Specific Substructure Research Articles

A simplified error estimator for the CB method and its application to error control

In this paper, we simplify the error estimation technique developed for the Craig–Bampton (CB) method (Kim et al., 2014). The original formulation is simplified by neglecting insignificant terms, a new error estimator is obtained, and thus computational cost is significantly reduced with negligible accuracy loss. In addition, the contribution of a specific substructure to a relative eigenvalue error can be estimated using the new formulation, in which the estimated relative eigenvalue error is represented by a simple summation of the substructural errors estimated. Therefore, the new formulation can be employed for error control by using the detailed errors estimated for a certain substructure. Through various numerical examples, we verify the accuracy and computational efficiency of the new formulation, and demonstrate an error control strategy.

Proteomic insight into the molecular function of the vitreous.

The human vitreous contains primarily water, but also contains proteins which have yet to be fully characterized. To gain insight into the four vitreous substructures and their potential functions, we isolated and analyzed the vitreous protein profiles of three non-diseased human eyes. The four analyzed substructures were the anterior hyaloid, the vitreous cortex, the vitreous core, and the vitreous base. Proteins were separated by multidimensional liquid chromatography and identified by tandem mass spectrometry. Bioinformatics tools then extracted the expression profiles, signaling pathways, and interactomes unique to each tissue. From each substructure, a mean of 2,062 unique proteins were identified, with many being differentially expressed in a specific substructure: 278 proteins were unique to the anterior hyaloid, 322 to the vitreous cortex, 128 to the vitreous base, and 136 to the vitreous core. When the identified proteins were organized according to relevant functional pathways and networks, key patterns appeared. The blood coagulation pathway and extracellular matrix turnover networks were highly represented. Oxidative stress regulation and energy metabolism proteins were distributed throughout the vitreous. Immune functions were represented by high levels of immunoglobulin, the complement pathway, damage-associated molecular patterns (DAMPs), and evolutionarily conserved antimicrobial proteins. The majority of vitreous proteins detected were intracellular proteins, some of which originate from the retina, including rhodopsin (RHO), phosphodiesterase 6 (PDE6), and glial fibrillary acidic protein (GFAP). This comprehensive analysis uncovers a picture of the vitreous as a biologically active tissue, where proteins localize to distinct substructures to protect the intraocular tissues from infection, oxidative stress, and energy disequilibrium. It also reveals the retina as a potential source of inflammatory mediators. The vitreous proteome catalogues the dynamic interactions between the vitreous and surrounding tissues. It therefore could be an indirect and effective method for surveying vitreoretinal disease for specific biomarkers.

Social insect colony as a biological regulatory system: modelling information flow in dominance networks.

Social insects provide an excellent platform to investigate flow of information in regulatory systems since their successful social organization is essentially achieved by effective information transfer through complex connectivity patterns among the colony members. Network representation of such behavioural interactions offers a powerful tool for structural as well as dynamical analysis of the underlying regulatory systems. In this paper, we focus on the dominance interaction networks in the tropical social wasp Ropalidia marginata-a species where behavioural observations indicate that such interactions are principally responsible for the transfer of information between individuals about their colony needs, resulting in a regulation of their own activities. Our research reveals that the dominance networks of R. marginata are structurally similar to a class of naturally evolved information processing networks, a fact confirmed also by the predominance of a specific substructure-the 'feed-forward loop'-a key functional component in many other information transfer networks. The dynamical analysis through Boolean modelling confirms that the networks are sufficiently stable under small fluctuations and yet capable of more efficient information transfer compared to their randomized counterparts. Our results suggest the involvement of a common structural design principle in different biological regulatory systems and a possible similarity with respect to the effect of selection on the organization levels of such systems. The findings are also consistent with the hypothesis that dominance behaviour has been shaped by natural selection to co-opt the information transfer process in such social insect species, in addition to its primal function of mediation of reproductive competition in the colony.

The concept of the onychodermis (specialized nail mesenchyme): an embryological assessment and a comparative analysis with the hair follicle

Recently, an intriguing concept was introduced into the literature that defines the area underlying the nail bed as a specific mesenchymal substructure unique to the nail organ. It has been termed onychodermis. The onychodermis expresses CD10 with remarkable specificity. Herein, we compare adult and fetal human hair follicles with fetal nail organs in an attempt to draw analogies for the mesenchyme associated with both adnexal structures. We examined immunohistochemically samples from adult and fetal hair follicles for the expression of CD10, CD34 and the mesenchymal stem cell marker nestin and compared the antigen profile with that of the fetal nail organ. The CD10-positive/CD34-negative onychodermis is prominently visible at the end of the second trimester. A corresponding follicular structure was not identified, either in the adult or in the developing hair follicle. Nestin staining does not define the onychodermis. The concept of the onychodermis is equally valid in the developing nail organ where it is also defined by its expression for CD10. Its function may be related to the anchorage of the overlying nail bed but may also involve a more dynamic role in the induction of hard keratins in the latter, contributing to the formation of the nail plate.

Mitochondrial haplotypes reveal olive fly (Bactrocera oleae) population substructure in the Mediterranean

The olive fly (Bactrocera oleae) is the most important olive tree (Olea europaea) pest. In the Mediterranean basin, where 98% of its main hosts are concentrated, it causes major agricultural losses, due to its negative effect on production and quality of both olive and olive oil. Previous phylogeographic analyses have established that Mediterranean olive fly populations are distinct from other Old World populations, but did not agree on the specific population substructure within this region. In order to achieve a higher resolution of the diversity of olive fly populations, particularly in Central and Western Mediterranean (home to 70% of the world production), we comparatively analyzed a set of samples from Portugal in the context of published mitochondrial sequences across the species' worldwide range. Strong evidence of population substructure was found in the Central and Western Mediterranean area, with two clearly separate phylogenetic branches. Together with previously published data, our results strongly support the existence of at least three distinct Mediterranean populations of the olive fly, raise the possibility of additional regional substructure and suggest specific avenues for future research. This knowledge can be instrumental in the development of better management and control strategies for a major pest of Mediterranean agriculture.

Controlling Human Striatal Cognitive Function via the Frontal Cortex

Cognitive flexibility is known to depend on the striatum. However, the striatum does not act in isolation to bias cognitive flexibility. In particular, cognitive flexibility also implicates the frontal cortex. Here we tested the hypothesis that the human frontal cortex controls cognitive flexibility by regulating striatal function via topographically specific frontostriatal connections. To this end, we exploited a repetitive transcranial magnetic stimulation (TMS) protocol over frontal cortex that is known to increase dopamine release in the striatum. This intervention was combined with functional magnetic resonance imaging to determine the functional and topographic specificity of its consequences at the whole brain level. Participants were scanned both before and after off-line TMS while performing a cognitive switching task that is known to depend on a specific striatal substructure, the putamen. Frontal stimulation perturbed task-specific functional signals in the putamen, while reducing fronto-striatal functional connectivity. There were no such effects of TMS over the medial parietal cortex. These data strengthen the hypothesis that cognitive flexibility involves topographic frontal control of striatal function.

A zwitterionic squaraine dye with a large Stokes shift for in vivo and site-selective protein sensing

A novel squaraine dye (SQ) exhibits improved fluorescence response toward protein detection by incorporation of a zwitterionic structure. With the aid of a dansylamide (DNSA) substituent, the new probe (DNSA-SQ) exhibits remarkable selectivity in binding to site I (a specific substructure in protein).

A Molecular Dynamics Study of Ras Clustering in Membrane Domains

Ras proteins are small GTP-hydrohydrolyzing enzymes that function as conformational switches controlling cell proliferation, differentiation, and development. Ras nanolcustering on the plasma membrane and segregation of the clusters into specific membrane substructure driven by competing effects from the lipidated C-terminus and the globular catalytic domain, has attracted much interest in recent years. In this work, we study the clustering behavior of the full length H-ras protein in a model membrane using coarse-grained Molecular Dynamics (MD) simulations. Our model membrane is a phase-separted bilayer comprised of 3840 DPPC, 2304 DLiPC and 1536 cholesterol molecules. Initial results from the simulations suggest that the same fundamental forces that drive clustering of the minimal H-ras membrane anchor also underlie the clustering behavior of the whole protein. However, steric effects in the full-length protein modulate the size and distribution of its clusters, as well as the elastic properties of the bilayer. The results provide previously unavailable molecular insight into the nanoscale organization of lipidated proteins on the plasma membrane.

Synchronized Cluster Formation in Coupled Laser Networks

We experimentally investigate the phase dynamics of laser networks with homogenous time-delayed mutual coupling and establish the fundamental rules that govern their state of synchronization. We identified a specific substructure that imposes its synchronization state on the entire network and show that for any coupling configuration the network forms at most two synchronized clusters. Our results indicate that the synchronization state of the network is a nonlocal phenomenon and cannot be deduced by decomposing the network into smaller substructures, each with its individual synchronization state.

Human stanniocalcin-1 interacts with nuclear and cytoplasmic proteins and acts as a SUMO E3 ligase

Human stanniocalcin-1 (STC1) is a glycoprotein that has been implicated in different physiological process, including angiogenesis, apoptosis and carcinogenesis. Here we identified STC1 as a putative molecular marker for the leukemic bone marrow microenvironment and identified new interacting protein partners for STC1. Seven selected interactions retrieved from yeast two-hybrid screens were confirmed by GST-pull down assays in vitro. The N-terminal region was mapped to be the region that mediates the interaction with cytoplasmic, mitochondrial and nuclear proteins. STC1 interacts with SUMO-1 and several proteins that have been shown to be SUMOylated and localized to SUMOylation related nuclear bodies. Although STC1 interacts with SUMO-1 and has a high theoretical prediction score for a SUMOylation site, endogenous co-immunoprecipitation and in vitro SUMOylation assays with the purified recombinant protein could not detect STC1 SUMOylation. However, when we tested STC1 for SUMO E3 ligase activity, we found in an in vitro assay, that it significantly increases the SUMOylation of two other proteins. Confocal microscopic subcellular localization studies using both transfected cells and specific antibodies for endogenous STC1 revealed a cytoplasmic and nuclear deposition, the latter in the form of some specific dot-like substructure resembling SUMOylation related nuclear bodies. Together, these findings suggest a new role for STC1 in SUMOylation pathways, in nuclear bodies.

Ultrastructure, development and histochemistry of the polysaccharide‐containing subcuticular compartments in Origanum dictamnus L. peltate glandular hairs

AbstractPeltate glandular hairs of Origanum dictamnus at the stage of secretion create two subcuticular chambers; one large and bladder‐like, at the apex of the head (containing essential oil), and one small and ring‐like, at the bottom of the head (containing polysaccharides). In the apical chamber, along with the essential oil, a small lateral compartment containing polysaccharides, also exists. This compartment surrounds peripherally the apical chamber creating a second ring‐like structure. The apical plasmalemma of the head cells exhibits a high electron density and presumably has a specific substructure to facilitate passing to the subcuticular chamber of the secretory product. The latter probably exists in the form of glucosides, which, after passing across the plasmalemma and entering the apical chamber, become hydrolysed into the aglycone fraction (essential oil) and the sugar fraction (polysaccharides). Copyright © 2010 John Wiley & Sons, Ltd.

Advanced PLS Technique Focusing on Visualization and Chemical Interpretation - SOMPLS Analysis of Serine Protease Inhibitors -

In quantitative structure activity relationships (QSAR), partial least squares (PLS) are of particular interest as a statistical method. Since successful applications of PLS to QSAR data set, PLS has evolved for coping with more demands associated with complex data structures. Especially, PLS variants focusing on visualization and chemical interpretation are highly desirable for molecular design. In this paper, we employed the self-organized map PLS (SOMPLS) approach to predict multiple inhibitory activities against three serine protease receptors (Factor Xa, Tryptase and urokinase-type Plasminogen Activator (uPA)). Retrosynthetic Combinatorial Analysis Procedure (RECAP) fingerprints were used as chemical descriptors that express the existence of specific substructure in the molecule. From the SOMPLS analysis and the subsequent correlation map, essential fragments for each serine protease were easily identified. From the correlation map, we designed best combinations of fragments at each substituent position for each serine protease protein. The essential fragments could be validated from X-ray crystal structures of serine protease receptors in computer graphics. SOMPLS is an unique approach that makes data-mining feasible from visualization of structure-activity data biased to ligand-based view point.

The Economic Molecule Structure: Theoretical Framework

The economic molecule structure is an alternative multidimensional graphical and analytical tool to study the GDP behavior of any country. The construction of the economic molecule structure depends in the uses of multidimensional graphs and prototypes. We are considered that each variable into the GDP such as consumption, investment, government expending, exports and imports represent a specific sub-structure (SS) into the main structural (S) of the economic molecule structure. Hence, the idea to build the economic molecule structure is to observe the changes of each micro-structure (MS), sub-structure (SS) and the main structure (S). Moreover, we suggest that into the main structure (S), sub-structures (SS) and micro-structures (MS) the application of real time multidimensional graphical modeling, it is to observe on live the permanent changes of each micro-structure, sub-structure and the main structure into the economic molecule structure

Linear program-based algorithm for the optimal design of wastewater treatment systems

This paper presents a new approach for the optimal design of distributed wastewater treatment networks with multiple contaminants. It consists of a two-stage solution strategy. In the first stage, a decomposition method is employed that replaces the general non-linear program (NLP) by a succession of linear programs, one for each treatment unit. In the second stage, the resulting network is used as a starting point for the solution of the general NLP by a local optimization solver. The decomposition process considers a specific substructure, where it is assumed that the wastewater streams go through the treatment units in sequence. To consider all combinations, the two-stage solution strategy is applied as many times as the number of possible sequences. This allows considering multiple and structurally different starting points, thus increasing the probability of finding global optimal solutions. The results have shown that the proposed approach can find better solutions than other approach reported in the literature, however with a drawback of being more demanding computationally.

Study of the properties of the surface of gallium arsenide by scanning atomic force microscopy

Using the method of atomic force microscopy, complex studies of the profile, potential distribution φ(x,y), and distributions of the phase contrast of the surface of n-GaAs subjected to various types of chemical treatment are carried out. The distribution of the potential and phase contrast at a microlevel, in general, correlates with the profile character. The surface treated in the solution H2SO4: H2O = 1: 10 is characterized by a high degree of nonuniformity with an average roughness of the main profile Δh≈ 10 nm. A considerable part of the surface is covered by hills 20–60 nm in height and 100–500 nm in diameter forming a specific substructure, which correspond to potential jumps as large as 50–60 mV against a general background of 0.77–0.80 V. At a nanolevel, correlation between the profile and phase contrast is clearly pronounced, but no correlation is found between the profile and potential distribution. Treatment of the surface of n-GaAs in a concentrated aqueous NH4OH solution leads to a decrease in the value of φ(x,y) by ∼0.2 V, and in its roughness by more than an order of magnitude (∼0.75 nm). The distribution of the profile and phase contrast over the surface is close to the ideal Gaussian distribution for relatively small areas of the surface (200 × 200 nm2). As the area increases, deviation from the Gaussian distribution becomes substantial because of smooth variation in the potential over the contact area. Conservation of the Gaussian character of the surface profile and a simultaneous rise in the average level of the roughness with an increase in the analyzed area indicates the fractal mechanism of formation of the surface profile.

Gradual in Silico Filtering for Druglike Substances

The suitability of decision trees in comparison to support vector machines for the classification of chemical compounds into drugs and nondrugs was investigated. To account for the requirements upon screening virtual compound libraries, schemes for successive filtering steps with gradual increasing computational cost are outlined. The obtained prediction accuracy was similar between decision trees and support vector machine approaches for the applied compound data sets. By using rapidly computable variables such as druglikeness indices, XlogP, and the molar refractivity, at least 39% of the nondrugs can be filtered out, while retaining more than 83% of the actual drugs. Computationally more demanding descriptors such as specific substructure queries and quantum chemically derived variables can be postponed to subsequent classification schemes for the reduced set of compounds, whereby up to 92% of the nondrugs can be sorted out without loosing considerably more drugs. Using all available computed descriptors simultaneously in the first step did not yield significantly better results. Furthermore, the generated decision trees are used to derive guidelines for the design of druglike substances. The numerical margins found at the branching points suggest several criteria that separate drugs from nondrugs: a molecular weight higher than 230, a molar refractivity higher than 40, and the presence of one or more rings as well as one or more functional groups. Also reported are additionally required parameters to compute values for XlogP, SlogP, and the molar refractivity of boron and silicon containing compounds.

A Kinetic Intermediate that Regulates Proper Folding of a Group II Intron RNA

The D135 group II intron ribozyme follows a unique folding pathway that is direct and appears to be devoid of kinetic traps. During the earliest stages of folding, D135 collapses slowly to a compact intermediate, and all subsequent assembly events are rapid. Collapse of intron domain 1 (D1) has been shown to limit the rate constant for D135 folding, although the specific substructure of the D1 kinetic intermediate has not yet been identified. Employing time-resolved nucleotide analog interference mapping, we have identified a cluster of atoms within the D1 main stem that control the rate constant for D135 collapse. Functional groups within the κ–ζ element are particularly important for this earliest stage of folding, which is intriguing given that this same motif also serves later as the docking site for catalytic domain 5. More important, the κ–ζ element is shown to be a divalent ion binding pocket, indicating that this region is a Mg2+-dependent switch that initiates the cascade of D135 folding events. By measuring the Mg2+ dependence of the compaction rate constant, we conclude that the actual rate-limiting step in D1 compaction involves the formation of an unstable folding intermediate that is captured by the binding of Mg2+. This carefully orchestrated folding pathway, in which formation of an active-site docking region is early and rate limiting, ensures proper folding of the intron core and faithful splicing. It may represent an important paradigm for the folding of large, multidomain RNA molecules.

Stable chromosomal units determine the spatial and temporal organization of DNA replication.

DNA replication occurs in mammalian cells at so-called replication foci occupying defined nuclear sites at specific times during S phase. It is an unresolved problem how this specific spatiotemporal organization of replication foci is determined. Another unresolved question remains as to what extent DNA is redistributed during S phase. To investigate these problems, we visualized the replicating DNA and the replication machinery simultaneously in living HeLa cells. Time-lapse analyses revealed that DNA was not redistributed to other nuclear sites during S phase. Furthermore, the results showed that DNA is organized into stable aggregates equivalent to replication foci. These aggregates, which we call sub-chromosomal foci, stably maintained their replication timing from S phase to S phase. During S-phase progression, the replication machinery sequentially proceeded through spatially adjacent sets of sub-chromosomal foci. These findings imply that the specific nuclear substructure of chromosomes and the order of their stable subunits determine the spatiotemporal organization of DNA replication.

Localization of dibenzodioxocin substructures in lignifying Norway spruce xylem by transmission electron microscopy-immunogold labeling.

The lignification process in mature Norway spruce [ Picea abies (L.) H. Karsten] xylem cell walls was studied using transmission electron microscopy (TEM)-immunogold detection with a polyclonal antibody raised against a specific lignin substructure, dibenzodioxocin. The study reveals for the first time the exact location of this abundant eight-ring structure in the cell wall layers of wood. Spruce wood samples were collected in Southern Finland at the time of active growth and lignification of the xylem cell walls. In very young tracheids where secondary cell wall layers were not yet formed, the presence of the dibenzodioxocin structure could not be shown at all. During secondary cell wall thickening, the dibenzodioxocin structure was more abundant in the secondary cell wall layers than in the middle lamella. The highest number of gold particles revealing dibenzodioxocin was in the S2+S3 layer. Statistically significant differences were found in the frequency of gold particles present in various cell wall layers. For comparison, wood sections were also cut with a cryomicrotome for light and fluorescence microscopy.

Uptake and intracellular transport of RNA Aptamers in African trypanosomes suggest therapeutic “Piggy-Back” approach

African trypanosomes are protozoan organisms that multiply as extracellular parasites in the blood of humans and other mammals. The parasites escape destruction by the host immune system by periodically changing their glycoprotein surface coat. This phenomenon is known as antigenic variation and is responsible for the inability of the infected host to clear the infection. Previously we reported the selection of RNA aptamers that bind to a 42 kDa surface protein of Trypanosoma brucei. The polypeptide is localised within a specific substructure on the parasite surface, the so-called flagellar pocket. Here we analyse the fate of the aptamers upon binding to the flagellar pocket. At elevated temperatures, both terminal ends of the RNAs are degraded to form a stable core structure of approximately 50 nucleotides. The RNAs become rapidly internalised by endocytosis and are transported to the lysosome by vesicular transport. The endocytotic process is sequence specific and does not occur with randomised RNA sequences or significantly shortened aptamer fragments. Co-localisation experiments with transferrin suggest a receptor-mediated uptake. The identified internalisation and transport pathway was used to target aptamer-coupled biotin molecules to the lysosome. This demonstrates that the RNAs can be used as ‘piggy-back’ molecules to target aptamer-coupled compounds/toxins to the lysosomal compartment of the parasite.