.; Palau, A.; Mills, E. A. C.

    2015-09-01

    Context. The Kleinmann-Low nebula in Orion (Orion-KL) is the nearest example of a high-mass star-forming environment. Studying the resolved chemical substructures of this complex region provides important insight into the chemistry of high-mass star-forming regions (HMSFRs), as it relates to their evolutionary states. Aims: The goal of this work is to resolve the molecular line emission from individual substructures of Orion-KL at high spectral and spatial resolution and to infer the chemical properties of the associated gas. Methods: We present a line survey of Orion-KL obtained from combined Submillimeter Array (SMA) interferometric and IRAM 30 m single-dish observations. Covering a 4 GHz bandwidth in total, this survey contains over 160 emission lines from 20 species (25 isotopologues), including 11 complex organic molecules (COMs). Spectra are extracted from individual substructures and the intensity-integrated distribution map for each species is provided. We then estimate the rotation temperature for each substructure, along with their molecular column densities and abundances. Results: For the first time, we complement 1.3 mm interferometric data with single-dish observations of the Orion-KL region and study small-scale chemical variations in this region. (1) We resolve continuum substructures on ~3'' angular scale. (2) We identify lines from the low-abundance COMs CH3COCH3 and CH3CH2OH, as well as tentatively detect CH3CHO and long carbon-chain molecules C6H and HC7N. (3) We find that while most COMs are segregated by type, peaking either towards the hotcore (e.g., nitrogen-bearing species) or the compact ridge (e.g., oxygen-bearing species like HCOOCH3 and CH3OCH3), the distributions of others do not follow this segregated structure (e.g., CH3CH2OH, CH3OH, CH3COCH3). (4) We find a second velocity component of HNCO, SO2, 34SO2, and SO lines, which may be associated with a strong shock event in the low-velocity outflow. (5) Temperatures and molecular

  5. The Tension between Organisational Sub-structures in Secondary Schools and Educational Reform.

    ERIC Educational Resources Information Center

    Imants, Jeroen; Sleegers, Peter; Witziers, Bob

    2001-01-01

    Explores how Dutch secondary schools can provide supportive working contexts that promote teacher learning, focusing on integration of two substructures (subject departments and student guidance units). Analyzes tensions between the substructures, summarizes insights into teacher learning communities, and discusses integrated teacher teams'…

  6. In Search of an Efficient Photoswitch for Functional RNA: Design Principles from a Microscopic Analysis of Azobenzene-linker-RNA Dynamics with Different Linkers.

    PubMed

    Mondal, Padmabati; Biswas, Mithun; Goldau, Thomas; Heckel, Alexander; Burghardt, Irene

    2015-08-27

    The design of optimal photoswitches to regulate nucleic acid functionality is a considerable challenge. Azobenzene switches that are covalently bound to the nucleic acid backbone are a paradigm example that has been studied using different types of linker species connecting the chromophore to the backbone. To support experimental efforts to construct optimal azobenzene-linker-RNA combinations, we introduce here a systematic approach for theoretical analysis, which provides criteria for the local embedding of the chromophore via a chosen linker. Using a local reference frame adapted to the chromophore, quantitative measures are provided for (i) the propensity of stacking in competition with a drift toward the minor or major groove, (ii) the tendency to disrupt the native hydrogen bond network, (iii) the structural flexibility of the chromophore-linker combination, and (iv) the correlations with the presence of a base in the opposite strand. Large differences in structural stability between the trans and cis forms of the azobenzene chromophore, according to these criteria, indicate good functionality and lead to significant differences in melting temperatures. In particular, a recently synthesized deoxyribose linker proves optimal within the set of azobenzene-linker-RNA combinations considered. PMID:26125118

  7. Knowledge Linkers and the Flow of Educational Information. An Occasional Paper from ERIC at Stanford.

    ERIC Educational Resources Information Center

    Farr, Richard S.

    The flow of knowledge from researchers to users is aided by knowledge linkers who activate the interpersonal network of communication within the target audience. The linker enters this network by contacting (through periodicals, mass media, conventions, and directly) individuals in the audience who are more active than others (gatekeepers). Once…

  8. TA-Doc Linker Role. Draft. Documentation and Technical Assistance in Urban Schools.

    ERIC Educational Resources Information Center

    Holmes, Manford L.

    One of the aims of the Documentation and Technical Assistance (DTA) Project is to apply educational information that has been utilized for problem solving in one organization to other settings with their own unique characteristics. Within the staff of the DTA project, the position of Technical Assistance-Documentation Linker (TA-Doc Linker) was…

  9. Linker Installation: Engineering Pore Environment with Precisely Placed Functionalities in Zirconium MOFs.

    PubMed

    Yuan, Shuai; Chen, Ying-Pin; Qin, Jun-Sheng; Lu, Weigang; Zou, Lanfang; Zhang, Qiang; Wang, Xuan; Sun, Xing; Zhou, Hong-Cai

    2016-07-20

    Precise placement of multiple functional groups in a highly ordered metal-organic framework (MOF) platform allows the tailoring of the pore environment, which is required for advanced applications. To realize this, we present a comprehensive study on the linker installation method, in which a stable MOF with coordinatively unsaturated Zr6 clusters was employed and linkers bearing different functional groups were postsynthetically installed. A Zr-MOF with inherent missing linker sites, namely, PCN-700, was initially constructed under kinetic control. Twelve linkers with different substituents were then designed to study their effect on MOF formation kinetics and therefore resulting MOF structures. Guided by the geometrical analysis, linkers with different lengths were installed into a parent PCN-700, giving rise to 11 new MOFs and each bearing up to three different functional groups in predefined positions. Systematic variation of the pore volume and decoration of pore environment were realized by linker installation, which resulted in synergistic effects including an enhancement of H2 adsorption capacities of up to 57%. In addition, a size-selective catalytic system for aerobic alcohol oxidation reaction is built in PCN-700 through linker installation, which shows high activity and tunable size selectivity. Altogether, these results exemplify the capability of the linker installation method in the pore environment engineering of stable MOFs with multiple functional groups, giving an unparalleled level of control. PMID:27345035

  10. Molecular design of light-harvesting photosensitizers: effect of varied linker conjugation on interfacial electron transfer.

    PubMed

    Jiang, Jianbing; Swierk, John R; Hedström, Svante; Matula, Adam J; Crabtree, Robert H; Batista, Victor S; Schmuttenmaer, Charles A; Brudvig, Gary W

    2016-07-28

    Interfacial electron transfer dynamics of a series of photosensitizers bound to TiO2via linkers of varying conjugation strength are explored by spectroscopic and computational techniques. Injection and recombination depend on the extent of conjugation in the linker, where the LUMO delocalization determines the injection dynamics but both the HOMO and HOMO-1 are involved in recombination. PMID:27364769

  11. Flexibility of C3h -Symmetrical Linkers in Tris-oligonucleotide-Based Tetrahedral Scaffolds.

    PubMed

    Panagiotidis, Christos; Kath-Schorr, Stephanie; von Kiedrowski, Günter

    2016-02-01

    Flexibility of tris-oligonucleotides is determined by the length of their connecting hydrocarbon chains. Tris-oligonucleotides are branched DNA building blocks with three oligonucleotide arms attached to a C3h -symmetrical linker core at these chains. Four tris-oligonucleotides hybridise into a tetrahedral nanocage by sequence-determined self-assembly. The influence of methylene, ethylene and propylene chains was studied by synthesising sets of tris-oligonucleotides and analysing the relative stability of the hybridisation products against digestion by mung bean nuclease by using gel electrophoresis. Linkers with ethylene chains showed sufficient flexibility, whereas methylene-chain linkers were too rigid. Tris-oligonucleotides based on the latter still formed tetrahedral scaffolds in intermixing experiments with linkers of higher flexibility. Thus, a new generation of versatile isocyanurate-based linkers was established. PMID:26593127

  12. Impact of linker strain and flexibility in the design of a fragment-based inhibitor

    PubMed Central

    Chung, Suhman; Parker, Jared B.; Bianchet, Mario; Amzel, L. Mario; Stivers, James T.

    2011-01-01

    The linking together of molecular fragments that bind to adjacent sites on an enzyme can lead to high affinity inhibitors. Ideally, this strategy would employ linkers that do not perturb the optimal binding geometries of the fragments and do not have excessive conformational flexibility that would increase the entropic penalty of binding. In reality, these aims are seldom realized due to limitations in linker chemistry. Here we systematically explore the energetic and structural effects of rigid and flexible linkers on the binding of a fragment-based inhibitor of human uracil DNA glycosylase. Analysis of the free energies of binding in combination with co-crystal structures shows that the flexibility and strain of a given linker can have a significant impact on binding affinity even when the binding fragments are optimally positioned. Such effects are not apparent from inspection of structures and underscore the importance of linker optimization in fragment-based drug discovery efforts. PMID:19396178

  13. Thermodynamic Insight in the High-Pressure Behavior of UiO-66: Effect of Linker Defects and Linker Expansion

    PubMed Central

    2016-01-01

    In this Article, we present a molecular-level understanding of the experimentally observed loss of crystallinity in UiO-66-type metal–organic frameworks, including the pristine UiO-66 to -68 as well as defect-containing UiO-66 materials, under the influence of external pressure. This goal is achieved by constructing pressure-versus-volume profiles at finite temperatures using a thermodynamic approach relying on ab initio derived force fields. On the atomic level, the phenomenon is reflected in a sudden drop in the number of symmetry operators for the crystallographic unit cell because of the disordered displacement of the organic linkers with respect to the inorganic bricks. For the defect-containing samples, a reduced mechanical stability is observed, however, critically depending on the distribution of these defects throughout the material, hence demonstrating the importance of judiciously characterizing defects in these materials. PMID:27594765

  14. Effects of Magnetic Fields on Bar Substructures in Barred Galaxies

    NASA Astrophysics Data System (ADS)

    Kim, Woong-Tae

    2015-03-01

    To study the effects of magnetic fields on the properties of bar substructures, we run two-dimensional, ideal MHD simulations of barred galaxies under the influence of a non-axisymmetric bar potential. In the bar regions, magnetic fields reduce density compression in the dust-lane shocks, while removing angular momentum further from the gas at the shocks. This evidently results in a smaller and more distributed ring, and a larger mass inflows rate to the galaxy center in models with stronger magnetic fields. In the outer regions, an MHD dynamo due to the combined action of the bar potential and background shear operates, amplifying magnetic fields near the corotation resonance. In the absence of spiral arms, the amplified fields naturally shape into trailing magnetic arms with strong fields and low density. The reader is refereed to Kim & Stone (2012) for a detailed presentation of the simulation outcomes.

  15. Potent Oxazolidinone Antibacterials with Heteroaromatic C-Ring Substructure

    PubMed Central

    2013-01-01

    Novel oxazolidinone analogues bearing a condensed heteroaromatic ring as the C-ring substructure were synthesized as candidate antibacterial agents. Analogues 16 and 21 bearing imidazo[1,2-a]pyridine and 18 and 23 bearing [1,2,4]triazolo[1,5-a]pyridine as the C-ring had excellent in vitro antibacterial activities against methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus faecalis (VRE), and penicillin-resistant Streptococcus pneumoniae (PRSP). They also showed promising therapeutic effects in a mouse model of lethal infection. Preliminary safety data (inhibitory effects on cytochrome P450 isoforms and monoamine oxidases) were satisfactory. Further evaluation of 18 and 23 is ongoing. PMID:24900607

  16. Resolving the Chemical Substructure of Orion-KL

    NASA Astrophysics Data System (ADS)

    Feng, Siyi; Beuther, Henrik; Semenov, Dmitry; Henning, Thomas; Palau, Aina

    2013-07-01

    Context. The Kleinmann-Low nebula in Orion (Orion-KL) is the closest example of a high-mass star forming environment. Studying the resolved chemical structure of this complex region can provide important insight for relating the chemistry of high mass star forming regions with their evolutionary state. We present a line survey of Orion-KL obtained from the combined Submillimeter Array (SMA) and IRAM 30 m single-dish data. Covering 4 GHz bandwidth in total, this survey contains at least 160 emission lines from 27 chemical species. Aims. The goal of this work is to resolve the molecular line emission from individual substructure in Orion-KL at high spectral and spatial resolution, inferring the chemical properties of the associated gas. Methods. The spectra from different substructures are extracted and the intensity-integrated distribution maps for different molecules are imaged. We then calculate column densities, and abundances for each molecule in each identified substructure, assuming local thermal equilibrium (LTE), and that the lines are both optically thin and have uniform widths for all species. Results. By complementing interferometric data of the Orion-KL region with single-dish data to recover the short spacing information, we are able to study spatial abundance variations in this region for the first time. On one hand, at the spatial resolution of 4 arcsec, several substructures appear on the continuum map. The strongest emission from nitrogen-bearing molecules comes from the main hot core, which has chemistry typical of an active region, while sulfur-bearing and carbon monoxides have extended emission covering the cooler southern ridge and outflow regions. In contrast, the distribution of saturated complex organics is more complicated. Most of them peak at either the hot core (e.g., CH3OH) or the compact ridge (e.g., HCOOCH3), while others peak at intermediate positions between the hot core and the compact ridge (e.g., CH3CH2OH). But nevertheless, no

  17. Modeling of ion complexation and extraction using substructural molecular fragments

    PubMed

    Solov'ev; Varnek; Wipff

    2000-05-01

    A substructural molecular fragment (SMF) method has been developed to model the relationships between the structure of organic molecules and their thermodynamic parameters of complexation or extraction. The method is based on the splitting of a molecule into fragments, and on calculations of their contributions to a given property. It uses two types of fragments: atom/bond sequences and "augmented atoms" (atoms with their nearest neighbors). The SMF approach is tested on physical properties of C2-C9 alkanes (boiling point, molar volume, molar refraction, heat of vaporization, surface tension, melting point, critical temperature, and critical pressures) and on octanol/water partition coefficients. Then, it is applied to the assessment of (i) complexation stability constants of alkali cations with crown ethers and phosphoryl-containing podands, and of beta-cyclodextrins with mono- and 1,4-disubstituted benzenes, and (ii) solvent extraction constants for the complexes of uranyl cation by phosphoryl-containing ligands. PMID:10850791

  18. Substructure drag effects and recrystallization textures in aluminium

    SciTech Connect

    Higginson, R.; Bate, P.

    1999-03-10

    Many important recrystallization texture components in metals such as aluminium originate from nuclei in which the mobile high-angle boundary exists prior to, or is formed in the early stages of, annealing. Nucleation can then occur by a process known as strain-induced boundary migration (SIBM). It is possible that this process will involve several growing subgrains, and the drag from that substructure can then have a significant effect. A simple model is used to demonstrate how changes in the overall driving force for recrystallization and Zener drag can affect recrystallization textures when SIBM is involved. This is discussed in relation to experimental observations and the evidence for this process is reviewed.

  19. Population substructure in Cache County, Utah: the Cache County study

    PubMed Central

    2014-01-01

    Background Population stratification is a key concern for genetic association analyses. In addition, extreme homogeneity of ethnic origins of a population can make it difficult to interpret how genetic associations in that population may translate into other populations. Here we have evaluated the genetic substructure of samples from the Cache County study relative to the HapMap Reference populations and data from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Results Our findings show that the Cache County study is similar in ethnic diversity to the self-reported "Whites" in the ADNI sample and less homogenous than the HapMap CEU population. Conclusions We conclude that the Cache County study is genetically representative of the general European American population in the USA and is an appropriate population for conducting broadly applicable genetic studies. PMID:25078123

  20. Construction of preconditioners for elliptic problems by substructuring. I

    SciTech Connect

    Bramble, J.H.; Pasciak, J.E.; Schatz, A.H.

    1986-07-01

    We consider the problem of solving the algebraic system of equations which arise from the discretization of symmetric elliptic boundary value problems via finite element methods. A new class of preconditioners for the discrete system is developed based on substructuring (also known as domain decomposition). The resulting preconditioned algorithms are well suited to emerging parallel computing architectures. The proposed methods are applicable to problems on general domains involving differential operators with rather general coefficients. A basic theory for the analysis of the condition number of the preconditioned system (which determines the iterative convergence rate of the algorithm) is given. Techniques for applying the theory and algorithms to problems with irregular geometry are discussed and the results of extensive numerical experiments are reported.

  1. Cold Dark Matter Substructures in Early-type Galaxy Halos

    NASA Astrophysics Data System (ADS)

    Fiacconi, Davide; Madau, Piero; Potter, Doug; Stadel, Joachim

    2016-06-01

    We present initial results from the “Ponos” zoom-in numerical simulations of dark matter substructures in massive ellipticals. Two very highly resolved dark matter halos with M vir = 1.2 × 1013 {M}ȯ and M vir = 6.5 × 1012 {M}ȯ and different (“violent” versus “quiescent”) assembly histories have been simulated down to z = 0 in a ΛCDM cosmology with a total of 921,651,914 and 408,377,544 particles, respectively. Within the virial radius, the total mass fraction in self-bound M sub > 106 {M}ȯ subhalos at the present epoch is 15% for the violent host and 16.5% for the quiescent one. At z = 0.7, these fractions increase to 19% and 33%, respectively, as more recently accreted satellites are less prone to tidal destruction. In projection, the average fraction of surface mass density in substructure at a distance of R/R vir = 0.02 (∼5–10 kpc) from the two halo centers ranges from 0.6% to ≳2%, significantly higher than that measured in simulations of Milky Way-sized halos. The contribution of subhalos with M sub < 109 {M}ȯ to the projected mass fraction is between one-fifth and one-third of the total, with the smallest share found in the quiescent host. We assess the impact of baryonic effects via twin, lower-resolution hydrodynamical simulations that include metallicity-dependent gas cooling, star formation, and a delayed-radiative-cooling scheme for supernova feedback. Baryonic contraction produces a super-isothermal total density profile and increases the number of massive subhalos in the inner regions of the main host. The host density profiles and projected subhalo mass fractions appear to be broadly consistent with observations of gravitational lenses.

  2. Galaxy Properties and Substructure in the Cluster Abell 160

    NASA Astrophysics Data System (ADS)

    Koontz, Craig; Pinkney, Jason

    2008-10-01

    We continue development of a procedure for building a large catalog of cluster galaxies and their photometric properties, as measured with CCDs. Our first case, Abell 160, is relatively nearby and we have already obtained spectroscopic redshifts for its brightest galaxies. We have mosaiced this cluster in R and V filters using a CCD imager on the 1.3-meter McGraw-Hill telescope. For each CCD frame we fit a WCS (world coordinate system), remove bright cosmic rays, and extract sources using ``SExtractor.'' We create software for merging source catalogs in such a way as to reject residual cosmic rays and other invalid sources, and to combine redundant measurements without double counting. The measured properties include magnitude, ellipticity, position angle, size, and color (V-R). We compare our data to those of the HST (Hubble Space Telescope) and SDSS (Sloan Digital Sky Survey) archives to examine the accuracy of our star/galaxy separation and our color measurements. For our substructure investigation, we draw several subsamples of galaxies based on stellarity index, color (the color-magnitude relation), magnitude and velocity. The smallest subsample of spectroscopically confirmed members produces significant substructure signals from 1D (velocity) and 3D (x,y,velocity) diagnostics - a small, offset group may be the culprit. The 2D (x,y) diagnostics applied to the larger samples produce some significant statistics, the cause does not seem to be a large-scale merger, but perhaps several small groups. This is consistent with previous X-ray data showing X-ray emitting gas clumped around small groupings of galaxies.

  3. Cold Dark Matter Substructures in Early-type Galaxy Halos

    NASA Astrophysics Data System (ADS)

    Fiacconi, Davide; Madau, Piero; Potter, Doug; Stadel, Joachim

    2016-06-01

    We present initial results from the “Ponos” zoom-in numerical simulations of dark matter substructures in massive ellipticals. Two very highly resolved dark matter halos with M vir = 1.2 × 1013 {M}ȯ and M vir = 6.5 × 1012 {M}ȯ and different (“violent” versus “quiescent”) assembly histories have been simulated down to z = 0 in a ΛCDM cosmology with a total of 921,651,914 and 408,377,544 particles, respectively. Within the virial radius, the total mass fraction in self-bound M sub > 106 {M}ȯ subhalos at the present epoch is 15% for the violent host and 16.5% for the quiescent one. At z = 0.7, these fractions increase to 19% and 33%, respectively, as more recently accreted satellites are less prone to tidal destruction. In projection, the average fraction of surface mass density in substructure at a distance of R/R vir = 0.02 (˜5–10 kpc) from the two halo centers ranges from 0.6% to ≳2%, significantly higher than that measured in simulations of Milky Way-sized halos. The contribution of subhalos with M sub < 109 {M}ȯ to the projected mass fraction is between one-fifth and one-third of the total, with the smallest share found in the quiescent host. We assess the impact of baryonic effects via twin, lower-resolution hydrodynamical simulations that include metallicity-dependent gas cooling, star formation, and a delayed-radiative-cooling scheme for supernova feedback. Baryonic contraction produces a super-isothermal total density profile and increases the number of massive subhalos in the inner regions of the main host. The host density profiles and projected subhalo mass fractions appear to be broadly consistent with observations of gravitational lenses.

  4. TGF-beta and HGF transmit the signals through JNK-dependent Smad2/3 phosphorylation at the linker regions.

    PubMed

    Mori, Shigeo; Matsuzaki, Koichi; Yoshida, Katsunori; Furukawa, Fukiko; Tahashi, Yoshiya; Yamagata, Hideo; Sekimoto, Go; Seki, Toshihito; Matsui, Hirofumi; Nishizawa, Mikio; Fujisawa, Jun-ichi; Okazaki, Kazuichi

    2004-09-23

    Although hepatocyte growth factor (HGF) can act synergistically or antagonistically with transforming growth factor-beta (TGF-beta) signaling, molecular mechanism of their crosstalk remains unknown. Using antibodies which selectively distinguished receptor-regulated Smads (R-Smads) phosphorylated at linker regions from those at C-terminal regions, we herein showed that either HGF or TGF-beta treatment of normal stomach-origin cells activated the JNK pathway, thereafter inducing endogenous R-Smads phosphorylation at linker regions. However, the phosphorylation at their C-terminal regions was not induced by HGF treatment. The activated JNK could directly phosphorylate R-Smads in vitro at the same sites that were phosphorylated in response to TGF-beta or HGF in vivo. Thus, the linker regions of R-Smads were the common phosphorylation sites for HGF and TGF-beta signaling pathways. The phosphorylation induced by simultaneous treatment with HGF and TGF-beta allowed R-Smads to associate with Smad4 and to translocate into the nucleus. JNK pathway involved HGF and TGF-beta-mediated infiltration potency since a JNK inhibitor SP600125 caused the reduction of invasive capacity induced by HGF and TGF-beta signals. Moreover, a combined treatment with HGF and TGF-beta led to a potent increase in plasminogen activator inhibitor type 1 transcriptional activity through Smad3 phosphorylation at the linker region. In contrast, HGF treatment reduced TGF-beta-dependent activation of p15INK4B promoter, in which Smad3 phosphorylation at the C-terminal region was involved. In conclusion, HGF and TGF-beta transmit the signals through JNK-mediated R-Smads phosphorylation at linker regions. PMID:15326485

  5. THE EFFECTS OF HALO-TO-HALO VARIATION ON SUBSTRUCTURE LENSING

    SciTech Connect

    Chen, Jacqueline; Koushiappas, Savvas M.; Zentner, Andrew R. E-mail: koushiappas@brown.edu

    2011-11-10

    We explore the halo-to-halo variation of dark matter (DM) substructure in galaxy-sized DM halos, focusing on its implications for strongly gravitational lensed systems. We find that the median value for projected substructure mass fractions within projected radii of 3% of the host halo virial radius is approximately f{sub sub} Almost-Equal-To 0.25%, but that the variance is large with a 95 percentile range of 0 {<=} f{sub sub} {<=} 1%. We quantify possible effects of substructure on quadruply imaged lens systems using the cusp relation and the simple statistic, R{sub cusp}. We estimate that the probability of obtaining the large values of the R{sub cusp} which have been observed from substructure effects is roughly {approx}10{sup -3} to {approx}10{sup -2}. We consider a variety of possible correlations between host halo properties and substructure properties in order to probe possible sample biases. In particular, low-concentration host DM halos have more large substructures and give rise to large values of R{sub cusp} more often. However, there is no known observational bias that would drive observed quadruply imaged quasars to be produced by low-concentration lens halos. Finally, we show that the substructure mass fraction is a relatively reliable predictor of the value of R{sub cusp}.

  6. Stability, Intracellular Delivery, and Release of siRNA from Chitosan Nanoparticles Using Different Cross-Linkers

    PubMed Central

    Abdul Ghafoor Raja, Maria; Katas, Haliza; Jing Wen, Thum

    2015-01-01

    Chitosan (CS) nanoparticles have been extensively studied for siRNA delivery; however, their stability and efficacy are highly dependent on the types of cross-linker used. To address this issue, three common cross-linkers; tripolyphosphate (TPP), dextran sulphate (DS) and poly-D-glutamic acid (PGA) were used to prepare siRNA loaded CS-TPP/DS/PGA nanoparticles by ionic gelation method. The resulting nanoparticles were compared with regard to their physicochemical properties including particle size, zeta potential, morphology, binding and encapsulation efficiencies. Among all the formulations prepared with different cross linkers, CS-TPP-siRNA had the smallest particle size (ranged from 127 ± 9.7 to 455 ± 12.9 nm) with zeta potential ranged from +25.1 ± 1.5 to +39.4 ± 0.5 mV, and high entrapment (>95%) and binding efficiencies. Similarly, CS-TPP nanoparticles showed better siRNA protection during storage at 4˚C and as determined by serum protection assay. TEM micrographs revealed the assorted morphology of CS-TPP-siRNA nanoparticles in contrast to irregular morphology displayed by CS-DS-siRNA and CS-PGA-siRNA nanoparticles. All siRNA loaded CS-TPP/DS/PGA nanoparticles showed initial burst release followed by sustained release of siRNA. Moreover, all the formulations showed low and concentration-dependent cytotoxicity with human colorectal cancer cells (DLD-1), in vitro. The cellular uptake studies with CS-TPP-siRNA nanoparticles showed successful delivery of siRNA within cytoplasm of DLD-1 cells. The results demonstrate that ionically cross-linked CS-TPP nanoparticles are biocompatible non-viral gene delivery system and generate a solid ground for further optimization studies, for example with regard to steric stabilization and targeting. PMID:26068222

  7. Structurally diverse cyclisation linkers impose different backbone conformations in bicyclic peptides.

    PubMed

    Chen, Shiyu; Morales-Sanfrutos, Julia; Angelini, Alessandro; Cutting, Brian; Heinis, Christian

    2012-05-01

    Combinatorial libraries of structurally diverse peptide macrocycles offer a rich source for the development of high-affinity ligands to targets of interest. In this work we have developed linkers for the generation of genetically encoded bicyclic peptides and tested whether the peptides cyclised by them have significant variations in their backbone conformations. Two new cyclisation reagents, each containing three thiol-reactive groups, efficiently and selectively cyclised linear peptides containing three cysteine moieties. When the mesitylene linker of the bicyclic peptide PK15, a potent inhibitor of plasma kallikrein (K(i)=2 nM), was replaced by the new linkers, its inhibitory activity dropped by a factor of more than 1000, suggesting that the linkers impose different conformations on the peptide. Indeed, structural analysis by solution-state NMR revealed different NOE constraints in the three bicyclic peptides, indicating that these relatively small linkers at the centres of bicyclic peptide structures significantly influence the conformations of the peptides. These results demonstrate the prominent structural role of linkers in peptide macrocycles and suggest that application of different cyclisation linkers in a combinatorial fashion could be an attractive means to generate topologically diverse macrocycle libraries. PMID:22492661

  8. Linker histone partial phosphorylation: effects on secondary structure and chromatin condensation.

    PubMed

    Lopez, Rita; Sarg, Bettina; Lindner, Herbert; Bartolomé, Salvador; Ponte, Inma; Suau, Pedro; Roque, Alicia

    2015-05-19

    Linker histones are involved in chromatin higher-order structure and gene regulation. We have successfully achieved partial phosphorylation of linker histones in chicken erythrocyte soluble chromatin with CDK2, as indicated by HPCE, MALDI-TOF and Tandem MS. We have studied the effects of linker histone partial phosphorylation on secondary structure and chromatin condensation. Infrared spectroscopy analysis showed a gradual increase of β-structure in the phosphorylated samples, concomitant to a decrease in α-helix/turns, with increasing linker histone phosphorylation. This conformational change could act as the first step in the phosphorylation-induced effects on chromatin condensation. A decrease of the sedimentation rate through sucrose gradients of the phosphorylated samples was observed, indicating a global relaxation of the 30-nm fiber following linker histone phosphorylation. Analysis of specific genes, combining nuclease digestion and qPCR, showed that phosphorylated samples were more accessible than unphosphorylated samples, suggesting local chromatin relaxation. Chromatin aggregation was induced by MgCl2 and analyzed by dynamic light scattering (DLS). Phosphorylated chromatin had lower percentages in volume of aggregated molecules and the aggregates had smaller hydrodynamic diameter than unphosphorylated chromatin, indicating that linker histone phosphorylation impaired chromatin aggregation. These findings provide new insights into the effects of linker histone phosphorylation in chromatin condensation. PMID:25870416

  9. Protein inter-domain linker prediction using Random Forest and amino acid physiochemical properties

    PubMed Central

    2014-01-01

    Background Protein chains are generally long and consist of multiple domains. Domains are distinct structural units of a protein that can evolve and function independently. The accurate prediction of protein domain linkers and boundaries is often regarded as the initial step of protein tertiary structure and function predictions. Such information not only enhances protein-targeted drug development but also reduces the experimental cost of protein analysis by allowing researchers to work on a set of smaller and independent units. In this study, we propose a novel and accurate domain-linker prediction approach based on protein primary structure information only. We utilize a nature-inspired machine-learning model called Random Forest along with a novel domain-linker profile that contains physiochemical and domain-linker information of amino acid sequences. Results The proposed approach was tested on two well-known benchmark protein datasets and achieved 68% sensitivity and 99% precision, which is better than any existing protein domain-linker predictor. Without applying any data balancing technique such as class weighting and data re-sampling, the proposed approach is able to accurately classify inter-domain linkers from highly imbalanced datasets. Conclusion Our experimental results prove that the proposed approach is useful for domain-linker identification in highly imbalanced single- and multi-domain proteins. PMID:25521329

  10. Glycosylated linkers in multimodular lignocellulose-degrading enzymes dynamically bind to cellulose.

    PubMed

    Payne, Christina M; Resch, Michael G; Chen, Liqun; Crowley, Michael F; Himmel, Michael E; Taylor, Larry E; Sandgren, Mats; Ståhlberg, Jerry; Stals, Ingeborg; Tan, Zhongping; Beckham, Gregg T

    2013-09-01

    Plant cell-wall polysaccharides represent a vast source of food in nature. To depolymerize polysaccharides to soluble sugars, many organisms use multifunctional enzyme mixtures consisting of glycoside hydrolases, lytic polysaccharide mono-oxygenases, polysaccharide lyases, and carbohydrate esterases, as well as accessory, redox-active enzymes for lignin depolymerization. Many of these enzymes that degrade lignocellulose are multimodular with carbohydrate-binding modules (CBMs) and catalytic domains connected by flexible, glycosylated linkers. These linkers have long been thought to simply serve as a tether between structured domains or to act in an inchworm-like fashion during catalytic action. To examine linker function, we performed molecular dynamics (MD) simulations of the Trichoderma reesei Family 6 and Family 7 cellobiohydrolases (TrCel6A and TrCel7A, respectively) bound to cellulose. During these simulations, the glycosylated linkers bind directly to cellulose, suggesting a previously unknown role in enzyme action. The prediction from the MD simulations was examined experimentally by measuring the binding affinity of the Cel7A CBM and the natively glycosylated Cel7A CBM-linker. On crystalline cellulose, the glycosylated linker enhances the binding affinity over the CBM alone by an order of magnitude. The MD simulations before and after binding of the linker also suggest that the bound linker may affect enzyme action due to significant damping in the enzyme fluctuations. Together, these results suggest that glycosylated linkers in carbohydrate-active enzymes, which are intrinsically disordered proteins in solution, aid in dynamic binding during the enzymatic deconstruction of plant cell walls. PMID:23959893

  11. Three-dimensional deformation analysis of two-phase dislocation substructures

    NASA Technical Reports Server (NTRS)

    Freed, Alan D.; Raj, S. V.; Walker, Kevin P.

    1992-01-01

    Three-dimensional deformation analysis of two-phase dislocation substructures was carried out, extending the Qian and Fan (1991) approach to 3D stress-strain fields by using the Budiansky and Wu (1962) criterion for strain compatibility between the 'hard' and 'soft' regions. The result is a rate-dependent viscoplastic theory, named the dislocation substructure viscoplasticity (DSV), which incorporates a self-consistent effect of dislocation substructure on material response. An algorithm developed for numerical implementation of the DSV theory is presented.

  12. Effect of load eccentricity and substructure deformation on ultimate strength of shuttle orbiter thermal protection system

    NASA Technical Reports Server (NTRS)

    Sawyer, J. W.

    1981-01-01

    The effect of load eccentricity and substructure deformation on the ultimate strength and stress displacement properties of the shuttle orbiter thermal protection system (TPS) was determined. The LI-900 Reusable Surface Insulation (RSI) tiles mounted on the .41 cm thick Strain Isolator Pad (SIP) were investigated. Substructure deformations reduce the ultimate strength of the SIP/tile TPS and increase the scatter in the ultimate strength data. Substructure deformations that occur unsymmetric to the tile can cause the tile to rotate when subjected to a uniform applied load. Load eccentricity reduces SIP/tile TPS ultimate strength and causes tile rotation.

  13. Jet Substructure: Boosting the Search for New Physics at the LHC

    NASA Astrophysics Data System (ADS)

    Thaler, Jesse

    2016-03-01

    Collisions at the Large Hadron Collider (LHC) are dominated by jets, collimated sprays of particles that are proxies for underlying quarks and gluons. With the remarkable performance of the ATLAS and CMS detectors, jets can now be characterized not just by their overall direction and energy but also by their substructure. In this talk, I highlight the ways that jet substructure has enhanced the search for new physics at the LHC, including recent excitement over a possible diboson excess. I also explain how theoretical studies of jet substructure have taught us surprising lessons about the nature of the strong force.

  14. Impact of linker length on the activity of PROTACs

    PubMed Central

    Cyrus, Kedra; Wehenkel, Marie; Choi, Eun-Young; Han, Hyeong-Jun; Lee, Hyosung; Swanson, Hollie

    2013-01-01

    Conventional genetic approaches have provided a powerful tool in the study of proteins. However, these techniques often preclude selective manipulation of temporal and spatial protein functions, which is crucial for the investigation of dynamic cellular processes. To overcome these limitations, a small molecule-based novel technology termed “PROteolysis TArgeting ChimeraS (PROTACs)” has been developed, targeting proteins for degradation at the post-translational level. Despite the promising potential of PROTACs to serve as molecular probes of complex signaling pathways, their design has not been generalized for broad application. Here, we present the first generalized approach for PROTAC design by fine-tuning the distance between the two participating partner proteins, the E3 ubiquitin ligase and the target protein. As such, we took a chemical approach to create estrogen receptor (ER)-α targeting PROTACs with varying linker lengths and the loss of the ER in cultured cells was monitored via western blot and fluorometric analyses. We found a significant effect of chain length on PROTAC efficacy, and in this case, the optimum distance between the E3 recognition motif and the ligand was a 16 atom chain length. The information gathered from this experiment may offer a generalizable PROTAC design strategy to further the expansion of the PROTAC toolbox, opening new possibilities for the broad application of the PROTAC strategy in the study of multiple signaling pathways. PMID:20922213

  15. Impact of linker length on the activity of PROTACs.

    PubMed

    Cyrus, Kedra; Wehenkel, Marie; Choi, Eun-Young; Han, Hyeong-Jun; Lee, Hyosung; Swanson, Hollie; Kim, Kyung-Bo

    2011-02-01

    Conventional genetic approaches have provided a powerful tool in the study of proteins. However, these techniques often preclude selective manipulation of temporal and spatial protein functions, which is crucial for the investigation of dynamic cellular processes. To overcome these limitations, a small molecule-based novel technology termed "PROteolysis TArgeting ChimeraS (PROTACs)" has been developed, targeting proteins for degradation at the post-translational level. Despite the promising potential of PROTACs to serve as molecular probes of complex signaling pathways, their design has not been generalized for broad application. Here, we present the first generalized approach for PROTAC design by fine-tuning the distance between the two participating partner proteins, the E3 ubiquitin ligase and the target protein. As such, we took a chemical approach to create estrogen receptor (ER)-α targeting PROTACs with varying linker lengths and the loss of the ER in cultured cells was monitored via western blot and fluorometric analyses. We found a significant effect of chain length on PROTAC efficacy, and, in this case, the optimum distance between the E3 recognition motif and the ligand was a 16 atom chain length. The information gathered from this experiment may offer a generalizable PROTAC design strategy to further the expansion of the PROTAC toolbox, opening new possibilities for the broad application of the PROTAC strategy in the study of multiple signaling pathways. PMID:20922213

  16. Lecithin-Linker Microemulsion Gelatin Gels for Extended Drug Delivery

    PubMed Central

    Xuan, Xiao-Yue; Cheng, Yu-Ling; Acosta, Edgar

    2012-01-01

    This article introduces the formulation of alcohol-free, lecithin microemulsion-based gels (MBGs) prepared with gelatin as gelling agent. The influence of oil, water, lecithin and hydrophilic and lipophilic additives (linkers) on the rheological properties and appearance of these gels was systematically explored using ternary phase diagrams. Clear MBGs were obtained in regions of single phase microemulsions (μEs) at room temperature. Increasing the water content in the formulation increased the elastic modulus of the gels, while increasing the oil content had the opposite effect. The hydrophilic additive (PEG-6-caprylic/capric glycerides) was shown to reduce the elastic modulus of gelatin gels, particularly at high temperatures. In contrast to anionic (AOT) μEs, the results suggest that in lecithin (nonionic) μEs, the introduction of gelatin “dehydrates” the μE. Finally, when the transdermal transport of lidocaine formulated in the parent μE and the resulting MBG were compared, only a minor retardation in the loading and release of lidocaine was observed. PMID:24300183

  17. Direct detection of linker DNA bending in defined-length oligomers of chromatin.

    PubMed Central

    Yao, J; Lowary, P T; Widom, J

    1990-01-01

    Linker DNA, which connects between nucleosomes in chromatin, is short and, therefore, may be essentially straight and inflexible. We have carried out hydrodynamic and electron microscopic studies of dinucleosomes--fragments of chromatin containing just two nucleosomes--to test the ability of linker DNA to bend. We find that ionic conditions that stabilize the folding of long chromatin cause linker DNA in dinucleosomes to bend, bringing the two nucleosomes into contact. The results uphold a key prediction of the solenoid model of chromosome folding and suggest a mechanism by which proteins that are separated along the DNA can interact by direct contact. Images PMID:2217191

  18. Flexibility of NS5 Methyltransferase-Polymerase Linker Region Is Essential for Dengue Virus Replication

    PubMed Central

    Zhao, Yongqian; Soh, Tingjin Sherryl; Chan, Kitti Wing Ki; Fung, Sarah Suet Yin; Swaminathan, Kunchithapadam; Lim, Siew Pheng; Shi, Pei-Yong; Huber, Thomas; Lescar, Julien

    2015-01-01

    We examined the function of the conserved Val/Ile residue within the dengue virus NS5 interdomain linker (residues 263 to 272) by site-directed mutagenesis. Gly substitution or Gly/Pro insertion after the conserved residue increased the linker flexibility and created slightly attenuated viruses. In contrast, Pro substitution abolished virus replication by imposing rigidity in the linker and restricting NS5's conformational plasticity. Our biochemical and reverse genetics experiments demonstrate that NS5 utilizes conformational regulation to achieve optimum viral replication. PMID:26269182

  19. New Structural-Dynamics Module for Offshore Multimember Substructures within the Wind Turbine Computer-Aided Engineering Tool FAST: Preprint

    SciTech Connect

    Song, H.; Damiani, R.; Robertson, A.; Jonkman, J.

    2013-08-01

    FAST, developed by the National Renewable Energy Laboratory (NREL), is a computer-aided engineering (CAE) tool for aero-hydro-servo-elastic analysis of land-based and offshore wind turbines. This paper discusses recent upgrades made to FAST to enable loads simulations of offshore wind turbines with fixed-bottom, multimember support structures (e.g., jackets and tripods, which are commonly used in transitional-depth waters). The main theory and strategies for the implementation of the multimember substructure dynamics module (SubDyn) within the new FAST modularization framework are introduced. SubDyn relies on two main engineering schematizations: 1) a linear frame finite-element beam (LFEB) model and 2) a dynamics system reduction via Craig-Bampton's method. A jacket support structure and an offshore system consisting of a turbine atop a jacket substructure were simulated to test the SubDyn module and to preliminarily assess results against results from a commercial finite-element code.

  20. Dark Halos and Substructure from Arcs & Einstein Rings

    NASA Astrophysics Data System (ADS)

    Koopmans, Leon

    2006-07-01

    statistically and individually the incidence of mass-substructure {with or without obvious luminous counter-parts such as dwarf galaxies}. Since dark-matter substructure could be more prevalent at higher redshift, both results provide a direct test of this prediction of the CDM hierarchical structure-formation model.

  1. Investigation of defect copper substructure disrupted in creep condition under the action of magnetic field

    NASA Astrophysics Data System (ADS)

    Konovalov, S. V.; Yaropolova, N. G.; Zaguyliaev1, D. V.; Gromov, V. E.; Ivanov, Yu F.; Komissarova, I. A.

    2015-09-01

    The defect substructure of M00b copper samples loaded up to disruption in creep condition both under and without the action of 0.35 T magnetic field is investigated in the paper. Material near the disrupted surface and at certain distances from it received the serious study. It has been ascertained that when copper disrupting without magnetic action on creep process the main type of dislocation substructure is the cellular one irrespectively of the distance to disruption surface. As the result of magnetic field influence on creep process the main type of dislocation substructure is replaced by the stripe-like one. The distinctive quantitative characteristics of dislocation substructures are observed. Moreover, a gradient behavior of the number of stress raisers has been revealed when moving away from disruption surface both in deformation conditions with and without a magnetic field.

  2. 20. Top 30/3. Plan of exposed substructure elevations. Wyoming ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    20. Top 30/3. Plan of exposed substructure elevations. - Wyoming Valley Flood Control System, Woodward Pumping Station, East of Toby Creek crossing by Erie-Lackawanna Railroad, Edwardsville, Luzerne County, PA

  3. COLUMN DETAIL WITH SUBSTRUCTURE/STEEL BEAM/CONCRETE BEAM AT FIRST AVENUE ONRAMP. ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    COLUMN DETAIL WITH SUBSTRUCTURE/STEEL BEAM/CONCRETE BEAM AT FIRST AVENUE ON-RAMP. TRIANGLE BUILDING AT RIGHT SIDE OF PHOTOGRAPH. - Alaskan Way Viaduct and Battery Street Tunnel, Seattle, King County, WA

  4. Two Principles of Reticular Chemistry Uncovered in a Metal-Organic Framework of Heterotritopic Linkers and Infinite Secondary Building Units.

    PubMed

    Catarineu, Noelle R; Schoedel, Alexander; Urban, Philipp; Morla, Maureen B; Trickett, Christopher A; Yaghi, Omar M

    2016-08-31

    Structural diversity of metal-organic frameworks (MOFs) has been largely limited to linkers with at most two different types of coordinating groups. MOFs constructed from linkers with three or more nonidentical coordinating groups have not been explored. Here, we report a robust and porous crystalline MOF, Zn3(PBSP)2 or MOF-910, constructed from a novel linker PBSP (phenylyne-1-benzoate, 3-benzosemiquinonate, 5-oxidopyridine) bearing three distinct types of coordinative functionality. The MOF adopts a complex and previously unreported topology termed tto. Our study suggests that simple, symmetric linkers are not a necessity for formation of crystalline extended structures and that new, more complex topologies are attainable with irregular, heterotopic linkers. This work illustrates two principles of reticular chemistry: first, selectivity for helical over straight rod secondary building units (SBUs) is achievable with polyheterotopic linkers, and second, the pitch of the resulting helical SBUs may be fine-tuned based on the metrics of the polyheterotopic linker. PMID:27517606

  5. Composite materials with metal oxide attached to lead chalcogenide nanocrystal quantum dots with linkers

    DOEpatents

    Fuke, Nobuhiro; Koposov, Alexey Y; Sykora, Milan; Hoch, Laura

    2014-12-16

    Composite materials useful for devices such as photoelectrochemical solar cells include a substrate, a metal oxide film on the substrate, nanocrystalline quantum dots (NQDs) of lead sulfide, lead selenide, and lead telluride, and linkers that attach the NQDs to the metal oxide film. Suitable linkers preserve the 1s absorption peak of the NQDs. A suitable linker has a general structure A-B-C where A is a chemical group adapted for binding to a MO.sub.x and C is a chemical group adapted for binding to a NQD and B is a divalent, rigid, or semi-rigid organic spacer moiety. Other linkers that preserve the 1s absorption peak may also be used.

  6. Sequential Linker Installation: Precise Placement of Functional Groups in Multivariate Metal-Organic Frameworks

    SciTech Connect

    Yuan, S; Lu, WG; Chen, YP; Zhang, Q; Liu, TF; Feng, DW; Wang, X; Qin, JS; Zhou, HC

    2015-03-11

    A unique strategy, sequential linker installation (SLI), has been developed to construct multivariate MOFs with functional groups precisely positioned. PCN-700, a Zr-MOF with eight-connected Zr6O4(OH)(8)(H2O)(4) clusters, has been judiciously designed; the Zr-6 clusters in this MOF are arranged in such a fashion that, by replacement of terminal OH-/H2O ligands, subsequent insertion of linear dicarboxylate linkers is achieved. We demonstrate that linkers with distinct lengths and functionalities can be sequentially installed into PCN-700. Single-crystal to single-crystal transformation is realized so that the positions of the subsequently installed linkers are pinpointed via single-crystal X-ray diffraction analyses. This methodology provides a powerful tool to construct multivariate MOFs with precisely positioned functionalities in the desired proximity, which would otherwise be difficult to achieve.

  7. The Use of Aryl Hydrazide Linkers for the Solid Phase Synthesis of Chemically Modified Peptides

    SciTech Connect

    Woo, Y; Mitchell, A R; Camarero, J A

    2006-11-03

    Since Merrifield introduced the concept of solid phase synthesis in 1963 for the rapid preparation of peptides, a large variety of different supports and resin-linkers have been developed that improve the efficiency of peptide assembly and expand the myriad of synthetically feasible peptides. The aryl hydrazide is one of the most useful resin-linkers for the synthesis of chemically modified peptides. This linker is completely stable during Boc- and Fmoc-based solid phase synthesis and yet it can be cleaved under very mild oxidative conditions. The present article reviews the use of this valuable linker for the rapid and efficient synthesis of C-terminal modified peptides, head-to-tail cyclic peptides and lipidated peptides.

  8. Linker histones are not essential and affect chromatin condensation in vivo.

    PubMed

    Shen, X; Yu, L; Weir, J W; Gorovsky, M A

    1995-07-14

    We have (separately) disrupted all of the expressed macronuclear copies of the HHO gene encoding macronuclear histone H1 and of the micronuclear linker histone (MLH) gene encoding the protein MicLH in Tetrahymena thermophila. These disruptions are shown to eliminate completely the expression of each protein. Strains without either linker histone grow at normal rates and reach near-normal cell densities, demonstrating that linker histones are not essential for cell survival. Histone H1 knockout (delta H1) cells have enlarged DAPI-stained macronuclei and normal-sized micronuclei, while MicLH knockout (delta MicLH) cells have enlarged micronuclei and normal-sized macronuclei. delta MicLH cells undergo mitosis normally. However, the micronuclear mitotic chromosome structure is less condensed. These studies provide evidence that linker histones are nonessential and are involved in chromatin packaging and condensation in vivo. PMID:7606784

  9. Linker-Region Modified Derivatives of the Deoxyhypusine Synthase Inhibitor CNI-1493 Suppress HIV-1 Replication.

    PubMed

    Schröder, Marcus; Kolodzik, Adrian; Windshügel, Björn; Krepstakies, Marcel; Priyadarshini, Poornima; Hartjen, Philip; van Lunzen, Jan; Rarey, Matthias; Hauber, Joachim; Meier, Chris

    2016-02-01

    The inhibition of cellular factors that are involved in viral replication may be an important alternative to the commonly used strategy of targeting viral enzymes. The guanylhydrazone CNI-1493, a potent inhibitor of the deoxyhypusine synthase (DHS), prevents the activation of the cellular factor eIF-5A and thereby suppresses HIV replication and a number of other diseases. Here, we report on the design, synthesis and biological evaluation of a series of CNI-1493 analogues. The sebacoyl linker in CNI-1493 was replaced by different alkyl or aryl dicarboxylic acids. Most of the tested derivatives suppress HIV-1 replication efficiently in a dose-dependent manner without showing toxic side effects. The unexpected antiviral activity of the rigid derivatives point to a second binding mode as previously assumed for CNI-1493. Moreover, the chemical stability of CNI-1493 was analysed, showing a successive hydrolysis of the imino bonds. By molecular dynamics simulations, the behaviour of the parent CNI-1493 in solution and its interactions with DHS were investigated. PMID:26725082

  10. Linker peptide and affinity tag for detection and purification of single-chain Fv fragments.

    PubMed

    Küttner, Gabriele; Giessmann, Elke; Wessner, Helga; Scholz, Christa; Reinhardt, Dina; Winkler, Karsten; Marx, Uwe; Höhne, Wolfgang

    2004-05-01

    The peptide tag GATPQDLNTML, corresponding to amino acids 46-56 of the human immunodeficiency virus type 1 (HIV-1) capsid protein p24, is the linear epitope of the murine monoclonal antibody CB4-1. This antibody shows high affinity (KD = 1.8 x 10(-8) M) to the free epitope peptide in solution. The original p24 peptide tag and mutant derivatives were fused to the C terminus of a single-chain antibody (scFv) and characterized with respect to sensitivity in Western blot analyses and behavior in purification procedures using affinity chromatography. The p24 tag also proved to be a suitable alternative to the (Gly4Ser)3 linker commonly used to connect single-chain antibody variable regions derived from a heavy (VH) and light chain (VL). Binding of CB4-1 antibody to the p24 tag was not hampered when the tag was located internally in the protein sequence, and the specific antigen affinity of the scFv was only slightly reduced. All scFv variants were solubly expressed in Escherichia coli and could be purified from the periplasm. Our results highlight the p24 tag as a useful tool for purifying and detecting recombinantly expressed scFvs. PMID:15152607